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Chiral ansa-Ligated Ruthenium(II) η6-Arene

Complexes –

An Odyssey towards a Revised Design of Enantioselective Transfer Hydrogenation Catalysts

Den Naturwissenschaftlichen Fakultäten

der Friedrich-Alexander-Universität Erlangen-Nürnberg

zur

Erlangung des Doktorgrades

vorgelegt von

Immo Weber

aus Tübingen

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Als Dissertation genehmigt von den Naturwissenschaftlichen Fakultäten der

Friedrich-Alexander-Universität Erlangen-Nürnberg.

Tag der mündlichen Prüfung: 29. Mai 2006

Vorsitzender der

Promotionskommission: Prof. Dr. Donat-Peter Häder

Erstberichterstatter: Prof. Dr. Ulrich Zenneck

Zweiberichterstatter: Prof. Dr. Lutz Dahlenburg

Drittberichterstatterin: Prof. Dr. Evamarie Hey-Hawkins (Universität Leipzig)

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Diese Arbeit widme ich in Dankbarkeit meiner Familie und all denjenigen Menschen,

die mir in Freude und Leid Teil meines Lebens sind, die ich Freunde nennen darf

und die ich nicht missen möchte.

Amicus certus in re incerta cernitur!

Dem Andenken an meine Großmutter Therese Ursula Nickolay,

an meinen Großvater Hans-Joachim Weber, Herrn Dr. Wolf Harm, Ursula

Heintzmann und Travis Moulton

Das wirklich Gute eines Menschen offenbart sich darin, inwieweit er in unserem

Herzen weiterlebt.

„Unsere Jahre sind im Raum der Zeit

nur ein kleines Teilchen,

unser Leben ist im Raum der Zeit

nur ein kleines Weilchen,

unser Werk ist im Mosaik der Zeit

vielleicht ein helles Steinchen“

Rudolf Burger

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Die vorliegende Arbeit wurde in der Zeit von Januar 2002 bis Februar 2005 am

Institut für Anorganische Chemie II der Friedrich-Alexander-Universität Erlangen-

Nürnberg unter der Anleitung von Herrn Prof. Dr. Ulrich Zenneck angefertigt. Mein

Dank gilt Herrn Prof. Dr. Ulrich Zenneck für die Aufgabenstellung, für seine

Förderung und für den großen Freiraum bei der Gestaltung dieser Arbeit.

Herrn Prof. Dr. Lutz Dahlenburg danke ich für die freundliche Übernahme des

Koreferats, Frau Prof. Dr. Evamaria Hey-Hawkins (Universität Leipzig) für das

Drittgutachten, Herrn Prof. Dr. Hans H. Brand für die Nebenfachprüfung und Herrn

Prof. Dr. Rolf Saalfrank für den Prüfungsvorsitz.

Die Arbeiten über β-Aminothioether chelatisierte Ruthenium(II)-η6-Arenkomplexe

(Kapitel 3) widme ich dem Andenken an Herrn Prof. Dr. Dieter Sellmann. Sie beruhen

auf seiner Initiative und wurden mir als ursprüngliches Thema meiner Dissertation

von Herrn Prof. Dr. Ulrich Zenneck anvertraut. Für sehr weiterführende, äußerst

motivierende und entscheidende Diskussionsbeiträge danke ich den Herren Prof. Dr.

Walter Bauer, Prof. Dr. Henri B. Kagan (Université Paris-Sud, Frankreich), Prof. Dr.

Antonio Togni (Eidgenössische Technische Hochschule Zürich, Schweiz), Dr. Frank

Heinemann, Dr. Ralph Puchta, Dr. Guido Marconi (jetzt Università Pisa, Italien) und

Dr. Wolfgang Utz.

Dem Graduiertenkolleg "Homogener und Heterogener Elektronentransfer“ des

Sonderforschungbereiches 583 der Deutschen Forschungsgemeinschaft danke ich

für die Gewährung eines Stipendiums 2002 und dem Chemie Computer Centrum der

Friedrich-Alexander-Universität Erlangen-Nürnberg für einen Gastaufenthalt 2003.

Der Kunststoff- und Metallwarenfabrik GmbH & Co. KG Erlangen danke ich für die

Teilzeiteinstellung ab Januar 2005, für die Chemikalienspenden zur Unterstützung

des Ferrocenprojektes (Kapitel 5) und für die großzügige Übernahme der Druckosten

der vorliegenden Dissertation. Der Firma Braun danke ich für die kontinuierlichen

Spenden von Einwegspritzen.

Bei den Herren Dr. Frank Heinemann und Panos Bakatselos bedanke ich mich für

die vielen und häufig komplizierten Röntgenstrukturanalysen. Bei Herrn Prof. Dr.

Walter Bauer, Herrn Dr. Achim Zahl, Herrn Dr. Matthias Moll und Herrn Bob O´Brien

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bedanke ich mich für die zahlreichen und oft nicht routinemäßigen NMR-Messungen.

Herrn Prof. Dr. Stefano Superchi (Università della Basilicata, Italien) danke ich für die

Durchführung und Expertise der CD-Spektren der {[σ(P):η6-(Aren-ansa-phosphinit)]-

ruthenium(II)aminokomplexe (Kapitel 4). Herrn Dr Konrad Szaciłowski (Wydział

Chemii, Uniwersytet Jagielloński, Kraków, Polen) danke ich für CV-Messungen zur

Klärung der notwendigen Bedingungen für eine erfolgreiche Umsetzung von

Cyclohexadienderivaten zu Ruthenium(II)-η6-Arenkomplexen (Kapitel 5). Den Herren

Prof. Dr. Andreas Hirsch und Prof. Dr. Peter Gmeiner danke ich, daß ich in ihren

Arbeitskreisen alle polariemetrischen Messungen, die Aufnahme der CD-Spektren

der β-Aminothioether chelatisierten Ruthenium(II)-η6-Arenkomplexe (Kapitel 3) und

sämtliche Schmelzpunktbestimmungen durchführen konnte.

Frau Christina Wronna danke ich für die Durchführung der Elementaranalysen. Den

Herren Dieter Wein und Hans Zöbelein danke ich für die Anfertigung als auch

Reparatur von Glasgeräten.

"Es ist die Aufgabe der Naturwissenschaften, durch eine wirkliche Einsicht in die

Zusammenhänge der Natur dem Menschen die richtige Stellung in ihr zuzuweisen.“

Werner Heisenberg

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Parts of this thesis were extracted as separate manuscripts planned to be published

or are already submitted for publication:

• Immo Weber, Frank W. Heinemann, Walter Bauer, Ulrich Zenneck;

“Configurational Stability of Epimeric β-Aminothioether-Chelated Ruthenium(II)

η6-Arene Complexes – Can it be controlled?”; to be published.

• Immo Weber, Frank W. Heinemann, Walter Bauer, Stefano Superchi, Achim

Zahl, Joanna Procelewska, Slawomir Procelewski, Daniela Richter, Ulrich

Zenneck; "Structural Relaxation of Diastereomeric {[η6:σ(P)-(Arene-ansa-

phosphinite)]Ruthenium(II) Amino} Cations under Configurational Stabilization

of Chiral Ruthenium(II) Centers"; to be published.

• Frank W. Heinemann, Immo Weber, Ulrich Zenneck; "Crystal structures of (-)-

(SS, 1R, 2S, 5R)-menthyl p-tolyl sulfinate and (+)-(SS)-[(p-tolyl)sulfinyl]-

ferrocene"; Journal of Chemical Crystallography, submitted.

• Immo Weber, Frank W. Heinemann, Ulrich Zenneck; "A Synthesis Detour to

Planar Diastereomeric Ferrocene Derivatives around an Unusual

Rearrangement of ortho-Lithiated Kagan's Template (+)-(SS)-[(p-Tolyl)sulfinyl]-

ferrocene ", to be published.

• Immo Weber, Frank W. Heinemann, Panos Bakatselos, Ulrich Zenneck; "A

Cornucopia of Catalysis Intermediates and Byproducts from a Stille

Crosscoupling of a Planar Chiral Ferrocene", to be published.

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Contents

Numbering and Nomenclature of Compounds Abbreviations

Zusammenfassung....................................................................................1

Abstract..........................................................................................................5

1 Theoretical Background....................................................................9

1.1. Chirality…………………………………………………………………….....9

1.2. Pseudopolyhedral hapto-Arene Complexes

with Chiral Metal Centers……………………………………………….....19

1.3. Principles of Enantioselective Catalysis exemplified on CaTHy

Reactions..............................................................................................23

1.4. Catalysts Design for Enantioselective Ketone Hydrogenation by

the Octant Rule…………………………………………….…………….....40

1.5. Anticipated Use of Chiral ansa-Ligated Ruthenium(II) η6-Arene

Complexes as THy Catalysts…………………………………..……...….54

1.6. Chiral ansa-Thioether Ru(II) η6-Arene THy Catalysts as

initial goal of this work………………………………………………...……67

2 Preexperiments.....................................................................................73

2.1 Ruthenium(II) η6-Benzene Precursor Complexes…………………...….73

2.2. Synthesis Attempts of ansa-Thioether and ansa-Thiolato

Ruthenium(II) η6-Arene Complexes ……….……………………...……..77

3 Preparation and Study of Epimeric β-Aminothioether-

Chelated Ruthenium(II) η6-Arene Complexes....................82 3.1 Synthesis of Chiral β-Aminothioether Ligands…… …………...........…85 3.2 Epimeric σ(N):σ(S)-β-Aminothioether Ruthenium(II)

η6-Arene Complexes.............................................................................95

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4 Preparation and Study of Diastereomeric {[σ(P):η6-

(Arene-ansa-Phosphinite)] Ruthenium(II) Amino} Complexes............................................................................................121

4.1 Synthesis............................................................................................122

4.2 Circular Dichroism Study....................................................................143

4.3 NMR Study and Epimerization Barrier................................................146

4.4 Catalytic Experiments and Conclusions.............................................156

5 Revised Design of Enantioselective ansa-Ligated

Ru(II) η6-Arene THy Catalysts - Outlook towards Planar

Chiral ansa-Ferrocenyl Ligands..............................................162

5.1 Precursors and Reagents...................................................................165

5.2 Synthesis of and ortho Lithiation Studies with Kagan's Template......169

5.3 Towards a Racemic {σ(N):η6-[1-(2'-aminomethylferrocenyl)-

benzene]} Ruthenium(II) Complex......................................................178

6 Conclusion and Closing Remarks..........................................188

7 Experimental Part..............................................................................189

7.1. Materials and Methods........................................................................189

7.2. Precursor Compounds........................................................................194

7.2.1 General Procedure for Birch Reductions............................................194

1-Methoxycarbonylcyclohexa- 2, 5-diene 3........................................ 195

1,3,5-Trimethylcyclohexa-1,4-diene 5................................................196

1-(3’-Hydroxypropyl)cyclohexa-1,4-diene 17.......................................197 7.2.2 General Procedure for the Synthesis of Di-µ-chlorobis[chloro-

{η6-arene}ruthenium(II)} Complexes..................................................198

Di-µ-chlorobis{chloro[η6-(methoxycarbonyl)benzene]ruthenium(II)} 7.......198

Di-µ-chlorobis{chloro[η6-(1,3,5-trimethylbenzene)]ruthenium(II)} 8...........199 Di-µ-chlorobis[chloro{η6-[1-methyl-4-(methylethyl)benzene]}-

ruthenium(II)] 9.............................................................................199

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Di-µ-chlorobis{chloro[η6-(3-hydroxypropyl)benzene]ruthenium(II)} 18.......200

7.2.3 Di-µ-bromobis{bromo[η6-(3-hydroxypropyl)benzene]ruthenium(II)} 19......201 7.2.4 Dibromo[η6-(3-bromopropyl)benzene]triphenylphosphino-

ruthenium(II)} 20...........................................................................202

7.3. Syntheses of Epimeric σ(N):σ(S)-β-Aminothioether Ruthenium(II)

η6-Arene Complexes..........................................................................203

7.3.1 (-)-(R)-Phenylglycinol 27R..............................................................203

7.3.2 (-)-(4R)-4-Phenyl-2-oxazolidinone 29R..............................................205

7.3.3 (-)-(2R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-phenylethanol 30R.......207 7.3.4 (-)-(1R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-methylsulfonyloyx-1-

phenylethane 31R........................................................................208 7.3.5 General Procedure for the Syntheses of chiral β-Aminothioether Ligands

by Nucleophilic Ringopening of (-)-(4R)-4-Phenyl-2-oxazolidinone

29R by the Ishibashi Protocol..........................................................209

(-)-(1R)-1-Phenyl-2-[(phenylmethyl)thio]ethylamine 32R............210

(+)-(1R)-1-Phenyl-2-(phenylthio)ethylamine 33R......................210

(+)-(1R)-1-Phenyl-2-(2’-naphthylthio)ethylamine 36R................211 7.3.6 General Procedure for the Syntheses of chiral β-Aminothioether Ligands

by Nucleophilic Substitution of Methylsulfonate Group of 31R................212

(-)-(1R)-1-Phenyl-2-[(phenylmethyl)thio]ethylamine 32R............212

(+)-(1R)-1-Phenyl-2-(phenylthio)ethylamine 33R......................213

(-)-(1R)-1-Phenyl-2-(1’-naphthylthio)ethylamine 34R.................213

(+)-(1R)-1-Phenyl-2-(2’-naphthylthio)ethylamine 36R................214

7.3.7 (-)-(2R)-2-Amino-2-phenylethanthiol hydrochloride 37R........................214 7.3.8 (-)-(1R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-methylcarbonylthio-1-

phenylethane 38R........................................................................216

7.3.9 (-)-(2R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-phenylethanthiol 39R...218

7.3.10 (-)-(1R)-1-Phenyl-2-[(3’-methylbut-2’-enyl)thio]ethylamine 40R..............219 7.3.11 General Procedure for the Syntheses of σ(N):σ(S)-β-Aminothioether

Ruthenium(II) η6-Arene Complexes..................................................220

(+)-(RRu,1’’ R)-Chloro-η6-[1-methyl-4-(1’-methylethyl)benzene]-σ(N):σ(S)

-[1’’-phenyl-2’’-(phenylthio)ethylamino]ruthenium(II)]

hexafluorophosphate 41R...............................................................221 (+)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-

(phenylthio)ethylamino]ruthenium(II)] hexafluorophosphate 42R............223

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(-)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-

(2’’-naphthylthio)ethylamino]ruthenium(II)] hexafluorophosphate 43R......224 (+)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-

(3’’-methylbut-2’’-enylthio)ethylamino]ruthenium(II)]

hexafluorophosphate 44R...............................................................225

7.4 Syntheses of Diastereomeric {[σ(P):η6-(Arene-ansa-Phosphinite)]

Ru(II) Amino} Complexes....................................................................227

7.4.1 (+)-(S)-Mandelic acid methyl ester 48S..............................................228

7.4.2 (1S)-1-Methoxy-1-phenyl acetic acid methyl ester 49S..........................228

7.4.3 (+)-(2S)- 2-Methoxy-2-phenylethanol 50S...........................................229

7.4.4 (+)-(2S)-P-(2-Methoxy-2-phenylethyloxy)-P,P-diphenylphosphine 51S......230 7.4.5 (1R)-Dichloro{σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-methoxy-ethyl)-

benzene]}ruthenium(II) 53R.............................................................231

7.4.6 General Procedure for Amine Complexation Reactions.........................232 (RRu, 1R)-[σ-chloro {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-

methoxyethyl)benzene]}-σ(N)-phenylamino ruthenium(II)]

hexafluorophosphate 54R...............................................................234 (1’R)-[σ-chloro- σ(N)-(4-fluorophenylamino)- {σ(P):η6-[(2’-(P,P-diphenyl-

phosphinoxy)-1’-methoxyethyl)-benzene]} ruthenium(II)]

hexafluorophosphate 55R...............................................................235 (SRu, 1R, 1’R)-[σ-chloro- {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-

methoxyethyl)benzene]}- σ(N)-(1’-phenylethylamino)ruthenium(II)]

hexafluorophosphate 56RR............................................................236 (1R, 1’S)-[σ-chloro- {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-methoxy-

ethyl)benzene]}- σ(N)-(1’-phenylethylamino)ruthenium(II)]

hexafluorophosphate 56RS.............................................................237

7.5 Planar Chiral Ferrocenyl Derivatives...................................................239

7.5.1 2,2,5,5-Tetramethyl-2,5-disila-1-azacyclopentane 58............................239

7.5.2 N,N,N',N'-Tetramethylmethylenediamine 59........................................240

7.5.3 N,N-Dimethylmethyleneiminium chloride (Eschenmoser salt) 60.............240

7.5.4 1-Bromo-2,4,6-tri(methylethyl)benzene 62..........................................241 7.5.5 (-)-(SS, 1R, 2S, 5R)-1-[(4’-methylphenyl)sulfinoxy]-2-methylethyl-5-

methylcyclohexane 64S.................................................................243

7.5.6 (+)-(SS)-[(4-Methylphenyl)sulfinyl]ferrocene 67S...................................245

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7.5.7 (+)-(SS)-[(4-(2-Hydroxyethyl)phenyl)sulfinyl]ferrocene 68S.....................247

7.5.8 (+)-(SS)-[(4-(2-Methylsolfonoxyethyl)phenyl)sulfinyl]ferrocene 69S...........249 7.5.9 rac. (l)-1-Formyl-2-[(4'-methylphenyl)sulfinyl]ferrocene 70 and rac.

(l)-1-Hydroxymethyl-2-[(4'-methylphenyl)sulfinyl]ferrocene 71.................250 7.5.10 rac. (l)-1-(N,N-Dimethylaminomethyl)-2-[(4'-methylphenyl)sulfinyl]-

ferrocene 72.................................................................................252

7.5.11 N,N, Dimethylaminomethylferrocene 73.............................................254

7.5.12 rac. 1-N,N-Dimethylaminomethyl-2-tributylstannylferrocene 74...............255

7.5.13 rac. 1-N-Phthalimidomethyl-2-tributylstannylferrocene 75.......................256

7.5.14 rac. 1-Phenyl-2-(N-phthalimidomethyl)ferrocene 77..............................258

7.5.15 rac. 1-Aminomethyl-2-phenylferrocene 81...........................................260

7.5.16 rac. 1-Aminomethyl-2-(cyclohexa-2',5'-dienyl)ferrocene 82.....................261

7.6 Kinetic Epimerization Study.................................................................262

7.7 Catalytic Transfer Hydrogenation Experiments...................................267

8 Appendix - CD Spectra...................................................................270

33R, 35R, 36R...................................................................................................270

41R, 42R, 43R, 44R............................................................................................271

53R, 54R, 55R...................................................................................................272

56RR, 56RS......................................................................................................273

9 Appendix - Crystallographic Data...........................................274

20 (IW0303)...................................................................................................275

35R (IW0307)................................................................................................276

41R (IW0301)................................................................................................277

42R (IW0305)................................................................................................278

43R (IW0306)................................................................................................279

44R (IW0308)................................................................................................280

53R (IW0309)................................................................................................281

54R (IW0402)................................................................................................282

55R (IW0404)................................................................................................283

56RR (IW0401).............................................................................................284

56RS (IW0501).............................................................................................286

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64S (IW0403)................................................................................................287

67S (IW0405)................................................................................................288

69S (IW0406)................................................................................................289

72 (IW0407)...................................................................................................290

77 (IW0502)...................................................................................................291

78 (IW0507)...................................................................................................292

79 (IW0506)...................................................................................................293

80 (IW0503)...................................................................................................294

10 Literature.................................................................................................295

Mein persönlicher Dank gebührt…. .....................................................................314

Lebenslauf .......................................................................................................317

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Numbering and Nomenclature of Compounds

In this thesis only such compounds are numbered, which were directly used and / or

synthesized during this work or are directly related to it in the order in which they

appear. Stereochemical descriptors (R, S, P, M) given behind the numbers are

related to the original enantiomer the particular compound evolved from. If two chiral

and enantiomerically pure compounds were reacted to a new one under preservation

of the original chiral center(s), then all stereochemical descriptors from the original

compounds are denoted after the number of the new diastereomeric compound. If

the original chiral center is lost or converted, then the stereochemical descriptors

denote the absolute configuration of the actual enantiomer. No stereochemical

descriptors are given behind the numbers of racemates or in case of undefined chiral

centers. If the absolute configuration of a chiral center could not be denoted

according to CIP resp. IUPAC, then a nomenclature system consistent with existing

IUPAC rules and at least logically consistent within this thesis is applied and

explained (Chapter 1). Generally all compounds numbered were named according to

IUPAC nomenclature at least once, but for the ease of reading and discussion trivial

names where common were used also. Disclaimer: Trademarks were generally not

marked within this text. For commercial purposes they are not generally free of use.

This is also valid to procedures as well as compounds based on or referred to

patents cited in this text.

- 18 -

Abbreviations

Å Angstrøm (10-10 m)

[α]DT specific optical rotation (at temperature T and sodium D-line)

Al(OiPr)3 aluminium triisopropanolate (aluminium tri(1-methy-lethanolate))

aq. aqueous

aqua dest. distilled water

BArF- tetrakis[3,5-bis(trifluoromethyl)phenyl]borate

BINAP (P)- or (M)-2,2'-bisdiphenylphosphino-1,1'-binaphthalene

bp. boiling point [° C]

Bn benzyl (phenylmethyl)

BOC tert. butoxycarbonyl (1,1-dimethylethoxycarbonyl)

(BOC)2O tert. butyl pyrrocarbonate (1,1-dimethylethyl pyrrocarbonate)

C catalyst

° C degree Celsius

CaTHy catalytic transfer hydrogenation

CD circular dichroism

CHCl3 / CDCl3 chloroform / deutero-chloroform

CH2Cl2 dichloromethane

CHP p-cymene hydroperoxide

CIP Cahn-Ingold-Prelog nomenclature system for chiral molecules

COSY correlation spectroscopy

Cp cyclopentadienyl

Cp* 1,2,3,4,5-pentamethylcyclopentadienyl

CR conversion rate (catalysis)

CV cyclovoltammetry

d doublet

δ chemical shift [ppm]

dba dibenzylideneacetone (1,5-diphenylpenta-1,4-dien-3-one)

∆ε positive / negative Cotton effect (circular dichroism)

d.e. diastereomeric excess

DET (R,R)- or (S,S)-diethyl tartrate

DEPT decoupled enhanced polarisation transfer spectroscopy

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DFT density functional theory

∆G‡ free activation energy [kJ / mol]

∆H‡ activation enthalpy [kJ / mol]

DMF dimethylformamide

DMSO / DMSO-d6 dimethylsulfoxide / hexadeutero-dimethylsulfoxide

DPEN (R,R)- or (S,S)-1,2-diamino-1,2-diphenylethane

∆S‡ activation entropy [J / mol K]

E electrophile

E0 electrochemical standard potential

EA elemental analysis

e.e. enantiomeric excess

en 1,2-diaminoethane / 1,2-diaminoethyl

Et ethyl

Et2O diethylether

EtOAc ethyl acetate

EtOH ethanol

EXSY exchange spectroscopy

fac facial

FC flash chromatograph

Fc ferrocene / ferrocenyl

FcLi ferrocenyllithium / lithioferrocene

FDA United States Federal Food and Drug Administration

FG field gradient in NMR spectroscopy

FGI functional group interconversion

FMO frontier molecular orbital

g gramm

GC gas chromatography

h hour, heptet (NMR spectroscopy) or

Planck constant (6.626176 10-34 Js)

H3CI iodomethane (methyl iodide)

HCl hydrogen chloride

H3CSO2Cl mesyl chloride (chlorosulfonylmethane)

HMB hexamethylbenzene

HMBC heteronuclear multiple bond correlation

- 20 -

HMQC heteronuclear multiple quantum correlation

HOAc acetic acid

HOMO highest occupied molecular orbital

HPLC high performance liquid chromatography

HV high vacuum

Hz Hertz

iPr isopropyl (1-methylethyl)

iPrOH isopropanol (1-methylthanol)

IUPAC International Union of Pure and Applied Chemistry

J Joule

k rate constant or kilo

K Kelvin

kB Boltzmann constant (1.380662 10-23 J/K)

KSAc potassium thioacetate

KSCPh3 potassium triphenylmethylthiolate

l liter

λ wavelength

LDA lithium diispropylamide

LTP lithio-2,4,6-tri(methylethyl)benzene

LMCT ligand to metal charge transfer

LUMO lowest unoccupied molecular orbital

m milli or multiplet (NMR spectroscopy)

m meta

M metal (center) or mega

mer meridonal

min. minutes

MeCN / MeCN-d3 acetonitrile / trideutero-acetonitrile

MeOH methanol

mp. melting point [° C]

MS mass spectroscopy

Naph naphthyl

nBu (n-C4H9) n-butyl

nBuli n-butyllithium

nm nanometer (10-9 m)

- 21 -

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

NOESY nuclear Overhauser and exchange spectroscopy

Nu nucleophile

o ortho

p para

Pd2(dba)3.CHCl3 tris(η2:η2-dibenzylideneacetone)dipalladium(0) chloroform adduct

PE petroleum ether (light petroleum, ligroin, hexanes mixture)

Ph phenyl

ppm parts per million

Prn prenyl (3-methylbut-2-enyl)

q quartet

R (organic) molecule substituent or

gas constant (8.31441 J / mol K)

Rf retention factor (TLC)

RS resolution (GC and HPLC)

RV rotary evaporation

S substrate

s seconds or singlet in NMR spectroscopy

sat. saturated

SOMO single occupied molecular orbital

T temperature

t time in kinetics or triplet in NMR spectroscopy

t½ half-life

tR retention time (GC and HPLC)

tBu tert. butyl (1,1-dimethylethyl)

tBuLi tert. butyllithium (1,1-dimethylethyllithium)

tBuOK potassium tert. butanolate (potassium 1,1-dimethylethoxide)

TFA trifluoroacetic acid

THy transfer hydrogenation

THF tetrahydrofuran

TLC thin layer chromatography

Ti(OiPr)4 titanium(IV) tetraisopropanolate (titanium(IV) tetra(1-methyl-

ethanolate)

- 22 -

TolBINAP (P)- or (M)-2,2'-bisdi(4'-methylphenyl)phosphino-1,1'-

binaphthalene

Trop tropylium

UV ultraviolet

VE valence electron

w peak half-width (GC and HPLC)

Xyliphos (R,P)- or (S,M)-1-{1-[bis(3',5'-dimethylphenyl)phosphino]ethyl}-2-

diphenylphosphinoferrocene

- 1 -

Zusammenfassung

Anhand der Synthesen, Stabilitätsstudien und Katalyseexperimenten von zwei

Substanzklassen wird ein neues Design für chirale ansa-verknüpfte Ruthenium(II)-η6-

Arenkomplexe als mögliches Konzept für enantioselektive Katalysatoren für die

Transferhydrierung von enantiotopen Carbonylverbindungen zu chiralen Alkoholen

und Aminen entwickelt.

OP

RuCl

NH2

Ph

Ph

OCH3

** (R)

PF6

R

54R R = Ph > 99.9 % d.e. (RRu, R) like nach Umkristallisieren und Epimerisierung am Ru(II)-Chiralitätszentrum in Aceton-d6!

55R R = (p-F)C6H4 kein d.e. nach Umkristallisieren!

56RR R = (R)-C*H(CH3)Ph > 99.9 % d.e. (SRu, R, R) unlike-like nach Umkristallisieren und keine Epimerisierung in Aceton-d6!

56RS R = (S)-C*H(CH3)Ph kein d.e. nach Reinisolierung

(S)

unlike

NH2

(R)

PhS

H

Ru*

*

ClR4

*R3

PF6R1

R2

R1 41R R1 = H R2 = CH3 R3 = iPr R4 = Ph 42R R1 = R2 = CH3 R3 = H R4 = Ph43R R1 = R2 = CH3 R3 = H R4 = β-Naph44R R1 = R2 = CH3 R3 = H R4 = Prn

like

PF6O

P

Ru

H2NCl

O*

(R)

(R)

R

*

H

Ph

Ph

CH3

Abb. 0.0.1 Potentielle Transferhydrierungs-Präkatalysatoren: 41R - 44R N(SR)-Chelat-Ru(II)-η6-

Arenkomplexe (oben); 54R - 56RS Ru(II)-η6-ansa-Phosphinitarenaminokomplexe

(unten).

- 2 -

Ausgehend von (R)-Phenylglycin 26R wurden die chiralen N(SR)-Chelat-Ru(II)-η6-

Arenkomplexe 41R – 44R hergestellt und sowohl in Lösung mit NMR als auch im

Festkörper durch Röntgenstrukturanalyse charakterisiert (Abb. 0.0.1 oben). 41R liegt

in dem untersuchten Kristall enantiomerenrein als anti-syn--Diastereomer vor,

während die untersuchten Kristalle der η6-Mesitylenkomplexe 42R – 44R anti-syn-

und syn-anti-Diastereomere im Verhältnis von 1:1 enthalten. In Lösung liegt ein

Gleichgewicht zwischen den vier möglichen as-, aa-, sa- und ss-Diastereomeren vor,

das durch die Natur des η6-koordinierten Arens und nicht durch die Größe des

Thioethersubstiuenten R4 bestimmt wird. Die hohe konfigurative Labilität des chiralen

Mercaptozentrums ließ sich nicht unterdrücken; lediglich bei 41R erweist sich in

Lösung das pseudotetraedrische Ru(II)-Zentrum mit (R)-Konfiguration als stabil,

während das Mercaptozentrum in einem Gleichgewicht ca. (R):(S) = 1 : 0.32 vorliegt.

Ausgehend von natürlicher (S)-Mandelsäure 47S wurden in insgesamt sechs

Schritten die σ(P):η6-Aren-ansa-Phosphinit-Ru(II)-Aminokomplexe 54R – 56RS

hergestellt (Abb. 0.0.1 unten). Schlüsselschritte dieser Synthese sind jeweils eine

Ruthenium(II)-η6-Benzoesäuremethylester-Austauschreaktion gefolgt von einer

nucleophilen Substitution eines Chloridliganden durch verschiedene Amine. Diese

nucleophile Substitution verlief zwar in Abhängigkeit vom eingesetzten Amin mit

Diastereomeren-überschüssen von bis zu 99 % d.e., allerdings verursachten

Kristallpackungseffekte entweder eine Anreicherung eines Diastereomeren oder

völlige Epimerisierung am chiralen Ru(II)-Zentrum. Während 56RR unlike-like und

die 1:1 like und unlike Diastereomerengemische 55R und 56RS in Lösung stabil sind,

epimerisiert 54S like in Aceton-d6 irreversibel am chiralen Ru(II)-Zentrum. Es wurde

eine Inversionsbarriere von ca. ∆G‡ = 98.6 kJ / mol mit einer Entropie von ca. ∆S‡ =

23 - 67 J / mol K bestimmt. Von 54R – 56RS konnten Kristalle hinreichender Qualität

für eine Röntgenstrukturanalyse erhalten werden und so deren absolute

Konfiguration neben physikalisch unabhängigen NMR- und CD-Studien zweifelsfrei

bestätigt werden.

Sowohl die N(SR)-Chelat-Ruthenium(II)-η6-Arenkomplexe 41R – 42R als auch die

ansa-Phosphinitkomplexe 54R – 56RS zeigen eine mäßige katalytische Aktivität bei

der Transferhydrierung von Acetophenon zu 1-Phenylethanol, aber nur eine niedrige

Enantioselektivität (Abb. 0.0.2).

- 3 -

Ph CH3

O

Ph CH3*

OHH1 - 2 mol % 41R - 42R, 54R - 56RS

2 - 4 mol % tBuOK

H3C

H3COH

HH3C

H3C

O+ +

Abb. 0.0.2 Katalytische Transferhydrierung (CaTHy).

Ein Hauptgrund dafür ist die potentielle Konfigurationslabilität des Ru(II)-Zentrums,

die bei beiden Katalysatorklassen vorherrscht. Ein Lösungsansatz bietet dabei die

Einführung eines planar chiralen Ferrocenfragmentes als ansa-Rückgrat, das

unabhängig von der Natur der Ligandengruppen allein durch seine Geometrie seiner

endo-Seite eine diastereotope Seite des Metallreaktionszentrums so abriegeln dürfte,

daß ein Hydridtransfer auf das Ru(II)-Zentrum und von diesem auf das Substrat nur

von der exo-Seite erfolgen kann und damit das Epimerisierungsdilemma des Ru(II)-

Zentrums relativiert werden dürfte.

Ausgehend vom Kagan-Templat 67S wurden durch eine völlig diastereoselektive

ortho-Lithiierung gefolgt von einer elektrophilen Addition in situ die planar chiralen

Derivate 70 und 72 erhalten (Abb. 0.0.3). Allerdings zeigte sich, daß beim Einsatz

des nur mäßig reaktiven Elektrophils Paraformaldehyd unter den Reaktionsbe-

dingungen ausschließlich der unerwartete homologisierte Alkohol 68S entsteht, was

nur durch eine zwischenzeitliche und vollständige Umlagerung der ortho-lithiierten

Spezies erklärt werden kann. Das eigentlich gewünschte Produkt 71 wurde dann mit

DMF als Elektrophil und anschließender Reduktion des ungereinigten Aldehydes 70

gewonnen. Mit dem elektronisch stark desaktivierten planar chiralen Ferrocenderivat

71 als Racemat gelang eine Aktivierung als Bromid gefolgt von einer SN1-Reaktion in

situ über ein hapto-koordiniertes Fulveniumkation zum Dimethylaminomethylderivat

72 unter Erhalt der relativen Konfiguration alternativ zur direkten Synthese von 72

durch ortho-Lithiierung von 67S und direkter Umsetzung mit Eschenmosers Salz 60.

Durch Röntgenstrukturanalysen von 67S, 72 und Derivat 69S konnten die regio- als

auch diastereoselektive Reaktionsverläufe physikalisch unabhängig von NMR be-

wiesen werden. Da bei 72 die p-Tolylsulfinylgruppe via tBuLi-Addition mit

verschiedensten Elektrophilen austauschen lassen dürfte, ist mit dieser Arbeit eine

Grundlage für einen weiteren kombinatorisch beliebigen synthetischen Zugang zu

- 4 -

planar chiralen Ferrocenliganden eröffnet worden. Ausgehend von Ferrocen 65

wurde in sechs Schritten der ansa-Ferrocenligand 82 als Racemat erhalten. Auch

unter variierten Bedingungen gelang keine Komplexierung zum entsprechenden

ansa-Ferrocenyl-Ru(II)-η6-Benzolkomplex.

Fe

65 Ferrocen

Fe

* S

O

(S)

67S Kagan Templat 86 - 94 % e.e. nach Umkristallisieren

Fe

* S

O

(S)

CH2E

* (M)

70 E = CHO

71 E = CH2OH

72 E = CH2N(CH3)2(auch direkt erhalten durch o-Lithiierung undAbfangen mit Eschenmoser-Salz)

68S E = CH2OH

69S E = CH2OSO2CH3

1) LDA / -78 ° C

2) Elektrophil

1) LDA / -78 ° C2) Elektrophil

Racemischer Planar Chiraler ansa-Ferrocenligand

Fe

NH2

(M) *+ ent.

82

H3C

Fe

* S

O

(S)

H3C

E> 99.9 d.e.

Ausprobiert an Racemat!

(min. 86.4 % e.e.)

+ ent.

Abb. 0.0.3 Ferrocen-Synthesen.

- 5 -

Abstract

A novel design of chiral ansa-ligated ruthenium(II) η6-arene complexes as one

possible concept for highly enantioselective catalysts for transfer hydrogenation of

enantiotopic carbonyl compounds to chiral alcohols and amines is developed by the

syntheses of, stability studies of and catalytic experiments with two substance

classes.

OP

RuCl

NH2

Ph

Ph

OCH3

** (R)

PF6

R

54R R = Ph > 99.9 % d.e. (RRu, R) unlike after recrystallization and epimerization on chiral Ru(II) center in acetone-d6!

55R R = (p-F)C6H4 no d.e. after recrystallization !

56RR R = (R)-C*H(CH3)Ph > 99.9 % d.e. (SRu, R, R) unlike-like after recrystallization and no epimerization in acetone-d6!

56RS R = (S)-C*H(CH3)Ph no d.e. after purification

(S)

unlikelike

PF6O

P

Ru

H2NCl

O*

(R)

(R)

R

*

H

Ph

Ph

CH3

NH2

(R)

PhS

H

Ru*

*

Cl

R4

*R3

PF6R1

R2

R1 41R R1 = H R2 = CH3 R3 = iPr R4 = Ph 42R R1 = R2 = CH3 R3 = H R4 = Ph43R R1 = R2 = CH3 R3 = H R4 = β-Naph44R R1 = R2 = CH3 R3 = H R4 = Prn

Pic. 0.0.4 Potential transfer hydrogenation precatalysts: 41R - 44R N(SR)-chelate Ru(II)-η6-arene

complexes (top); 54R - 56RS Ru(II)-η6-ansa-phosphinite arene amino complexes

(bottom).

- 6 -

Starting from (R)-phenylglycine 26R the chiral N(SR)-chelate Ru(II) η6-arene

complexes 41R – 44R were synthesized and characterized in solution by NMR as

well as in solid state by X-ray structure analysis (Pic. 0.0.4, top). In the examined

crystal 41R was found to be the enantiomerically pure anti-syn diastereomer only,

while the examined crystals of the η6-mesitylene complexes 42R – 44R contain the

anti-syn and syn-anti diastereomers in a 1:1 ratio. The four possible as, aa, sa and ss

diastereomers are in equilibrium in solution, which depends rather from the nature of

the η6-coordinated arene than from the size of the thioether substituent R4. The high

configuration lability of the chiral mercapto center could not be suppressed; only the

(R)-configurated pseudo-tetrahedral Ru(II) center of 41R is stable in solution, while

the mercapto center is in a ca. (R) : (S) = 1 : 0.32 equilibrium.

Starting from natural (S)-mandelic acid 47S σ(P):η6-arene-ansa-phosphinite Ru(II)

amino complexes 54R – 56RS were synthesized in overall six steps (Pic. 0.0.4,

bottom). A ruthenium(II) η6-benzoic acid methylester exchange reaction followed by

nucleophilic substitution of one chloride ligand by various amines are the key steps of

this synthesis. The nucleophilic substitution was accompanied with diastereoselec-

tivities up to 99 % d.e. depending from the individual amine, but crystal packing

effects caused weather an enrichment of one diastereomer or a total epimerization

on the chiral Ru(II) center. While 56RR unlike and the 1:1 like and unlike

diastereomeric mixtures 55R and 56RS are stable in solution, 54R like epimerizes in

acetone-d6 irreversibly at the chiral Ru(II)-center. An inversion barrier of ca. ∆G‡ =

98.6 kJ / mol with an entropy of ca. ∆S‡ = 23 - 67 J / mol K was determined. Crystals

of suitable quality for X-ray structure analysis were obtained from 54R – 56RS and so

the absolute configuration was confirmed beyond doubt and physically independent

from NMR and CD studies.

The ansa-phosphinite complexes 54R – 56RS as well as the N(SR)-chelate Ru(II) η6-

arene complexes 41R – 44R are only moderately active catalysts in the transfer

hydrogenation of acetophenone to 1-phenylethanol, but with only low enantio-

selectivity (Pic. 0.0.5).

- 7 -

Ph CH3

O

Ph CH3*

OHH1 - 2 mol % 41R - 42R, 54R - 56RS

2 - 4 mol % tBuOK

H3C

H3COH

HH3C

H3C

O+ +

Pic. 0.0.5 Catalytic transfer hydrogenation (CaTHy).

The potential configurational lability of the Ru(II) center of both catalyst types is the

main reason for this behavior. The introduction of a planar chiral ferrocene fragment

as an ansa-backbone offers a solution concept, which should close up one

diastereotopic side of the metal reaction center by the geometry of its endo side in

such a way the hydride transfer onto and from the Ru(II) center can only occur from

the exo side and which should relativate the epimerization dilemma of the Ru(II)

center in this way.

Starting from Kagan’s template 67S planar chiral derivatives 70 and 72 were

obtained by a total diastereoselective ortho lithiation followed by quenching with an

electrophile (Pic. 0.0.6). However, exclusively the homologized alcohol 68S is

obtained surprisingly, if the only moderately reactive electrophile paraformaldehyde is

used under same reaction conditions, which can be explained only by an

intermediate and complete rearrangement of the ortho lithiated species. The

originally desired product 71 was then obtained with DMF as electrophile followed by

reduction of the crude aldehyde 70. The activation of the strong electronically

desactivated racemic planar chiral ferrocene derivative 70 as a bromide was

successful, which was followed by a SN1 reaction in situ via a hapto coordinated

fulvenium cation to the dimethylamino methyl derivative 72 under full preservation of

the relative configuration. This is an alternative to the direct synthesis of 72 via ortho

lithiation of 67S followed by quenching with Eschenmoser salt 60. X-ray structure

analysis of 67S, 72 and derivative 69S confirmed the regio- as well as

diastereoselective reaction pathways physically independent from NMR. Hence the

p-tolylsulfinyl moiety of 72 could be exchanged via tBuLi addition against various

electrophiles, a basis for a further combinatorial synthetic methodology for planar

- 8 -

chiral ferrocene ligands is achieved. Starting from ferrocene 65 racemic ansa-

ferrocenyl ligand 82 was obtained in six steps. Even under varied conditions a

complexation to the corresponding ansa-ferrocenyl Ru(II) η6-benzene complex failed.

Fe

65 ferrocene

Fe

* S

O

(S)

67S Kagan's Template 86 - 94 % e.e. after recrysatllization

Fe

* S

O

(S)

CH2E

* (M)

70 E = CHO

71 E = CH2OH

72 E = CH2N(CH3)2(also directly obtained by o-lithiation and quenching with Eschenmoser salt)

68S E = CH2OH

69S E = CH2OSO2CH3

1) LDA / -78 ° C

2) electrophile

1) LDA / -78 ° C2) electrophile

Racemic Planar Chiral ansa-Ferrocene Ligand

Fe

NH2

(M) *+ ent.

68

H3C

Fe

* S

O

(S)

H3C

E> 99.9 d.e.

tried on racemate!

(min. 86.4 % e.e.)

+ ent.

Pic. 0.0.6 Ferrocene syntheses.

- 9 -

1 Theoretical Background

1.1 Chirality

The intention of this general discussion is not to carry owls to Athens here [1], but to

show up one more bridge between inorganic and organic chemistry, create a frame

for the chiral complexes and ligands described in this thesis and to develop it into a

logical consistent descriptor system for the absolute configuration of central chiral

pseudo polyhedral metal hapto-arene complexes in accordance with the CIP

respectively IUPAC nomenclature in this context. For most combinations of atoms a

number of molecular structures that differ from each other in the sequence of bonding

of the atoms are possible. Each individual molecular assembly is called an isomer,

and the constitution of a compound is the particular combination of bonds and

sequence of atoms (molecular connectivity) which is characteristic of that structure [2

(1)]. When structures of the same constitution differ in spatial arrangement, they are

stereoisomers. Stereoisomers are described by specifying their topology and the

nature of their relationship to other stereoisomers of the same constitution.

Stereoisomers differ geometrically only in configuration, but do usually show different

physical and chemical properties. In order to distinguish between stereoisomeric

compounds, it is necessary to specify their configuration (e / z, cis / trans, syn / anti;

fac / mer).

Pasteur separated ammonium sodium tartrate under a microscope into two sorts of

crystals with planes of non congruent mirror images he called “dissymmetric” [2 (2)].

Each sort of these enantiomorphous crystals showed equivalent physical and

chemical properties except they caused the plane of linear polarized light to rotate by

opposite but equal amounts. After dissolving crystals of one mirror image he always

obtained back the same sort of enantiomorphous crystals, so he assigned the

“dissymmetric” crystals’ shape to the geometric property of the tartrate molecules

themselves in the sense of non congruent mirror images and called such molecules

enantiomers. Because all organic enantiomers isolated between 1860 and 1874

contained at least one carbon atom connected to four different substituents and

- 10 -

differed only in opposite optical rotation van’t Hoff and LeBel [2 (3-4)] concluded

tetravalent carbon atoms must be tetrahedral, because the molecule would not be

“dissymmetric” otherwise. A “true” racemate contains both enantiomers in the unit cell

of its crystals or is not crystalline at all. Enantiomerically enriched crystalline material

can be recrystallized to enantiomerically pure one only, if it crystallizes as a

conglomerate, which consists of two sorts of crystals containing only one enantiomer

each per unit cell. Conglomerates show a eutecticum and racemates often only a

dystecticum in their phase diagrams.

A molecule and generalized any geometric object is chiral (χειρα = hand) resp.

asymmetric, if no n-fold improper axis of rotation Sn, no symmetry plane S1 and no

inversion center S2 = i are present, but n-fold proper rotation axes Cn are allowed. If

two chiral stereoisomers are related by being nonsuperimposable mirror images, the

molecules are enantiomeric. All physical and spectroscopic properties of two related

enantiomers are identical, except each enantiomer causes the plane of linear

polarized light to rotate by opposite but equal amounts. Although enantiomers do not

differ in energy within experimental error of current available analytical methods the

question is still unanswered, why most chiral molecules of natural origin are

dominating in the universe in one enantiomeric form only, such as amino acids (see

alanine in Pic. 1.1.1) and sugars. As a reason violation of parity rules caused by

electroweak quantum forces is seriously discussed, which are causing energy

differences in enantiomers of the magnitude of 10 -11 J way too weak to be measured

directly by current available methods [2 (5)].

If the center of asymmetry (*) is located inside the position of an atom, then the

chirality of the particular molecule is central (Pic. 1.1.1). The absolute configuration of

a tetrahedral chiral center, requiring four different substituents, is denoted by the

Cahn-Ingold-Prelog (CIP) rules and the CIP descriptors (R) and (S) are assigned by

using the sequence rule to assign a priority order to the substituents on the chiral

atom [3 (1-6)]. The substituents or ligand atoms are assigned by decreasing priority

in the order of decreasing atomic number and a free electron pair has the lowest

order, in example for sulfoxides. The same is valid for isotopes of an element by their

decreasing isotope number. When two or more of the substituent atoms are the same

element, the next attached atoms in those substituents are compared. This process

- 11 -

of substituent comparison is continued until the order of priority of all substituents has

been established. An atom that is multiply bonded is counted once for each formal

bond. When the substituent group priority has been established, the molecule or

complex is viewed in an orientation which places the lowest-priority substituent

behind the chiral center. The remaining substituents project toward the viewer. The

remaining substituents have one of two possible arrangements. The substituents

decrease in priority in either clockwise or in a counterclockwise manner. In the former

case, the configuration R (rectus) is assigned, in the later S (sinister). If two

substituents on a chiral atom or central ion differ only in absolute configuration, then

(R) has priority before (S), or in general, the chiral substituent with clockwise priority

sequence. An atom or a central ion carrying exclusively different substituents or

ligands, is per se chiral and the CIP nomenclature is applied analogously. Central

chirality is not restricted to central ions or atoms with different substituents or ligands

only as can bee seen on the examples of the Werner complexes Co(en)33+ or cis-

Co(en)2Cl2+, where the ∆ / Λ-assignment rules apply (Pic. 1.1.1) [3 (7-8)].

A special case is the class of pseudopolyhedral, in example pseudotetrahedral chiral

metal complexes (Pic. 1.1.1), where one or more ligands are hapto-coordinated, for

which a chirality descriptor system is yet to be recommended by IUPAC. In an ad hoc

suggested descriptor formalism the hapto-bound ligands are considered simply as

pseudoatoms with an atomic number equivalent to the sum of the atomic numbers of

the atoms of the hapto-ligand bound to the metal atom [3 (9-11)]. However, this is

contradicting the CIP system itself, in which the atomic number criteria overrules any

bond connectivity first. Furthermore, this system does not allow an unambiguous

assignment of the absolute configuration of the example η5-(1,2-dimethyl-Cp)-η5-(1,3-

dimethyl-Cp)Mo(IV)ClH (Pic. 1.1.1), because it cannot distinguish between hapto-

bound isomers. Therefore it is suggested to draw an imaginary line from the metal

center to the hapto-bound atom with the highest CIP priority of the hapto-bound

ligand first (dotted in Pic. 1.1.1 in the structure of the Mo(IV)-complex). Then starting

from this position in the hapto-ligand the shortest way to the hapto position of the

next succeeding priority is determined in accordance to CIP resp. IUPAC, which is

then further extended to the substituents / ligands additionally bound on the hapto-

ligand and so on until the priority according to CIP respectively IUPAC is fully

established.

- 12 -

Central Chirality

RuPPh3

Cl

RH2N

Cl

Ru

RH2N PPh3

RuPh3P

Cl

NH2R* *

(R) (S)

Cl

Ru

NH2RPh3P

* *

σ

RuPPh3

RH2N

HRu

Ph3PNH2R

H* *

(R) (S)

Mo

ClH

H3C

H3CCH3

H3C

1

2

3

1

2

Mo

ClH

H3C

H3CCH3

H3C

1

2

3

1

2

mirror plane σ

imaginary axis to hapto-bound atom with highest CIP-priority

=

(S)

(R)

COO

CH3N

CH3

H

COO

CNH3

H3C

H

COO

CH3N H

CH3

COO

C NH3H

CH3

CIP : (R)-Alanine (S)-Alanine

* ** *

(L)Fischer : (D)

σ

CoNH2

NH2H2N

NH2

H2N

H2N

CoH2N

H2NH2N

NH2

NH2

NH2

* *

3 3

CoNH2

NH2Cl

Cl

H2N

H2N

(∆)

CoH2N

H2N Cl

Cl

NH2

NH2

(Λ)

* *

(∆) (Λ)σ

Pic. 1.1.1 Examples of central chirality: amino acids (top); octahedral complexes (middle);

pseudotetrahedral metal complexes with hapto-ligands (bottom).

- 13 -

Fe A

OH

HO

Acentral Chirality

OH

HO

planar chirality

planar, axial or helical chirality?

helical chirality

σ

"Z"B

*

A

B"Z"

* (P)

* (M)

"Z"

A

B

A B

AB

"Z"

"Z"

*

*

hexahelicene

(P)-BINOLcommon: (S)

(M)-BINOLcommon: (R)

IUPAC: (P )Schlögl: (Rp)

FeA"Z"

B

*

IUPAC: (M )

σ

B A

Fe

A B

Fe

Schlögl: (Sp)

planar or axial chirality?

.

H

H3CCH3

H

.

H3C

HCH3

H

*

*

A B

Z

(P)

(M)

*

A B

Z*

"Z"

"Z"

A

A

.

.

Pic. 1.1.2 Examples of acentral chirality: 1,2-disubstituted ferrocenes (top); allenes, 1,1'-

binaphthyl derivatives and helicenes (bottom, from left to right).

- 14 -

The different (hapto-)ligands are now compared, their priority assigned and the

absolute configuration determined as described above. In the Mo(IV) example the

priority is therefore Cl > η5-(1,2-dimethyl-Cp) > η5-(1,3-dimethyl-Cp) > H. Because

this suggested assignment system is in full accordance with existing IUPAC rules,

unambiguous and logical consistent at least within this thesis it is applied throughout

for the Ru(II) η6-benzene complexes reported (see example in Pic. 1.1.1). It can be

also extended by exactly the same algorithm to heteroatom containing hapto-ligands,

for instance for hapto-mono-, -di- and -triphospholyl ligands.

Certain compounds do not contain atoms as chiral centers and are nevertheless

chiral, for which the structural classification acentral chirality is suggested. For these

compounds one can draw two perpendicular planes neither of which can be bisected

by a plane of symmetry (exemplified in on 1,3-dimethylallene in Pic. 1.1.2) [4].

Unsymmetric 1,2-disubstituted ferrocenes [4 (2)] and cyclophanes are commonly

referred to planar chirality. Axial chirality is attributed to allenes as well to trans

cyclooctenes, binaphthyls and certain biphenyls, which are often called also

atropisomers in regard to their hindered rotation or ring inversion “fixing” their

chirality. Certain atropisomers or supramolecular assemblies are referred to helical

chirality in case of helicenes, found also in DNA resp. RNA double helices and in

protein α-helices in nature. Topological isomers, such as catenanes and rotaxanes

are out of the scope of this introduction. As illustrated (Pic. 1.1.2) the different

subclassifications of acentral chirality are not well distinguishable formally or even

ambiguous. However, for all these subclasses one common formal descriptor system

for the absolute configuration has been developed by the extension of the CIP rules

[3 (1-8)], fully justifying their uniform classification as acentral chirality in this way.

First the plane with the two substituents of highest CIP priority in its edges is

identified (exemplified on a planar chiral ferrocene in Pic. 1.1.2, A before B). This

plane is turned in that manner these two substituents show directly towards the

viewer and in this way the other perpendicular plane with the moiety or substituent

“Z” of following CIP priority is placed into the background. The substituents decrease

in priority again in either clockwise or in a counterclockwise manner going from the

viewer’s position from A to “Z” to B. In the former case, the absolute configuration P

(plus) is assigned, in the later M (minus). Borderlines of planar and central chirality

should not be concealed. In many cases η2-complexed olefins are bended out of a

- 15 -

planar structure and are more similar to a metalla cyclopropane. Hexaethylborazine

is bound to the chromium(0)-tricarbonyl fragment in a σ(N):σ(N):σ(N)- rather than in a

η6-mode [5]. However, it is suggested to switch from the PM to the RS nomenclature

only, if the planarity of the coordinating arene or olefin is severely distorted, which

has to be judged case by case.

A necessary requirement for the isolation of enantiomers is their configurational

stability, of course. Hence the inversion barrier of ammonia is only around 23.4 kJ /

mol equivalent to an oscillation frequency of 2.39 x 10 10 Hz and the one of tertiary

amines around 16 – 40 k J / mol [4 (1)], enantiomers of amines with three different

alkyl groups cannot be isolated, except if they are “locked" in a bicyclic rigid system,

such as Tröger’s base. Tertiary phosphines [4 (1-2)] have a higher inversion barrier

of 126 – 147 kJ / mol, so they can be isolated at room temperature, but do racemize

at elevated temperatures. The inversion barriers of tertiary arsines and stibanes are

even higher [6 (1)]. Sulfoxides are also nonplanar, and there is a similar inversion

barrier at the sulfur atom compared to phosphines that unsymmetric pyramidal

sulfoxides are chiral and maintain their configuration at room temperature [6 (1, 3-6)].

Sulfonium salts with three nonidentical ligands are also chiral as a result of their

pyramidal shape. Conclusively an enantiomer is isolable at room temperature, if its

inversion barrier is at least ~ 110 kJ / mol. It is thermally stable under usual reaction

conditions, if the inversion barrier is above 170 kJ / mol. In certain enantiomorphous

crystals such as Tiefquartz and NaClO3 chirality is only caused by crystal packing of

achiral components [6 (7)]. If a chiral molecular compound can be obtained

crystalline, then anomalous X-ray scattering is the only direct and unambiguous

method to determine the absolute configuration, first performed by Bijvoet [6 (8)] in

1951. Previously all chiral molecular compounds were related by tedious chemical

transformation to (R)- or (S)-glyceraldehyde. Its absolute configuration was arbitrarily

assigned as a relative standard by optical rotation which proved to be the right one

later on. The absolute configuration of a chiral compound can be only determined

empirically by optical rotary dispersion (ORD) and circular dichroism (CD), if it can be

related to the chiroptical properties of a similar compound with known absolute

configuration [7]. The chief uncertainty of resulting conclusions by this method arises

from failure to satisfy adequately the criteria of “similarity” in the nature of the

electronic transitions and in the structures of the molecules themselves.

- 16 -

Diastereomers

76SS

Fe

*

O

p-Tol (S)

(H3C)2N

* (M)

S

Fe

*

O

p-Tol (S)

* (P)

N(CH3)2

H3C

FeHOOC

* (P) (M) *

COOH

CH3

* (P)

CH3

FeCOOH

COOH

H3C

(M) *

CH3

FeCOOH

CH3

COOH

meso

achiral!!

76R

l (like) u (unlike)

S

Fe

*

O

p-Tol (R)

(H3C)2N

* (P)

S

Fe

*

O

p-Tol (R) N(CH3)2

* (M)

σ

enantiomer enantiomer

2 diastereomeric pairs of enantiomers

σ

σ

two planes of opposite chirality result in one symmetry planeinside the molecule

Pic. 1.1.3 Diastereomeric relationships: central and acentral chirality (top); acentral chirality only

(bottom); note central chirality has always priority before acentral, (R) resp. (P) before

(S) resp. (M).

- 17 -

Diastereomers are defined as stereoisomers that are not related as an object and its

mirror image, like exemplified on the structures of 1-N,N-dimethylaminomethyl-2-[(p-

tolyl)sulfinyl]ferrocene 72 and 1,1’-dimethyl ferrocene-2,2’-dicarboxylic acid with the

indicated configurations (Pic. 1.1.3). Each of the four structures of 72 is

stereoisomeric with respect to any of the others. The (SS, M) and (RS, P)

stereoisomers are enantiomeric with relative l (like) configuration, as are the (SS, P)

and (RS, M) pair with relative u (unlike) configuration. The (SS, M) isomer is

diastereomeric with the (SS, P) and (RS, M) isomers and vice versa for the (RS, P)

isomer since they are stereoisomers but not enantiomers. This is resulting in two

diastereomeric pairs of enantiomers with relative l and u configuration each. If several

chiral centers or planes in a molecule are arranged in such a way a plane of

symmetry is generated inside, the molecule is achiral resulting in a meso

stereoisomer (Pic. 1.1.3, bottom right). Note in nomenclature central is always

denoted before acentral chirality.

Diastereomers differ in both, physical and chemical properties (melting- and boiling

point, solubility, dielectric constant, spectroscopic and crystallization properties, etc.).

The specific rotations of diastereomeric molecules can differ both in magnitude and

sign. The difference in chemical reactivity can be a slight difference in rate or two

diastereomers can lead to entirely different products, depending on the nature and

mechanism of the particular reaction in an individual structure-reactivity relationship.

Already in the 19th century it was recognized complex chemical pathways in life resp.

biological systems are based on chiral molecules and that biological systems are

even constructed of chiral building blocks themselves [8 (1-2)]. Two chiral molecules

react in a diastereomeric fashion in that way the reaction rates and products depend

from the absolute configuration of both molecules. In this way enzymes can

distinguish between resp. recognize differentially opposite enantiomers for instance,

so enantiomers show often very different physiological properties (Pic. 1.1.4), which

is crucial for living organisms as well as for the applications of enantiomers as

perfume or food additives and most important as pharmaceuticals and agrochemicals

[8 (3)]. Increasing knowledge about the relation of molecular chirality to physiological

effects motivated the United States Federal Food and Drug Administration (FDA) to

permit only the sale of enantiopure pharmaceuticals [8 (4-5)].

- 18 -

O O

O

HN COOCH3

NH2

Ph

HOOC

* *

* *

O

HNH3COOC

NH2

Ph

COOH

**

HSCOOH

NH2

* SHHOOC

NH2

*

O

O

NH

O

O*

O

O

HN

O

O *

(R)-Carvone

spearmint leaves

(S)-Carvone

caraway seed

(S, S)-Aspartam sweet (R, R)-Aspartam bitter

(S)-Penicillamine

antiarthritic

(R)-Penicillamine

severely toxic

(R)-Thalidomide ™ (Conatagan ™)

analgetic

(S)-Thalidomide ™ (Conatagan ™)

severely teratogen

Racemization under physiological conditions!

σ

Pic. 1.1.4 Examples of physiological properties of enantiomers.

- 19 -

Therefore the synthesis of enantiopure compounds is of increasing economical and

industrial importance. The production of enantiopure chemicals based on natural or

biological resources (“chiral pool”) for a long time only, but nowadays following

methods for the preparation of enantiopure compounds are available:

1) Diastereomeric separation of mixtures of enantiomers [9 (1-4)]

2) Chemical transformation of chiral natural products [9 (5-10)] 3) Enantioselective Synthesis [9 (11-15)]

For a given synthesis problem the choice of method is limited by technical

possibilities, but governed by economic reasons and costs of course. In most cases

the third method is the option of choice, because with the use of a recoverable chiral

auxiliary or more preferable with the use of an enantioselective (homogenous) chiral

catalyst in substoichiometric amounts losses by the formation of the undesired

enantiomer are minimized. If the resolution of enantiomers by intermediate

transformation into diastereomers or on chiral stationary phase by chromatography is

left as the only applicable method, then the loss by the undesired enantiomer is at

least 50 %.

1.2 Pseudopolyhedral hapto-Arene Complexes with Chiral Metal Centers

The three different preparation methods of enantiopure compounds can be directly

shown on the syntheses of pseudopolyhedral hapto-arene complexes with chiral

metal centers (Pic. 1.2.1, Pic. 1.2.2). Brunner resolved (η5-Cp)Mn*(II)PPh3(NO)

(CO)+PF6- by addition of sodium (-)-mentholate, followed by chromatographic

separation of the resulting diastereomers and final acidic cleavage of the chiral

auxiliary to the pure enantiomers of the original complex [10]. Gladysz [11] and

Davies [12] obtained similar Re(III) and Fe(II) complexes in an analogous way (Pic.

1.2.1). All these examples are configurationally stable, but if aryl lithium is added to

Brunner’s Mn(III) complex, racemization at the chiral Mn(III) center of the resulting σ-

carbonylate complex occurs rapidly at room temperature.

- 20 -

Diastereomeric Resolution of Racemate

CO

MnPh3P NO

COOR*Mn

Ph3PNO

COOR*

MnPh3P NO

PF6

1) R*ONa

2) separartion of diastereomers

+*

*

*

3) HCl

4) NaPF6CO

MnPh3P NO

*

PF6

PF6

COMn

Ph3PNO

*(R)

(S)

R* = (-)-(1R,2S, 5R)-menthyl

H. Brunner

RePh3P

NO

*

RBF4

J. Gladysz

CO

FePh3P

*O

S. G. Davies

MnAr3P NO

*

PF6

COMn

Ar3PNO

*

Ar' O

MnAr3P

NO

*

Ar'

OAr'Li Racemization!

toluene / 20 ° C

Ar = Ph Ar' = Ph t 1/2 = 49.5 min.Ar = Ph Ar' = (p-N(CH3)2)C6H4 t 1/2 = 3.6 min.Ar = Ph Ar' = (p-CF3)C6H4 t 1/2 = 418.0 min.

Ar = (p-CF3)C6H4 Ar' = Ph t 1/2 = 5.9 min.Ar = (p-OCH3)C6H4 Ar' = Ph t 1/2 = 337.0 min.R

Configurative stabilization by electronic fine tuning of attached ligands!

H. Brunner

Pic. 1.2.1 Diastereomeric resolution and configurative stabilization of pseudotetrahedral η5-Cp

Mn(III), Re(III) an Fe(II) complexes.

Electronic “fine tuning” can enhance the configurational stability of Brunner’s σ-

carbonylate complex, if electronwithdrawing substituents are introduced in p-position

of the acyl phenyl ring and if electrondonating substituents are attached in p-positions

of the phosphine phenyl rings. This is increasing its half-life t½ up to factor eight.

- 21 -

If a chiral ligand is complexed to an enantiotopic pseudotetrahedral metal hapto-

arene fragment under thermodynamic control, a diastereomeric excess (d.e.) is only

observed, if there is a considerable steric interaction between the chiral center of the

introduced ligand. No d.e. is observed otherwise (Pic. 1.2.3, example on top). This

does not mean the resulting diastereomeric complexes are not different in their

physical properties, hence the (η5-Cp)Mo*(II)(CO)(NO)(aminophosphane) complexes

can be separated by crystallization or column chromatography [13]. On the other

hand, if there is a considerable steric interaction between the introduced chiral ligand

and the created chiral metal center, then a diastereomeric excess results, such as for

Brunner’s diastereomeric (η7-Trop)Mo*(II)(CO) chelate complex [14], which is

configurationally stable also at higher temperatures and in various solvents.

However, if a chiral metal center of a diastereomeric pseudotetrahedral metal hapto-

arene complex is not stable and if there is a steric interaction with the other chiral

center of the bound ligand, then a diastereomeric thermodynamic equilibrium at the

chiral metal center results in solution as shown by Pfeffer (Pic. 1.2.3) [15]. The first

experimental hint for this fact is the impossibility to separate the diastereomers by

fractional crystallization or column chromatography. Often such equilibrium is solvent

and much more temperature dependent, so it can be proven by a van’t Hoff plot with

NMR. A true thermodynamic equilibrium exists only, if both diastereomers inter-

convert fast and reversible. Transient NMR experiments allow a verification of a

thermodynamic equilibrium, if a chemical exchange between the two diastereomers

is observed. But this is only the case, if the exchange rate constants kex are in the

range of 10-1 to 103 s-1 [16 (1)], diagnosed by crosspeaks in EXSY-NMR spectra for

instance. Asymptotic kinetic behavior of a first order epimerization curve does not

justify an equilibrium assumption alone, especially in cases of slow reaction rates.

However, if an exchange on the NMR time scale is to slow to be observed, this does

not necessarily mean an equilibrium does not exist, but cannot be proven in turn.

Brunner discussed the configurational stability of hapto-Arene complexes with

tetrahedral chiral metal centers in solution and their kinetic relaxation into

thermodynamic equilibrium [3 (9), 16 (2)], but did not support the claims of equilibria

with appropriate NMR exchange experiments concerning this aspect. Sometimes the

exchange rates are so fast NMR signals of all involved diastereomeric complexes

collapse to one set of signals pretending the presence of only one diastereomer in

- 22 -

solution. Configurational stability of diastereomeric pseudopolyhedral hapto-arene

metal complexes can be proven then with NMR experiments then and only then, if

they are performed at different temperatures and solvents.

Co(H3C)2N I

N

MoN CO

Ph

CO

MoOC NO Ph N

PPh2*

(R)

+

CO

MoP NO

NPh

Ph Ph

(R)

* *

(S)

NO

MoP CO

NPh

Ph Ph

(R)

* *

(R)

CO

heat

thermodynamic control

- no steric interaction between chiral centers- no diastereoselectivity of raction

- confugarionally stable and therefore separable by column chromatography

I

Co

(H3C)2N

*

* *

*

thermodynamic equilibrium M. Pfeffer

19 unlike : 1 like (91 % d.e.)

- Metal configuration not stable, but- u-diastereomer sterically preferred!

BF4

thermodynamic product H. Brunner

- Metal configuration stable and- l-diastereomer preferred product!

* *

Pic. 1.2.2 Examples for thermodynamic control, equilibrium and product formation of pseudo-

tetrahedral η5-Cp Mo(0 and II) and Co(III) complex syntheses.

While chiral metal centers of (diastereomeric) pseudopolyhedral metal hapto-arene

complexes are stable in solid state they are not necessarily in solution. Packing

effects during crystallization can cause racemization (epimerization) and even

complete interconversion of the chiral metal center (Chapter 4). Crystalline material is

can exist also in different modifications, so X-ray structure analysis alone cannot

prove an absolute configuration, but only if it is accompanied with spectroscopic

- 23 -

evidence such as NMR, ORD and CD. But how can the configurational stability of a

chiral metal center be controlled? A coarse survey of literature cited here temptates

to relate an increased configurational stability of a chiral metal center to lowered

metal electron density by increasing the π-acceptor capability of the bound ligands.

This is only valid as long as decreasing electron density for enhancing π-acceptor

capability of ligands does not reduce their polarizability and therefore their σ-donor

capability (Pic. 1.2.1). This often causes an antagonistic effect concerning

configurational stability of the chiral metal center in turn. How σ-polarizability alone is

affecting configurational stability can be seen on the example (η5-Cp)Fe*(II)(CO)X

(PPh2-NR*R), where half-life increases with X = H3C > I >> Br > Cl [16 (5)]. In turn

the polarizability of the metal center has also to be considered also. As mentioned

before Davies’ reagent is configuratively stable, but Brunner’s isoelectronic complex

(η5-Cp)Mn*(III)(NO) (CO-Ph)(PPh3) is not. How steric aspects alone can govern the

configurational stability of chiral metal centers will become evident during the next

two sections and is one of the key questions addressed in this thesis here. In most

cases, but not always, this issues is inherent important for enantioselective catalytic

applications.

1.3 Principles of Homogenous Enantioselective Catalysis exemplified on CaTHy Reactions

Transfer hydrogenations are classified as such reactions, where hydrogen H2 is

formally transferred from a donor molecule (DH2 = primary and secondary alcohols,

formic acid / triethylamine 5 : 2 [17 (2)], ammonium formiate, cyclohexene, cyclohex-

adiene, etc.) to a substrate, mostly carbonyl compounds (aldehydes, ketones, imines)

resulting in a reduction to an alcohol or an amine and in the oxidized donor D [17].

Molecular hydrogen is not involved or intermediary formed during this reaction type.

A leading example of a transfer hydrogenation and permethylation in tandem fashion

is the Leuckart-Wallach reaction of ketones to tertiary dimethylamines (one of many

methods of reductive amination) [17 (3-5)]. In catalytic transfer hydrogenations

(CaTHy) main group as well transition metals are involved as catalysts. The driving

forces of transfer hydrogenations are the higher electrochemical standard potential

- 24 -

E0 of the substrate compared to the indirect hydrogen source DH2 as reducing agent,

the presence of the reducing agent in a high excess and, if applicable, continuous

removal of the oxidized donor (distillation, etc.). This reaction type is often reversible.

The Meerwein-Ponndorf-Verley reduction is the first CaTHy reaction discovered

already in 1925 with aluminium triisopropylate as catalyst (Pic. 1.3.1, reduction of

acetophenone to 1-phenylethanol) [17 (6-12)]. Without aluminium triisopropylate no

reaction is observed. The reaction can be reversed, if 1-phenylethanol is reacted with

Al(OiPr)3 in a high excess of acetone. A catalyst cannot influence a thermodynamic

equilibrium, but can only accelerate its formation. Conclusively a catalyst is a

species, which accelerates a reaction by lowering its free activation energy ∆G‡ in the

way it forms intermediates of lower particular free activation energy ∆G‡i and is finally

regenerated in cyclic fashion under the release of the product. The particular

reactions to the intermediates can be endothermic, as far as the overall reaction is

exothermic under the conditions it is run and as long as all activation energies ∆G‡ i

of the formations of all intermediates are significantly lower than the activation energy

∆G‡ of the uncatalyzed reaction. The overall exothermicity is the driving force of a

catalytic reaction. The efficiency of a catalytic system is given by its turnover number

(TON) and its activity by the turnover frequency (TOF), which both determine the

needed substoichiometric amounts of the catalyst for a practically or industrially

applicable conversion.

In the Meerwein-Ponndorf-Verley reduction the carbonyl carbon atom is first

positively polarized by Lewis acid complexation of the carbonyl oxygen atom by

aluminium triisopropylate (Pic. 1.3.1). In a chair-like arrangement under the lowest

possible A1,3-interaction [18 (1-3)] a hydride from one isopropylate ligand is

transferred to the carbonyl carbon atom. This chair-like arrangement preserves the

Bürgi-Dunitz trajectory [18 (4)] of 110° of the incoming hydride nucleophile. The

hydride transfer is concerted and therefore this chair-like arrangement is interpreted

as a transition state of a [1,5]-supra sigmatropic shift [19]. The driving force of this

reaction step is the synergism of alternating polarizations in the transition state.

Although synthetic applications of this reaction are displaced by an arsenal of

reductions with hydride complexes [20] it is often the methodological alternative for

the reduction of sensitive carbonyl compounds.

- 25 -

Ph CH3

O

Ph CH3*

OHHH3C

H3COH

HH3C

H3C

O+ +Al[OCH(CH3)2]3

O

AlO

H

CH3

Ph

O

O

O

AlO

H

CH3

Ph

O

O

O

Ph

CH3

a

b c SiRe

ca. 110 °

Enantiotopicity of nucleophilic attack in Bürgi-Dunitz-trajectory:

chair-like transisiton states ([1,5]-supra sigmatropic shift):

Fixation and activation by Al3+ as Lewis-acid :

1

23

45

1

leading to (S)-product

leading to (R)-product

Pic. 1.3.1 Meerwein-Ponndorf-Verley reduction and transition states.

In the classical Meerwein-Ponndorf-Verley reduction of acetophenone racemic 1-

phenylethanol is formed. The two enantiomeric transition states are equal in energy,

resulting in an equally preferred nucleophilic attack at Re- and the Si-face of the

enantiotopic trigonal planar carbonyl center leading to the racemate (Pic. 1.3.1).

In 1995 Noyori presented the first highly enantioselective chiral transitionmetal based

transfer hydrogenation catalyst (η6-p-cymene)Ru(II)Cl((S,S)-TsDPEN) (Pic. 1.3.2).

This complex is configuratively stable at the chiral Ru(II) center and is moderately

active under basic conditions in the reduction of unsymmetric ketones in isopropanol

[21 (1-2)] and in the kinetic resolution of racemic chiral alcohols in acetone [21 (3)]

with up to 97 % e.e.. The rigid ligand (S, S)-TsDPEN alone provides the chiral

information to the catalytic Ru(II) center, which in turn transfers it on the achiral

substrate. Because the chiral auxiliary as a catalyst is needed only in substoichio-

metric amounts this transfer can be seen as a “multiplication of chirality”.

- 26 -

N

H2N

RuCl

HH

(S)

(S)

(S)

Ph CH3

O

OH

(S)

(R)

Ph CH3

OH

Ph CH3

OH

O

**

*

Catalyst loading:

1 mol % Complex +2 mol % Base (KOH, tBuOK)

+

**

+

+

up to 97 % e.eTON = 1000TOF = 1000 h-1

SO

O

H3C

Pic. 1.3.2 First highly enantioselective transfer hydrogenation (pre)catalyst (η6-p-cymene)-

Ru(II)Cl((S,S)-TsDPEN) for the reduction of unsymmetric aryl ketones and kinetic

resolution of chiral 1-aryl alcohols.

- Without addition of base almost no reaction is observed, so the chloride

complex (Pic. 1.3.2) cannot be the catalytic active species itself, weather in the

reduction nor in the resolution reaction. Usually 1 mol % catalyst precursor

complex and 2 mol % alkali base in regard to the substrate are applied.

- Once the ketone reduction reaches the thermodynamic equilibrium with a

product : substrate ratio of ca. 70 : 30, erosion of the enantiomeric excess

down to racemate is observed. Usually a substrate concentration of 0.1 mol / l

in isopropanol under reflux conditions (ca. 80° C) are the optimal conditions

reaching the equilibrium within ca. 2 h. Because (1R)- and (1S)-1-

phenylethanol are equal in energy within experimental error these facts clearly

show the formation of (1S)-1-phenylethanol occurs only under kinetic but not under thermodynamic control. The kinetic resolution is preferably performed

with a 0.1 mol / l substrate concentration in acetone over a period of ca. 30 h

at room temperature.

- 27 -

- Higher substrate concentrations accelerate the reduction, but cause also an

erosion of the enantiomeric excess in turn. The equilibrium shifts irreversibly

and completely to the product side with no erosion of enantiomeric excess by

continuous distillative removal of acetone as one of the volatile reaction

products. Without a high excess of acetone for the kinetic resolution an

erosion of the enantiomeric excess is observed, too.

- Reduction and kinetic resolution deliver each the opposite enantiomer of the

chiral alcohol regarding the common related ketone, but almost with the same

enantiomeric excess (in example, 97 % e.e (1S)-1-phenylethanol by the

reduction of acetophenone and 98 % e.e. (1R)-1-phenylethanol by the kinetic

resolution of the racemate).

- High enantiomeric excesses can be only achieved with aryl ketones or 1-aryl

alcohols, but not with alkyl ketones or alkyl alcohols.

These findings fit well to the mechanism shown below (Pic. 1.3.3, Pic. 1.3.4, Pic.

1.3.5, Pic. 1.3.6) and intermediates of this catalytic cycle were isolated and

characterized unambiguously with NMR an X-ray crystal structure analysis [21 (2)].

Furthermore it is supported by DFT calculations [21 (4)] on model substrates and

catalysts as well as with crossexperiments [21 (1-3)] with catalyst analogs. A

concerted basic syn elimination of chloride and the axial proton from the acidic

coordinated amino group leads to the pseudotrigonal planar Ru(II) amido complex C,

which is the particular catalytic active species. The original chiral Ru(II) center is lost

and the “chiral information” is provided by the (S,S)-TsDPEN ligand exclusively. It is

obvious this catalytic active species should be rather seen as a 18 VE imido than as

a 16 VE amido complex, because the imido center is definitely planer (Ru=NH-C all

in plane, see molecular crystal structure [21 (2)]) with identical bond angles all of

121.2° and a Ru=N bondlength of 1.897(6) Å compared to 2.065(6) Å of Ru-N(Tos).

This and the planarity both of the Ru(II) and the imido center are unambiguously

diagnostic for a considerable backbonding of the imido N atom to the Ru(II) center,

resulting with the electron accepting η6-coordinated arene in an additional stabilizing

donor-acceptor synergism.

- 28 -

In the first step the imido catalyst C reacts with isopropanol nearly exclusively to the

configuratively stable (RRu)-(η6-p-cymene)Ru(II)-hydrido ((S,S)-TsDPEN) complex IR

(less than 1 % of the (SRu)-hydride diastereomer IS was detected in the separate

reaction of the imido complex C with isopropanol in toluene-d7), confirmed by NMR

and X-ray crystal structure analysis. This equals an overall retention of configuration

at the chiral Ru(II) center related to the previous elimination of HCl (Note retention of

configuration is given if the reaction pathway proceeds at one enantiotopic or

diastereotopic side exclusively, regardless of denotation change of the absolute

configuration at the chiral center before and after the reaction occurred). First

incoming isopropanol associates with the catalyst C by an imido-hydroxy hydrogen

bond [21 (5)], but not through a metal-hydroxo coordination. This is again in

accordance with the proposed 18 VE structure by backbonding of the catalytic active

species. Out of this association two diastereomeric sixmembered boat like

sigmatropic [1,5]-supra transition states with lowest free activation energies ∆G‡1

Re

and ∆G‡1

Si can be reasoned by DFT calculations (Pic. 1.3.4). Due to steric repulsion

of the phenyl rings and η6-p-cymene ∆G‡1

Re is magnitudes higher than ∆G‡1

Si,

explaining well the exclusive (RRu)-hydride complex IR formation by a preferred Si-

face attack of isopropanol on the Ru(II) center. However, the formation k1Si of the

hydride intermediate IR by isopropanol dehydration is slower than the backreaction

k -1Si of acetone (k -1Si > k1Si, k1

Si = 2.5 x 10-3 mol l-1 s-1). Therefore the first step of the

catalytic cycle is reversible and can become even turnover limiting for the whole

reduction. In this way both rate constants k1Si and k -1Si need to be taken into account

for a general steady state approximation outlined below (Pic. 1.3.5), while k -1Re and

k1Re can be neglected. With a high excess of isopropanol or the continuous removal

of acetone by distillation in the ketone reduction the backreaction of the hydride

complex can be suppressed or can be overcome irreversibly.

- 29 -

H3C Ph

O

(S)

Ru

N NHTos

Ph Ph

NNH2

Ph

Ru

Cl Tos

Ph

H

H

(S)KOH

(S)

H2O + KCl

NN

Ph

Ru

Tos

Ph

H

H

HH

O

H3C

H3C

(S)

H3C CH3

HO H

H3C CH3

O

(S)

(R)

NNH2

Ph

Ru

H Tos

Ph

H

H

(S)

(S)

(R)

NN

Ph

Ru

Tos

Ph

H

H

HH

OH3C

(S)

(S)

H3C Ph

OH(S)

1

2

hydride transferto ketone

substrate association

**

*

Precursor

Catalytic Active Species

**

**

*

Hydride Transferring Intermediate

**

*

*

Re-face attack!!

DiastereomericTransition States

Slow!

Accelerated by high excess of iPrOH!

* * (S)(S)

catalyst activation by deprotonation to imido complex

HH

k1

k2

[C]

[A]

[PS]

Pic. 1.3.3 Summarized prototype mechanism of hapto-Arene M(d6) complex mediated enantio-

selective CaTHy reactions.

- 30 -

SO2

NN

Ru

O2S

H

H

HH

O

H3C

H3C

(S)

(S)

**

H

NN

H

Ru

H

HH

O

CH3

CH3

(S)

(S)

*

*

H

H3C

Si RuRe Ru

(R)

NNH2

Ph

Ru

H Tos

Ph

H

H

(S)

(S)

**

*(S)

NH2N

H

Ru

HTos

H

Ph

Ph

(S)

(S)

**

*

CH3

k -1Re >> k -1Si > k1Si >> k1

Re

and conclusively

∆G‡-1

Re << ∆G‡-1

Si < ∆G‡

1Si <<< ∆G‡

1Re

[IS] [IR]

= k1Re [C] [iPrOH] -

k -1Re [IS] [acetone]

(neglected completly)

= k1Si [C] [iPrOH] -

k -1Si [IR] [acetone]

favored!!

[C] = conc. of catalytic active species

k1Re

k -1Re k1Sik -1Si

d [IS]dt dt

d [IR]dt dt

Pic. 1.3.4 Step 1: hydride transfer from reductand isopropanol (iPrOH) to hapto-arene M(d6)

imido complex C, the "true" catalyst.

- 31 -

Re-face attack on ketonedue to ππ-attraction favored!!

(R)

NN

Ph

Ru

Tos

Ph

H

H

HH

OH3C

(S)

(S)

**

* H

ππ(R)

NN

Ph

Ru

Tos

Ph

H

H

HH

O

H3C

(S)

(S)

**

* H

SiRe

Note there is no steric repulsion between the acetophenone phenyl ring and the tosylate moiety!

k -2Re > k -2Si > k2Re > k2

Si

and conclusively

∆G‡-2

Re < ∆G‡-2

Si < ∆G‡

2Re < ∆G‡

2Si

Ph CH3

OH

*(S)

Ph CH3

OH

*(R)

k2Re k2

Si

PS PR

general steady state approximation ([IR] = const.):

d[IR]dt = 0 = k1

Si [C] [iPrOH] - k -1Si [IR] [acetone] - (d[PS] / dt) - (d[PR] / dt)

= k1Si [C] [iPrOH] - k-1

Si [IR] [acetone] - k2Re [IR] [A] + k-2

Re [PS] [C] - k2Si [IR] [A]+ k-2

Si [PR] [C]

= k1Si [C] [iPrOH] - k -1Si [IR] [acetone] - (k2

Re + k2Si) [IR] [A] + (k -2Re [PS]+ k -2Si [PR]) [C]

!!

d[PS] / dt = k2Re [IR] [A] - k -2Re [PS] [C] d[PR] / dt = k2

Si [IR] [A] - k -2Si [PR] [C]

[A] = acetophenone conc.

k-2Sik-2

Re

k -1Si > k1Si > k -2Re > k -2Si > k2

Re > k2Si

Pic. 1.3.5 Step 2: hydride transfer from hapto-arene M(d6) hydrido complex, the intermediate IR,

to the carbonyl substrate (ketone here, imine analog) A via diastereomeric transition

states to the chiral products PR and / or PS; general steady state approximation

(bottom).

- 32 -

Eyring Equation (general)k = =kB T

h e∆G‡

RT∆S‡

R∆H‡

RT- kB T

h e e

ln = ln kB 2h

1T

∆G‡

R- = ln kB

2h∆S‡

R+ 1

T∆H‡

R-

Linear plots only for small temperature intervalls ∆T valid!!

d[IR]dt = 0 = k1

Si [C] [iPrOH] - (k2Re + k2

Si) [IR] [A]!!Reduction of Acetophenone:

[IR] =k1

Si [C] [iPrOH]

(k2Re + k2

Si) [A]subsitution of [IR] in 1-phenylethanol formation:

= k2Re [IR] [A] = k2

Re = k2Si [IR] [A] = k2

Sik1

Si [C] [iPrOH]

(k2Re + k2

Si)

k1Si [C] [iPrOH]

(k2Re + k2

Si)

d[PS]dt

d[PR]dt

;

k2Re

k2Siln = ∆G‡

2Re - ∆G‡

2Si = ∆∆G‡

2

product formation and only dependent from rate limiting enantioselective step k2; subsitution of rate constant ratio in Eyring equation:

100 % + e.e. (S)100 % - e.e. (S)

[PS][PR] = e

∆∆G‡2

RT=-

Kinetic Resolution of rac. 1-Phenylethanol:

d[IR]dt = 0 = - k -1Si [IR] [acetone] + (k -2Re [PS] + k -2Si [PR]) [C]

!!

product formation and only dependent from rate limiting enantioselective step k-2; direct comparision of rate constants in Eyring equation:

d[PR]dt = k -2Si [PR] [C]

d[PS]dt = k -2Re [PS] [C]

k -2Re

k -2Siln = ∆G‡-2

Re - ∆G‡-2

Si = ∆∆G‡2

100 % + e.e. (R)100 % - e.e. (R)

[PR][PS] = e

∆∆G‡2

RT=-

kT

Pic. 1.3.6 Summarized Eyring equations for the enantioselective reduction of acetophenone A

and kinetic resolution of racemic 1-phenylethanol PR + PS (imines / amines analog).

- 33 -

In the second step the ketone substrate A associates with the hydride intermediate IR

via a hydrogen bond of the carbonyl oxygen atom with the axial proton of the

coordinated amino group [21 (5)] resulting in two diastereomeric boat like sigmatropic

[1,5]-supra transition states again (Pic. 1.3.3 and Pic. 1.3.5). These transition states

lead weather to the formation of (1S)- or to (1R)-1-phenylethanol accompanied with

the common release of catalyst C, which in turn can enter the catalytic cycle again.

Surprisingly a free activation energy of ∆G‡2

Re = ca. 40 kJ / mol is obtained for the

proximal transition state resulting in a Re-face hydride attack on the trigonal planar

carbonyl center of acetophenone leading to (1S)-1-phenylethanol PS compared to

∆G‡2

Si = ca. 52 kJ / mol distal transition state leading to (1R)-1-phenylethanol PR.

Therefore the reduction (1S)-1-phenylethanol PS is kinetically preferred by ∆∆G‡2 =

ca. 12 kJ / mol. This reduction step is calculated to be endothermic by ∆G2 = ca. 20

kJ / mol and is reversible, so conclusively the corresponding rate constants decrease

in the order k -2Re > k -2Si > k2Re > k2

Si.

By consideration of the van der Waals radii for this fact steric repulsive interactions of

the acetophenone phenyl ring with the (S,S)-TsDPEN ligand cannot be accounted for

the preference of the preferred proximal transition state[ 21 (4)]. The calculations

revealed due to its decreased electron density the η6-coordinated p-cymene unit

preferably “snuggles up” to the substrate arene moiety via ππ-attracting interactions,

stabilizing the crowded proximal transition state over the less crowded one. That p-

cymene must act as a π-acceptor is obvious by the decreasing enantioselectivities for

the reduction of para-substituted acetophenones with the order N(CH3)2 > OCH3 >

CH3 > = H >> CF3. LFER plots prove unambiguously an electronic effect together

with the fact aliphatic ketones usually give lowest enantioselectivities. A donor-

acceptor synergism summarizes the overall stabilization of the proximal transition

state: First the hydrogen bond fixation activates the carbonyl carbon atom by positive

polarization, which promotes the hydride approach to it. In turn the Ru(II) center is

positively polarized, too, increasing the π-acceptor capability of the η6-arene ligand.

The resulting ππ-interaction of the η6-arene ligand with the substrate arene moiety is

increasing not only from this side, but also from the hydride approach to the carbonyl

carbon atom. This is decreasing simultaneously the electron withdrawal by the

carbonyl functionality from the substrate arene moiety increasing the π-donor

capability of the phenyl ring of acetophenone in turn. With different η6-arene ligands

- 34 -

the reactivity decreases in the order benzene > p-cymene > mesitylene >

hexamethylbenzene, while mesitylene and or p-cymene display a better enantio-

selection than unsubstituted benzene interestingly. The presence of the NH2 terminus

in the TsDPEN ligand is crucially important. The NHCH3 analogue shows a

comparable enantioselectivity but with much lower reactivity; the N(CH3)2 derivative

gave very poor reactivity and poor enantioselectivity as well. The acidity of the NH2

protons is proven by a rapid H / D exchange in H3COD. These crossexperiments

prove clearly hydrogen bonds are fundamentally involved in the “diastereomeric

fixation” of the transition states. Like in the Meerwein-Ponndorf-Verley reaction also

any other primary or secondary alcohol can be employed as reducing agents, but not

tert. butanol. This clearly proves the first dehydrogenation step of the catalytic cycle

by these crossexperiments. Also the oxidation state of the Ru(II) center is preserved

through the whole catalytic cycle. However, different to the Meerwein-Ponndorf-

Verley reaction a discrete metal hydride intermediate IR is involved.

Although the dehydrogenation of isopropanol to the hydride intermediate IR is faster

than all reaction steps of acetophenone and 1-phenylethanol, it is still overall rate

limiting due to its backreaction k -1Si with acetone. With k -1

Si > k1Si > k -2

Re > k -2Si >

k2Re > k2

Si, the general steady state approximation (Pic. 1.3.5) and the Eyring

equation (Pic. 1.3.6) these two cases of enantioselective reduction of acetophenone

and the kinetic resolution of racemic 1-phenylethanol can be distinguished each.

Because in the reduction of acetophenone isopropanol is present in high excess with

nearly a constant concentration and 1-phenylethanol and acetone are not or only in

low concentrations available in the beginning, the partial rate terms of backreactions

k -1Si, k -2

Re and k -2Si in the particular steady state approximation can be neglected.

The enantioselective steps k2Re and k2

Si become overall rate limiting in this way, so

the enantiomeric ratio is determined by ∆∆G‡2 exclusively. In the kinetic resolution

the catalyst C “fishes out” with k -2Re (1S)-1-phenylethanol PS faster than with k -2

Si

(1R)-1-phenylethanol PR out of the racemate. By an analogous steady state

consideration with a high acetone concentration the enantioselective steps k -2Re and

k -2Si become overall rate limiting, so the enantiomeric ratio is determined by ∆∆G‡

2

exclusively again and of same magnitude like in the reduction, but with the opposite

(R)-enantiomer PR in excess compared to the reduction as shown (Pic. 1.3.6). These

approximations and conclusions are valid for any enantioselective catalysis.

- 35 -

The obstacle of equilibrium influence on conversion and enantioselectivity in the

reduction of ketones can be overcome by the use of such hydride donors, which

reduce the catalyst C to the hydride transferring intermediate IR irreversibly and with

exothermicity leading to a total kinetic control of the reaction. For industrial

applications the direct use of cheap molecular hydrogen is desirable, which adds to

the catalyst C in toluene at room temperature, but only at 80 atm [21 (2)]. The

transition state of the H2 addition incorporates a charge separation of the neutral

hydrogen molecule (Pic. 1.3.7). This requires a high activation energy naturally,

which cannot compensated by a positive charge increase on the metal center by an

oxidative addition pathway in this case requiring therefore high pressure as a driving

force.

H2

NN

Ph

Ru

Tos

Ph

H

H

HH

(S)

(S)

O

NN

Ph

Ru

Tos

Ph

H

H

HHO

(S)

(S)

Ru

N NH

Tos

Ph Ph

(S)(S)

(R)

NNH2

Ph

Ru

H Tos

Ph

H

H

(S)

(S)

CO2

δδ

**

**

*

* *

**

5 eq HCOOH + 2 eq NEt3

[IR]

Pic. 1.3.7 Total kinetic control by irreversibility of the hydride transfer with formic acid

triethylamine aceotrope (left) and polar H2 addition to the Ru(II) center (right).

- 36 -

If a formic acid / triethylamine 5 : 2 aceotrope is used as an indirect hydrogen source,

the ketone reduction proceeds smoothly at room temperature to completion and with

high enantioselectivity (Pic. 1.3.7) [17 (2), 21 (6)]. As can be seen on the sigmatropic

transition state the free activation energy is decreased due to the higher polarity of

formic acid resulting in a stronger donor-acceptor polarization synergism compared to

isopropanol. Of course the irreversible release of carbon dioxide gas is the

thermodynamic driving force of this reaction.

Today the main challenge in designing catalysts for enantioselective transfer

hydrogenation is the increase of catalysts activity and substrate tolerance in regard to

highest enantioselectivity in general [22 (1-6)]. So far only Ru(II), Rh(III) and Ir(III)

halfsandwich π-complexes have to be proven useful as catalytic centers (Pic. 1.3.8).

The hapto-arene fragments are mostly p-cymene, mesitylene and Cp*. From the

natural and synthetically available reservoir of chiral bidentate amino ligands only a

few proved to be effective, namely amino alcohols and ephedrine derivatives as well

as montosylated diamines. These ligands adopt always a distal position towards the

arene fragment in the precursor complex due to steric repulsion and all these

precursor catalyst complexes are configuratively stable (Pic. 1.3.8). Noteworthy

analogs build up by simple amino acids are not configuratively stable and are only

mediocre selective [22 (8)], so the electronic requirement for configurative

stabilization of the precursor complex by the second spectator ligand group cannot

be simplified by using just an “hard” spectator ligand following the Pearson concept in

this sense. However, configurative stability is not always a requirement for a highly

enantioselective transfer hydrogenation catalysts as proven by Pfeffer (Pic. 1.3.8

middle) [22 (6)]. While the N,N-dimethylamino complex was not active, the amino

complex achieved 89 % e.e. (1R)-1-phenylethanol under the usual conditions. The

enantioselectivity is then independent from the configurative stability, if weather one

hydride transferring species is present in highest excess in a preequilibrium or if one

of them reacts ways faster with the substrate as a bare kinetic argument.

Furthermore all these successful chiral bidentate ligands are rigid, which seems to be

another structural requirement. The question of catalyst activity was addressed by

Andersson, who optimized azanorbornane-based ligands by subsequent introduction

of a dioxolane in the backbone and a methyl group in the α-position of the hydroxy

group (Pic. 1.3.8, bottom) [22 (7)].

- 37 -

(R)

(S)*

*

OM

H2N

Cl

(S)*

Ph

Ph

(S)

(S)*

*

NM

H2N

Cl

(S)*SO2(p-Tol)

NH

OH

NH

OH

O

O

*

* *

* *

** *

NH

OH

O

O

*

* *

* * *

O

H2N R

RuCl

HH

(S)

(S)

(S)

**

*

R

M = Rh(III), Ir(III)

Avecia Catalysts

- highly selective (up to 99 % e.e.)!

- high substrate tolerance (aromatic and aliphatic ketones and imines)!

<<

Andersson Ligands with increasing catalytic CaTHy activity

Ru

NH2

NC

CH3

PF6

Ru

N(CH3)2

NC

CH3

PF6

* *

Pfeffer Complexes (configuratively not stable!)

Not active!! up to 89 % e.e. (1R)-1-phenylethanol!!

(R) (R)

Pic. 1.3.8 Survey of best CaTHy systems in regard to enantioselectivity and activity.

- 38 -

Y

O

R R'

O

R

N

R

N

R

NPOR'2

Y = Alkyl, CH2-Hal, (CH2)nCOOEt, CH(R')NHCOR''type 1

R = Naph, HetAr, Alkyne

type 2 type 3

X

O

Ar

type 4 type 5 type 6

R = Naph, n-C4H9

NCl

O COOCH3

pharmaceutical intermediate: L-699,392 (LTD4 antagonist), 92 % e.e. (S) Noyori

type 1 olefinic bond unaffected!!

Pic. 1.3.9 Substrates for enantioselective CaTHy reactions.

The Rh(III)- and Ir(III)(η5-Cp*) complexes were developed by Avecia for technical

applications (Pic. 1.3.8) [22 (4-5)]. The 1-aminoindan-2-ol complexes can be applied

for transfer hydrogenations of ketones of type 1 and type 2 on a 200 l scale (iPrOH /

iPrONa, s / c = 1000, TOF = 500 – 2500 h-1, 87 – 97 e.e., 95 % yield) (Pic. 1.3.9).

The hydrogenation of type 5 imine is in development and the reduction of phosphonyl

amines type 6 gave up to 95 % e.e. (TOF = 1000 h-1). Contrary to Noyori’s Ru(II)-η6-

arene complexes the high selectivity of the Avecia catalysts is based on steric

repulsion and not on ππ-attraction. In the analog enantioselective resp.

diastereomeric transition states the larger substituent of the ketone or imine prefers a

distal position to the Cp*-ligand (compare Pic. 1.3.3 and Pic. 1.3.5). This explains

also the higher substrate tolerance of the Avecia catalysts including simple alkyl

ketones. The Avecia catalysts belong so far to the most active and most stable

- 39 -

enantioselective transfer hydrogenation catalysts, so in catalytic application air does

not need to be excluded vigorously. In all enantioselective CaTHy reactions alkene

and alkyne bonds are generally unaffected. This and the example of the highly

enantioselective synthesis of the LTD4 antagonist demonstrate the synthetic potential

of the enantioselective catalytic transfer hydrogenation (Pic. 1.3.10) [21 (6)]. This

method complementary to classic hydrogenation methods, where olefinic and alkyne

bonds are hydrogenated, but ketones and imines are not.

A major drawback of enantioselective CaTHy reactions is the use of quite expensive

hydrogen transfer reagents (isopropanol, formic acid / triethylamine) compared to

hydrogen preferred for industrial applications. On the other hand pressure equipment

and elaborate safety precautions connected with the explosion hazard of hydrogen

can be circumvented. Furthermore unsubstituted η5-Cp and η6-benzene catalysts are

only merely solulable and therefore not highly active and not highly enantioselective.

This is one of the core reasons, why homogenous is generally preferred over

heterogeneous catalysis for all enantioselective synthesis in industrial applications.

Conclusively the demands on an industrially suitable homogenous enantioselective

catalytic system can be summarized in general:

- Highest enantioselectivity (< 95 % e.e.) for a wide variety of substrates with a

high functionality tolerance (no side reactions, high regioselectivity).

- High catalyst efficiency (TON) and activity (TOF) combined with complete

conversion under minimum energy (temperature, pressure) and solvent use

with cheap and environmentally safe bulk reagents. Only then the total loss of

the expensive catalyst (ligand and metal!) can be economically justified.

- No or low air sensitivity (important for bulk reaction scales under the

avoidance of costs for special equipment, maintenance and for inert gas).

- Easy and quantitative product separation from reaction medium and from

catalyst.

- 40 -

1.4 Catalysts Design for Enantioselective Ketone Hydrogenation by the Octant Rule

“Most excellent new catalysts are optimized forms of existing catalysts

rather then being truly novel. Neither current sophisticated quantum

theory nor elaborate force field methods or combinations thereof can

yet predict the best catalyst.”

Ryoji Noyori [23 (2)]

Catalysts within the scope of this thesis are built up by a central metal as the reactive

center surrounded by one or more (chiral) ligands. The design of an enantioselective

catalyst for a particular reaction starts generally from an achiral catalyst giving the

products as racemates. After tuning up the catalyst activity by ligand and metal

variation, a “chiral environment” or “chiral pocket” is created by the introduction of

chiral ligands, which allows a reagent transfer from the catalytic center preferably or

only to one enantiotopic side of the substrate by binding through diastereomeric

transition states. The correct choice of the metal as well as the choice of the ligand(s)

is crucial for a successful catalytic application. Configuration and conformational

rigidity of the catalyst complex and configuration in unity with the electronic and

configurational properties of the ligand(s) do all influence the catalytic performance.

For example, enantioselective hydrogenation has undergone such a process. In 1968

Knowles [24 (1)] and Horner [24 (2)] performed first attempts via chiral derivatization

of Wilkinson catalyst [RhCl(PPh3)3] by replacement of triphenylphosphine with chiral

monophosphanes. The enantioselectivities achieved were very low due to the

conformational flexibility of these pioneer catalysts, which did not allow the formation

of a well defined chiral pocket. Henri B. Kagan succeeded in the breakthrough for

practical application with the discovery the almost classic bidentate, rigid and C2-

symmetric chiral DIOP ligand achieving the first time over 99 % e.e.; he systemized

the kinetic principles of enantioselective catalysis [24 (3)].

- 41 -

In the last three decades a bonanza of enantioselective catalytic methods has been

developed, from which cyclopropanations [25 (1-4)], hydrogenations [23 (3-13)] and

dihydroxylation [25 (5-6)] and epoxidation reactions [25 (7-12)] of (functionalized)

olefins emerged as industrially applied processes. Kagan discovered even nonlinear

effects in enantioselective catalysis and even autocatalytic enantioselective reactions

touching the fundamentals of the evolution of life [26]. All these achievements were

recognized with the Nobel prize only for Ryoji Noyori, K. Barry Sharpless and William

S. Knowles in 2001 [27] so far.

Instead of presenting in a standard manner surveys of ligands, central metals and

various catalytic reactions forcibly at the cost of in-depth discussion of the crucial

relationship between structure, reactivity and selectivity here the challenge is taken to

focus mainly on the hydrogenation and transfer hydrogenation of ketones and imines

in combination with up-to-date design concepts for enantioselective metal complex

catalysts regarding these aspects. Of course this survey cannot be complete, but will

be highlighted on individually selected leading examples [23 (1-2)].

As a nmemotechnical “cartoon” the metal reaction center is placed into the center of

an octant for three different catalyst types with four different transition states for the

(enantioselective) hydride transfer to the bound carbonyl substrate (Pic. 1.4.1). These

“nmemotechnical octants” will become later very useful to explain the geometric

aspects of enantioselectivity in the sense of a “chiral pocket” or in the sense of the

“key-lock-principle”. Since electrophilic metals tend to form σ complexes rather than π

complexes with carbonyl compounds [28 (1-5)] the relative locations of the

nucleophile and carbonyl carbon are usually inappropriate for a hydride transfer from

the metal hydride species MH in catalytic hydrogenation (Pic. 1.4.1, TS 1 and TS 2).

Such a geometric difficult 3-endo-trigonal process can be only kinetically favored with

coordinatively unsaturated and strained catalysts as shown below (Pic. 1.4.6). The

requisite interaction between the M-H bond and the π-face of the C=O group is

achieved normally only under drastic geometric changes of the ground state σ-

structures. The ground state π-complexation is possible only with electropositive

transition metals and carbonyl compounds with a low-lying LUMO, which facilitates

the metal to substrate backbonding in such an unfavored [2π + 2σ] process [28 (6),

11 (1)].

- 42 -

1

2

4

7

3

5

6

8

MO

H

MO

H

1

2

4

7

3

5

6

8

O

12

4

7

3 56

8 12

4

7

3 5

6

8

O

β-hydride insertion via σ(O)-complexation

1

2

4

7

3

5

6

8

M O

H

LH

1

2

4

7

3

5

6

8

ML

H

H

O

inner sphere reaction via π-complexation outer sphere reaction via [5,1]-supra TS

substrate fixation via hydrogen bonds with protic ligand LH

Difficult :

− σ(O)-complexation requires one free coordination side of catalyst (intermediate)!

- β-H elimination mostly preferred!

TS 1 TS 2

TS 3 TS 4

= inert spectator ligand or anion

Pic. 1.4.1 "Cartoons" of possible transition states inside a "nmemotechnical octants" regarding

hydride transfers from a catalytic metal center to associated or fixed carbonyl

substrate.

- 43 -

Protonation of or hydrogen bonding to the carbonyl oxygen would be normally

expected to activate the π-face attack of a nucleophile from the metal center, but

addition of strong acids alone does not assist hydrogenation of an unfunctionalized

ketone due to the lack of substrate binding to the reactive metal center. In fact, the

binding problem can be overcome with a functionalized ketone, which intermediary

coordinates on a vacant side of the metal center (TS 3 in Pic. 1.4.1, Pic. 1.4.2, Pic.

1.4.3). This transition state represents also the hydride transfer by {[(M)-TolBINAP]

RuCl2[(R,R)-DPEN]} catalysts (Pic. 1.4.4). TS 4 visualizes the outer sphere hydride

transfer by Rh(III), Ir(III) and Ru(III) hapto-arene transfer hydrogenation catalysts

finally (Chapter 1.3). Furthermore, due to the π-coordination mode the metal alkoxide

intermediate resulting from TS 1 - 3 may undergo reverse β-elimination, unless a

subsequent process rapidly cleaves the M-O bond. This is a general kinetic

drawback.

Particularly 1,3-diketo compounds or 1,3-ketoamines can be hydrogenated with up to

99 % e.e. (R)-product using simple (M)-BINAP catalysts (Pic. 1.4.3 with the proposed

catalytic cycle) [29 (1)]. The hydrogenation probably proceeds via a Ru(II)

monohydride formed by heterolysis of a hydrogen molecule by the {[(M)-

BINAP]RuCl2} precatalyst. The Ru(II) hydride interacts reversibly with the keto ester

to form a chelate (step1). Protonation of the keto oxygen changes the geometry from

a σ to the π-complex, and, at the same time, increases the electrophilicity of the

carbonyl carbon. This is then facilitating an intramolecular hydride transfer (step 2),

which is the rate limiting enantioselective step with the diastereomeric transition

state(s) (Pic. 1.4.3). The resulting Ru(II) hydroxy ester complex readily releases the

chiral product by the action of solvent molecules (step 3). The cationic Ru(II) species

as the supposed catalytic active species reacts with hydrogen to revert back to the

Ru(II) monohydride (step 4), completing the catalytic cycle [29 (2-7)].

The C2-symmetry of the (M)-BINAP ligand binding to the Ru(II) center provides a

chiral backbone with a fixed seven-membered chelate ring in a rigid conformation

similar to cyclohexene from the front view. As already obvious from the catalytic cycle

all reactions proceed at the first or front octants (1, 2, 3, 4) of the Ru(II) (M)-BINAP

fragment, while the back octants are closed up by the naphthyl “paddles”.

- 44 -

PPh2

RuCl2(solv)2

PPh2

* (M)

PPh2

Ru

PPh2

* (M)

(BINAP)ClHRu

O

O

R

R

(BINAP)ClHRu

O

O

R

RH* (R)

[RuCl(BINAP)(sol)n]

R R

O O

C2

R R

OH O

14

23

76

85

Octant View from aboveOctant View from below *

(R)

1 mol % [RuCl2((M)-BINAP)(sol)2] /EtOH / 80 bar H2

Precatalyst (in situ generation of HCl as cocatalyst!)

- up to 99 % e.e. (R)

- substrates: 1,3-diketones, 1,3-ketoesters, 1,3-ketoamines

H

Cl

(solv)

(solv)

(II)

catalytic active species

H2

HCl

Start

(II)

(II)

1 2

34solv

H

Cl

H2

HCl

R R

O O

solv HCl

Cl

substrate coordination

enantio-selecive insertion step

product dissociationhydrogen addition

Pic. 1.4.2 Enantioselective hydrogenation of 1,3-dicarbonyl compounds with simple, C2-

symmetric {[(M)-BINAP]RuCl2} as precatalyst.

In the Si hydride insertion transition state leading to the (R)-product the chiral

template accommodates the keto compound in such a way the nonbonded

interaction with the equatorial phenyl rings is minimized. In the Re hydride insertion

transition state a significant nonbonded repulsion between the substituent R of the

keto substrate and the equatorial phenyl ring of one phosphine group is present.

Therefore the Si hydride insertion is kinetically preferred (Pic. 1.4.3) [29 (2, 7- 9)].

- 45 -

P PRu

Cl

HR

O

R

OP PRu

Cl

H

H

12

3 4

PP Ru

Cl

H R

O

R

O

H

1 2

34

Si-attack favored!

R

O

R

O

2

3

1

4

axial

equatorial

PP Ru

Cl

HR

O

R

O

2

3

1

4

axial

equatorial

Re-attack unfavored!

Pic. 1.4.3 Diastereomeric transition states of hydride insertion into 1,3-dicarbonyl compounds

coordinated to C2-symmetric {[(M)-BINAP]Ru(II)ClH} (binaphthyl backbone omitted for

clarity, conformational geometry comparable with cyclohexene).

Due to the C2-symmetry the hydride addition to the Ru(II) (M)-BINAP fragment leads

to two rotational invariant monohydride complexes, from which two rotational

invariant preferred diastereomeric Si transition states result in turn. In other words,

the two diagonal pairs of the front octants are geometrically equivalent. Because of

this geometrical advantage it was believed for a long time high enantioselectivities

could be reached with C2-symmetric bidentate ligands only.

The first promising hydrogenation of unfunctionalized ketones was achieved by the in

situ introduction of phenylphosphonic acid as a protic coligand on the Ru(II) center,

which can facilitate the hydride transfer via an inner sphere reaction by hydrogen

bonding in this way (TS 3 in Pic. 1.4.1, Pic. 1.4.4, top) [29 (10)]. This catalyst system

effected hydrogenation of ketones with 78 % e.e. The enantioselectivity is too low

and the reaction too slow to meet standards for industrial application. Possibly the

phosphonate coligands are too large diminishing reactivity and too acidic for stable

hydrogen bonds resulting in a simple protonation of the carbonyl oxygen atom as a

side reaction. Therefore such a situation has to be avoided in the design of highly

selective systems for catalytic hydrogenation of unfunctionalized ketones.

- 46 -

PAr2

Ru

PAr2

* (M)

* (R)

O

O

O

O

PAr2

Ru

PAr2

* (M)

H2N

NH2

Cl

Cl

PAr2

Ru

PAr2

* (M)

H2N

NH2

Cl

Cl

[((M)-TolBINAP)RuCl2 (R,R)-DPEN]

[((M)-TolBINAP)RuCl2 (S,S)-DPEN]

*(R)

(S)

(S)*

*

100 atm H2 / 100 ° C / ClCH2CH2Cl,S / C = 700 : 1, slow reaction

99 % yield, 78 % e.e. (1S)-1-phenylethanol

catalyst prepared in situ:

[((M)-XylBINAP)Ru(OAc)2] + 2 PhPO(OH)2Ar = m-xylyl

4 atm H2 / 28 ° C / iPrOH / 1 h,TOF = 72 s-1

S / C = 50,000 : 1,

99 % yield, 97 % e.e. (1S)-1-(α-nahthyl)ethanol

unlike: match!All diagonal octantsgeometrically equivalent!

Ar = p-Tol

Ar = p-Tol

+ 2 KOH

+ 2 KOH

4 atm H2 / 28 ° C / iPrOH / 1 h,TOF = 72 s-1

S / C = 50,000 : 1,

99 % yield, 14 % e.e. (1S)-1-(α-nahthyl)ethanol

like: missmatch!

P

O

OHOH

(octant numbering ommitted for clarity)

Pic. 1.4.4 Enantioselective hydrogenation of unfunctionalized ketones: first promising system

with too acidic coligands (top) proceeding through an inner sphere hydride transfer

transition state (TS 3 in Pic. 1.4.1), (M)-BINAP systems with bidentate chiral diamine

coligands (middle, bottom) showing nonlinear effects and proceeding through an outer

sphere hydride transfer transition state (TS 4 in Pic. 1.4.1).

- 47 -

Noyori’s combination of a bisphosphine and a diamine around a Ru(II) center gives

(pre)catalysts of highest activity in the hydrogenation of ketones so far (Pic. 1.4.4

middle) [23 (2), 30], but only in the presence of two equivalents alkali base. Variation

of the bisphosphine and the diamine allow a wide tuning of substrate tolerance

including saturated and cyclic ketones. Under the same conditions these catalysts

are totally inactive in transfer hydrogenation reactions. Isopropanol as well as

acetone behave simply as inert solvents. A large variety of functional groups (amines,

amides, F, Cl, Br, etc.) are tolerated. Presumably the hydrogen addition occurs on a

preformed imido complex (compare Pic. 1.3.8) and is obviously kinetically preferred.

This might also explain, why olefinic bonds are not hydrogenated, because a free

metal coordination side for an olefinic bond is missing in the resulting hydride

complexes, which exact constitutions could not be revealed so far. However, terminal

acetylenes retard the reaction, possibly due to σ-complexation as inhibition of the

Ru(II) center. Otherwise internal alkynes are also not affected. Possibly the

enantioselective hydride transfer proceeds through an outer sphere transition state

(TS 4 in Pic. 1.4.1) in an analog fashion like discussed for the Ru(II) η6-arene

complexes (compare Pic. 1.3.4 and Pic. 1.3.6).

Hydrogenation of 1-acetonaphtone with a catalyst system consisting of [RuCl2((M)-

BINAP)(dmf)n], (R,R)-DPEN and KOH (1 : 1 : 2 mol % ratio) in isopropanol under 4

atm hydrogen at 28° C afforded the (S)-alcohol in 97 % e.e. in quantitative yield (Pic.

1.4.4, middle) [30 (1)]. The high degree of enantioselectivity is a result of the

synergistic effects of the chiral bisphosphine and the chiral diamine [30 (3)].

Replacement of the (R,R)-amine with the (S,S)-enantiomer led to the (S)-alcohol in

only 14 % e.e. with a much lower activity (Pic. 1.4.4, bottom). A combination of

[RuCl2((P)-BINAP)(dmf)n] and achiral ethylene-diamine formed the (R)-alcohol with a

moderate e.e. value. Complementary to these findings hydrogenation of 2, 4, 4-

trimethylcyclohex-2-enone with racemic TolBINAP and enantiomerically pure (S,S)-

DPEN afforded still the (R)-alcohol with 95 % e.e., which is an extremely strong

positive nonlinear effect [30 (4)]. Comparison of the crystal structures of trans-

[RuCl2((M)-TolBINAP)]{(R,R)-DPEN} and trans-[RuCl2((M)-TolBINAP)]{(S,S)-DPEN}

reveals that only in the unlike diastereomer the diagonal pairs of the front octants are

geometrically equivalent. In other words, only trans-[RuCl2((M)-TolBINAP)]{(R,R)-

DPEN} bears four independent, but geometrically equivalent reaction respectively

- 48 -

binding sites (Pic. 1.4.4, middle). This multiple reaction center feature increases the

substrate binding probality by a factor of four logically, which might account for the

high activity of especially these catalysts. No example of a catalytic system with only

one reaction side of comparable activity could be found in parenthesis. This general

applicable and easy tunable catalytic system was industrially implemented by

Takasago International Co. for the production of pharmaceutical intermediates.

Ligands and catalysts with C1-symmetry and especially planar chiral ferrocenyl

ligands found wide applications in enantioselective catalysis [31 (1-4)]. Planar chiral

ferrocenyl ligands are easily prepared diastereomerically pure starting from chiral

ferrocene templates. The steric and electronic properties of their ligating groups can

also be easily optimized in almost a combinatorial fashion for catalytic applications

[31 (1-6)]. The steric key feature of planar chiral ferrocene ligands are their stability

(not airsensitive!), the steric rigidity of the ferrocenyl backbone itself and the steric

inaccessibility of their endo moiety accounting for the high enantioselectivity.

Chiral amines constitute an important class of biologically active molecules. The key

steps in the industrial synthesis of the herbicide (S)-Metolachlor (Syngenta, the (R)-

enantiomer is biologically inactive) is an enantioselective imine hydrogenation

catalyzed by solulable chiral iridium ferrocenyldiphosphane complexes with ligands

such as (M,S)-Xyliphos (Pic. 1.4.5) [31 (7-9)]. The hydrogenation of 2-methyl-6-

ethylphenyl-1’methyl-2’-methoxyethylimine (MEA-imine) to enantiomerically enriched

(ca. 80 % e.e.) (S)-MEA-amine is the largest scale enantioselective catalytic process

in industry. (S)-Metolachlor (Dual-Magnum) is sold in amounts of 10,000 t per annum.

With “magic mixture” ([Ir(I)Cl(COD)]2 : (S, M)-Xyliphos = 1 : 1 / S : C = 106 / iodide /

H2SO4 or HOAc) applied a TOF of 1.8 x 106 h -1 can be exceeded. This process is the

fastest and most efficient one in applied homogenous catalysis.

Some crucial mechanistic details have been revealed [31 (10-11)]. The Iodide

present forms highly active catalytic active dimeric species, while the acid present

facilitates the oxidative addition of hydrogen (Ir(I) / Ir(III) cycle). Again, like in the

functionalized ketone hydrogenation with {[(M)-BINAP)]RuCl2} (Pic. 1.4.2, Pic. 1.4.3)

the methoxy functionality is crucial for substrate binding and “diastereomeric fixation”

in the transition states.

- 49 -

(M) *

N

O

HN

O

N

O

O

Cl(S) * (S) *

(S)-Metolachlor

H2 (80 bar) / 150 ° C

"magic mixture"

ca. 80 % e.e.TOF = 1.8 x 106 h-1

Fe

PPh2

Ir

(Xyl)2P N

H

O

H

*(S)

H3C CH3

*

(M) *Fe

PPh2

Ir

(Xyl)2P H

N

O

H

*(S)

H3C

*

(b)

1

2

3

4

6

7

2

3

(M) *Fe

PPh2

Ir

(Xyl)2P H

N

H

O

*(S)

*

CH3

CH3

TA 1 TA 2

TA 3 TA 4

(M) *Fe

PPh2

Ir

(Xyl)2P N

H

H

O

*(S)

*

H3CCH3

Exo coordination and Re-face β-H-insertion preferred !

Endo octants of ferrocene sterically closed !

(a)

Pic. 1.4.5 (a) Syngenta (S)-Metolachlor process ("magic mixture": ([Ir(I)Cl(COD)]2 : (S, M)-

Xyliphos = 1 : 1 / S : C = 106 / iodide / H2SO4 or HOAc); (b) transitions state analoga

studied with NMR (TA 1 : TA 2 : TA 3 : TA 4 : = 45 : 42 : 10 : 3, note: isolation actually

performed on the (R,P) ferrocenyl ligand enantiomer leading to (R)-Metolachlor [31

(10)]; mirror images shown here for clarity).

- 50 -

Transition state analogs have been prepared and studied with NMR in situ [31 (10)],

which might be even real intermediates (Pic. 1.4.5). Analogs TA 1 - 4 are formed in a

45 : 42 : 10 : 3 ratio under kinetic control. Due to the least steric repulsive exo

coordination mode of the substrate the formation of TA 1 and TA 2 are kinetically

preferred and both, TA 1 and TA 2, lead to the desired (S)-amine via Re-cis-β-

hydride insertion in the same fashion of a σ / π interconversion mode as previously

discussed (Pic. 1.4.2 and Pic. 1.4.3). These two nearly energetically equal, but

geometrically independent transition states possibly account for the high activity of

especially this catalyst, which increase the substrate binding probality by a factor of

two. This is complementary to the multiple reaction center feature of trans-

[RuCl2((M)-TolBINAP)]{(R,R)-DPEN}, but here with a slightly decreased enantio-

selectivity. TA 3 and TA 4 are kinetically much less favored due to the steric repulsive

endo coordination mode of the substrate, which also lead both to the undesired (R)-

amine. The molar ratio of the transition state analogs correlates nearly to the reached

80 % e.e. and complementary kinetic dissociation studies underline the high probality

TA 1 – 4 might be real intermediates [31 (11)].

An example of a β-hydride insertion via σ(O) complexation into a ketone substrate

(Pic 1.4.1, TS 2) is given for a coordinatively unsaturated, but rigid and

configurational stable planar chiral ferrocene catalyst (Pic. 1.4.6) [31 (12)]. Contrary

to the previous transfer hydrogenation cycle (Chapter 1.3) the isopropanol(ate)

transmetallates on the Ru(II) center and can undergo a β-hydride elimination to a

bishydride complex proven by NMR.

In the enantioselective step the ketone coordinates preferably on the Ru(II) center

into the rigid “chiral pocket” in the sense of the “key-lock-principle” following the least

steric repulsion in the drawn energetically lowest transition state. Because the ketone

coordination requires sterically at least two octants it is unavoidable that it partially

reaches into the endo moiety of the ferrocene backbone. Of course steric repulsions

of the phosphine ligand and the isopropyl group are ways higher than the diminished

steric repulsion by the endo moiety of the ferrocene backbone, accounting for the

high enantioselectivity of 99 % e.e.; but compared to the Syngenta process above

the activity is retarded by ca. 105. This is obviously due to the overall steric

inaccessibility as well as to the presence of only one reaction center.

- 51 -

(M) *Fe

PPh2 *

(S)

*

O

N

H

RuCl

Cl

PPh3

(M) *Fe

P *

(S)

*

O

N

H

Ru

HH

PPh3

O

H3CPh

Ph

Ru O

H

CH3

CH3

H3C

OH

*

- basic conditions (iPrOH / iPrONa)

- > 99 % e.e. (R)

- TON = 60; TOF = 10 h -1

coordination of iPrOH and β-hydride elimination

favored enantioselectiveSi transition state :

Substrate coordination into endo-moiety of ferrocene(octant 2)!!

Si Re

precatalyst

Pic. 1.4.6 Transfer hydrogenation of tBuCOCH3 with coordinatively unsaturated Ru(II) complex

via β-H-shift (compare Meerwein-Ponndorf-Verley reduction, Chapter 1.3, Pic 1.3.1).

One can postulate from all these facts and conclusions common design principles for

(all known) chiral Noyori type hapto-Arene M (d6) = Ru(II), Os(II), Rh(III), Ir(III)

transfer hydrogenation (pre)catalysts (Pic. 1.4.7):

- The chiral “backbone” of the σ-chelate ligand provides the “chiral information”

and should be therefore rigid.

- In all successful catalyst primary amino groups are present as ligated proton

donors. This is possibly due to their pKA value of 9 -10 giving the most stable

hydrogen bonds with the incoming ketone in the transition state.

- 52 -

outer sphere reaction via [5,1]-supra TS

inert and hardspectator ligand

NH

M

HH

OR

*

ππ

Re

R

1 8

4 5

7 2

6 3

M NH

H

H

OR

Ar*

NH

M

HH

O

R

R

*

large

Si

1 8

4 5

7 2

6 3

M NH

H

H

OR

R

*

large

* *

Proton Donor

Backboneprovider of chiral information

- η6-Arene electron withdrawing!

- Hydride transferring metal center (M = Ru(II), Os(II)) positvely polarized! - Enantioselectivity due to ππ-attraction "into" octants 1 and 2!!

- η5-Cp* electron pushing!

- Hydride transferring metal center (M = Rh(III), Ir(III)) electronically enriched! - Enantioselectivity due to steric repulsion "from" octants 1 and 2!!

- In both catalyst types octant 3 and 4 sterically free!

- pKA (proton donor) ca. 9 - 10 (amino groups only)!

Pic. 1.4.7 Octant design rules for chiral hapto-arene M(d6) catalysts for enantioselective CaTHy

reactions considering selectivity directing modes (ππ-attraction and steric repulsion).

- 53 -

- Moderate to high enantioselectivities are only reported for relatively hard and

sterically not demanding inert spectator groups (alkoxides, sulfonamides, etc.).

Octants 3 and 4 have to be free for an unhindered ketone / imine approach,

for both, the η6-arene Ru(II)- and the η5-Cp* Rh(III) / Ir(III)-(pre)catalysts.

Introduction of a diphenylphosphino group as an inert spectator ligand on an

ephedrine backbone gave only catalysts of lowest activity and enantio-

selectivity as a counterproof [32].

- Concerning the η6-benzene Ru(II) (pre)catalysts the enantioselectivity is

generally based on ππ-attraction of the substrates arene moiety, even for

hexamethylbenzene [21 (4)]. Introduction of sterically demanding arene

substituents does not reverse the selectivity, but retards it only. Hence octants

1 and 2 are sterically required for a maximum ππ-interaction, para substituted

(example p-cymene) η6-arene ligands must give the best results, if the

substituents do not electronically enrich the arene by a resonance effect too

much. The introduction of at least one alkyl substituent is required to ensure

adequate solubility crucial for high activity and selectivity.

- Concerning the η5-Cp* Rh(III) / Ir(III)-(pre)catalysts the enantioselectivity is

generally based on steric repulsion from octants 1 and 2. For this reason η5-

Cp* gives better results than η5-Cp. Studies of electronic and steric variations

of η5-Cp ligands are not available, but following the “just-fit principle”

introduction of more sterically demanding substituents will presumably retard

the substrate approach as a whole, which will retard the catalysts’ activity and

selectivity as well.

- Configurative stability of (pre)catalysts and hydride transferring intermediates

seems not to be so crucial, as long as one of the two diastereomeric hydride

transferring intermediates reacts faster and highly selective with the substrate

at least by the factor of ten or is present in high excess [22 (6)].

However, these conclusions for common design principles base on known catalyst

systems and therefore it cannot be excluded they have to be revised by upcoming

future results. They shall serve only as nmemotechnical crutches for better designs.

- 54 -

1.5 Anticipated Use of Chiral ansa-Ligated Metal(d6) hapto-Arene Complexes as THy Catalysts

The central metal oxidation state of η6-arene ruthenium halfsandwich complexes are

usually (II) or (0), they have a low-spin d6 or d8 configuration, are diamagnetic and

usually tend to form 18 VE complexes with appropriate ligands. While Ru(II) η6-arene

complexes are usually airstable, the Ru(0) η6-arene complexes are airsensitive and

considerably thermolabile.

Ru(II) η6-arene complexes are directly accessible in alcoholic solutions from

ruthenium(III) halogenides with cyclohexadienes under reflux in inert gas (Pic. 1.5.1).

The resulting halogenide complexes dimerize with µ-halogenido bridges adopting an

18 VE configuration. They were first prepared by Zelonka and Baird in 1972 [33 (1-

2)]. Mechanistic details of this dehydrogenative reaction are unknown. The dimers

are cleaved under complexation easily with ligands such as amines, phosphines,

pyridines, imines, nitriles and other medium to soft σ-donors including anions [33 (3-

5)]. The bis-µ-chloro Ru(II) η6-arene dimers can be reduced in the presence of 1,5-

COD and base to η2:η2-(1,5-COD) Ru(0) η6-arene complexes. In turn these can be

oxidized back to the Ru(II) complexes, but only in acetone with stoichiometric

amounts of HCl or HPF6 [33 (6-7)].

A more general route to η2:η2-(1,5-COD) Ru(0) η6-arene complexes is the arene

exchange reaction of η2:η2-(1,5-COD) Ru(0) η6-naphtalene [34 (1-4)] with nearly

arbitrarily substituted benzenes, as long the substituents are not too bulky, not acidic

and are no medium to soft σ-donors [34 (5-11)]. Furthermore η2:η2-(1,5-COD) Ru(0)

η6-arene complexes can be prepared easily by acetylene trimerization starting from

the η6-naphtalene complex [34 (12)]. Ru(0) η6-haloarene complexes can be

substituted by halo / lithio exchange and final quenching with an electrophile (Pic.

1.5.1) [34 (5-11)]. In recent years a large family of halfsandwich, sandwich and triple-

decker Ru(0) η6-arene complexes have been prepared and derivatized in the groups

of Bennett, Vitulli and Zenneck [34 (5-14), 35 (2-4)]].

- 55 -

R

L

Ru

ClCl

R R

Ru

RuCl3(H2O)3

RuO

O

O

O

THF / 0 ° C to RT

(acac)H

Na2CO3 /DMF / heat

COD

EtOH

Na

[(COD)RuCl2]2

(II)

(0)

Ru (0)

R

Arene Exchange

> 4.00 eq PhR / THF / 1 drop cat. MeCN / 40 ° C

or

Ru Ru

Cl

ClCl

Cl

R

RR = hal, alkyl, aryl, protected alcohols and amines

Oxidation :

2.00 eq HCl / acetone

Reduction :

COD / EtOH / Na2CO3 /reflux / 24 h

(II)

(II)

> 2.00 eq

RuCl3(H2O)3 /EtOH or MeOH reflux

1/2

Ru (0)

E

L = NR2; PR2; AsR2; pyridines, nitriles, isonitriles, CO, etc.

E = Cl, Br, I

1) nBuLi / THF / - 78 ° C2) RX or electrophile

Lithio-ExchangeReaction

Pic. 1.5.1 General Routes to Ru(II) η6-arene complexes.

- 56 -

Ansa-ligated hapto metal complexes, especially chiral ansa-ligated Ru(II) η6-arene

complexes have evoked considerable synthetic interests with high perspectives for

their use as robust, rigid and enantioselective catalysts. The ansa chain must consist

of at least two atoms. Strain free ansa complexes are obtained with three chain

atoms, but to the best of knowledge ansa complexes with four and more chain atoms

have not been described in literature so far. Syntheses of ansa-ligated Ru(II) η6-

arene complexes can be accomplished by following methods, here mostly

exemplified on results obtained by the group of Zenneck, on which this thesis is

based upon (Pic. 1.5.2).

Ansa-hydroxy or ansa-amino Ru(II) η6-arene complexes can be obtained by

complexation of the already “tethered” and Birch reduced arene (Chapter 2.1) directly

with RuCl3 [34 (11), 35 (1)] followed by more or less in situ ansa-complexation. The

amino group has to be protected as a hydrochloride salt in this case. Alternatively

ansa-hydroxy Ru(II) η6-arene complexes can be prepared under mild conditions by

arene exchange to an η2:η2-(1,5-COD) Ru(0) η6-arene with the free hydroxy side

chain followed by oxidation with HCl [35 (3-5)]. Both methods were applied

successfully for the first examples of chiral ansa-N,O Ru(II) η6-arene complexes by

Marconi and Baier (Pic. 1.5.2) [34 (11), 35 (2-5)]. The detour via η2:η2-(1,5-COD)

Ru(0) η6-arene complexes is the method of choice, if the particular “tethered” arene

cannot be Birch reduced to the corresponding cyclohexadiene or if thermal sensitivity

arises in any case. Of course due to decreasing Pearson hardness the ansa-amino

are more stable than the ansa-hydroxy complexes, furthermore, alcohol (not

alkoxide) Ru(II) η6-arene complexes even require stabilization by ansa-linkage.

Both previous methods fail in preparation oh ansa-phosphine Ru(II) η6-arene

complexes due to the strong donor capabilities of the phosphine group. Werner

developed a semi in situ method by reducing first RuCl3(H2O)3 with isoprene to a

Ru(II) alkene adduct of unknown composition, which reacts than further with

“phosphine tethered” benzenes to various ansa-phosphine Ru(II) η6-arene

complexes (Pic. 1.5.2, second example) [36 (1)]. Theses compounds were then

transformed further to vinylidene- and allenylidene ansa-phosphine Ru(IV) η6-arene

complexes and applied as highly active catalysts for cyclooctene ROMP reactions.

- 57 -

P

Ru

ClCl

Ph

Ph

L1

COOCH3

P

Ru

ClCl

R

R

L

Ru

ClCl

R

R

PhCOOCH3

L1Ru

ClCl

Ru (0)

OH

L1 = OH, NH3+Cl-

L1 = OH, NH2

G. Marconi Direct Complexation

*

*

*

(S)

(S)

Ph *(S)

P. Pinto Arene Exchange

PPh2Ph

L

Ru

ClCl

R

R

BirchReduction

RuCl3(H2O)3 / EtOH / reflux

(R)2.00 eq HCl

acetone

PhX P(tBu)2

X = O, CH2

RuCl3(H2O)3

H. Werner Direct complexation

1) isoprene

iPrOH / 80 ° C

2)X

P(tBu)2

Ru

ClCl

*

(S)

H2 / THF / 75 °C

[Ru(η6-PhCOOCH3)Cl](µ-Cl)2

CH2Cl2 / RT 120 ° C

pressure Schlenk tube

tBuOK

THF

J. H. Nelson

intramolecularMichael cyclization

L = P, As

FGI

*(R)

Pic. 1.5.2 Synthesis methods of ansa-ligated Ru(II) η6-arene complexes.

- 58 -

A more versatile route to ansa-phosphine Ru(II) η6-arene complexes is the Ru(II) η6-

arene exchange reaction. First A. J. Wright reported thermal displacement of p-

cymene from the phosphine coordinated derivative [RuCl2{σ-PPh2-(CH2)3Ph}(η6-p-

cymene)] in dichlorobenzene at 130° C to give the ansa-complex [RuCl2{η6:σ-PPh2-

(CH2)3Ph}] [36 (2)]. However, the displacement of η6-p-cymene could not be

reproduced by any other group! Subsequently Noels [36 (3)] and Fürstner [36 (4)]

have independently obtained ansa-phosphine complexes of the type [RuCl2{η6:σ-

PR2-(CH2)3Ph}] by using [RuCl(η6-PhCOOCH3)]2(µ-Cl)2 as an arene exchange

precursor. Consistently Bennett reported a screening of ansa-phosphine ligands by

arene exchange with [RuCl(η6-o-TolCOOCH3)]2(µ-Cl)2 [36 (4)]. Obviously the π-donor

capability of the arene to be exchanged has to be decreased, so the thermodynamic

driving force of this reaction is the higher π-donor capability of the incoming, tethered

arene. Pinto prepared then an ansa-phosphine Ru(II) η6-arene complex with a chiral

ansa chain from [RuCl(η6-PhCOOCH3)]2(µ-Cl)2 in CH2Cl2 in a pressure Schlenk tube

at 120° C (Pic. 1.5.2, third example) [36 (6-7)]. This method has the advantage of

avoiding the hustle accompanied with the workup of solutions in high boiling solvents

such as dichlorobenzene. In the presence of acetonitrile the arene exchange

precursor reacts exclusively to trans-Ru(II)(PR3)(NCCH3)3Cl2 and in the presence of

any free amines total decomposition results! To the best of knowledge this exchange

reaction has been only reported to be succesful with phosphines. N-donor ligands

failed for instance [35 (5)]. Therefore this reaction should be performed only in

noncoordinating and halogenated solvents. Preferably CH2Cl2 in a pressure Schlenk

tube at 120 ° C, eventually with some drops of THF as “canopener” catalyst should

be chosen as reaction conditions! The σ-complexation of the precursor [RuCl(η6-

PhCOOCH3)]2(µ-Cl)2 with the ansa-phosphine followed by the arene exchange can

also be performed conveniently in situ as presented later in this work (Chapter 4).

A different approach for the synthesis of ansa-phosphine and ansa-arsine Ru(II) η6-

arene complexes was developed by Nelson (Pic. 1.5.2, fourth example) [36 (9)]. A

vinyl phosphine or vinyl arsine is complexed to a dichloro Ru(II) η6-arene toluene

fragment, which is then deprotonated with tBuOK on the methyl group leading via

intramolecular Michael cyclization to the desired ansa complex. Interestingly the

reaction was reported to be performed in acetonitrile under reflux.

- 59 -

PPh2

Ru

ClCl

F3CSO3

unlike

EtOOC

PPh2

Ru

ClCl

NN*

*

(R)

(S)

PPh2

Ru

ClCl

* (M) * (P)

PPh2

Ru

H2ON

N

*

*

(R)(S)

* (M)

PPh2

Ru

NN

* *

(R) (S)

* (P)

H2O

F3CSO3

(R) (S) *

(R) (S) *

2 2

exc. AgO3SCF3 / H2O exc. AgO3SCF3 / H2O

1) CH2Cl2 / 120 ° C / pressure Schlenk tube2) separation of diastereomers by chromatography

Arene ExchangeT. R. Ward

Pic. 1.5.3 Direct routes to diastereomeric ansa-ligated Ru(II) η6-arene complexes.

- 60 -

A major breakthrough in the stabilization of chiral metal centers of pseudopolyhedral

hapto-arene complexes was achieved by Ward by anchoring the metal in a rigid

bicyclic framework (Pic. 1.5.3) [36 (10)]. Arene exchange leads to two planar chiral

diastereomers, which were separated by column chromatography. Silver scavenging

of one chloride ligand allowed the coordination of the pyrazole moiety affording the

two diastereomers in pure form each. The absolute diastereoselectivity of the latter

reaction as well as the extraordinary configurative stability is based on the geometric

rigidity of the overall bicyclic ligand framework. Any attempt of epimerization by either

heating or irradiation resulted in decomposition only, but not in epimerization at the

chiral Ru(II) center.

PPh2

RuHOPh2P

F3CSO3

*

*

(S)

(P)

*

(M)

*

PPh2

RuPh

PPh OH

RO

PPh2

Ru

PPh2

* (P)O

O

O

O

F3CSO3H

H2O

F3CSO3

F3CSO3

+ ROH /- F3CSO3H

*

*

(S)

(P)

(M)

Inversion onchiral Ru(II)-center

- total diastereoselctiviy control due to rigid (P)-BINAP backbone - stabilization of otherwise labile η6-naphtalene ligand- Ru(II) center configuratively stable

P. S. Pregosin

Pic. 1.5.4 Direct and selective route to diastereomeric ansa-ligated Ru(II) η6-naphthalene

complexes.

Pregosin achieved the first configurative stabilization of a diastereomeric ansa-

phosphine Ru(II) η6-naphthalene complex with planar and central chirality by simple

reaction of ((P)-BINAP)Ru(II)(OAc)2 with trifluoromethanesulfonic acid (Pic. 1.5.4) [36

- 61 -

(11)]. The resulting complex reacts with alcohols under clean inversion of

configuration at the chiral Ru(II) center under a remarkable CP activation to an

configuratively stable phenyl Ru(II) η6-naphthalene complex also. This stabilization is

surely related to the rigid (P)-BINAP framework, hence normally Ru(II) η6-

naphthalene complexes are notoriously labile like the Ru(0) η6-naphthalene analogs.

Wills tethered Noyori type catalysts at the sulfonamide position (Pic. 1.5.5) [36 (12)].

Not quite unexpected in turn the resulting ansa-complexes did not only prove highly

configurative stable, but also as highly enantioselective (pre)catalysts in transfer

hydrogenation reactions of aryl ketones. While the TON is increased compared to the

original Noyori catalysts, the TOF is retarded. This can be reasoned as an additional

stabilization of the η6-arene moiety by molecular linkage and steric repulsion of the

ansa chain at the same time. These results are encouraging chiral ansa-ligated M(d6)

hapto-arene complexes might be not only an alternative solution to almost

conventional chiral M(d6) hapto-arene catalysts for enantioselective transfer

hydrogenation reactions of ketones.

(R)

NH2N

Ph

Ru

ClS

Ph

H

H

(R)

(R)

**

*

O

O

NH2 ClPh

NHPh

O2S Wills 2004

1) RuCl3(H2O)3 / EtOH / 21 h reflux

2) base

- 96 % e.e. (R) in the reduction of acetophenone (iPrOH / base and HCOOH / NEt3 5 : 2) in full accordance with Noyori mechanism!

- S / C = 1000; higher TON, but lower TOF and retarded reversibility!

(R)

(R)*

*

ansa-bridge stabilizes η6-benzene ligand and acts sterically repulsive!

Pic. 1.5.5 First highly enantioselective ansa-ligated Ru(II) η6-arene Noyori type catalyst.

- 62 -

Rn

D

H

*

ansa- Backbone

Provider of Chiral Information

Substituents on arene: steric and / or electronic modulation

tight binding, kinatically inertand thermodynamic stable ligating group; no reactivity in catalytic cycle

CoordinatedProton Donor

Chiral Metal Center

Ru X*

Rn

**

D

H

X

D = ROH, H2NR

D = O, NH, NR

= O or OR, PR2 or PR3, NR2 or NR3

Ru

X = Cl precatalyst

X = H hydride transferring species

Pic. 1.5.6 General design of ansa-ligated Ru(II) η6-arene transfer hydrogenation catalysts

followed in the Zenneck group; diastereomeric interactions: chiral ansa-backbone

considered as responsible for configurative stabilization of the chiral metal center as

well as for the enantioselective hydride transfer to the carbonyl substrate in synergism

with the hapto-arene ligand; envisaged advantages: steric and electronic modulation

in an easy divergent-combinatorial manner.

- 63 -

In this way the Zenneck group is following a design concept of ansa-ligated Ru(II) η6-

arene (pre)catalysts (Pic. 1.5.6), which is based on a chiral ansa-ligated Ru(II) η6-

arene framework as a provider of chiral information and configurative stability as well.

Therefore the choice of this backbone in regard to its geometric rigidity is crucial,

because it must close up one diastereotopic side of the Ru(II) center completely,

while leaving the other totally steric accessible. Potential substrates of these catalyst

types are limited to aryl ketones in that sense enantioselectivity is based on ππ-

attraction. Therefore the required steric accessibility of the η6-arene has to be

preserved, if additional substituents are introduced at the tethered η6-arene.

In this way electronic modulation of the η6-arene ligand is best achieved with small

substituents in para position. Steric modulation is only reasonable, if large

substituents are introduced in the diastereotopic meta position of the η6-arene ligand.

This position is sterically closed up by the chiral ansa chain anyway, giving rise to

additional planar chirality and causing a repulsive interaction with the incoming

substrate in synergistic cooperation with the chiral ansa chain.

The ansa-ligating group can be the protic donor functionality D(H) as well as the inert

spectator ligand, and then, the second untethered ligand vice versa. The donor

functionality D(H) can be only a primary amine (Chapter 1.4). However, both

cooperating ligand(s) (functionalities) should be limited in size to preserve the steric

accessibility of the catalytic active Ru(II) center.

The nearly unlimited steric and electronic modulation possibilities in almost a

combinatorial approach are the main attractivity of this design concept. The stepwise

methodology of choice is then the preparation of various chiral ansa-ligated Ru(II) η6-

arene templates first. On these potential candidates various spectator or amine

ligands are introduced at the Ru(II) center and then the course of diastereoselectivity

is evaluated and compared. Although the configurative stability of the chiral Ru(II)

center is not necessarily an requirement for a highly enantioselective catalyst (Pic.

1.3.8, middle) [22 (6)], it is nevertheless believed to be beneficial (Chapter 1.3).

Finally the most promising (pre)catalysts are tested for enantioselective transfer

hydrogenation, then. Depending from the catalytic results the design of the particular

(pre)catalyst family is then reevaluated or optimized.

- 64 -

Ligand substitution of coordinatively saturated low-spin complexes are dissociative

(SN1-type) via coordinatively unsaturated 16 VE pseudotrigonal planar intermediates,

in example via the loss of one halogenide ligand [22 (8), 37 (1-6)]. This is also the

case for the chiral ansa-ligated Ru(II) η6-arene templates investigated by the

Zenneck group [34 (11), 35 (2-5), 36 (6-8)]. The diastereoselectivities of the individual

ansa-hydroxy and ansa-amino Ru(II) η6-arene complex formation depend strongly on

the position and the size of the chiral center of the ansa chain as well as on the order

of attachment of the untethered and the tethered donor on the Ru(II) center (Pic.

1.5.7). Both ansa-hydroxy complexes (Pic. 1.5.7, first two examples) are obtained by

ansa-donor complexation in the last step. Diastereoselectivity increases the closer

the chiral center is positioned to the ansa-donor functionality due to the sterically

closer interaction with Ru(II) center during the course of the reaction [35 (4-5)]. This

argument is supported complementary by the introduction the phosphine ligand on

the ansa-amino complex with the chiral center in γ-position to the ansa-amino

functionality, which proceeds with an almost comparable diastereoselectivity in

regard to the analog ansa-hydroxy complex despite of the application of smoother

reaction conditions (Pic. 1.5.7, third example) [35 (4-5), 36 (6-7)]. If the same chiral

center is shifted into α-position to the ansa-amino functionality (fourth example), the

diastereoselectivity increases from 22 % to 82 % due to the sterically closer

interaction with Ru(II) center again [35 (4-5), 36 (6-7)]. If the complexation of the ansa

chain amino group is performed as the last step by the Kurosawa protocol [35 (1)],

then only a marginal d.e. is observed [35 (4-5), 36 (6-7)]. Compared to the second

example the steric interaction of the methyl group is too small to achieve a high

diastereoselection with this method. The benzylic substituents of Pinto's chiral ansa-

diphenylphosphine Ru(II) η6-arene complexes prefer to adopt a sterically favorable

exo conformation to the hapto-arene metal fragment (Pic. 1.5.8), stabilizing the very

favorable chair-like conformation of the ansa chain in consequence, which in turn

geometrically fixes the phosphine coordination mode in that way one phenyl group

adopts a fixed axial (ax) and the other a fixed equatorial (eq) position [36 (6-7)]. DFT

calculations support that this fixed chair-like conformation with the methyl group in

exo position is preserved upon chloride abstraction, explaining well a sterically

preferred Si-attack of the incoming amine due to the steric repulsion of the equatorial

phenyl group with up to 90 % d.e. for aniline leading to the configurationally stable

unlike diastereomer.

- 65 -

G. Marconi, H. Baier and P. Pinto

*(R)

OHPh3P

Ru

ClCl

O

Ru

ClPh3P

*(R)

*

*(R)

OHPh3P

Ru

ClCl

O

Ru

ClPh3P

** (R)

NH2

Ru

ClCl

*(R)

BF4

BF4

AgBF4

CH2Cl2 / MeOH

AgBF4

CH2Cl2 / MeOH

17 % d.e.

40 % d.e.

H

H

NH2

Ru

ClPh3P

*(R)

*

PF6

PPh3 / KPF6

CH2Cl2 / MeOH

22 % d.e.

NH2

Ru

ClCl

* NH2

Ru

ClPh3P

**

*NH3 ClPh3P

Ru

ClCl

PF6

1) PPh3 2) NaOH / KPF6

MeOH 12 % d.e.

82 % d.e.

PPh3 / KPF6

CH2Cl2 / MeOH

Pic. 1.5.7 SN1-type reactions of ansa-N and ansa-O Ru(II) η6-arene complexes; diastereoselec-

tivities depending from the position of the chiral center in regard to the ansa-donor

functionality and the order of tethering and chloride substitution.

- 66 -

Ph

Cl

P

Ru

ClCl

Ph

Ph

*(R)

P. Pinto and G. Marconi

BF4

RNH2 / NaBF4

CH2Cl2 / MeOH

P

Ru

ClNH2

Ph

Ph

*(R)

R

(S)

Cl

Ru

NH2

PR

Ph like

Si sterically favored

eq

ax *

*

Ru

P

Ph

eq

ax *

*

Re

==

R = Ph 90 % d.e.

R = Bn 86 % d.e.

R = Cy 86 % d.e.

R = nBu 82 % d.e.

max. 25 % e.e. in transfer hydrogenation of acetophenone to 1-phenylethanol

(1 mol % cat. / 2 mol % tBuOK / iPrOH / 80 ° C / 1 h)

P

Ru

ClCl

(S)R

R

*

*(S)

Ansa-Phosphetane Complexes

RNH2 / NaPF6

CH2Cl2 / MeOHP

Ru

ClNH2

(S)R

R

*

*(S)

PF6

R = Cy 88 % d.e.

R = tBu 85 % d.e.

R = iPr 84 % d.e.

No enantioselectivity in transfer hydrogenation of acetophenone to 1-phenylethanol!

(S)

Pic. 1.5.8 SN1-type reactions of ansa-phosphine Ru(II) η6-arene complexes; diastereoselec-

tivities depending from geometric fixation of the phosphine coordination mode in that

way one phenyl group adopts a fixed axial (ax) and the other a fixed equatorial (eq)

position caused by the sterically preferred and fixed exo conformation of the chiral

benzylic methyl group to the η6-arene moiety (overall chair-like conformation of the

ansa chain in consequence).

- 67 -

The aniline (ansa-P) Ru(II) η6-arene complex with the chiral ansa chain was reported

to achieve as (pre)catalyst 25 % e.e. in the transfer hydrogenation of acetophenone

to 1-phenylethanol under basic conditions in iPrOH (Pic. 1.5.8) [36 (6)]. The

enantiomeric excess was determined with polarimetry, but interestingly the absolute

configuration of the product was not mentioned. A lower enantiomeric excess was

obtained performing the reaction at room temperature instead under reflux, which can

be reasoned by solubility problems of the catalyst at lower temperatures. With an

analog synthesis methodology Pinto prepared N(ansa-phosphetane) Ru(II) η6-arene

(pre)catalysts, which are also active in transfer hydrogenation reactions, but not

enantioselective at all [36 (7,8)]. All of Pinto’s N(ansa-P) Ru(II) η6-arene complexes

were not active in transfer hydrogenation with formic acid / triethylamine 5 : 2 or in

direct hydrogenation of acetophenone.

1.6 Chiral ansa-Thioether Ruthenium(II)-η6-Arene

THy Catalysts as initial goal of this work

Sulfide S2-, thiolato RS- (cysteine) and thioethers R’SR (methionine) are widespread

ligands in inorganic chemistry [38 (1-2)]. Sulfide and thiolates are soft and electron

rich donors, which bind strongly to middle to late transition metals and tend to

stabilize high oxidation states of metals. Therefore sulfide and thiolato complexes are

usually sensitive to oxidation, especially with metals in low oxidation states.

Thioethers are ligands of relatively weak coordination strength, but stronger binding

occurs with chelating or macrocyclic crown thioethers. The homologs of selenium and

tellurium behave similarly. Sulfide and thiolates have a remarkable tendency for µ-

bridging and stabilizing clusters (Pic. 1.6.1). Iron sulfur clusters, such as [4Fe-4S] in

ferredoxine I, in 4Fe-ferredoxine and in HiPIP are centers of electron transferring

enzymes with multiple, reversible and low standard potentials (Pic. 1.6.1) and a [3Fe-

4S] cluster is the reactive center of aconitase, part of the citric acid cycle underlying

their importance in mother nature’s toolbox [38 (5)]. The inversion barriers of µ-

thiolato complexes are already so high to distinguish syn and anti stereoisomers

spectroscopically, but they are to low to isolate them.

- 68 -

MS

MM S M

M

MS

M

MM

SM

S M M

S

S

Fe

Fe

Fe

SS

S

FeMM

S

MM

SS

M

S

MM

S

MMM

M

SM M

M

MS

M

R

MS

MS

R

R

MS

MS

R

R

S

MMM

R

M X

R'R

*M X

R'

RM X

R'R

*

µ-coordination mode of sulfide

µ-coordination mode of sulfide in clusters

µ-coordination mode of thiolates

syn anti

inversion equilibrium of σ-bisalkylchalcogenide complexes

d π donator mode

∆G= (X = S) = 51 - 56 kJ / mol ∆G= (X = Se) = 60 - 66 kJ / mol

d σ* acceptor mode

M X

R'

R

*

- Acceptor strength of thioethers weak compared to phosphines!

- If carbocation of R stabilized (tBu, trityl, etc.), then often fragmentation observed!

Pic. 1.6.1 Coordination modes of sulfide S2-, thiolate RS- and thioethers R'SR to middle and late

transition metals (selenium and tellurium derivatives analog); electronic models for

inversion equilibrium and donor-acceptor synergism of thioethers ligated to metals.

- 69 -

MSM and M(SR)M bridges show π-bonding interactions between metal dπ and sulfur

pπ + σ* orbitals, but the donor capabilities by metal dπ and sulfur pπ−interaction of

the sulfide and thiolato ligands predominate still, which increase the electron density

at the metal center in turn. Thioethers have two lone electron pairs so that when one

is involved in metal binding, there is a potential for inversion of a trigonal pyramidal

center and for chirality at the sulfur atom in case of unsymmetric thioethers (Pic.

1.6.1). Inversion was studied by NMR and the barriers determined in compounds

such as Cl2Pt(XR2) (X= S, Se) are in the range of 51 to 56 kJ / mol for SR2 and in the

range of 60 to 66 kJ / mol for SeR2 [38 (3-4)]. Conclusively enantiomers of such

thioether complexes are not isolable at room temperature. Compared to

configurationally stable trisalkyl sulfonium salts thioethers as ligands can interact with

the transition metal in a pπ to dπ−donor mode, where one lone electron pair of sulfur

delocalizes its electrons into an unoccupied metal d-orbital by changing the sulfur

center geometry from pyramidal to trigonal planar, which in turn facilitates inversion.

This can be caricatured as a transition state (Pic. 1.6.1, second from below). In a

synergism thioethers behave as weak to medium pπ + σ* acceptors (Pic. 1.6.1,

bottom), because the pπ to dπ−donor interaction positively polarizes the sulfur atom.

In turn the energies of the antibonding sulfur alkyl orbitals σ* are lowered, which now

can overlap with filled metal d-orbitals by delocalizing their electrons into one of these

two antibonding orbitals σ*. Although the acceptor strength of thioether ligands is

much weaker than the ones of phosphines this electronic effect becomes evident by

often observed sulfur alkyl fragmentation reactions of complexed thioethers giving

metal thiolate complexes. Of course the alkyl group forming the more stable

carbocation is the preferred leaving group, which is briefed in some more detail later

on (Chapter 3).

Thioether and thiolato Ru(II) η6-arene complexes or selenium or tellurium analogs

thereof are rare (Pic. 1.6.2) [39]. Mashima prepared bisthiolato, thiolato and µ-

bridged thiolato, selenolate and tellurolate Ru(II) η6-arene complexes, which exhibit

almost all expected properties of chalcogenide complexes discussed before [39 (1-

2)]. They are airsensitive and deeply colored due to strong LMCT effects and / or by

pπ−backbonding from the chalcogene atom to the Ru(II) center. Only then the BDT

chelate Ru(II) η6-arene complexes do not dimerize, if the η6-arene ligand is

considerably large, such as η6-HMB. In this way the monomer complexes have to be

- 70 -

seen rather as 16 VE species, which can only adopt an 18 VE configuration by

dimerization. This means backbonding from sulfur to the metal is much weaker than

in Noyori’s pseudotrigonal planar imido Ru(II) η6-arene complexes [21 (3)]. The

phenylchalcogenide dimer cation adopts with three equivalent µ-bridging ligands an

18 VE configuration in an unusual coordination mode as well, which is

unprecedented for Ru(II) η6-arene complexes (Pic. 1.6.2, middle left).

R

Ru

L

Ru

PF6

S S

*

*S

Ru

S

Ru

S

S

* *

R

R

RS

SL

L = CNtBu, PR3

K. Mashima

Ru

X

Ru

X

X

PhPh

Ph

R

M. A. Bennett

S

Ru

SS

PF6

S

Ru

SS*

*S

Ru

SS*

*

X = S, Se, Te

tBuOK /THF

tBuOK /THF

- Chalcogenido complexes very airsensitive!

- Tendency to dimerize to obtain 18 VE configuration dependent from η6-arene size!

- "X to Ru(II)" weaker than "amide to Ru(II)" backbonding!

18VE 18VE16VE

Pic. 1.6.2 Chalcogenide and ansa-thioether Ru(II) η6-arene complexes.

- 71 -

Bennett placed a Ru(II) η6-HMB fragment into an trithio crown ether, which was

opened under base induced fragmentation to a bisthiolato Ru(II) η6-HMB in the first

step and underwent also base induced intramolecular Michael cyclization to the first

ansa-thioether Ru(II) η6-arene complex described in literature so far (Pic. 1.6.2,

bottom) [39 (3-5)]. All of these complexes where fully spectroscopically characterized,

including X-ray structure analysis. The fragmentation is in full accordance with the

aforementioned pπ + σ* acceptor properties of coordinated thioethers, while the

Michael cyclization is paralleled by Nelson’s method for the preparation of analog

ansa-phosphine and ansa-arsine Ru(II) η6-arene complexes (Chapter 1.5., Pic. 1.5.2,

fourth example) [36 (9)].

Rn

NH2

*

ansa- Backbone

Provider of Chiral Information

Chiral sulfur center "configuratively fixed" by rigidity of ansa-backbone; provider of "additional chiral information"??

coordinatedProton Donor

Chiral Metal Center

RuX

S

*

R

*

R

Pic. 1.6.3 Original thesis topic: incorporation of ansa-thioethers as inert spectator ligand functio-

nalities into the general design framework of ansa-ligated Ru(II) η6-arene transfer

hydrogenation catalysts followed in the Zenneck group (Chapter 1.5, compare Pic.

1.5.6).

Inspired by these facts the author was entrusted with the incorporation of ansa-

thioethers as inert spectator ligand functionalities into the general design framework

of ansa-ligated Ru(II) η6-arene complexes as envisaged highly active and enantio-

selective (pre)catalysts for transfer hydrogenation reactions as initial goal of this work

(Pic. 1.5.6) [40 (1)]. It was believed steric modulation of the chiral ansa-backbone

- 72 -

could raise the inversion barrier at the sulfur atom by more than 50 kJ / mol by steric

repulsion necessary to “fix” the chiral sulfur center in this way. A fixed chiral sulfur

center directly adjuncted to the Ru(II) reaction center was proposed as beneficial for

high enantioselectivity by providing “additional chiral information”. This goal was the

more ambitious, because three to four parameters were envisaged to be modulated

altogether at the same time: finding a highly active and enantioselective ansa-ligated

Ru(II) η6-arene transfer hydrogenation (pre)catalyst generally speaking, exploring a

completely new ligand / metal system for this type of reaction with its unusual

electronic features, solving the old problem of stabilizing a chiral sulfur center of a

complexed thioether and possibly to develop a completely new synthesis method of a

class of ansa-ligated Ru(II) η6-arene complexes, of which only one example is

established in literature so far [39 (3-5)]. This goal was especially thrilling, hence only

few examples of sulfur containing ligands are known, which were applied

successfully in enantioselective (transition) metal catalysis [41 (2-7)]. In these cases

an oscillating epimerization of a complexed chiral sulfur center cannot influence the

catalytic performance anyway from a steric point of view or a metal binding of the

thioether moiety does not occur at all presumably. Although the modulation of only

one parameter, even on a known successful system might appear as “linear”, "too

close" and "not academic" it allowed Wills to succeed in the endeavor of a highly

enantioselective ansa-ligated Ru(II) η6-arene (pre)catalyst by respecting mother

nature’s authority and nothing else (Chapter 1.5, Pic. 1.5.5) [36 (12)].

- 73 -

2 Preexperiments

2.1 Ruthenium(II) η6-Benzene Precursor Complexes

Literature syntheses of the di-µ-chlorobis[chloro{η6-arene}-ruthenium(II)] precursor

complexes were optimized to routine scaled-up procedures during the course of this

work (Pic. 2.1.1). They are briefly discussed here to provide the author’s successors

in the Zenneck group an easy and fast start with their own research in this field.

OCH3H3CO

0.03 eq cat. p- TolSO3H / MeOH / reflux / 84 %

0.33 eq RuCl3 95 %MeOH / reflux

1 2 3

via 1,3-Isomerization

0.16 eq RuCl3

EtOH / reflux / 61 %

6 (+)-(S)-Limonene

R3

R2

Ru Ru

Cl

Cl

R2

R3

R3

R3

R1

R1

Precursor Complexes:8 R1 = R4 = H R2 = R3 = CH39 R1 = CH3 R2 = iPr R3 = R4 = H

CH3

CH3H3C

CH3

CH3H3C

NH3(l) / EtOH /9.28 eq Li

- 80 o C / 78 %

4

0.34 eq RuCl3 / 60 %EtOH / reflux

Exchange Reagent:7 R1 = COOCH3 R2 = R3 = R4 = H

Cl

Cl

5

R4

R4

R4

R4

Birch Reduction

NH3(l) / EtOH / 3.29 eq Li

- 80 o C / 98 %

1.25 eq

*

COOH COOH COOCH3

Pic. 2.1.1 Ru(II) η6-arene precursors.

- 74 -

Also for the Birch reduction [41 (1-5)] of benzoic acid 1 [41 (6-8)], mesitylene 4 [41

(9)] and later (Chapter 2.2, Pic. 2.2.1) 3-phenylpropanol 16 [36 (4), 41 (10)] to the

corresponding 1,4-dihydrobenzenes a general scaled-up procedure was developed.

The Birch reduction is a stepwise, radical reduction of an arene with solvated

electrons in liquid ammonia at a temperature of maximal - 60 ° C and an appropriate

cosolvent, which serves as a required proton source (alcohols).

The electron transfer and later on the protonation of the (radical) benzene anions is

totally FMO-controlled (Pic. 2.1.2) [41 (3-5)]. While electron pushing first order substi-

tuents lower the antibonding ψ* A1u benzene orbital, electron withdrawing second

order substituents lower the antibonding ψ* B2g benzene orbital in energy. These

orbitals become then the particular SOMO’s upon electron transfer into the arene

moiety. Therefore the radical anions of alkylbenzenes have their highest electron

density in ortho and meta position and do get protonated at these positions, while

benzoate has its highest electron density in ipso and less in para position and does

get protonated preferably at the ipso position. The resulting pentadienyl radicals are

then reduced in the next step giving pentadienylide anions, which have the highest

electron density at the central carbon atom in the conjugated chain (nonbonding ψ0 is

now HOMO!) and are protonated only at that position. This is the explanation for the

kinetic preference of the 1,4-dihydro over the principally thermodynamically favored

1,2-dihydro product and for the different regioselectivities of the Birch reduction for

benzenes with first and second order substituents.

Overreduction of benzenes to cyclohexene and cyclohexane derivatives does not

usually occur, but for benzoic acid reduction side products are observed sometimes.

While carboxylate groups are tolerated (stabilization via delocalization), esters and

keto as well as imino groups (if not protected as acetals or aminals) are cleanly

reduced under Birch conditions. Benzylic alcohols and benzylic ethers are also

reduced, but alkyl side chain amino, hydroxy and ether groups are tolerated without

any protection and under preservation of enantiopurity, if applicable. Chiral benzylic

amines and chiral benzylic alkyl centers are not affected under Birch conditions and

racemization does not occur. Saturated rings fused on benzenes are tolerated with a

ring size greater than three, but fused cyclopropanes are opened cleanly. Any

halogen at any position is cleanly removed also.

- 75 -

R

COO

R

R

R

1.27

1.25

1.01

1.27

1.25

e

SOMO (from LUMO ψ* A1u)

==Birch Reduction of Alkylbenzenes

R

H

H

R

H

H

R

H

H

e

R

H

H

e

R

H

H

H

H

==

H

OO

H

H

COO

SOMO (from LUMO ψ* B2g)Birch Reduction

of Benzoic Acid

e==

COOH

H

COOH

Hworkup

COOHH

H H

2

Reaction FMO-controlled :

Protonation on position of highest π-electron density in all cases and steps!

Pic. 2.1.2 Reaction mechanism of the Birch reduction under FMO control (numbers on benzene

rings represent overall π-electron density).

- 76 -

All Birch reductions were adjusted to one common procedure of a 0.1 – 0.3 mol scale

for the particular benzene derivatives during the course of this work. Generally the

Birch reductions are performed at around - 80° C and the arene is added in absolute

and well degassed ethanol to liquid ammonia prior to the portionwise addition of

lithium pieces, which proved to be superior over sodium. Generally an excess of

lithium was used, except for benzoic acid 1, which showed two times an

overreduction to a complex mixture with only traces of 2. Satisfactory results for 2

were also not obtained, if not recrystallized and dry benzoic acid 1 was used. The

yields were high (95 - 98 % for 2 and 17) except for 1,4-dihydro mesitylene 5 due to

the considerable volatility of this product. All Birch products were sufficiently pure to

be carried to the next step without further purification. Although distillation can be

performed easily the profit of purity is diminished by unnecessary loss of material.

1,4-dihydrobenzoic acid 2 was then directly converted to its methyl ester 3 by a

modified literature protocol [41 (7)] in 84 % yield. 1,4-cyclohexadienes usually do not

give correct elementary analysis results due to residual traces of aromatics.

Also partially known literature protocols for dehydrogenative complexations to the di-

µ-chlorobis[chloro{η6-arene}-ruthenium(II)] precursor complexes were optimized to

scaled up versions in regard to yield under minimization of the amount of

dehydrobenzene necessary to achieve complete complexation of ruthenium(III)

chloride (Pic. 2.1.1). In this way 3.03 eq 3 are required for the synthesis of Ru(II) η6-

arene exchange reagent 7 [36 (7)], 2.90 eq 5 for dimer 8 [41 (11)], 3.42 eq 17 to

tethered dimer 18 [36 (4), 41 (10)], but the complexation to the η6-p-cymene dimer 9

[41 (12)] required 6.14 eq (S)-limonene 6 possibly related to the intermediary 1,3-

isomerization of the exocyclic double bond. Best results were obtained, if the

complexations were preformed in “wet” but degassed ethanol under reflux, but the

complexation of 3 to 7 must be performed in methanol to avoid partial

transesterification. The mechanism of the complexation reaction is unknown. The di-

µ-chloro-bis[chloro{η6-arene}-ruthenium(II)] dimers are usually sparingly solulable

except in coordinating solvents like acetonitrile or DMSO, in which often

decomposition to e. g. trans-(MeCN)Ru(II)Cl2 is observed. Therefore these solvents

should be used to record NMR spectra only. The η6-p-cymene dimers 9 is solulable

in chlorinated solvents and to a lesser extend in THF and alcohols. The yields of the

η6-arene dimers decrease in the order 7 95 % > 17 94 % > 9 61 % > 8 60 %.

- 77 -

2.2 Synthesis Attempts of ansa-Thioether and ansa-

Thiolato Ruthenium(II) η6-Arene Complexes

All known ansa-thioether Ru(II) η6-arene complexes [39 (3-5)] are fully coordinative

saturated, in other words, a hard ligand with the ability to dissociate is missing and it

is not possible to introduce an amino ligand as a proton donor, which are the

structural requirements for a Ru(II) η6-arene transfer hydrogenation catalyst in

general (Chapters 1.3 – 1.5). The first main task focused on was to find an efficient

synthesis route to µ-bridged ansa-thiolato σ-chloro Ru(II) η6-arene complexes such

as 13 and ansa-thioether σ-dichloro Ru(II) η6-arene complexes such as 15 (Pic.

2.2.1), which could serve as backbones, on which in turn primary amino ligands could

be introduced (Chapter 1.5 – 1.6). Such complexes would then have one chloro

ligand ready to dissociate in the catalytic transfer hydrogenation cycle. Unfortunately

any attempts to obtain theses complexes via direct reaction of RuCl3 with tethered

1,4–cyclohexadienes containing a protected or unprotected mercapto functionality

(10 - 12 in Pic. 2.2.1) or containing a thioether moiety (14 in Pic. 2.2.1) failed, even by

varying reaction conditions. The affinity of the sulfur functionality to stabilize simply

Ru(III) is obviously too strong. Therefore the 1,4-cyclohexadiene route was

abandoned.

Inspired by the work of Kemmitt and Garcia-Granda [42 (1-2)] it was then tried to

introduce the thiolato ansa functionality by an intramolecular exo-tetragonal

nucleophilic substitution (Pic. 2.2.1, below). The direct reaction of RuCl3 with 1-(3'-

bromopropyl)cyclohexa-1,4-diene lead to the formation of the expected Ru(II) η6-

arene complex with a free 3-bromopropyl ansa chain, but unfortunately this reaction

was accompanied with a bromo-chloro exchange, probably Lewis-acid catalyzed by

the Ru(II) center itself in an intramolecular fashion. Using RuBr3 with or without an

excess of alkali bromide lead to sluggish results, too. To prevent such an

intramolecular Finkelstein reaction [42 (3-8)] dimer 18 was converted to its bromide

analog 19 with excess bromide in aqueous solution in air by the method of Zelonka

and Baird [33 (2)]. The driving force of this reaction is the exchange of the harder

chloride against the softer bromide ligand binding preferably to moderately soft Ru(II),

of course.

- 78 -

RuS

Ph

ClCl

*

Ru Ru

Cl

ClS

S

13

14 15

S(PG)RuCl3 / EtOH

reflux

10 PG = H11 PG = Ac12 PG = CO(NHPh)

RuCl3 / EtOH

reflux

SPh

Ru Ru

Cl

ClCl

Cl

Ru Ru

Br

BrBr

Br

HO

OH OH

HO

excess NaBr

H2O / RT / 89 %

OH

OH

16

0.29 eq RuCl3 /EtOH / reflux / 94 %

NH3(l) / EtOH / Li / - 80° C / 95 %

17

18 19

Ph3P

Ru

BrBr

Br

204.89 eq PPh3 / 3.04 eq CBr4 /THF / RT / 81 %

S

Ru

Ph3PBr

*21

total decomposition byreaction with KSCPh3 !

Pic. 2.2.1 Synthesis attempts via direct reaction of RuCl3 with 1,4-cyclohexadienes (PG =

protecting group such as acetyl or N-phenylcarbamino).

- 79 -

Dimer 19 was then reacted in situ with carbon tetrabromide and triphenylphosphine

[42 (9-10)] to the triphenylphosphine complex 20 with the electrophilic activated

bromo ansa-chain, which crystallized from THF in 81 % yield as deep purple crystals

suitable for X-ray structure analysis (Pic. 2.2.2).

Pic. 2.2.2 Thermal ellipsoid plot (50 % probality) of molecular structure of complex 20; selected

bond distances and angles see Table 2.2.1.

As expected due to larger van der Waals radii the Ru(II)-Br bond lengths of ca. 2.55

Å are elongated compared to 2.17 Å of a Ru(II)-Cl bond of a similar Ru(II) η6-arene

complex with a free hydroxy ansa chain (Pic. 1.5.8, second example) [35 (2-3)], but

the Ru(II)-P bond length of 2.36 Å is almost equal with 2.34 Å of the complex

compared. Also the trans influence of the phosphine ligand on the C(1) - C(6) bond is

comparable, which leads to a slight structural distortion of the η6-arene ring. The

bond angles P-Ru(II)-C(i)(η6-arene) characterize the geometrical constellation best.

The angles exceed 150° for the two carbon atoms C(1) and C(6) trans to PPh3, but

are always smaller than 150° for all other η6-arene ring carbon atoms (Table 2.2.1).

As can be seen from the crystal structure the ansa chain adopts an all-antiperiplanar

conformation. Interestingly the ansa chain bromide Br(3) adopts an endo position

towards the Ru(II) center, but the Ru(1) – Br(3) distance is too long to assume any

stabilizing interaction of the metal center with the halogen substituent and also the

C(9) – Br(3) bond length of app. 1.97 Å is within in the expected value.

- 80 -

distances [Å] angles [ °]

Ru(1) - Br(1) 2.5472(6) Br(1) - Ru(1) - Br(2) 92.19(2)

Ru(1) - Br(2) 2.5500(6) P(1) - Ru(1) - Br(1) 88.18(3)

Ru(1) - P(1) 2.3580(1) P(1) - Ru(1) - Br(2) 89.77(3)

Ru(1) - C(1) 2.247(4) P(1) - Ru(1) - C(1) 160.8(2)

Ru(1) - C(2) 2.180(4) P(1) - Ru(1) - C(2) 123.1(2)

Ru(1) - C(3) 2.189(5) P(1) - Ru(1) - C(3) 94.7(2)

Ru(1) - C(4) 2.173(5) P(1) - Ru(1) - C(4) 90.6(2)

Ru(1) - C(5) 2.199(4) P(1) - Ru(1) - C(5) 114.6(2)

Ru(1) - C(6) 2.286(4) P(1) - Ru(1) - C(6) 151.2(2)

C(6) - C(7) 1.502(6) C(6) - C(7) - C(8) 115.8(4)

C(7) - C(8) 1.529(7) C(7) - C(8) - C(9) 113.3(4)

C(8) - C(9) 1.507(6) C(8) - C(9) - Br(3) 112.8(3)

C(9) – Br(3) 1.973(5) Ru(1) - P(1) - C(11) 107.6(2)

Table 2.2.1 Selected bond distances and angles of complex 20.

Tritylthiolate serves as reagent for the introduction of the thiol functionality into alkyl

chains. The trityl alkyl thioether resulting from the reaction of an alkylhalogenide can

be cleaved to the free alkylthiol even with HCl or with mercury(II) acetate due to the

high stability of the triphenylmethyl carbocation. The trityl group found therefore wide

application as a protective group of the thiol functionality of cysteine in peptide

synthesis [42 (11-14)]. It was then envisaged to react complex 20 to the

corresponding mono tritylthiolate complex and then via intramolecular exo-tetragonal

nucleophilic substitution under cleavage of the trityl sulfur bond to the ansa-thiolate

Ru(II) η6-arene complex 21 in tandem fashion in situ (Pic. 2.2.1). Despite broad

variation of the reaction conditions weather the desired ansa-complex 21 nor the trityl

thioether intermediate could be isolated.

As a last chance for the synthesis of an ansa-thioether Ru(II) η6-arene complexes the

intramolecular η6-arene displacement reaction [36 (3-4, 6-7)] was left, but only one

rather controversial method for the synthesis of such complexes via a displacement

of triphenylphosphine is described in literature so far [42 (15)].

- 81 -

S 0.49 eq 7 / CH2Cl2

120 o C (pressure Schlenk Tube)

22 R = Bn23 R = iPr

RuS

R

ClCl

*24 R = Bn25 R = iPr

R

Pic. 2.2.3 Synthesis attempts via intramolecular arene exchange.

Therefore the phenylethyl thioethers 22 and 23 were subjected to the aforementioned

intramolecular η6-arene displacement protocol with 7 (Pic. 2.2.3). The thioether

adducts of 7 could be observed by NMR, but the non chelating thioether ligands

proved to be too labile towards dissociation, so the adducts could not be isolated.

Heating this “dynamic mixture” in dichloromethane resulted in total decomposition

only. Obviously this type of reaction requires a ligand with strong σ-donor and

acceptor capabilities as well, which are possibly only restricted to phosphines and

analogs thereof. However, although all synthesis attempts of suitable µ-bridged ansa-

thiolato σ-chloro and ansa-thioether σ-dichloro Ru(II) η6-arene backbone complexes

13, 15, 21, 24 and 25 failed, complex 20 with its activated and nonbonded ansa chain

might be an interesting precursor for reactivity studies with other nucleophiles leading

to other ansa complexes. The most interesting candidates would be N-alkyl

imidazoles targeting at the first Arduengo type ansa-carbene complexes as possible

catalysts for ROMP reactions [36 (1)].

- 82 -

3 Preparation and Study of Epimeric

β-Aminothioether-Chelated Ruthenium(II)

η6-Arene Complexes

After it became evident ansa-thioether and ansa-thiolato Ru(II) η6-arene complexes

suitable as backbones for potential enantioselective transfer hydrogenation catalysts

cannot easily be prepared it was decided to pay mother nature the required respect

by changing only one parameter in the design of new CaTHy systems and to orient

on known, simple chelate systems first [22 (1-8)]. In this way the (1R)-1-amino-1-

phenylethane moiety based on the chiral aminoalcohol (1R)-phenylglycinol was

chosen as a chelate backbone. It was then envisaged to substitute the hydroxy group

with various thioethers and certainly also by the mercapto group to test the principles

outlined as a hypothesis (Chapter 1.6) as the initial goal of this work (Pic. 3.0.1).

- The anti-syn and the anti (like) diastereomers should be sterically preferred! Are they configuratively stable at the Ru(II) and at the sulfur center?

- How do the electronic and steric differences compared to chiral β-amino alcohols influence the catalytic performance and selectivity?

NH2(R)

PhS

H

Ru

*

*

(R)

Cl

R1

Ph(R)

*

*

(R)

*

X

SH2N

Ru

Cl R4

H

R1

Pic. 3.0.1 Design of N(SR)- and NS-chelated Ru(II) η6-arene complexes oriented on Noyori and

Avecia type CaTHy systems (Chapter 1.3).

- 83 -

Besides ligand and precatalyst syntheses the first main question to be addressed

was how the configurational stability of the envisaged thiolato and thioether

complexes is influenced by the steric properties of the η6-coordinated arene

(modulation of alkyl substituents R1) and in case of the thioether complexes by the

size of the adjuncted substituent R2 additionally. Furthermore it was expected that the

soft and electron rich thiolato functionality will electronically enrich the Ru(II) center,

which in turn is expected to destabilize the Ru(II)-hydride bond and to diminish the

acceptor capabilities of the η6-arene ligand reversing the enantioselectivity governing

parameters of the Noyori type catalysts from a ππ-acceptor synergism to a steric

repulsive selectivity determining interaction as described for the Avecia type catalysts

(Chapter 1.3) [21, 22]. In this way increasing steric demand of the η6-arene ligand in

the envisaged thiolato complexes should increase the enantioselectivity. Furthermore

compared to the β-amino alcohol complexes destabilization of the Ru(II)-hydride

bond should lead to a higher catalytic activity (TOF), but with possible antagonistic

effect on the enantioselectivity if not compensated by the steric demand of the η6-

arene ligand.

While the β-amino thioether Ru(II) η6-arene complexes should be easily accessible

by common halogenide abstraction protocols (Chapter 1.5) preparation of the

corresponding thiolato complexes directly from β-amino thiolates was considered

difficult right from the beginning due to their expected sensitivity. In this way an

indirect method was sought based on a reactivity “domestication” of the thiol

functionality. In his report about the preparation and study of ansa-O, S and P-Ru(II)

η5-Cp complexes van der Zeijden [43 (1)] reported about a fragmentive decompo-

sition of an anticipated chiral ansa-thioether Ru(II) η5-Cp complex (Pic. 3.0.2), but the

corresponding ansa-thiolato complex could not be isolated or characterized. Of

course the group which forms the more stable carbocation is going to fragmentize, in

the example cited here the menthyl substituent is forming a secondary carbocation

prone to elimination upon complexation to the Ru(II) center, which is preferred over

the fragmentation of the ethyl ansa chain resulting only in a less stable primary

carbocation.

- 84 -

Ru

**

F3CSO3

ClPh3PPh3P

S

*

A. H. A. van der Zeijden

Ru

**

SPh3PPh3P

*

AgO3SCF3

instable!

RuSPh3P

Ph3P

?

Fragmentation

NH2

(R)

PhS

H

Ru*

*

Cl

*

PF6

48R with or without aid of base

envisaged allyl-conjugative fragmentation of prenyl group

H2C

CH3

H

HH

NH2

(R)

PhS

H

Ru*

*

Cl

(R)

+ HPF6 +

49R

R R

?

Pic. 3.0.2 Observed and envisaged fragmentation reactions to NS-chelated Ru(II) hapto-arene

complexes.

Based upon this report these findings were considered as advantageous for a

smooth preparation of the anticipated chiral β-aminothiolate Ru(II) η6-arene

complexes by an intermediary introduction of a prenyl group on the thio functionality

(Pic. 3.0.2). It was hoped upon complexation a σ*-π-σ destabilization of the S-allyl

bond would lead to an allyl-conjugative fragmentation of the prenyl group forming the

desired complex and a 3,3-dimethylallyl cation, which then in turn eliminates to

isoprene. As an alternative a trityl group could also be envisaged for that purpose,

but its steric demand, way too high sensitivity and its more cumbersome removal as

trityl salt out of the reaction mixture compared to volatile isoprene lets it appear only

as a second choice.

- 85 -

3.1 Synthesis of Chiral β-Aminothioether Ligands

Ph COOH

NH2

* (R)

26R (+)-(R)-phenylglycine

for R = Bn, Ph, β-Naph only :

2.27 - 4.28 eq RSNa /1.23 - 2.91 eq RSH / nPrOH / 12 h reflux

Ph

HN

OH

O

O

Ph

HN

O

O

O

Ph

NH232R R = Bn33R R = Ph34R R = α-Naph36R R = β-Naph

SR

2.44 eq NaBH4 +1.01 eq I2

THF / 18 h reflux

87 %

1.51 eq NEt3 /1.23 eq H3CSO2Cl /CH2Cl2 / 0° C to RT /89 % crude

1.10 eq (Boc)2O

CH2Cl2 / RT

1) 1.00 - 2.21 eq RSK / THF / RT2) conc. aq. HCl (deprotection)3) basic workup

27 - 53 %SO2CH3 * (R)

* (R)

* (R)

30R

31R

95 %

O

HN

Ph

O

* (R)

c) 1.76 eq K2CO3 / acetone / RT / 81 %, overall 80 %

0.71 eq Cl3CO-COCl /2.91 eq NaOH / CH2Cl2 / H2O /-10 o C to RT 98 % crude yield, 89 % recryst.

a)

29R

PhOH

NH2

* (R)

1.08 eq Cl3COCl 1.20 eq DMAP

THF / RT / 99 % crude27R

b)

PhOH

HN

* (R)

O

CCl3

26 - 84 %

28R

Pic. 3.1.1 Summarized syntheses of chiral β-aminothioether ligands 32R - 34R, 36R.

Especially β-aminothioethers and β-aminothiols are versatile intermediates of actual

interest employed as key structural elements of biologically active compounds, such

as third generation penicillin antibiotics [43 (2)]. The syntheses of the chiral β-

aminothioether ligands employed here for the complexation to Ru(II) η6-arene

fragments were accomplished first via ringopening of (4R)-4-phenyl-2-oxazolidinone

- 86 -

29R as synthetic aziridine equivalent [43 (6-7)] and second via linear FGI of the BOC-

protected β-aminoalcohol 27R, activation of the hydroxy group as mesylate 31R and

in situ nucleophilic substitution with thiolates followed by deprotection to the desired

ligands and intermediates 32R - 36R under practical improvement of analog literature

protocols [43 (8-9)] (Pic. 3.1.1). Although intermediates 27R - 30R are commercially

available their optimized syntheses is discussed and described here, because they

are rather expensive compared to the root precursor (R)-phenylglycine 26R and

might be of future interest in the Zenneck group.

Starting from enantiopure (R)-phenylglycine 26R (1R)-phenylglycinol 27R was

prepared by a Meyers' protocol [43 (3)] with NaBH4 and BH2I (formed in situ from

NaBH4 and iodine) in 87 % yield being superior over the conventional reduction with

LiAlH4, which gives usually not more than 20 % yield [20]. Due to the strong

polarization by iodide BH2I has the required Lewis acidity to activate the carbonyl

bond of the carboxylic acid functionality. In this way the couple NaBH4 / BH2I

develops even a reduction power close to the one of LiAlH4. The preparative

advantage is given by the fact the resulting borate chelate complex is much easier

cleaved under basic workup conditions compared to the corresponding β-

aminoalkoxy aluminium(III) chelate. This minimizes losses of the desired reduction

product.

The preparation of oxazolidinone 29R can be accomplished directly with diphosgene

(method a) [43 (4)] or via fragmentive cyclization of intermediary (1R)-N-trichloro-

acetyl phenylglycinol 28R [43 (5)] (method b and c). The fragmentative cyclization

occurs only in aprotic polar solvents (acetone) and in the presence of K2CO3.

PhO

N

* (R)

O

CCl3

H

H

PhO

N

* (R)

C

H

O

O

HN

Ph

O

* (R)

29R

Base

isocyanateHBase

CHCl3neighbor group effect!

28R

Pic. 3.1.2 Proposed mechanism for oxazolidinone preparation method c.

- 87 -

The required reaction conditions are suggestive the fragmentive cyclization proceeds

via intermediary base catalyzed isocyanate formation (Pic. 3.1.2) rather than via an

intramolecular 5-exo-trigonal attack of the hydroxy group on the trigonal planar

carbonyl center of 28R, which should proceed in any solvent without the presence of

a base catalyst. Of course the driving force of the reaction is the lability of the

trichloromehtyl group based on the strong positive polarization of its carbon atom by

the chlorine substituents. Because trichloroacetyl chloride is less toxic, easier to

handle, more stable and cheaper than diphosgene and because yields are

comparable (method a 89 % yield, method b and c 80 % overall yield) the

fragmentive cyclization is a considerable synthetic alternative.

Ph

NH2

32R, 33R, 36RS

* (R)

O

HN

Ph

O

* (R)

29R

Ph

HN

S * (R)

O

O

R Ph

HN

S * (R)

O

O

R

H

S

R

carbamate carbamic acidRSH

RS

CO2

R

Pic. 3.1.3 Proposed mechanism for Ishibashi reaction.

However, the ringopening of 29R to the desired chiral β-aminothioethers requires not

only a higher excess of thiolates (> 2 eq) by the Ishibashi protocol [46 (6-7)], but also

an excess of thiol (> 1 eq additionally). Not maintaining a buffered system in this

sense (consider pKA (alkylthiols) = ca. 10 – 11; pKA (arylthiols) = ca. 6 – 8) does not

lead to complete or to any conversion to the products. It is also obvious the

ringopening does not proceed via protonation of the carbonyl oxygen atom (consider

pKA (R2C=OH+) = ca. - 10) hence the reaction does also not occur in neat TFA with

excess thiol. Therefore the ringopening of 29R must proceed under a direct

nucleophilic attack by thiolate (Pic. 3.1.3) leading to a carbamate, which can only

decarboxylate if it is protonated to a carbamic acid. That the driving force of this

reaction is more determined by CO2 evolution than by the strong nucleophilicity of

- 88 -

thiolates becomes obvious by the failed attempt to prepare an isopropyl thioether with

iPrSH / iPrSNa in a closed pressure Schlenk tube maintaining buffered conditions by

avoidance of the evaporation of iPrSH (bp. = 53° C / 1 atm). The higher pKA value is

not the reason for this failure, because the same reaction with much higher boiling n-

octylthiol is reported to be successful [43 (6-7)]. However, from a practical point of

view yields of that reaction are only high (32R 84 %; 33R 75 %), if excess thiol can

be removed nearly completely already under workup conditions as thiolate into the

strongly basic aqueous phase or by evaporation. Therefore yield dropped to 26 % for

36R (R = β-Naph), because β-thionaphthol could not be removed under workup

conditions. It also underwent additionally oxidation reactions, so the severely impure

crude product had to be purified by cumbersome column chromatography and

recrystallization leading to losses. Therefore this method was not applied for the

synthesis of 34R and is restricted to volatile or easily removable and cheap thiols.

Standard BOC protection of (1R)-phenylglycinol 27R gave 30R in 95 % crude yield

sufficiently pure for the next step [43 (8-9)]. Instead of converting the hydroxy group

into a p-tosylate and running into purification problems leading to product losses by

cumbersome removal of excess p-tosylchloride (55 % reported yield) [43 (8)], 30R

was converted to the mesylate 31R in 89 % crude yield (Pic. 3.1.1). Excess

mesylchloride could be easily removed by washing with sat. aq. NaHCO3 solution or

by evaporation. The crude product did not show any considerable impurities, so it

was used directly for the next reactions.

31R reacted smoothly with 1 - 2.2 eq thiolates to the desired thioethers at ambient

temperature, which were directly deprotected with aqueous HCl in situ to the desired

chiral β-aminothioethers 32R - 36R. Also here yields were dependent from efforts

necessary for purification (32R 99 % crude yield sufficiently pure for the next step; 33R 70 % yield after recrystallization; 34R 53 % yield after chromatography),

especially from 29R as a side product formed during the substitution reaction up to

20 % (36R 29% yield after cumbersome threefold recrystallization) via an

intramolecular allowed 5-exo-tetrahedral nucleophilic substitution process (Pic.

3.1.4). Although this linear FGI method is generally applicable, it should not be held

back this side reaction, which is difficult to control and to parameterize, is a severe

disadvantage compared to the Ishibashi protocol.

- 89 -

O

HN

Ph

O

* (R)

29RPh

NH

O

O

(R)31R

O

H3CO2S

H

H

H

*H3CSO3H +

Intramolecular side reaction!Up to 20 % byproduct!

Pic. 3.1.4 5-exo-tetrahedral nucleophilic substitution process leading to 29R as side product.

Interestingly this side reaction is not reported in analog literature applying this

methodology with analog sulfur nucleophiles and with even more reactive and

instable p-tosylates [43 (8-12)]. On the other hand this side reaction might be

developed into an alternative synthesis protocol for oxazolidinones, where

conventional methods fail [43 (4-5)].

However, the specific optical rotations of ß-aminothioethers 32R - 36R do not fit into

a regular pattern (Table 3.1.1). Of course the values itself as well the signs do not

allow any conclusions regarding the absolute configuration, which would only Cotton

effects do. On the other hand chiral benzylamines are configuratively very stable and

hence the carbon-nitrogen bond was not attacked during the course of the reactions,

even partial racemization is unlikely anyway.

______________________________________________

32R [α]23D = - 46.2 (CH2Cl2, c = 0.0017)

33R [α]23D = + 29.4 (CH2Cl2, c = 0.0042)

34R [α]23D = - 5.5 (CH2Cl2, c = 0.0195)

35R [α]23D = + 14.0 (MeOH, c = 0.0053)

36R [α]23D = + 63.7 (CH2Cl2, c = 0.0029)

______________________________________________ Table 3.1.1 Specific optical rotations of β-amino thioethers 32R - 36R.

While for 32R, 33R and 36R the preservation of the chiral benzylic center was

indirectly proven upon complexation to Ru(II) η6-arene fragments followed by X-ray

structure analysis, 34R was characterized as its hydro p-tosylate salt 35R by X-ray

structure analysis directly (Pic. 3.1.5, Table 3.1.2, Table 3.1.3).

- 90 -

Pic. 3.1.5 Thermal ellipsoid plot (50 % probality) of molecular structure of p-tosylate salt 35R;

selected bond distances and angles see Table 3.1.2 and for hydrogen bonding Table

3.1.3.

distances [Å] angles [ °]

N(1) - C(7) 1.502(3) N(1) - C(7) - C(8) 108.4(2)

S(1) - C(8) 1.806(2) N(1) - C(7) - C(6) 120.8(2)

S(1) - C(9) 1.777(3) C(7) - C(8) - S(1) 112.0(2)

C(7) - C(8) 1.525(3) C(6) - C(7) - C(8) 113.0(2)

C(6) - C(7) 1.516(3) C(8) - S(1) - C(9) 102.8(2)

S(2) - O(1) 1.441(2) O(1) - S(2) - O(2) 113.4(2)

S(2) - O(2) 1.459(2) O(1) - S(2) - O(3) 133.3(2)

S(2) - O(3) 1.461(2) O(2) - S(2) - O(3) 110.5(2)

S(2) - C(19) 1.779(2) O(3) - S(2) - C(19) 106.1(1)

Table 3.1.2 Selected bond distances and angles of hydro p-tosylate salt 35R.

- 91 -

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...O(3) 0.91 1.87 2.769(3) 171.4

N(1) - H(1B)...O(2) #1 0.91 2.01 2.834(3) 149.3

N(1) - H(1B)...O(1) #2 0.91 2.36 2.930(3) 120.2

N(1) - H(1C)...O(3) #3 0.91 2.29 3.180(3) 167.0

N(1) - H(1C)...O(2) #3 0.91 2.36 3.007(3) 127.7

Table 3.1.3 Interionic hydrogen bonds in hydro p-tosylate salt 35R (#1: -x+1, y-1, -z+1; #2: -x+1, y,

-z+1; #3: x, y-1, z).

Ph

H3N

HS (α-Naph)

HH(p-Tol)SO3

σ * σ

σ σ* effect average bondlengths [A°]:

N-H 1.04C-H 1.09 C-C 1.54C=C 1.33C-N 1.48C-S 1.81

Delocalization of electrons ofbonding σ(CS)-orbital intoantibonding σ*(CN)-orbital:

- Carbon - Acceptor bond elongated!- Carbon - Carbon bond shortened!- Carbon - Donator bond shortened!

Acceptor

Donator

Pic. 3.1.6 Stereoelectronic σ/σ*-effect exemplified on 35R (table gives average bond length

without any (stereo)electronic interactions).

Not unexpected the ethyl chain of the β-ammoniumthioether 35R adopts an

antiperiplanar conformation. Hydrogen bonding between the p-tosylate anion and the

ammonium cation is also evident (see Table 3.1.3). The slightly shortened C(7) - C(8)

and elongated C(7) - N(1) bonds (Table 3.1.2) speak for a weak σ-σ* effect (Pic.

1.3.6) [44]: The more electropositve the donor group D (here sulfur) the easier the

electrons of the bonding σ(CD) orbital are delocalized into the antibonding σ*(CA)

orbital of the acceptor group A (here ammonium) in the sense of a "bond - no bond

resonance" only possible for an ap conformation and stabilizing it. In a synergisitc

fashion the electropositive character of the ammonium acceptor group is even

increased by hydrogen bonding, which lowers the more the energy level of the

antibonding σ*(CA) orbital required for an effective overlap.

- 92 -

____ 33R ----- 35R ........ 36R Pic. 3.1.7 CD spectra of β-amino thioether derivatives 33R, 35R and 36R (MeOH, RT, c ~ 10-3

mol/l); for numbering see Pic. 3.1.1 and 3.1.5 and for enlarged spectra Chapter 8.

Compounds 33R, 35R and 36R show each characteristic positive Cotton effects in

the expected aromatic absorption region of 250 - 320 nm (Pic. 3.1.7). Additionally

33R shows a second, weak positive Cotton effect, possibly due to two UV absorption

maxima. Hence the naphthalene π-electron system is more extended than the one of

benzene and hence the naphthalene substituents are not attached to a chiral center,

derivatives 35R and 36R show less intense Cotton effects due to compensating UV

absorption with characteristic bathochromic shifts of almost the same magnitude

compared to 33R. Summarized all CD spectra of the chiral β-aminothioether

derivatives are comparable, so their common (R) configuration is physically and later

(Chapter 3.2) chemically independent confirmed.

For the synthesis of (2R)-2-amino-2-phenylethanethiol 37R and of the corresponding

prenyl thioether 40R a linear protection-deprotection FGI protocol had to be

developed (Pic. 3.1.8). Of course one is temptated to envisage the synthesis of 37R by reaction of 31R with excess sulfide and of 40R by reaction of 31R with prenylthiol

according to the method used for the preparation of β-amino thioethers 32R - 34R

and 36R (Pic. 3.1.1, bottom). Unfortunately nucleophilic substitution reactions with

sulfide are dominated by bisalkyl thioether formation due to the much stronger

nucleophilicity of alkyl thiolates compared to sulfide. Prenylthiol is the main

component of the very volatile North American skunk's secretion to repel predators,

so applying this methodology for the synthesis of 40R requires a psycho-pathological

masochistic attitude of the experimentator the author refused to fulfill.

- 93 -

Ph

NH3 Cl

SH

1) 4.85 eq Na / NH3(l) / THF / 1.25 eq tBuOH 2) conc. HCl / MeOH / 76 %

Ph

NH(BOC)

Ph

NH(BOC)

Ph

NH(BOC)

Ph

NH2

in situ :1) 1.20 eq KSAc2) gas. NH3THF / RT / 40 %

1) 1.10 eq PPh3 / 1.10 eq CBr4 / THF / RT / 14 h 2) 1.15 eq HSAc / 1.62 eq NEt3 / RT / 26 h / 41 %

Ph

NH(BOC)

Ph

NH2

S

1) 1.80 eq tBuOK / 2) 1.10 eq PrnBr / MeOH / RT3) conc. HCl / basic workup / 96 % crude

1) 1.05 eq tBuOK / 2) 1.05 eq PrnBr / MeOH / 0 o C to RT / 99 % crude

* (R)

* (R)

* (R)

* (R)

* (R)

* (R)

* (R)

30R

37R

31R

39R

38R

40R

32R

OSO2CH3OH

1.16 eq KSAc

MeOH / RT / 89 %

SAc

SHSBn

34 % overall

Pic. 3.1.8 Linear protection-deprotection FGI protocol to 37R and 40R.

The synthesis of 37R was then accomplished by debenzylation of 32R in liquid

ammonia with sodium in 76 % yield following Mellor's analog protocol for rac. 2-

acetamido-2-phenylethanethiol [43 (11)]. 37R was directly isolated as hydrochloride

salt necessary for protection towards oxidation to the disulfide. Preparation of chiral

β-amino thiols via BOC amino protection of amino alcohols followed by linear FGI is

described in literature [43 (10-12)]. In this way 30R was directly converted to the

BOC-protected β-amino bromide followed by in situ reaction to the thioacetate 38R.

Although no traces of 29R could be found in the crude product and although product

formation was complete, yield dropped to 41 % due to the difficulty to separate

triphenylphosphine oxide and excess carbon tetrabromide from the desired product

by chromatography and crystallization as well. On the other hand 38R could be easily

- 94 -

obtained from 31R via nucleophilic substitution with thioacetate in 89 % yield after

recrystallization without formation of 29R as side product. This reaction was then

developed further to an in situ procedure, where the thioacetate was directly

deprotected by bubbling ammonia through the reaction mixture giving the BOC-

protected thiol 39R in 40 % total yield after chromatography. Interestingly during the

amminolysis step formation of 29R in considerable amounts was observed again,

what cannot be explained at this stage. This caused the significant yield decrease.

Applying the BOC-deprotection protocol for the (R)-valinthiol [43 (9)] on 39R lead

only to quantitative formation of 29R instead of desired 37R interestingly, even under

variation of reaction conditions. This is especially mysterious because hydrosulfide

belongs to one of the poorest leaving groups and because BOC-deprotection of the

corresponding disulfide of 39R was reported to be successful [43 (10)] under similar

reaction conditions.

In situ deprotonation of 37R and 39R with tBuOK followed by allylation of the

particular thiolate functionalities with prenyl bromide and then addition of aqueous

HCl lead to clean formation of the desired β-aminoprenylthioether 40R after alkaline

workup in 96 - 99 % yield without formation of 29R as byproduct for 39R. Addition of

HCl to both reactions before alkaline workup is necessary for the removal of the BOC

group on the one hand and on the other for cleavage of any amino prenyl bonds

formed by use of excess prenyl bromide leading to additional allylation of the amino

resp. amido functionalities. Column chromatography of the combined nearly pure

crude products gave rise to an overall yield of 34 % 40R, which is themosensitive.

- 95 -

3.2 Epimeric σ(N):σ(S)-β-Aminothioether

Ruthenium(II) η6-Arene Complexes

The β-aminothioether ligands 33R, 34R and 36R reacted smoothly with the Ru(II) η6-

arene dimers 8 and 9 in all combinations with excess sodium hexafluorophosphate to

the resulting σ(N):σ(S) β-aminothioether η6-arene Ru(II) chelate complexes, but only

the combinations of dimer 9 with 33R and of dimer 8 with 33R and 36R gave

crystalline and pure complexes 41R - 44R, which could be characterized by X-ray

structure analysis (Pic. 3.2.1, Pic. 3.2.2, Pic. 3.2.3, Pic. 3.2.4 and Pic. 3.2.5).

Surprisingly dimer 8 reacted with the β-amino prenylthioether ligand 40R only to the

σ(N):σ(S) β-amino thioether η6-arene Ru(II) complex 44R (Pic. 3.2.1), which could

also be characterized by X-ray structure analysis (Pic. 3.2.5). All β-amino thioether

complexes 41R - 44R are airstable in the solid state and solution as well. However,

from all crystals examined only η6-(p-cymene) complex 41R crystallizes as pure as

diastereomer [RRu, RS, R; relative diastereotopicities related to the absolute

configuration of the chiral benzylic center of the chelate ligand backbone, here: η6-(p-

cymene) anti (a) and R4 = Ph syn (s) in regard to benzylic Ph, formally like-like (ll)],

while in the examined crystals of the η6-mesitylene complexes 42R - 44R the as and

sa [SRu, SS, R for R4 = Ph, β-Naph formally unlike-unlike (uu); SRu, RS, R for R4 = Prn

formally unlike-like (ul)] diastereomers are found in a 1:1 ratio in the particular unit

cells, which are all chiral (spacegroup C2 (no. 5) for 41R and 44R, P21 (no. 4) for

42R and 43R) and in which the benzylic center of the chiral ligand backbone is

always (R)-configurated. Any attempt to fragmentize 44R to β-aminothiolato Ru(II) η6-

mesitylene complex 45R under varying reaction conditions led only to a complex

mixture of Ru(II) η6-arene complexes. Direct reaction of β-aminothiol from 37R with

dimer 8 under basic conditions in MeOH led only to decomposition products.

Reaction of 37R with dimer 9 under same conditions led to the corresponding

σ(N):σ(S) β-amino thiolato η6-(p-cymene) Ru(II) complex 46R, which exist in an

equilibrium of two diastereomers in solution. It is instable, very airsensitive and could

not be characterized sufficiently. Therefore further attempts to prepare σ(N):σ(S) β-

amino thiolato η6-arene Ru(II) complexes were abandoned.

- 96 -

R3

R1

R2

R1

R3

R1

R2

R1

Ph

NH2

SR4

* (S)

Ru Ru

Cl

Cl

R3R3

R1

R1

8 R1 = R2 = CH3 R3 = H9 R1 = H R2 = CH3 R3 = iPr

Cl

Cl

R1

R2

R2

R1

41R R1 = H R2 = CH3 R3 = iPr R4 = Ph67 % (crystallizing with (CH2Cl2)0.5(H3COH)),in solid state: as : sa = 1 : 0

42R R1 = R2 = CH3 R3 = H R4 = Ph80 %, in solid state: as : sa = 1 : 1

+ > 2.05 eq

excess NaPF6 MeOH / RT

* (R)

33R R = Ph36R R = β-Naph40R R = Prn

43R R1 = R2 = CH3 R3 = H R4 = β-Naph83 %; in solid state: as : sa = 1 : 1

44R R1 = R2 = CH3 R3 = H R4 = Prn78 % (crystallizing with (CH2Cl2)0.5),in solid state: as : sa = 1 : 1

(R)

*

*

(R)

*PF6

SH2N

Ru

Cl R4

H

R3

R1

R2

R1

H

(R)

**

SNH2

Ru

ClR4

PF6

+

NH2

(R)

PhS

H

Ru*

*

Cl

*

PF6

H3C

Ch3

H3C

44R

H2C

CH3

H

HH

NH2

(R)

PhS

H

Ru*

*

Cl

(R)

?45R R1 = R2 = CH346R R1 = H R2 = CH3 R3 = iPrComplex mixture only!!

Ph

NH3 Cl

SH * (R)

37R

+ 2.00 eq tBuOK

?0.500 eq 8 - 9

MeOH / RT

anti-syn

(RS) for R4 = Ph, β-Naph(SS) for R4 = Prn

syn-anti

(SS) for R4 = Ph, β-Naph(RS) for R4 = Prn

Pic. 3.2.1 Summarized syntheses of the σ(N):σ(S)-β-aminothioether Ru(II) η6-arene complexes

41R - 44R and synthesis attempts of β-aminothiolato complexes 45R - 46R.

- 97 -

Pic. 3.2.2 Thermal ellipsoid plot (50 % probality) of molecular structure of η6-(p-cymene)

complex 41R as hexafluorophosphate salt; selected bond angles and distances see

Table 3.2.1 and for hydrogen bonding see Table 3.2.2.

top view on η6-(p-cymene) of complex cation:

priority for chiral Ru(II) center: Cl > S > N > η6-(p-cymene)

(RRu)

(RS) (hydrogen atoms omitted for clarity)

(R)

H

NHC

[Ru(II)]

PF

F

F

F

F

F

OCH3

H

(14) (12)

(11)

(11)

H-bonding system between PF6

-, MeOH and coordinated amino group

Part of unit cell of complex 41R: only anti-syn (formally ll) diastereomer in crystal examined (PF6

- and “half” CH2Cl2 omitted for clarity)

- 98 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.392(2) Cl(1) - Ru(1) - S(1) 90.40(4)

Ru(1) - S(1) 2.369(2) Cl(1) - Ru(1) - N(1) 82.4(1)

Ru(1) - N(1) 2.129(4) S(1) - Ru(1) - N(1) 82.2(1)

Ru(1) - C(1) 2.200(4) S(1) - Ru(1) - C(6) 159.0(2)

Ru(1) - C(2) 2.193(4) S(1) - Ru(1) - C(1) 153.2(2)

Ru(1) - C(3) 2.229(4) N(1) - Ru(1) - C(4) 157.3(2)

Ru(1) - C(4) 2.197(5) N(1) - Ru(1) - C(5) 156.2(2)

Ru(1) - C(5) 2.189(4) Cl(1) - Ru(1) - C(3) 157.8(2)

Ru(1) - C(6) 2.239(5) Cl(1) - Ru(1) - C(2) 153.4(2)

N(1) - C(11) 1.511(5) C(19) - S(1) - C(12) 117.1(2)

S(1) - C(12) 1.827(4) S(1) - C(12) - C(11) 106.0(3)

C(11) - C(12) 1.522(6) C(12) - C(11) - N(1) 108.2(3)

C(11) - C(13) 1.513(6) C(12) - C(11) - C(13) 112.9(3)

S(1) - C(19) 1.799(4) Ru(1) - S(1) - C(12) 99.5(2)

Ru(1) - N(1) - C(11) 115.3(3)

Table 3.2.1 Selected bond distances and angles of complex 41R.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...F(14) #2 0.92 2.34 3.218(5) 158.7

N(1) - H(1B)...O(1) 0.92 1.98 2.887(5) 170.2

O(1) - H(1)...F(12) #3 0.84 2.07 2.864(5) 158.1

O(1) - H(1)...F(11) #3 0.91 2.51 3.207(5) 140.9

Table 3.2.2 Hydrogen bonds between complex cation, MeOH and PF6

- in 41R (#1: -x+1, y -z; #2:

-x+½, y-1, -z+1; #3: -x+½, y+½, -z+1).

- 99 -

Pic. 3.2.3 Thermal ellipsoid plot (50 % probality) of molecular structure of η6-mesitylene complex

42R as hexafluorophosphate salt; selected bond angles and distances see Table

3.2.3 and for hydrogen bonding see Table 3.2.4.

Unit cell of complex 42R : - anti-syn (ll) and syn-anti (uu) diastereomers in 1 : 1 ratio in crystal examined - hydrogen bonding between PF6

- and coordinated amino groups and between cations via [Ru(II)]-Cl…H-NH[Ru(II)] as well

anti-syn

syn-anti

(RRu)

(RS)

(SRu)

(SS)

(R) (R)

(hydrogen atoms omitted for clarity)

top view on η6-mesitylene of anti-syn complex cation

top view on η6-mesitylene of syn-anti complex cation

- 100 -

distances [Å] angles [ °]

Ru(2) - Cl(2) 2.407(1) Cl(2) - Ru(2) - S(2) 88.53(4)

Ru(2) - S(2) 2.373(1) Cl(2) - Ru(2) - N(2) 83.07(9)

Ru(2) - N(2) 2.144(3) S(2) - Ru(2) - N(2) 81.45(9)

Ru(2) - C(25) 2.193(4) S(2) - Ru(2) - C(25) 167.8(2)

Ru(2) - C(26) 2.225(4) S(2) - Ru(2) - C(30) 142.2(2)

Ru(2) - C(27) 2.226(4) N(2) - Ru(2) - C(26) 145.9(2)

Ru(2) - C(28) 2.198(4) N(2) - Ru(2) - C(27) 165.5(2)

Ru(2) - C(29) 2.202(4) Cl(2) - Ru(2) - C(28) 146.9(2)

Ru(2) - C(30) 2.223(4) Cl(2) - Ru(2) - C(29) 164.4(2)

N(2) - C(35) 1.504(5) C(43) - S(2) - C(36) 101.5(2)

S(2) - C(36) 1.814(4) S(2) - C(36) - C(35) 107.1(3)

C(35) - C(36) 1.523(5) C(36) - C(35) - N(2) 108.0(3)

C(35) - C(37) 1.512(5) C(36) - C(35) - C(37) 113.9(3)

S(2) - C(43) 1.793(4) Ru(2) - S(2) - C(36) 99.3(2)

Ru(2) - N(2) - C(35) 117.0(2)

Ru(1) - Cl(1) 2.400(1) Cl(1) - Ru(1) - S(1) 91.43(3)

Ru(1) - S(1) 2.400(2) Cl(1) - Ru(1) - N(1) 83.26(8)

Ru(1) - N(1) 2.148(3) S(1) - Ru(1) - N(1) 81.42(9)

Ru(1) - C(1) 2.190(4) S(1) - Ru(1) - C(1) 168.1(2)

Ru(1) - C(2) 2.240(4) S(1) - Ru(1) - C(6) 135.4(2)

Ru(1) - C(3) 2.216(4) N(1) - Ru(1) - C(2) 140.5(2)

Ru(1) - C(4) 2.203(4) N(1) - Ru(1) - C(3) 169.3(2)

Ru(1) - C(5) 2.199(4) Cl(1) - Ru(1) - C(4) 141.2(2)

Ru(1) - C(6) 2.203(4) Cl(1) - Ru(1) - C(5) 166.1(2)

N(1) - C(11) 1.491(5) C(19) - S(1) - C(12) 105.6(2)

S(1) - C(12) 1.824(4) S(1) - C(12) - C(11) 110.2(3)

C(11) - C(12) 1.533(5) C(12) - C(11) - N(1) 106.9(3)

C(11) - C(13) 1.526(5) C(12) - C(11) - C(13) 111.5(3)

S(1) - C(19) 1.784(4) Ru(1) - S(1) - C(12) 100.3(2)

Ru(1) - N(1) - C(11) 114.9(2)

Table 3.2.3 Selected bond distances and angles of as (upper half) and sa cation (lower half) of

42R as hexafluorophosphate salt.

- 101 -

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...Cl(2) #1 0.92 2.67 3.508(3) 152.0

N(1) - H(1B)...F(24) #2 0.92 2.27 3.126(4) 155.4

N(2) - H(2A)...F(14) #3 0.84 2.46 3.078(4) 124.8

Table 3.2.4 Hydrogen bonds between complex cations [Ru(II)]-Cl…H-NH[Ru(II)] and PF6

- in 42R

(#1: -x+1, y-½, -z+1; #2: x+1, y, z; #3: -x, y-½, -z+1).

distances [Å] angles [ °]

Ru(2) - Cl(2) 2.398(2) Cl(2) - Ru(2) - S(2) 88.97(6)

Ru(2) - S(2) 2.386(2) Cl(2) - Ru(2) - N(2) 81.0(2)

Ru(2) - N(2) 2.145(5) S(2) - Ru(2) - N(2) 81.5(2)

Ru(2) - C(31) 2.180(6) S(2) - Ru(2) - C(35) 165.7(2)

Ru(2) - C(32) 2.198(7) S(2) - Ru(2) - C(36) 146.6(2)

Ru(2) - C(33) 2.206(6) N(2) - Ru(2) - C(33) 164.7(2)

Ru(2) - C(34) 2.206(6) N(2) - Ru(2) - C(34) 148.6(2)

Ru(2) - C(35) 2.188(6) Cl(2) - Ru(2) - C(31) 159.8(2)

Ru(2) - C(36) 2.231(6) Cl(2) - Ru(2) - C(32) 151.1(2)

N(2) - C(41) 1.507(6) C(49) - S(2) - C(42) 100.4(3)

S(2) - C(42) 1.819(5) S(2) - C(42) - C(41) 108.8(3)

C(41) - C(42) 1.521(6) C(42) - C(41) - N(2) 109.1(4)

C(41) - C(43) 1.514(7) C(42) - C(41) - C(43) 109.2(4)

S(2) - C(49) 1.798(6) Ru(2) - S(2) - C(42) 98.3(2)

Ru(2) - N(2) - C(41) 118.7(3)

Table 3.2.5 Selected bond distances and angles of as cation of 43R.

- 102 -

Pic. 3.2.4 Thermal ellipsoid plot (50 % probality) of molecular structure of η6-mesitylene complex

43R as hexafluorophosphate salt; selected bond angles and distances see Table

3.2.5 (as cation), Table 3.2.6 (sa cation) and for hydrogen bonding see Table 3.2.7.

Unit cell of complex 43R : - anti-syn (ll) and syn-anti (uu) diastereomers in 1 : 1 ratio in crystal examined - hydrogen bonding of PF6

- via fluoride to protons of coordinated amino groups

top view on η6-mesitylene of anti-syn complex cation

top view on η6-mesitylene of syn-anti complex cation

(hydrogen atoms omitted for clarity)

(RRu)(R) (R)

(SS) (RS)

(SRu)

syn-anti

anti-syn

- 103 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.398(2) Cl(1) - Ru(1) - S(1) 93.64(6)

Ru(1) - S(1) 2.382(2) Cl(1) - Ru(1) - N(1) 81.1(2)

Ru(1) - N(1) 2.181(5) S(1) - Ru(1) - N(1) 81.2(2)

Ru(1) - C(1) 2.209(6) S(1) - Ru(1) - C(1) 164.5(2)

Ru(1) - C(2) 2.234(6) S(1) - Ru(1) - C(6) 144.3(2)

Ru(1) - C(3) 2.225(7) N(1) - Ru(1) - C(2) 149.5(2)

Ru(1) - C(4) 2.230(7) N(1) - Ru(1) - C(3) 166.7(2)

Ru(1) - C(5) 2.210(6) Cl(1) - Ru(1) - C(4) 150.2(2)

Ru(1) - C(6) 2.232(6) Cl(1) - Ru(1) - C(5) 158.3(2)

N(1) - C(11) 1.478(6) C(19) - S(1) - C(12) 106.3(3)

S(1) - C(12) 1.829(5) S(1) - C(12) - C(11) 110.4(3)

C(11) - C(12) 1.516(6) C(12) - C(11) - N(1) 107.6(4)

C(11) - C(13) 1.528(7) C(12) - C(11) - C(13) 114.6(4)

S(1) - C(19) 1.808(6) Ru(1) - S(1) - C(12) 100.8(2)

Ru(1) - N(1) - C(11) 112.7(3)

Table 3.2.6 Selected bond distances and angles of sa cation of compound 43R.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...F(21) 0.92 2.17 3.084(6) 171.8

N(1) - H(1B)...F(11) #1 0.92 2.44 3.334(6) 164.9

N(2) - H(2B)...F(14) #1 0.92 2.24 3.038(6) 144.2

Table 3.2.7 Hydrogen bonds between complex cations and PF6

- in 43R (#1: x, y-1, z).

- 104 -

Pic. 3.2.5 Thermal ellipsoid plot (50 % probality) of molecular structure of η6-mesitylene complex

44R as hexafluorophosphate salt; selected bond angles and distances see Table

3.2.8 (as cation), Table 3.2.9 (sa cation) and for hydrogen bonding see Table 3.2.10.

Unit cell of complex 44R (PF6- and “half” CH2Cl2 molecule omitted for clarity):

- anti-syn (lu) and syn-anti (ul) diastereomer in 1 : 1 ratio unit in crystal examined - hydrogen bonding between PF6

- and coordinated amino groups and between cations via [Ru(II)]-Cl…H-NH[Ru(II)] as well

(hydrogen atoms omitted for clarity)

top view on η6-mesitylene of anti-syn complex cation

top view on η6-mesitylene of syn-anti complex cation

(RRu)

(SS)

(SRu)

(RS)

(R) (R)

syn-anti

anti-syn

- 105 -

distances [Å] angles [ °]

Ru(2) - Cl(2) 2.409(2) Cl(2) - Ru(2) - S(2) 88.35(5)

Ru(2) - S(2) 2.364(2) Cl(2) - Ru(2) - N(2) 83.8(2)

Ru(2) - N(2) 2.147(4) S(2) - Ru(2) - N(2) 81.7(2)

Ru(2) - C(24) 2.182(6) S(2) - Ru(2) - C(28) 162.7(2)

Ru(2) - C(25) 2.193(5) S(2) - Ru(2) - C(29) 148.5(2)

Ru(2) - C(26) 2.202(5) N(2) - Ru(2) - C(26) 161.0(2)

Ru(2) - C(27) 2.220(5) N(2) - Ru(2) - C(27) 152.8(2)

Ru(2) - C(28) 2.196(5) Cl(2) - Ru(2) - C(24) 160.1(2)

Ru(2) - C(29) 2.230(6) Cl(2) - Ru(2) - C(25) 152.0(2)

N(2) - C(33) 1.509(6) C(41) - S(2) - C(34) 100.5(3)

S(2) - C(34) 1.836(5) S(2) - C(34) - C(33) 107.6(3)

C(33) - C(34) 1.490(7) C(34) - C(33) - N(2) 108.0(4)

C(33) - C(35) 1.512(7) C(34) - C(33) - C(35) 113.9(4)

S(2) - C(41) 1.836(6) Ru(2) - S(2) - C(34) 98.8(2)

C(41) - C(42) 1.492(8) Ru(2) - N(2) - C(33) 116.6(3)

C(42) - C(43) 1.310(10) C(41) - S(2) - C(34) 100.5(3)

C(43) - C(44) 1.526(9) S(2) - C(41) - C(42) 109.4(4)

C(43) - C(45) 1.492(10) C(41) - S(2)- Ru(2) 112.7(2)

C(41) - C(42) - C(43) 126.5(6)

C(42) - C(43) - C(44) 120.6(6)

C(42) - C(43) - C(45) 126.1(6)

C(44) - C(43) - C(45) 113.3(6)

Table 3.2.8 Selected bond distances and angles of as cation of compound 44R.

- 106 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.399(2) Cl(1) - Ru(1) - S(1) 91.88(5)

Ru(1) - S(1) 2.390(2) Cl(1) - Ru(1) - N(1) 84.1(2)

Ru(1) - N(1) 2.127(4) S(1) - Ru(1) - N(1) 81.8(2)

Ru(1) - C(1) 2.203(6) S(1) - Ru(1) - C(1) 163.5(2)

Ru(1) - C(2) 2.210(5) S(1) - Ru(1) - C(6) 146.1(2)

Ru(1) - C(3) 2.180(6) N(1) - Ru(1) - C(2) 151.3(2)

Ru(1) - C(4) 2.189(6) N(1) - Ru(1) - C(3) 162.6(2)

Ru(1) - C(5) 2.191(7) Cl(1) - Ru(1) - C(4) 151.3(2)

Ru(1) - C(6) 2.237(6) Cl(1) - Ru(1) - C(5) 158.3(2)

N(1) - C(11) 1.493(6) C(19) - S(1) - C(12) 101.9(3)

S(1) - C(12) 1.821(5) S(1) - C(12) - C(11) 110.6(3)

C(11) - C(12) 1.526(6) C(12) - C(11) - N(1) 107.8(4)

C(11) - C(13) 1.521(7) C(12) - C(11) - C(13) 111.5(4)

S(1) - C(19) 1.839(6) Ru(1) - S(1) - C(12) 100.5(2)

C(19) - C(20) 1.472(8) Ru(1) - N(1) - C(11) 115.3(3)

C(20) - C(21) 1.315(9) C(19) - S(1) - C(12) 101.9(3)

C(21) - C(22) 1.501(9) S(1) - C(19) - C(20) 111.7(4)

C(21) - C(23) 1.52(2) C(19) - S(1)- Ru(1) 110.4(2)

C(19) - C(20) - C(21) 128.9(6)

C(20) - C(21) - C(22) 122.7(7)

C(20) - C(21) - C(23) 123.0(6)

C(22) - C(21) - C(23) 114.2(7)

Table 3.2.9 Selected bond distances and angles of sa cation of compound 44R.

- 107 -

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...F(21) 0.92 2.44 3.351(8) 170.3

N(1) - H(1B)...F(23) 0.92 2.63 3.368(9) 137.6

N(1) - H(1B)...Cl(2) 0.92 2.41 3.321(4) 170.6

N(2) - H(2A)...Cl(1) 0.92 2.61 3.299(4) 132.0

N(2) - H(2B)...F(31) #4 0.92 2.41 3.106(6) 132.7

Table 3.2.10 Hydrogen bonds between complex cations [Ru(II)]-Cl…H-NH[Ru(II)] and PF6

- in 44R

(#1: -x+1, y, -z+1; #2: -x+1, y, -z; #3: -x, y, -z; #4: x, y+1, z).

All bond lengths and angels are in the expected range so far and the ligand

backbone C-N and the C-S bonds are only slightly elongated. The average Ru-S

bond length of 2.38 Å compares well to the ones of similar phosphine Ru(II)-η6-arene

complexes. Comparison of the averaged bond angels φ trans greater or equal 150°

reveal slight trans influences, but without general tendencies (Table 3.2.11).

complex φ trans S φ trans N φ trans Cl

41R 156.1 156.8 155.6

42R 153.3 155.3 154.6

43R 155.3 157.4 154.9

44R 155.2 157.0 155.4

Table 3.2.11 Averaged angels φ trans = X-Ru(II)-C(i)(η6-arene) (X = N, S, Cl trans to C(i) of η6-arene)

of all diastereomers of the particular complexes as a measure of the trans influence;

for numbering see Pic. 3.2.1.

The missing dominance of the thioether trans influence can be valued just as another

proof thioethers are much weaker σ-donor and much weaker π-acceptor ligands than

phosphines, which cannot be influenced or modulated by substituent variation.

Thioethers are even weaker σ-donors than amines.

- 108 -

σ *

General average bond lengths [A°]:

C-H 1.09 C-S 1.81 C-C 1.54 C=C 1.33

Vinylog delocalization of electrons of bonding σ(CH) orbital intoantibonding σ*(CS) orbital; expectedinfluences on bond lengths:

- Carbon - Acceptor bond elongated!- Allylic -CH2-C=C bond shortened!- one C=C(CH3) bonds shotened!- Carbon - Donor bond shortened!

Donor

H3CSRu

R (backbone)

H

HH

σ

π (LUMO)

Ru(II)-S(backbone)prenyl segment from anti-syn cation 44R

Ru(II)-S(backbone)prenyl segment from syn-anti cation 44R

Arrangement equivalent to 1,3-butadiene LUMO!

Acceptor

Pic. 3.2.6 Structural details of Ru(II)-S(backbone)prenyl segments from η6-mesitylene complex

44R and stereoelectronic σ-π*-σ* effect; complete structures see Pic. 3.2.5.

Compared to van der Zeijden's η5-Cp-complexes [43 (1)] complex 44R does not

fragmentize spontaneously to the corresponding thiolato complex (Pic. 3.0.2, Pic.

3.2.1). The much more electron withdrawing η6-mesitylene ligand should even

promote this fragmentation by increasing the electrophilicity of the Ru(II) center via its

trans effect in additional combination with the prenyl cation as a much better leaving

group compared to a simple secondary carbocation. Looking on the geometric

arrangements of the prenyl fragments in the crystal structure of complex 44R (Pic.

3.2.6, Tables 3.2.8 and 3.2.9) only a weak σ*-π*-σ effect becomes evident. The S-

CH2 bonds are almost arranged parallel to the alkene π-bonding plane as required for

a σ*-π* overlap, but the S-CH2 bonds are only slightly elongated with 1.839(6) Å for

S(1) - C(19) and 1.836(6) Å for S(2) - C(41) and are of comparable lengths of the S-

C(backbone) bonds. The allyl (-CH2-CH=C) bond lengths with 1.472(8) Å for C(19) -

- 109 -

C(20) and 1.492(10) Å for C(41) - C(42) are also not deviating strongly from the value

of ca. 1.51 Å for an allyl bond without the influence of a stereoelectronic σ*-π*-σ

interaction. The differences of the C=C(CH3)2 bonds of 0.016 Å for the prenyl

fragment of the sa and of 0.034 Å for the prenyl fragment of the as diastereomer do

also speak only for a slight σ-π*-σ* effect. A satisfying explanation for this unexpected

weakness of this σ*-π*-σ effect without drifting into bare speculation cannot be given

at this point.

Interestingly complexes 41R - 44R show all hydrogen bridging of the hydrogen atoms

of the coordinated amino groups with the fluorine atoms of the hexafluorophosphate

anion in solid state (Table 3.2.2, Table 3.2.4, Table 3.2.7, Table 3.2.10). Furthermore

the diastereomeric cations 42R and 44R are associated via [Ru(II)]-Cl…H-NH[Ru(II)]

bridges in the crystals examined (Table 3.2.4, Table 3.2.10). Complex 41R

crystallizes with one molecule MeOH, which results in a particular threefold centered

hydrogen bridge system with the amino group and hexafluorophosphate anion (Pic.

3.2.2, Table 3.2.2). However, of course this threefold centered system cannot

account for a transition state analog of substrate binding and / or product release, but

will be regarded later as evidence in the discussion regarding activity and

enantioselectivity of cationic transfer hydrogenation catalysts.

While the η6-(p-cymene) complex 41R crystallizes only as the as diastereomer, the

as and sa diastereomers in of the η6-mesitylene complexes 42R - 44R are found in a

1:1 ratio independent from the size of the thioether moiety in the examined crystals.

This already allows the preliminary conclusion the energetic preference of the

particular diastereomer is dominated by the steric demand of the η6-arene ligand.

This steric demand is higher for p-cymene than for mesitylene. If steric repulsion is

the limiting factor for the energetic preference of one or two particular diastereomers

over the four possible (as, aa, sa, ss), then the energetic preference should be as >

aa > sa >> ss (Pic. 3.2.7, diastereomers drawn in their particularly preferred

conformation of least steric repulsion of the η6-arene ligand in regard to the backbone

phenyl moiety and thioether substituent R4). Of course great care has to be taken

drawing conclusions from structures in solid state for the "free" species in solution for

instance, but the isostructural but not isomorph features here justify the claim of a

general tendency for the "free" cations despite still possible crystal packing effects.

- 110 -

R3

R1

R2

R1

(R)

*

*

(S)

*

PF6 PF6

41R R1 = H R2 = CH3 R3 = iPr R4 = Ph42R R1 = R2 = CH3 R3 = H R4 = Ph43R R1 = R2 = CH3 R3 = H R4 = β-Naph44R R1 = R2 = CH3 R3 = H R4 = Prnn

R3

R1

R2

R1

* (S)(R)

*

*

(R)

*

PF6anti-syn

SH2N

Ru

Cl R4

H

R3

R1

R2

R1

H

(R)

**

SNH2

Ru

ClR4

PF6syn-anti

*

(R)

**

(R)

RuH2NS

Cl

R4

H

H

Ru NH2S

Cl

R4

R3

R1

R2

R1

anti-anti

(SS) for R4 = Ph, β-Naph(RS) for R4 = Prn

syn-syn

(RS) for R4 = Ph, β-Naph(SS) for R4 = Prn

Pic. 3.2.7 Diastereomer equilibria of σ(N):σ(S)-β-aminothioether Ru(II) η6-arene complexes 41R

- 44R in solution; energetic preferences: as > aa > sa >> ss.

Already from the CD spectra (Pic. 3.2.8) it becomes obvious complexes 41R - 44R

are in a thermodynamic equilibrium of diastereomers (Pic. 3.2.7). Between 250 - 300

nm the CD spectra match almost the ones of the free ligands (Pic. 3.1.7) with a slight

bathochromic shift, which accounts for the complexation and the preservation of the

absolute configuration of the particular ligand backbones at the same time. However,

only for the η6-(p-cymene) complex 41R a positive medium Cotton effect is observed

in the 380 - 410 nm the Ru(II) transition region, while for the η6-mesitylene

- 111 -

complexes 42R - 44R the Cotton effects in that region are much weaker but of

comparable magnitudes, and also positive. This shows clearly that only for 41R one

diastereomer with a chiral Ru(II) center dominates in the solution equilibrium, while

for 42R - 44R an epimerization equilibrium is observed due to a pseudo enantiomeric

relationship of diastereomers with opposite configuration at the Ru(II) center. The CD

spectra do not reveal any information about the chiral sulfur centers so far. If 41R -

44R would not be in a solution equilibrium in regard to the solid state structures, then

for 41R a much stronger Cotton effect would have been observed, while for 42R -

44R no effects would be visible in the 380 - 410 nm region.

Pic. 3.2.8 CD spectra of β-amino thioether Ru(II) η6-arene complexes (MeOH, RT, c ~ 10-3

mol/l); for numbering see Pic. 3.2.7and for enlarged spectra Chapter 8.

(complete, overlaid spectra for comparison)

(enlarged for details)

______ 41R ............ 42R (lower curve) .-.-.-. 44R 43R (upper curve)

44R 41R 43R42R

44R41R

42R

44R 41R

43R

44R

44R 43R42R 44R

41R

- 112 -

RT

0° C

- 20° C

- 30° C

- 10° C CH3

CH3

H3C

H

H

Ru

H2N

Cl

S *

*

*

CH

Ph

Ph

H

H

1

1'

2

2'

η6-(p-cymene) protons planar diastereotopic :

Ratio of diastereomers at - 30° C (CDCl3): 1.00 : 0.32 (not changing significantly at RT)

2'aa

2as

2aa

1'as

1'aa 1aa

1as 2'as

Pic. 3.2.9 6.2 - 5.0 ppm region of the 1H-NMR spectrum of 41R at various temperatures (CDCl3,

400 MHz) and relative assignment of the diastereotopic η6-(p-cymene) protons.

Indeed, in the NMR spectrum of η6-(p-cymene) complex 41R two sets of signals

belonging to two diastereomers are present (Pic. 3.2.9). The 1 : 0.32 signal ratio in

solution is independent from the number of recrystallization cycles clearly proving a

thermodynamic equilibrium of diastereomers in solution. For 41R the signal ratio is

also independent from temperature and only slightly from solvent (CDCl3, acetone-d6,

Table 3.2.12). For the determination of the diastereomer ratio the methyl signals of

the η6-(p-cymene) ligand are diagnostic. The aromatic η6-(p-cymene) protons split

completely into two sets of four doublets for each diastereomer due to planar

diastereotopicity going from ambient temperature down to - 30° C. Only a signal

broadening but no coalescence could not be observed at + 70° C in DMSO-d6.

- 113 -

Pic. 3.2.10 NOE irradiations on p-methyl group of η6-(p-cymene) ligand of 41R (CDCl3, 500 MHz,

- 30° C): (a) on as and (b) on aa diastereomer; for numbering see Pic. 3.2.11.

CH2Cl2MeOH

CH2Cl2MeOH

a)

b)

4as

4as

1'as 1as

3as

4aa

1'aa 1aa

3aa

H3C

H

H

H

CH3

Ph(R)

*

*

(R)

*

(R)

anti-syn

SH2N

Ru

Cl

H

anti-anti

*

(S)Ph

(R)

**

(R)

RuH2NS

Cl

H

H

H

H

H

H

1as

1'as

3as

4as

4as

3aa

1aa

1'aa

4aa

4aa

- Strong NOE on o-protons of η6-(p-cymene)!

- Weak NOE on o-protons of -S-Ph

- No NOE on protons of ligand backbone Ph!!

4aa

- 114 -

H3C

H

H

H

CH3

Ph(R)

*

*

(R)

*

(R)

anti-syn

S CH2

H2N

Ru

Cl

H

anti-anti

*

(S)Ph

(R)

**

(R)

RuH2NS

Cl

H

H

H

H

CH

H

H

H3CCH3

1as

1'as

3as

4as

4as

3aa

1aa

1'aa

4aa

4aa

HH

H

H

H

2as

2'as

5as5as

5as

7as

8as

9lu

10as10'as

(H of both diastereomers partially omitted for clarity )

6as

2aa

2'aa

9aa

10aa

10'aa

8aa

7aa

6aa 5aa

5aa

5aaH

H

H

Pic. 3.2.11 JHJH-COSY spectrum (CDCl3, 500 MHz, - 30° C): as and aa diastereomers of 41R in

thermodynamic equilibrium.

- 115 -

NOE irradiations on the two p-methyl singlets of the η6-(p-cymene) ligand (Pic.

3.2.10) lead to the response of the two sets of the corresponding (2,6)-protons of the

arene ligand and of the (2,6)-protons of the thiophenyl ring only. No NOE response

could be observed for the protons of the ligand backbone phenyl substituents (7.34

ppm, m). From the CD spectrum of 41R it is evident both diastereomers must have

the same absolute configuration on the Ru(II) center, leaving the choice only to the

as + aa and the sa + ss pairs of diastereomers. Therefore the absence of a NOE

response of the ligand backbone phenyl substituents suggests these phenyl rings are

in anti position to the η6-(p-cymene) ligand, leaving finally the choice to the as + aa

pair of diastereomers only. Because a weaker A1,2 repulsion of the thiophenyl moiety

from the coordinated arene in the as than in the aa diastereomer must be expected,

the as diastereomer should be energetically preferred. Therefore the signals

belonging to the major species present in solution are assigned to the as

diastereomer of 41R. All other 1H resonances were assigned by COSY (Pic. 3.2.11),

by coupling constants and / or similarity relationship, which were then correlated to

the signals in 13C-spectrum by DEPT and HMQC.

A totally different situation is given for the η6-mesitylene complexes 42R - 44R in

solution (Pic. 3.2.12, Table 3.2.12). The aromatic protons of the η6-mesitylene ligand

(5.2 - 5.8 ppm) are not planar diastereotopic due to its C3 symmetry, so each of these

signals corresponds to one diastereomer of 42R - 44R. An equivalent splitting is also

observed for the mesitylene methyl protons (1.5 - 2.4 ppm). Depending from varying

resolution the integrals of these signal sets are suitable for the determination of the

diastereomer ratio. Four of these signals are observed for complex 42R at - 30° in a

1.0 : 0.40 : 0.10 : 0.07 ratio. Considering the axial repulsion effects in a five

membered chelate they can be assigned by their ratio to the as, aa, sa and ss

diastereomers tentatively, but unfortunately this signal assignment could not be

confirmed with NOESY due to the number of artifacts. Going from - 30° C to ambient

temperature the sa and ss signals of 42R collapse into each other accompanied with

general signal broadening also for the as and aa diastereomers. With as : aa : (sa +

ss) = 1.0 : 0.36 : 0.29 only a slight temperature change is observed also. In analogy

this assignment of diastereomer signals was then transferred also to complexes 43R

and 44R in solution (Pic. 3.2.12, Table 3.2.12), but unfortunately the possibility of low

temperature measurements for a better resolution was not provided.

- 116 -

Pic. 3.2.12 6.0 - 5.0 ppm region (aromatic η6-mesitylene protons) of the 1H-NMR spectrum of 42R

- 44R (CDCl3, acetone-d6, 300 - 400 MHz).

42S (CDCl3, 400 MHz, - 30° C)

42S (CDCl3, 400 MHz, RT)

42S (acetone-d6, 300 MHz, RT)

43S (acetone-d6, 300 MHz, RT)

44S (acetone-d6, 300 MHz, RT)

44S (CDCl3, 400 MHz, RT)

as

aa sa

ss

as

aa

sa + ss sa + ss

aa

as

Ph-CH-

as

aa

sa + ss

CH2Cl2 as

aa sa + ss

as

aa

sa + ss

Ph-CH-

- 117 -

complex solvent temperature diastereomer ratio

41R CDCl3 1) a) ambient as : aa = 1.0 : 0.32

CDCl3 1) a) - 30° C as : aa = 1.0 : 0.32

acetone-d6 2) b) ambient as : aa = 1.0 : 0.4

42R CDCl3 1) a) ambient as : aa : (sa + ss) = 1.00 : 0.36 : 0.29

CDCl3 1) a) - 30° C as : aa : sa : aa = 1.00 : 0.40 : 0.10 : 0.07

acetone-d6 2) b) ambient as : aa : (sa + ss) = 0.9 : 1.0 : 0.6

43R acetone-d6 2) b) ambient (as + aa) : (sa + ss) = 1.0 : (< 0.5)*

44R CDCl3 2) b) ambient as : aa : (sa + ss) = 0.9 : 1.0 : (< 0.7)*

acetone-d6 2) b) ambient as : aa : (sa + ss) = 0.53 : 1.00 : 0.93

Table 3.2.12 Diastereomer ratio determined by 1H-NMR (1) 400 MHz; 2) 300 MHz; a) via integration

of the singlets of the η6-arene methyl groups; b) via integration of η6-arene ring

protons; * difficult to determine due to overlap and / or low resolution).

The diastereomer ratios of η6-mesitylene complexes 42R - 44R in solution show a

moderate dependency from solvent and the thioether moiety. Although the (as + aa) :

(sa + ss) ratio was generally in favor for the (as + aa) pair, it balanced more in

acetone-d6 than in CDCl3. Obviously the energy differences of the diastereomers are

smaller in acetone-d6 than in CDCl3. Interestingly for 42R in acetone-d6, for 43R and

for 44R in acetone-d3 and CDCl3 as well the ratio of the aa was equal to or in favor of

the as diastereomer at ambient temperature. This effect increases going from the

steric demanding aryl to the more flexible prenyl moiety attached at the sulfur atom.

Unfortunately 43R is not sufficiently solulable in CDCl3 after recrystallization. So an 1H-NMR spectrum could be recorded in this solvent. These experiments confirm a

low inversion barrier of the chiral sulfur center for this class of complexes simply by

thermodynamic temperature compensation, too. If this is true, then the as should

dominate over the aa diastereomer at low temperatures again. In this way low

temperature NMR measurements would also support the tentative assignment of the

NMR signals of the particular diastereomers. Nevertheless a sufficient assignment of

the NMR signals of 42R - 44R was possible with COSY, DEPT and HMQC.

- 118 -

The reason for the configurational instability of the diastereomeric complexes 41R -

44R in solution must not be concluded from the low inversion barrier at the sulfur

atom of complexed thioethers alone, but also from the weaker σ-donor capability of

thioethers in general. Note that for a binding of the thioether moiety forming finally

41R - 44R sodium hexafluorophosphate as a chloride trapping reagent was required,

while for the synthesis of β-aminoalcoholate chelated Ru(II) η6-arene complexes

heating of the β-amino alcohol with the Ru(II) precursor in protic polar solvents is

sufficient alone [22 (2, 4-5)]. The dominance of particularly the as, followed by the aa,

sa and ss diastereomers is governed rather by the steric demand of the η6-arene

ligand than by the size or flexibility of the thioether moiety. The η6-arene ligand can

be understood as a unit in continuous rotation around the complexation axis to the

Ru(II) center. Therefore only the η6-(p-cymene) ligand is capable to induce a

sufficient A1,3 repulsion with the ligand backbone phenyl moiety, forcing it exclusively

into an anti position and to stabilize the resulting the chiral Ru(II) in (R)-configuration

exclusively. The steric demand of the η6-mesitylene ligand is not sufficient for that

purpose. The thioether moiety influences with increasing size or rigidity only the

inversion stability of the chiral sulfur center by stabilizing the as and / or sa over the

aa and / or ss diastereomer by increasing the repulsive A1,2 interaction of the

coordinated η6-arene, but not sufficiently enough for the preference of one

diastereomer exclusively. In this way the thermodynamic preference for one

diastereomer in solution decreases in the order 41R > 42R = 43R > 44R with the

general thermodynamic preference of the as > aa > sa > ss diastereomers.

catalysts mol %

catalyst

mol %

tBuOK

molar ratio iPrOH /

acetophenone

T [° C] reaction

time [h]

conversion

[%]

41R 0.25 0.52 3.2 80 41 50

41R 1.12 1.16 39.2 80 49 73

42R 1.00 1.13 12.7 80 1.1 55

Table 3.2.13 Catalytic transfer hydrogenation experiments of acetophenone to 1-phenylethanol in

iPrOH with tBuOK.

- 119 -

Complexes 41R and 42R were then tested as catalysts in the transfer hydrogenation

of acetophenone with isopropanol to 1-phenylethanol; 43R proved to be too

insolulable. No reaction at all was observed with triethylamine / formic acid as hydride

source. Because of the general low solubility of 41R and 42R in iPrOH even at higher

temperatures a moderate activity could be reached only, when the molar ratio of

iPrOH / acetophenone was decreased from usual 100 : 1 [21 (1-2)] down to 39 : 1,

but with negligible enantioselectivity in all cases (Table 3.2.13). Also tBuOK instead

of KOH as a base had to be used. Addition of DMF as a cosolvent enhanced the

catalysts' solubility, but this does not seem to increase the activity here. So as a

reason for this low activity and selectivity not only the general low solubility under the

usual catalytic standard conditions have to be blamed.

Although configurative stability is not a necessary requirement for highly

enantioselective transfer hydrogenation catalysts [22 (6)], the requirement for a high

selectivity is still that one diastereomeric hydride intermediate reduces the substrate

with particular high enantioselectivity. At the same time this intermediate must

strongly dominate in the reaction solution in a thermodynamic sense or must react

ways faster with the substrate than the other hydride species present in a kinetic

sense. Due to the number and ratio of diastereomers present for precatalysts 41R -

42R in solution the thermodynamic dominance of one hydride transferring

intermediate thereof under catalytic reaction conditions is very unlikely. The retarded

activity of 41R - 42R in general compared to Noyori's catalysts [21 (1-2)] show clearly

the aforementioned kinetic requirement is also not fulfilled.

Re

1 8

4 5

7 2

6 3

S Ru NH

H

H

OH3C

Ph*

Si

1 8

4 5

7 2

6 3

S Ru NH

H

H

OPh

CH3

*

Ar

Ar

Ar

Ar

* *

Total steric repulsion by the thioether moiety causes weak substratebinding resulting in no enantioselectivity!

Pic. 3.2.13 Proposed diastereomeric transition states of N(SR)-chelated η6-Arene Ru(II) hydride

complexes with acetophenone in octant projection.

- 120 -

Drawing each of the two possible transition states for the Re and for the Si face

attack of the hydride transferring species on acetophenone under consideration of

the two possible sulfur configurations it becomes obvious that for all sulfur

configurations the substrate's access is sterically blocked (Pic. 3.2.13, note the ligand

backbone phenyl moiety in the backoctants 5 or 8 is omitted for clarity, because it

does not influence the substrate approach directly by steric interaction). This effect is

obviously stronger than the ππ-attraction between the substrate's phenyl moiety and

the η6-arene ligand (compare Pic. 1.4.7) and in this way the enantiodiscriminative

effect of octants 1 and 2 are totally outflanked by this hindrance of the substrate's

approach (Chapter 1.4). Therefore introducing larger substituents on the η6-benzene

ligand might finally suppress the diastereomer equilibrium of σ(N):σ(S) β-

aminothioether chelated η6-arene Ru(II) complexes, but on costs of any catalytic

activity and selectivity as well. Additionally larger substituents on the η6-benzene

ligand might compensate the ππ-attraction by steric repulsion of the substrate's aryl

moiety and might retard the enantioselectivity also in this way. These findings are

complemented by the fact similar β-aminobisarylphosphine chelate Ru(II) η6-arene

Ru(II) complexes did not show any catalytic activity in transfer hydrogenation

reactions at all due to the higher steric demand of the phosphine moiety carrying two

large substituents instead of one like the analog thioether functionalities [32 (2)].

Therefore any further attempts to develop highly active and selective σ(N):σ(S) β-

aminothioether Ru(II)-η6-arene TH catalysts were aborted at this point.

- 121 -

4 Preparation and Study of Diastereomeric

{[σ(P):η6-(Arene-ansa-Phosphinite)]

Ruthenium(II) Amino} Complexes

The high configurational stability as well as the described highly diastereoselective

formation of Pinto's ansa-phosphine Ru(II) η6-arene complexes [36 (6-7)] (Chapter

1.5, Pic. 1.5.9) seem to contradict obviously their poor performance as supposed

enantioselective transfer hydrogenation catalysts. This required a thorough

examination of the ansa concept followed in the Zenneck group as a whole.

Therefore suitable ansa-ligated Ru(II) η6-arene complexes were in demand, which do

have a structural similarity with Pinto's complexes on the one hand, but could also be

easily and quickly prepared in large quantities for thorough screening. This in turn

required an ansa-arene phosphine ligand, which could also be prepared in large

quantities. This is mostly hampered by the airsensitivity of aliphatic substituted

phosphine ligands themselves and also by the high costs of Pinto's chiral starting

template (3S)-3-phenyl butanoic acid. To eliminate the problematic airsensitivity from

a practical point of view analog phosphinite ligands R2P-OR' were envisaged as a

suitable alternative, because they are airstable and do have very similar coordinative

and electronic properties like phosphines themselves. Phosphinites have therefore

found wide applications as ligands in transitionmetal catalysis way too much to

survey in the scope of this thesis [45 (1)]. RajanBabu's already classic Ni(0)

catalyzed enantioselective alkene hydrocyanation [45 (2)] might just serve as an

outstanding example. The π-acceptor capability is decreasing in the order P(OR)3 >

PR3 > R2P-OR', but for the σ-donor capability no general trend is given [45 (3, 4)].

The σ-donor capability rather depends from the steric bulk of the phosphorous

substituents influencing the cone angle in turn combined with the individual electronic

properties of the particular substituents themselves. Because phosphinites can be

easily prepared by base assisted alcoholysis a cheer unlimited synthetic access to a

large variety is given. This includes "electronic fine tuning" to stronger π-acceptor

ligands with strongly electron withdrawing substituents R on phosphorous, which

often improve the regio- and enantioselectivities of transitionmetal catalysts [45 (2)].

- 122 -

4.1 Synthesis

Kurosawa prepared the first ansa-phosphinite Ru(II) η6-arene complex [41 (10)] by

coordination of chlorophosphines on 3-hydroxypropyl Ru(II) η6-arene dimer 18

followed by base promoted intramolecular alcoholysis (Pic. 4.1.1).

Ru Ru

Cl

ClCl

Cl

HO

OH

18PR2

Ru

ClCl

H. Kurosawa

ClPR2 / EtN(iPr)2

O

R = Ph, iPr

Pic. 4.1.1 First example of an ansa-phosphinite Ru(II) η6-arene complex prepared by electro-

phile coordination followed by base promoted intramolecular alcoholysis.

To the best of knowledge this is the only example of an ansa-phosphinite Ru(II) η6-

arene complex described in literature so far. Applying this concept on chiral aryl

alcohols would result in a three step synthesis, consisting of a Birch reduction, Ru(II)

complexation and the aforementioned in situ coordination of chlorophosphines on the

Ru(II) η6-arene dimer followed by base promoted intramolecular alcoholysis.

However, this very attractive methodology is only restricted to such chiral aryl

alcohols, which do not bear a benzylic hydroxy or alkoxy group (Chapter 2.1),

because benzylic hydroxy or alkoxy groups are cleaved under Birch conditions.

However, to the best of knowledge an intramolecular η6-arene exchange reaction

with precoordinated aryl phosphinites leading to ansa-phosphinite Ru(II) η6-arene

complexes is not reported in literature so far and promises the most general synthetic

access to this class of complexes.

As a cheap template natural (+)-(S)-mandelic acid 47S was chosen here (Pic. 4.1.2),

which was cleanly converted to its methylester 48S oriented on a modified literature

protocol [46 (1)]. Mandelic acid and its derivatives are prone to racemization under

basic conditions. Therefore the conversion of 48S to the methoxy derivative 49S was

- 123 -

accomplished by a solid-liquid biphase system consisting of silver(I) oxide and methyl

iodide based on a protocol [46 (2)] adjusted to modern standards. The driving force

of this reaction is the formation of silver iodide of course. Per one equivalent methyl

iodide activated by silver(I) oxide half an equivalent oxide still "fixed" in the solid

phase is available. This can trap the proton of the reacting hydroxy group of 48S. In

this way the virtual base concentration does not exceed the actual proton

concentration on the one hand and on the other the base is not in direct contact with

48S due to solid state fixation. In this way a base induced keto-enol tautomerization

resulting in racemization is suppressed. Because silver iodide can be simply and

quantitatively filtrated off and recycled during workup this procedure is also

economically justified despite the high yield of 91 % of 49S.

O

P

Ru

ClCl

Ph

Ph

OCH3

(R)*

Ph COOCH3

OCH3

Ph

OCH3

OH

0.61 eq Ag2O / 6.62 eq H3CI

DMF / RT / 91 %

1.04 eq LiAlH4 /THF / RT / 83 %

48S 49S

COOCH3

OH

*Ph *

*

50S

COOH

OH

*Ph

47S (+)-(S)-mandelic acid

1.62 eq

cat. TosOH / MeOH / RT / 89 - 95 %

H3CO OCH3

Ph

OCH3

O

1.05 eq Ph2PCl /1.11 eq NEt3

THF / 60° C / 85 %

PPh2*

51S

62 % after recryst.

53R

COOCH3

O

P

Ru

ClCl

Ph

Ph

52S not isolated!

PhH3CO *

(S)

120° C

11 h

1) RT / 20 min.

in situ η6-arene exchangein pressure Schlenk tube

0.49 eq 7 / CH2Cl2 : THF= 20 : 1

Pic. 4.1.2 Synthesis of [σ(P):η6-(arene-ansa-phosphinite)]Ru(II) template 53R via in situ η6-arene

exchange with labile {[η6-(PhCOOCH3)]Ru(II)Cl}2(µ-Cl)2 7.

- 124 -

Standard lithium alanate reduction of crude 49S [46 (3-4)] lead to the chiral ansa-

ligand frame 50S in 83 % yield after distillation. Chiral β-methoxyalcohol 50S can be

alternatively obtained from epoxide ring opening [46 (5-6)] and is also commercially

available, but very expensive. Finally the chiral ansa-phosphinite arene ligand 51S

was obtained on a 5 - 6 g scale of 50S by simple base promoted alcoholysis with

chlorodiphenylphosphine in 85 % yield, which is airstable and not moisture sensitive

towards hydrolysis.

In analog reactions [36 (3-8, 10)] the phosphine adducts with Ru(II) η6-arene

exchange reagent 7 were isolated prior to the actual exchange reaction. To prevent

yield losses accompanied with prior adduct isolation ligand 51S was directly

subjected to an in situ tandem coordination arene exchange reaction (Pic. 4.1.2) in a

pressure Schlenk tube. The coordination of 51S with dimer 7 to adduct 52S was

followed by 31P-NMR. After complete coordination the resulting clear deep red

solution was simply stirred at 120° C under pressure until the 31P-NMR signal of 52S

disappeared: 31P{1H}-NMR (CDCl3, 109 MHz): δ = 116.47 (s, 1P, 51S); 109.95 (s, 1P,

52S); 125.08 (s, 1P, 53R). For this reaction a CH2Cl2 : THF = 20 : 1 solvent mixture

was found to be optimal. After recrystallization 53R was obtained in 62 % yield. Note

the denotation of the absolute configuration of the chiral center of the ansa-arene

complex 53R changes formally to (R)! Single crystals suitable for X-ray diffraction

structure analysis were grown by slow evaporation from CH2Cl2 (Pic. 4.1.3, Table

4.1.1).

Compared to Pinto's analog ansa-phosphine complex [36 (6-7)] (Chapter 1.5, Pic.

1.5.2) the methoxy group adopts not truly an exo- but rather an "out of plane"

conformation to the η6-arene Ru(II) fragment forcing the ansa chain into a chair-like

conformation, which in turn geometrically fixes the phosphinite coordination mode in

that way one phenyl group adopts a fixed axial (ax) and the other a fixed equatorial

(eq) position. However, this steric effect is also slightly decreased due to the higher

rotational flexibility of the methoxy compared to the methyl group in Pinto's complex.

Nevertheless both phenyl rings are clearly distinguishable in the 13C-NMR spectrum

at ambient temperature by giving rise to two sets of signals for each phenyl ring.

Therefore it can be concluded this chair-like conformation is also fixed in solution for

53R.

- 125 -

Pic. 4.1.3 Thermal ellipsoid plot (50 % probality) of molecular structure of chiral template

complex 53R, selected bond distances and angles see Table 4.1.1.

Interestingly the Ru(1)-Cl bond lengths of 2.41 Å are clearly elongated compared to

Pinto's complex with 2.22 Å in average, but the Ru(1)-P(1) bond with 2.29 Å is only

slightly shorter than 2.32 Å of the complex compared. Therefore it can be concluded

that for 53R the Ru(1) - Cl bonds are weakened, while the Ru(1) - P(1) bond is

strengthened compared to Pinto's complex. Also the trans influence of the

phosphinite ligand on C(2) and C(3) of the η6-arene ligand seems to be retarded

compared to complex 20 (Table 4.1.1). A slight elongation is given for the C(8) - O(1)

bond with 1.45 Å compared to C(7) - O(2) with 1.42 Å and to C(9) - O(2) with 1.43 Å.

Therefore a slight destabilization of the C(8) - O(1) bond can be diagnosed. These

differences compared to Pinto's analog complex are clear evidences the phosphinite

here is a slightly weaker π-acceptor but a slightly better σ-donor ligand than the

phosphine. This is in full accordance with the ndd-donor synergism compensating the

dσ*-acceptor effect presented as a hypothetic model (Pic. 4.1.4).

- 126 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.4079(8) Cl(1) - Ru(1) - Cl(2) 86.51(3)

Ru(1) - Cl(2) 2.4089(8) P(1) - Ru(1) - Cl(1) 89.20(3)

Ru(1) - P(1) 2.2928(8) P(1) - Ru(1) - Cl(2) 90.90(3)

Ru(1) - C(1) 2.185(3) P(1) - Ru(1) - C(1) 117.36(2)

Ru(1) - C(2) 2.290(3) P(1) - Ru(1) - C(2) 154.82(9)

Ru(1) - C(3) 2.289(3) P(1) - Ru(1) - C(3) 152.12(9)

Ru(1) - C(4) 2.184(3) P(1) - Ru(1) - C(4) 114.54(9)

Ru(1) - C(5) 2.187(3) P(1) - Ru(1) - C(5) 88.3(2)

Ru(1) - C(6) 2.213(3) P(1) - Ru(1) - C(6) 89.71(9)

P(1) - O(1) 1.634(2) C(9) - O(2) - C(7) 113.2(3)

C(8) - O(1) 1.446(4) C(6) - C(7) - O(2) 111.5(3)

C(7) - C(8) 1.509(5) C(6) - C(7) - C(8) 112.3(3)

C(6) - C(7) 1.520(5) C(7) - C(8) - O(1) 110.4(3)

C(7) - O(2) 1.419(4) C(8) - O(1) - P(1) 118.6(2)

C(9) - O(2) 1.431(4) O(1) - P(1) - Ru(1) 111.05(8)

Table 4.1.1 Selected bond distances and angles of chiral template 53R.

M P

R

O

dd σ* acceptor mode

R R'

M P

R

O

Rσ*

d full d emptyd empty d empty

n full

dd n donor mode

R'

M P

R

OR'

R

d full

d σ* acceptor mode metalla Arbusov - Michaelis Reaction

L4Ru P

OH3C

OCH3

OCH3(0)L4Ru P

O

OCH3

OCH3

CH3

(II)

150° C

L = P(OCH3)3

σ*

Pic. 4.1.4 ndd-donor, dσ*- and ddσ*-acceptor synergism models for phosphorous ligands.

- 127 -

Delocalization of the nonbonding O(1) orbital electrons of 53R into an empty metal d

orbital via the empty P(1) d orbital leads to a ndd-donor mode, which decreases the

π-acceptor capability of the phosphinite ligand given by the dσ*-acceptor mode.

However, the π-acceptor capability can only be partially compensated, since 51S is

still capable to undergo the arene exchange reaction to 53R. In the ddσ*-acceptor

mode electrons of a filled metal d orbital are delocalized into the antibonding CO

orbital. This effect is only observed for metals in an unusual low oxidation state in full

accordance with certain metalla Michealis - Arbusov reaction types as chemical

argument [45 (3)], which lead to a carbocation migration to the metal in the sense of

an intramolecular oxidative addition driven by the oxophilicity of phosphorous.

Following the proposed (pre)catalyst design (Pic. 1.5.6) template 53R was subjected

to nucleophilic substitution reactions of one chloride ligand at the diastereotopic

Ru(II) center with various primary amines leading to an additional chiral center on the

metal (Pic. 4.1.5). Template 53R is not well solulable in MeOH, so the substitution

reactions had to be performed in MeOH / CH2Cl2 mixtures with NaPF6 as chloride

trapping reagent. The solvent ratios were adjusted to optimum selectivity and

conversion. As primary amines were chosen: aniline, because Pinto reports 25 %

e.e. for her corresponding complex (Pic. 1.5.9) [36 (6-7)] as transfer hydrogenation

catalyst; p-fluoroaniline to check for possible electronic effects; then finally (R)- and

(S)-1-phenylethylamine to see, if there were match and mismatch effects concerning

diastereoselectivity and to check the enantiopurity of template 53R at the same time.

While Pinto reports definite diastereoselectivities a rather peculiar behavior is

observed for the amine substitution reactions examined here (Pic. 1.4.5). From

aliquots directly taken out of the reaction solutions and subjected to 1H- and 31P-NMR

measurements (Chapter 4.3 for 1H- and 31P-NMR signal assignment) only for aniline

and p-fluoroaniline complexes 54R - 55R a moderate to high d.e. could be

determined, but almost no or not at all for the complexes 56RR - 56RS with (R)- and

(S)-1-phenylethylamine as ligands. Interestingly after workup partial or complete

epimerization at the chiral Ru(II) center was observed except for 56RR, where

starting diastereomer enrichment was noticed after workup. Because quantitative

crude yields were obtained solvent dependent crystal packing effects can be

proposed, leading to diastereomer enrichment for 54R (in CH2Cl2) and 56RR (in

MeOH), but total epimerization for 55R (in MeOH).

- 128 -

O

P

Ru

ClCl

Ph

Ph

OCH3

(R)*

OP

RuCl

H2NPh

Ph

O

*

(R)

PF6(S)

unlike

*

1 - 2 eq RNH2 /excess NaPF6

MeOH / CH2Cl2 / RT53R

R

like

PF6O

P

Ru

H2NCl

O*

(R)

(R)

R

*

H

Ph

Ph

CH3

54R R = Ph 55R R = (p-F)C6H4

56RR R = (R)-C*H(CH3)Ph56RS R = (S)-C*H(CH3)Ph

CH3

complex 31P{1H}.NMR

δ [ppm]

d.e.

final yield (after recrystallization for 54R -

56RR and crush out for 56RS)

54R 131.75 l 1)

131.05 u 1)

> 99 % d.e. l before workup;

74 % d.e. l after workup

72 %, > 99 % d.e. like instable!

55R 133.29 l 2)

129.83 u 2)

66 % d.e. l before workup;

no d.e. after workup in some

batches

51%, no d.e.!

like : unlike = 1 : 1

56RR 135.29 ll 3)

132.19 ul 3)

no d.e. before workup in some

batches; 7 % d.e. ul after workup

27 %, > 99 % d.e. unlike - like stable!

56RS 133.77 3)

129.16 3)

no d.e. before and after workup 27 %, no d.e.! like - unlike :

unlike - unlike = 1 : 1

Pic. 4.1.5 Formation and diastereoselectivities of diastereomeric complexes 54R - 56RS; NMR:

1) (acetone-d6, 121 MHz), 2) (CDCl3, 109 MHz), 3) (acetone-d6, 109 MHz) with PF6-

counter anion as internal reference standard.

- 129 -

This behavior is already diagnostic for a potentially low inversion barrier at the chiral

Ru(II) center of the diastereomeric {[σ(P):η6-(arene-ansa-phosphinite)] Ru(II) amino}

complexes 54R - 56RS, which is obviously solvent dependent in solution. Although

the NMR samples were prepared and measured quickly low inversion barriers at the

chiral Ru(II) centers cause analytical variations for sure (for important details of

sample preparation see Chapter 7.4.6). Therefore the measured d.e. values in the

table (Pic. 4.1.5) should be rather seen as a tendency only.

Amino complexes 54R - 56RR crystallized nicely to homogenous, well defined

crystalline material purified in this way, which was also suitable for X-ray diffraction

structure analysis: Complex 54R crystallized exclusively as the like diastereomer (Pic

4.1.7, Table 4.1.2, Table 4.1.2), 55R in a 1 : 1 ratio of the like and unlike (Pic. 4.1.8,

Table 4.1.4, Table 4.1.5, Table 4.1.6) and 56RR exclusively as the unlike-like

diastereomer again (Pic. 4.1.9, Table 4.1.7, Table 4.1.8). Complex 56RS crushed

only out as 1: 1 mixture of a pair of diastereomers by NMR and CD (Chapter 4.2),

showing clearly a "diastereomeric mismatch effect" of the chiral amine ligand, but

only in the crystallization behavior. Eventually from one batch some single crystals of

56RS could be obtained which consisted of the like-unlike diastereomer only (Pic.

4.1.10, Table 4.1.9, Table 4.1.10). Furthermore aliquots taken out of the reaction

mixtures showed only two 31P-NMR signals each for 56RR and 56RS corresponding

each to two pairs of diastereomers. Because for 56RR and 56RS the common

enantiomerically pure amine ligand but with opposite absolute configuration was

chosen, accidental isochrony as a counterargument is excluded by a minimum of

probality. In this way the enantiopurity of template 53R is proven indirectly in a bare

chemical way. The preservation of the original (R) configuration of the chiral benzylic

center of the ansa chain was also confirmed by X-ray diffraction structure analysis

and by CD (Chapter 4.2) for all complexes 54R - 56RS. The absolute and preserved

configurational integrity of the benzylic center is therefore with three physically

independent methods and one chemical method beyond any reasonable doubt.

The unlike-like diastereomer of 56RR did not epimerize in acetone-d6 and other

solvents over periods of weeks. It is therefore thermodynamically stable. The

configurative stability of 56RR is in full agreement with Pinto's analog unlike {[σ(P):η6-

(arene-ansa-phosphine)] Ru(II) amino complexes [36 (6-7)] (Chapter 1.5, Pic. 1.5.9).

- 130 -

The crystal structure of 56RR unlike-like (Pic. 4.1.9) shows clearly the methoxy group

adopts a sterically favored "out of plane" conformation to the η6-arene Ru(II)

fragment again (compare 53R, Pic. 4.1.3). This stabilizes the very favorable chair-like

conformation of the ansa chain in consequence, which in turn geometrically fixes the

phosphinite coordination mode in that way also one phenyl group adopts a fixed axial

(ax) and the other a fixed equatorial (eq) position. Coordinating from the Si face the

amine ligand adopts the position with the longest distance to the equatorial phenyl

ring with a minimum of steric repulsion. Therefore it is generalized diastereomeric

{[σ(P):η6-(arene-ansa-phosphinite)] Ru(II) amino complexes based on template 53R

with the absolute configuration (S) of the Ru(II) center and the absolute configuration

(R) of the chiral benzylic center in the relative diastereomeric relation unlike to each

other are thermodynamically favored over the related like diastereomer.

Complementary 54R like epimerized within hours at ambient temperature in acetone-

d6 to the unlike diastereomer (Chapter 4.2 and 4.3), so it is obviously the less

thermodynamically favorable diastereomer. The crystal structure of 54R (Pic. 4.1.7)

with the absolute configuration (R) of the Ru(II) center shows clearly the methoxy

group adopts the sterically unfavored "in plane" conformation to the η6-arene Ru(II)

fragment. Also in this case a favorable chair-like conformation of the ansa chain is

fixed, but with a stronger strain compared to 56RR. Therefore the phosphinite

coordination geometry is also fixed in an "ax-eq" mode, but with opposite

diastereotopic orientation causing the amine to coordinate from the Re face here, but

again with a minimum of steric repulsion. If the methoxy group would adopt an "out of

plane" conformation just by a conformational change, then the ansa chain would

have to escape into a very strained "all-twist" conformation to preserve a least steric

repulsion with the amine ligand with the two phenyl rings of the phosphinite moiety in

apical position, then. But if the ansa chain would escape just into the opposite chair-

like conformation, then the phenyl rings would also exchange their equatorial and

axial position with each other and now the amine ligand would be in the shortest,

sterically very unfavorable position to the now equatorial phenyl ring. Therefore the

like diastereomer of 54R can only escape from its configurational and fixed

conformational dilemma by epimerization, which explains well its configurational

metastability (see determination of inversion barrier in Chapter 4.3).

- 131 -

These stereochemical considerations can be generalized by referring to the crystal

structure of 55R (Pic. 4.1.8), where both like and unlike diastereomers are present in

one crystal unit cell. 55R like adopts exactly the same conformation like 54R like and

56RS like-unlike and 55R unlike the same conformation like 56RR unlike-like. In all

cases of the like diastereomers the methyl group of the methoxy moiety "turns away"

from the η6-arene ring leaving all steric interactions to the oxygen atom alone.

Because the volume of a methyl group is larger than the one of an oxygen atom it is

no wonder why Pinto observed exclusively the formation of the like in high favor over

the unlike diastereomer of her analog complexes (Chapter 1.5, Pic. 1.5.9) [36 (6-7)].

Complementary it can now be understood, why the configurationally instable like

diastereomer of 54R can be isolated at all.

Contrary and fully unexpected to Pinto's analog systems [36 (6-7)] the unfavored like

diastereomers of 54R and 55R are formed under kinetic conditions. In no case the

formation of the unlike diastereomers was preferred. Only a 1 : 1 diastereomer

mixture for 56RR and 56RS resulted. The direction of the kinetic diastereoselectivity

depends therefore only from the nature of the template 53R, while its magnitude is

determined by the nature of the amine ligand.

If one considers an SN1-type reaction mode via cationic 16 VE {[σ(P):η6-(arene-ansa-

phosphinite)] Ru(II) intermediates by loss of one chloride ligand (Chapter 1.5, Pic.

1.5.8) [36 (6-7)] with a conformational geometry resembling the ansa-phosphinite

coordination modes given by the molecular structures in solid state, then two

intermediates with an "out of plane" and "in plane" conformation of the methoxy

group for each of these intermediates can be formulated (Pic. 4.1.6). Certainly it is

then expected the cationic intermediate with the sterically preferred "out of plane"

conformation will dominate in the reaction solution, promote a sterically favored Si

face attack of the incoming amine ligand, which in turn should lead to the formation of

the more stable unlike amine complex diastereomer. For the intermediate with the "in

plane" conformation a preferred Re face attack of the incoming amine ligand leading

to the less stable like diastereomer should be given in turn. If there are no other

interactions, then for both intermediates a nearly equivalent geometric trajectory is

obvious for the incoming amines from the particularly sterically preferred faces of

attack. So the diastereomeric excess should be only determined by the ratio of the "in

- 132 -

plane" and "out of plane" conformers of the pseudo trigonal planar cationic

intermediates. The diastereoselectivity is then expected to be in favor of the unlike

amine complex diastereomer in accordance to Pinto's reports [36 (6-7)].

However, the observed putatively contrary diastereoselectivities can be explained by

a delivery effect complemented in literature in other variations for chromium(0)

tricarbonyl η6-arene complexes [46 (7-8)]: The methoxy group forms possibly a

hydrogen bond with the approaching amine, which can only by delivered to the Ru(II)

center by twisting into an "in plane" conformation. Such a delivery effect should

increase with the strength of the hydrogen bond, which in turn should increase with

the acidity of the nitrogen protons. A strengthening of the hydrogen bond should

result in an increased nucleophilicity of the nitrogen atom by a stronger negative

polarization. The decreasing acidities of aniline (pKA ~ 25) > p-fluoroaniline > 1-

phenylethylamine (pKA ~ 34) correlate with the observed diastereoselectivities.

This argumentation does not contradict Pinto's reports [36 (6-7)], because her

reported selectivities base on bare steric arguments. It should be emphasized at this

point this delivery effect hypothesis is only based on geometrical aspects given by

the molecular structures in solid state and by the diastereoselectivities themselves in

only four cases. Further investigations to confirm this hypothetic but plausible

explanation of these surprising diastereoselectivities could be only revealed by

further experiments or DFT calculations of the energy profiles of the cationic 16 VE

{[σ(P):η6-(arene-ansa-phosphinite)] Ru(II) intermediates and of possible hydrogen

bridged amine species as well.

- 133 -

unlike Si sterically favored

eq

ax

Re

Ru

Cl

P

O

H

Ph* O

CH3

Cl

Ru

RH2N P Pheq

O

H

Phax *

*

O

CH3

"out of plane"

Ru

Cl

P

O

* O

HCH3

Ph

NH2R

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

Si

eq

ax

sterically favored

Re

"in plane"

(RRu)

(SRu)

like

OP

RuCl

Ph

Ph

O

(R) *

H3C

N

H

H

Re

Delivery Effect??

Ru

Cl

P

O

* O

HCH3

Ph

eq

ax

Re

"in plane"

H

N

Ph

H

+ PhNH2

=

Pic. 4.1.6 Permutations of nucleophilic ligand attack on proposed cationic 16 VE {[σ(P):η6-

(arene-ansa-phosphinite)] Ru(II) intermediates and proposed delivery effect (top

views).

- 134 -

Pic. 4.1.7 Thermal ellipsoid plot (50 % probality) of molecular structure of like complex cation

54R; selected bond distances and angles see Table 4.1.2 and for hydrogen bonding

see Table 4.1.3.

Only like diastereomer! (PF6

- omitted for clarity)

ax

eq

(RRu)

(R)

methoxy group “in plane”

priority for chiral Ru(II) center: Cl > P > N > η6-phenyl

relative configuration: like

top view on η6-phenyl moiety of complex cation 54R

(hydrogen atoms partially omitted for clarity)

- 135 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.3958(6) Cl(1) - Ru(1) - P(1) 86.99(2)

Ru(1) - P(1) 2.2944(6) Cl(1) - Ru(1) - N(1) 82.62(5)

Ru(1) - N(1) 2.183(2) P(1) - Ru(1) - N(1) 90.73(5)

Ru(1) - C(1) 2.197(2) P(1) - Ru(1) - C(2) 154.33(6)

Ru(1) - C(2) 2.288(2) P(1) - Ru(1) - C(3) 152.73(6)

Ru(1) - C(3) 2.278(2) N(1) - Ru(1) - C(4) 153.49(8)

Ru(1) - C(4) 1.192(2) N(1) - Ru(1) - C(5) 157.47(7)

Ru(1) - C(5) 2.194(2) Cl(1) - Ru(1) - C(1) 155.46(6)

Ru(1) - C(6) 2.194(2) Cl(1) - Ru(1) - C(6) 157.73(6)

P(1) - O(1) 1.623(2) C(9) - O(2) - C(7) 115.2(2)

C(8) - O(1) 1.444(3) C(6) - C(7) - O(2) 106.8(2)

C(7) - C(8) 1.523(3) C(6) - C(7) - C(8) 114.1(2)

C(6) - C(7) 1.524(3) C(7) - C(8) - O(1) 113.3(2)

C(7) - O(2) 1.417(3) C(8) - O(1) - P(1) 119.3(2)

C(9) - O(2) 1.419(3) O(1) - P(1) - Ru(1) 111.94(6)

N(1) - C(31) 1.456(3) Ru(1) - N(1) - C(31) 117.2(2)

Table 4.1.2 Selected bond distances and angles of complex cation 54R.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1A)...F(25) 0.89(3) 2.24(3) 3.059(2) 154(3)

Table 4.1.3 Hydrogen bond between complex cations and PF6

- in 54R.

- 136 -

Pic. 4.1.8 Thermal ellipsoid plot (50 % probality) of molecular structure of diastereomeric

complex cations of 55R; selected bond angles and distances see Table 4.1.4 (like),

Table 4.1.5 (unlike) and for hydrogen bonding Table 4.1.6.

ax

eq

eq

ax

like

unlike

Unit cell of 55R (PF6- and

“half” MeOH molecule omitted for clarity)

like

unlike

(RRu)(R) methoxy group

“in plane”

(R)

(SRu)methoxy group“out of plane”

top views on η6-phenyl moieties of diastereomeric complex cations of 55R (hydrogen atoms omitted for clarity)

- 137 -

distances [Å] angles [ °]

Ru(2) - Cl(2) 2.396(2) Cl(2) - Ru(2) - P(2) 86.37(5)

Ru(2) - P(2) 2.287(2) Cl(2) - Ru(2) - N(2) 83.2(2)

Ru(2) - N(2) 2.181(4) P(2) - Ru(2) - N(2) 87.6(2)

Ru(2) - C(41) 2.219(6) P(2) - Ru(2) - C(42) 149.7(2)

Ru(2) - C(42) 2.262(5) P(2) - Ru(2) - C(43) 158.4(2)

Ru(2) - C(43) 2.235(6) N(2) - Ru(2) - C(44) 150.4(2)

Ru(2) - C(44) 2.197(6) N(2) - Ru(2) - C(45) 161.4(2)

Ru(2) - C(45) 2.212(5) Cl(2) - Ru(2) - C(41) 160.8(2)

Ru(2) - C(46) 2.222(5) Cl(2) - Ru(2) - C(46) 151.5(2)

P(2) - O(3) 1.624(4) C(49) - O(4) - C(47) 114.8(4)

C(48) - O(3) 1.446(6) C(46) - C(47) - O(4) 108.1(4)

C(47) - C(48) 1.534(6) C(46) - C(47) - C(48) 113.5(4)

C(46) - C(47) 1.525(8) C(47) - C(48) - O(3) 111.4(4)

C(47) - O(4) 1.415(5) C(48) - O(3) - P(2) 117.2(3)

C(49) - O(4) 1.437(6) O(3) - P(2) - Ru(2) 112.2(2)

N(2) - C(71) 1.468(7) Ru(2) - N(2) - C(71) 117.9(3)

F(2) - C(74) 1.366(6)

Table 4.1.4 Selected bond distances and angles of like complex cation of 55R.

- 138 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.387(2) Cl(1) - Ru(1) - P(1) 86.76(5)

Ru(1) - P(1) 2.294(2) Cl(1) - Ru(1) - N(1) 82.9(2)

Ru(1) - N(1) 2.154(4) P(1) - Ru(1) - N(1) 88.3(2)

Ru(1) - C(1) 2.176(5) P(1) - Ru(1) - C(2) 153.5(2)

Ru(1) - C(2) 2.275(5) P(1) - Ru(1) - C(3) 155.9(2)

Ru(1) - C(3) 2.302(5) N(1) - Ru(1) - C(4) 152.9(2)

Ru(1) - C(4) 2.200(6) N(1) - Ru(1) - C(5) 158.8(2)

Ru(1) - C(5) 2.201(6) Cl(1) - Ru(1) - C(1) 156.5(2)

Ru(1) - C(6) 2.176(5) Cl(1) - Ru(1) - C(6) 156.3(2)

P(1) - O(1) 1.622(4) C(9) - O(2) - C(7) 114.2(4)

C(8) - O(1) 1.449(6) C(6) - C(7) - O(2) 108.7(4)

C(7) - C(8) 1.528(6) C(6) - C(7) - C(8) 115.9(4)

C(6) - C(7) 1.502(7) C(7) - C(8) - O(1) 111.6(4)

C(7) - O(2) 1.409(5) C(8) - O(1) - P(1) 119.7(3)

C(9) - O(2) 1.423(6) O(1) - P(1) - Ru(1) 112.6(2)

N(1) - C(31) 1.455(7) Ru(1) - N(1) - C(31) 116.2(3)

F(1) - C(34) 1.377(5)

Table 4.1.5 Selected bond distances and angles of unlike complex cation of 55R.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1B)...F(32) #1 0.92 2.10 2.989(6) 161.5

N(2) - H(2B)...F(41) #2 0.92 2.07 2.993(6) 176.3

O(100) - H(100)..Cl(1) 0.84 2.52 2.314(5) 158.7

Table 4.1.6 Hydrogen bonds between complex cations, MeOH and PF6

- in 55R (#1: x+1, y, z; #2:

x-1, y, z).

- 139 -

Pic. 4.1.9 Thermal ellipsoid plot (50 % probality) of molecular structure of unlike-like complex

cation 56RR; selected bond distances and angles see Table 4.1.7 and for hydrogen

bonding see Table 4.1.8.

Only unlike - like diastereomer! (PF6

- and one MeOH molecule omitted for clarity)

ax

eq (R)

unlike - like

(SRu)

(R)

methoxy group “out of plane”

top view on η6-phenyl moiety of diastereomeric complex cation of 56RR (hydrogen atoms omitted for clarity)

- 140 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.414(2) Cl(1) - Ru(1) - P(1) 86.60(5)

Ru(1) - P(1) 2.293(2) Cl(1) - Ru(1) - N(1) 87.4(2)

Ru(1) - N(1) 2.183(4) P(1) - Ru(1) - N(1) 91.2(2)

Ru(1) - C(1) 2.216(5) P(1) - Ru(1) - C(2) 151.6(2)

Ru(1) - C(2) 2.284(5) P(1) - Ru(1) - C(3) 155.6(2)

Ru(1) - C(3) 2.292(5) N(1) - Ru(1) - C(4) 149.3(2)

Ru(1) - C(4) 2.207(5) N(1) - Ru(1) - C(5) 158.5(2)

Ru(1) - C(5) 2.216(5) Cl(1) - Ru(1) - C(1) 158.6(2)

Ru(1) - C(6) 2.224(5) Cl(1) - Ru(1) - C(6) 151.1(2)

P(1) - O(1) 1.625(4) C(9) - O(2) - C(7) 115.3(5)

C(8) - O(1) 1.435(7) C(6) - C(7) - O(2) 111.6(5)

C(7) - C(8) 1.501(8) C(6) - C(7) - C(8) 111.9(4)

C(6) - C(7) 1.525(7) C(7) - C(8) - O(1) 111.5(5)

C(7) - O(2) 1.420(7) C(8) - O(1) - P(1) 120.3(3)

C(9) - O(2) 1.412(8) O(1) - P(1) - Ru(1) 112.7(2)

N(1) - C(30) 1.502(7) Ru(1) - N(1) - C(30) 121.5(3)

Table 4.1.7 Selected bond distances and angles of complex cation 56RR.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1B)...F(26) 0.92 2.33 3.244(5) 171.8

N(1) - H(1B)...F(23) 0.92 2.53 3.073(6) 118.4

Table 4.1.8 Hydrogen bond between complex cations and PF6

- in 56RR.

- 141 -

Pic. 4.1.10 Thermal ellipsoid plot (50 % probality) of molecular structure of like-unlike cation of crystal

examined from diastereomeric 1 : 1 mixture of 56RS; selected bond distances and angles

see Table 4.1.9 and for hydrogen bonding see Table 4.1.10.

Only like - unlike diastereomer in crystal examined, but 1 : 1 mixture obtained after purification!!

(PF6- omitted for clarity)

eq

ax

(S)

like - unlike methoxy group“in plane”

(R)

top view on η6-phenyl moiety of diastereomeric complex cation of 56RS

(hydrogen atoms omitted for clarity)

(RRu)

- 142 -

distances [Å] angles [ °]

Ru(1) - Cl(1) 2.4038(7) Cl(1) - Ru(1) - P(1) 87.61(3)

Ru(1) - P(1) 2.2928(7) Cl(1) - Ru(1) - N(1) 81.83(7)

Ru(1) - N(1) 2.150(2) P(1) - Ru(1) - N(1) 89.08(7)

Ru(1) - C(1) 2.184(3) P(1) - Ru(1) - C(2) 153.65(8)

Ru(1) - C(2) 2.261(3) P(1) - Ru(1) - C(3) 156.38(8)

Ru(1) - C(3) 2.266(3) N(1) - Ru(1) - C(4) 150.8(1)

Ru(1) - C(4) 2.211(3) N(1) - Ru(1) - C(5) 159.89(9)

Ru(1) - C(5) 2.218(3) Cl(1) - Ru(1) - C(1) 156.07(8)

Ru(1) - C(6) 2.202(3) Cl(1) - Ru(1) - C(6) 156.06(7)

P(1) - O(1) 1.621(2) C(9) - O(2) - C(7) 113.1(2)

C(8) - O(1) 1.445(4) C(6) - C(7) - O(2) 110.2(2)

C(7) - C(8) 1.527(4) C(6) - C(7) - C(8) 114.2(2)

C(6) - C(7) 1.527(4) C(7) - C(8) - O(1) 113.2(2)

C(7) - O(2) 1.428(3) C(8) - O(1) - P(1) 119.3(2)

C(9) - O(2) 1.432(4) O(1) - P(1) - Ru(1) 112.74(9)

N(1) - C(30) 1.504(3) Ru(1) - N(1) - C(30) 124.8(2)

Table 4.1.9 Selected bond distances and angles of like-unlike complex cation of 56RS.

distances

D-H...A

d(D-H)

[Å]

d(H...A)

[Å]

d(D...A)

[Å]

angles (DHA) [°]

N(1) - H(1B)...F(24) #1 0.92 2.08 2.962(3) 158.9

Table 4.1.10 Hydrogen bond between complex cations and PF6

- in 56RS (#1: x+1, y, z).

- 143 -

4.2 Circular Dichroism Study

UV and CD spectra of recrystallized complexes 53R, 54R, 55R, 56RR and 56RS

were recorded in the 210-600 nm range in methanol (Table 8.0.1 and separate CD

spectra in Chapter 8, Pic. 4.2.1, Pic. 4.2.2), in order to get further information about

absolute and relative configuration at the chiral centers of these complexes also in

solution and deeper insight into the epimerization process of 54R like physically

independent from NMR (Chapter 4.3). The UV spectrum of 53R (Table 8.0.1 in

Chapter 8) shows two absorption bands at 473 and 353 nm which, from intensity and

energy position can be ascribed to either d-d and MLCT transitions [46 (9-10)],

followed by a more intense absorption band at 228 nm. The CD spectrum of 53R

(Pic. 4.2.1) shows four main Cotton effects at 475 nm (∆ε -0.25), 389 nm (∆ε 0.81),

316 nm (∆ε -0.32), and 258 nm (∆ε -0.79) which, apart from the lower energy band,

are not situated at the same wavelength as the UV absorption bands. All these CD

signals can be ascribed to the chiral Ru(II) η6-arene chromophore, because in the

observed spectral range the free aromatic ligand shows only very low CD signals [46

(11)]. It is interesting to note that the same sequence of CD bands with nearly the

same intensity, and wavelength position is displayed by Brunner's [46 (12)] and

Marconi's [35 (4-5] Ru(II) η6-arene complexes having a benzylic chiral center on the

η6-arene moiety. Moreover in all these complexes a correspondence between the

sign of the CD bands and the absolute configuration at the benzylic carbon can be

empirically observed. The CD spectrum of 54R (99% d.e.) displays Cotton effects

(Pic. 4.2.2) at 461 nm (∆ε 1.18), 404 nm (∆ε -3.05), 350 nm (∆ε 3.72), 295 nm (∆ε -

5.45), and 240 nm (6.55). These bands, which are about five times more intense than

for 53R, are clearly only due to the presence of the additional (R) configurated chiral

Ru(II) center and completely overlap those due to the chiral η6-arene chromophore,

then confirming that the high diastereomeric purity of 54R obtained after

crystallization is retained also in methanol solution. The CD analysis of 55R (1:1

diastereomeric mixture) (Pic. 4.2.1) showed complete epimerization at the metal

center, but retaining of the absolute configuration at the benzylic carbon. Its CD

spectrum, in fact, showed the same band sequence of 53R, with the same sign and

signal intensity, although with a 30 nm hypsochromic shift, due to the presence of a

different ligand at the metal. Interestingly, the CD spectrum of 54R re-recorded after

- 144 -

some days was almost superimposable to the spectrum of 55R, showing only the

bands due to the chiral arene chromophore and the disappearance of the bands

allied to the metal chiral center. Such observation points out that 54R like is

configurationally unstable also in methanol, undergoing complete epimerization at the

Ru(II) center and complete retention of (R) absolute configuration at the benzylic

carbon. The CD spectrum of 56RR (99 % d.e. unlike-like) (Pic. 4.2.2) was in an

almost mirror image relationship with the one of 54R (99 % d.e. like), revealing an

opposite absolute (S) configuration at the chiral Ru(II) center in this complex. Also in

this case the Cotton effects in the CD spectrum are only due to the chirality at the

Ru(II) center, because the chiral (R)-1-phenylethylamine ligand displays only very

weak CD signals in the observed spectral range [46 (11, 13)]. Probably, only the

strong negative Cotton effect at 233 nm can result from a partial contribution of the

chiral amine chromophore, being in correspondence to the absorption band at 228

nm in the UV spectrum, which could be ascribed to a bathochromic shifted 1La

aromatic transition of the amine [46 (13)]. Differently from 54R, CD spectrum of 56RR

appeared unchanged even after one month on standing, revealing the high

configurational stability of this complex in methanol solution. Finally, the CD spectrum

of 56RS (1:1 diastereomeric mixture) (Table 8.0.1 in Chapter 8) appeared quite

similar, as intensity, position, and sign of the CD bands to the one of 55R, showing

then the presence of the sole chiral Ru(II) η6-arene chromophore, with retention of

benzylic absolute configuration, and complete epimerization at the metal center.

In conclusion, this CD analysis shows that: (i) as expected, in all the complexes

examined the absolute configuration at the benzylic chiral center is retained; (ii) the

complexes 54R (99 % d.e. like) and 56RR (99 % d.e. unlike-like) have opposite

absolute configuration at the chiral Ru(II) center; (iii) the crystallized samples of 55R

and 56RS shows complete epimerization at the chiral metal center; (iv) the like

diastereomer of complex 54R epimerizes at the metal center in methanol solution

while in the same conditions 56RR is configurationally stable.

- 145 -

λ / nm

-2

-1

0

1

2

600500400300

6

8

∆ε

Pic. 4.2.1 CD spectra of complexes 53R (bathochromic shift) and epimerized 55R in methanol.

λ / nm

-16

-8

0

8

16

600500400300

7l

9ul

∆ε

Pic. 4.2.2 CD spectra of complexes 54R (like) and 56RR (unlike-like) in MeOH; note opposite

Cotton effects due to opposite configurations (RRu) for 54R and (SRu) for 56RR.

54R

56RR

53R

55R

- 146 -

4.3 NMR Study and Epimerization Barrier

The assignments of the 1H-NMR and 13C-NMR signals belonging to the particular

diastereomers of the epimeric mixtures of 55R and 56RS were accomplished by

similarity correlation of NOE measurements of diastereomerically pure 54R. General

protocol was followed for correlative assignment: First NOE irradiation on one of the

methoxy singlet belonging to one diastereomer or NOESY crosspeaks allowed

unambiguously the identification of key 1H-NMR signals of the diastereotopic η6-

arene ortho protons, the chiral benzylic proton (η6-Ph)CH- of the ansa chain and

eventually protons of the amine ligand. In the next step the relative correlation of the 13C- to the 1H-NMR signals was accomplished by HMQC, allowing certainly also the

absolute assignment of the key 1H-NMR signals from NOE interactions to the

corresponding 13C-NMR signals at the same time. Now the correlation of all 1H- and 13C-NMR signals to and with each other was achieved by HMBC eventually

complemented with JHJH-FG-COSY. The support by HMBC was necessary to

establish connectivity between the ansa chain and the η6-arene 1H- and 13C-NMR

signals, because in the COSY spectrum these two sets of signals split in turn into two

separate spin coupling systems not related to each other. In this way each of the two

sets of 1H- and 13C-NMR signals could be assigned to one particular of the two

diastereomers present in epimeric mixtures of 55R and 56RS. It is important to

mention the 2D spectra were not symmetrized after the 90° mixing pulse and

detection, because this often causes misleading artifacts and pseudo crosspeaks

paid as high prize for aesthetic narcissism!

Once the absolute assignments of the methoxy 1H-singlets to the particular

diastereomers were established, the corresponding 31P- and 1H-signals of the NMR

spectra of aliquots taken out of the reaction solutions or of the crude products were

then correlated to each other by common integrals of same magnitude and the 31P-

NMR signals assigned to the particular diastereomer of relative configuration. Of

course this was not possible for 56RS, because it was found to be a 1 : 1 mixture of

diastereomers at all steps of the reaction and preparation (Pic. 4.1.5).

- 147 -

54R like (R) (RRu)NOE interactions by irridiation on 1l

"in plane"

NH2

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

OP

Ru

NH2 Cl

O*

Ph

*

HHH

H

H H

1l

2l3l

4l

5l 6l

7l

8Ph

CH3

H

H8

12

11

12

12

10

9

9

9

H

H

H

H

H

9

11

H

H

H

H

H HH

H H

H

1l

6l

5l

4l

3l

2l

7l

(top view on η6-phenyl moiety)

11 12

9

10 8 87l

1l

6l

3l

2l5l4l

9

6l

7l

acetone-d6

-NH2--NH2-

Pic. 4.3.1 NOE irradiation on methoxy singlet of 54R (acetone-d6, 500 MHz).

- 148 -

Pic. 4.3.2 NOE irradiations on methoxy singlets of 55R (acetone-d6, 500 MHz): 55R like (left

column), 55R unlike (right column).

Cl

Ru

NH2

P Pheq

O

H

Phax *

*

HH

H H

HO

1uCH3

2u or 6u

7u

5u or 3u4u

3u or 5u

10

10

9

9

6u or 2u

H

HH

H

F

55R like (R) (RRu)

NOE interactions by irridiation on 1l and 1u (top view on η6-phenyl moieties)

"in plane"

NH2

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

9 9

H

H

H

H

H

1l

6l

5l

4l

3l

2l

7l

F

H

H

H

H 1010

55R unlike (R) (SRu)

"out of plane"

1l 1u

10

9 9

10

15

15

15

15

8l + 8u 8l + 8u 8l + 8u 8l + 8u

7l

7l

7u

7u

7u 7l 6l

6l

6l 5l 2l

(2 or 6)u (6 or 2)u

(2 or 6)u (6 or 2)u

- 149 -

Pic. 4.3.3 6.8 – 4.3 ppm region of JHJH-FG-COSY spectrum of 55R like and 55R unlike

(acetone-d6, 500 MHz); for numbering see also Pic. 4.3.4 (a).

4l

4l

4u

4u 3l

3l

(3 or 5)u

(3 or 5)u

(2 or 6)u

(6 or 2)u

2l

5l

6l

(5 or 3)u

(5 or 3)u

(8l + 8u)

(8l + 8u)

(7l + 7u)

Cl

Ru

H2N P

R

Pheq

O

H

Phax *

*

HH

H H

HO

CH3

2u or 6u

6u or 5u

5u or 3u4u

3u or 5u

55R like 55R unlike

"in plane"

NH2R

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

H

H

H

H

H

1l

6l

5l4l

3l

2l

7l

"out of plane"

- 150 -

OP

RuCl

NH2

Ph

Ph

O

*

*

(p-F)C6H4

H H

H

CH3

HH

H

H H

1u

2u or 6u3u or 5u

4u

5u or 3u

6u or 2u

7u

8u

8u

15

15

ax

OP

Ru

NH2 Cl

O*

(p-F)C6H4

*

HHH

H

H H

1l

2l3l

4l

5l 6l

7l

8lPh

Ph

CH3

H

H8l

1515 ax

55R like (R) (RRu) 55R unlike (R) (SRu)

6l

2l

3l

4l5l

13l

"in plane"

NH2R

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

H

H

H

H

H

7l

Cl

Ru

RH2N P Pheq

O

H

Phax *

*

HH

H H

HO

H3C

2u or 6u

6u or 5u

5u or 3u4u

3u or 5u

13u

"out of plane"

(a)

(b)

Pic. 4.3.4 Extended numbering (a) and 3JH3JC-HMBC coupling pattern (b) of 55R like and 55R

unlike (acetone-d6, 500 MHz).

Cl

Ru

RH2N P Pheq

O

H

Phax *

*

HH

H H

HO

CH3

(3 or 5)u

(2 or 6)u

4u (5 or 3)u

(6 or2)u

1u

7u

*

11l

"in plane"

NH2

Ru

Cl

P

O

*

*

O

H

CH3

Pheq

Phax

H

H

H

H

H

1l

6l

5l

4l

3l

2l

7l

H CH3

Ph

56RS like-unlike (R) (RRu) (S) 56RS unlike-unlike (R) (SRu) (S)

NOESY interactions (top view on η6-phenyl moieties)

"out of plane"

Pic. 4.3.5 NOESY interactions of 56RS like-unlike and 56RS unlike-unlike (acetone-d6, 500

MHz; 2D spectrum not shown due to complexity).

- 151 -

Both, the like and unlike diastereomers of the amine complexes 54R - 56RS can be

well distinguished by NOE irradiation or by NOESY crosspeaks of the methoxy

singlets. Irradiation on one of the methoxy groups causes a NOE response only of

one of the two diastereotopic ortho protons of the η6-phenyl moiety. This is only

possible, if the methoxy group is "in plane" with the η6-phenyl moiety and in a

significant larger distance to the other diastereotopic ortho proton. Therefore this

particular methoxy singlet can only belong to the like diastereomer with the

corresponding 1H-NMR signal set for the η6-phenyl moiety and the responding ortho

proton must then be of the relative planar or acentral diastereotopicity unlike (Pic.

4.3.1, Pic. 4.3.2 and Pic. 4.3.4).

However, the irradiated methoxy group, which causes all of the two diastereotopic

ortho protons of the η6-phenyl moiety to interact, must then be in similar distance to

both of them, which is only possible if the methoxy group is an "out of plane"

conformation. Therefore this particular methoxy singlet can only belong to the unlike

diastereomer with the corresponding 1H-NMR signal set for the η6-phenyl moiety.

Nota bene the absence of a NOE is not per se an argument, but because the

absolute configuration of 54R is known to be (RRu, R) (to which all NMR

measurements were related) and because complexes or diastereomeric complex

mixtures 55R and 56RS show equivalent effects upon NOE irradiation, this

argumentation is here fully justified. Furthermore the distinct assignable NOE effects

to one diastereomer with particular relative configuration are also a clear evidence

the conformation of the ansa chain must be fixed and is not flexible, which would lead

otherwise to a response of all diastereotopic ortho protons of the η6-phenyl moiety for

both diastereomers. For 54R like and 56RS like-unlike NOE response was also

shown by the coordinated amine ligand, but not for 55R. This allowed in this way

total and absolute signal assignment of the diastereomers also for 56RS, although

consisting of a diastereomeric 1 : 1 mixture.

Finally the epimerization of 54R like in acetone-d6 was followed by time dependent 31P-NMR (Pic. 4.3.6). Note NMR cannot deliver information if epimerization occurs at

the chiral Ru(II) center or, although unlikely, at the chiral benzylic center of the ansa

chain, but exclusive epimerization at the Ru(II) center was physically independent

confirmed by CD (Chapter 4.2). For both, the decay of 54R like and the buildup of

- 152 -

54R unlike, equivalent but antipodal and concentration independent first order rates

were found within experimental error. Between 25° C and 50° C rates between 3.87 x

10-5 s-1 and 1.46 x 10-3 s-1 were found in average, from which two Eyring plots for the

decay and the buildup (Pic. 4.3.7) each were established. The average activation

enthalpy ∆H‡ = 112.5 kJ / mol and the average free activation energy ∆G‡ = 98.6 kJ /

mol from both plots are in good agreement. Naturally the determination of the

average activation entropy ∆S‡ = 23 - 67 J / mol K varies more for dimensional than

for statistical reasons.

From these data a bare dissociative mechanism can be excluded. In such a case

accumulation of an intermediate, an acetone adduct for example, would have been

observed. This would have disappeared later on during the course of the reaction.

Furthermore the buildup of 54R unlike would not be time parallel and not of first

order. The rate laws would be also concentration dependent. A Berry pseudo-rotation

[47 (1)] as a highly organized transition state accompanied with a negative activation

entropy can be excluded. Because the activation entropy does not exceed the one of

a truly bimolecular inversion pathway [47 (2-10)], the dissociative ligand position

exchange inside a solvent cage (Pic. 4.3.8) is the most likely one, although

complexes with aliphatic amine ligands usually do racemize via an intramolecular

bending mode [47 (8-9)].

Unfortunately epimerization rates could only be measured in polar solvents, because

recrystallized 54R is only sparingly solulable in CH2Cl2 and other less polar solvents.

Nevertheless there seems to be a qualitative solvent dependency of decreasing

epimerization rates in MeCN > acetone >> MeOH, supporting a dissociative inversion

pathway inside a solvent cage. Of course one is temptated by the asymptotic

behavior of the rate curves to postulate a relaxation into a thermodynamic

equilibrium. Unfortunately no crosspeaks in the 31P31P-EXSY could be found proving

the presence of such an epimerization equilibrium under these conditions for 54R

and 55R as well. However, the missing crosspeaks do not prove an epimerization

equilibrium does not exist, but only that spin polarization transfer is too slow on the

NMR time scale to be detected. Nevertheless the concentration of 54R unlike slightly

increases over the one of the like diastereomer in the asymptotic region of the rate

curves, confirming again clearly the unlike diastereomer is energetically favored.

- 153 -

Pic. 4.3.6 Kinetic study of epimerization at the chiral Ru(II) center of 54R like.

117118119120121122123124125126127128129130131132

(ppm)

like

like

unlike

unlike

OP

RuCl

PhH2NPh

Ph

OCH3

*

(R)

PF6(S)

54R unlike

*

54R like

PF6O

P

Ru

PhH2NCl

OCH3*

(R)

(R)

*

H

Ph

Ph

acetone-d6

Epimerization of 54R at 30° C within 17 h monitored with 31P-NMR (acetone-d6, 121 MHz; only every third peak presented for clarity) like : 131.75 ppm unlike : 131.05 ppm

time [s]

int. [like, unlike]

decay of like

buildup of unlike

d [like] / dt = - kl [like]

d [unlike] / dt = + ku [unlike] First order epimerization rates of 54R at 25° C with: + d [unlike] / dt = - d [like] / dt

- 154 -

0,00305 0,00310 0,00315 0,00320 0,00325 0,00330 0,00335

-16,0

-15,5

-15,0

-14,5

-14,0

-13,5

-13,0

-12,5

-12,0ln

(k/T

)

1/T [1/K]

0,00305 0,00310 0,00315 0,00320 0,00325 0,00330 0,00335

-16,0

-15,5

-15,0

-14,5

-14,0

-13,5

-13,0

-12,5

-12,0

ln(k

/T)

1/T [1/K]

decay of 54R like:

∆H‡ = (118 ± 1.0) kJ / mol∆S‡ = (67 ± 4.0) J / mol K∆G‡ = 97.8 – 98.2 kJ / mol

buildup of 54R unlike:

∆H‡ = (107 ± 0.4) kJ / mol∆S‡ = (23 ± 1.3) J / mol K∆G‡ = 99.8 kJ / mol

Pic. 4.3.7 Eyring plots of epimerization of 54R (∆H‡ from slope, ∆S‡ from axial section, ∆G‡

calculated from ∆H‡ and ∆S‡).

- 155 -

OPRu

Ph

Ph

OCH3

(R)*

H2N

Cl

OPRu

Ph

Ph

OCH3

(R)*

Cl

NH2

Ph

Ph

OP

RuCl

Ph

Ph

OCH3

(R)*

O

D3C CD3

HNH

Ph solvent cage

or

Berry Pseudo Rotation

Highly organized, pseudo quadratic planar transition states!

- Somewhat, but not totally loose!

- Maybe stabilized by hydrogen bonds

- Charge stabilization by polarity of solvent (racemization observed in acetone, MeOH, MeCN)!

Pic. 4.3.8 Cartoons of possible or postulated inversion transition states at chiral Ru(II) center of

54R like.

- 156 -

4.4 Catalytic Experiments and Conclusions

Complexes 54R - 56RS were then tested as (pre)catalysts in the transfer

hydrogenation of acetophenone with isopropanol to 1-phenylethanol (Table 4.4.1).

Also here the reaction conditions had to be adjusted to the low solubility of the

catalysts (compare Chapter 3.2, catalytic experiments with η6-arene Ru(II) N(SR)-

chelate complexes 41R and 42R) by going down to a molar iPrOH / acetophenone

ratio of 12.7 constantly for all experiments. Only with the aniline complex 54R an

onset of ca. 9 % e.e. (R) of 1-phenylethanol was achieved, while almost no e.e. can

be reported for the other catalysts. These results are in good agreement with Pinto's

reports [36 (6-7)]. At least these experiments raise hope the amine stays somehow in

the coordination sphere of the Ru(II) center, because otherwise no difference in

catalytic performance would have been found. Of course the conversion to the

desired chiral alcohol were of comparable magnitude like for the η6-arene Ru(II)

N(SR)-chelate complexes 41R and 42R due to the lower substrate / reductand ratio.

To check the possibility of the based induced racemization of the chiral benzylic

center, a substoichiometric amount of tBuOK in regard to the (pre)catalysts was used

(entry 2 in Table 4.4.1), but almost the same e.e. onset of the previous experiment

was achieved indicating this chiral benzylic center is configuratively stable under the

reaction conditions.

catalyst mol %

catalyst

mol %

tBuOK

molar ratio

iPrOH /

acetophenone

T [° C] reaction

time [h]

conversion

[%]

e.e. [%]

54R 0.27 0.77 12.7 45 21.2 55 9.4 (R)

54R 1.03 0.09 12.7 45 20.0 52 9.0 (R)

55R 1.03 2.35 12.7 RT 46.8 79 1.4 (R)

56RR 0.25 0.79 12.7 45 21.2 83 < 1

56RR 0.51 1.48 12.7 45 6.0 83 < 1

56RS 0.51 1.57 12.7 RT 47.8 83 1.5 (R)

Table 4.4.1 Catalytic transfer hydrogenation experiments of acetophenone to 1-phenylethanol in

iPrOH with tBuOK.

- 157 -

Ph CH3

O

Ph CH3

H OH

Ph CH3

HO H

acetophenone

(R)-1-phenylethanol

(S)-1-phenylethanol

+

+ 1.47 mol % tBuOK

acetone +

*

*(R)

(S)*

*

OM

H2N

Cl

(S)*

1.17 mol %precatalyst

1.00 eq

molar ratio acetophenone / iPrOH : 12.7

reaction temperature : RTreaction time : 1.3 hconversion : 75 %

e.e. (S) = 58.2 %

Pic. 4.4.1 Catalytic crossexperiment with Avecia catalyst under the same reaction conditions like

for 54R - 56RS.

In a crossexperiment the performance of the Avecia Ir(III)(η5-Cp*) catalyst [22 (4-5)]

was checked, which belongs to the most successful transfer hydrogenation catalysts

reported to date (Pic. 4.4.1). Under the catalysis conditions for 54R - 56RS the e.e.

was retarded from > 99 % down to 58.2 % (S)! If these reaction conditions for 54R -

56RS have to be chosen to achieve any activity (TON, TOF) at all, and if the best

catalyst shows under the same reaction conditions a strongly retarded

enantioselectivity, then it can never be expected that similar systems like 54R - 56RS

can be tuned to transfer hydrogenation catalysts of highest activity and

enantioselectivity.

The first issue to be addressed is the low solubility of the catalysts of course, which

could be achieved simply by proper choice of the counter anion. Most striking is the

fact a hydrogen bonding system between PF6- and the coordinated amino group is

found in all precatalysts described in this thesis. Pinto did not comment on possible

hydrogen bonding in her systems with BF4- as counter anion or presented sufficient

data to allow any conclusions [36 (6-7)]. For 55R, crystallizing with one molecule

MeOH per molecular unit, this hydrogen bonding system is much extended (Pic.

4.4.2, Table 4.1.6), but less for 54R (Table 4.1.3).

- 158 -

Pic. 4.4.2 Thermal ellipsoid plot (50 % probality) of supramolecular structure of the hydrogen

bonding system between PF6-, MeOH and coordinated amino group in the unit cell of

55R (amine and phosphine ligand phenyl rings and partially hydrogen omitted for

clarity).

For complex 41R (Pic. 3.2.2, Table 3.2.2) a hydrogen bonding system even between

the coordinated amino group, MeOH and PF6- is found in solid state. So it cannot be

denied hydrogen bonding between PF6- and the coordinating amino group or

between PF6- and the proton of the hydroxy group of iPrOH in a synergistic manner

might also be present in the catalytic reaction. This might have an inhibitory effect

upon reductand or substrate fixation weather on the catalytically active imino complex

or the intermediate hydride transferring complex, especially if the hydrogen bonds of

PF6- would be stronger than the hydrogen bonds between the imino or amino group

with iPrOH or the ketone substrate. Systematic studies about the influence of anions

on the enantioselectivity of catalytic reactions have been done [48 (1)]. However, this

argumentation is not valid for such catalytic transfer hydrogenation systems involving

no hydrogen bonding [31 (13)] or for uncharged catalysts and intermediates [22 (6)].

Therefore as noncoordinating and non hydrogen bond forming counter anion BArF-

[48 (2-4)] is suggested, which proved already to be the solution for similar catalytic

Ru(II) transfer hydrogenation systems [48 (3)].

- 159 -

OP

RuH

RH2NPh

Ph

OCH3

*

(R)

(R)

unlike

*

like

OP

Ru

RH2NH

OCH3*

(R)

(S)

*

H

Ph

Ph Re sterically favored

eq

ax

Si

Ru

RHN

P

O

H

Ph* O

CH3

"out of plane"

Ru

NHR

P

O

* O

HCH3

Ph

Re

eq

ax

sterically favored

Si

"in plane"

+ iPrOH

- acetone

+ iPrOH

- acetone

Configurationally stable or instable??

"in plane"

"out of plane"

Cout

Cin

conformational equilibrium!!

IR

IS

Pic. 4.4.3 Conformational and steric analysis of the formation of the two hydride transferring

species IS and IR.

More insight into further reasons for the low selectivity can be demonstrated in depth

by conformational and steric analysis of the formation of the two possible hydride

transferring species IS and IR (Pic. 4.4.3) and of the four possible diastereomeric

transition states for the hydride transfer to acetophenone as the enantioselective step

(Pic. 4.4.4). These considerations are rationalized in accordance with established

mechanistic studies (Chapter 1.3) [21 (1-4)]. Deprotonation of the precatalysts 54R -

56RS leads presumably to pseudotrigonal planar imino complexes as the real

catalytic active species under the loss of chirality at the Ru(II) center (Pic. 4.4.3). The

catalytic active imino complex can be assumed to be in an preequilibrium of two

conformers Cout and Cin, where the methoxy group of the ansa chain is again in a

favorable "out of plane" (Cout) and in a less favorable "in plane" position (Cin). For

Cout the approach of iPrOH is sterically strongly favored from the Re and for Cin from

- 160 -

the Si side. However, without changing the conformation of the ansa chain it

becomes obvious the approach of iPrOH on both conformers will "push" the nitrogen

ligand very close and sterically very unfavorable towards the equatorial phenyl group

of each phosphinite ligand. Therefore the hydride transfer from iPrOH can only be

successful, if the ansa chains change at the same time their conformation. Such a

process, complementing the Deslongchamp rule [48 (5)] with a bare steric argument,

but with same consequences for the transition state energies, is very unfavorable,

high in energy and will preferably lead to decay into the educts. Therefore it is

reasonable to assume the formation of the hydride transferring species IS from Cout and IR from Cin are the rate limiting steps here with drastic consequences for the

desired enantioselectivity of the overall reaction in general. Furthermore in IS and IR

the chloride ligands from the precatalysts are formally exchanged against electron

rich hydride ligands. The negative charge enrichment of the Ru(II) center might

decrease the inversion barrier ways lower than ∆G‡ = 98.6 kJ / mol of 54R, which

then cannot be compensated by steric effects of the ansa chain. This is well

established for not ansa chain stabilized complexes (Chapter 1.2) [10]. Therefore it

cannot be excluded IS and IR are in an inversion equilibrium at the chiral Ru(II) center.

For the enantioselective hydride transfer step from IS and IR to acetophenone four

possible transition states can be envisaged. Because ππ-attraction is determining the

enantioselection [21 (4)], only these two out of four are considered (Pic. 4.4.4, first

two transition states on the top). These transition states lead one time to the

formation of (1S)-1-phenylethanol (Re transfer from Ir) and another to the formation

of (1R)-1-phenylethanol (Si transfer from IS). If both transition states are equal in

energy, but considerably lower in energy than all others, then the enantioselectivity

can be only determined by the molar ratio of intermediates IS and IR. If IS and IR are

present in equal molar ratio under catalytic conditions, then the enantiomeric excess

is only dependent from the energy difference of the two resulting transition states.

Although an onset e.e. of 9 % (R) with 54R as (pre)catalyst was determined, and

although it is suggestive the Si transfer from IS should be faster (note the nearly

equivalent geometric trajectories for incoming acetophenone in both transition states,

but the higher steric strain of IS due to the methoxy group in "in plane" position), a

definite and general statement concerning enantioselectivity cannot be made due to

the low and few values obtained.

- 161 -

Ru

H NHR

Ru

H

Cout Cin

IRIS

"in plane"

NH P Pheq

O

H

Phax *

*

O

CH3

P

O

*

*

O

H

CH3

Pheq

Phax

(RRu)(SRu)

"out ofplane"

O

H

R

Ph

CH3

H

OPh

H3C

Ru

H NHR

P

O

*

*

O

H

CH3

Pheq

Phax

R

H

OH3C

Ph

Ru

H

NH P Pheq

O

H

Phax *

*

O

CH3

O

H

R

CH3

Ph

ISIR

(SRu)(RRu)

H3C Ph

HO H

*(R)

H3C Ph

H OH

*(S)

"in plane""out ofplane"

ππRe Si

ππ

+ + +

Pic. 4.4.4 Permutation of four possible diastereomeric transition states of the enantioselective

hydride transfer step from IS and IR to acetophenone.

To eliminate possible antagonistic kinetic effects (Pic. 4.4.3), to avoid ligand

dissociation, to control satisfactorily the inversion barrier at the chiral Ru(II) center or

to outflank its effects to achieve an acceptable enantioselectivity in last consequence,

the general design concept of enantioselective ansa-ligated Ru(II)-η6-arene transfer

hydrogenation catalysts (Chapter 1.5, Pic. 1.5.6) needs to be totally revised based on

total steric control by the ansa ligand following strictly the octant rule (Chapter 1.4).

- 162 -

5 Revised Design of Enantioselective ansa-

Ligated Ru(II) η6-Arene THy Catalysts -

Outlook towards Planar Chiral ansa-Ferrocenyl Ligands

Planar chiral bidentate and monodentate ferrocenyl ligands gained an important role

in enantioselective catalysis [31 (1-4)], so no wonder they started to establish also for

applications in enantioselective catalytic transfer hydrogenation reactions [48 (3)]

besides the Syngenta metolachlor process (Chapter 1.4) [31 (7-9)].

Fe E *1) nBuLi / THF / - 78° C2) E synthon / - 78° C to RT

*

Fe

N(CH3)2

CH3 H

*

(R)-FA

Fe E *

H

CH3

*

N(CH3)2

H

CH3

(R) (R)

Fe E *

*Nu

H

CH3

(R)

endo moietysterically closed!

Diastereoselctive ortho Lithiation& Electrophile Quenching

Nu exo

HOAc /nuclephile /80 - 100° C

Retention of Configuration!

η4:η2-fulvenium complex

planar chiral ferrocenyl ligand (modified (R)-FA derivative)

SN1

Pic. 5.0.1 Diastereoselective route to planar chiral ferrocenyl ligands via a combinatorial

sequence of ortho lithiation and nucleophilic substitution protocols.

- 163 -

The most established synthetic route to these robust ligands is the diastereoselective

ortho lithiation of a central chiral ferrocenyl template followed by electrophile

quenching [31 (1-4)]. Ugi's (R)- or (S)-N,N-dimethyl-1-ferrocenyl ethylamine (FA) [49

(1-3)] is the most established central chiral ferrocenyl template and is produced on

industrial scale by enzymatic resolution [49 (4-6)], but it is very expensive. After intro-

duction of the ortho substituent E the N,N-dimethylamino group can be exchanged

against virtually any nucleophile under retention of configuration by nucleophilic

substitution under acidic conditions (Pic. 5.0.1) [49 (7)]. In this way a large variety of

planar chiral ferrocenyl ligands is accessible in almost a combinatorial manner.

This special type of SN1 reaction via an extraordinary stabilized η4:η2-fulvenium

complex is an example at glance, how strongly the endo moiety of the ferrocenyl

backbone is sterically closed against nearly any reagent approach. This allows only a

nucleophilic attack from the exo side leading after completion of the reaction to total

retention of configuration at the central chiral center. Such η4:η2-fulvenium cations

have been isolated [49 (8)]. Because of these unique steric properties it was

envisaged to integrate a planar chiral ferrocenyl backbone into the general design of

ansa-ligated Ru(II) η6-arene transfer hydrogenation catalysts in such a manner that it

closes up one of the two diastereotopic sides of the pseudotetrahedral Ru(II) reaction

center (Pic. 5.0.2) [49 (9)] under consideration of the octant rule (Chapter 1.4).

As the ansa-ligating group exclusively a primary amino group as the required proton

donor for a Noyori type THy catalyst was envisaged in the (pre)catalyst prototype

shown (Pic. 5.0.2, top). This amino group is therefore not a structural variable. This

allows to use the related {σ(N):η6-[1-(2'-aminomethylferrocenyl)benzene]} Ru(II) core

just as a template in this way. This is also more advantageous from a synthetic-

combinatorial point of view for multiple screening of and fine tuning with appropriate

inert spectator ligands L of the proposed (pre)catalysts. By the resulting chelate effect

the potential for dissociation of the amino group (Chapter 4.3) under catalytic reaction

conditions should be decreased to a minimum, too. Furthermore substrate

association via hydrogen bonding will not lead to a steric repulsive interaction of the

incoming substrate with the ferrocenyl backbone in this way, like it would have to be

expected if a primary amine would be the "untethered" ligand and the inert ligating

spectator group L "tethered" instead.

- 164 -

6

Fe

X

H2N

** (P)Ru

L

NH2

RuCl

hydride transfering species

precatalyst

Fe * (M)

*

NH2

Ru

H

Fe * (M)

*

NH

Ru

Fe * (M)

catalyst

3 + 4sterically closed!

"reaction octant"

5 + 8sterically closed!

4 + 5sterically closed, but8 open!

"reaction octant"

1 1 1

L L

L

(Pre)catalyst Prototype Steric requirements for inert spectator ligand Lby the "just-fit principle"

- not too bulky, so coordination into endo moiety still possible and without "gluing up" the reaction octant at all! - preferably hard and anionic ligand: ArO-, RO-, achiral and chiral sulfonamides

Fe* (M)

H2NH

1

2

4

7

3

5

8

L

*Ru

exo substrate approach

Pic. 5.0.2 Revised design of ansa-ligated Ru(II) η6-arene THy catalysts by the octant rule:

(pre)catalyst prototype (top), net retention at metal center in catalytic cycle (middle),

substrate approach on Ru(II) reaction center drawn inside octant (bottom).

- 165 -

As potential candidates for L preferably hard to medium hard ligands such as

phenolates, alkoxides and achiral as well as chiral sulfonamides should be

envisaged, which are not only close to the Noyori system and most promising for

success, but should be almost inert towards dissociation, too. If phosphines or

analogs thereof (phosphinites, phosphites) are envisaged, then the (pre)catalyst will

become cationic in nature, so BArF- should be chosen as counter anion (Chapter 4.4)

[48 (1-4)]. It should be considered to choose not too bulky inert spectator ligands L,

which still could "coordinate into" the endo moiety and which doe not "glue up" the

reaction octant as a whole.

If one subjects the precatalyst prototype to the commonly accepted catalytic cycle

(Pic. 5.0.2, middle; compare Chapter 1.3), then it can be expected the endo moiety of

the ferrocenyl backbone will totally close up octants 3 and 4 leading possibly to a

highly diastereoselective Ru(II) hydride complex formation accompanied with a

formal net inversion at the chiral Ru(II) center (in regard to the precatalyst) during the

whole repetitive reaction cycle. The approach of the reductand (iPrOH) as well as the

ketone substrate should be only possible from the exo moiety in regard to the

ferrocenyl backbone, so octant 1 is expected to be the exclusive reaction octant,

what can be seen as a "chiral pocket" (Pic. 5.0.2, bottom). If for any reason

epimerization of the Ru(II) hydride complex should occur, then the hydride ligand

adopts an endo position sterically not accessible by substrate approach, so the

formation of the opposite product enantiomer by this route should be suppressed. In

this way the configuration dilemma of the Ru(II) hydride complex is relativated by two

strategies based on one common steric aspect of the planar chiral ansa-ferrocenyl

backbone.

Two synthetic routes to this catalyst class were envisaged and followed

simultaneously. The first is based on a diastereoselective transformation of a central

chiral ferrocenyl template with envisaged removal of the previous central chiral

auxiliary group later on. The second aims at the synthesis of the racemic {σ(N):η6-[1-

(2'-aminomethylferrocenyl)benzene]} Ru(II) template, which was envisaged to be

separated into its enantiomers by fractional crystallization after conversion into

diastereomers. These two routes are complementing each other so far, because both

have common synthetic steps to be optimized on racemic compounds first, of course.

- 166 -

5.1 Precursors and Reagents

1.00 eq H2CO +

2.00 eq HN(CH3)2 NCH2

CH3

H3C H2C N

CH2

CH3

Eschenmoser Salt

simple mixing of

aqueous soutions

NH3C CH3

Cl1.20 eq AcOCl

Et2O / - 78 o C

59 60

57 %

iPr

iPr

Li

iPr

iPr

iPriPr

1.37 eq Br2 /0.09 eq cat. Fe /CH2Cl2 / 0 o C

94 %

61 62 LTP

prepared in situ and used immediatly!!

2.00 eq tBuLi /THF / -78 o C

Br

Sterically hindered Li-Aryl-Base for Diastereoselective o-Lithiation

63S (-)-(1R, 2S, 5R)-menthol

OS

O

*

CH3

OH

CH3

**

**

**

64S (-)-(SS, 1R, 2S, 5R)-menthyl p-tolyl sulfinate

44 % yield and > 99.9 % d.e. after 2 x recryst.

1) 1.20 eq TosCl / 1.22 eq NEt3 / 1.53 eq P(OMe)3 / CH2Cl2 / 12 h reflux

2) rep. recryst.3) mother liquor: epimerization with gas. HCl & rep. recryst.

(S)

CH3

Cl(H3C)2SiSi(CH3)2Cl

NH

SiSi

H3C

H3C

CH3

CH3

57 58 55 %2.31 eq NEt3 /

excess gas. NH3

Et2O / 0° C to RT

86 %

Synthon for Chiral Sulfoxides

Pic. 5.1.1 Summarized syntheses of precursors and reagents for the preparation of the envi-

saged {σ(N):η6-[1-(2'-aminomethylferrocenyl)benzene]} Ru(II) template.

- 167 -

The alternative Gabriel reagent 58 [50 (1)] was prepared from commercially available

57 after a modified literature protocol by amminolysis in 55 % yield after distillation.

Yield losses are due to its considerable volatility and 58 slowly hydrolyses if exposed

to moisture, but the N-alkylated products are usually air and moisture stable [50 (2)].

Aminal 59 was simply prepared by mixing aqueous solutions of formaldehyde and

dimethylamine [50 (3)], but yield losses were unavoidable after distillation over

calcium hydride to obtain anhydrous material. Although Eschenmoser's original

procedure [50 (4)] for iminium salt 60 (as iodide) was once applied on an industrial

scale it does not compile to modern environmental standards and is not convenient if

applied in smaller scales. A modified protocol [50 (5)] describing the reaction of 59

with diiodomethane gave only sluggish results in the hands of the author. For small to

medium scales Danishefsky's method [50 (6)] worked satisfactorily. However,

following this protocol acetyl chloride was dropped to a solution of 59, but the isolated

product contained also polymeric {(H3C)2N[CH2-N(CH3)2]nCH2N(CH3)2}+Cl-, which

does react as a synthetic equivalent of the Eschenmoser salt itself. Therefore the

product was used for further reactions without any difficulties.

Lithium 2,4,6-tri(isopropyl)benzene (LTP) is used as a sterically hindered strong and

irreversibly deprotonating base [50 (7)]. It was prepared by bromo-lithio exchange of

62 (prepared by electrophilic aromatic substitution of 61 in turn, commercially not

available) in THF at -78°C and used immediately, because its THF solutions are

instable over longer periods of time and temperatures above + 10° C [50 (7)].

The in situ Sharpless procedure [50 (8)] for the preparation of (-)-(SS)-menthyl p-tolyl

sulfinate 64S required no optimization. However, to avoid formation of side products

the reaction must be performed in diluted solutions under vigorous exclusion of air.

Scales of ca. 30 g (-)-menthol can be conveniently handled. The (SS)-diastereomer

64S can be easily obtained pure after two times crystallization of the crude epimeric

product. Because the combined mother liquors, enriched with the (RS)-diastereomer,

can be epimerized by saturation of an acetone solution with HCl gas, overall yield of

64S can be increased nominally up to 60 - 70 % by recycling combined mother

liquors of several batches. Although 64S is a standard synthon for the preparation of

enantiomerically pure sulfoxides [6 (3-6)] and is also commercially available, its

- 168 -

absolute configuration was proven only by indirect methods so far. Here in this work

the absolute configuration was unambiguously confirmed by X-ray structure

determination (Pic. 5.1.2, Table 5.1.1). Single crystals were obtained by very slow

crystallization from acetone.

Pic. 5.1.2 Thermal ellipsoid plot (50 % probality) of molecular structure of (-)-(SS)-menthyl p-tolyl

sulfinate 64S; selected bond distances and angles see Table 5.1.1.

distances [Å] angles [ °]

C(11) - S(1) 1.794(2) C(11) - S(1) - O(1) 93.61(8)

S(1) - O(2) 1.473(2) C(11) - S(1) - O(2) 105.56(9)

S(1) - O(1) 1.631(2) O(1) - S(1) - O(2) 109.41(8)

O(1) - C(6) 1.474(2) S(1) - O(1) - C(6) 116.9(2)

Table 5.1.1 Selected bond distances and angles of (-)-(SS)-menthyl p-tolyl sulfinate 64S.

- 169 -

5.2 Synthesis of and ortho Lithiation Studies with Kagan's Template

As a central chiral ferrocenyl template Kagan's p-tolylsulfinyl ferrocene 67S was

chosen (Pic. 5.2.1) [51 (2-4)]. Although it has broader divergent-combinatorial

synthetic varieties (Pic. 5.2.3) compared to Ugis's template (R)- or (S)-FA (Pic. 5.0.1),

the widespread of its use is hampered by the quite cumbersome synthesis. The

enantioselective oxidation of the corresponding thioether with (R,R)-DET / Ti(OiPr)4 /

CHP is highly selective with up to 88 % e.e. (RS) [51 (4-7)], but can only be

performed on small scale. Although recently breakthroughs in the catalytic

enantioselective oxidation of thioethers to sulfoxides were achieved, they are

restricted to aryl alkyl sulfides only [51 (8-11)]. Focusing on the mean purpose

Kagan's more classical route via reaction of 64S under nucleophilic substitution of

mentholate with lithioferrocene (FcLi) 66 [51 (2-3)] was chosen therefore and tried to

be optimized (Pic. 5.2.1).

Fe

* S

O

(S)

(+)-(Ss)-p-tolylsulfinylferrocene

67S

Kagan Template

H3C

Fe

65

77.3 % e.e. of product after chromatography; 74 % yield

86.4 - 94.2 % e.e after recrystallization; 45 - 16 % yield

Fe

Li 66

1) 1.00 eq tBuLi / 0.14 eq tBuOK

THF / - 78° C1.28 eq 1.00 eq

2) canuled slowly to: 1.74 eq 64S / THF / - 30° C

Pic. 5.2.1 Synthesis of Kagan's central chiral ferrocene template 67S.

- 170 -

Simple lithiation of ferrocene 65 with alkyllithium reagents leads normally to a mixture

of ferrocene 65, 1,1'-dilithio- and 1-lithioferrocene 66. This can be circumvented by a

stannylation / destannylation detour [51 (1-2)], but 65 can also be directly and

selectively monolithiated by adding 0.10 - 0.15 eq tBuOK to the reaction solution [51

(3)] under otherwise identical conditions. Adopting the latter method Kagan added a

solution of 1.00 eq 66 (from 2.00 eq 65 / 0.10 eq tBuOK) to 1.00 eq 64S to obtain

67S in 69 % yield with 83 % e.e (SS) after chromatography [51 (3)] under full

retention of configuration at the chiral sulfur center. His procedure was reproduced

under almost identical conditions (1.99 eq 65 / 0.10 eq tBuOK / 1.00 eq tBuLi / 1.11

eq 64S) to obtain 67S in 75 % yield with 71.3 % e.e (SS) after chromatography, but

with 74 % yield and 77.3 % e.e (SS) after chromatography under modified conditions

using 1.28 eq 65 / 0.14 eq tBuOK / 1.00 eq tBuLi / 1.74 eq 64S (Pic. 5.2.1).

The clue for achieving an acceptable enantiomeric excess of 67S is a very slow

addition of the solution of 66 to 64S to avoid a temporary accumulation of 66 in the

reaction solution leading to a racemization equilibrium of 66 with 67S. However,

increasing the stoichiometric ratio of 64S did not improve the enantiomeric excess.

Enantiomeric enrichment was achieved up to 94 % e.e. by recrystallization (see

important details in Chapter 7.5.6) and eventually crystals suitable for X-ray structure

determination were obtained in the same way confirming the absolute configuration

at the chiral sulfur center to be (S).

distances [Å] angles [ °]

S(1) - C(11) 1.799(2) C(11) - S(1) - O(1) 106.2(2)

S(1) - O(1) 1.499(2) C(10) - S(1) - O(1) 107.9(2)

S(1) - C(10) 1.770(3) C(10) - Fe(1) - C(1) 123.8(2)

C(6) - Fe(1) 2.038(2) C(10) - Fe(1) - C(2) 160.5(1)

C(7) - Fe(1) 2.054(3) C(10) - Fe(1) - C(3) 157.3(1)

C(8) - Fe(1) 2.046(3) C(10) - Fe(1) - C(4) 121.9(2)

C(9) - Fe(1) 2.048(3) C(10) - Fe(1) - C(5) 107.5(2)

C(10) - Fe(1) 2.016(2)

Table 5.2.1 Selected bond distances and angles of (+)-(SS)-p-tolylsulfinyl ferrocene 67S.

- 171 -

Pic. 5.2.2 Thermal ellipsoid plot (50 % probality) of molecular structure of Kagan's template (+)-

(SS)-p-tolylsulfinyl ferrocene 67S, selected bond distances and angles see Table

5.2.1.

During the ortho lithiation of Kagan's template 67S with LDA or LTP (Pic. 5.1.1)

followed by electrophile quenching only the particular diastereomer is quantitatively

formed, which results from the intermediary like ortho-lithio chelate diastereomer (Pic.

5.2.3). The like o-lithio diastereomer is energetically preferred over unlike, because in

the former case the p-tolyl substituent can adopt a much more favorable exo position.

As a kinetic argument the oxygen atom of the sulfinyl group associates with the lithio

base and delivers it then into the favored ortho like position for deprotonation

resulting finally in the diastereomerically pure chelate. Of course the diastereo-

selective ortho lithiation of Ugi's template can be explained in an analog way, but

alternatively the diastereoselectivity is often explained by an high preference of the

analog unlike ortho-lithio chelate diastereomer with the methyl group in exo position

[31 (1-4), 49 (1-3)].

- 172 -

While for Ugi's template principally all aryl- and alkyllithium reagents can be used for

deprotonation, the sulfinyl group of Kagan's template 67S is exchanged against

lithium with not sterically hindered aryl- and alkyllithium reagents. Therefore

diastereoselective ortho lithiation of 67S is exclusively restricted to LDA or LTP. On

the other hand in a second step (Pic. 5.2.3) the lithio exchange of the sulfinyl group,

preferably with tBuLi, can be used to quench the resulting stabilized lithio chelate

with a second electrophile synthon to obtain an 1,2-disubstituted ferrocene with

planar chirality only under nearly complete preservation of the original enantiopurity

[50 (7), 51 (2-4), 52 (1-2)]. As electrophile synthon for Y virtually any reagent can be

used, as long as it is compatible with the previous introduced substituent X. Of

course X has to be inert against tBuLi. In this way a larger synthetic variety is given

for 67S compared to Ugi's template (R)- or (S)-FA, because applying the reaction

sequence shown above (Pic. 5.0.1) on Ugi's template leads only to diastereomeric

1,2-disubsituted ferrocenyl derivatives with planar and central chirality under

structural and configurational preservation of the original central chiral auxiliary

element.

Fe

* S

p-Tol

O

(S)

67S

S

FeLi

*O

p-Tol

(S)

* (M)

S

FeX

*

O

p-Tol (S)

Fe

* S

p-Tol

O(S)

exo

Li

endo

* (P)

*

Y

FeX *

(deep orange)

unlike

like

1) base (LDA, LTP) / THF / - 78° C2) X synthon / - 78° C to RT

Diastereoselctive ortho Lithiation& Electrophile Quenching

1) tBuLi / THF / - 78° C2) Y synthon / - 78° C to RT

Lithio Exchange of Chiral Auxiliary Group& Electrophile Quenching

(yellow)

Pic. 5.2.3 Divergent-combinatorial synthetic variety of Kagan's template 67S leading to 1,2-

disubsituted ferrocenes with planar chirality only.; note in the case here there is no

thermodynamic equilibrium between the diastereomeric ortho-lithiated species, but the

diastereoselectivity of the ortho lithiation is kinetically driven only.

- 173 -

With nearly enantiopure Kagan's template 67S in hands and multigrams of its

racemate available for test reactions suitable synthetic possibilities for the

diastereoselective introduction of a N,N-dimethylaminomethyl group were

investigated by a systematic lithiation study (Pic. 5.2.4). To avoid time consuming

preparation of LTP and Eschenmoser salt 60 the diastereoselective introduction of a

hydroxymethyl group on 67S leading to 71 followed by linear FGI was the first goal.

Diastereoselective ortho lithiation of 67S (86.4 % e.e.) with LDA and quenching with

paraformaldehyde did not lead to the 1,2-disubsituted diastereomer 71S, but to

ferrocene derivative 68S in 49 % yield. This result is the more surprising, because

racemic 71 is described to be obtained under the same reaction conditions, but using

66 or LTP as base [50 (7), 52 (2)]. While 66 and LTP deprotonate irreversibly,

diisopropylamine, the corresponding acid to LDA, is obviously not an innocent

spectator in ortho lithiation reactions. It has been found in the deuteration of various

compounds that the deuterium incorporation is sometimes incomplete, because

diisoprpylamine is coordinated to lithium cations and being enhanced in acidity [52

(3-6)]. In this sense diisopropylamine lithium complexes can simply act reversibly as

acid. Therefore diisoprpylamine lithium complexes might catalyze the rearrangement

of the ortho-lithiated ferrocene template to the thermodynamically favored product

(consider the p-tolyl methyl group is more acidic than the coordinated electron rich

Cp- ligands), if the subjected electrophile is considerably low reactive

(paraformaldehyde is a polyacetal) and thermodynamic conditions are reached

during warmup of the reaction solution. This leads finally to trapping of the

thermodynamically more stable base. This explanation might be complemented with

the fact ortho lithiation of 67S followed by electrophile quenching never leads to

complete conversion to the desired 1,2-disubstituted ferrocene. Conclusively the

diastereoselectivity of the ortho lithiation of 67S must be kinetically driven only and

there is no thermodynamic equilibrium between the diastereomeric ortho-lithiated

species. This is supported by the fact that all ortho lithiation reactions performed here

were fully diastereoselective by NMR after analysis of the crude products!

Rearrangement product 68S (min. 86.4 % e.e.) was then converted to mesylate

derivative 69S in 98 % yield. Crystals suitable for X-ray structure determination were

obtained from a saturated CH2Cl2 solution with some drops of EtOAc (Pic. 5.2.6,

Table 5.2.2). In this way the rearrangement and trapping reaction of 67S to 68S,

unprecedented in literature to the best of knowledge [52 (3)], is proven beyond doubt.

- 174 -

Fe

* S

p-Tol

O

(S)

67S

71

66 %overall yield

S

Fe

*

O

p-Tol (S)

HO

* (M)

70 crude

S

FeOHC

*

O

p-Tol (S)

* (M)

72

S

Fe

*

O

p-Tol (S)

(H3C)2N

* (M)

1) 1.98 eq LDA / THF / - 78 o C

2) 5.78 eq DMF / - 78 o C to RT

3) "1.05 eq" NaBH4 / MeOH / RT

1) addition to: 1.14 eq PPh3 + 1.21 eq CBr4 / CH2Cl2 / - 70° C

2) 2.98 eq 59 / 1.19 eq AgBF4 / RT / 12 %

Fe

* S

O

(S)

Fe

* S

O

(S)

1) 2.03 eq LDA / THF / - 78 o C2) 5.81 eq (H2CO)n / - 78 o C to RT

O OH

1.22 eq H3CSO2Cl / 1.45 eq NEt3 / CH2Cl2 / 0° C to RT 68S 49 %69S 98 %

Rearrangement of o-lithiated species to thermodynamic product!!

SO2CH3

(performed on racemate)

(performed on material with 86.4 % e.e.)

1) 2.00 eq LTP / THF / - 78 o C 2) 4.18 eq 60 / - 78 o C to RT

52 %(performed on racemate)

(performed on racemate)

+ ent.+ ent.

+ ent.

Pic. 5.2.4 Summarized lithiation studies of Kagan's template 67S with electrophile reactivity

dependent regioselectivities.

Racemic 70 was then obtained by ortho lithiation of racemic 67 followed by

quenching with more reactive DMF. Aldehyde 70 was described to be obtained under

the same reaction conditions, but using LTP as base and ethyl formate as

electrophile [52 (2)]. Crude 70 was then directly reduced with NaBH4 to 71 allowing

- 175 -

then an easy removal of residual 67S from the previous reaction by purification with

column chromatography to obtain pure 71 in 66 % overall yield. Having Salzer's

electrophilic activation of benzylic positions as chlorides in chromium(0) tricarbonyl

η6-arene complexes in mind [52 (7)], racemic 71 was converted to the corresponding

bromide with the preformed PPh3 / CBr4 adduct (necessary to avoid reduction of the

sulfinyl group to the corresponding thioether by PPh3). This in turn was then reacted

in situ with AgBF4 and 59 a synthetic equivalent for free dimethylamine to the desired

diastereomerically pure N,N-dimethylaminomethyl ferrocenyl derivative 72. But only

12 % yield were obtained after chromatography (Pic. 5.2.5). To the best of the

knowledge this is the first successful activation and substitution reaction at a fulvenic

position of a 1,2-disubstituted ferrocene containing a strongly deactivating sulfinyl

group. This reaction might be developed further into a general procedure for the

preparation of various bidentate planar chiral ferrocenyl ligands of that particular type.

71

S

Fe

*

O

p-Tol (S)

HO

* (M)

72

S

Fe

*

O

p-Tol (S)

(H3C)2N

* (M)

2) 59 / AgBF4

+ ent.

+ ent.

S

Fe

*

O

p-Tol (S)

Br

* (M)+ ent.

S

Fe

*

O

p-Tol (S)

N

* (M)+ ent.

NH3C

CH3

CH3

H3C

Br3C PPh3 Br

preformed!1)

in situ

Pic. 5.2.5 In situ electrophilic activation and nucleophilic substitution reaction.

This reaction was then finally complemented with the successful diastereoselective

ortho lithiation of racemic 67 with LTP followed by quenching with Eschenmoser salt

60 to racemic 72, but in a more practicable yield of 52 %. After addition of 60 to the

ortho-lithiated intermediate the deep orange color turned clear yellow within minutes,

- 176 -

underlining the strong electrophilic potential of 60 compared to DMF and ways ahead

of paraformaldehyde. After applying an unorthodox trick (Chapter 7.5.10) single

crystals of racemic 72 suitable for X-ray structure determination could be obtained

from a saturated EtOAc solution. The crystal examined contained both enantiomers

of 72 (Pic. 5.2.7, Table 5.2.3). Conclusively now the method for preparing

enantiomerically pure 72S is given, but at that time no lab space was then provided

anymore.

Pic. 5.2.6 Thermal ellipsoid plot (50 % probality) of molecular structure of 69S obtained from

rearrangement product 68S; selected bond distances and angles see Table 5.2.2.

distances [Å] angles [ °]

S(2) - C(11) 1.797(2) C(11) - S(2) - O(1) 106.91(9)

S(2) - O(1) 1.488(2) C(10) - S(2) - O(1) 108.1(1)

S(2) - C(10) 1.777(2) C(18) -O(2)- S (3) 119.3(2)

S(3) - O(2) 1.574(2) O(3) - S(3) - O(4) 119.5(2)

S(3) - O(3) 1.429(2) O(2) - S(3) - C(19) 103.3(2)

S(3) - O(4) 1.428(2) C(10) - Fe(1) - C(1) 125.36(9)

S (3) - C(19) 1.758(2) C(10) - Fe(1) - C(2) 158.83(9)

O(2) - C(18) 1.471(2) C(10) - Fe(1) - C(3) 160.49(9)

C(10) - Fe(1) 2.028(2) C(10) - Fe(1) - C(4) 126.57(9)

C(5) - Fe(1) 2.057(2) C(10) - Fe(1) - C(5) 111.92(9)

Table 5.2.2 Selected bond distances and angles of 68S.

- 177 -

Pic. 5.2.6 Thermal ellipsoid plots (50 % probality) of the arrangement of the two symmetrically

independent molecules representing the two enantiomers of 72 like as (SS, M)-72

(left), (RS, P)-72 (right): Note that due to the inversion center of the space group

P1 (no. 2) the corresponding inversion image of this arrangement is also present in

the unit cell. The two independent molecules differ only slightly in their conformation.

Selected bond distances and angles see Table 5.2.3.

- 178 -

distances [Å] angles [ °]

S(1) - C(11) 1.796(2) C(11) - S(1) - O(1) 106.65(8)

S(1) - O(1) 1.496(2) C(10) - S(1) - O(1) 106.91(8)

S(1) - C(10) 1.777(2) C(9) - C(18) - N(1) 113.1(2)

C(18) - C(9) 1.506(3) C(18) - N(1) - C(19) 109.8(2)

N(1) - C(18) 1.469(2) C(18) - N(1) - C(20) 110.5(2)

N(1) - C(19) 1.458(2)

N(1) - C(20) 1.462(2)

S(2) - C(31) 1.792(2) C(31) - S(2) - O(2) 106.60(8)

S(2) - O(2) 1.496(2) C(30) - S(2) - O(2) 106.96(8)

S(2) - C(30) 1.779(2) C(29) - C(38) - N(2) 113.4(2)

C(38) - C(29) 1.508(3) C(38) - N(2) - C(39) 109.6(2)

N(2) - C(38) 1.477(2) C(38) - N(2) - C(40) 110.6(2)

N(2) - C(39) 1.460(2)

N(2) - C(40) 1.459(2)

Table 5.2.3 Selected bond distances and angles of racemic 72.

5.3 Towards a Racemic {σ(N):η6-[1-(2'-aminomethyl-

ferrocenyl)benzene]} Ruthenium(II) Complex

Starting from ferrocene 65 N,N-dimethylaminomethyl ferrocene 73 [50 (3)] and its

racemic ortho-stannylated derivative 74 [52 (8)] were prepared after modified

protocols and yields optimized (Pic. 5.3.1). By the Weissensteiner method [52 (9-10)]

the amino group of a planar chiral N,N-dimethylaminomethyl ferrocene derivative is

activated by permethylation and then substituted against nucleophiles under reflux in

a polar aprotic solvent (DMF , MeCN, etc.). However, this method is not easily

applicable for ferrocene derivatives with highly activating electron donor substituents

such as trisalkylstannyl groups. In these cases the corresponding η4:η2-fulvenium

complex (compare Pic. 5.0.1) is formed quickly under the extrusion of trimethylamine,

but decomposes quicker than reaction with the nucleophile can occur in turn.

- 179 -

Fe

NH2

(M) *+ ent.

81 89 %

Fe

N(M) * O

O

+ ent.

Stille Coupling

0.025 eq Pd2(dba)3.CHCl3 /

0.15 eq AsPh3 / 0.50 eq CuI1.93 eq PhI / DMF / 70 ° C / 14 h

Catalyst (in situ) :5 mol % Pd(0)(AsPh3)2 76

77 74 %

10.44 eq N2H4(H2O)

EtOH / 70 ° C / 1 h

Birch Reduction

Fe

65

Fe

N(CH3)2

73 92 %

1.70 eq 59

1.51 eq H3PO4 / HOAc / 100° C

74 89 %

+ ent.

Sn(n-C4H9)3

Fe

N(CH3)2

(P) *

Sn(n-C4H9)3

Fe

N(P) * O

O

75 84 %

in situ in pressure Schlenk tube :

1) 1.12 eq H3CI / DMF / RT 2) 0.44 eq NEt2 / DMF / RT 3) 1.35 eq potassium phthalimide / 100° C / 15 h

1) 1.19 eq nBuLi / Et2O / RT2) 1.32 eq ClSn(nBu)3 / - 78° C to RT

+ ent.

Fe

NH2

(M) *+ ent.

82 96 %

(crude)

1) 12.47 eq Li / NH3 (l) / EtOH / THF / - 78 ° C2) 13.77 eq NH4Cl / defrost to RT

Pic. 5.3.1 Synthesis of racemic planar chiral ansa-ferrocene ligand.

- 180 -

For substitution of comparable (R)-FA derivatives with pyrazoles or phosphines

stirring of such silylated or stannylated derivatives together with excess nucleophile in

glacial acetic acid at lower temperatures is one solution [52 (11)], but of course this

method is not applicable for potassium phthalimide as nucleophile. Therefore the

Weissensteiner protocol [52 (9-10)] was optimized to an in situ procedure for the

synthesis of racemic phthalimidomethyl ferrocenyl derivative 75 from 74. Ferrocene

derivative 74 was directly permethylated in a pressure Schlenk tube in DMF with

methyl iodide followed by addition of potassium phthalimide and heating under

pressure afterwards. Pressurizing the reaction in this way decelerates the formation

of the η4:η2-fulvenium complex sufficiently enough to give the phthalimide enough

time to react, because gaseous trimethylamine cannot escape the closed system.

Choosing DMF as solvent has the advantage 75 is constantly removed out of the

reaction phase, because it separates out as a second less polar liquid phase. In this

way racemic 75 was obtained 84 % yield after purification.

Some Pd(0) catalyzed Stille crosscoupling reactions [53 (1-3)] of stannylated

ferrocenes [51 (2), 52 (8)] with aryl bromides and iodides are reported in literature,

but the protocols applied vary in detail (ligands, additives, solvents, temperature),

which must be adjusted respectively optimized in regard to the stannylated ferrocene.

Phosphines or arsines are required as Pd (0/II) ligands, which can stabilize both,

Pd(0) and Pd(II). In general CuI or CuO have to be added to the catalytic reaction,

which does not proceed otherwise. For the Stille crosscoupling of racemic 75 with

iodobenzene to racemic 77 it was oriented on a procedure [53 (4)] for coupling

electron rich and sterically demanding stannyl compounds with iodobenzene close to

the objective given here. "Satan's Mixture" of 5 mol % Pd(0) from 2.5 mol %

Pd2(dba)3.CHCl3 : CuI : AsPh3 = 1 : 10 : 3 in DMF was found to be optimal. After

recrystallization racemic 77 was obtained in 74 % yield. Unfortunately traces of other

byproducts could not be removed from 77, also not by column chromatography. The

mechanism of the Stille coupling is not fully revealed yet (Pic. 5.3.2). The actual

catalyst formed in situ is obviously Pd(0)(AsPh3)2 76. Oxidative addition of

iodobenzene leads to Pd(II) intermediate 78 (step 1), which transmetallates on 75

possibly via an associative transition state resulting in a phenyl ferrocenyl Pd(II)

bis(triphenylarsine) complex (step 2), which in turn undergoes reductive elimination

back to Pd(0) catalyst 76 and to 77 after isomerisation to a cis complex.

- 181 -

N

Stille Crosscoupling

Sn(n-C4H9)3

Fe

N(P) * O

O

+ ent.75

Fe

N(M) * O

O

+ ent.77 74 %

PdPh3As AsPh3

PdI Ph

AsPh3

AsPh3

Snn-Bu

n-Bu

n-Bu

Pd

AsPh3Ph3As

Ph I

FeO

O

Pd

Fe

* (P)

AsPh3

AsPh3

O O

(0)

Catalyst 76

associativetransition state ???

CuI for successful catalysis required, but role not known!

- trapping of escess ligand ??- "associative activation" of -Sn(n-Bu)3??

(II)

(II)

(II)

I Sn(n-Bu)3

transmetallation

oxidative addition

reductiveelimination

77 PhI

75

1

2

3

78

"Satan's Mixture"

5 mol % Pd(0) (Pd : CuI : AsPh3 = 1 : 10 :3)

1.93 eq PhI / DMF / 70 ° C / 14 h

Pic. 5.3.2 Generally accepted catalytic cycle proposed on Stille crosscoupling of 75 to chiral 1,2-

disubstituted ferrocene derivative 77.

- 182 -

The role of the copper salts is unclear, which might serve as "associative activator" of

the tin carbon bond enabling transmetallation. They also could trap excess ligand,

but this is of debate, because they have to be added also to stoichiometrically

preformed Pd(0) catalysts containing bidentate ligands [51 (2)].

From crystallization of combined motherliquors in the sense of trace enrichment a

cornucopia of single crystals of rac. 77 (Pic. 5.3.4, Table 5.3.1), catalytic intermediate

78 (Pic. 5.3.5, Table 5.3.2), rac. dimer byproduct 79 (Pic. 5.3.3, Pic. 5.3.6, Table

5.3.3) and trans-I2Pd(II)(AsPPh3)2 80 (Pic. 5.3.7, Table 5.3.4) were obtained by

tedious sorting under a microscope. These products can be also partially identified in

the NMR spectra of the crude product (8 - 7 ppm, 6 - 4 ppm). The formation of

racemic dimer 79 is possibly due to traces of Cu(II) resulting then in transmetallation

of 75 followed by an Ullmann-type analog reductive elimination [53 (5-7)].

Fe

N

(P)

*

O

O

+ ent.Fe

N

*

(P)

O

O

79

(P) *75 + Cu(II) XSn(nBu)3

R Cu R+

Pic. 5.3.3 Ullmann-type analog reductive elimination leading to racemic 79 as byproduct.

distances [Å] angles [ °]

N(1) - C(11) 1.458(2) N(1) - C(11) - C(10) 111.2(2)

C(11) - C(10) 1.513(2) C(11) - C(10) - C(9) 126.7(2)

C(10) - C(9) 1.441(2) C(10) - C(9)- C(20) 128.6(2)

C(9) - C(20) 1.486(2) C(9) - Fe(1) - C(1) 149.28(7)

C(9) - Fe(1) 2.053(2) C(9) - Fe(1) - C(2) 169.08(7)

C(10) - Fe(1) 2.047(2) C(10) - Fe(1) - C(2) 148.77(7)

C(10) - Fe(1) - C(3) 169.26(7)

Table 5.3.1 Selected bond distances and angles of racemic 77.

- 183 -

Pic. 5.3.4 Thermal ellipsoid plot (50 % probality) of molecular structure of racemic 77; selected

bond distances and angles see Table 5.3.1.

Pic. 5.3.5 Thermal ellipsoid plot (50 % probality) of molecular structure of catalytic intermediate

Pd(II) complex 78; selected bond distances and angles see Table 5.3.2.

distances [Å] angles [ °]

Pd(1) - As(1) 2.4335(6) As(1) - Pd(1) - As(2) 171.77(2)

Pd(1) - As(2) 2.4187(6) C(1) - Pd(1) - I(1) 173.5(2)

Pd(1) - I(1) 2.6743(7) C(1) - Pd(1) - As(2) 83.9(2)

Pd(1) - C(1) 2.010(5) I(1) - Pd(1) - As(1) 94.47(2)

Table 5.3.2 Selected bond distances and angles of catalytic intermediate 78.

- 184 -

Pic. 5.3.6 Thermal ellipsoid plot (50 % probality) of molecular structure of racemic ferrocene

dimer 79; selected bond distances and angles see Table 5.3.3.

distances [Å] angles [ °]

N(1) - C(11) 1.469(3) N(1) - C(11) - C(10) 113.0(2)

C(11) - C(10) 1.502(4) C(11) - C(10) - C(9) 126.4(3)

C(10) - C(9) 1.441(4) C(10) - C(9)- C(28) 125.2(2)

C(9) - C(28) 1.472(4) C(9) - C(28) - C(29) 125.7(2)

C(28) - C(29) 1.434(4) C(28) - C(29) - C(30) 126.0(3)

C(29) - C(30) 1.501(4) C(29) - C(30) - N(2) 112.6(2)

C(30) - N(2) 1.464(3) C(9) - Fe(1) - C(4) 165.6(2)

C(10) - Fe(1) 2.041(3) C(9) - Fe(1) - C(5) 164.0(2)

C(9) - Fe(1) 2.056(3) C(10) - Fe(1) - C(5) 153.1(2)

C(28) - Fe(2) 2.060(3) C(28) - Fe(2) - C(20) 155.4(2)

C(29) - Fe(2) 2.036(3) C(29) - Fe(2) - C(22) 166.1(2)

Table 5.3.3 Selected bond distances and angles of racemic ferrocene dimer 79.

- 185 -

Pic. 5.3.7 Thermal ellipsoid plot (50 % probality) of molecular structure of complex trans-

I2Pd(II)(AsPh3)2 80; selected bond distances and angles see Table 5.3.4.

distances [Å] angles [ °]

Pd(1) - As(1) 2.4356(3) As(1) - Pd(1) - As(1A) 180.0

Pd(1) - As(1A) 2.4356(3) I(1) - Pd(1) - I(1A) 180.000(9)

Pd(1) - I(1) 2.6060(3) As(1) - Pd(1) - I(1) 88.042(10)

Pd(1) - I(1A) 2.6069(3) I(1A) - Pd(1) - As(1A) 88.042(10)

Table 5.3.4 Selected bond distances and angles of trans-I2Pd(II)(AsPh3)2 80.

The catalytic intermediate trans-(Ph3As)2Pd(II)IPh 78 is isostructural to corresponding

trans-(Ph3P)2Pd(II)IPh [53 (8)], but not isomorph in solid state. 78 shows furthermore

an extraordinary trans influence, because nearly all ligands are bended out of the

planar square geometry (compare with nearly perfect square planar structure of

trans-I2Pd(II)(AsPh3)2 80).

Racemic ferrocene 77 was then deprotected with hydrazine to the free primary amine

81 in 89 % yield after chromatography to give then also a correct EA (Pic. 5.3.1).

Birch reduction of 81 required ca. 12.5 eq lithium. Due to the low solubility in EtOH at

- 186 -

low temperature THF had to be used as a cosolvent. Nevertheless the potential

ansa-ferrocenyl ligand 82 was obtained nearly pure in 96 % crude yield and the

ferrocene backbone stayed intact during the Birch reduction. However, all attempts to

complex 82 with RuCl3 under standard conditions (ammonium salt, EtOH) failed due

to the oxidation of the ferrocene moiety by Ru(III) (Pic. 5.3.8). It was also tried to let

82 react with "ruthenium ink" (preformed by refluxing RuCl3 in EtOH), which failed

also. A brief investigation by CV of this "blue ink", which is said to consist of Ru(II)

ions only, was found to be a "living solution" possibly consisting of dynamic Ru(III)

species with standard potentials around 700 mV, way above the one of 450 - 500 mV

typically found for ferrocene derivatives. Therefore this route to the template

dichloro{σ(N):η6-[1-(2'-aminomethylferrocenyl)benzene]} ruthenium(II) 83 had to be

abandoned.

A synthetic alternative or perspective might be the detour via introduction of a Ru(0)

fragment targeting directly enantiomerically pure 83M (Pic. 5.3.8 from bottom to top).

The sulfinyl group of 72S is directly exchanged against the tributylstannyl group as

previously discussed (Chapter 5.2., Pic 5.2.3) to give then enantiomerically pure

74M. Preparing 84M analog to 75 was already in progress, when labspace was not

provided anymore.

It was envisaged to exchange the stannyl group of 84M against lithium with nBuLi

followed by transmetallation to the zinc derivative, which was planned to be

crosscoupled with η2:η2-cyclooctadienyl Ru(0) η6-iodobenzene [34 (5-10)] to 85P

according to the Negishi protocol [53 (9-10)]. The Pd(0) catalyzed Negishi

crosscoupling reaction proceeds analog to the catalytic cycle of the Stille coupling

(Pic. 5.3.2) except a zincaryl is the transmetallating reagent. More compatible with

rather sensitive Ru(0) η6-arene complexes the Negishi coupling can be performed at

room temperature or below and does not require "magic additives". Furthermore

zincaryl compounds do not isomerize. The Negishi crosscoupling of planar chiral

ferrocenes under preservation of the chiral plane is described in literature [51 (3), 53

(11-12)]. Oxidation of 85M with an equimolar amount of HCl in acetone should then

give template 83M following established procedures [35 (3)]. A general incompatibility

of ferrocene an Ru(II) η6-arene complex moieties can be excluded, because a variety

of Ru(II) η6-arene complexes ligated to bidentate ferrocenyl ligands exist [53 (13)].

- 187 -

Fe

NH2

Fe

Cl

Cl

Ru

H2N

82 + ent. decomposition! 83M

72S

S

Fe

*

O

p-Tol (S)

(H3C)2N

* (M)

(n-C4H9)3Sn

Fe

(H3C)2N

* (M)

(n-C4H9)3Sn

Fe

N

* (M)

SiSi

84M

74M

* (P)

as ammonium salt, RuCl3 / EtOH

* (M)

Fe

N

* (P)

SiSi

85P

Ru(0)(η2:η2-COD)

acetone / HCl

1) tBuLi / THF / -78° C

2) ClSn(nBu)4

in situ in pressure Schlenk tube :

1) H3CI / DMF / RT2) 58 / 100° C

Negishi Coupling

1) nBuLi / THF / - 78° C2) excess ZnCl2

3) (COD)Ru(0)(η6-PhI)4) Pd(0)L4 / RT

Pic. 3.5.8 Perspectives for the enantioselective synthesis of planar chiral template dichloro-

{σ(N):η6-[1-(2'-aminomethylferrocenyl)benzene]} ruthenium(II) 83.

- 188 -

6 Conclusion and Closing Remarks

The impossibility to succeed in the anticipated goal of developing novel, highly

selective and active transfer hydrogenation catalysts with original thesis topic is more

than obvious. However, the preparation and study of diastereomeric σ(N):σ(S) β-

aminothioether η6-arene ruthenium(II) chelate complexes gave at least insight into

metal configuration governing aspects, which are determined by the steric nature of

the η6-arene ligand mostly. Coordinated thioethers cannot be configurationally

stabilized. As a positive side effect synthetic routes to chiral β-aminothioether

derivatives could be modified to almost standard protocols, which might be of interest

in the preparation of second generation penicillin type antibiotics.

The diastereomeric {[σ(P):η6-(arene-ansa-phosphine)] ruthenium(II) amino complex

prototype class developed in the Zenneck group could be extended to corresponding

phosphinites as supposed enantioselective CaTHy systems. Surprising

diastereoselectivities in regard to their formation from the corresponding template

were found and could be explained. However, even because of the configurational

instability of one member of this subclass some stereochemical general aspects

governing the configurational stability of this whole class of these complexes could be

revealed by in depth NMR studies in combination with X-ray crystallography and

determination of inversion energy barriers. With catalytic transfer hydrogenation

experiments and crossexperiments related to the aforementioned studies possible

reasons for the failure of this prototype class as enantioselective catalysts could be

uncovered also.

These insights lead then finally to a revised design of ansa-ligated Ru(II) η6-arene

transfer hydrogenation catalysts strictly applying the octant rule. This design bases

on an incorporation of a planar chiral ferrocenyl backbone into the ansa chain

relativating the inherent problem of configurational stability. The synthesis of such a

prototype catalyst was nearly completed. During the course of this work new

diastereoselective routes to planar chiral ferrocenyl derivatives were explored, one

surprising rearrangement reaction characterized and catalytic intermediates and

byproducts of a Stille crosscoupling reaction isolated.

- 189 -

7 Experimental Part

7.1 Materials and Methods

Commercially available chemicals and solvents were purchased from Acros, Aldrich,

Fluka, Fisher Scientific, Merck, Pressure Chemicals and Strem and were used as

received if not otherwise noted. General Schlenk inert gas techniques and glassware

were used throughout. All glassware, stainless steel needles and canulas were

heated in an oven at 200° C overnight prior to use. If not stated otherwise disposable

medical plastic syringes and silicon septa were used for reagent additions

throughout, which were stored in a descicator over P2O5 overnight prior to use. If

precise regular additions over a longer time period were required, an automatic

electromechanical syringe pump was used. Addition funnels were used only, if

reagents were incompatible with plastic and / or steel such as bromine or iodine

solutions. Unless noted otherwise all reactions were performed under an atmosphere

of dry nitrogen or argon (prepurified technical grade, passed over KOH and charcoal

prior to use) in degassed anhydrous solvents, preferably distilled prior to use: Et2O

and THF were distilled from sodium benzophenone ketyl; MeOH, EtOH, nPrOH and

iPrOH were refluxed over activated magnesium and then distilled; CH2Cl2, CHCl3

(CDCl3), CCl4, DMF, DMSO (DMSO-d6), MeCN (MeCN-d3), NEt3, HNEt2, and

HN(iPr)2 were distilled from calcium hydride. If not stated otherwise all workups were

performed in air. Exceptional moisture and / or air sensitivity of products is therefore

explicitly mentioned in the individual procedures. The concentration of alkyllithium

reagents was determined by inverse titration prior to use [54]:

COOH

Ph

Ph

COOLi

Ph

Ph

Ph

Ph

OLi

OLi

1.00 eq

diphenyl acetic acid

M (C14H12O2) = 212.25 g/mol

1.00 eq RLi RH RH> 1.00 eq RLi

endpoint

(pale yellow)c (RLi) =m (Ph2CHCOOH)

M (Ph2CHCOOH) x V tit. (RLi)

Pic. 7.1.1

- 190 -

Caution! Alkyllithium solutions are pyrophoric! They are handled under strict

exclusion of air and moisture and are stored at – 30° C! The titration is performed at

RT. To avoid volume errors the alkyllithium solutions are defrosted to RT before

titration and use for reactions as well. To precisely weighed 220 – 230 mg diphenyl

acetic acid (not hygroscopic) dissolved in ca. 6 – 8 ml Et2O in a Schlenk tube with a

small diameter (better visibility of endpoint) is added dropwise under well stirring

through a septum the alkyllithium solution (alkyllithium concentration range ca. 1.3 –

2.0 mol/l; nBuLi (M = 64.06 g/mol) in hexanes, tBuLi in pentane) with a 1 ml plastic

syringe (0.01 ml graduation; needle diameter max. 0.2 mm). The white lithium

carboxylate precipitates out immediately. The titration endpoint is indicated by the

formation of a persisting pale yellow color due to enolate formation. The exact

alkyllithium concentration is then calculated by its titration volume as shown above

(Pic. 7.1.1).

Silica gel F60 purchased from Fluka or Merck was used for preparative column

chromatography throughout and heated out at 200° C overnight in an oven in air prior

to use. The columns were packed in air without the exclusion of oxygen, but

chromatography itself was performed under medium pressure with nitrogen

throughout (“flash technique”). As eluents technical grade solvents were used, which

were prepurified prior to use by distillation in a rotary evaporator (RV). The substance

was applied as solution in the particular eluent or, if not well solulable in the particular

eluent, in a silica gel matrix (prepared by RV to dryness of a suspension consisting of

silica gel and the substance preferably in CH2Cl2 or in a suitable solvent of choice).

Thin layer chromatography (TLC) was performed on Merck F 60 silica plates with a

364 nm fluorescence indicator. Spots were detected by visibility, UV-fluorescence

depletion, by iodine oxidation in case of unsaturated non-aromatic compounds and /

or by ninhydrine spraying in case of primary amines. Retention factors Rf given are

meant for a rough estimation of separation.

NMR spectra were recorded on Jeol EX-270 Delta (270 MHz), Bruker AMX 300 (300

MHz), Jeol Lambda-400 (400 MHz) and Jeol A-500 (500 MHz) in deuterated

solvents. 1H-NMR-spectra were recorded without and 13C-NMR spectra with broad

band decoupling. The deutero solvents were used as internal reference standard

relative to TMS (δ = 0 ppm, s) for the 1H- and 13C-NMR spectra (Table 7.1.1).

- 191 -

Solvent 1H-NMR δ [ppm]

(m = 2S+1, JHD [Hz])

13C-NMR δ [ppm]

(m = 2S+1, JCD [Hz])

benzene-d6 7.15 (1) 28.0 (3, 1J = 24.0)

CDCl3 7.24 (1) 77.0 (3, 1J = 32.0)

acetone-d6 2.04 (5, 1J = 2.2) 206.0 (13, 2J = 0.9); 29.8 (7, 1J = 20.0)

D3C-CN 1.93 (5, 1J = 2.5) 118.2 (br); 1.3 (7, 1J = 21.0)

DMSO-d6 2.49 (5, 1J = 1.7) 39.5 (7, 1J = 21.0)

Table 7.1.1 1H- and 13C-NMR spectra with multiplicities of deuterated solvents.

Irradiation frequency

Deuterated Solvent

δ [ppm] PF6- as

[(nBu)4N]+ -PF6-

δ [ppm]

P(OCH3)3

δ [ppm]

Ph3P

109 MHz CDCl3 - 143.726

(h, 1JPF = 713 Hz)

- 4.393

(s)

+ 141.676

(s)

121 MHz CDCl3 - 143.725

(h, 1JPF = 713 Hz)

- 4.804

(s)

+ 141.580

(s)

109 MHz acetone-d6 - 142.771

(h, 1JPF = 708 Hz)

- 4.167

(s)

+ 141.578

(s)

121 MHz acetone-d6 - 142.754

(h, 1JPF = 708 Hz)

- 4.199

(s)

+ 141.525

(s)

Table 7.1.2 NMR-signals and multiplicities of 31P-reference substances in deuterated solvents.

31P-NMR-spectra were recorded at 109 and 120 MHz with broad-band decoupling

and were referenced directly to external 85 % aq. H3PO4 or to internal standards

(Table 7.1.2), which were referenced to external 85 % aq. H3PO4 (δ = 0 ppm, s). In

case of hexafluorophosphate salts the PF6- resonance and coupling were therefore

omitted, because they did not change in all cases presented here (Table 7.1.2, third

column). The NMR data are presented in the following order: Chemical shift δ [ppm],

signal multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, h = heptet, m =

multiplet, br = broad), coupling constant J [Hz], number of nuclei and structure

fragment assignment. All spectra are interpreted according to first order coupling.

Multiplicities of higher order are denoted generally as multiplets or in case of regular

geometry as pseudo first order multiplicities (pseudo d, etc.) without denoting a

- 192 -

coupling constant. In case of diastereomerically pure complexes the relative

configurations are always denoted before the data listing. In cases of diastereomeric

mixtures both diastereomers were listed together in the NMR spectrum of the

particular nucleus and each signal (if possible) assigned to the particular

diastereomer. Relative configurations and relative topicities were only assigned to the

particular NMR signal, if the assignment could be concluded from NOE or NOESY

measurements or from unambiguous similarity relationships. The relative

configurations (l for like, u for unlike; s for syn, a for anti) are always related to the

chiral center of the chelate ligand (41R - 44R) or to the chiral center of the ansa chain

(54R - 56RS) to the chiral Ru(II) center (RRu or SRu) followed by all others in the same

manner. Also in the same manner the relative topicities of diastereotopic η6-arene

protons were denoted according to their CIP priority in relation to the chiral center of

the ansa chain for complexes 54R - 56RS (CH(2) for ortho like; CH(6) for ortho

unlike; CH(3) for meta like; CH(5) for meta unlike).

Mass spectra were recorded on a Varian MAT 212 spectrometer by the Analytical

Service of the Institut für Anorganische Chemie II at the Friedrich-Alexander

Universität Erlangen-Nürnberg using field desorption (FD) or fast atom bombardment

(FAB) techniques. The MS-data are presented in the following order: Mass to charge

ratio signal [m/z], abundance [%], structure fragment, charge. All signals are

referenced to the highest peak (100 % abundance). Structure fragment signals

consisting of several isotope peaks are referenced to the highest of the particular

isotope peak and denoted as such.

Specific optical rotation was measured in a 10 cm (1 dm) cuvette with 589 nm

(sodium D-line) on a Perkin Elmer 341 polarimeter at the Institut für Organische

Chemie I in the group of Prof. Dr. A. Hirsch, Friedrich-Alexander-Universität

Erlangen-Nürnberg; the specific optical rotation are given in the following order: sign,

value [°(ml)/(dm)g], solvent and concentration [g/ml] in parentheses. Melting points

were determined on a Büchi 530 melting point apparatus in the group of Prof. Dr. P.

Gmeiner and are not corrected. Elementary microanalyses were performed also by

the Analytical Service of the Institut für Anorganische Chemie II at the Friedrich-

Alexander Universität Erlangen-Nürnberg using a Carlo Erba elemental analyzer

model 1106 (C, H, N), 1108 (C, H, N, S) and model Euro EA 3000 (Euro Vector).

- 193 -

Conversion CR [%] of catalytic reactions (Pic. 7.1.2) were followed roughly with GC

without using an internal standard. GC analyses were performed on a Shimadzu GC-

17 with a 10 m Carbowax column using hydrogen / oxygen as carrier gas and FID as

detection method. The computer program Class LC 101.64 was used for the analysis

of the GC chromatograms. The GC separation data are presented in the following

order: temperature, retention times tR(i) without death time correction and resolution

RS (Pic. 7.1.2).

| tR1 - tR2 |w1 + w2

tR1; tR2

w1; w2

= retention times

= peak half-widthresolution : RS = 2

conversion rate : CR = 100 %[product]

[product] + [educt]

enatiomeric excess: e.e. = 100 %[maj. enant.] - [min. enant.]

[maj. enant.] + [min. enant.]

Pic. 7.1.2

The determinations of enantiomeric excesses or purities were performed with HPLC

(pump: Knauer K-501; UV detector: two-channel Bio-Tek HPLC detector 535;

column: Daicel OD-H 0.46 cm diam. x 25.00 cm length; injection volume: 20 µl in

loop of analyte diluted in eluent; pressure: 15 bar; chromatogram analysis software:

Eurochrom 2000). As eluents mixtures of degassed n-hexane and iPrOH were used

throughout. Note other solvents than EtOH, iPrOH and alkanes destroy the chiral

stationary phase of OD columns in general! Peak assignments to the particular

enantiomers are based on analyses of enantiomerically enriched samples with one

enantiomer of known configuration in excess. These in turn were confirmed by

measurement of the optical rotations and ensuring sufficient separation or resolution

RS at the same time in this way. Of course the use of an internal standard is not

required for the analysis of the enantiomeric purity. In this way the enantiomeric

excess was calculated directly by the corresponding peak integrals (Pic. 7.1.2). Note

retentions times and resolutions depend from the individual machinery parameters

and manufacturers. The HPLC separation data are presented in the following order:

column, eluent, pressure, flow rate, detection wavelength, retention times tR(i) without

death time correction and resolution RS (Pic. 7.1.2).

- 194 -

7.2 Precursor Compounds

7.2.1 General Procedure for Birch Reductions [41 (1-10)]

All reductions were performed with lithium. Argon had to be used as an inert gas. All

operations were performed in a well ventilated hood! Best results were obtained for

0.1 - 0.3 mol scales of the arene. A 2 l three-necked round bottom flask with a

nitrogen gauge equipped with a gas tight mechanical stirrer, with a pressure

equalizing gas inlet device connected to an oil bubbler and sealed with a septum was

thoroughly flushed with argon. After cooling down to - 78° C in a dry ice / EtOH bath

gaseous ammonia from a tank was passed through in a moderate stream until 600 -

1000 ml of liquid ammonia have condensed. The reduced argon flush was stopped

when ca. 100 ml of liquid ammonia had condensed. During the condensation the

tube from the gas inlet device was kept shortly above the liquid surface by regular

adjustment. It is not recommended to dispense directly liquid ammonia into the flask

by turning the tank upside down or through a liquid outlet gauge, because the liquid

ammonia inside the tank is contaminated with iron, which inhibits the Birch reduction!!

After flushing the setup carefully with argon again and starting the mechanical stirrer

the arene dissolved in ethanol was canula transferred from a Schlenk flask into the

reaction vessel by argon overpressure. To avoid losses of ammonia the Schlenk flask

was cooled down to - 60° C and the reaction vessel to - 90° C prior to transfer. Then

preferably lithium granules or pea-sized lithium chunks (M = 6.94 g/mol) with a blank

shiny surface were added subsequently to the reaction solution in such time intervals

until the resulting blue color disappeared (initially the color persisted ca. 5 - 10 min.

and with the progress of the reaction ca. 15 min.). The lithium amount added was

sufficient, when the reaction solution did not decolorize for more than 1 h. Sometimes

this endpoint indication was not observed! Usually a minimum of 3 - 4 eq of lithium

per arene unit were used; if the arene contained additionally acidic functional groups,

then a minimum of 1 eq lithium more per group on the arene were required. Sterically

hindered arenes required up to 10 eq lithium. Overreduction had been observed only

once a while for benzoic acid and usually does not occur. After complete addition the

reaction was quenched in small portions (virulent reaction!) with solid ammonium

chloride (M = 53.49 g/mol; 1.1 eq in regard to the added lithium) and stirred until the

reaction solution became colorless and all lithium had reacted. The mechanical stirrer

- 195 -

was shut down and all equipment disconnected from the flask. From the open flask

all ammonia was evaporated overnight at RT outside the cooling bath in the back of

the hood. After aqueous workup the crude product was obtained (details below). In

case of incomplete arene reduction the crude product can be simply subjected to this

procedure again. Birch products should be stored 0° C.

1-Methoxycarbonylcyclohexa- 2, 5-diene 3 [41 (6-8)]

COOH COOCH3COOH

OCH3H3CO

MeOH / refluxcat. 0.03 eq p-TolSO3H

(M = 190.22 g/mol)

NH3 (l) / 3.29 eq Li

then 3.80 eq NH4Cl

1 3

1.25 eq

2 98 %a) b)

84 %, overall 82 %

M (C8H10O2) = 138.16 g/molM (C7H8O2) = 124.14 g/molM = 122.12 g/mol

M = 104.25 g/mold = 0.847 g/ml

Pic. 7.2.1

a) Benzoic acid 1 must be recrystallized from EtOH and dried over P2O5 in a

vacuum descicator prior to use. 8.03 g (0.066 mol) 1 in 50 ml EtOH were reduced

with 1.50 g (0.216 mol) lithium in ca. 600 ml liquid ammonia and quenched with 13.36

g (0.250 mol) ammonium chloride according to the general procedure above. After

acidic aqueous workup (pH = 1 , HCl), three times with Et2O, drying of the combined

organic layers with MgSO4, filtration, removal of solvents by RV and further drying

under HV 8.02 g (0.065 mol, 98 % yield) 2 were obtained as a viscous rancid

smelling oil sufficiently pure for the next step. 1H-NMR (CDCl3, 270 MHz): δ = 5.89 -

5.82 (m, 4H, olef. CH(2,3,5,6)-cyC6H7); 3.77 – 3.76 (m, 1H, CH(1)-cyC6H7); 2.70 -

2.66 (m, 2H, CH2(4)-cyC6H7). 13C{1H}-NMR (CDCl3, 75 MHz): δ = 179.24 (COOH);

126.77 (olef. CH(2,6)-cyC6H7); 121.39 (olef. CH(3,5)-cyC6H7); 41.42 (CH(1)-cyC6H7);

25.68 (CH2(4)-cyC6H7). MS (FD+, CH2Cl2): m/z (%) = 43 (96) [C2H3O]+, 57 (62)

[C3H5O]+, 69 (35) [C4H5O]+, 99 (31) [M-C2H]+, 122 (23) [M-2H]+, 124 (92) [M]+.

- 196 -

b) 8.07 g (0.065 mol) 2, 10 ml (8.47 g, 0.081 mol) 2,2-dimethoxyopropane and

0.37 g (0.002 mol) p-toluene sulfonic acid monohydrate in 30 ml in MeOH were

refluxed for 1.5 h at 80° C. The reaction was monitored with TLC (CH2Cl2, Rf (2) =

0.17, Rf (3) = 0.62). Workup: After cooling down to RT the solvents were removed

from the reaction solution by RV. The residue was suspended in sat. aq. NaHCO3

and three times extracted with Et2O. The combined organic layers were dried with

MgSO4, filtrated, solvents removed by RV and the crude product was dried further

under HV to give 8.20 g (0.059 mol, 91 % crude yield) 3 as a nearly colorless oil. The

crude product pure enough for the next step can be further purified by distillation (bp.

= 40 – 41° C / 0.01 mbar): 7.52 g (0.054 mol, 84 % yield, 82 % overall yield, benzoic

acid methylester ≤ 3 % by NMR) 3 colorless fruity smelling oil. 1H-NMR (CDCl3, 270

MHz): δ = 5.86 – 5.81 (m, 4H, olef. CH(2,3,5,6)-cyC6H7); 3.77 – 3.67 (m, 1H, CH(1)-

cyC6H7); 3.72 (s, 3H, -COOCH3); 2.70 – 2.64 (m, 2H, CH2(4)-cyC6H7). 13C{1H}-NMR

(CDCl3, 100 MHz): δ = 172.75 (COO-CH3); 126.17 (olef. CH(2,6)-cyC6H7); 121.90

(olef. CH(3,5)-cyC6H7); 51.87 (-COOCH3); 41.44 (CH(1)-cyC6H7); 25.56 (CH2(4)-

cyC6H7). MS (FD+, CDCl3 / CH2Cl2): m/z (%) = 136 (100) [M-2H]+, 138 (48) [M]+.

1,3,5-Trimethylcyclohexa-1,4-diene 5 [41 (9)]

NH3 (l) / 9.28 eq Li

then 9.44 eq NH4Cl

4

M = 120.19 g/mol d = 0.8675 g/ml

5 78 % crude (volatile!)

M (C9H14) = 122.21 g/mol

H3C CH3

CH3 CH3

H3C CH3

Pic. 7.2.2.

25.0 g (28.8 ml, 0.21 mol) mesitylene 4 in 130 ml EtOH were reduced with 13.4 g

(1.93 mol) lithium and quenched with 105.1 g (1.96 mol) ammonium chloride

according to the general procedure above. After evaporation of ammonia the residue

was suspended aqua dest. and extracted once with Et2O. The separated organic

layer was dried with MgSO4, filtrated and the solvent removed carefully by RV at RT

- 197 -

(product is considerably volatile!) to give 19.8 g (0.16 mol, 78 % crude yield) 5 as a

nearly clear oil sufficiently pure for the next step. 1H-NMR (CDCl3, 270 MHz): δ = 5.30

(m, 2H, olef. CH(2,6)-cyC6H5); 2.74 - 2.68 (m, 1H, CH(1)-cyC6H5); 2.42 (m, 1H,

CH(4)-cyC6H5); 2.39 (m, 1H, CH(4)-cyC6H5); 1.67 (not res. d, 6H, (3,5)-CH3); 0.99 (d, 3J = 7.01, 3H, (1)-CH3). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 130.05 (olef. C(3,5)-

cyC6H5); 125.03 (olef. CH(2,6)-cyC6H5); 35.87 (CH(1)-cyC6H5); 32.26 (CH2(4)-

cyC6H5); 23.07 ((3,5)-CH3); 22.54 ((1)-CH3).

1-(3’-Hydroxypropyl)cyclohexa-1,4-diene 17 [36 (4), 41 (10)]

NH3 (l) / 4.82 eq Li

then 5.37 eq NH4Cl 17 95 % crude

OH OH

16

M = 136.19 g/mol, d = 1.004 g/ml M (C9H14O) = 138.21 g/mol Pic. 7.2.3

16.40 g (16.3 ml, 0.12 mol) 3-phenylpropanol 16 in 80 ml EtOH are reduced with 4.03

g (0.58 mol) lithium and quenched with 34.61 g (0.65 mol) ammonium chloride

according to the general procedure above. After evaporation of ammonia the residue

is suspended in Et2O and the organic phase washed three times with brine. The

separated org. layer is dried with MgSO4, filtrated and the solvent removed by RV

and further under HV to give 15.88 g (0.11 mol, 95 % crude yield) 17 as a nearly

clear and fruity smelling oil sufficiently pure for the next step. 1H-NMR (CDCl3, 270

MHz): δ = 5.75 – 5.63 (m, 2H, olef. CH(4,5)-cyC6H7); 5.46 (m, 1H, olef. CH(2)-

cyC6H7); 3.65 (t, 3J = 6.5, 2H, -CH2-OH); 2.76 – 2.64 (m, 2H, CH2(3)-cyC6H7); 2.64 –

2.54 (m, 2H, CH2(6)-cyC6H7); 2.04 (t, 3J = 7.5, 2H, -CH2-CH2-CH2-OH); 1.69 (tt, 3J =

7.5, 3J = 6.5, 2H, -CH2-CH2-CH2-OH); 1.42 (br s, 1H, -CH2-CH2-CH2-OH). 13C{1H}-

NMR (CDCl3, 68 MHz): δ = 134.49 (olef. C(1)-cyC6H7); 124.24 (olef. CH(5)-cyC6H7);

124.20 (olef. CH(4)-cyC6H7); 118.73 (olef. CH(2)-cyC6H7); 62.80 (-CH2-OH); 33.71

(-CH2-CH2-CH2-OH); 30.20 (-CH2-CH2-CH2-OH); 28.87 (CH2(6)-cyC6H7); 26.73

(CH2(3)-cyC6H7).

- 198 -

7.2.2 General Procedure for the Synthesis of Di-µ-chlorobis[chloro{η6-arene}-

ruthenium(II)] Complexes

MeOH or EtOH were used as solvents and their absolutation was not required. To

2.90 - 6.20 eq of the cyclohexadiene derivative in MeOH or EtOH were added 1.00

eq ruthenium(III) chloride trihydrate (M(RuCl3(H2O)3) = 261.48 g/mol). If anhydrous

ruthenium(III) chloride (M(RuCl3) = 207.43 g/mol) was used, then 0.5 - 2.0 ml aqua

dest. were added to the reaction solution to afford complete solvatation. After

degassing with nitrogen the reaction mixture was stirred 17 – 28 h under reflux. In the

beginning of the reaction color often turned from dark red to bluish-green, but this

was not always observed. The reaction was complete, if the solution had decolorized

and an orange to red precipitate had formed. Workup: After cooling down to RT the

reaction mixture was placed in a fridge at - 30° C overnight to precipitate out the

reaction product completely. The product was then filtrated off in air on a glass sinter,

washed with EtOH, then with Et2O and with hexanes and finally dried by air suction.

The complexes are air stable in solid state and moderately airstable in solution.

Except 9 they are only solulable in MeCN and DMSO or other coordinating solvents.

In MeCN decomplexation of the arene occurs within hours, so it should be avoided

and used for recording NMR-spectra only.

Di-µ-chlorobis{chloro[η6-(methoxycarbonyl)benzene]ruthenium(II)} 7 [36 (7)]

RuCl3(H2O)3 / MeOH / 21 h reflux

7 95 %

3.06 eq

3

Ru Ru

Cl

ClCl

Cl

H3COOC

COOCH3

M (C16H16Cl4O4Ru2) = 616.25 g/mol

COOCH3

Pic. 7.2.4

According to the general procedure above from 4224 mg (16.15 mmol) RuCl3(H2O)3

and 6883 mg (49.46 mmol) 3 in 100 ml MeOH for 21 h under reflux. Workup as

above, but additionally dried in a descicator over P2O5 under vacuum overnight: 4750

mg (7.71 mmol, 95 % yield) 7 as a brick-red powder. If EtOH instead of MeOH is

used as solvent, than transesterification occurs to certain extent! 1H-NMR (MeCN-d3,

- 199 -

270 MHz, as acetonitrile adduct): δ = 6.45 (d, 3J = 5.8, 2H, CH(2,6)-(η6-PhCOOCH3)

Ru(II)(NCCD3)Cl2); 6.01 (dd, 3J = 4J = 5.8, 1H, CH(4)-η6-Ph); 5.80 (dd, 3J = 3J = 5.8,

2H, CH(3,5)-η6-Ph); 3.93 (s, 3H, -COOCH3). 13C{1H }-NMR (MeCN-d3, 68 MHz, as

acetonitrile adduct): δ = 165.49 (η6-PhCOOCH3); 89.87 (CH(4)-η6-Ph); 88.58

(CH(3,5)-η6-Ph); 82.02 (CH(4)-η6-Ph); 80.55 (C(1)-η6-Ph); 53.04 (-COOCH3).

Di-µ-chlorobis{chloro[η6-(1,3,5-trimethylbenzene)]ruthenium(II)} 8 [41 (11)]

RuCl3

EtOH / 17 h reflux

8 60 %

2.90 eq

CH3

H3C CH3CH3

CH3

Ru Ru

Cl

Cl

H3C

CH3

H3C

H3C

Cl

Cl

5

M (C18H24Cl4Ru2) = 584.34 g/mol Pic. 7.2.5

According to the general procedure above from 1219 mg (5.88 mmol) RuCl3 and

2080 mg (49.46 mmol) 5 in 35 ml EtOH and some drops of aqua dest. for 17 h under

reflux. Workup and isolation as above gave 1035 mg (1.77 mmol, 60 % yield) 8 as a

brown-reddish powder. 1H-NMR (MeCN-d3, 270 MHz, as acetonitrile adduct): δ =

5.02 (s, 3H, CH-(η6-mesitylene)Ru(II)(NCCD3)Cl2); 2.13 (s, 9H, -CH3).

Di-µ-chlorobis[chloro{η6-[1-methyl-4-(methylethyl)benzene]}-

ruthenium(II)] 9 [41 (12)]

RuCl3

EtOH / 28 h reflux

M (C20H28Cl4Ru2) = 612.39 g/mol

6 (+)-(S)-limonene

M = 136.24 g/mold = 0.84 g/ml

Ru Ru

Cl

ClCl

Cl

6.14 eq

9 61 %

*

Pic. 7.2.6

- 200 -

According to the general procedure above from 3332 mg (16.06 mmol) RuCl3 and 16

ml (13.44 g, 98.65 mmol) (+)-(S)-limonene 6 in 100 ml EtOH and some drops of aqua

dest. for 28 h under reflux. Workup: The hot reaction mixture was filtrated off

ruthenium oxide byproducts over a D4-glass sinter with filter flakes, the byproduct

cake was washed thoroughly with CH2Cl2 and the solvents of the combined red

colored filtrates are removed by RV. The product was precipitated out with n-pentane

and filtrated off limonene over a D4-glass sinter, washed further with n-pentane and

dried by air suction to give 3016 mg (4.92 mmol, 61 % yield) 9 as brick-red

microcrystalline powder. 1H-NMR (CDCl3, 270 MHz): δ = 5.45 (d, 3J = 6.1, 4H,

CH(2,6)-[(η6-(p-cymene))Ru(II)Cl]2(µ-Cl)2); 5.32 (d, 3J = 6.1, 4H, CH(3,5)-η6-(p-

cymene)); 2.90 (h, 3J = 7.0, 2H, -CH(CH3)2 of p-cymene); 2.14 (s, 6H, -CH3 of p-

cymene); 1.26 (d, 3J = 7.0, 12H, -CH(CH3)2). 13C{1H}-NMR (CDCl3, 68 MHz): δ =

101.19 (C(4)-η6-(p-cymene)); 96.71 (C(1)-η6-(p-cymene)); 81.29 (CH(2,6)-η6-(p-

cymene)); 80.52 (CH(3,5)-η6-(p-cymene)); 30.68 (-CH(CH3)2 of p-cymene); 22.22

(-CH(CH3)2); 19.00 (-CH3 of p-cymene).

Di-µ-chlorobis{chloro[η6-(3-hydroxypropyl)benzene]-

ruthenium(II)} 18 [36 (4), 41 (10)]

RuCl3(H2O)3

EtOH / 23 h reflux

M (C18H24Cl4O2Ru2) = 616.34 g/mol

Ru Ru

Cl

ClCl

Cl

17

OH3.42 eq

HO

OH

18 94 %

Pic. 7.2.7

According to the general procedure above from 2242 mg (10.81 mmol) RuCl3 and

5115 mg (37.01 mmol) 17 in 90 ml EtOH and some drops of aqua dest. for 23 h

under reflux. After workup as above 2626 mg (4.23 mmol, 79 % yield) 18 were

obtained as brown-reddish microcrystalline powder from the first crop. The solvent of

the combined washing solutions was removed by RV, the brown-reddish residue

triturated with Et2O, precipitated completely at - 30° C overnight. After filtration the

material was combined with the first crop and dried in a descicator over P2O5 under

- 201 -

vacuum overnight. Overall 3125 mg (5.07 mmol, 94 % yield) 18 were obtained. Mp. =

204 - 206° C (dec.). 1H-NMR (MeCN-d3, 270 MHz, as acetonitrile adduct): δ = 5.70

(m, 2H, CH(3,5)-(η6-Ph-CH2-CH2-CH2-OH)Ru(II)(NCCD3)Cl2); 5.60 (m, 1H, CH(4)-η6-

Ph); 5.45 (d, 3J = 6.1, 2H, CH(2,6)-η6-Ph); 3.58 (dt, 3J = 5.4, 3J = 5.9, 2H, -CH2-OH);

2.80 (t, 3J = 5.4 (coupling not always observed), 1H, -OH); 2.60 (t, 3J = 7.8, 2H, -CH2-

CH2-CH2-OH); 1.82 (tt, 3J = 5.9, 3J = 7.8, 2H, -CH2-CH2-CH2-OH). 13C{1H}-NMR

(MeCN-d3, 68 MHz, as acetonitrile adduct): δ = 103.49 (C(1)-η6-Ph); 86.59 (CH(2,6)-

η6-Ph); 82.59 (CH(3,5)-η6-Ph); 81.64 (CH(4)-η6-Ph); 61.46 (-CH2-CH2-CH2-OH);

32.80 (-CH2-CH2-CH2-OH); 30.40 (-CH2-CH2-CH2-OH).

7.2.3 Di-µ-bromobis{bromo[η6-(3-hydroxypropyl)benzene]ruthenium(II)} 19

M (C18H24Br4O2Ru2) = 794.14 g/mol

Ru Ru

Cl

ClCl

Cl

18

HO

OH

Ru Ru

Br

BrBr

Br

HO

OHexcess NaBr

(M = 102.89 g/mol)

aqua dest. (in air) / RT

19 83 %

Pic. 7.2.8

The reaction does not need to be performed under inert gas atmosphere. 8.08 g

(13.1 mmol) 18 and 15.50 g (179.8 mmol) sodium bromide were suspended in 250 ml

aqua dest. and swirled for 5 min.. The solution becomes clear and deep red. The

black oxides precipitated during the course of the reaction were filtered off through a

simple paper filter. The water was completely removed by RV, the residue was

dissolved in MeCN and filtrated off excess sodium bromide and sodium chloride

through a D4-sinter. MeCN and residual water were removed by RV and in a second

cycle by coevaporation with MeOH. The product was crystallized from MeOH at - 30°

C overnight. The blood red microcrystals were filtrated off, washed with Et2O and

dried over P2O5 under vacuum in a descicator for several days to give 8.66 g (10.9

mmol, 83 %) 18. 1H-NMR (MeCN-d3, 270 MHz, as acetonitrile adduct): δ = 5.78 –

5.64 (m, 3H, CH(3,4,5)-(η6-Ph-CH2-CH2-CH2-OH)Ru(II)(NCCD3)Br2); 5.54 (d, 3J =

- 202 -

5.3, 2H, CH(2,6)-η6-Ph); 3.58 (dt, 3J = 6.2, 3J = 5.3, 2H, -CH2-OH); 2.76 (t, 3J = 5.3

(coupling not always observed), 1H, -OH); 2.65 (t, 3J = 7.8, 2H, -CH2-CH2-CH2-OH);

1.82 (tt, 3J = 6.2, 3J = 7.8, 2H, -CH2-CH2-CH2-OH). 13C{1H}-NMR (MeCN-d3, 68 MHz,

as acetonitrile adduct): δ = 102.97 (C(1)-η6-Ph); 85.91 (CH(2,6)-η6-Ph); 83.82

(CH(3,5)-η6-Ph); 82.80 (CH(4)-η6-Ph); 61.37 (-CH2-OH); 33.26 (-CH2-CH2-CH2-OH);

30.95 (-CH2-CH2-CH2-OH). MS (FAB): m/z (%) = 714 (43) [M-Br]+ isotope peak, 634

(10) [M-2Br]+ isotope peak, 137 (92) [Ph-CH2-CH2-CH2-OH2]+, 136 (100) [Ph-CH2-

CH2-CH2-OH]+, 89 (50) [C7H5]+, 77 (48) [C6H5]+. EA anal.calc for C18H24Br4O2Ru2

(794.14): C 27.22, H 3.05; found: C 27.06, H 3.00.

7.2.4 Dibromo[η6-(3-bromopropyl)benzene]triphenylphosphino-

ruthenium(II)} 20

M (C27H26Br3PRu) = 722.26 g/mol

19

Ru Ru

Br

BrBr

Br

HO

OH

PPh3

Ru

BrBr

Br

4.89 eq PPh3 (M = 262.28 g/mol)/3.04 eq CBr4(M = 331.63 g/mol)

THF / RT2.00 eq

20 81 %

Pic. 7.2.9

2312 mg (2.91 mmol) 19 and 3735 mg (14.24 mmol) triphenylphosphine were stirred

in 120 ml THF until the reaction solution became clear and deep red after ca. 10 min.;

then 2934 mg (8.85 mmol) solid carbon tetrabromide were added in one portion and

triphenylphosphine oxide started to precipitate out. The mixture was stirred 1d at RT

before quenching with 20 ml EtOH. After solvent removal by RV and further by HV

8572 mg of a red solid foam were obtained. After twofold recrystallization from

CH2Cl2 / MeOH at - 30° C the purple crystals suitable for X-ray structure

determination were filtrated of, washed first with small amounts of MeOH, then with

Et2O and finally dried by air suction to give 3415 mg (4.73 mmol, 81 %) airstable 23.

Mp. > 165° C (dec.). 1H-NMR (CDCl3, 270 MHz): δ = 7.74 – 7.63 (m, 6H, CH(2,6)-

Ph3PRu(II)Br2(η6-Ph-CH2-CH2-CH2-Br)); 7.43 – 7.23 (m, 9H, CH(3,4,5)-PPh3); 5.35

- 203 -

(d, 3J = 5.7, 2H, CH(2,6)-η6-Ph); 5.14 (ddd, 3J = 5.7, 3J = 5.4, 3JHP = 1.6, 2H, CH(3,5)-

η6-Ph); 4.69 (td, 3J = 5.4, 3JHP = 2.4, 1H, CH(4)-η6-Ph); 3.45 (t, 3J = 6.3, 2H, -CH2-Br);

2.92 (t, 3J = 7.7, 2H, -CH2-CH2-CH2-Br); 2.22 (tt, 3J = 6.3, 3J = 7.7, 2H, -CH2-CH2-

CH2-Br). 13C{1H}-NMR (CDCl3, 70 MHz): δ = 134.20 (d, 2JCP = 9.2, CH(2,6)-PPh3);

133.65 (br, C(1)-PPh3); 130.32 (d, 4JCP = 2.5, CH(4)-PPh3); 127.91 (d, 3JCP = 10.0,

CH(3,5)-PPh3); 108.82 (2JCP = 7.0, C(1)-η6-Ph); 89.89 (2JCP = 5.6, CH(2,6)-η6-Ph);

87.55 (2JCP = 1.1, CH(3,5)-η6-Ph); 83.44 (CH(4)-η6-Ph); 32.65 (-CH2-Br); 32.03 (d, 3JCP = 0.8, -CH2-CH2-CH2-Br); 31.80 (d, 4JCP = 0.8, -CH2-CH2-CH2-Br). 31P{1H}-NMR

(CDCl3, 109 MHz): δ = 25.05 (s, 1P). MS (FD+, CDCl3): m/z (%) = 721 (67) [M]+

isotope peak, 460 (24) [M-PPh3]+, 382 (52) [M-PPh3-Br]+ isotope peak, 342 (100)

isotope peak, 263 (96) [PPh3]+. EA anal.calc for C27H26Br3PRu (722.26): C 44.90, H

3.63; found: C 44.80, H 3.51.

7.3 Syntheses of Epimeric σ(N):σ(S)-β-Amino-

thioether Ruthenium(II) η6-Arene Complexes

7.3.1 (-)-(R)-Phenylglycinol 27R [43 (3)]

Ph COOH

NH2

* (R)

Ph

NH2

OH

1) addition to: 2.44 eq NaBH4 (M = 37.83 g/mol) + 1.01 eq I2 (M = 253.81 g/mol) / - 5° to 0° C / THF

2) 18 h reflux

M (C8H11NO) = 137.18 g/mol

1.00 eq

26R 27R 87 %

* (R)

M = 151.16 g/mol

Pic. 7.3.1

The reaction should not be scaled up above 15 g of (R)-phenylglycine 26R due to

lower yields obtained then. 6.95 g (183.8 mmol) sodium borohydride suspended in

200 ml THF in a 500 ml three neck round bottom flask connected with an inert gas

inlet gauge and a reflux condenser with an oil bubbler were cooled down to ca. - 5°

C. To the well stirred suspension were added dropwise within 1 h 19.31 g (76.1

- 204 -

mmol) iodine in 50 ml THF through a pressure equalizing addition funnel. Caution!

Addition of the iodine solution must be performed slowly enough to keep the vigorous

hydrogen evolution under reasonable control! The dropping rate was adjusted in that

manner the suspension was completely decolorized before addition of the next

aliquot and the temperature was kept always below 0° C. For well stirring the use of a

ca. 6 cm x 1 cm Teflon coated magnetic stirring bar is recommended. The residual

iodine in the addition funnel was dissolved in 20 ml THF and added to the

suspension in the same manner. After exchanging the addition funnel against a glass

stopper 11.36 g (75.2 mmol) 26R (> 99.5 e.e., Acros) were added in one portion. The

mixture was stirred at RT for 15 min. and inert conditions were ensured by passing

through nitrogen through the gas inlet gauge during this time. After stopping the

nitrogen flux the mixture was heated 18 h under reflux at 80° C under well stirring.

The beginning of the reduction was marked by foaming and hydrogen evolution,

which ceased after a while. Workup: The white suspension was cooled down to RT

under nitrogen flux. MeOH was then carefully added in portions until the mixture

became clear (Caution! Hydrogen evolution!). All solvents were removed by RV, the

white residue was stirred 4 h at RT in ca. 500 ml of a 40 % aq. NaOH solution and an

organic layer separated on the surface. The mixture was extracted four times with

CH2Cl2 (Note: organic layer separated above aqueous phase!) and the combined

organic layers were dried with Na2SO4 overnight. After filtration, removal of all

solvents by RV and further drying under HV 9.18 g (66.9 mmol, 89.0 % crude yield)

27R were obtained as yellowish microcrystals or as a viscous oil. The crude product

was crystallized from a minimum amount of hot toluene down to - 30° C overnight.

After warming to RT the white microcrystals were filtrated from the mother liquor,

washed with pentane and dried in air to give 8.37 g (61.0 mmol, 81.1 % yield) 27R.

From the mother liquor a second crop of 0.61 g pure (4.4 mmol, 5.9 %) 27R could be

obtained in the same manner, giving rise to an overall yield of 8.98 g (65.4 mmol,

87.0 % yield) 27R. Mp. = 75° C, Mp. (lit) = 75 - 79° C. [α]23D = - 47.2 (CH2Cl2, c =

0.047); [α]23D (lit.) = -22.5 (MeOH, c = 6). 1H-NMR (CDCl3, 270 MHz): δ = 7.38 – 7.20

(m, 5H, Ph); 4.03 (dd, 3J = 8.2, 3J = 4.3, 1H, Ph-CH(NH2)-CH2-OH); 3.72 (dd, 2J =

10.7, 3J = 4.3, 1H, -CH2-); 3.53 (dd, 2J = 10.7, 3J = 8.2, 1H, -CH2-); 1.90 ( br s, 3H,

-NH2,-OH). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 142.27 (C(1)-Ph); 128.46 (CH(3,5)-

Ph); 127.25 (CH(4)-Ph); 126.38 (CH(2,6)-Ph); 67.69 (-CH2-); 57.30 (-CH-).

- 205 -

7.3.2 (-)-(4R)-4-Phenyl-2-oxazolidinone 29R [43 (4-5)]

O

HN

Ph

O

* (R)

PhOH

NH2

* (R)

29R M (C9H9NO2) = 163.07 g/mol

1.08 eq Cl3COCl (M = 181.83 g / mol, d = 1.629 g/ml) /

1.20 eq DMAP(M = 122.17 g/mol) / THF / RT / 99 % crude

PhOH

HN

* (R)

28R M (C10H10Cl3NO2) = 282.55 g/mol

O

CCl3

1.76 eq K2CO3(M = 138.21 g/mol)acetone / RT / 81 % overall 80 %

0.71 eq Cl3CO-COCl(M = 197.83 g/mol, d = 1.640 g/ml)

2.91 eq NaOH (M = 40.00 g/mol) /CH2Cl2 : H2O = 2.4 : 1 /-10 o C to RT / 98 % crude yield, 89 % recryst.

27R

a)

b)

c)

Pic. 7.3.2

a) Caution! All reactions with toxic diphosgene must be performed in a well

ventilated hood! Diphosgene decomposes to extremely toxic and gaseous phosgene

over a period of time! All glassware and tools contaminated with diphosgene have to

be rinsed with an ethanolic ammonia solution! The original procedure [43 (4)] was

modified as follows. A suspension of 3541 mg (25.8 mmol) 27R in 50 ml CH2Cl2 p.a.

mixed with 21 ml (75.1 mmol) of a 12.6 % aq. NaOH solution in a 250 ml Schlenk

flask closed with a septum and connected via a needle adapter to an oil bubbler was

degassed by passing through nitrogen carefully under vigorous stirring. At ca. - 10° C

2.2 ml (3608 mg, 18.2 mmol) diphosgene in 12 ml dry CH2Cl2 under nitrogen were

added dropwise with a syringe through a canula with a syringe pump within 40 min.

to the well stirred suspension. After addition the mixture was stirred for 2 h defrosting

to RT. Workup: The mixture was poured into a sat. NaHCO3 solution, extracted twice

with CH2Cl2, the combined organic layers were dried with MgSO4, filtrated and the

solvents removed by RV. The crude, nearly colorless microcrystalline product 29R

was dried further under HV to give 4114 mg (25.2 mmol, 98 %), which is purified by

recrystallization from a minimum amount of hot EtOAc and some drops of hexanes

from RT down to - 30° C. The colorless crystals were filtrated from the cold mother

liquor, washed with pentane, dried in air and further under HV to give 3756 mg (23.0

mmol, 89 %) 29R. From the mother liquor another crop of 406 mg (2.5 mmol, 10 %)

- 206 -

29R was obtained by recrystallization, which was kept for further purification. Mp. =

122 - 123° C, Mp. (lit) = 129 - 132° C. [α]23D = - 61.1 (CH2Cl2, c = 0.007), [α]23

D (lit.) =

- 49.5 (CHCl3, c = 2). 1H-NMR (CDCl3, 270 MHz): δ = 7.46 – 7.28 (m, 5H, Ph); 5.69

(br s, 1H, -NH-CO-); 4.94 (dd, , 3J = 6.9, 2J = 8.2, 1H, Ph-CH(NH-)-C(HRe)(HSi)-O-);

4.72 (dd, 3J = 8.7, 2J = 8.2, 1H, -C(HRe)(HSi)-); 4.17 (dd, 3J = 8.7, 3J = 6.9, 1H, -CH-). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 159.46 (-NH-CO-); 139.37 (C(1)-Ph); 129.22

(CH(3,5)-Ph); 128.89 (CH(4)-Ph); 126.04 (CH(2,6)-Ph); 72.52 (-CH2-); 56.36 (-CH-).

MS (EI): m/z (%) = 163 (43) [M]+, 162 (46) [M - H]+, 145 (39) [M – H2O]+, 133 (63)

[C9H9O]+, 132 (28) [C9H8O]+, 105 (78) [C9H8]+, 104 (100) [C8H8]+, 91 (46) [C7H7]+.

b) 1.80 ml trichloroacetyl chloride (2932 mg, 16.1 mmol) were added dropwise at

RT to 2048 mg (14.9 mmol) 27R and 2048 mg DMAP (18.7 mmol) in 100 ml THF. A

white precipitate was formed immediately. The reaction solution was stirred for 12 h.

Workup: The solution was poured on 200 ml 1 % aq. HCl and the aqueous phase is

extracted once with ca. 150 ml CH2Cl2. The org. phase was washed twice with brine,

dried over MgSO4, filtered off, the solvents removed by RV and the crude product

dried further under HV to give 4161 mg (14.7 mmol, 99 % crude yield) 28R as white

microcrystals sufficiently pure for the next step. 1H-NMR (CDCl3, 270 MHz): δ = 7.49 -

7.13 (m, 5H, Ph), 5.39 (td, 3J = 5.6, 3J = 2.4, 1H, Ph-CH(NH-CO-CCl3)-CH2-OH); 4.70

(d, 3J = 5.6, 2H, -CH2-). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 161.64 (Ph-CH(NH-CO-

CCl3)-CH2-OH); 161.50 (-CO-CCl3); 135.36 (C(1)-Ph); 129.07 (CH(3,5)-Ph); 128.79

(CH(4)-Ph); 126.44 (CH(2,6)-Ph); 69.18 (-CH2-); 53.93 (-CH-). MS (FD+, THF /

CH2Cl2): m/z (%) = 281 [M]+ isotope peak.

c) 4161 mg (14.7 mmol) 28R and 3575 mg (25.9 mmol) potassium carbonate in

90 ml acetone were stirred for 65 h at RT (Note: If not anhydrous acetone is used

hydrolysis of the amide occurs to high extend!). Workup: The reaction solution was

filtered off from potassium carbonate, ca. 100 ml CH2Cl2 were added, the organic

solution dried over MgSO4, filtered, the solvents removed by RV and the crude

product dried further under HV to give 2649 mg 29R as dirty microcrystals.

Recrystallization as described above gave 1946 mg (11.9 mmol, 81 % yield, 80 %

overall yield) pure 29R as colorless needles.

- 207 -

7.3.3 (-)-(2R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-phenylethanol 30R

Ph

NH2

OH

27R

* (R)

Ph

HN

OH * (R)

O

O 30R

95 % crude, M (C13H19NO3) = 237.30 g/mol

1.10 eq (tBuOCO)2O (M ((BOC)2O) = 218.25 g/mol

CH2Cl2 / RT

Pic. 7.3.3

The reaction does not require anaerobic and / or anhydrous conditions. To a clear

solution of 10.16 g (74.03 mmol) 27R in 130 ml CH2Cl2 were added under well

stirring in one portion 17.80 g (81.57 mmol) solid (BOC)2O (Low melting point,

substance has to be weighed cold!). Shortly after carbon dioxide evolution was

observed. After 1 h stirring the solvent was removed by RV, the off-white crystalline

mass was suspended in pentanes, collected by filtration, washed with pentanes

further and dried over P2O5 in a descicator overnight to give 16.75 g (70.56 mmol, 95

% yield) 30R as a white powder sufficiently pure for the next step. If the removal of

tBuOH should not be complete, then the product is suspended in toluene and tBuOH

removed by coevaporation by RV repetitively in a warm water bath. Mp. = 122 - 124°

C (inc.), Mp. (lit) = 137 - 139° C. [α]23D = - 44.4 (CH2Cl2, c = 0.022), [α]23

D (lit.) = -38.0

(CHCl3, c = 1). The NMR-spectra are broadened due to the hindered rotation of the

tBu group! 1H-NMR (DMSO-d6, 270 MHz): δ = 7.31 – 7.16 (2 m, 5H, Ph); 4.76 (br s,

1H, -NH-); 4.50 (q, 3J = 6.9, 1H, Ph-CH(NH[CO(OtBu)])-CH2-OH); 3.47 (d, 2J = 6.9,

2H, -CH2-OH); 1.35 (br s, 9H, OC(CH3)3). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 156.0

(-CO-OC(CH3)3); 139.5 (C(1)-Ph); 128.5 (CH(3,5)-Ph); 127.5 (CH(4)-Ph); 126.4

(CH(2,6)-Ph); 79.9 (-OC(CH3)3); 66.5 (-CH2-); 56.8 (-CH-); 28.3 (-OC(CH3)3). MS

(FD+, CH2Cl2): m/z (%) = 206 (100) [M-2O]+ isotope peak, 238 (57) [M]+ isotope

peak.

- 208 -

7.3.4 (-)-(1R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-methylsulfonyloyx-1- phenylethane 31R

31R

Ph

HN

OH * (R)

O

O30R

M (C14H21NO5S) = 315.39 g/mol

Ph

HN

O * (R)

O

O

SCH3

O O

1.51 eq NEt3 (M = 101.19 g/mol, d = 0.726 g/ml) /CH2Cl2 / 0° C to RT

1.23 eq H3CSO2Cl(M = 114.55 g/mol, d = 1.477 g/ml)

89 % crude

Pic. 7.3.4

Exclusion of moisture is crucial during the reaction! The solid product is airstable, but

should be stored in fridge. 31R is a strong alkylating agent with potential neighbor

group activation, so it is considered as toxic and as a potential carcinogen! To 24.86

g (0.105 mol) 30R and 22.0 ml (15.97 g, 0.158 mol) NEt3 in 300 ml CH2Cl2 were

added within 10 min. dropwise with a syringe through a silicone septum (latex rubber

will be affected by the sulfonating agent) at 0° C under well stirring 10.0 ml (14.77 g,

0.129 mol) methylsolfonylchloride. After ca. 1 min. the clear colorless solution turned

yellowish and triethylammonium chloride started to precipitate out. The mixture was

stirred 16 h under defrosting to RT. Workup: The reaction solution was washed with

sat. aq. NaHCO3 solution until the aqueous phase was neutral. The organic phase

was washed once with brine, dried over MgSO4, filtrated and the solvent was

removed by RV. After drying under HV 29.53 g (0.094 mol, 89 % crude yield) 31R

were obtained as slightly yellowish powder sufficiently pure for the next step. Mp. =

82° C starting dec., 102 - 103° C melt. [α]23D = - 29.2 (CH2Cl2, c = 0.0082). The

NMR-spectra are broadened due to hindered rotation of the tBu group! 1H-NMR

(DMSO-d6, 270 MHz): δ = 7.71 (br pseudo d, 1H, Ph-CH(NH[CO(OtBu)])-CH2-O-

SO2CH3); 7.36 – 7.26 (m, 5H, Ph); 4.85 (not res. dd, 1H, -CH-); 4.23 (2 not res. dd,

2H, -CH2-); 3.14 (s, 3H, -SO2CH3); 1.34 (br s, 9H, OC(CH3)3). 13C{1H}-NMR (DMSO-

d6, 68 MHz, dominant rotamer): δ = 154.85 (-CO-OC(CH3)3); 138.78 (C(1)-Ph);

128.30 (CH(3,5)-Ph); 127.53 (CH(4)-Ph); 126.93 (CH(2,6)-Ph); 78.22 (-OC(CH3)3);

71.30 (-CH2-); 53.30 (-CH-); 36.86 (-SO2CH3); 28.21 (-OC(CH3)3). MS (FD+, CH2Cl2):

m/z (%) = 163 (100) [4-phenyl-2-oxazolidinone]+ isotope peak, 316 (71) [M]+ isotope

peak. A correct EA could not be obtained.

- 209 -

7.3.5 General Procedure for the Syntheses of chiral β-Aminothioether Ligands

by Nucleophilic Ringopening of (-)-(4R)-4-Phenyl-2-oxazolidinone 29R by the Ishibashi Protocol [43 (6-7)]

Ph

NH2

S * (R)O

HN

Ph

O

*

29R

R

32R R = Bn M (C15H17NS) = 243.37 g/mol 84 %33R R = Ph M (C14H15NS) = 229.35 g/mol 75 %36R R = β-Naph M (C18H17NS) = 279.41 g/mol 26 %

RSH:

R = Bn M = 124.21 g/mol, d = 1.058 g/mlR = Ph M = 101.17 g/mol, d = 1.078 g/mlR = β-Naph M = 160.24 g/mol

1.23 eq RSH : 2.27eq RSNa R = Bn2.34 eq RSH : 3.41eq RSNa R = Ph2.91eq RSH : 4.28 eq RSNa R = β-Naph

nPrOH / reflux(R)

pic. 7.3.5

Exclusion of moisture and air is crucial during the reaction, hence thiols and thiolates

are sensitive to oxidation and in case of residual moisture also hydroxide can act as a

nucleophile opening 29R to 27R! Due to the perverse stench of the thiols the reaction

and workup should be performed in an efficient fume hood! Caution! Especially

aromatic thiols are severe skin irritants and toxic! The original procedure [43 (6-7)] had

to be changed as follows. After refluxing for at least 3 h over activated magnesium

under nitrogen nPrOH was directly distilled into the reaction Schlenk flask, in which

was then an aliquot of freshly cut sodium is dissolved. After sodium had dissolved

completely an excess of the particular thiol was added under a stream of nitrogen,

whereupon the solution became slightly warm and developed a pinkish color: The

reaction required ca. 2.3 – 4.3 eq of thiolate in the presence of ca. 1.2 – 2.9 eq

excess thiol (buffered solution) in regard to the oxazolidinone! Then 29R was added

to the solution, the Schlenk flask was connected to a reflux condenser equipped with

an oil bubbler. The whole system was then thoroughly flushed with nitrogen. After

shutting down the nitrogen flux the solution was stirred under gentle reflux in an oil

bath (130° - 135°C) for at least 12 – 24 h until slightly turbid and yellowish. Workup:

After cooling down under nitrogen stream the reaction solution was poured into a

threefold volume of 40 % aq. NaOH solution, which was extracted once with CH2Cl2

- 210 -

(upper layer!). The separated organic phase was washed at least twice with 40 % aq.

NaOH solution to remove at least most of the excess thiol. To the combined washing

solutions 30 % aq. hydrogen peroxide solution were added to oxidize the thiolates to

sulfonates for appropriate disposal. The organic extraction phase was dried over

MgSO4, filtrated and the solvent removed by RV and further by HV. The particular

crude products obtained as yellowish oils or taffy microcrystalline masses were then

purified as described below. To avoid humiliating stench all glassware used must be

rinsed with hydrogen peroxide solution right after use and left in a KOH / iPrOH bath

overnight. All rubber tubings and the bubbler’s oil should be disposed! Correct EA's could not be obtained and were also not reported for 33R.

(-)-(1R)-1-Phenyl-2-[(phenylmethyl)thio]ethylamine 32R

According to the general procedure above from 661 mg (28.75 mmol) sodium, 5.20

ml (5502 mg, 44.29 mmol) benzylthiol and 2062 mg (12.64 mmol) 29R in 30 ml

nPrOH for 24 h under reflux to give 2706 mg (11.12 mmol, 88 % crude yield) 32R as

a slightly turbid yellowish oil. Kugelrohr distillation (bp. > 160° C / 0.0001 mbar) gave

2586 mg (10.63 mmol, 84 % yield) 32R as clear and colorless oil smelling only like

rotten straw. [α]23D = - 46.2 (CH2Cl2, c = 0.0017). 1H-NMR (CDCl3, 270 MHz): δ =

7.34 – 7.19 (2 m, 10H, Ph-CH(NH2)-CH2-S-CH2-Ph); 3.99 (dd, 3J = 8.9, 3J = 4.3, 1H,

-CH-); 3.65 (s, 2H, -CH2-S-CH2-Ph); 2.73 (dd, 2J = 13.5, 3J = 4.3, 1H, -CH2-S-CH2-

Ph); 3.53 (dd, 2J = 13.5, 3J = 8.9, 1H, -CH2-S-CH2-Ph); 1.77 (br s, 2H, -NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 144.26 (C(1)-Ph-CH(NH2)-); 138.04 (C(1)-Ph-

CH2-S-); 128.69 (CH(3,5)-Ph-CH(NH2)-); 128.30 (CH(2,6)-Ph-CH2-S-); 128.29

(CH(3,5)-Ph-CH2-S-); 127.16 (CH(4)-Ph-CH(NH2)-); 126.85 (CH(4)-Ph-CH2-S-);

126.14 (CH(2,6)-Ph-CH(NH2)-); 54.60 (Ph-CH(NH2)-CH2-S-); 41.16 (-CH2-S-CH2-Ph);

36.40 (Ph-CH2-S-). MS (FD+, CH2Cl2): m/z (%) = 244 (100) [M + H]+ isotope peak.

(+)-(1R)-1-Phenyl-2-(phenylthio)ethylamine 33R [43 (7)]

According to the general procedure above from 290 mg (12.61 mmol) sodium, 2.00

ml (2156 mg, 21.31 mmol) thiophenol and 604 mg (3.70 mmol) 29R in 20 ml nPrOH

for 12 h under reflux: 790 mg (3.44 mmol, 93 % crude yield) 33R as brownish

- 211 -

microcrystals. The crude product was recrystallized from EtOH and some drops of

hexanes at – 30° C, the crystals filtrated off from the cold mother liquor, washed with

pentanes and dried by air suction and in HV to give 636 mg (2.77 mmol, 75 % yield)

33R as filthy white crystals. Mp. = 72 - 73° C, Mp. (lit) = 69 - 70° C. [α]23D = + 29.4

(CH2Cl2, c = 0.0042); [α]23D (lit. for (S)-enantiomer) = - 24.2 (CHCl3, c = 1.00). 1H-

NMR (CDCl3, 270 MHz): δ = 7.42 – 7.14 (2 m, 10H, Ph-CH(NH2)-CH2-SPh); 4.07 (dd, 3J = 9.5, 3J = 4.00, 1H, -CH-); 3.28 (dd, 2J = 13.4, 3J = 4.0, 1H, -CH2-); 2.99 (dd, 2J =

13.4, 3J = 9.5, 1H, -CH2-); 1.75 (br s, 2H, -NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ =

144.20 (C(1)-Ph-CH-); 135.72 (C(1)-PhS-); 129.63 (CH(3,5)-PhS-); 128.95 (CH(2,6)-

PhS-); 128.54 (CH(3,5)-Ph-CH-); 127.49 (CH(4)-Ph-CH-); 126.32 (CH(2,6)-Ph-CH-);

126.26 (CH(4)-PhS-); 54.55 (-CH-); 43.77 (-CH2-). MS (FD+, CH2Cl2): m/z (%) = 230

(100) [M + H]+ isotope peak.

(+)-(1R)-1-Phenyl-2-(2’-naphthylthio)ethylamine 36R

According to the general procedure above from 642 mg (27.93 mmol) sodium, 7519

mg (56.92 mmol) β-thionaphthol and 1064 mg (6.52 mmol) 29R in 40 ml nPrOH for

18 h under reflux to give 3652 mg crude 36R as yellowish solid mass. The crude

product was purified twice by FC (hexanes : CH2Cl2 : MeOH = 10 : 10 : 1, Rf (36R) =

0.38 on TLC; green-yellowish byproducts leave column first) and then recrystallized

twice from a minimum amount of hot CHCl3 layered with the double amount of

pentanes from RT to - 30° C to give finally 475 mg (1.70 mmol, 26 % yield) nearly

pure 36R as brownish microcrystals. Mp. = 98 - 99° C. [α]23D = + 63.7 (CH2Cl2, c =

0.0029). 1H-NMR (CDCl3, 270 MHz): δ = 7.74 – 7.66 (m, 4H, CH(5,6,7,8)-(β-Naph)S-

); 7.45 – 7.14 (series of m, 8H, Ph-CH(NH2)-CH2-S(β-Naph)); 4.07 (dd, 3J = 9.3, 3J =

4.0, 1H, -CH-); 3.34 (dd, 2J = 13.4, 3J = 4.0, 1H, -CH2-); 3.05 (dd, 2J = 13.4, 3J = 9.3,

1H, -CH2-); 1.64 (br s, 2H, -NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 144.21 (C(1)-

Ph-CH-); 133.65 (C(8a)-(β-Naph)S-); 133.11 (C(2)-(β-Naph)S-); 131.81 (C(4a)-(β-

Naph)S-); 128.57 (CH(3,5)-Ph-CH-); 128.50 (CH(4)-(β-Naph)S-); 127.64 (CH(4)-Ph-

CH-); 127.56 (CH(8)-(β-Naph)S-); 127.55 (CH(5)-(β-Naph)S-); 127.03 (CH(6,7)-(β-

Naph)S-); 126.55 (CH(1)-(β-Naph)S-); 126.34 (CH(2,6)-Ph-CH-); 125.76 (CH(3)-(β-

Naph)S-); 54.70 (-CH-); 43.71 (-CH2-). MS (FD+, CH2Cl2): m/z (%) = 280 (100) [M +

H]+ isotope peak. A correct EA could not be obtained.

- 212 -

7.3.6 General Procedure for the Syntheses of chiral β-Aminothioether Ligands

by Nucleophilic Substitution of Methylsulfonate Group of 31R

Ph

NH2

S * (R)

R

34R R = α-Naph 53 %36R R = β-Naph 29 %

2.09 eq tBuOK / 2.11 eq BnSH2.17 eq tBuOK / 2.21 eq PhSH1.01 eq tBuOK / 1.00 eq (α-Naph)SH 1.11 eq tBuOK / 1.11 eq (β-Naph)SH

THF or MeOH / RT /acidic workup (aq. HCl)

31R

Ph

NH(BOC)

O * (R)

SO2CH3

d ((α-Naph)SH) = 1.150 g/mlM (tBuOK) = 112.22 g/mol

32R R = Bn < 99 % (crude)33R R = Ph 70 %

Pic. 7.3.6

To the particular thiol in MeOH or THF at RT was added solid tBuOK in one portion,

whereupon the potassium thiolate precipitated out in case THF is used as solvent. To

the solution / suspension was added in one portion 31R and potassium

methylsulfonate started to precipitate out immediately and sometimes a slight

warming was observed. To ensure completion of the reaction the mixture was stirred

overnight (12 h – 18 h) at RT (due to similar Rf-values the proceeding of the reaction

was generally difficult to monitor by TLC). Then 20 – 40 ml aq. 36 % HCl were added

to remove the BOC protection group in situ, whereupon the mixture becomes warm

and was stirred ca. 30 min. at RT before workup. After solvent removal by RV

(stench!) the residue was suspended in 40 % aq. NaOH. After cooling down to RT

the aqueous phase was extracted twice with CH2Cl2 (organic layer is above aqueous

phase!). The combined organic layers were dried over Na2SO4, filtrated and the

solvent removed by RV and further under HV to give crude 32R – 34R and 36R,

which were purified as described below. Up to 20% 29R was formed as a byproduct!

(-)-(1R)-1-Phenyl-2-[(phenylmethyl)thio]ethylamine 32R

According to the general procedure above from 3801 mg (33.87 mmol) tBuOK, 4.00

ml (4232 mg, 34.07 mmol) benzylthiol and 5100 mg (16.17 mmol) 31R in 100 ml THF

and 30 ml MeOH for 18 h at RT to give 3926 mg (16.13 mmol, > 99 % crude yield)

32R as a slightly turbid orange oil, nearly pure by NMR and only with traces of 29R.

- 213 -

(+)-(1R)-1-Phenyl-2-(phenylthio)ethylamine 33R

According to the general procedure above from 2353 mg (20.97 mmol) tBuOK, 2.00

ml (2156 mg, 21.31 mmol) thiophenol and 3047 mg (9.66 mmol) 31R in 20 ml MeOH

for 18 h at RT (reaction monitored with MS: M (Ph-CH[NH(BOC)]-CH2-SPh) =

329.46 g/mol, MS (FD+, reaction mixture diluted with CH2Cl2): m/z (%) = 329 (100)

[M]+ isotope peak) to give 2289 mg (containing ca. 20 % 29R by NMR) 33R as a

yellow oil crystallizing at RT later on. Two times recrystallization from hot EtOH

layered with pentanes at RT down to - 30° C and applying this procedure to the

combined mother liquors gave overall 1559 mg (6.80 mmol, 70 % yield) pure 33R as

snow white microcrystals.

(-)-(1R)-1-Phenyl-2-(1’-naphthylthio)ethylamine 34R

According to the general procedure above from 2445 mg (21.79 mmol) tBuOK, 3.03

ml (3483mg, 21.74 mmol) α-thionaphthol and 6833 mg (21.67 mmol) 31R in 20 ml

MeOH for 20 h at RT to give 5632 mg (20.16 mmol, 93 % crude yield) 34R as a

brown turbid oil containing only traces of 29R by NMR. The crude product was

purified twice by FC (gradient elution with hexanes : CH2Cl2 : MeOH: first 10 : 10 : 0

to flush out impurities with Rf (34R) = 0.01 and then with 10 : 10 : 1 to obtain the

product with Rf (34R) = 0.28 on TLC). After solvent removal by RV and drying under

HV 3191 mg (11.42 mmol, 53 % yield, traces of impurities by NMR) 34R were

obtained as slightly yellowish oil. [α]23D = - 5.5 (CH2Cl2, c = 0.0195), [α]23

D = - 11.8

(CHCl3, c = 0.1992). 1H-NMR (CDCl3, 270 MHz): δ = 8.37 (pseudo d, 1H, CH(5 or 8)-

Ph-CH(NH2)-CH2-S(α-Naph)); 7.81 – 7.16 (series of m, 11H, Ph-CH-); 4.01 (dd, 3J =

9.4, 3J = 4.0, 1H, -CH-); 3.27 (dd, 2J = 13.1, 3J = 4.0, 1H, -CH2-); 3.03 (dd, 2J = 13.1, 3J = 9.4, 1H, -CH2-); 1.78 (br s, 2H, -NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ =

143.86 (C(1)-Ph-CH-); 133.62 (C(1)-(α-Naph)S-); 132.69 (C(4a)-(α-Naph)S-); 132.66

(C(8a)-(α-Naph)S-); 128.35 (CH(5)-(α-Naph)S-); 128.30 (CH(8)-(α-Naph)S-); 128.16

(CH(3,5)-Ph-CH-); 127.21 (CH(4)-Ph-CH-); 127.09 (CH(3)-(α-Naph)S-); 126.18

(CH(6)-(α-Naph)S-); 126.05 (CH(2,6)-Ph-CH-); 125.94 (CH(7)-(α-Naph)S-); 125.22

(CH(4)-(α-Naph)S-); 124.73 (CH(2)-(α-Naph)S-); 54.33 (-CH-); 43.85 (-CH2-). MS

(FD+, CH2Cl2): m/z (%) = 280 (100) [M + H]+ isotope peak. A correct EA could not be

obtained. Characterization as hydro tosylate 35R: To 3409 mg (12.20 mmol) crude

- 214 -

34R obtained according to this procedure in 15 ml EtOH p. a. in air were added at RT

2339 mg (12.30 mmol) solid p-toluene sulfonic acid monohydrate in one portion.

From the saturated solution at - 30° C tosylate 35R crystallized out as white needles,

which was repeated twice. The white crystalline needles were washed with Et2O and

dried in air to obtain 1715 mg (M = 451.61 g/mol, 3.80 mmol, 31 % yield in regard to

crude 34R) 35R suitable for X-ray structure determination. Mp. = 169 - 170° C. [α]23D

= + 14.0 (MeOH, c = 0.0053). 1H-NMR (DMSO-d6, 300 MHz): δ = 8.50 (br s, 3H, -

NH3+); 8.25 - 7.27 (series of m, 12H, Ph-CH(NH3

+)-CH2-S(α-Naph)); 7.89 (d, 2J = 8.3,

2H, CH(3,5)-(p-TolSO3-)); 7.08 (d, 2J = 8.3, 2H, CH(2,6)-(p-TolSO3

-)); 4.39 (dd, 3J =

8.6, 3J = 6.0, 1H, -CH-); 3.61 (dd, 2J = 13.6, 3J = 6.0, 1H, -CH2-); 3.51 (dd, 2J = 13.6, 3J = 8.6, 1H, -CH2-); 2.29 (s, 3H, -CH3 of p-TolSO3

-). 13C{1H}-NMR (DMSO-d6, 75

MHz): δ = 145.48 (C(1)-Ph-CH-); 137.74 (C(1)-(p-TolSO3-)); 136.12 (C(4)-(p-

TolSO3-)); 133.76 - 124.26 (C and CH of Ph, (α-Naph)S-, p-TolSO3

-); 53.51 (-CH-);

37.04 (-CH2-); 20.76 (-CH3 of p-TolSO3-). A correct EA could not be obtained.

(+)-(1R)-1-Phenyl-2-(2’-naphthylthio)ethylamine 36R

According to the general procedure above from 1183 mg (10.54 mmol) tBuOK, 1690

mg (10.55 mmol) β-thionaphthol and 2997 mg (9.50 mmol) 31R in 20 ml MeOH for 19

h at RT (reaction monitored with MS: M (Ph-CH[NH(BOC)]-CH2-S(β-Naph)) = 379.41

g/mol, MS (FD+, CH2Cl2): m/z (%) = 379 (100) [M]+) to give 2344 mg 36R as a brown

oil containing ca. 20 % 29R by NMR. Three times recrystallization as described gave

finally 757 mg (2.71 mmol, 29 % yield) 36R with only traces of 29R by NMR.

7.3.7 (-)-(2R)-2-Amino-2-phenylethanthiol hydrochloride 37R [43 (8-12)]

Ph

NH2

S * (R)

32R

Ph

NH3 Cl

SH * (R)

37R 76 %

M (C8H12ClNS) = 189.71 g/molM (C8H11NS) = 153.25 g/mol (free base)

1) 4.88 eq Na (M = 22.99 g/mol) / 1.26 eq tBuOH (M = 74.12 g/mol, d = 0.780 g/ml) / NH3(l) / THF / - 78° C, then 7.39 eq NH4Cl2) EtOH / 36 % aq. HCl

Ph

Pic. 7.3.7

- 215 -

This procedure is based on a modified analog literature protocol [43 (11)] and is

similar to the general procedure of the Birch reduction in 7.2.1. To ca. 165 ml

condensed liquid ammonia at ca. - 80° C were added portionwise within 5 min. 1861

mg (80.95 mmol) sodium brittles to give a deep blue solution of solvated electrons.

Within 2 min. from a Schlenk flask 4036 mg (16.58 mmol) 32R (crude product can be

taken if free of 29R) and 1.98 ml (1548 mg, 20.89 mmol) tBuOH dissolved in 40 ml

THF were canula transferred through a septum into the reaction flask by nitrogen

overpressure. The still blue solution was stirred 45 min. inside the cooling bath and

then 1 h outside before the reaction was quenched with 6556 mg (122.56 mmol) solid

ammonium chloride. Workup: Ammonia was blown away within 2 – 3 h with nitrogen

(β-aminothiols are somewhat sensitive to oxidation in solution), the residue was

suspended in EtOH, acidified to pH = 1 -2 with 36 % aq. HCl and filtrated off NaCl.

The clear solution was evaporated by RV to dryness, the white residue dissolved in

CH2Cl2 / iPrOH / MeCN 1 : 1 : 1 and filtrated off residual NaCl again. After solvent

removal by RV the crude product was dissolved in CH2Cl2, crushed out with Et2O,

filtrated off, dried by air suction and further overnight over P2O5 under vacuum in a

descicator to give 2389 mg (12.59 mmol, 76 %) 37R as a nearly white powder

sufficiently pure for the next step. During the course of the reaction no 1,4-dihydro

product was detected. Mp. = 153 - 155° C. [α]23D = - 7.5 (MeOH, c = 0.00296). 1H-

NMR (DMSO-d6, 270 MHz): δ = 8.77 (br s, 3H, Ph-CH(NH3+)-CH2-SH); 7.53 – 7.10

(m, 5H, Ph); 4.32 (not res. dd, 1H, -CH-); 3.34 (s, 1H, -SH); 3.08 – 2.85 (2 not res.

dd, 2H, -CH2-). 13C{1H}-NMR (DMSO-d6, 68 MHz): δ = 136.33 (C(1)-Ph); 128.62

(CH(4)-Ph); 128.51 (CH(3,5)-Ph); 127.58 (CH(2,6)-Ph); 56.35 (-CH-); 27.9 (-CH2-).

Characterization of the free base: analytical aliquot of 37R mixed with Na2CO3 in 2

- 3 ml MeOH and one drop aqua dest.; the solvent was removed by RV, the residue

dissolved in CDCl3, filtrated over a pipette filled with glasswool and MgSO4 and the

NMR spectrum was recorded. The free base is considerably airsensitive and disulfide

formation is nearly unavoidable. 1H-NMR (CDCl3, 270 MHz): δ = 7.40 – 7.15 (m, 5H,

Ph-CH(NH2)-CH2-SH); 4.26 (dd, 3J = 9.2, 3J = 4.0, 1H, -CH-); 3.01 (dd, 2J = 13.4 , 3J

= 4.0, 1H, -CH2-); 2.78 (dd, 2J = 13.4, 3J = 9.2, 1H, -CH2-); 1.76 (2 br s, 3H, -SH,

-NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 143.87 (C(1)-Ph); 128.55 (CH(3,5)-Ph);

127.45 (CH(4)-Ph); 126.42 (CH(2,6)-Ph); 54.34 (-CH-); 43.58 (-CH2-).

- 216 -

7.3.8 (-)-(1R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-methylcarbonylthio-1- phenylethane 38R

M (C15H21NO3S) = 295.40 g/mol 38R

Ph

NH(BOC)

R * (R)

Ph

NH(BOC)

S * (R)

CH3

Omethod a): 1) 1.10 eq PPh3 / 1.10 eq CBr4 / THF / RT / 23 h 2) 1.62 eq NEt3 / 1.15 eq HSAc (M = 76.12 g/mol, d = 1.068 g/ml) / RT / 26 h method b): 1.16 eq KSAc (M = 114.21 g/mol) / MeOH / RT / 12 h

30R R = OH31R R = OSO2CH3

for 30R: method a) 41 %for 31R: method b) 89 %

Pic. 7.3.8

a) To 6311 mg (26.60 mmol) 30R and 7676 mg (29.27 mmol) triphenylphosphine

in 300 ml THF at RT were added in one portion under a stream of nitrogen 9712 mg

(29.29 mmol) solid carbon tetrabromide. After 10 min. stirring triphenylphosphine

oxide started to precipitate out and the white suspension is stirred 23 h further at RT.

From a Schlenk flask a mixture of 6.00 ml (4356 mg, 43.05 mmol) NEt3 and 3.00 ml

(3204 mg, 42.09 mmol) thioacetic acid (Stench!) in 20 ml THF was transferred with a

syringe to the reaction solution, which became slightly warm upon addition and after

5 min. triethylammonium bromide started to precipitate out. The suspension was

stirred 26 h at RT to ensure completion, hence the reaction is difficult to monitor with

TLC. Workup (Stench!): 20 ml EtOH were added to reaction mixture and after stirring

for 5 min. it was poured on brine and extracted once with EtOAc. The organic phase

was washed twice with brine, dried over MgSO4, filtrated and after solvent removal by

RV and HV 19.204 g crude product containing 38R, triphenylphosphine oxide and

carbon tetrabromide were obtained as a brown oil. Most of the triphenylphosphine

oxide and carbon tetrabromide were removed by FC (substance applied as

suspension in eluent, hexanes : EtOAc = 3 : 1 + 10 % NEt3). 38R was collected

running from the column as a broad yellow band. After solvent removal by RV ca.

11.25 g impure 38R was obtained as yellowish microcrystals, which was

- 217 -

recrystallized from hot EtOH down to - 30° C overnight. Residual triphenylphosphine

oxide was removed by filtration of an EtOAc solution. Recrystallization from hot

EtOAc as described above including crystallization from the mother liquors in the

same manner gave overall 3195 mg (10.82 mmol, 41 % yield) 38R. Mp. = 130 - 131°

C. [α]23D = - 29.2 (CH2Cl2, c = 0.0042). 1H-NMR (DMSO-d6, 270 MHz): δ = 7.71 -

7.53 (m, 4H, CH(2,3,5,6)-Ph-CH(NH[CO(OtBu)])-CH2-S-COCH3); 7.37 – 7.21 (m, 1H,

CH(4)-Ph); 4.54 (dd, 3J = 9.7, 3J = 5.1, 1H, -CH-); 3.17 (dd, 2J = 13.5 , 3J = 5.1, 1H,

-CH2-); 3.00 (dd, 2J = 13.5, 3J = 9.7, 1H, -CH2-); 2.37 (s, 3H, -S-COCH3); 1.35 (s, 9H,

OC(CH3)3). 13C{1H}-NMR (DMSO-d6, 75 MHz): δ = 195.13 (-S-COCH3); 154.96

(-CO-OC(CH3)3); 142.37 (C(1)-Ph); 128.36 (CH(3,5)-Ph); 127.22 (CH(4)-Ph); 126.29

(CH(2,6)-Ph); 78.01 (-OC(CH3)3); 54.11 (-CH-); 34.87 (-CH2-); 30.67 (-S-COCH3);

28.17 (-OC(CH3)3). MS (FD+, CH2Cl2 / CDCl3): m/z (%) = 294 (100) [M - H]+ isotope

peak. A correct EA could not be obtained.

b) To a stirred solution of 12.05 g (38.2 mmol) 31R in 130 ml MeOH in air were

added in one portion 5.06 g (44.3 mmol) potassium thioacetate at RT. After ca. 5 min.

potassium methylsulfonate started to precipitate out and the solution was stirred at

RT for further 12 h. Workup (Stench!): After solvent removal by RV the residue was

suspended in EtOAc, poured on brine, the organic phase washed twice with brine,

dried over MgSO4, filtrated and the solvent removed by RV. The crude product was

directly dissolved in a minimum amount of hot EtOAc layered with some drops

pentanes at RT and recrystallized at - 30° C overnight. The colorless needles were

filtrated off, washed with pentanes, dried by air suction and further over P2O5 in a

descicator under vacuum overnight. Further crystallization from the mother liquors

gave finally overall 9.99 g (33.8 mmol, 89 %) 38R.

- 218 -

7.3.9 (-)-(2R)-[(1’,1’-Dimethylethoxycarbonyl)amino]-2-phenylethanthiol 39R 31R 39R 40 %

M (C13H19NO2S) = 253.37 g/mol

1) 1.49 eq KSAc / MeOH : THF = 1 : 1 / RT / 24 h 2) excess NH3 (g) / RT / 22 h Ph

HN

SH * (R)

O

O

Ph

HN

OSO2CH3 * (R)

O

O

Pic. 7.3.9

To 3815 mg (33.40 mmol) potassium thioacetate in 50 ml MeOH and 50 ml THF were

added 7063 mg (22.39 mmol) 31R in one portion at RT and the suspension was

stirred 24 h at RT to ensure completion of the reaction, which was difficult to monitor

with TLC due to identical Rf-values. The solution was saturated for 10 min. with

ammonia gas, whereupon some heat was evolved and color changed intermediately

to green, while stirring 22 h at RT it adopted its original color again. Workup

(Stench!): After solvent removal by RV the residue was suspended in EtOAc, washed

once with 1 % aq. HCl and then three times with brine. The separated organic phase

was dried over MgSO4, filtrated and the solvents removed by RV and under HV to

give 4146 mg crude 39R containing considerable amounts of 29R by NMR. The

product was purified by FC (solid substance applied on column; first gradient elution

with hexanes : EtOAc 2 : 1 to flush out 39R with Rf (39R) = 0.41 and Rf (29R) = 0.07

on TLC, then with CH2Cl2 to obtain 29R); after solvent removal by RV and drying

under HV 2212 mg (8.73 mmol, 40 % yield) 39R as a yellowish-white powder and

225 mg (1.38 mmol, 6 % yield in regard to 31R) 29R were obtained. Mp. = 144° C.

[α]23D = - 47.3 (CH2Cl2, c = 0.0030). The NMR-spectra are broadened due to

hindered rotation of the tBu group! 1H-NMR (DMSO-d6, 270 MHz): δ = 7.29 – 7.18

(m, 5H, Ph-CH(NH[CO(OtBu)])-CH2-SH); 4.75 – 4.46 (2 not res. dd of 2 rotamers,

1H, -CH-); 3.14 – 2.97( 2 not res. dd, 2H, -CH2-); 2.28 (s, 1H, -SH); 1.29 - 1.11 (2 br s

of rotamers, 9H, OC(CH3)3). 13C{1H}-NMR (DMSO-d6, 75 MHz, at least 3 rotamers):

δ = 154.94 (-CO-OC(CH3)3]-); 142.34 (C(1)-Ph); 128.33 (CH(3,5)-Ph); 127.19 (CH(4)-

Ph); 126.27 (CH(2,6)-Ph); 77.98 (-OC(CH3)3); 66.98 (-CH-) 54.08 (-CH-); 34.85

(-CH2-); 30.47 (-OC(CH3)3); 28.15 (-OC(CH3)3); 25.07 (-OC(CH3)3). MS (FD+,

CH2Cl2): m/z (%) = 504 (100) [2M - 2H (disulfide)]+ isotope peak.

- 219 -

7.3.10 (-)-(1R)-1-Phenyl-2-[(3’-methylbut-2’-enyl)thio]ethylamine 40R

Ph

R

SH * (R)

40R M (C13H19NS) = 221.37 g/mol

Ph

NH2

S * (R)

37R R = NH3+Cl-

39R R = NH(BOC)

method a): 1) 1.181 eq tBuOK / MeOH / RT / 10 min. 2) 1.12 eq PrnBr (M = 149.03 g/mol, d = 1.270 g/ml) / RT / 19 h 3) acidic workup (aq. HCl)

method b): 1) 1.10 eq tBuOK / THF / RT / 10 min. 2) 1.19 eq PrnBr / / RT / 19 h 3) acidic workup (aq. HCl)

for 37R: method a) 99 % crudefor 39R: method b) 96 % crude

34 % overall (after pruification of combined crude products)

Pic. 7.3.10

a) To 1180 mg (6.22 mmol) 37R in 35 ml MeOH were added under a stream of

nitrogen in one portion 1264 mg (11.26 mmol) solid tBuOK, a white precipitate was

formed immediately and the suspension was stirred for 10 min. before 0.82 ml (1041

mg, 6.99 mmol) prenyl bromide were syringed to it. After stirring for 19 h at RT 2 ml

37 % aq. HCl were added to the reaction mixture, which is then stirred for 10 min.

before workup: After solvent removal by RV the resulting slurry was suspended in

aqua dest. and brought to pH = 14 with 40 % aq. NaOH. The aqueous phase was

extracted twice with Et2O and the combined organic layers were dried over Na2SO4

overnight. After filtration and removal of the solvents by RV and HV 1369 mg (6.18

mmol, 99 % crude yield) slightly impure 40R were obtained as an orange oil.

b) To 1201 mg (4.74 mmol) 39R in 35 ml THF were added under a stream of

nitrogen in one portion 585 mg (5.21 mmol) solid tBuOK and the slightly turbid

solution was stirred for 10 min. before 0.66 ml (838 mg, 5.62 mmol) prenyl bromide

were syringed to it. After stirring 19 h at RT 10 ml 37 % aq. HCl were added to the

reaction mixture into the open flask. The solution became warm and was stirred for

40 min. before workup as described above gave 1006 mg (4.54 mmol, 96 % crude

yield) impure 40R as brownish oil.

- 220 -

c) Purification of combined crude products: Note distillation under HV will lead to

partial decomposition! The crude products were purified by FC (substance applied in

eluent; elution with hexanes : CH2Cl2 : MeOH: first 10 : 10 : 1 with Rf (40R) = 0.37) to

give 831 mg (3.75 mmol, 34 % overall yield) pure 40R as a slightly yellowish oil.

[α]23D = - 38.1 (CHCl3, c = 0.114). 1H-NMR (CDCl3, 270 MHz): δ = 7.33 – 7.24 (m,

5H, Ph-CH(NH2)-CH2-S-CH2-CH=C(CH3)2); 5.20 (pseudo t, 1H, -CH2-CH=C(CH3)2);

4.05 (dd, 3J = 9.2, 3J = 4.0, 1H, -CH-); 3.11 (m, 2H, -CH2-CH=C(CH3)2); 2.78 (dd, 2J

= 13.4, 3J = 4.0, 1H, Ph-CH(NH2)-CH2-); 2.59 (dd, 2J = 13.4, 3J = 9.2, 1H, Ph-

CH(NH2)-CH2-); 1.76 (s, 2H, -NH2); 1.71 (not res. d, 3H, -CH2-CH=C(CH3 cis)(CH3));

1.64 (not res. d, 3H, -CH2-CH=C(CH3)(CH3 trans)). 13C{1H}-NMR (CDCl3, 68 MHz): δ =

144.47 (C(1)-Ph); 135.04 (-CH2-CH=C(CH3)2); 128.25 (CH(3,5)-Ph); 127.08 (CH(4)-

Ph); 126.11 (CH(2,6)-Ph); 120.39 (-CH2-CH=C(CH3)2); 54.82 (-CH-); 41.10 (Ph-

CH(NH2)-CH2-); 29.63 (-CH2-CH=C(CH3)2); 25.60 (-CH2-CH=C(CH3 cis)(CH3)); 17.74

(-CH2-CH=C(CH3) (CH3 trans)). 1H- and 13C-signal assignments were confirmed by

COSY and HMQC. MS (FD+, CH2Cl2): m/z (%) = 222 (100) [M + H]+ isotope peak. A

correct EA could not be obtained.

7.3.11 General Procedure for the Syntheses of Epimeric σ(N):σ(S)-β−

Aminothioether Ruthenium(II) η6-Arene Complexes

The β-aminothioether ligand and the [{η6-arene}Ru(II)Cl]2(µ-Cl)2 precursor complex

were stirred at RT in MeOH until the reaction mixture turned clear and yellow, which

required sometimes stirring overnight. Then an excess of NaPF6 was added in one

portion under a stream of nitrogen. NaCl started to precipitate out and the mixture

was stirred overnight at RT for completion giving a turbid yellow to orange solution.

Workup: The solvent was removed by RV and the residue was taken up in CH2Cl2,

filtrated off NaCl and excess NaPF6 over a pipette filled with filter flakes, which was at

least washed out twice. After solvent removal the product was directly recrystallized

as described below to remove excess ligand. Crystals obtained in this way were all

suitable for X-ray structure determination. The complexes are not air sensitive, but

are in diastereomeric equilibrium in solution. Assignment of the 1H- and 13C-NMR-

signals of the particular diastereomers were accomplished by HMQC, COSY and

NOE cross measurements, if possible.

- 221 -

Ph

NH2

S

H2N (R)

Ph

S H

Ru

**

Cl

R4

*

R3R1

R4

R2

R1

PF6

1) 1.00 eq 8 - 9 / MeOH / RT2) excess NaPF6 (M = 167.95 g/mol)

* (R)

33R R = Ph36R R = β-Naph40R R = Prn

for 41R M (C24H29ClF6NPRuS) = 645.05 g/mol,calc. new M' (M(CH2Cl2)0.5(H3COH)) = 719.56 g/mol: 2.08 eq 33R / 3.53 eq NaPF6 67 %in solid state: as : aa : sa : ss = 1 : 0 : 0 : 0

for 42R M (C23H27ClF6NPRuS) = 631.03 g/mol:2.15 eq 33R / 4.47 eq NaPF6 80 %in solid state: as : aa : sa : ss = 1 : 0 : 1 : 0

for 43R M (C27H30ClF6NPRuS) = 682.09 g/mol:2.17 eq 36R / 4.52 eq NaPF6 83 %in solid state: as : aa : sa : ss = 1 : 0 : 1 : 0

for 44R M (C22H31ClF6NPRuS) = 623.05 g/mol,calc. new M (M(CH2Cl2)0.5) =665.51 g/mol:2.13 eq 40R / 3.06 eq NaPF6 78 %in solid state: as : aa : sa : ss = 1 : 0 : 1 : 0

Pic. 7.3.11

(+)-(RRu, 1’’ R)-Chloro-η6-[1-methyl-4-(1’-methylethyl)benzene]-σ(N):σ(S)-[1’’-

phenyl-2’’-(phenylthio)ethylamino]ruthenium(II)] hexafluorophosphate 41R

According to the general procedure above 606 mg (0.990 mmol) 9 and 471 mg

(2.054 mmol) 33R were stirred 40 min. at RT in 25 ml MeOH. After addition of 587

mg (3.495 mmol) NaPF6 the mixture was stirred 17 h and worked up as described

above. The crude product was crystallized from a saturated MeOH / CH2Cl2 1 : 1

solution overnight at - 30° C. After pipetting off the mother liquor the crystals were

collected, washed with Et2O and dried by air suction to give 956 mg (1.329 mmol, 67

% yield) 41R as yellow needles crystallizing with one molecule MeOH and half a

molecule of CH2Cl2 per formula unit (from X-ray structure determination, NMR and

EA). In the crystal examined only the as diastereomer was found, but in solution at

- 30° C an equilibrium of as : aa = 1.00 : 0.32 of the diastereomers was determined

by NMR in CDCl3, which does not change significantly at RT, but in acetone-d6 at RT

a diastereomer equilibrium of as : aa = 1.0 : 0.4 was determined. Mp. = 105 - 106° C.

[α]23D = + 10.3 (CH2Cl2, c = 0.00276). 1H-NMR (CDCl3, 400 MHz, - 30° C; contains

- 222 -

CH2Cl2 and MeOH; integration referenced to CH3-singlet of the η6-(p-cymene) ligand

assigned to the as diastereomer by NOE and set equivalent to 3 protons): δ = 7.90 -

7.88 (pseudo d, 2H, CH(2,6)-Ph-S[Ru(II)-η6-(p-cymene)]-CH2-, as); 7.78 - 7.76

(pseudo d, 0.64H, CH(2,6)-Ph-S[Ru(II)]-, aa); 7.67 - 7.61 (m, 3H, CH(3,4,5)-Ph-

S[Ru(II)]-, as); 7.50 - 7.42 (m, 0.96H, CH(3,4,5)-Ph-S[Ru(II)]-, aa); 7.34 (m, 7.92H,

Ph-CH(NH2[Ru(II)-η6-(p-cymene)])-CH2-, as and aa); 6.28 (br s, 2.64H, -NH2-, as and

aa); 6.06 - 6.0 (not res. d, 0.32H, CH(3 or 5)-η6-(p-cymene), aa); 5.98 (d, 3J = 5.8,

1H, CH(3 or 5)-η6-(p-cymene), as); 5.89 (d, 3J = 5.8, 0.32H, CH(5 or 3)-η6-(p-

cymene), aa); 5.81 (d, 3J = 5.8, 1H, CH(6 or 2)-η6-(p-cymene), as); 5.75 (d, 3J = 5.8,

0.32H, CH(2 or 6)-η6-(p-cymene), aa); 5.68 (d, 3J = 5.8, 0.32H, CH(6 or 2)-η6-(p-

cymene), aa); 5.37 (d, 3J = 5.8, 1H, CH(2 or 6)-η6-(p-cymene), as); 5.21 (d, 3J = 5.8,

1H, CH(5 or 3)-η6-(p-cymene), as); 4.34 (not res. dd, 1H, -CH-, as); 3.91 (not res. dd,

0.32H, -CH-, aa); 3.31 - 3.15 (3 not res. dd, 1.64H, -CH2-, as and aa); 2.86 (h, 3J =

6.8, 0.32H, -CH(CH3)2 of p-cymene, aa); 2.67 (dd, 2J = 13.8, 3J = 4.2, 1H, -CH2-, as);

2.54 (h, 3J = 6.8, 0.32H, -CH(CH3)2, as); 2.25 (s, 0.96H, -CH3 of p-cymene, aa); 2.13

(s, 3H, -CH3, as); 1.31 (d, 3J = 6.8, 3H, -CH(CH3)2, as); 1.30 (d, 3J = 6.80, 0.96H,

-CH(CH3)2, aa); 1.22 (d, 3J = 6.8, 0.96H, -CH(CH3)2, aa); 1.18 (d, 3J = 6.80, 3H,

-CH(CH3)2, as). 13C{1H}-NMR (CDCl3, 75 MHz): δ = 136.67 (C(1)-Ph-CH(NH2[Ru(II)])

-CH2-, as and aa); 133.05 (CH(2,6)- Ph-S[Ru(II)]-, as); 132.47 (CH(4)-Ph-S[Ru(II)]-,

as); 131.42 (CH(2,6)-Ph-S[Ru(II)]-, aa); 131.32 (CH(3,5)-Ph-S[Ru(II)]-, aa); 130.89

(CH(3,5)-Ph-S[Ru(II)]-, as); 129.81 (CH(3,5)-Ph-CH(NH2[Ru(II)])-CH2-, aa); 129.60

(CH(2,6)-Ph-CH-, as and aa; CH(3,5)-Ph-CH-, as); 129.14 (CH(4)-Ph-S[Ru(II)]-, aa);

127.22 (CH(4)-Ph-CH-, as); 126.96 (CH(4)-Ph-CH-, aa); 108.76 (C(4)-[η6-(p-

cymene)], aa); 106.13 (C(4)-η6-(p-cymene), as); 101.68 (C(1)-η6-(p-cymene), as);

101.28 (C(1)-η6-(p-cymene), aa); 87.84 (CH(5 or 3)-η6-(p-cymene), as); 85.43 (CH(2

or 6)-η6-(p-cymene), as); 85.26 (CH(5 or 3)-η6-(p-cymene), aa); 84.80 (CH(3 or 5)-η6-

(p-cymene), as); 83.94 (CH(6 or 2)-η6-(p-cymene), aa); 81.64 (CH(6 or 2)-η6-(p-

cymene), as); 60.37 (-CH-, aa); 60.22 (-CH-, as); 45.96 (-CH2-, as); 43.54 (-CH2-,

aa); 31.18 (-CH(CH3)2, as); 30.98 (-CH(CH3)2, aa); 23.14 (-CH(CH3)2, as); 22.30

(-CH(CH3)2, aa); 22.14 (-CH(CH3)2, as); 21.90 (-CH(CH3)2, aa); 18.42 (-CH3, aa);

18.15 (-CH3, as). MS (FAB+): m/z (%) = 500 (100) [M - PF6]+ isotope peak, 464 (18)

[M - PF6 - Cl]+ isotope peak. EA anal.calc for C24H29ClF6NPRuS(CH2Cl2)0.5(H3COH)

(719.56): C 42.56, H 4.76, N 1.95, S 4.46; found: C 42.46, H 4.45, N 2.00, S 4.60.

- 223 -

(+)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-(phenyl-

thio)ethylamino]ruthenium(II)] hexafluorophosphate 42R

According to the general procedure above 301 mg (0.515 mmol) 8 and 254 mg

(1.107 mmol) 33R were stirred 13 h at RT in 25 ml MeOH. Then 387 mg (2.304

mmol) NaPF6 were added, the mixture was stirred 30 h and worked up as described

above to give 688 mg crude product as a yellow foam after drying under HV. The

crude product was dissolved in a minimum amount of warm CH2Cl2, layered at RT

with MeOH and then with pentanes to be crystallized out at - 30° C overnight. The

orange crystals were sucked off from the cold mother liquor, washed with pentanes

and dried by air suction to give 523 mg (0.829 mmol, 80 % yield) 42R crystallizing

with one cation of the as and sa diastereomer each per unit cell in the crystal

examined, but in solution an equilibrium of as : aa : sa : ss = 1.00 : 0.40 : 0.10 : 0.07

(CDCl3, - 30° C,), as : aa : (sa + ss) = 1.00 : 0.36 : 0.29 (CDCl3, RT) and of as : aa :

(sa + ss) = 0.9 : 1:0 : 0.6 (acetone-d6, RT) of the diastereomers was determined by

NMR. After recrystallization the compound is only merely solulable in CHCl3 or

CH2Cl2 and moderately in acetone. Mp. = 214 - 216° C. [α]23D = + 20.8 (CH2Cl2, c =

0.00284). 1H-NMR (CDCl3, 400 MHz, - 30° C; assignment difficult due to number of

diastereomers, low solubility and overlap; integration referenced to CH3-singlet of the

η6-mesitylene ligand tentatively assigned to the as diastereomer and set equivalent

to 9 protons): δ = 7.96 and 7.90 and 7.82 ( 3 pseudo d, 1.55H, CH(2,6)-Ph-S[Ru(II)-

η6-mesitylene]-CH2-); 7.68 - 7.30 (series of m, 13.36H, Ph-S[Ru(II)]-, Ph-

CH(NH2[Ru(II)])-CH2-); 5.49 (s, 3H, CH-η6-mesitylene, as); 5.44 (s, 1.20H, CH-η6-

mesitylene, aa); 5.36 (br s, -NH2 -); 5.24 (s, 0.30H, CH-η6-mesitylene, sa); 5.19 (s,

0.21H, CH-η6-mesitylene, ss); 5.08 (br s, -NH2 -); 4.72 (not res. dd, 0.55H, -CH-);

4.42 (not res. dd, 0.29H, -CH-); 4.25 - 4.10 (2 not res. dd, 1.07H, -CH-); 3.69 (not res.

dd, 0.73H, -CH2-); 3.54 (m, 1.31H, -CH2-); 3.35 (not res. dd, 0.80H, -CH2-); 3.12 (not

res. dd, 1.07H, -CH2-); 2.71 (dd, 2J = 13.8, 3J = 3.8, 0.30H, -CH2-); 2.25 (s, 9H, -CH3

of mesitylene, as); 2.02 (s, 3.60H, -CH3, aa); 1.87 (s, 0.63H, -CH3, ss); 1.70 (s,

0.90H, -CH3, sa). 13C{1H}-NMR (acetone-d6, 75 MHz, due to low resolution of HMQC

assignment of diastereomers not possible): δ = 139.18 (C(1)-Ph); 138.61 (C(1)-Ph);

134.05 (C(1)-Ph); 132.79 - 127.77 (Ph-S[Ru(II)]-, Ph-CH(NH2[Ru(II)])-CH2-); 105.86

(C-η6-mesitylene); 104.93 (C-η6-mesitylene); 82.52 (CH-η6-mesitylene); 81.77 (CH-

η6-mesitylene); 81.45 (CH-η6-mesitylene); 62.17 (-CH-); 61.60 (-CH-); 60.15 (-CH3 of

- 224 -

mesitylene); 46.79 (-CH2-); 43.46 (-CH2-); 39.55 (-CH2-); 18.71 (-CH3 of mesitylene).

MS (FAB+): m/z (%) = 486 (100) [M - PF6]+ isotope peak, 450 (23) [M - PF6 - Cl]+

isotope peak, 331 (27) [M - PF6 - Cl - mesitylene]+ isotope peak, 257 (24) [M - PF6 -

Cl - mesitylene - Ph]+ isotope peak. EA anal.calc for C23H27ClF6NPRuS (631.03): C

43.78, H 4.31, N 2.22, S 5.08; found: C 43.84, H 4.59, N 2.21, S 5.03.

(-)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-(2’’-naph-

thylthio)ethylamino]ruthenium(II)] hexafluorophosphate 43R

According to the general procedure above 302 mg (0.517 mmol) 8 and 313 mg

(1.120 mmol) 36R were stirred 13 h at RT in 25 ml MeOH. Then 392 mg (2.334

mmol) NaPF6 were added, the mixture was stirred 30 h and worked up as described

above. The product is not well solulable in CH2Cl2 and solubility decreases from

acetone = MeCN > CH2Cl2 ≥ THF >> MeOH. The crude product was directly

crystallized from CH2Cl2 layered with some drops of MeOH at - 30° C, the orange

crystals were collected by filtration of the cold mother liquor to give 499 mg (0.732

mmol, 71 % yield) 43R and from the mother liquor 83 mg (0.122 mmol, 12 % yield)

43R were obtained in the same way, giving rise to overall 582 mg (0.853 mmol, 83 %

overall yield) 43R crystallizing with one cation of the as and sa diastereomer each per

unit cell in the crystal examined. In solution at ambient temperature an equilibrium of

ca. as : aa : (sa + ss) = 0.97 : 1.00 : 0.91 of the diastereomers is determined by NMR

in acetone-d6, which is equivalent to (as + aa) : (sa + ss) = 1.00 : < 0.5 in regard to

overlapping in the 1H-NMR spectrum. Mp. = 221 - 222° C. [α]23D = - 8.6 (CH2Cl2, c =

0.00266). 1H-NMR (acetone-d6, 300 MHz, assignment and integration due to number

of diastereomers, low solubility and resolution difficult and integration referenced to

CH-η6-mesitylene signal tentatively assigned to the aa diastereomer and set

equivalent to 3 protons): δ = 8.65 - 7.42 (series of m, 80.63H, (β-Naph)-S[Ru(II)]-, Ph-

CH(NH2[Ru(II)-η6-mesitylene])-CH2-); 6.38 (br s, -NH2 -); 6.07 (not res. dd, 0.83H,

-CH-); 5.81 (s, 2.92H, CH-η6-mesitylene, as); 5.71 (s, 3H, CH-η6-mesitylene, aa);

5.48 (2 br not res. s, 2.72H, CH-η6-mesitylene, sa and ss); 5.34 (br s, -NH2[Ru(II)]-);

4.64 (not res. dd, 0.53H, -CH-); 4.33 - 3.82 (2 not res. dd, 3.39H, Ph-CH(NH2[Ru(II)])-

CH2-); 3.75 (dd, 2J = 32.9, 3J = 12.4, 2.10H, -CH2-); 3.46 - 2.90 (series of m, 5.23H,

Ph-CH(NH2[Ru(II)])-CH2-); 2.37 (s, 8.78H, -CH3 of mesitylene, as); 2.36 (s, 9H, -CH3

- 225 -

of mesitylene, aa); 2.18 (2 not res. s, 8.16H, -CH3 of mesitylene, sa and ss). 13C{1H}-

NMR (acetone-d6, 75 MHz, due to low resolution of HMQC assignment of

diastereomers not possible): δ = 138.71 (C(1)-Ph or C-(β-Naph)); 138.17 (C(1)-Ph or

C-(β-Naph)); 134.34 - 126.26 ((β-Naph)-S[Ru(II)], Ph-); 105.33 (C-η6-mesitylene);

104.28 (C-η6-mesitylene); 82.27 (CH-η6-mesitylene); 81.45 (CH-η6-mesitylene);

81.13 (CH-η6-mesitylene); 61.72 (-CH-); 61.06 (-CH-); 59.58 (Ph-CH-); 50.20 (-CH2-);

46.64 (-CH2-); 43.11 (-CH2-); 38.82 (-CH2-); 31.98 (-CH3 of mesitylene); 31.47 (-CH3);

20.15 (-CH3). MS (FAB+): m/z (%) = 537 (100) [M - PF6]+ isotope peak, 501 (70) [M -

PF6 - Cl]+ isotope peak. EA anal.calc for C27H30ClF6NPRuS (682.09): C 47.54, H

4.43, N 2.05, S 4.70; found: C 47.24, H 4.54, N 2.01, S 4.66.

(+)-(1’ R)-Chloro-η6-[1,3,5-trimethylbenzene]-σ(N):σ(S)-[1’-phenyl-2’-(3’’-methyl-

but-2’’-enylthio)ethylamino]ruthenium(II)] hexafluorophosphate 44R

According to the general procedure above 411 mg (0.703 mmol) 8 and 332 mg

(1.500 mmol) 40R were stirred 15 min. at RT in 6 ml MeOH. Then 361 mg (2.149

mmol) NaPF6 were added, the mixture was stirred 16 h and worked up as described

above. The crude product was crystallized directly from a minimum amount of warm

MeOH with some drops CH2Cl2 from RT down to - 30° C overnight. The cold mother

liquor was pipetted off, the yellow crystals were washed carefully with MeOH, then

with Et2O and dried under HV to give 726 mg (1.091 mmol, 78 % yield) 40R

crystallizing with a half CH2Cl2 molecule per formula unit (from X-ray structure

determination, NMR and EA). In the crystal examined one cation of the as and sa

diastereomer each per unit cell were found. In solution at ambient temperature an

equilibrium of as : aa : (sa + ss) = 0.9 : 1.0 : < 0.7 in CDCl3 (low resolution and

overlap in this solvent) of the diastereomers was determined by NMR. In acetone-d6

at ambient temperature an equilibrium of as : aa : (sa + ss) = 0.53 : 1.00 : 0.93 was

determined. Mp. = 133 - 134° C. [α]23D = + 17.6 (CH2Cl2, c =0.0017). 1H-NMR

(CDCl3, 300 MHz, integration referenced to CH-η6-mesitylene signal tentatively

assigned to the aa diastereomer and set equivalent to 3 protons): δ = 7.48 - 7.30 (m,

11.07H, Ph-CH(NH2[Ru(II)-η6-mesitylene])-CH2-); 5.40 (s, 2.44H, CH-η6-mesitylene,

as); 5.36 (s, 3H, CH-η6-mesitylene, aa); 5.28 (2 not res. s, 1.83H, CH-η6-mesitylene,

- 226 -

sa and ss); 5.27 - 5.19 (3 m, 1.93H, -[Ru(II)]S-CH2-CH=C(CH3)2); 5.16 - 4.96 (not res.

dd, 1.93H, -CH-); 4-14 - 4.00 (not res. dd, 1.42H, -CH-); 3.78 - 3.34 (series of m,

8.70H, Ph-CH(NH2[Ru(II)])-CH2-); 3.08 (dd, 2J = 3J = 13.6, 1.17H, -CH2-CH=C(CH3)2,

as + aa or sa + ss); 2.83 (not res. dd, 0.92H, -CH2-CH=C(CH3)2, sa + ss or as + aa);

2.67 (dd, 2J = 13.7, 3J = 11.3, 1.00H, -CH2-CH=C(CH3)2, sa + ss or as + aa); 2.46 -

2.42 (m, 1.15H, -CH2-CH=C(CH3)2, as + aa or sa + ss); 2.20 (s, 7.32H, -CH3 of

mesitylene, as); 2.19 ( s, 9H, -CH3 of mesitylene, aa); 1.81 and 1.75 (2 not res. d, 4Jcis = 10.2 and 4Jtrans = 16.1; 11.81H, -CH2-CH=C(CH3)2, all diastereomers); 1.39 (s,

0.48H, -CH3 of mesitylene, ss); 1.09 (s, 1.36H, -CH3 of mesitylene, sa). 13C{1H}-NMR

(CDCl3, 75 MHz): δ = 141.77 (C(1)-Ph); 141.65 (C(1)-Ph); 137.68 (C(1)-Ph); 136.37

(-CH2-CH=C(CH3)2); 129.63 (CH(4)-Ph); 129.54 (CH(3,5)-Ph); 129.43 (CH(4)-Ph);

127.16 (CH(2,6)-Ph); 126.89 (CH(2,6)-Ph); 115.82 (-CH2-CH=C(CH3)2); 115.76

(-CH2-CH=C(CH3)2); 105.21 (C-η6-mesitylene); 103.77 (C-η6-mesitylene); 81.07 (CH-

η6-mesitylene, sa); 80.35 (CH-η6-mesitylene, aa); 62.61 (-CH-); 60.78 (-CH-); 59.76

(-CH3 of mesitylene, ss); 40.46 (-CH2-CH=C(CH3)2, as + aa or sa + ss); 38.13 (-CH2-

CH=C(CH3)2, sa + ss or as + aa); 36.86 (Ph-CH(NH2[Ru(II)])-CH2-); 35.46 (Ph-

CH(NH2[Ru(II)])-CH2-); 31.79 (Ph-CH(NH2[Ru(II)])-CH2-); 31.22 (-CH3 of mesitylene,

sa); 25.90 (-CH2-CH=C(CH3 cis)(CH3)); 18.51 (-CH2-CH=C(CH3)(CH3 trans) and -CH3 of

mesitylene, as + aa). MS (FAB+): m/z (%) = 479 (100) [M – PF6]+ isotope peak, 374

(38) [M - PF6 - Cl - Prn]+ isotope peak, 254 (22) [M - PF6 - Cl - Prn - mesitylene]+

isotope peak. EA anal.calc for C22H31ClF6NPRuS(CH2Cl2)0.5 (665.51): C 40.61, H

4.85, N 2.10, S 4.82; found: C 40.59, H 4.88, N 2.08, S 4.81.

- 227 -

7.4 Syntheses of Diastereomeric {[σ(P):η6-(Arene-

ansa-phosphinite)] Ru(II) Amino} Complexes

7.4.1 (+)-(S)-Mandelic acid methyl ester 48S [46 (1)]

*(S)

1.00 eqPh COOCH3

OH

(S)COOH

OH

Ph

1.62 eq (H3C)2C(OCH3)2 / 0.03 eq cat.TosOH(H2O)

MeOH / RT*

48S 89 - 95 %

M (C9H10O3) = 166.18 g/mol

47S

M = 152.15 g/mol Pic. 7.4.1

Compared to literature [46 (1)] this procedure was adjusted to less harsh conditions

and to a higher scale. It can be scaled down to one quart. To 19.89 g (0.13 mol) (S)-

(+)-mandelic acid 47S in 70 ml MeOH were added first 26 ml (22.02 g, 0.21 mol) 3,3-

dimethoxy propane and then 0.77 g (4.32 mmol) p-toluene sulfonic acid

monohydrate. The clear solution was stirred at RT and the progress of the reaction

was monitored with TLC (CH2Cl2, detection: UV, Rf (47S) = 0.07, Rf (48S) = 0.62)

until all 47S was consumed (23 – 26 h). Workup: After reducing the reaction solution

to one quart of its volume by RV the residue was dissolved in EtOAc, washed two

times with sat. NaHCO3 / brine mixture until the aqueous layer was neutral and then

two times with brine. The organic layer was separated and dried over MgSO4. After

filtration, removal of all volatiles by RV and further drying under HV 19.23 - 20.55 g

(0.116 – 0.124 mol, 89 – 95 %) 48S were obtained as a clear, colorless and pure oil,

which crystallized spontaneously under considerable heat evolution and could be

used for the next step without further purification. Note: Mandelic acid and its esters

are prone to racemization under basic conditions and contact with strong bases

(including alkali carbonates), ammonia and amines must be avoided! Mp. (lit) = 54 -

58° C. [α]23D (lit.) = + 142.0 (MeOH, c = 2). 1H-NMR (CDCl3, 270 MHz): δ = 7.41 –

7.29 (m, 5H, Ph-CH(OH)-COOCH3); 5.16 (s, 1H, -CH(OH)-); 3.75 (s, 3H, -COOCH3);

2.68 (br s, 1H, -OH). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 173.83 (-COOCH3); 138.07

(C(1)-Ph); 128.40 (CH(3,5)-Ph); 128.28 (CH(4)-Ph); 126.41 (CH(2,6)-Ph); 72.79

(-CH-); 52.86 (-COOCH3). MS (FD+, MeOH): m/z (%) = 166 [M]+.

- 228 -

7.4.2 (1S)-1-Methoxy-1-phenyl acetic acid methyl ester 49S [46 (2)]

49S 91 % crude

Ph COOCH3

OCH3

COOCH3

OH

Ph

48S 1) 0.61 eq Ag2O (M = 231.74 g/mol) / 6.62 eq H3CI (M = 141.94 g/mol, d = 2.280 g/ml) / DMF / 2 d stirring at RT 2) quenching with 7.05 eq NaOAc (M = 82.03 g/mol)

*(S)

*(S)

M (C10H12O3) = 180.20 g / mol Pic. 7.4.2

Caution! Methyl iodide is a volatile strong carcinogen! Dimethylformamide (DMF) is

teratogen and also a cancer suspect agent! All operations have to be performed in a

hood. To minimize the risk of diffusion contamination it is recommended to wear two

disposable gloves below a long sleeved thick rubber glove on each hand. All

glassware and tools used are washed thoroughly with a saturated ammonia solution

and left overnight in the hood. The original procedure [46 (2)] was adjusted to modern

safety standards. To 12.11 g (72.84 mmol) 48S and 10.27 g (44.30 mmol)

silver(I)oxide in 100 ml DMF were added dropwise 30 ml (68.40 g, 481.89 mmol)

methyl iodide. The mixture was stirred at RT for 2 d until all 48S was consumed. In

the beginning of the reaction the mixture became slightly warm. Its progress was

indicated by formation of white-yellowish precipitated silver iodide and was monitored

by TLC (hexanes / EtOAc 1 : 1, Rf (48S) = 0.46, Rf (49S) = 0.54). Excess methyl

iodide was quenched portionwise with solid sodium acetate, the mixture was stirred

overnight and diluted with ca. 300 ml aqua dest.. After addition of EtOAc silver iodide

was sucked off from the mixture, which was washed with aqua dest., then with

EtOAc. It was finally dried in a vacuum descicator over P2O5 for recycling. Ca. 5 – 10

g sodium thiosulfate were added to the combined filtrates to reduce any traces of

iodine. The separated organic phase was washed ten times with brine until free of

DMF and dried over MgSO4. After filtration, solvent removal by RV and further drying

under HV 11.88 g (65.92 mmol, 91 % crude yield) 49S were obtained as a yellowish

oil sufficiently pure for the next step. The product should be stored at – 30° C! 1H-

NMR (CDCl3, 270 MHz): δ = 7.44 – 7.29 (m, 5H, Ph-CH(OCH3)-COOCH3); 4.76 (s,

1H, -CH-); 3.70 (s, 3H, -COOCH3); 3.39 (s, 3H, -OCH3). 13C{1H}-NMR (CDCl3, 68

MHz): δ = 170.46 (-COOCH3); 135.70 (C(1)-Ph); 128.18 (CH(4)-Ph); 128.07

(CH(3,5)-Ph); 126.65 (CH(2,6)-Ph); 81.94 (-CH-); 56.75 (-OCH3); 51.66 (-COOCH3).

- 229 -

7.4.3 (+)-(2S)- 2-Methoxy-2-phenylethanol 50S [46 (3-4)]

50S 98 % crude; 83 % after dist.

Ph

OCH3

COOCH3

OCH3

Ph

49S1.04 eq LiAlH4

(M = 36.95 g/mol)

THF / 0o C to RT*(S)

OHM (C9H12O2) = 152.19 g/mol;d = 1.054 g/ml*

(S) Pic. 7.4.3

Caution! Lithium aluminum hydride is moisture sensitive, can ignite in air, should be

weighed quickly in air only in a hood and stored in a Schlenk tube under inert gas!

50S is also commercially available and the original procedure [46 (3-4)] was slightly

modified. To a clear solution of 13.33 g (73.95 mmol) 49S in 300 ml THF at 0° C

were added in portions 2.83 g (76.59 mmol) lithium aluminum hydride pellets under

vigorous stirring and under inert gas stream. Reaction occurred immediately

accompanied with hydrogen gas evolution. To avoid overpressure the gas was

released through a needle connected via a tubing to an oil bubbler in the back of the

hood until hydrogen evolution ceased after ca. 15 min.. The mixture was stirred 12 h

at RT without cooling. Excess lithium aluminum hydride was quenched carefully with

40 % aq. NaOH solution under ice cooling until gas evolution ceased. The mixture

was diluted with aqua dest., poured on 40 % aq. NaOH in a separation funnel and

the aqueous phase was extracted three times with Et2O. The combined organic

layers were dried over MgSO4. Solvent removal by RV and further drying under HV

afforded 11.07 g (72.74 mmol, 98 % crude yield) 50S as a yellowish clear oil

contaminated only with traces of (S)-1,2-dihydroxy-1-phenylethane. The crude

product was distilled under HV in a short path into an ice cooled Schlenk tube (bp. =

68 - 70° C / 0.031 mbar) to give 9.32 g (61.25 mmol, 83 % yield) 50S as a clear

colorless oil free of any byproducts by NMR. Exceeding 1.20 eq of lithium aluminum

hydride leads to an increased formation of (S)-1,2-dihydroxy-1-phenylethane, while

below 1.00 eq the reduction is usually not complete! [α]23D = + 112.0(4) (acetone, c =

0.52), [α]23D (Lit.) = + 133 (acetone, c = 1). 1H-NMR (CDCl3, 270 MHz): δ = 7.40 –

7.24 (m, 5H, Ph-CH(OCH3)-CH2-OH); 4.29 (dd, 3J = 8.1, 3J = 4.0, 1H, -CH-); 3.70 –

3.56 (2 not res. dd, 2 diastereotopic H, -CH2-); 3.29 (s, 3H, -OCH3); 2.23 ( br s, 1H, -

OH). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 138.13 (C(1)-Ph); 128.46 (CH(3,5)-Ph);

128.07 (CH(4)-Ph); 126.77 (CH(2,6)-Ph); 84.57 (-CH-); 67.39 (-CH2-); 56.92 (-OCH3).

- 230 -

7.4.4 (+)-(2S)-P-(2-Methoxy-2-phenylethyloxy)-P,P-diphenylphosphine 51S

51S 85 %

PhO

OCH3

P

Ph

Ph

1.24 eq NEt3 /1.11 eq ClPPh2 (M = 220.64 g/mol, d = 1.229 g/ml)

THF / 60 o C

50S

PhOH

OCH3

* (S)

* (S)

M (C21H21O2P) = 336.37 g/mol

Pic. 7.4.4

To 5.72 g (37.6 mmol) 50S and 6.50 ml (4.72 g, 46.6 mmol) NEt3 in 200 ml THF were

added dropwise 7.50 ml (9.22 g, 41.8 mmol) chlorodiphenylphosphine within 5 min.

at RT and triethylammonium hydrochloride started to precipitate out immediately. The

mixture was then stirred at 60° C. The progress of the reaction was monitored by

TLC (hexanes : EtOAc = 3 : 1 + 5 % NEt3, Rf (50S) = 0.28, Rf (51S) = 0.59) until 50S

was not detectable anymore after 12 h. Workup: To the reaction mixture were added

first 15 ml NEt3 and then ca. 10 g hydrated silica gel to absorb most of excess

chlorodiphenylphosphine. The suspension was stirred 10 min. and filtrated. Removal

of all volatiles of the resulting clear solution by RV and under HV furnished 13.05 g

crude 51S as a slightly turbid oil, which was purified by FC (hexanes : EtOAc = 3 : 1

+ 5 % NEt3). Extended drying under HV gave 10.79 g pure 51S (32.1 mmol, 85 %) as

a clear, colorless, air- and hydrolysis stable oil. [α]23D = + 39.8 (CHCl3, c = 0.18).

1H-NMR (CDCl3, 270 MHz): δ = 7.49 – 7.20 (series of m, 15H, Ph-CH(OCH3)-CH2-O-

PPh2); 4.36 (dd, 3J = 7.8, 3J = 3.8, 2H, -CH-); 4.09 – 3.87 (2 not res. ddd, 2H, -CH2-);

3.13 (s, 3H, -OCH3). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 142.19 (d, 1JCP = 12.1, C(1)-

Ph2P-); 141.93 (d, 1JCP = 12.1, C(1)-Ph2P-); 138.38 (C(1)-Ph-CH-); 130.42 (d, 2JCP =

4.7, CH(2 or 6)-Ph2P-); 130.10 (d, 2JCP = 4.7, CH(6 or 2)-Ph2P-); 129.06 (CH(4)-Ph-

CH-); 128.35 (CH(3,5)-Ph-CH-); 128.17 (d, 3JCP = 1.4, CH(3 or 5)-Ph2P-); 128.07 (d, 3JCP = 1.4, CH(5 or 3)-Ph2P-); 127.94 (CH(4)-Ph2P-); 126.98 (CH(4)-Ph- CH-); 83.90

(d, 3JCP = 5.9, -CH-); 74.39 ((d, 2JCP = 17.8, -CH2-); 56.83 (-OCH3). 31P{1H}-NMR

(CDCl3, 109 MHz): δ = 116.47 (s, 1P). MS (FD+, CH2Cl2): m/z (%) = 336 [M+]. EA

anal.calc for C21H21O2P (336.37): C 74.99, H 6.29; found: C 74.78, H 6.27.

- 231 -

7.4.5 (1R)-Dichloro{σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-methoxy-ethyl)-

benzene]}ruthenium(II) 53R

O

P

Ru

ClCl

Ph

Ph

OCH3

(R)*

CH2Cl2 : THF = 20 : 1

53R 62 % after recryst.

COOCH3

O

P

Ru

ClCl

Ph

Ph

52S not isolated!

PhH3CO *

(S)

1.00 eq 7 +

2.33 eq 51S

120 o C / 11 h

Pressure Schlenk Tube

RT

20 min.

M (C21H21Cl2O2PRu) = 508.35 g/mol pic. 7.4.5

1773 mg (2.88 mmol) 7 and 2251 mg (6.69 mmol) 51S were stirred in a pressure

Schlenk tube (capable of withstanding a minimum pressure of 120 bar) in 30 ml

CH2Cl2 and 1.5 ml THF at RT. Within 20 min. the suspension of 7 turned to a clear,

deep red solution and complete conversion to adduct 52S was checked by 31P{1H}-

NMR (CDCl3, 109 MHz): δ = 109.95 (s, 1P). Upon complete complexation of 7 the

reaction mixture was stirred 11 h at 120 o C (Caution! Autoclave burst protection

equipment mandatory! The reaction vessel must be cooled down to RT slowly before

opening!). Complete conversion to the ansa-complex 53R was checked by 31P{1H}-

NMR again. Workup: The red-brownish reaction solution was filtered through a plug

of cellulose and the solvents were removed by RV. The slimy crude product was

washed once with Et2O, then redissolved in THF and the solvent removed by RV giving a micro-crystalline product, which was recrystallized directly from a minimum

of hot THF down to - 30° C. After filtration from the cold mother liquor the product

was washed once with a small amount of cold THF, then with MeOH, finally with Et2O

and dried on air to give 1751 mg (3.44 mmol, 59.8 %) 53R as air stable red

microcrystals. From the mother liquor additional 75 mg (0.15 mmol, 2.6 %) 53R were

obtained similarly, giving an overall yield of 1826 mg (3.59 mmol, 62 %). Single

crystals suitable for X-ray diffraction structure analysis were grown by slow

evaporation from CH2Cl2. Mp. = 188 - 190° C (dec.). [α]23D = + 7.4 (CH2Cl2, c =

0.0034). 1H-NMR (CDCl3, 270 MHz): δ = 7.88 – 7.74 (m, 4H, CH(2,6)-

- 232 -

Cl2Ru(II)[η6:σ(P)-Ph-CH(OCH3)-CH2-O-PPh2]); 7.41 – 7.27 (m, 6H, CH(3,4,5)-PPh2);

6.47 (pseudo t, 1H, CH(3 or 5)-η6-Ph); 6.06 (pseudo t, 1H, CH(5 or 3)-η6-Ph); 5.64 –

5.56 (m and d, 2H, CH(2 or 6)- and CH(4)-η6-Ph); 5.25 (d, 3J = 5.1, 1H, CH(6 or 2)-

η6- Ph); 4.37 – 4.18 (2 not res. ddd, 2H, -CH2-); 4.12 (dd, 3J = 5.3, 3J = 3.1, 1H,

-CH(OCH3)-); 3.41 (s, 3H, -OCH3). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 136.46 (d, 1JCP = 57.1, C(1)-PPh2); 134.51 (d, 1JCP = 56.4, C(1)-PPh2); 131.43 (d, 2JCP = 9.6,

CH(2,6)-PPh2); 131.27 (d, 2JCP = 9.6, CH(6 or 2)-PPh2); 130.97 (d, 4JCP = 2.7, CH(4)-

PPh2); 130.82 (d, 4JCP = 2.6, CH(4)-PPh2); 128.04 (d, 3JCP = 11.0, CH(3,5)-PPh2);

127.78 (d, 3JCP = 11.0, CH(3,5)-PPh2); 104.05 (d, 2JCP = 9.6, CH(3 or 5)-η6-Ph));

93.60 (d, 2JCP = 8.0, CH(5 or 3)-η6-Ph); 90.56 (C(1)-η6-Ph); 86.97 (CH(4)-η6-Ph);

86.91 (CH(6 or 2)-η6-Ph); 85.05 (CH(2 or 6)-η6-Ph); 75.64 (d, 3JCP = 1.1,

-CH(OCH3) ); 70.3 (-CH2-); 57.56 (-OCH3). 31P{1H}-NMR (CDCl3, 109 MHz): δ =

125.08 (s, 1P). MS (FD+, CH2Cl2): m/z (%) = 502 (29) [M]+ isotope peak, 508 (75)

[M]+, 509 (100) [M]+ isotope peak. EA anal.calc for C21H21Cl2O2PRu (508.35): C

49.62, H 4.16; found: C 49.57, H 4.46.

7.4.6 General Procedure for Amine Complexation Reactions

53R was first dissolved in CH2Cl2, followed by the addition of the amine and finally of

MeOH. Then solid NaPF6 was added in one portion and the mixture was stirred at RT

overnight (12 – 16 h). Before workup the d.e. was determined by 31P- and 1H-NMR.

Workup: After solvent removal by RV the crude product was dissolved in CH2Cl2 and

filtrated off excess NaCl and NaPF6 over a disposable pipette filled with cellulose

filter flakes. The resulting clear yellow to orange solution was evaporated to dryness

by RV. The residue was washed free of excess amine with Et2O inside the round

bottom flask. The crude product was dried thoroughly under HV, weighed and the

d.e. was determined by NMR. The crude product was then recrystallized or crushed

out starting from RT down to - 30° C to afford the particular pure complex. The cold

mother liquors were pipetted off and disposed because no further product could be

obtained from them.

- 233 -

1.00 eq 53R + RNH2 +excess NaPF6

OP

RuCl

NH2

Ph

Ph

OCH3

**

(R)

PF6

R

56RS R = (S)-C*H(CH3)Ph M (C29H32ClF6NO2P2Ru) = 739.04 g/mol

(S)O

P

RuNH2

ClPh

Ph

OCH2

*

(R)

(R)

R

unlikelike

*

+

54R R = Ph M (C27H28ClF6NO2P2Ru) = 710.99 g/mol

55R R = (p-F)C6H4 M (C27H27ClF7NO2P2Ru) = 728.98 g/mol, calc. new M' (M(H3COH)0.5) = 745.00 g/mol

56RR R = (R)-C*H(CH3)Ph M (C29H32ClF6NO2P2Ru) = 739.04 g/mol

RNH2 = aniline M = 93.13 g/mol d = 1.0213 g/ml

RNH2 = p-fluoraniline M =111.12 g/mol d = 1.1570 g/ml

RNH2 = (R)-PhC*H(NH2)CH3 M =121.18 g/mol d = 0.9500 g/ml

RNH2 = (S)-PhC*H(NH2)CH3 M =121.18 g/mol d = 0.9500 g/ml

CH2Cl2 / MeOH / RT

l72 % after recryst.

l : u 1 : 151 % after recryst.

ul27 % after recryst.

lu : uu 1 : 115 % after crushing out

PF6

Pic. 7.4.6

Preparation of NMR samples and d.e. determination: To avoid measuring a virtually

higher or lower d.e. due to possible solvent dependent configurational metastability of

the complexes it is important to perform sample preparations and measurements as

quickly as possible! Aliquots taken from reaction solutions were evaporated to

dryness by RV, dissolved in the NMR solvent and filtrated over a pipette filled with

filterflakes directly into the NMR tube. Any product as a red residue held back in the

filterflakes was washed out into the NMR tube to ensure a representative sample. To

obtain a representative NMR sample it must be assured during the preparation that

the complex mixture dissolves completely in the NMR solvent! The NMR samples of

the crude products were prepared in an analog way. The relative d.e. was

determined by the integrals of the particular 31P-NMR signals. To avoid ambiguities

and miscorrelations 31P-NMR spectra were referenced to PF6- as internal standard

already present. The 31P-NMR signals of the diastereomers were then correlated to

the methoxy singlets in the 1H-NMR spectrum by integral comparison, which allowed

then in turn the assignment to the particular diastereomers (Chapter 4.1. and 4.3.).

- 234 -

(RRu, 1R)-[σ-chloro {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-methoxyethyl)-

benzene]}-σ(N)-phenylamino ruthenium(II)] hexafluorophosphate 54R

According to the procedure above from 300 mg (0.590 mmol) 53R, 010 ml (102 mg,

1.097 mmol) freshly distilled aniline and 326 mg (1.941 mmol) NaPF6 in 4 ml CH2Cl2

and 4 ml MeOH. Before workup an aliquot was taken directly out of the reaction

solution and > 99 % d.e. l was determined by NMR (31P{1H}-NMR (acetone-d6, 121

MHz; u): δ = 131.05 (s, 1P); 1H-NMR (acetone-d6, 270 MHz; u): δ = 3.40 (s, 3H, -

OCH3)). After workup 504 mg crude 54R as an orange solid were obtained, but with

74 % d.e. l. One time recrystallization from CH2Cl2 afforded 302 mg (0.425 mmol, 72

%) pure 54R with > 99 % d.e. l by NMR. The crystals were suitable X-ray structure

determination. After recrystallization the compound is only sparingly solulable in

CH2Cl2 or CHCl3, but moderately in acetone (in which it epimerizes within hours at

RT) and in acetonitrile (in which it epimerizes within minutes at RT). Mp. = 199° C

(dec.). [α]23D = - 111.5 (CH2Cl2, c = 0.0029). 1H-NMR (acetone-d6, 500 MHz; l): δ =

7.86 - 7.80 (m, 4H, CH(2,6)-{(σ(N)-PhNH2)ClRu(II)[η6:σ(P)-Ph-CH(OCH3)-CH2-O-

PPh2]}+); 7.64 – 7.50 (m, 6H, CH(3,4,5)-PPh2); 7.37 - 7,33 (m, 4H, CH(2,3,5,6)-

PhNH2); 7.24 – 7.20 (m, 1H, CH(4)-PhNH2); 6.56 (pseudo t, 1H, CH(4)-η6-Ph); 6.09

(pseudo t, 1H, CH(5)-η6-Ph); 5.75 (m, 1H, CH(2)-η6-Ph); 5.60 (not res. d, 1H, -NH2-);

5.51 (m, 1H, CH(6)-η6-Ph); 5.48 (m, 1H, CH(3)-η6-Ph); 4.91 (not res. d, 1H, -NH2-);

4.62 (not res. ddd, 1H, -CH2-), 4.57 (not res. ddd, 1H, -CH(OCH3)-); 4.44 (ddd, 2J =

17.0, 3J = 12.5, 3JHP = 2.5, 1H, -CH2-); 3.56 (s, 3H, -OCH3). 13C{1H}-NMR (acetone-

d6, 126 MHz; l): δ = 148.54 (C(1)-PhNH2); 134.45 (d, 2JCP = 13.4, CH(2, 6)-PPh2);

133.21 (d, 4JCP = 62.1, CH(4)-PPh2); 131.65 (d, 2JCP = 10.3, CH(2,6)-PPh2); 130.24

(d, 3JCP = 11.4, CH(3,5)-PPh2); 130.16 (CH(3,5)-PhNH2); 129.52 (d, 3JCP = 11.3,

CH(3,5)-PPh2); 126.84 (CH(4)-PhNH2); 121.75 (CH(2,6)-PhNH2); 107.56 (CH(6)-η6-

Ph); 103.10 (d, 2JCP = 10.3, CH(4)-η6-Ph); 95.85 (C(1)-η6-Ph); 86.97 (CH(5)-η6-Ph);

82.54 (CH(3)-η6-Ph); 81.71 (CH(2)-η6-Ph); 73.23 (-CH(OCH3)-); 68.19 (-CH2-); 58.24

(-OCH3). 31P{1H}-NMR (acetone-d6, 121 MHz; l): δ = 131.75 (s, 1P). MS (FAB): m/z

(%) = 436 (59) [M-Cl-PhNH2-PF6-]+ isotope peak, 472 (100) [M-PhNH2-PF6

-]+ isotope

peak, 565 (43) [M-PF6-]+ isotope peak. EA anal.calc for C27H28ClF6NO2P2Ru

(710.99): C 45.61, H 3.97, N 1.97; found: C 45.35, H 4.03, N 1.83.

- 235 -

(1’R)-[σ-chloro- σ(N)-(4-fluorophenylamino)- {σ(P):η6-[(2’-(P,P-diphenylphos-

phinoxy)-1’-methoxyethyl)-benzene]} ruthenium(II)] hexafluorophosphate 55R

According to the procedure above from 392 mg (0.771 mmol) 53R, 035 ml (405 mg,

3.644 mmol) p-fluoroaniline and 406 mg (2.417 mmol) NaPF6 in 4.5 ml CH2Cl2 and 9

ml MeOH. Before workup an aliquot was taken directly out of the reaction solution

and 66 % d.e. l was determined by NMR. After workup 686 mg crude 55R were

obtained as brownish microcrystalline powder. In other batches no d.e. was found

after workup. The crude product was recrystallized from hot MeOH down to - 30° C to

give finally 293 mg (0.393 mmol, 51 %) pure 55R with l : u 1 : 1 by NMR. The crystals

were suitable X-ray structure determination and the compound crystallizes with a half

molecule MeOH per formula unit. The compound is also solulable in CH2Cl2, CHCl3

and in acetone. Mp. = 188 - 190° C (dec.). [α]23D = - 34.9 (CH2Cl2, c = 0.0038). 1H-

NMR (acetone-d6, 500 MHz, contains MeOH; l : u = 1 : 1): δ = 7.90 - 7.75 and 7.63 -

7.50 (m, 20H, CH-{(σ(N)-(p-F)C6H4NH2)ClRu(II)[η6:σ(P)-Ph-CH(OCH3)-CH2-O-

PPh2]}+); 7.40 (m, 4H, CH(2,6)-(p-F)C6H4NH2); 7.10 (pseudo t, 4H, CH(3,5)-(p-

F)C6H4NH2); 6.59 (pseudo t, 1H, CH(4)-�6-Ph, l); 6.56 (pseudo t, 1H, CH(4)-η6-Ph,

u); 6.11 (pseudo t, 1H, CH(3)-η6-Ph, l); 6.08 (pseudo t, 1H, CH(3 or 5)-η6-Ph, u); 6.01

(br s, 2H, -NH2-); 5.87 (pseudo t, 1H, CH(2 or 6)-η6-Ph, u); 6.77 (pseudo d, 1H, CH(6

or 2)-η6-Ph, u); 5.75 (pseudo t, 1H, CH(2)-η6-Ph, l); 5.65 (m, 1H, CH(5)-η6-Ph, l);

5.63 (pseudo t, 1H, CH(6)-η6-Ph, l); 5.38 (m, 1H, CH(5 or 3)-η6-Ph, u); 4.95 (not res.

br d, 2H, -NH2-); 4.69 (m, 2H, -CH2-, l and u); 4.56 (m, 1H, -CH(OCH3)-, l); 4.54 (m,

1H, -CH(OCH3)-, u); 4.52 - 4.42 (m, 2H, -CH2-, l and u); 3.56 (s, 3H, -OCH3, l); 3.42

(s, 3H, -OCH3, u). 13C{1H}-NMR (acetone-d6, 126 MHz, contains MeOH; l : u = 1 : 1):

δ = 161.13 (d, 1JCF = 127.2, C(4)-(p-F)C6H4NH2, l and u); 145.03 (d, 1JCF = 100.3,

C(1)-(p-F)C6H4 NH2, l and u); 136.42 (d, 1JCP = 63.1, C(1)-PPh2); 135.67 (d, 1JCP =

63.1, C(1)-PPh2); 134.50 - 129.36 (series of d, CH-PPh2); 123.79 (d, 3JCF = 8.3,

CH(2,6)-(p-F)C6H4NH2, l or u); 123.39 (d, 3JCF = 8.3, CH(2,6)-(p-F)C6H4NH2, u or l);

116.86 (d, 2JCF = 19.6, CH(3,5)-(p-F)C6H4NH2, l or u); 116.68 (d, 3JCF = 18.6,

CH(3,5)-(p-F)C6H4NH2, u or l); 108.32 (CH(5 or 3)-η6-Ph, u); 107.41 (CH(5)-η6-Ph, l);

102.98 (CH(4)-η6-Ph, l and u); 96.05 (C(1)-η6-Ph, l); 94.73 (C(1)-η6-Ph, u); 87.63

(CH(3 or 5)- η6-Ph, u); 87.17 (CH(3)- η6-Ph, l); 83.68 (d, 2JCP = 7.3, CH(6 or 2)- η6-

Ph, u); 82.44 (CH(2 or 6)- η6-Ph, u; CH(6)- η6-Ph, l); 81.78 (CH(2)-�6-Ph, l); 75.18

- 236 -

(-CH(OCH3)-, u); 73.25 (-CH(OCH3), l); 70.31 (-CH2-, l and u); 58.19 (5JCP = 6.2,

-OCH3, l); 57.75 (-OCH3, u). 31P{1H}-NMR (CDCl3, 109 MHz; l : u = 1 : 1): δ = 133.29

(s, 1P, l); 129.83 (s, 1P, u). MS (FAB): m/z (%) = 438 (94) [M-Cl-((p-F)C6H4NH2)-

PF6-]+ isotope peak, 472 (100) [M-((p-F)C6H4NH2)-PF6

-]+ isotope peak, 585 (28) [M-

PF6-]+ isotope peak. EA anal.calc for C27H27ClF7NO2P2Ru (728.98): C 44.49, H 3.73,

N 1.92; found: C 44.31, H 3.65, N 1.91; recalculated for C27H27ClF7NO2P2Ru

(MeOH)0.5 = C27.5H29ClF7NO2.5P2Ru (745.00): C 44.34, H 3.92, N 1.88.

(SRu, 1R, 1’R)-[σ-chloro- {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-

methoxyethyl)benzene]}- σ(N)-(1’-phenylethylamino)ruthenium(II)]

hexafluorophosphate 56RR

According to the procedure above from 389 mg (0.765 mmol) 53R, 0.27 ml (257 mg,

2.117 mmol) (R)-1-phenylethylamine and 440 mg (2.620 mmol) NaPF6 in 3 ml CH2Cl2

and 9 ml MeOH. In other batches no d.e was detectable by NMR in aliquots taken

from the reaction solution by NMR. After workup 699 mg crude 56RR were obtained

as yellow solid foam with 7 % d.e. ul (of course within in the experimental error, but

sufficient to assign the 31P-NMR signal to the particular diastereomers); (31P{1H}-

NMR (acetone-d6, 109 MHz; ll): � = 135.29 (s, 1P); 1H-NMR (acetone-d6, 270 MHz;

ll): � = 3.49 (s, 3H, -CH(OCH3))). The crude product was recrystallized from a

minimum amount MeOH at - 30° C to give 151 mg (0.204 mmol, 27 %) pure 56RR

with > 99 % d.e. ul by NMR. The crystals were suitable X-ray structure determination.

The compound is solulable in CH2Cl2, CHCl3 and in acetone. Mp. = 169° C. [α]23D = +

38.4 (CH2Cl2, c = 0.0037). 1H-NMR (acetone-d6, 400 MHz; ul): δ = 7.88 – 7.82 and

7.75 – 7.70 and 7.61 – 7.47 (3m, 10H, CH-{[(σ(N)-PhCH(CH3)NH2]ClRu(II) [η6:σ(P)-

Ph-CH(OCH3)-CH2-O-PPh2]}+); 7.34 – 7.27 (m, 3H, CH(3,4,5)-PhCH(CH3)NH2); 7.10

- 7.06 (m, 2H, CH(2,6)-PhCH(CH3)NH2); 6.79 (pseudo t, 1H, CH(4)-η6-Ph); 6.68

(pseudo t, 1H, CH(3 or 5)-η6-Ph); 6.22 (pseudo t, 1H, CH(2 or 6)-η6-Ph); 6.01

(pseudo t, 1H, CH(6 or 2)-η6-Ph); 5.20 (pseudo d, 1H, CH(5 or 3)-η6-Ph); 4.40 (m,

1H, -CH(OCH3)-); 4.35 (2 m, 2H, -CH2-); 3.80 (q, 3J = 6.5; 1H, PhCH(CH3)NH2); 3.65

(br s, 2H, -NH2-); 3.36 (s, 3H, -OCH3); 1.23 (d, 3J = 6.5, 3H, PhCH(CH3)NH2). 13C{1H}-NMR (acetone-d6, 68 MHz; ul): δ = 143.90 (C(1)-PhCH(CH3)NH2); 135.82 (d, 1JCP = 59.9, C(1)-PPh2); 134.28 (d, 2JCP = 12.3, CH(2,6)-PPh2); 133.20 (d, 4JCP = 2.5,

- 237 -

CH(4)-PPh2); 132.86 (d, 4JCP = 2.8, CH(4)-PPh2); 132.09 (d, 1JCP = 52.1, C(1)-PPh2);

131.23 (d, 2JCP = 10.3, CH(2,6)-PPh2); 130.26 (d, 3JCP = 10.6, CH(3,5)- PPh2); 129.69

(CH(3,5)-PhCH(CH3)NH2); 129.28 (d, 3JCP = 11.4, CH(3,5)-PPh2); 129.00 (CH(4)-

PhCH(CH3)NH2); 126.99 (CH(2,6)-PhCH(CH3)NH2); 103.25 (d, 2JCP = 7.5, CH(4)-η6-

Ph); 101.89 (d, 2JCP = 10.6, CH(3 or 5)-η6-Ph); 93.82 (C(1)-η6-Ph); 90.97 (CH(2 or 6)-

η6-Ph); 82.94 (CH(6 or 2)-η6-Ph); 82.19 (CH(5 or 3)-η6-Ph); 75.28 (-CH2-); 68.87

(-CH(OCH3)-); 58.13 (PhCH (CH3)NH2); 57.66 (-OCH3); 23.81 (PhCH(CH3)NH2). 31P{1H}-NMR (acetone-d6, 109 MHz; ul): δ = 133.19 (s, 1P). MS (FAB): m/z (%) =

436 (76) [M-Cl-PhCH(NH2)CH3-PF6-]+ isotope peak, 472 (100) [M-PhCH(NH2)CH3-

PF6-]+ isotope peak, 593 (43) [M-PF6

-]+ isotope peak. EA anal.calc for

C29H32ClF6NO2P2Ru (739.04): C 47.13, H 4.36, N 1.90; found: C 47.06, H 4.39, N

1.93.

(1R, 1’S)-[σ-chloro- {σ(P):η6-[(2-(P,P-diphenylphosphinoxy)-1-methoxyethyl)-

benzene]}- σ(N)-(1’-phenylethylamino)ruthenium(II)] hexafluorophosphate 56RS

According to the procedure above from 392 mg (0.771 mmol) 53S, 0.23 ml (219 mg,

1.803 mmol) (S)-1-phenylethylamine and 432 mg (2.572 mmol) NaPF6 in 3 ml CH2Cl2

and 9 ml MeOH. In other batches no d.e was detectable by NMR in aliquots taken

from the reaction solution. After workup 665 mg crude 56RS were obtained as

brownish solid foam with no d.e. visible by NMR. The crude product was crushed out

from MeOH at - 30° C to give 84 mg (0.204 mmol, 27 %) 56RS as a brown powder

with lu : uu = 1 : 1 by NMR. In one batch eventually one crystal could be found in the

crushed out powder (which is not crystalline otherwise), which was suitable for X-ray

structure determination and contained only the lu diastereomer. Another crystal

contained both diastereomers in a 1 : 1 ratio, but the quality of the crystal did not

allow an X-ray structure determination with the common accuracy standards. The

compound is solulable in CH2Cl2, CHCl3 and in acetone. Mp. = 156 - 157° C. [α]23D =

- 49.1 (CH2Cl2, c = 0.0018). 1H-NMR (acetone-d6, 400 MHz; lu : uu = 1 : 1): δ = 7.89 –

7.80 and 7.67 – 7.49 (2m, 20H, CH-{[(σ(N)-PhCH(CH3)NH2]ClRu(II)[ η6:σ(P)-Ph-

CH(OCH3)-CH2-O-PPh2]}+); 7.36 - 7.21 (m, 6H, CH(3,4,5)-PhCH(CH3)NH2); 7.09 -

7.05 (m, 4H, CH(2,6)-PhCH(CH3)NH2); 6.74 (pseudo t, 1H, CH(5)- η6-Ph, lu); 6.61

(pseudo q, 2H, CH(4)- η6-Ph, lu and uu); 6.21 (pseudo t, 1H, CH(3)-η6-Ph, lu); 6.17

- 238 -

(pseudo t, 1H, CH(3 or 5)-η6-Ph, uu); 6.03 (pseudo t, 1H, CH(2 or 6)-η6-Ph, uu); 6.00

(pseudo t, 1H, CH(5 or 3)-η6-Ph, uu); 5.87 (m, 1H, CH(2)-η6-Ph, lu); 5.64 (pseudo d,

1H, CH(6 or 2)-η6-Ph, uu); 5.33 (pseudo d, 1H, CH(6)-η6-Ph, lu); 4.77 (ddd, 2J = 23.3, 3J =13.0, 3JHP = 4.0, 1H, -CH2-, lu); 4.54 (m, 1H, -CH(OCH3)-, lu); 4.46 (not res. ddd,

1H, -CH2-, uu); 4.32 (m, 1H, -CH(OCH3)-, uu); 4.30 (not res. q, 1H, PhCH(CH3)NH2,

uu); 4.26 (m, 1H, -CH2-, uu); 4.20 (not res. ddd, 1H, -CH2-, lu); 3.82 (q, 3J = 6.5, 1H,

PhCH(CH3)NH2, lu); 3.59 (s, 3H, -OCH3, lu); 3.36 (s, 3H, -OCH3, uu); 1.30 (d, 3J =

6.5, 3H, PhCH(CH3)NH2, uu); 1.05 (d, 3J = 6.5, 3H, PhCH(CH3)NH2, lu). 13C{1H}-

NMR (acetone-d6, 126 MHz; lu : uu = 1 : 1): δ = 144.19 (C(1)-PhCH(CH3)NH2, uu);

143.96 (C(1)-PhCH(CH3)NH2, lu); 135.83 - 129.12 (series of d, C(1)- and CH-PPh2);

133.06 (CH(4)-PhCH(CH3)NH2, lu and uu); 129.86 (CH(3,5)-PhCH(CH3)NH2, lu or

uu); 129.73 (CH(3,5)-PhCH(CH3)NH2, uu or lu); 127.12 (CH(2,6)-PhCH(CH3)NH2, lu

or uu); 127.07 (CH(2,6)-PhCH(CH3)NH2, uu or lu); 103.58 (CH(5)-η6-Ph, lu or CH(5

or 3)-η6-Ph, uu); 103.53 (CH(5 or 3)-η6-Ph, uu or CH(5)-η6-Ph, lu); 102.11 (d, 2JCP =

10.3, CH(4)-η6-Ph, uu); 101.70 (d, 2JCP = 10.3, CH(4)-η6-Ph, lu); 95.00 (C(1)-η6-Ph,

lu); 93.97 (C(1)-η6-Ph, uu); 89.97 (CH(3)-η6-Ph, lu); 89.72 (CH(3 or 5)-η6-Ph, uu);

83.23 (CH(2 or 6)-η6-Ph, uu); 82.35 (CH(6 or 2)-η6-Ph, uu); 81.62 (CH(2)-η6-Ph, lu);

79.85 (CH(6)-η6-Ph, lu); 75.15 (-CH(OCH3)-, uu); 72.58 (-CH(OCH3)-, lu); 69.63

(-CH2-, uu); 66.65 (-CH2-, lu); 59.22 (PhCH(CH3)NH2, lu); 58.83 (PhCH(CH3)NH2,

uu); 58.20 (-OCH3, lu); 57.69 (-OCH3, uu); 24.68 (PhCH(CH3)NH2, uu); 24.26

(PhCH(CH3)NH2, lu). 31P{1H}-NMR (acetone-d6, 109 MHz; lu : uu = 1 : 1): δ = 133.77

(s, 1P); 129.16 (s, 1P). MS (FAB): m/z (%) = 438 (88) [M-Cl-PhCH(NH2)CH3-PF6-]+

isotope peak, 474 (100) [M-PhCH(NH2)CH3-PF6-]+ isotope peak, 595 (39) [M-PF6

-]+

isotope peak. EA anal.calc for C29H32ClF6NO2P2Ru (739.04): C 47.13, H 4.36, N

1.90; found: C 47.48, H 4.29, N 2.01.

- 239 -

7.5 Planar Chiral Ferrocenyl Derivatives 7.5.1 2,2,5,5-Tetramethyl-2,5-disila-1-azacyclopentane 58 [50 (1)]

Cl(H3C)2SiSi(CH3)2Cl

NH

SiSi

H3C

H3C

CH3

CH3

57 M = 215.27 g/mol 58 M(C6H17NSi2) = 159.38 g/mol 55 %

2.31 eq NEt3 /excess gas. NH3

Et2O / 0° C to RT

Pic. 7.5.1

The original procedure [50 (1)] was modified. A solution of 10.03 g (46.57 mmol) 1,2-

bis(chlorodimethylsilyl)ethane 57 and 15.0 ml (10.89 g, 107.62 mmol) triethylamine in

190 ml Et2O was saturated under vigorous stirring with dry ammonia gas (passed

through a gas washing bottle filled with sodium hydroxide pellets) for 10 min. at 0° C.

White triethylammonium chloride precipitated immediately and the white suspension

was stirred 8 h at RT. Workup: The suspension was filtered off triethylammonium

chloride over a D4-sinter, the volatiles were removed by RV at RT at not less than

200 mbar (58 is considerably volatile) to obtain 6.23 g (39.10 mmol, 84 % crude

yield) 58 as a colorless oil containing NEt3 and Et2O. The product was distilled under

HV in a short path into a Schlenk tube, which was cooled in an EtOH / dry ice bath to

obtain 4.09 g (25.66 mmol, 55 % yield) 58 as a colorless oil containing traces of NEt3

and Et2O, but sufficiently pure for the next step. The product should be stored at 0° C

under exclusion of moisture and should be redistilled prior to use. 1H-NMR (CDCl3,

270 MHz): δ = 0.68 (s, 4H, -CH2-CH2-); 0.05 (s, 12H, 2 x -Si(CH3)2N-). 13C{1H}-NMR

(CDCl3, 68 MHz): δ = 7.90 (d, -CH2-CH2-); 0.68 (d, 1JCSi = 53.8, -Si(CH3)2N-).

- 240 -

7.5.2 N,N,N',N'-Tetramethylmethylenediamine 59 [50 (3)]

M(C5H14N2) = 102.18 g/mold = 0.749 g/ml

H2O

0° C to RT

1.00 eq H2CO (M = 30.02 g/mol, d (37 % in H2O) = 1.04 g/ml) +

2.00 eq HN(CH3)2 (M = 45.07 g/mol, d(40 % in H2O) = 0.89 g/ml)

59 57 %(H3C)2N N(CH3)2

Pic. 7.5.2

Caution! 59 is severely lachrymatory and operations should be performed in an

efficient fume hood! In the need of anhydrous product the original procedure [50 (3)]

was modified. To 60 ml (23.08 g, 0.77 mol) 37 % aqueous formaldehyde solution in

an open Erlenmeyer flask in air in an ice bath at 0° C were added within 10 min. in

portions under well stirring 195 ml (69.42 g, 1.54 mol) 40 % aqueous dimethylamine

solution in such a way the reaction temperature was kept below 15° C. After stirring

the clear and colorless solution 30 min. under defrosting to RT ca. 130 g potassium

hydroxide pellets were added until an organic phase separated above the aqueous

solution. The organic phase was separated without the aid of any solvent, predried

over potassium hydroxide pellets overnight, decanted and directly absolutated over

calcium hydride in a mini reflux distill under nitrogen (bp. = 83 - 84° C / 1 atm) to give

44.46 g (0.44 mol, 57 % yield) 59 as a colorless oil. The product should be stored

under nitrogen, is hygroscopic and should be redistilled over calcium hydride, if

anhydrous reaction conditions have to be assured. 1H-NMR (CDCl3, 270 MHz): δ =

2.68 (s, 2H, H2C(N(CH3)2)2); 2.20 (s, 12H, H2C(N(CH3)2)2).

7.5.3 N,N-Dimethylmethyleneiminium chloride (Eschenmoser salt) 60 [50 (6)]

60 86 %

M(C3H8ClN) = 93.56 g/mol

(H3C)2N N(CH3)2

1.05 eq AcOCl (M = 78.50 g/mol, d = 6.00 g/ml)

Et2O / - 78° CN

H

CH3

CH3

H

59

Cl

Pic. 7.5.3

- 241 -

Contrary to the original Danishevsky protocol [50 (6)] the product was isolated. To

11.00 ml (8.24 g, 80.63 mmol) freshly distilled and anhydrous 59 in 50 ml Et2O in a

Schlenk flask in an dry ice / EtOH bath at - 78° C were syringed within 2 min. 6.00 ml

(6.63 g, 84.47 mmol) freshly distilled acetyl chloride, whereupon white 60 precipitated

immediately. The suspension was stirred for 10 min. at - 78° C and then at RT for 15

min. before the product was filtered off via overpressure canula transfer over a D4

Schlenk sinter under nitrogen and vigorous exclusion of moisture. The reaction flask

was washed out twice with 40 ml anhydrous Et2O to collect any residual product.

After drying under HV in the Schlenk sinter and overnight over P2O5 in a descicator

under vacuum 6.47 g (69.14 mmol, 86 % yield calculated as pure substance) 60 was

obtained as a white powder. The product contains also polymeric {(H3C)2N[CH2-

N(CH3)2]nCH2N(CH3)2}+Cl-, which does react as a synthetic equivalent of the

Eschenmoser salt itself. Therefore the product was used for further reactions without

any difficulties. 60 is very hygroscopic and should be stored in an inert atmosphere

under moisture exclusion. If the material adopts a yellowish color it should be

disposed. 1H-NMR (CDCl3, 270 MHz): δ = 8.48 (s, 2H, H2C=N(CH3)2+); 3.73 (s, 6H,

H2C=N(CH3)2+). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 79.48 (H2C=N(CH3)2

+); 38.89

(H2C=N(CH3)2+).

7.5.4 1-Bromo-2,4,6-tri(methylethyl)benzene 62 [50 (7)]

1.37 eq Br2(M = 159.81 g/mol, d = 3.110 g/ml) / 0.09 eq cat. Fe (M = 55.85 g/mol)

CH2Cl2 / 0° C to RT

61

M = 204.36 g/mol,d = 0.840 g/ml

62 94 %

M (C15H23Br) = 283.25 g/mol

Br

Pic. 7.5.4

The original procedure [50 (7)] was scaled up and modified. To avoid any substitution

reaction on the isopropyl side chains the reaction had to be performed in the dark by

wrapping all reaction vessels in aluminium foil! To a well stirred solution at 0° C of

- 242 -

26.70 g (31.8 ml, 0.13 mol) 1,3,5-tri(isopropyl)benzene 61 and 659 mg (11.80 mmol)

iron flakes in 15 ml CH2Cl2 in a 250 ml Schlenk flask were added dropwise over a

period of 1 h 9.20 ml (28.61 g, 0.18 mol) bromine in 15 ml CH2Cl2 from a 50 ml

Schlenk tube via a double canula. The reaction temperature was maintained at 0° C

during the bromine addition, but was allowed to reach slowly RT while stirring for

another 12 h. Workup: The dirty red-brownish reaction mixture was diluted with

CH2Cl2, washed once with brine to remove FeBr3 (lower layer organic phase!), then

twice with 40 % aq. NaOH (upper layer organic phase!) to remove excess bromine

and finally once with diluted aq. HCl (lower layer organic phase!) to remove residual

iron traces. The organic phase was dried with MgSO4, filtrated, the solvent removed

by RV and the crude product was dried under HV to give 37.77 g (quantitative crude

yield) 62 as a brownish oil. Distillation in a short path (bp. = 115 -117° C / 5.7 x 10 -2

mbar) gave 34.86 g (0.12 mol, 94 % yield) 62 as a nearly colorless clear oil, which

should be stored in the dark under nitrogen and redistilled prior to use. 1H-NMR

(CDCl3, 270 MHz): δ = 6.98 (s, 2H, CH(3,5)-C6H2); 3.47 (h, 3J = 6.9, 2H, (2,6)-

CH(CH3)2); 2.86 (h, 3J = 6.9, 1H, (4)-CH(CH3)2); 1.24 (d, 3J = 6.9, 18H, -CH(CH3)2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 147.70 (C(4)-C6H2); 147.31 (C(2,6)-C6H2);

123.66 (C(1)-C6H2); 122.21 (CH(3,5)-C6H2); 34.11 ((4)-CH(CH3)2); 33.55 ((2,6)-

CH(CH3)2); 24.08 ((4)-CH(CH3)2); 23.14 ((2,6)-CH(CH3)2).

- 243 -

7.5.5 (-)-(SS, 1R, 2S, 5R)-1-[(4’-methylphenyl)sulfinoxy]-2-methylethyl-5-methyl-cyclohexane 64S [50 (8)]

63S

OS

O

*

CH3

OH

CH3

**

**

**

64S 44 %1.20 eq TosCl(M = 190.65 g/mol) /1.22 eq NEt3 /1.53 eq P(OMe)3(M = 124.08 g/mol, d = 1.052 g/ml)

CH2Cl2 / reflux

(S)

CH3

(R)

(S)

(R)

M (C17H26O2S) = 294.46 g / mol

(R)

(R)

(S)

M = 156.27 g/mol

Pic. 7.5.5

The Sharpless procedure [50 (8)] can be scaled up or down by any factor, but

following scale is recommended for routine preparation. Exclusion of air and moisture

are crucial! Caution! Trimethylphosphite is a considerable nerve toxin and mutagen!

All operations must be performed in a hood! To a well stirred clear solution of 31.26 g

(0.200 mol) (-)-(1R, 2S, 5R)-menthol 63S and 45.76 g (0.240 mol) p-tosyl chloride in

1 l CH2Cl2 in a 2 l Schlenk flask were added 34 ml (24.68 g, 0.244 mol) NEt3 and then

36 ml (37.87 g, 0.305 mol) trimethylphosphite in this order. The clear solution was

refluxed 12 – 16 h at 55 – 60° C. Workup: After cooling down to RT under nitrogen

flux the nearly colorless, clear reaction solution was reduced to half of its volume by

RV, whereupon triethylammonium chloride precipitated out. The organic phase was

washed once with diluted aq. HCl, twice with sat. aq. NaHCO3 solution until the

aqueous phase became neutral and finally twice with brine. The organic phase was

dried with MgSO4, filtrated and the solvent removed by RV. Most of residual 63S,

trimethylphosphite and trimethylphosphate were distilled off under HV into a trap

(round bottom flask with crude product and sufficient strong magnetic stirring bar

simply connected with a right angled adapter tube to a Schlenk flask) with a heat gun

until boiling of the crude oily product ceases (max. 140 o C). After cooling down to RT

and solidifying to a microcrystalline mass the crude product was dissolved in a

minimum amount of ca. 400 ml hexanes / Et2O 2 : 1 and filtered off bis-p-

tolyldisulfone by suction through a D4 glass sinter. After solvent removal by RV and

- 244 -

further drying under HV 60.21 g (quantitative yield) of microcrystalline crude product

were obtained, which contained 64 in a diastereomer ratio of 1 : 1 and only traces of

impurities determined by 1H-NMR. Diastereomerically pure 64S was obtained by two

times slow crystallization from boiling acetone down to – 30 o C overnight. The

colorless crystal needles were filtrated off the cold mother liquor, washed with a

minimum amount of pentane and then dried simply by air suction to give 26.06 g

(0.089 mol, 44 % yield) diastereomerically pure 64S without traces of impurities by 1H-NMR. The product is airstable, but should be stored at - 5° C for prolonged times.

Recycling of combined mother liquors by epimerization: A concentrated acetone

solution of combined mother liquors was saturated with dry HCl gas at RT in for ca.

10 min. under well stirring. HCl was removed by bubbling nitrogen through the

resulting slight yellowish solution. After solvent removal by RV traces of 63S and bis-

p-tolyldisulfone formed by hydrolysis as a side reaction were removed as described

above. Diastereomerically pure 64S was obtained again by two times crystallization

from acetone. Yields are varying between 60 -70 % overall and in some cases other

side products could not be removed. For convenience mother liquors of several

batches were combined and recycled by epimerization as described. Crystals

suitable for X-ray structure determination were obtained by slow crystallization from

acetone at RT. Mp. (lit) = 103 - 105°C. [α]23D = - 202.3 (CH2Cl2, c = 0.075), [α]23

D

(lit.) = - 200.2 (acetone, c = 1.23). 1H-NMR (CDCl3, 270 MHz): δ = 7.55 (d, 3J = 8.1,

2H, CH(2,6)-(p-tolyl)S(=O)-O-menthyl); 7.26 (d, 3J = 8.1, 2H, CH(3,5)-(p-tolyl)); 4.10

(ddd, 3J = 3J = 10.7, 3J = 4.3, 1H, CH(1)-menthyl); 2.34 (s, 3H, -CH3 of p-tolyl); 2.25 -

2.21 (m, 1H, CH2(6)-menthyl); 2.80 (m, CH(5)-menthyl); 1.64 and 1.60 (2 m, 4H,

CH2(3,4)-menthyl); 1.42 (m, 1H, -CH(CH3)2); 1.30 (m, 1H, CH(2)-menthyl); 1.67 (m,

1H, CH2(6)-menthyl); 0.90 (d, 3J = 6.5, 3H, -CH3); 0.81 (d, 3J = 7.0, 3H, -CH(CH3)2);

0.66 (d, 3J = 7.0, 3H, -CH(CH3)2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 142.93 (C(1)-

(p-tolyl)); 142.14 (C(4)-(p-tolyl)); 129.38 (CH(3,5)-(p-tolyl)); 124.76 (CH(2,6)-(p-tolyl));

79.90 (CH(1)-menthyl); 47.74 (CH(2)-menthyl); 42.86 (CH2(6)-menthyl); 33.92

(CH2(4)-menthyl); 31.64 (-CH(CH3)2); 25.13 (CH(5)-menthyl); 23.07 (CH2(3)-

menthyl); 22.02 (-CH3); 21.49 (-CH3 of p-tolyl); 20.80 (-CH(CH3)2); 15.4 (-CH(CH3)2).

- 245 -

7.5.6 (+)-(SS)-[(4-Methylphenyl)sulfinyl]ferrocene 67S [51 (3)]

Fe

*S

O(S)

67S M (C17H16FeOS) = 324.22 g/mol

Fe

65

77.3 % e.e. of product after chromatography; 74 % yield

86.4 - 94.2 % e.e after recrystallization; 45 - 16 % yield

Fe

Li66

1) 1.00 eq tBuLi / 0.14 eq tBuOK

THF / - 78° C1.28 eq 1.00 eq

M = 186.03 g/mol

2) canuled slowly to: 1.74 eq 64S / THF / - 30° C

H3C

Pic. 7.5.6

The original procedure [51 (3)] was modified to a minimum of ferrocene 65 required

and the amount of 64S was increased to reach a higher enantiomeric excess of 67S.

Ferrocene 65 was recrystallized from hexanes prior to use. Strict moisture exclusion

and temperature control, vigorous stirring and slow addition rates determine the

success of this reaction! General canula and septum techniques were used avoiding

opening of the reaction vessels and exposure to air at anytime! Only clear and not

turbid tBuLi solutions were used! To obtain a high enantiomeric purity of 67S slow

crystallization is required as described below! The following procedure is

representative. To 13.04 g (70.10 mmol) ferrocene 65 and 881 mg (7.81 mmol)

tBuOK in 300 ml THF in a 500 ml round bottom Schlenk flask at - 78° C in a dry ice /

EtOH bath were added dropwise within 10 min. under vigorous stirring 35.00 ml (c =

1.46 mol/l in n-pentane, 54.58 mmol) tBuLi solution with a syringe. The slightly turbid

lemon yellow solution turned slowly red and was stirred 170 min. to ensure complete

conversion of all tBuLi to lithioferrocene 66 strictly maintaining - 78° C. The solution

of 66 was transferred dropwise through a canula with nitrogen overpressure within 30

min. to a vigorous stirred clear solution of 28.02 g (95.16 mmol) 64S in 300 ml THF in

an 1 l round bottom Schlenk flask, which was strictly kept between - 25 and - 20° C

(at lower temperatures 64S crushed out leading to an accumulation of 66 resulting in

- 246 -

a lower enantiomeric excess of the desired product). While the solution of 66 was

kept further at - 78° C the canula itself was cooled with dry ice during the addition.

The dropping rate was adjusted in such a manner the red colorization disappeared

after adding one drop and the solution of 64S became absolutely clear before adding

the next drop of the solution of 66. The reaction solution of 64S turned slowly more

and more yellow during the progress of the addition. If the complete and direct

conversion of 66 to 67S was not assured in this way, then 66 accumulated resulting

in a lower enantiomeric excess of the desired product. After complete addition of 66

the reaction solution was stirred overnight defrosting to RT inside the cooling bath.

Workup: The resulting nearly clear orange solution was poured into brine and

extracted twice with Et2O. After drying the combined organic layers over MgSO4,

filtration and solvent removal by RV and further by HV 40.81 g crude product was

obtained as a red oil, which was purified by FC (substance applied in silica matrix;

gradient elution first with hexanes : Et2O = 1 : 1 to flush out 65, 64S and 63S with

Rf(67S) = 0.11 on TLC, then with Et2O : CH2Cl2 = 4 : 1 to obtain 67S with Rf(67S) =

0.44 on TLC). After solvent removal by RV and HV 13.07 g (40.32 mmol, 74 % yield,

77.3 % e.e. (S) by HPLC) 67S were obtained as yellow microcrystals.

Recrystallization to increase enantiomeric purity: The product was dissolved

completely in a minimum amount of boiling CH2Cl2 (ca. 20 ml) and then so much

Et2O was added the solution stayed clear (ca. 50 ml) or became clear again by

boiling. Such an amount of hexanes was added the solution became only slightly

turbid (ca. 20 ml) and was shortly warmed to boiling. In case the solution became too

saturated and crystallization started too quickly a sufficient aliquot of CH2Cl2 was

dropped into the solution again. Slow crystallization occurred during standing

overnight at RT and was completed by standing one more time at - 30° C overnight.

After defrosting to RT the mother liquor was pipetted off, the crystals were washed

inside the flask with some Et2O, sucked off and finally dried by air suction to give 7.98

g (24.62 mmol, 45 % yield) 67S with 86.4 % e.e. (S) by HPLC. Repeating this

crystallization procedure gave 2.834 g (8.74 mmol, 16 % yield) 67S with 94.2 % e.e.

(S). These crystals were suitable for x-ray structure determination. Mp. = 130 - 131°

C (94.2 % e.e.); Mp. (lit) = 142 - 144° C (> 99.9 % e.e.). [α]23D (lit.) = + 314 (CHCl3,

c = 0.56; > 99.9 % e.e.). 1H-NMR (CDCl3, 270 MHz): δ = 7.50 (d, 3J = 8.0, 2H,

CH(2,6)-(p-tolyl)S(=O)-Fc); 7.23 (d, 3J = 8.0, 2H, CH(3,5)-(p-tolyl)); 4.58 (m, 1H, CH-

η5-Cp); 4.35 - 4.30 (s and m, 8H, CH-η5-Cp and CH-η5-Cp'); 2.35 (s, 3H, -CH3 of

- 247 -

p-tolyl). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 142.78 (C(1)-(p-tolyl)); 140.88 (C(4)-

(p-tolyl)); 129.52 (CH(3,5)-(p-tolyl)); 124.25 (CH(2,6)-(p-tolyl)); 94.53 (C(1)-η5-Cp);

69.99 (CH-η5-Cp); 69.88 (CH-η5-Cp and CH-η5-Cp'); 67.79 (CH-η5-Cp); 65.24 (CH-

η5-Cp); 21.43 (-CH3 of p-tolyl). MS (FAB): m/z (%) = 186 (72) [Fc]+, 324 (100) [M]+

isotope peak. HPLC (Daicel OD-H, n-hexane : iPrOH = 90 : 10, 15 bar, 0.5 ml/min.,

254 nm): tR(67R) = 25.1 min., tR(67S) = 27.6 min., RS = 1.7.

e.e. (S) [%] c [g/ml] [α]23D [°(ml)/(dm)g] [φ]23

D [°l/(cm)mol]

7.7 0.01918 + 25.7 + 83.2

48.8 0.01490 + 117.7 + 381.4

76.8 0.01228 + 164.6 + 533.6

86.4 0.00250 + 226.8 + 735.3

89.6 0.01140 + 250.4 + 812.0

94.2 0.00258 + 255.0 + 829.8

Table 7.5.6 Specific optical rotations [α]23D and specific molar optical rotations [φ]23

D of 67S in

CH2Cl2 at 23° C in a 10 cm cuvette at sodium D-line.

7.5.7 (+)-(SS)-[(4-(2-Hydroxyethyl)phenyl)sulfinyl]ferrocene 68S

Fe

*S

O(S)

68S M (C18H18FeO2S) = 354.25 g/mol

67S (86.4 % e.e.)

1) 2.03 eq LDA / THF / - 78° C2) 5.81 eq (H2CO)n (M = 30.03 g/mol)/ - 78° C to RT

HO

49 % yield

HN LiN2.03 eq tBuLi / THF / - 20° C

M (HN(iPr)2) = 101.19 g/mol, d = 0.7200 g/ml

LDA

a) preparation of lithium diisopropylamide (LDA) solution:

b)

2.36 eq 2.03 eq

Pic. 7.5.7

- 248 -

a) Preparation of lithium diisopropylamide (LDA) solution: To a well stirred

solution of 8.00 ml (5.76 g, 56.92 mmol) HN(iPr)2 (freshly distilled over CaH2) in 20 ml

THF at - 20° C in a conic 100 ml Schlenk tube were dropped 31.00 ml (c = 1.58 mol/l

in n-pentane, 48.97 mmol) tBuLi solution with a syringe within 5 min.; the clear

colorless solution was stirred 10 min. at - 20° C and directly used held at this

temperature. LDA solutions are instable and should be always prepared freshly prior

to use! It is not recommended to use commercially available LDA solutions!

b) To a well stirred solution of 7.82 g (24.12 mmol) 67S (86.4 % e.e.) in 120 ml

THF at - 78° C in a 250 ml round bottom Schlenk flask were transferred dropwise

within 15 min. the prior prepared LDA solution with a double canula with nitrogen

overpressure. The reaction solution turned slowly deep orange and was stirred 90

min. at - 78° C, whereupon it turned into a deep orange suspension. To this

suspension was added in one portion under a nitrogen stream 4.21 g (140.13 mmol)

solid paraformaldehyde and the brew was stirred 16 h inside the cooling bath slowly

defrosting to RT to become a yellow suspension Workup: The suspension was

poured into brine saturated with NH4Cl and extracted twice with EtOAc. The

combined organic layers were dried with MgSO4, filtrated and the volatiles removed

by RV and further by HV to afford 9.02 g crude 68S as solid orange foam containing

also starting material 67S by NMR. The crude product was purified by FC (substance

applied in silica matrix; elution with hexanes : EtOAc = 1 : 3 to flush out 67S with

Rf(67S) = 0.43 on TLC and then to obtain 68S with Rf(68S) = 0.13 on TLC). After

solvent removal by RV and HV 4.17 g (11.78 mmol, 49 % yield, 86.4 % e.e.) 68S were obtained and 151 mg (0.47 mmol, 2 %) 67S recovered. Mp. = 139 - 140°C

(86.4 % e.e.). [α]23D = + 231.3 (CH2Cl2, c = 0.0029, 86.4 % e.e.). 1H-NMR (CDCl3,

270 MHz): δ = 7.52 (d, 3J = 8.1, 2H, CH(2,6)-[p-(HO-CH2-CH2)C6H4]S(=O)-Fc); 7.28

(d, 3J = 8.1, 2H, CH(3,5)-C6H4); 4.59 (m, 1H, CH-η5-Cp); 4.34 - 4.31 (s and m, 8H,

CH-η5-Cp and CH-η5-Cp'); 3.82 (t, 3J = 6.6, 2H, -CH2-CH2-OH); 2.85 (t, 3J = 6.6, 2H,

-CH2-CH2-OH); 1.82 (br s, -OH). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 143.91 (C(1)-

C6H4); 141.74 (C(4)-C6H4); 129.56 (CH(3,5)-C6H4); 124.42 (CH(2,6)-C6H4); 94.13

(C(1)-η5-Cp); 70.04 (CH-η5-Cp); 69.94 (CH-η5-Cp and CH-η5-Cp'); 67.92 (CH-η5-Cp);

64.99 (CH-η5-Cp); 63.19 (-CH2-CH2-OH); 38.96 (-CH2-CH2-OH). MS (FAB): m/z (%)

= 186 (43) [Fc]+, 339 (26) [M-O]+, 355 (100) [M]+ isotope peak. A correct EA could not

be obtained.

- 249 -

7.5.8 (+)-(SS)-[(4-(2-Methylsolfonoxyethyl)phenyl)sulfinyl]ferrocene 69S

Fe

*S

O(S)

69S M (C19H20FeO4S2) = 432.34 g/mol

68S (86.4 % e.e.)

1.45 eq NEt3 / 1.22 eq H3CSO2Cl

CH2Cl2 / 0° C to RT

O

98 % yieldSO2H3C Pic. 7.5.8

To a stirred solution of 4036 mg (11.39 mmol) 68S (86.4 % e.e.) and 2.30 ml (1670

mg, 16.50 mmol) triethylamine in 70 ml CH2Cl2 at 0° C were added dropwise with a

syringe 1.10 ml (1592 mg, 13.90 mmol) mesylchloride. The red clear solution was

stirred 12 h in the cooling bath defrosting to RT. Workup: The solution was poured

into a saturated NaHCO3 solution. The lower organic phase was washed once with

brine, dried over MgSO4, filtrated and all volatiles removed by RV and further by HV

to afford 4858 mg (11.24 mmol, 99 % crude yield) nearly pure 69S. The crude

product was purified by FC over a short column (applied in eluent, EtOAc) to give

after removal of all volatiles 4837 (11.19 mmol, 98 % yield, 86.4 % e.e.) 69S as

yellow microcrystals. Crystallization from CH2Cl2 and some drops EtOAc gave

crystals suitable for X-ray structure determination. Mp. = 111°C (min. 86.4 % e.e.).

[α]23D = + 199.6 (CH2Cl2, c = 0.0027, min. 86.4 % e.e.). 1H-NMR (CDCl3, 270 MHz): δ

= 7.56 (d, 3J = 8.1, 2H, CH(2,6)-[p-(H3CSO2-O-CH2-CH2)C6H4]S(=O)-Fc); 7.30 (d, 3J

= 8.1, 2H, CH(3,5)-C6H4); 4.57 (m, 1H, CH(2 or 5)-η5-Cp); 4.39 ( t, 3J = 6.7, 2H, -CH2-

CH2-O-); 4.37 - 4.31 (s and m, 8H, CH(3,4,5 or 2,3,4)-η5-Cp and CH-η5-Cp'); 3.06 (t, 3J = 6.7, 2H, -CH2-CH2-O-); 2.83 (s, 3H -CH3). 13C{1H}-NMR (CDCl3, 68 MHz): δ =

145.06 (C(1)- C6H4); 139.10 (C(4)- C6H4); 129.49 (CH(3,5)- C6H4); 124.54 (CH(2,6)-

C6H4); 94.27 (C(1)-η5-Cp); 70.08 (CH-η5-Cp); 69.95 (CH-η5-Cp' and -CH2-CH2-O-);

69.49 (CH-η5-Cp); 67.92 (CH-η5-Cp); 64.84 (CH-η5-Cp); 37.41 (-O2SCH3); 35.39

(-CH2-CH2-O-). MS (FD+, CH2Cl2): m/z (%) = 433 (100) [M]+ isotope peak. EA anal.calc for C19H20FeO4S2 (432.34): C 52.78, H 4.66, S 14.83; found: C 52.88, H

4.80, S 14.63.

- 250 -

7.5.9 rac. (l)-1-Formyl-2-[(4'-methylphenyl)sulfinyl]ferrocene 70 and rac. (l)-1-Hydroxymethyl-2-[(4'-methylphenyl)sulfinyl]ferrocene 71

Fe

* S

p-Tol

O

(S)

67

66 %overall yield

S

Fe

*

O

p-Tol (S)

HO

* (M)

S

FeOHC

*

O

p-Tol (S)

* (M)

1) 1.98 eq LDA / THF / - 78 o C

2) 5.78 eq DMF (M = 73.09 g/mol, d = 0.9400 g/ml) / - 78 o C to RT

3) "1.05 eq" NaBH4 / MeOH / RT

+ ent. + ent. + ent.

70M (C18H16FeO2S) = 352.23 g/mol

71M (C18H18FeO2S) =354.25 g/mol

95 % crude

Pic. 7.5.9

70 and 71 were obtained by different synthesis methods in literature [52 (2, 7)].

a) To 7212 mg (22.24 mmol) rac. 67 (obtained from recrystallization of combined

mother liquors) in100 ml THF at - 78° C were transferred dropwise within 15 min. a

freshly prepared LDA solution [from 7.00 ml (5040 mg, 49.81 mmol) HN(iPr)2 and

26.00 ml (c = 1.69 mol/l in n-pentane, 43.93 mmol) tBuLi in 20 ml THF at - 20° C as

described in 7.5.7] with a double canula with nitrogen overpressure. The solution

turned slowly to a deep orange suspension and was stirred 130 min. at - 78° C to

ensure completion of the diastereoselective ortho lithiation. The suspension was

quenched at - 78° C with 10.00 ml (9400 mg, 128.61 mmol) DMF and after 5 min.

stirring the suspension turned into a clear orange solution, which was stirred

overnight defrosting slowly to RT inside the cooling bath. Workup: The solution was

poured into brine and extracted once with EtOAc. The organic layer was washed five

times with brine to remove all DMF, dried over MgSO4, filtrated and after removal of

all volatiles by RV and further by HV 7448 mg (21.15 mmol, 95 % crude yield)

diastereomerically pure rac. 70 were obtained containing starting material 67. The

crude product can be purified by FC (substance applied in silica matrix; elution with

hexanes : EtOAc = 1 : 2 with Rf(67) = 0.40 and Rf(70) = 0.28 on TLC), but contained

- 251 -

still traces of 67 and yield dropped to 74 % in another batch, so the crude product

was directly taken to the next step and purified then. 1H-NMR (CDCl3, 270 MHz): δ =

10.46 (s, 1H, 1-(O=CH)-2-[(p-tolyl)S(=O)]Fc); 7.47 (d, 3J = 7.4, 2H, CH(2,6)-(p-tolyl));

7.22 (d, 3J = 7.4, 2H, CH(3,5)-(p-tolyl)); 4.99 (m, 1H, CH-η5-Cp); 4.73 (m, 1H, CH-η5-

Cp); 4.68 (pseudo t, 1H, CH-η5-Cp); 4.46 (s, 5H, CH-η5-Cp'); 2.34 (s, 3H, -CH3 of p-

tolyl). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 192.53 (-CHO); 142.12 (C(1)-(p-tolyl));

141.19 (C(4)-(p-tolyl)); 129.75 (CH(3,5)-(p-tolyl)); 124.03 (CH(2,6)-(p-tolyl)); 97.12

(C(2)-η5-Cp); 78.53 (C(1)-η5-Cp); 74.01 (CH-η5-Cp); 72.96 (CH-η5-Cp); 71.67 (CH-

η5-Cp'); 70.56 (CH-η5-Cp); 21.39 (-CH3 of p-tolyl).

b) All of the crude product 70 from above was dissolved in 160 ml MeOH and

then 841 mg (22.23 mmol) sodium borohydride was added in portion under a stream

of nitrogen to the well stirred solution at RT. The solution was stirred another 20 min.

until foaming and hydrogen evolution ceased. Workup: After quenching with 2 ml

EtOAc all volatiles were removed by RV and the residue was dissolved in EtOAc

again. The solution was washed once with brine, the organic layer separated and

dried with MgSO4, filtrated and volatiles removed by RV and further by RV to give

7358 g (20.77 mmol, 93 % crude yield) rac. 71 as a brown oil containing small

amounts 67 but not 70. The crude product was purified by FC (substance applied in

silica matrix; gradient elution first with Et2O : CH2Cl2 = 1 : 0 to flush out impurities

and 67S with Rf(67) = 0.32 and Rf(71) = 0.19 on TLC and then with 1 : 0, 3 : 1, 1 : 1

to obtain 71). After solvent removal by RV and HV of two collected fractions 644 mg

(1.99 mmol, 9 %) 67 were recovered and 5167 mg (14.59 mmol, 66 % overall yield)

rac. 71 were obtained as yellow microcrystalline powder. 1H-NMR (CDCl3, 270 MHz):

δ = 7.45 (d, 3J = 7.7, 2H, CH(2,6)-1-(HOCH2)-2-[(p-tolyl)S(=O)]Fc); 7.23 (d, 3J = 7.7,

2H, CH(3,5)-(p-tolyl)); 4.49 (s, 5H, CH-η5-Cp'); 4.44 (m, 1H, CH-η5-Cp); 4.36 (m,

1H, CH-η5-Cp); 4.26 (pseudo t, 1H, CH-η5-Cp); 4.13 (2 isochronic d, 2J = 6.1, 2H,

-CH2OH); 2.35 (s, 3H, -CH3 of p-tolyl); 1.63 (br s, 1H, -OH). 13C{1H}-NMR (CDCl3, 68

MHz): δ = 141.00 (C(1)-(p-tolyl)); 140.93 (C(4)-(p-tolyl)); 129.70 (CH(3,5)-(p-tolyl));

124.06 (CH(2,6)-(p-tolyl)); 90.67 (C(2)-η5-Cp); 89.12 (C(1)-η5-Cp); 72.33 (CH-η5-Cp);

70.37 (CH-η5-Cp'); 69.64 (CH-η5-Cp); 67.77 (CH-η5-Cp); 57.99 (-CH2OH); 21.26

(-CH3 of p-tolyl). MS (FAB): m/z (%) = 289 (91) [M-Cp]+, 337 (28) [M-OH]+ isotope

peak, 355 (100) [M]+ isotope peak.

- 252 -

7.5.10 rac. (l)-1-(N,N-Dimethylaminomethyl)-2-[(4'-methylphenyl)sulfinyl]- ferrocene 72

71

S

Fe

*

O

p-Tol (S)

HO

* (M)

1) addition to: 1.14 eq PPh3 + 1.21 eq CBr4 / CH2Cl2 / - 70° C

2) 2.98 eq 59 / 1.19 eq AgBF4 (M = 194.67 g/mol) / RT / 12 % after chromatography

Li

62

4.01 eq tBuLi

THF / -78 o C / 4h

Br

S

Fe

*

O

p-Tol (S)

(H3C)2N

* (M)Fe

S

p-Tol

O

*1) addition to 2.00 eq LTP / THF / - 78° C to - 40° C 2) 4.18 eq 60 / - 78 o C to RT / 52 % yield after chromatography

67

(S)

72 M (C20H23FeNOS) = 381.32 g/mol

a) preparation of lithio-2,4,6-triisopropylbenzene (LTP) solution:

LTIP

2.00 eq 2.00 eq

b) via diastereoselective ortho lithiation and quenchning with Eschenmoser salt 60:

+ ent.

+ ent.

+ ent.

c) via in situ electrophilic activation and fulvenium SN1 reaction:

Pic. 7.5.10

a) Preparation of lithio-2,4,6-triisopropylbenzene (LTP) solution [50 (7)]: To a

stirred solution of 1809 mg (6.387 mmol) 62 in 15 ml THF at - 78° C in a 100 ml

Schlenk tube were dropped within 7 min. 7.40 ml (c = 1.72 mol/l in n-pentane, 12.765

mmol) tBuLi solution with a syringe. The solution was stirred 4 h at -78° C and turned

slowly orange and LiBr precipitated out. The - 78° C cold solution was directly used!

- 253 -

b) To the freshly prepared LTP solution was transferred dropwise with a double

canula within 15 min. a solution of 1033 mg (3.186 mmol) rac. 67 in 25 ml THF held

at ca. - 40° C from a conic Schlenk tube. The suspension was stirred 2 h defrosting

very slowly to - 40° C inside the cooling bath to ensure complete ortho lithiation and it

turned slowly to a deep red clear solution. The solution was cooled again to - 78° C

and 1245 mg (13.307 mmol) solid 60 were added under stream of nitrogen in one

portion. The suspension was stirred inside the cooling bath for 15 h slowly defrosting

to RT. Workup: The solution was poured into brine, extracted twice with EtOAc, the

combined organic layers were dried with MgSO4, filtrated and all volatiles removed by

RV and further by HV to give 2541 mg crude product as a deep red oil containing

diastereomerically pure rac. 72, 61 and some 67 by NMR. The crude product was

purified by FC (gradient elution first with hexanes : EtOAc + 10 % NEt3 = 3 : 1 to flush

out impurities and 67, then with 1 : 1 with Rf(67) = 0.50 and Rf(72) = 0.21 on TLC

and finally with 1 : 2 to obtain 72). After solvent removal by RV and HV 630 mg

(1.652 mmol, 52 % yield) rac. 72 were obtained as a red oil solidifying on standing.

Single crystals suitable for X-ray structure determination were obtained by mixing the

purified product with EtOAc and with a few drops hexanes and CH2Cl2 to a red slime,

adding one corn Vogelsand and by standing at RT for several days. Mp. = 100° C

(rac.). 1H-NMR (CDCl3, 270 MHz): δ = 7.63 (d, 3J = 8.3, 2H, CH(2,6)-1-[(H3C)2NCH2]-

2-[(p-tolyl)S(=O)]Fc); 7.27 (d, 3J = 8.3, 2H, CH(3,5)-(p-tolyl)); 4.52 (m, 1H, CH-η5-Cp);

4.28 (m, 1H, CH-η5-Cp); 4.18 (s, 5H, CH-η5-Cp'); 4.15 (m, 1H, CH-η5-Cp); 3.56 (d, 2J = 13.3, 1H, -CH2-); 3.49 (d, 2J = 13.3, 1H, -CH2-); 2.39 (s, 3H, -CH3 of p-tolyl); 2.08

(s, 6H, (H3C)2N-). 13C{1H}-NMR (CDCl3, 75 MHz): δ = 141.57 (C(1)-(p-tolyl)); 141.16

(C(4)-(p-tolyl)); 129.05 (CH(3,5)-(p-tolyl)); 125.01 (CH(2,6)-(p-tolyl)); 91.64 (C(2)-η5-

Cp); 85.34 (C(1)-η5-Cp); 72.21 (CH-η5-Cp); 70.29 (CH-η5-Cp'); 68.89 (CH-η5-Cp);

68.35 (CH-η5-Cp); 56.03 (-CH2-); 44.87 ((H3C)2N-); 21.17 (-CH3 of p-tolyl). MS (FD+,

CH2Cl2 / EtOAc): m/z (%) = 382 (100) [M]+ isotope peak. EA anal.calc for

C20H23FeNOS (381.32): C 63.00, H 6.08, N 3.67, S 8.41; found: C 62.96, H 6.16, N

3.84, S 8.19.

c) To a clear solution of 2940 mg (11.209 mmol) triphenylphosphine in 20 ml

CH2Cl2 in a conic Schlenk tube were added at - 65° C in one portion 3957 mg

(11.932 mmol) carbon tetrabromide in one portion under a stream of nitrogen. The

solution turned immediately yellowish and the white phosphine adduct precipitated.

- 254 -

This suspension was stirred 20 min. outside the cooling bath defrosting to RT and

became clear. It is important to ensure the complete conversion to the phosphine

adduct in this way, because free phosphines reduce sulfoxides to the corresponding

thioether! This solution was canuled to a solution of 3481 mg (9.826 mmol) rac. 71 in

30 ml CH2Cl2 at - 70° C and the Schlenk tube was washed out twice with altogether

10 ml CH2Cl2. The washing solutions were transferred to the orange reaction

solution, which was stirred 26 h outside the cooling bath at RT. The volume of the

reaction solution was reduced to its half by blowing off the solvent with nitrogen with

a canula, then 4.00 ml (2996 mg, 29.321 mmol) 59 and then 2283 mg (11.728 mmol)

AgBF4 were added in this order. AgBr precipitated immediately. Workup after 5 min.

stirring at RT: The suspension was poured into brine, extracted twice with CH2Cl2,

the combined organic layers were dried over MgSO4, filtrated and after solvent

removal by RV and further by HV 8856 mg crude product as a complex mixture were

obtained containing diastereomerically pure 72 by NMR. The crude product was

purified twice by FC (applied in silica matrix, gradient elution first with hexanes :

EtOAc + 10 % NEt3 = 1 : 1, then with 2 : 1) to give 462 mg (1.212 mmol, 12 % yield)

72 finally free of triphenylphosphine oxide.

7.5.11 N,N, Dimethylaminomethylferrocene 73 [50 (3)]

Fe65

Fe

N(CH3)2 1.70 eq 59

1.51 eq H3PO4 (M = 98.00 g/mol, d (85 % in H2O) = 1.680 g/ml) /HOAc / 100° C

92 %

73 M (C13H17FeN) = 243.13 g/mol d = 1.2280 g/ml

Pic. 7.5.11

In the need of anhydrous material the original procedure [50 (3)] was slightly modified

and performed under nitrogen leading to a higher yield. To 200 ml glacial acetic acid

in a 500 ml Schlenk round bottom flask were added portionwise at 0° C 13.0 ml

(18.56 g, 0.189 mol) 85 % aqueous phosphoric acid under well stirring. To the clear

degassed solution were added dropwise with a syringe (exothermic reaction!) at 0°

C29.0 ml (21.72 g, 0.213 mol) 59 under well stirring also. Then 23.26 g (0.125 mol)

- 255 -

65 were added portionwise under a stream of nitrogen and the suspension was

stirred 16 h in the closed flask at 100° C to turn into a clear deep red solution.

Workup: After cooling to RT the solution was poured into 250 ml aqua dest. and

residual 65 removed by extracting the aqueous phase twice with hexanes in a

separation funnel. The aqueous phase inside the separation funnel was made

strongly alkaline by careful portionwise addition of solid sodium hydroxide and

extracted six times with Et2O. The combined organic layers were dried over Na2SO4

overnight, filtrated, all volatiles removed by RV and further by RV to give 29.32 g

(0.121 mol, 96 % crude yield) nearly pure 73 as a deep red oil. The product was

stirred under nitrogen over CaH2 and the directly distilled (bp. = 102° C / 0.12 mbar)

under HV in a short path into a Schlenk tube to give 27.81 g (0.114 mol, 92 yield)

pure 73 as a deep red, clear oil. To avoid moisture and carbon dioxide absorption the

product should be stored in a Schlenk flask under nitrogen, although it is not

particularly air sensitive otherwise. 1H-NMR (CDCl3, 270 MHz): δ = 4.13 (pseudo t,

2H, CH-η5-Cp); 4.10 - 4.05 (s and m, 7H, CH-η5-Cp and CH-η5-Cp'); 3.22 (s, 2H, Fc-

CH2-N(CH3)2); 2.14 (s, 6H, -N(CH3)2).

7.5.12 rac. 1-N,N-Dimethylaminomethyl-2-tributylstannylferrocene 74 [52 (6)]

Fe

N(CH3)2

73

+ ent.

Sn(n-C4H9)3

Fe

N(CH3)2

(P) *

1) 1.19 eq nBuLi / Et2O / RT 2) 1.32 eq ClSn(nBu)3 (M = 325.51 g/mol, d = 1.200 g/ml) / - 78° C to RT

M (C25H43FeNSn) = 532.18 g/mol

74 89%

Pic. 7.5.12

The original procedure [52 (5)] was modified and scaled up. To a stirred solution of

15.63 g (64.27 mmol) 73 in 110 ml Et2O at RT were dropped within 10 min. 50.0 ml (c

= 1.53 mol/l in n-hexane, 76.56 mmol) nBuLi solution with a syringe. The clear

solution was stirred 2.5 at RT and turned slowly deep red. After diluting with 40 ml

Et2O and cooling to - 78° C 23.0 ml (27.60 g, 84.79 mmol) freshly distilled

tributyltinchloride were dropped within 5 min. to the solution, which was stirred 13 h

inside the cooling bath slowly defrosting to RT. Workup: The solution was poured

- 256 -

onto brine made alkaline with some sodium hydroxide, extracted three times with

Et2O, the combined organic layers were dried over MgSO4, filtrated and all volatiles

removed by RV and further by HV to give 41.34 g crude product as a viscous oil. The

crude product was purified by FC (directly applied in substance, gradient elution first

with hexanes : EtOAc + 10 % NEt3 = 1 : 0 to flush out stannyl byproducts and then

74, then with 4: 1, 3 : 1 with Rf(73) = 0.26 and Rf(74) = 0.59 on TLC going down to 1 :

1 to recover unreacted 73) to obtain 30.29 (56.91 mmol, 89 % yield) pure rac. 74 as a

viscous red oil and to recover 5.80 g 73 containing large amounts of silica. 1H-NMR

(CDCl3, 270 MHz): δ = 4.27 (m, 1H, CH-η5-Cp); 4.23 (pseudo t, 1H, CH-η5-Cp); 4.01

(s, 5H, CH-η5-Cp'); 3.93 (m, 1H, CH-η5-Cp); 3,28 (d, 2J = 12.4, 1H, 1-[(H3C)2NCH2]-2-

[(H3C-CH2-CH2-CH2)3Sn]Fc); 3.02 (d, 2J = 12.4, 1H, -CH2-); 2.06 (s, 6H, -N(CH3)2);

1.62 - 0.75 (series of not res. t and q, 27H, -CH2-CH2-CH2-CH3). 13C{1H}-NMR

(CDCl3, 68 MHz): δ = 90.53 (d, 2JCSn = - 38.2, C(1)-η5-Cp); 74.80 (d, JCSn = - 21.6,

CH-η5-Cp); 72.12 (d, JCSn = - 31.9, CH-η5-Cp); 71.06 (C(2)-η5-Cp); 69.72 (d, JCSn = -

36.5, CH-η5-Cp); 68.48 (CH-η5-Cp'); 60.40 (-CH2-); 44.89 ((H3C)2N-); 29.23 (-CH2-

CH2-CH2-CH3); 27.50 (d, 2JCSn = - 61.7, -CH2-CH2-CH2-CH3); 13.71 (-CH2-CH2-CH2-

CH3); 10.47 (d, 1JCSn = - 334.0, -CH2-CH2-CH2-CH3). MS (FD+, CHCl3): m/z (%) = 477

(42) [M-nBu]+ isotope peak, 528 (100) [M]+ isotope peak.

7.5.13 rac. 1-N-Phthalimidomethyl-2-tributylstannylferrocene 75

74

+ ent.

Sn(n-C4H9)3

Fe

N(CH3)2

(P) *

Sn(n-C4H9)3

Fe

N(P) * O

O75 84 %

in situ in pressureSchlenk tube :

1) 1.12 eq H3CI / DMF / RT 2) 0.44 eq NEt2 / DMF / RT 3) 1.35 eq potassium phthalimide (M = 185.22 g/mol) / 100° C / 15 h

+ ent.

M (C31H41FeNO2Sn) = 634.23 g/mol

Pic. 7.5.13

- 257 -

All operations must be performed in a hood and the same safety precautions of 7.4.2

and 7.4.5 also apply here! To a suspension of 17.48 g (32.84 mmol) 74 in 35 ml DMF

in a pressure Schlenk tube were dropped with a syringe at RT 2.30 ml (5.34 g, 36.95

mmol) methyl iodide. The suspension was stirred at RT 30 min. until it became a

clear orange solution and heat evolution ceased. Excess methyl iodide was then

quenched with 2.00 ml (1.45 g, 14.35 mmol) NEt3. 8.19 g (44.21 mmol) solid

potassium phthalimide under a stream of nitrogen were added and the suspension

diluted with 10 ml DMF. The witches' brew was stirred 15 h at 100° C in the tightened

pressure Schlenk tube to become a nearly clear deep orange solution after reaching

the reaction temperature. The endpoint of the reaction was indicated by separation of

two liquid phases. Workup: After cooling down to RT excess potassium phthalimide

precipitated. The mixture was diluted with Et2O, filtrated off excess potassium

phthalimide over a D4-sinter with vacuum suction and the filter cake was washed out

with Et2O. The combined washing solutions were diluted with EtOAc, washed eight

times with brine until free of DMF, dried over MgSO4 and filtrated. All volatiles were

removed by RV and by HV to give 19.08 g (30.08 mmol, 92 % crude yield) nearly

pure 75, which was purified by FC (applied in eluent, hexanes : EtOAc = 2 : 1) over a

short column. After solvent removal by RV and further by HV 17.45 g (27.51 mmol)

pure rac. 75 were obtained as a red oil solidifying to a waxy semicrystalline mass

upon standing. Mp. = 65 - 67° C (rac.). 1H-NMR (CDCl3, 270 MHz): δ = 7.79 (m, 2H,

CH(3,6)-1-[(C6H4(CO)2N)-CH2]-2-[(H3C-CH2-CH2-CH2)3Sn]Fc); 7.66 (m, 2H, CH(4,5)-

C6H4(CO)2N-); 4.65 (d, 2J = 14.53, 1H, -CH2-); 4.53 (m, 1H, CH-η5-Cp); 4.43 (d, 2J =

14.53, 1H, -CH2-); 4.26 (pseudo t, 1H, CH-η5-Cp); 4.11 (s, 5H, CH-η5-Cp'); 3.91 (m,

1H, CH-η5-Cp); 1.60 - 1.52 (not res. t, 9H, -CH2-CH2-CH2-CH3); 1.42 - 1.28 (not res.

tt, 6H, -CH2-CH2-CH2-CH3); 1.20 - 1.09 (not res. qt, 6H, -CH2-CH2-CH2-CH3); 0.89 (t, 3J = 7.27, 6H, -CH2-CH2-CH2-CH3). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 167.78

(C6H4(CO)2N-); 133.74 (CH(4,5)-C6H4(CO)2N-); 132.08 (C(1,2)-C6H4(CO)2N-); 123.08

(CH(3,6)-C6H4(CO)2N-); 88.51 (d, 2JCSn = - 38.2, C(1)-η5-Cp); 75.13 (d, JCSn = - 22.5,

CH-η5-Cp); 71.98 (d, JCSn = - 28.2, CH-η5-Cp); 71.16 (d, JCSn = - 34.2, CH-η5-Cp);

70.48 (d, 1JCSn = - 29.9, C(2)-η5-Cp); 68.66 (CH-η5-Cp'); 38.51 (-CH2-); 29.31 (-CH2-

CH2-CH2-CH3); 27.48 (d, 2JCSn = - 61.7, -CH2-CH2-CH2-CH3); 13.68 (-CH2-CH2-CH2-

CH3); 10.95 (d, 1JCSn = - 320.8, -CH2-CH2-CH2-CH3). MS (FD+, CHCl3): m/z (%) = 634

(100) [M]+ isotope peak. EA anal.calc for C31H41FeNO2Sn (634.23): C 58.71, H 6.52,

N 2.21; found: C 58.47, H 6.75, N 2.20.

- 258 -

7.5.14 rac. 1-Phenyl-2-(N-phthalimidomethyl)ferrocene 77

Fe

N(M) * O

O

+ ent.

Stille Coupling

"Satan's Mixture"

1.93 eq PhI (M = 204.01 g/mol, d = 1.820 g/ml) / DMF / 70° C / 14 h

77 74 %

Sn(n-C4H9)3

Fe

N(P) * O

O75

+ ent.

"Satan's Mixture" :

0.025 eq Pd2(dba)3.CHCl3 M = 1035.08 g/mol 0.150 eq AsPh3 M = 306.24 g/mol 0.500 eq CuI M = 190.45 g/mol

M (C25H19FeNO2) = 421.28 g/mol

Catalyst : 5 mol % Pd(0)(AsPh3)2 76with ratio Pd : CuI : AsPh3 = 1 : 10 : 3

Fe

N

(P)

*

O

O

+ ent.

Fe

N

*

(P)

O

O

isolated besides 77 under micrsocope from crystal cornucopia (from mother liquors):

dimericferrocene byproduct 79

Pd I

AsPh3

AsPh3

I

Pd

I

Ph3As AsPh3

Pd(II) intermediate 78

80

(P) *

Pic. 7.5.14

Caution! Triphenylarsine is severely toxic and a cancer suspect agent! All operations

must be performed in a hood! Gloves must be worn at all times! All washing solutions

and solvents have to be carefully collected and separately disposed according

regulations! After isolation the product is not free of catalyst traces, so it is considered

also as potentially toxic! All glassware used for this reaction must be cleaned in a

base bath before, rinsed with aqua dest. only (not with acid or acetone!!) and heated

out at 200° C overnight in an oven! The reaction tolerates traces of moisture, but air

must be vigorously excluded! In a Schlenk tube were weighed in air first 8209 mg

(12.943 mmol) 75, then 335 mg (0.324 mmol) Pd2(dba)3.CHCl3 (in solid state not

- 259 -

airsensitive), then 1235 mg (6.485 mmol) copper iodide and finally 595 mg (1.943

mmol) triphenylarsine in this order. After three evacuation-nitrogenflush cycles the

mixture was suspended in 55 ml DMF. Then 2.80 ml (5096 mg, 24.979 mmol) freshly

distilled iodobenzene were syringed in and the cocktail was stirred 14 h at 70° C until

precipitation of "palladium black" indicated the endpoint of the reaction. Alternatively

the reaction was monitored with TLC (hexanes : EtOAc 2 : 1, Rf(75) = 0.56 and

Rf(77) = 0.42). Workup: After cooling to RT ca. 2.2 g potassium fluoride and then ca.

20 ml aqua dest. were added into the open Schlenk flask, whereupon the mixture

became warm and was stirred 30 min. at RT to ensure total cleavage of all

organostannyl compounds. The black suspension was filtered off all solid residues

over a D3-sinter with cellulose flakes by vacuum suction and the filter cake was

washed out with EtOAc. The combined washing solutions were diluted with EtOAc,

washed eight times with brine until free of DMF, dried over MgSO4 and filtrated. All

volatiles were removed by RV and by HV to give ca. 10.91 g of an orange

microcrystalline squash containing iodobenzene and 77 mostly. The crude product

was dissolved in a minimum amount of hot EtOAc, crystal growths started after

cooling down to RT, the solution was layered with pentane and crystallization was

completed overnight at - 30° C. The cold mother liquor was pipetted off, the crystals

washed with pentane inside the flask and recrystallized in the same manner to give

finally 4012 mg (9.523 mmol, 74 % yield) nearly pure rac. 77 as airstable deep

orange crystals. The combined motherliquors were crystallized at - 30° C only from

EtOAc to give a cornucopia of single crystals of rac. 77, of intermediate trans-

(Ph3As)2Pd(II)IPh 78, of rac. ferrocene dimer 79 as byproduct and of trans-

(Ph3As)2Pd(II)I2 80, which all could not be separated or isolated by chromatography

or in another way. Mp. = 146° C (rac.). 1H-NMR (CDCl3, 270 MHz): δ = 7.84 - 7.79

(m, 2H, CH(3,6)-1-Ph-2-[(C6H4(CO)2N)-CH2]Fc); 7.66 ( 2 m, 4H, CH(4,5)-C6H4(CO)2N

and CH(2,6)-Ph); 7.43 - 7.26 (m, 3H, CH(3,4,5)-Ph); 4.90 (d, 2J = 14.8, 1H, -CH2-);

4.70 (d, 2J = 14.8, 1H, -CH2-); 4.39 (pseudo d, 2H, CH-η5-Cp); 4.20 (pseudo t, 1H,

CH-η5-Cp); 4.12 (s, 5H, CH-η5-Cp'). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 167.95

(C6H4(CO)2N-); 137.58 (C(1)-Ph); 133.89 (CH(4,5)-C6H4(CO)2N-); 131.95 (C(1,2)-

C6H4(CO)2N-); 129.63 (CH(3,5)-Ph); 127.96 (CH(2,6)-Ph); 126.52 (CH(4)-Ph); 123.22

(CH(3,6)-C6H4(CO)2N-); 87.96 (C(2)-η5-Cp); 82.35 (C(1)-η5-Cp); 70.17 (CH-η5-Cp');

69.17 (CH-η5-Cp); 68.83 (CH-η5-Cp); 67.26 (CH-η5-Cp); 36.09 (-CH2-). MS (FD+,

CHCl3): m/z (%) = 422 (100) [M]+ isotope peak. A correct EA could not be obtained.

- 260 -

7.5.15 rac. 1-Aminomethyl-2-phenylferrocene 81

Fe

NH2

(M) *+ ent.

81 89 %

Fe

N(M) * O

O

+ ent.

77

10.44 eq N2H4(H2O)(M = 50.06 g/mol, d = 1.030 g/ml)

EtOH / 95° C / 75 min.

M (C17H17FeN) = 291.17 g/mol

Pic. 7.5.15

Caution! Hydrazine is a carcinogen! A degassed suspension of 5814 mg (13.80

mmol) 77 and of 7.00 ml (7210 mg, 144.03 mmol) hydrazine hydrate in 100 ml EtOH

p.a. was refluxed 75 min. at 95° C. White phthalazinodione started to precipitate out

once the reaction temperature was reached. Workup: after cooling down to RT Et2O

was added, the red solution was filtered off solid phthalazinodione over a D4-sinter

with filter flakes by vacuum suction and the filter cake was washed out with Et2O.

Most of the volatiles of the combined washing solutions were removed by RV,

redissolved in Et2O and the organic phase was washed once with brine made

alkaline with sodium hydroxide. The separated organic phase was dried over MgSO4,

filtrated and all volatiles removed by RV and by HV to give 4031 mg crude product

(quantitative yield), which was purified by FC over a short column (hexanes : CH2Cl2

= 1 : 5 + 10 % NEt3). After solvent removal by RV and HV 3584 mg (12.31 mmol, 89

% yield) pure rac. 81 were obtained as a red oil. 1H-NMR (CDCl3, 270 MHz): δ = 7.57

- 7.50 (m, 2H, CH(2,6)-2-Ph-1-(H2NCH2)Fc); 7.36 - 7.19 ( 2 m, 3H, CH(3,4,5)-Ph);

4.44 (pseudo t, 1H, CH-η5-Cp); 4.33 (pseudo t, 1H, CH-η5-Cp); 4.21 (pseudo t, 1H,

CH-η5-Cp); 4.09 (s, 5H, CH-η5-Cp'); 3.82 (d, 2J = 14.1, 1H, -CH2-); 3.76 (d, 2J = 14.1,

1H, -CH2-); 1.60 (br s, 2H, -NH2). 13C{1H}-NMR (CDCl3, 68 MHz): δ = 138.30 (C(1)-

Ph); 128.64 (CH(3,5)-Ph); 127.90 (CH(2,6)-Ph); 126.04 (CH(4)-Ph); 88.13 (C(1)-η5-

Cp); 86.41 (C(2)-η5-Cp); 69.64 (CH-η5-Cp' and CH-η5-Cp); 68.18 (CH-η5-Cp); 66.56

(CH-η5-Cp); 40.22 (-CH2-). MS (FD+, CHCl3): m/z (%) = 292 (100) [M+H]+ isotope

peak. EA anal.calc for C17H17FeN (291.17): C 70.13, H 5.88, N 4.81; found: C 70.12,

H 5.92, N 4.79.

- 261 -

7.5.16 rac. 1-Aminomethyl-2-(cyclohexa-2',5'-dienyl)ferrocene 82

Fe

NH2

(M) *+ ent.

81

Birch Reduction

Fe

NH2

(M) *+ ent.

82 96 % crude yield

1) 12.47 eq Li / NH3 (l) / EtOH / THF / - 78 ° C2) 13.77 eq NH4Cl / defrost to RT

M (C17H19FeN)= 293.19 g/mol

Pic. 7.5.16

2254 mg (7.741 mmol) rac. 81 in 10 ml EtOH and 45 ml THF were reduced with 670

mg (96.528 mmol) lithium in ca 130 ml liquid ammonia at - 78° C and quenched with

5703 mg (106.616 mmol) ammonium chloride according to the general procedure

7.2.1 above. The large amount of THF as cosolvent was necessary to afford

complete solvatation. Workup: After evaporation of ammonia the residue was poured

into brine made alkaline with sodium hydroxide and the aqueous phase was

extracted twice with Et2O. The combined organic layers were dried overnight over

Na2SO4 and after filtration, solvent removal by RV and further by HV 2184 mg (7.449

mmol, 96 % crude yield) rac. 82 free of any starting material by NMR were obtained

as a red oil, which did not require further purification. 1H-NMR (CDCl3, 270 MHz): δ =

6.00 - 5.76 (m, 2H, olef. CH(2,3)-2-cyC6H7-1-(H2NCH2)Fc); 5.76 - 4.48 (m, 2H, olef.

CH(5,6)-cyC6H7); 4.15 (m, 1H, CH-η5-Cp); 4.10 (CH-η5-Cp'); 4.04 (m, 2H, CH(1)-

cyC6H7); 4.00 (pseudo t, 1H, CH-η5-Cp); 3.96 (m, 1H, CH-η5-Cp); 3.63 (d, 2J = 14.2,

1H, -CH2-); 3.54 (d, 2J = 14.2, 1H, -CH2-); 2.68 – 2.65 (m, 2H, CH2(4)-cyC6H7). 13C{1H}-NMR (CDCl3, 68 MHz): δ =128.85 (olef. CH(2 or 6)-cyC6H7); 128.1 (olef.

CH(6 or 2)-cyC6H7); 124.41 (olef. CH(3 or 5)-cyC6H7); 123.17 (olef. CH(5 or 3)-

cyC6H7); 91.07 (C(2)-η5-Cp); 87.91 (C(1)-η5-Cp); 68.65 (CH-η5-Cp'); 67.65 (CH-η5-

Cp); 67.44 (CH-η5-Cp); 65.58 (CH-η5-Cp); 39.84 (-CH2-); 33.90 (CH(1)-cyC6H7);

25.92 (CH2(4)-cyC6H7). MS (FD+, CHCl3): m/z (%) = 294 (100) [M+H]+ isotope peak.

- 262 -

7.6 Kinetic Epimerization Study

OP

RuCl

NH2

Ph

Ph

OCH3

** (R)

PF6

Ph

(S)

like unlike

OP

RuNH2

ClPh

Ph

OCH3

*(R)

PF6(R)

Ph

* acetone-d6

NMR-tube

54R

interpretation according first order kinetics with d[unlike] / dt = - d[like] / dt :

decay of 54R like : d[like] / dt = - kl [like] ln[like] = ln[like]0 - kl t

buildup of 54R unlike: d[unlike] / dt = + ku [unlike] ln[unlike] = ln[unlike]0 + ku t

Eyring Plots

ln (kl / t) = ln (ku / t) ln kB 2h

∆S‡

R+ 1

T∆H‡

R-

kB = 1.380662 10-23 J/Kh = 6.626176 10-34 JsR = 8.31441 J/molK

Pic. 7.6.1

Under an atmosphere of nitrogen ca. 50 mg 54R were dissolved quickly under

warming in ca. 0.5 ml degassed acetone-d6 in a NMR-tube. Large sample amounts

were necessary to avoid integration errors, especially if running NMR-experiments at

higher temperatures with higher epimerization rates requiring shorter acquisition

intervals. Right after sample preparation the 31P-NMR-spectra were recorded in fixed

time intervals at fixed temperatures with the hexafluorophosphate anion as internal

calibration standard. The rate constants of the decay kl of 54R like and the buildup ku of 54R unlike were determined from the corresponding integrals proportional to the

relative concentrations by reading directly the NMR data respectively integrals of the

particular diastereomers from Bruker Win1DNMR computer files into the computer

program QuickKin according the first order kinetic equations in Pic. 7.6.1. From the

- 263 -

different rate constants at different temperatures two Eyring plots for the decay and

buildup each were generated by the same computer program giving directly the

activation enthalpy ∆H‡ from the slope and the activation entropy ∆S‡. From these

values the free activation energy ∆G‡ = ∆H‡ - T0 ∆S‡ was calculated. 31P{1H}-NMR

(acetone-d6, 121 MHz): δ = 131.75 (s, 1P, l); 131.05 (s, 1P, u).

25° C (298.15K) time [s]

25° C

(298.15K) integral

[like]

25° C

(298.15K) integral [unlike]

30° C

(303.15K) time [s]

30° C

(303.15K) integral

[like]

30° C

(303.15K) integral [unlike]

0 463954.96 37202.36 0 255585.8 29446.8 3605 425841.88 67403.44 1807 234756.1 46289.6 7207 393653.24 87098.34 3610 217236.7 60387.8 10808 371166.90 116504.98 5413 202067.8 72270.9 14410 347199.09 133712.86 7217 188334.6 84001.7 18013 326464.44 154145.84 9020 177658.9 93665.5 21614 310465.56 167027.49 10824 170398.6 102946.2 25217 297896.55 180081.52 12627 163173.2 108947.7 (28819) (281275.35) (189943.07) 14430 155603.1 112327.7 32420 251562.80 186514.70 16235 151804.0 120594.1 36023 241964.55 194422.80 18037 146979.5 123890.3 39624 235408.11 200516.57 19842 142850.2 126519.8 43227 228585.27 206799.33 21645 138513.2 128911.3 46830 223705.79 213508.74 23449 137924.7 133711.8 50432 219258.98 218507.65 25252 133218.4 136884.1 54034 214183.12 222147.96 27055 130736.0 136705.9 28859 128951.0 138874.8 30663 129819.5 143241.4 32467 128683.6 144989.9 34270 126399.0 144182.8 36074 123713.4 144480.4 37877 123542.1 145336.2 39681 121751.9 145067.4 41484 121234.9 145909.4 43288 119706.5 146079.0 45091 118474.5 147277.8 46896 118721.0 146479,8 48700 119621.5 146776,5 50503 121293.8 148448,7 52307 119905.6 149485,3 150506 117257.5 151718,7

Table 7.6.1 Time [s] and relative integrals at 25° C and 30° C; values in parentheses () omitted.

- 264 -

35° C (298.15K) time [s]

35° C

(298.15K) integral

[like]

35° C

(298.15K) integral [unlike]

50° C

(303.15K) time [s]

50° C

(303.15K) integral

[like]

50° C

(303.15K) integral [unlike]

0 105758.10 9115.15 0 35465.91 18128.90 905 95562.64 14537.52 907 27328.95 26280.91 1810 88542.42 22969.85 1810 23922.96 29414.88 2716 81307.97 30541.70 2714 21743.39 30929.85 3620 77876.67 28177.72 3617 22603.93 29362.20 4524 72653.91 34832.23 4522 22105.81 30172.22 5430 70602.17 35884.34 5426 21343.52 30274.29 6335 68514.37 40698.13 6329 21603.83 30427.26 7240 64955.07 45180.67 7234 23095.94 29431.08 8145 60960.78 50032.70 8138 22419.67 29582.96 9049 59657.54 52132.19 9041 22289.46 30092.80 9955 58224.15 51522.90 9946 22586.96 28823.38 10860 59496.71 50832.83 10849 22983.40 29120.72 11765 57747.95 50922.68 11753 22141.15 29623.40 12670 55990.93 53161.31 12654 21993.48 28805.08 13575 57198.64 47904.86 13557 22542.75 28725.09 14481 53766.90 55809.46 14462 23402.52 28689.51 15386 51479.39 57835.01 15366 24558.97 26374.96 16290 52456.22 55427.78 16270 23128.45 28347.43 17196 53731.50 52859.36 17174 22848.21 28255.55 19000 47306.16 62217.14 20804 49601.53 60866.78 22608 49819.26 60317.73 24412 49148.61 59246.09 26215 50430.98 58830.53 28019 53151.92 47439.29 29825 50622.26 58563.46 31628 50201.30 57963.33 33432 46578.59 61923.27 35236 50311.87 57767.76 37040 50489.09 57223.06 38841 47555.65 60945.08 40645 47174.33 61518.89 42449 49959.63 56633.51 44253 49081.28 58392.84 46057 51889.85 47351.75 47862 52197.32 49712.39 49666 48087.15 61202.83 51470 46734.89 61073.99 53273 50019.25 56282.20 66821 51056.42 53461.57

Table 7.6.2 Time [s] and relative integrals at 35° C and 50° C; values in parentheses ( ) omitted.

- 265 -

Pic. 7.6.2 Plots time [s] (x-axis) versus relative integrals (y-axis).

0 10000 20000 30000 40000 50000 60000

200000

250000

300000

350000

400000

450000

500000

Y Ax

is T

itle

X Axis Title

144.9-145.2

0 10000 20000 30000 40000 50000 600000

50000

100000

150000

200000

250000

Y Ax

is T

itle

X Axis Title

144.0-144.3

-20000 0 20000 40000 60000 80000 100000 120000140000 160000100000

120000

140000

160000

180000

200000

220000

240000

260000

B

Y Ax

is T

itle

X Axis Title-20000 0 20000 40000 60000 80000 100000 120000140000 160000

20000

40000

60000

80000

100000

120000

140000

160000

B

Y Ax

is T

itle

X Axis Title

-10000 0 10000 20000 30000 40000 50000 60000 7000040000

50000

60000

70000

80000

90000

100000

110000

B

Y Ax

is T

itle

X Axis Title-10000 0 10000 20000 30000 40000 50000 60000 700000

10000

20000

30000

40000

50000

60000

70000

B

Y Ax

is T

itle

X Axis Title

-2000 0 2000 4000 6000 8000 10000 12000 14000 16000 1800020000

22000

24000

26000

28000

30000

32000

34000

36000

B

Y Ax

is T

itle

X Axis Title-2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000

18000

20000

22000

24000

26000

28000

30000

32000

B

Y Ax

is T

itle

X Axis Title

time [s]

time [s]

time [s]

time [s] time [s]

time [s]

time [s]

time [s]

int. [like]

int. [like]

int. [like]

int. [like]

int. [unlike]

int. [unlike]

int. [unlike] int. [unlike]

int. [unlike]

T = 25° C T = 25° C

T = 30° C T = 30° C

T = 35° C T = 35° C

T = 50° C T = 50° C

- 266 -

T [° C]

1 / T [1 / K]

k l [1 / s]

k u [1 / s]

ln (k u / t) ln (k l / t)

25 3.3540 10 -3 4.3348 10 -5 3.3970 10 -5 - 15.743853 - 15.831705

30 3.2987 10 -3 8.7998 10 -5 8.4066 10 -5 - 15.052421 - 15.098141

35 3.2452 10 -3 1.7861 10 -4 1.8670 10 -4 - 14.360873 - 14.316589

50 3.0945 10 -3 1.2259 10 -3 1.6930 10 -3 - 12.482210 - 12.159397

Table 7.6.3 Rate constants and Eyring data (difference of rate constants statistically more

significant than individual standard deviations of each rate constant at a given

temperature).

0,00305 0,00310 0,00315 0,00320 0,00325 0,00330 0,00335

-16,0

-15,5

-15,0

-14,5

-14,0

-13,5

-13,0

-12,5

-12,0

ln(k

/T)

1/T [1/K]0,00305 0,00310 0,00315 0,00320 0,00325 0,00330 0,00335

-16,0

-15,5

-15,0

-14,5

-14,0

-13,5

-13,0

-12,5

-12,0

ln(k

/T)

1/T [1/K]

Pic. 7.6.3 Eyring plots and determination of ∆H‡, ∆S‡ and calculation of ∆G‡ at 298.15 K (20° C).

Decay of 54R like: ∆H‡ = (118 ± 1.0) kJ / mol ∆S‡ = (67 ± 4.0) J / mol K ∆G‡ = 97.8 – 98.2 k/J mol

Buildup of 54R unlike: ∆H‡ = (107 ± 0.4) kJ / mol ∆S‡ = (23 ± 1.3) J / mol K∆G‡ = 99.8 k/J mol

- 267 -

7.7 Catalytic Transfer Hydrogenation Experiments

7.7.1 General Procedure

Ph CH3

O

Ph CH3

H OH

Ph CH3

HO H

acetophenone (R)-1-phenylethanol (S)-1-phenylethanol

+tBuOK +

precatalyst+ iPrOH acetone +

M (iPrOH) = 60.10 g/mold (iPrOH) = 0.785 g/ml M = 122.17 g/ml, d =1.013 g/ml

M = 120.15 g/mold = 1.030 g/m

* *

Pic. 7.7.1

To the precatalyst in a Schlenk tube was added freshly distilled acetophenone and

the mixture was stirred until it became a clear solution. Then isopropanol iPrOH and

finally solid tBuOK was added in this order. After addition of iPrOH the clear solution

became turbid and upon addition of tBuOK the color changed immediately from

yellow-orange to deep red. The mixture was stirred at the given temperature and time

shown in Table 7.7.1 and the progress of the reaction was monitored with GC (150°

C; tR (acetophenone) = 4.34 min., tR (1-pehnylethanol) = 6.50 min.; RS > 6). Sample

preparation: A volume aliquot calculated on 5 - 10 mg acetophenone was taken out

of the reaction solution with a syringe under a stream of nitrogen, injected into

pentanes and filtered off the precipitated catalyst over a pipette filled with cellulose.

All solvents were removed by RV, the residue dissolved in ca. 5 ml carbon sulfide

and 1 µl directly injected into the GC. Workup of reaction solution: At RT the reaction

mixture is diluted with pentane and filtered off the precipitated catalyst over a pipette

filled with cellulose and silica. After solvent removal by RV the residue was purified

by Kugelrohr distillation under HV and an aliquot subjected to HPLC analysis (Daicel

OD-H, n-hexane : iPrOH = 90 : 10, 15 bar, 0.5 ml/min., 254 nm): tR (acetophenone) =

9.80 min., RS = 2.0; tR ((S)-1-phenylethanol) = 12.05 min.; tR ((R)-1-phenylethanol) =

13.32 min. RS = 1.1. Note the measured concentration of acetophenone by HPLC is

virtually higher due to its higher extinction coefficient compared to 1-phenylethanol

pretending a lower conversion; only the peak integrals of the two 1-phenylethanol

enantiomers can be compared in HPLC analysis with UV detection, because they

both have identical extinction coefficients and absorption maxima, of course!

- 268 -

catalyst mol %

catalyst

mol %

tBuOK

molar ratio

iPrOH /

acetophenone

T [° C] reaction

time [h]

conversion

[%]

e.e. [%]

41R 0.25 0.52 3.2 80 41.0 50 < 1

41R 1.12 1.16 39.2 80 49.0 73 < 1

42R 1.00 1.13 12.7 80 1.1 55 < 1

54R 0.27 0.77 12.7 45 21.2 55 9.4 (R)

54R 1.03 0.09 12.7 45 20.0 52 9.0 (R)

55R 1.03 2.35 12.7 RT 46.8 79 1.4 (R)

56RR 0.25 0.79 12.7 45 21.2 83 < 1

56RR 0.51 1.48 12.7 45 6.0 83 < 1

56RS 0.51 1.57 12.7 RT 47.8 83 1.5 (R)

Table 7.7.1 Catalytic transfer hydrogenation experiments of acetophenone to 1-phenylethanol in

iPrOH with tBuOK.

7.7.2 Control Experiment with Avecia Ir(III)(η5-Cp*) Catalyst

Ph CH3

O

Ph CH3

H OH

Ph CH3

HO H

acetophenone (R)-1-phenylethanol (S)-1-phenylethanol

+1.47 mol % tBuOK

acetone +* *

H2N

HO

**

1.43 mol%

0.59 mol % [Ir(III)(η5-Cp*)Cl](µ-Cl)2(M = 796.70 g/mol)

12.70 eq iPrOH

1.17 mol %

(R)

(S)*

*

OM

H2N

Cl

(S)*

in situ :

(1S, 2R)-1-aminoindan-2-olM = 149.19 g/mol

precatalyst

1.00 eq

molar ratio acetophenone / iPrOH : 12.7reaction temperature : RTreaction time : 1.3 hconversion : 75 %

e.e. = 58.2 % (S)

Pic. 7.7.2

- 269 -

The original procedure [22 (5)] was adjusted to the conditions in 7.1.1 for

comparison. In a Schlenk tube 22 mg (0.14746 mmol) (1S, 2R)-1-aminoindan-2-ol

and 48 mg (0.0602 mmol) [Ir(II)(η5-Cp*)Cl](µ-Cl)2 were dissolved in 10.00 ml (7850

mg, 130.62 mmol) iPrOH and stirred ca. 30 min. at 60° C until a clear deep purple

solution resulted, which indicated the formation of the precatalyst. After cooling to RT

1.20 ml (1236 mg, 10.29 mmol) freshly distilled acetophenone and then 44 mg

(0.39209 mmol) tBuOK were added in this order, whereupon the color changed to

deep red and the solution became slightly turbid. The solution was stirred 1.3 h at

RT, the reaction was monitored with GC and finally worked up as described above.

1008 mg product were obtained after Kugelrohr distillation, which contained

acetophenone and (S)-1-phenylethanol with 58.2 % e.e. by HPLC (see details in Pic.

7.1.2).

- 270 -

8 Appendix - CD Spectra

All ultra violet (UV) and circular dichroism spectra (CD) were recorded on Jasco J-

710 (33R, 35R, 36R, 41R - 44R) and J-600 (53R - 56RS) spectropolarimeter (c ~ 10-3

mol/l) in MeOH under nitrogen at RT.

33R

35R

36R

- 271 -

41R

42R

43R

44R

- 272 -

-2

-1

0

1

2

λ / nm

0

10

20

30

600500400300200

CD

UV

ε x 10-3 ∆ε

1S

-10

-5

0

5

10

λ / nm

0

10

20

30

600500400300200

CD

UV

ε x 10-3 ∆ε

2S

-2

-1

0

1

2

λ / nm

0

10

20

30

600500400300200

CD

UV

ε x 10-3 ∆ε

3S

53R

54R

55R

- 273 -

Complex UV λ(ε·10-3) CD λ(∆ε)

53R 473(0.24), 353(1.5),

228sh(21.4)

475(-0.25), 389(0.81), 316(-0.32), 258

(-0.79)

54R (l) 349(1.5), 276sh(5.9),

245sh(16.0)

461(1.18), 404(-3.05), 350(3.72), 295

(-5.45), 240(6.55)

55R 350(1.5), 275sh(6.2),

246sh(15.2)

444(0.04), 403(-0.17), 345(0.69), 294

(-0.75), 267(0.11), 248(-1.2)

56RR (ul) 340sh(1.27), 323(1.38),

228(22.81)

452(-0.66), 403(1.43), 352(-2.68),

301(4.91), 233(-15.62)

56RS 327(1.38), 228(20.67) 419(-0.41), 346(0.44), 301sh(-0.44),

230(-4.07)

Table 8.0.1 Main UV and CD spectral features of complexes 53R, 54R like, 55R, 56RR unlike-like,

and 56RS in MeOH.

-10

-5

0

5

10

λ / nm

0

10

20

30

600500400300200

CD

UV

ε x 10-3 ∆ε

4SR

-4

-2

0

2

4

λ / nm

0

10

20

30

600500400300200

CD

UV

ε x 10-3 ∆ε

4SS

56RR

56RS

- 274 -

9 Appendix - Crystallographic Data

Intensity data were collected on a Bruker-Nonius Kappa-CCD diffractometer using

Mo Kα radiation (λ = 0.71073 Å, graphite monochromator). The structures were

solved by direct methods and refined by full-matrix least-squares procedures on F 2

(formulas in Pic. 9.0.1) in the anisotropic approximation for all atoms except

hydrogen. Space groups were assigned according to the numbers in international

tables [55 (1)]. In case of chiral compounds absolute configurations were confirmed

respectively determined by anomalous dispersion (f' and f'') and corresponding

calculations of Flack's absolute structure parameters [55 (2)].

wR2 = R1 = GooF = S =

Quality Factors

Σ [w (F02 -Fc

2)2]Σ [w (F0

2)2]Σ ||F0| -|Fc||

Σ |F0|

12

for observed reflections:

Σ [w (F02 -Fc

2)2](n - p)

12

Weighting Scheme w = 1 / [σ2(F02) + (u P)2 + vP] P = [(F0

2) + 2 (Fc2)] / 3

Pic. 9.0.1

Absorption corrections were performed by either a numerical Gauss integration [55

(3)] or on a semi-empirical basis from multiple scans with SADABS [55 (6)]. The

hydrogen atoms are in positions calculated for optimized geometry and are assigned

to an isotropic displacement parameter equivalent to the 1.2 fold resp. 1.5 fold value

of the equivalent isotropic displacement parameter of the particular carbon, nitrogen

resp. oxygen atom bonded to these hydrogen atoms. In some cases hydrogen atom

positions were taken from a difference Fourier synthesis, their positional parameters

were refined while a common isotropic displacement parameter was kept fixed during

the refinement. Behind the substance number (see experimental part, Chapter 7) the

name of the data file is given in parentheses, which contains the crystallographic data

and structure refinement of the particular compound stored in the crystallographic

data base of the Institut für Anorganische Chemie II.

- 275 -

20 (IW0303)

empirical formula

C27H26Br3PRu

molecular weight [g/mol] 722.25

temperature [K] 100

crystal color and shape red, rhombic

crystal size [mm] 0.22 x 0.17 x 0.07

crystal system monoclinic

space group P21/n (no. 14)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 12.0193(8) α = 90.0

b = 15.9227(5) β = 92.137(5)

c = 12.9594(6) γ = 90.0

V = 2478.4(2) Z = 4

density ρ [g/cm3] (calculated) 1.936

µ [mm-1] 5.548

F (000) 1408

absorption correction SADABS; Tmin= 0.585, Tmax = 1.000

measured 2Θ interval [ °] 6.8 ≤ 2Θ ≤ 59.2

limiting indices -16 ≤ h ≤ 14; -22 ≤ k ≤ 20; -17 ≤ l ≤ 17

collected reflections 28398

independent reflections 6934

observed reflections (Fo ≥ 4.0 σ(F)) 4161

refined parameters 289

wR2 (all data) 0.0928

R1 (Fo > 4.0 σ(F)) 0.0463

GooF 0.872

weighting u = 0.0450; v = 0

residual electron density [e Å3] max. 0.827; min. – 0.900

- 276 -

35R (IW0307)

empirical formula

C25H25NO3S2

molecular weight [g/mol] 451.58

temperature [K] 100

crystal color and shape colorless, needle

crystal size [mm] 0.35 x 0.10 x 0.08

crystal system monoclinic

space group C2 (no. 5)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 28.108(3) α = 90.0

b = 5.2575(3) β = 102.052(6)

c = 15.758(2) γ = 90.0

V = 2277.4(4) Z = 4

density ρ [g/cm3] (calculated) 1.317

µ [mm-1] 0.261

F (000) 952

absorption correction SADABS; Tmin= 0.924, Tmax = 1.000

measured 2Θ interval [ °] 6.5 ≤ 2Θ ≤ 54.2 °

limiting indices - 35 ≤ h ≤ 35; - 6 ≤ k ≤ 6; - 20 ≤ l ≤ 20

collected reflections 28956

independent reflections 5006

observed reflections (Fo ≥ 4.0 σ(F)) 4220

refined parameters (p) 282

wR2 (all data) 0.0930

R1 (Fo > 4.0 σ(F)) 0.0418

GooF 1.024

absolute structure parameter - 0.05(7)

weighting u = 0.0455; v = 1.7372

residual electron density [e Å3] max. 0.466; min. – 0.334

The absolute configuration at the chiral benzylic center was determined to be (R) in

the crystal examined. Furthermore hydrogen bonding between tosylate (acceptor)

and the ammonium group (donor) of the β-ammonium thioether cation is evident.

- 277 -

41R (IW0301)

empirical formula

C25.5H34Cl2F6NOPRuS

molecular weight [g/mol] 719.54

temperature [K] 100

crystal color and shape yellow platelet

crystal size [mm] 0.37 x 0.24 x 0.05

crystal system monoclinic

space group C2 (no. 5)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 19.170(2) α = 90.0

b = 8.8851(5) β = 97.250(9)

c = 17.328(2) γ = 90.0

V = 2927.8(5) Z = 4

density ρ [g/cm3] (calculated) 1.632

µ [mm-1] 0.904

F (000) 1460

absorption correction numerical Gauss integration;

Tmin= 0.801, Tmax = 0.965

measured 2Θ interval [ °] 5.7 ≤ 2Θ ≤ 56.0

limiting indices - 23 ≤ h ≤ 25; - 11 ≤ k ≤ 11; - 22 ≤ l ≤ 22

collected reflections 26506

independent reflections 6830

observed reflections (Fo ≥ 4.0 σ(F)) 5283

refined parameters (p) 350

wR2 (all data) 0.0897

R1 (Fo > 4.0 σ(F)) 0.00433

GooF 1.036

absolute structure parameter - 0.05(3)

weighting u = 0.0430; v = 0

residual electron density [e Å3] max. 0.622; min. – 0.751

The unit cell contains one diastereomeric cation (1’’R, RRu, SS), one MeOH molecule

and a half CH2Cl2 molecule. The half CH2Cl2 molecule is positioned on a

- 278 -

crystallographic twofold axis. Hydrogen bonding between PF6- (acceptor), MeOH

(acceptor and donor) and the amino group (donor) of the chelate ligand is evident.

42R (IW0305)

empirical formula

C23H27ClF6NPRuS

molecular weight [g/mol] 631.01

temperature [K] 100

crystal color and shape yellow block

crystal size [mm] 0.16 x 0.13 x 0.07

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 10.1658(7) α = 90.0

b = 12.3733(5) β = 90.670(6)

c = 20.161(1) γ = 90.0

V = 2535.8(2) Z = 4

density ρ [g/cm3] (calculated) 1.653

µ [mm-1] 0.926

F (000) 1272

absorption correction SADABS; Tmin= 0.865, Tmax = 1.000

measured 2Θ interval [ °] 6.8 ≤ 2Θ ≤ 54.2

limiting indices - 12 ≤ h ≤ 12; - 15 ≤ k ≤ 15; - 25 ≤ l ≤ 25

collected reflections 50197

independent reflections 11067

observed reflections (Fo ≥ 4.0 σ(F)) 8952

refined parameters (p) 619

wR2 (all data) 0.0782

R1 (Fo > 4.0 σ(F)) 0.0382

GooF 0.919

absolute structure parameter - 0.02(2)

weighting u = 0.0450; v = 0.5554

residual electron density [e Å3] max. 0.461; min. - 0.405

- 279 -

The unit cell contains two symmetry independent diastereomeric (1’’R, RRu, SS) and

(1’’R, SRu, RS) complex cations. Hydrogen bonding between PF6- (acceptor) and the

ammonium group (donor) of the chelate ligands and in bridging fashion between the

complex cations via Cl(2) (acceptor) and N(1)-H(1A) (donor) is evident.

43R (IW0306)

empirical formula

C27H29ClF6NPRuS

molecular weight [g/mol] 682.09

temperature [K] 100

crystal color and shape orange block

crystal size [mm] 0.21 x 0.14 x 0.12

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 10.229(1) α = 90.0

b = 10.759(1) β = 93.626(6)

c = 24.477(2) γ = 90.0

V = 2688.4(4) Z = 4

density ρ [g/cm3] (calculated) 1.683

µ [mm-1] 0.880

F (000) 1376

absorption correction numerical Gauss integration;

Tmin= 0.844, Tmax = 0.905

measured 2Θ interval [ °] 7.2 ≤ 2Θ ≤ 54.2

limiting indices - 13 ≤ h ≤ 12; - 13 ≤ k ≤ 13; - 31 ≤ l ≤ 31

collected reflections 50387

independent reflections 11811

observed reflections (Fo ≥ 4.0 σ(F)) 8392

refined parameters (p) 691

wR2 (all data) 0.0819

R1 (Fo > 4.0 σ(F)) 0.0382

GooF 0.834

- 280 -

absolute structure parameter 0.01(3)

weighing u = 0.0500; v = 0

residual electron density [e Å3] max. 0.957; min. - 0.524

The unit cell contains two symmetry independent diastereomeric complex cations

with the absolute configurations (1’’R, RRu, SS) and (1’’R, SRu, RS). Hydrogen bonding

between PF6- (acceptor) and the amino group (donor) of the chelate ligands is

evident.

44R (IW0308)

empirical formula

C22.5H32Cl2F6NPRuS

molecular weight [g/mol] 665.51

temperature [K] 100

crystal color and shape yellow block

crystal size [mm] 0.18 x 0.18 x 0.16

crystal system monoclinic

space group C2 (no. 5)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 15.934(2) α = 90.0

b = 15.537(2) β = 104.67(2)

c = 23.330(3) γ = 90.0

V = 5587.4(9) Z = 8

density ρ [g/cm3] (calculated) 1.582

µ [mm-1] 0.937

F (000) 2696

absorption correction SADABS; Tmin= 0.860, Tmax = 1.000

measured 2Θ interval [ °] 6.0 ≤ 2Θ ≤ 52.8

limiting indices - 19 ≤ h ≤ 19; - 19 ≤ k ≤ 19; - 29 ≤ l ≤ 28

collected reflections 55165

independent reflections 11281

observed reflections (Fo ≥ 4.0 σ(F)) 9707

refined parameters (p) 670

wR2 (all data) 0.1088

- 281 -

R1 (Fo > 4.0 σ(F)) 0.0445

GooF 1.044

absolute structure parameter - 0.01(3)

weighting u = 0.0619; v = 11.0280

residual electron density [e Å3] max. 1.021; min. - 0.852

The unit cell contains two diastereomeric (1’’R, RRu, SS) and (1’’R, SRu, RS) complex

cations and a half disordered CH2Cl2 molecule. The only maximum of residual

electron density > 1.0 e Å-3 is located close to the CH2Cl2 position. Two half PF6-

anions are positioned on a crystallographic twofold axis each. Hydrogen bonding

between PF6- (acceptor), the amino group (donor) of the chelate ligands and between

the complex cations via Cl(1) (acceptor) and N(2)-H(2A) (donor) is evident.

53R (IW0309)

empirical formula

C21H21Cl2O2PRu

molecular weight [g/mol] 508.35

temperature [K] 100

crystal color and shape orange-brown irregular

crystal size [mm] 0.14 x 0.14 x 0.10

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 9.7487(3) α = 90.0

b = 9.9464(7) β = 91.709(3)

c = 10.4269(6) γ = 90.0

V = 1010.6(1) Z = 2

density ρ [g/cm3] (calculated) 1.670

µ [mm-1] 1.133

F (000) 512

absorption correction numerical Gauss integration;

Tmin= 0.871, Tmax = 0.923

measured 2Θ interval [ °] 6.9 ≤ 2Θ ≤ 57.4

limiting indices - 13 ≤ h ≤ 12; - 13 ≤ k ≤ 13; - 14 ≤ l ≤ 14

- 282 -

collected reflections 30994

independent reflections 5214

observed reflections (Fo ≥ 4.0 σ(F)) 4541

refined parameters (p) 308

wR2 (all data) 0.0620

R1 (Fo > 4.0 σ(F)) 0.0304

GooF 0.832

absolute structure parameter - 0.03(3)

weighting u = 0.0446; v = 0

residual electron density [e Å3] max. 0.568; min. - 0.763

The absolute configuration was determined (R) in the crystal examined. Hydrogen

atom positions were taken from a difference Fourier synthesis.

54R (IW0402)

empirical formula

C27H28ClF6NO2P2Ru

molecular weight [g/mol] 710.99

temperature [K] 100

crystal color and shape orange, platelet

crystal size [mm] 0.28 x 0.27 x 0.05

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 9.364(1) α = 90.0

b = 15.414(2) β = 93.54(1)

c = 9.544(2) γ = 90.0

V = 1374.9(4) Z = 2

density ρ [g/cm3] (calculated) 1.717

µ [mm-1] 0.852

F (000) 716

absorption correction SADABS; Tmin= 0.834, Tmax = 1.000

measured 2Θ interval [ °] 6.8 ≤ 2Θ ≤ 55.8

- 283 -

limiting indices - 12 ≤ h ≤ 12; - 20 ≤ k ≤ 20; - 12 ≤ l ≤ 12

collected reflections 38631

independent reflections 6543

observed reflections (Fo ≥ 4.0 σ(F)) 6135

refined parameters (p) 445

wR2 (all data) 0.0435

R1 (Fo ≥ 4.0 σ(F)) 0.0218

GooF 0.994

absolute structure parameter 0.01(2)

weighting u = 0.0250; v = 0.2000

residual electron density [e Å3] max. 0.290; min. - 0.430

The absolute configuration was determined (1R, RRu). Hydrogen atom positions were

taken from a difference Fourier synthesis. Hydrogen bonding between PF6-

(acceptor) and the hydrogen atoms of the coordinated amino group (donor) of aniline

is evident.

55R (IW0404)

empirical formula

C27.5H29ClF7NO2.5P2Ru

molecular weight [g/mol] 745.00

temperature [K] 100

crystal color and shape orange, prism

crystal size [mm] 0.28 x 0.28 x 0.14

crystal system triclinic

space group P1 (no. 1)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 10.9667(9) α = 76.588(5)

b = 10.9759(7) β = 89.832(5)

c = 14.2777(7) γ = 60.962(5)

V = 1449.4(4) Z = 2

density ρ [g/cm3] (calculated) 1.707

µ [mm-1] 0.819

- 284 -

F (000) 750

absorption correction numerical Gauss integration;

Tmin= 0.790, Tmax = 0.894

measured 2Θ interval [ °] 6.3 ≤ 2Θ ≤ 55.8

limiting indices - 12 ≤ h ≤ 12; - 20 ≤ k ≤ 20; - 12 ≤ l ≤ 12

collected reflections 43503

independent reflections 12743

observed reflections (Fo ≥ 4.0 σ(F)) 10553

refined parameters (p) 761

wR2 (all data) 0.0792

R1 (Fo > 4.0 σ(F)) 0.0531

GooF 1.022

absolute structure parameter - 0.01(2)

weighting u = 0.0425; v = 0.2000

residual electron density [e Å3] max. 0.834; min. - 0.535

The unit cell contains two diastereomeric (1R, RRu) and (1R, SRu) complex cations

and a half MeOH molecule. Hydrogen bonding between PF6- (acceptor) and the

hydrogen atoms of the coordinated amino groups (donor) of both complex cations

and between the Cl(2) (acceptor) of the unlike cation and MeOH (donor) is evident.

56RR (IW0401)

empirical formula

C30H36ClF6NO3P2Ru

molecular weight [g/mol] 771.06

temperature [K] 100

crystal color and shape yellow, block

crystal size [mm] 0.42 x 0.23 x 0.14

crystal system orthorhombic

space group P212121 (no. 19)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 10.554(2) α = 90

b = 13.150(1) β = 90

c = 23.409(4) γ = 90

- 285 -

V = 3248.8(9) Z = 4

density ρ [g/cm3] (calculated) 1.576

µ [mm-1] 0.730

F (000) 1568

absorption correction numerical Gauss integration;

Tmin= 0.773, Tmax = 0.930

measured 2Θ interval [ °] 6.4 ≤ 2Θ ≤ 54.2

limiting indices - 13 ≤ h ≤ 13; - 16 ≤ k ≤ 16; - 30 ≤ l ≤ 30

collected reflections 32057

independent reflections 7093

observed reflections (Fo ≥ 4.0 σ(F)) 6386

refined parameters (p) 401

wR2 (all data) 0.1109

R1 (Fo ≥ 4.0 σ(F)) 0.0619

GooF 1.163

absolute structure parameter 0.01(4)

weighting u = 0.0284; v = 10.5857

residual electron density [e Å3] max. 0.974; min. - 1.175

The unit cell contains one (1R, 1’R, SRu) complex cation and one molecule MeOH.

For the refinement of phenyl ring atoms C(31) - C(36) SAME restraints were applied.

The high displacement parameters Ueq for C(32), C(33) and C(34) indicate a

disorder, but reasonable alternative positions could not be refined. Hydrogen bonding

between PF6- (acceptor) and the hydrogen atoms of the coordinated amino group

(donor) is evident only.

- 286 -

56RS (IW0501)

empirical formula

C29H32ClF6NO2P2Ru

molecular weight [g/mol] 739.04

temperature [K] 100

crystal color and shape yellow, block

crystal size [mm] 0.23 x 0.21 x 0.19

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 9.4734(4) α = 90

b = 16.2505(8) β = 91.733(6)

c = 9.7948(7) γ = 90

V = 1507.2(2) Z = 2

density ρ [g/cm3] (calculated) 1.628

µ [mm-1] 0.781

F (000) 748

absorption correction SADABS; Tmin= 0.883, Tmax = 1.000

measured 2Θ interval [ °] 6.5 ≤ 2Θ ≤ 57.1

limiting indices - 12 ≤ h ≤ 11; - 21 ≤ k ≤ 21; - 13 ≤ l ≤ 12

collected reflections 39743

independent reflections 7577

observed reflections (Fo ≥ 4.0 σ(F)) 6701

refined parameters (p) 379

wR2 (all data) 0.0623

R1 (Fo > 4.0 σ(F)) 0.0420

GooF 1.075

absolute structure parameter - 0.01(2)

weighting u = 0.0278; v = 0.4000

residual electron density [e Å3] max. 0.509; min. - 0.501

The unit cell contains one diastereomeric (1R, 1’S, RRu) complex cation. Hydrogen

bonding between PF6- (acceptor) and the hydrogen atoms of the coordinated amino

group (donor) is evident.

- 287 -

64S (IW0403)

empirical formula

C17H26O2S

molecular weight [g/mol] 294.44

temperature [K] 100

crystal color and shape colorless, block

crystal size [mm] 0.50 x 0.20 x 0.16

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 8.2868(6) α = 90

b = 6.1399(3) β = 91.816(6)

c = 16.366(2) γ = 90

V = 832.3(2) Z = 2

density ρ [g/cm3] (calculated) 1.175

µ [mm-1] 0.194

F (000) 320

absorption correction SADABS; Tmin= 0.882, Tmax = 0.970

measured 2Θ interval [ °] 6.8 ≤ 2Θ ≤ 55.8

limiting indices - 10 ≤ h ≤ 10; - 8 ≤ k ≤ 8; - 21 ≤ l ≤ 21

collected reflections 21807

independent reflections 3946

observed reflections (Fo ≥ 4.0 σ(F)) 3435

refined parameters (p) 259

wR2 (all data) 0.0873

R1 (Fo > 4.0 σ(F)) 0.0390

GooF 1.074

absolute structure parameter - 0.03(7)

weighing u = 0.0431; v = 0.1938

residual electron density [e Å3] max. 0.319; min. - 0.254

The unit cell contains one diastereomeric (SS, 1R, 2S, 5R) molecule. Hydrogen atom

positions were taken from a difference Fourier synthesis.

- 288 -

67S (IW0405)

empirical formula

C17H16FeOS

molecular weight [g/mol] 324.21

temperature [K] 100

crystal color and shape orange, needle

crystal size [mm] 0.32 x 0.17 x 0.13

crystal system monoclinic

space group P21 (no. 4)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 5.8371(3) α = 90

b = 15.390(2) β = 97.748(6)

c = 16.143(2) γ = 90

V = 1436.9(3) Z = 4

density ρ [g/cm3] (calculated) 1.499

µ [mm-1] 1.186

F (000) 672

absorption correction SADABS; Tmin= 0.753, Tmax = 0.860

measured 2Θ interval [ °] 7.0 ≤ 2Θ ≤ 58.0

limiting indices - 7 ≤ h ≤ 7; - 20 ≤ k ≤ 20; - 21 ≤ l ≤ 21

collected reflections 39370

independent reflections 7373

observed reflections (Fo ≥ 4.0 σ(F)) 6199

refined parameters (p) 363

wR2 (all data) 0.0689

R1 (Fo ≥ 4.0 σ(F)) 0.0343

GooF 0.997

absolute structure parameter 0.01(1)

weighting u = 0.0395; v = 0.0405

residual electron density [e Å3] max. 0.724; min. - 0.455

The unit cell contains two symmetry independent molecules with different

conformations of the p-tolyl substituents, but of identical absolute configuration (SS).

- 289 -

69S (IW0406)

empirical formula

C19H20FeO4S2

molecular weight [g/mol] 432.34

temperature [K] 100

crystal color and shape orange, irregular

crystal size [mm] 0.21 x 0.10 x 0.07

crystal system orthorhombic

space group P212121 (no. 19)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 7.977(1) α = 90

b = 14.900(2) β = 90

c = 15.213(2) γ = 90

V = 1808.2(4) Z = 4

density ρ [g/cm3] (calculated) 1.588

µ [mm-1] 1.087

F (000) 896

absorption correction SADABS; Tmin= 0.843, Tmax = 0.930

measured 2Θ interval [ °] 7.4 ≤ 2Θ ≤ 56.0

limiting indices - 10 ≤ h ≤ 10; - 19 ≤ k ≤ 19; - 20 ≤ l ≤ 20

collected reflections 52022

independent reflections 4372

observed reflections (Fo ≥ 4.0 σ(F)) 3987

refined parameters (p) 295

wR2 (all data) 0.0582

R1 (Fo ≥ 4.0 σ(F)) 0.0278

GooF 1.048

absolute structure parameter 0.03(2)

weighting u = 0.0255; v = 0.8717

residual electron density [e Å3] max. 0.583; min. - 0.331

The unit cell contains one molecule with the absolute configuration (SS). The

displacement parameters were varied in relation to one common isotropic kept

constant during refinement.

- 290 -

72 (IW0407)

empirical formula

C20H23FeNOS

molecular weight [g/mol] 381.30

temperature [K] 100

crystal color and shape orange, irregular

crystal size [mm] 0.23 x 0.18 x 0.14

crystal system triclinic

space group P1 (no. 2)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 7.6883(7) α = 86.231(6)

b = 7.7400(4) β = 85.435(8)

c = 29.575(2) γ = 89.663(6)

V = 1750.6(2) Z = 4

density ρ [g/cm3] (calculated) 1.447

µ [mm-1] 0.987

F (000) 800

absorption correction numerical Gauss integration;

Tmin= 0.836, Tmax = 0.904

measured 2Θ interval [ °] 6.1 ≤ 2Θ ≤ 57.4

limiting indices - 10 ≤ h ≤ 10; - 10 ≤ k ≤ 10; - 39 ≤ l ≤ 39

collected reflections 47120

independent reflections 8984

observed reflections (Fo ≥ 4.0 σ(F)) 6781

refined parameters (p) 571

wR2 (all data) 0.0793

R1 (Fo > 4.0 σ(F)) 0.0352

GooF 1.021

weighting u = 0.0378; v = 0.5828

residual electron density [e Å3] max. 0.472; min. - 0.529

The unit cell contains two symmetry independent pairs of enantiomers of the like

diastereomer due to the centro symmetry of the space group. The enantiomers in

each pair differ slightly in conformation due to the inversion center of the space

group. Hydrogen atom positions were taken from a difference Fourier synthesis.

- 291 -

77 (IW0502)

empirical formula

C25H19FeNO2

molecular weight [g/mol] 421.28

temperature [K] 100

crystal color and shape yellow-orange, needle

crystal size [mm] 0.35 x 0.13 x 0.11

crystal system orthorhombic

space group Pbca (no. 61)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 16.318(2) α = 90

b = 7.9306(6) β = 90

c = 29.038(3) γ = 90

V = 3757.9(7) Z = 8

density ρ [g/cm3] (calculated) 1.489

µ [mm-1] 0.825

F (000) 1744

absorption correction SADABS; Tmin= 0.838, Tmax = 1.000

measured 2Θ interval [ °] 7.1 ≤ 2Θ ≤ 55.8

limiting indices - 21 ≤ h ≤ 21; - 10 ≤ k ≤ 10; - 38 ≤ l ≤ 38

collected reflections 37177

independent reflections 4474

observed reflections (Fo ≥ 4.0 σ(F)) 3677

refined parameters (p) 262

wR2 (all data) 0.0700

R1 (Fo > 4.0 σ(F)) 0.0439

GooF 1.021

weighting u = 0.0258; v = 3.3190

residual electron density [e Å3] max. 0.330; min. - 0.275

The unit cell contains two symmetry independent molecules being enantiomeric to

each other.

- 292 -

78 (IW0507)

empirical formula

C42H35As2IPd

molecular weight [g/mol] 922.84

temperature [K] 100

crystal color and shape orange, prism

crystal size [mm] 0.11 x 0.10 x 0.07

crystal system orthorhombic

space group Pbca (no. 61)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 19.503(2) α = 90

b = 10.846(2) β = 90

c = 33.315(3) γ = 90

V = 7047(2) Z = 8

density ρ [g/cm3] (calculated) 1.740

µ [mm-1] 3.296

F (000) 3616

absorption correction SADABS; Tmin= 0.783, Tmax = 1.000

measured 2Θ interval [ °] 7.3 ≤ 2Θ ≤ 54.2

limiting indices - 24 ≤ h ≤ 25; - 13 ≤ k ≤ 13; - 41 ≤ l ≤ 42

collected reflections 51608

independent reflections 7744

observed reflections (Fo ≥ 4.0 σ(F)) 6022

refined parameters (p) 415

wR2 (all data) 0.0893

R1 (Fo > 4.0 σ(F)) 0.0680

GooF 1.021

weighting u = 0.0190; v = 39.7588

residual electron density [e Å3] max. 1.863; min. - 0.910

The highest maximum of residual electron density is located in trans position to the

iodo ligand. Distance and location of this maximum are suggesting the crystal

structure contains traces of the corresponding diiodo complex trans-(Ph3As)2PdI2 of

not more than 3 %. Attempts to consider these traces by a disorder model did not

lead to satisfying results.

- 293 -

79 (IW0506)

empirical formula

C40.6H33.2Fe2N2O5.3

molecular weight [g/mol] 745.59

temperature [K] 100

crystal color and shape yellow-orange, block

crystal size [mm] 0.28 x 0.14 x 0.08

crystal system monoclinic

space group P21/C (no. 14)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 13.310(2) α = 90

b = 7.3722(6) β = 97.95(1)

c = 34.450(3) γ = 90

V = 3347.9(6) Z = 4

density ρ [g/cm3] (calculated) 1.479

µ [mm-1] 0.917

F (000) 1541

absorption correction SADABS; Tmin= 0.807, Tmax = 1.000

measured 2Θ interval [ °] 7.0 ≤ 2Θ ≤ 51.4

limiting indices - 16 ≤ h ≤ 16; - 8 ≤ k ≤ 8; - 42 ≤ l ≤ 42

collected reflections 38439

independent reflections 6250

observed reflections (Fo ≥ 4.0 σ(F)) 4956

refined parameters (p) 494

wR2 (all data) 0.1076

R1 (Fo ≥ 4.0 σ(F)) 0.0641

GooF 1.022

weighting u = 0.0349; v = 6.5686

residual electron density [e Å3] max. 0.857; min. - 0.933

The unit cell contains two symmetry independent molecules being enantiomeric to

each other. The compound crystallizes with ca. 0.65 molecules of EtOAc per formula

unit, which are disordered. Two preferred positions could be refined, which are

occupied by 44.5(6) % and 20.5(6) % in the crystal. Atoms in the less occupied

position were refined isotropically only.

- 294 -

80 (IW0503)

empirical formula

C36H30As2I2Pd

molecular weight [g/mol] 972.64

temperature [K] 100

crystal color and shape red, prism

crystal size [mm] 0.18 x 0.18 x 0.09

crystal system triclinic

space group P1 (no. 2)

unit cell dimensions

a, b, c [Å]; α, β, γ [°]; V [Å3]; Z

a = 10.1917(7) α = 84.614(8)

b = 12.6708(9) β = 77.726(7)

c = 13.1838(9) γ = 78.764(6)

V = 1629.3(2) Z = 2

density ρ [g/cm3] (calculated) 1.983

µ [mm-1] 4.504

F (000) 928

absorption correction SADABS; Tmin= 0.704, Tmax = 1.000

measured 2Θ interval [ °] 6.5 ≤ 2Θ ≤ 55.8

limiting indices - 13 ≤ h ≤ 13; - 16 ≤ k ≤ 16; - 17 ≤ l ≤ 17

collected reflections 35711

independent reflections 7759

observed reflections (Fo ≥ 4.0 σ(F)) 6408

refined parameters (p) 373

wR2 (all data) 0.0488

R1 (Fo > 4.0 σ(F)) 0.0340

GooF 1.026

weighting u = 0.0230; v = 0.5204

residual electron density [e Å3] max. 0.837; min. - 0.930

The unit cell contains two symmetry independent molecules in the asymmetric unit,

which are each located on crystallographic inversion centers.

- 295 -

10 Literature

Citation modalities: For clarity references related to one specific topic are

summarized in blocks and given in parentheses […]. If one statement is related to

one block completely, then the individual references (…) are not listed. If a statement

is related to several blocks, then it is marked as [1, 2,…]. In turn relation(s) to

individual references are cited as [ 1 (1-2); 2 (2-4), 3 (8-16), …] from different or one

block, respectively.

[1] Organic chemistry textbooks: (1) Eliel, E. L.; Wilen, S. H.; Mander, L. N.

Stereochemistry of Organic Compounds, John Wiley & Sons New York 1994;

(2) Carey, F. A.; Sundberg; R. J. Advanced Organic Chemistry, Part A:

Structure and Mechanisms; 3rd ed., Plenum Press New York 1990; (3) Carey,

F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and

Synthesis; 3rd ed., Plenum Press New York 1990; (4) March, J. Advanced

Organic Chemistry – Reactions, Mechanisms and Structure, 4th ed., John

Wiley & Sons New York 1992; inorganic and organometallic chemistry

textbooks: (5) Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th

ed., John Wiley & Sons New York 1988; (6) Collman, J. P.; Hegedus, L. S.;

Norton, J. R.; Finke, R. G. Principles and Applications of Organotransition

Metal Chemistry, University Science Books Mill Valley (Cal.) 1987.

[2] (1) ref. [1 (2)], chapter 2, 67 – 116 and references cited therein; historical

review about L. Pasteur (1822 - 1895) and tartraric acid: (2) Roth, K.; Hoeft-

Schleeh, S. Chem. uns. Zeit 1995, 29, 338 and references cited therein;

historical primary literature: (3) van’t Hoff, J. H. Arch. Neerl. Sci. Exactes Nat.

1874, 9, 445; (4) LeBel, J. A. Bull. Soc. Chim. Fr. 1874, 22, 337; weak

quantum forces presumably leading to a small energy difference of

enantiomers: (5) Quack, M. Angew. Chem. Int. Ed. 2002, 41, 4619 and

references cited therein.

[3] (1) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem. 1966, 78, 413; (2) IUPAC

commission for nomenclature of organic chemistry, recommendations from

- 296 -

1974 for section E: fundamentals of stereochemistry, Pure Appl. Chem. 1976,

45, 11; (3) Prelog, V.; Helmchen, G. Angew. Chem. 1982, 94, 614; (4) Mislow,

K.; Siegel, J. J. Am. Chem. Soc. 1984, 106, 3319; (5) Seebach, D.; Prelog, V.

Angew. Chem. 1982, 94, 696; somewhat old, but very illustrate: (6) Bähr, W.;

Theobold, H. Organische Stereochemie – Begriffe und Definitionen, Springer

Verlag Berlin 1973; (7) Werner, A. Ber. Dtsch. Chem. Ges. 1911, 44, 1887; (2)

IUPAC Bulletin 1968, 33, 68; for a still up to date discussion of classical

examples of chiral coordination compounds: (8) ref. [1 (5)], chapter 17, 638 –

648 and references cited therein; descriptor formalism of pseudo-polyhedral

complexes with hapto-coordinated ligands contradictory to IUPAC rules: (9)

Brunner, H. Angew. Chem. Int. Ed. 1999, 38, 1194; (10) Brunner; H.

Enantiomer 1997, 2, 133; (11) Lecomte, C.; Dusausoy, Y.; Protas, J.;

Tirouflet, J.; Dormond, A. J. Organomet. Chem. 1974, 73, 67.

[4] Acentral chirality: (1) ref. [1 (4)], chapter 4, 101 – 106 and references cited

therein; very common, but ambiguous and obsolete nomenclature for planar

chiral ferrocenes: (2) Schlögel, K. Top. Stereochem. 1967, 1, 39.

[5] Bended pseudo-hapto arene complexes: (1) Werner, H. Chem. Ber. 1969,

102, 95; (2) Huttner, G. Angew. Chem. 1971, 83, 541.

[6] Inversion of amines, phosphines, arsines, stibanes and sulfoxides: (1) ref. [1

(4)], chapter 4, 96 – 100 and references cited therein; examples of application

of chiral phosphinamides: (2) Burns, B.; Merifield, E.; Mahon, M. F.; Molloy, K.

C.; Wills, M. J. Chem. Soc. Perkin Trans. 1, 1993, 2243 and references cited

therein; leading examples of preparation and classical determination of

absolute configuration of chiral organic sulfoxides and sulfinates: (3) Axelrod,

M.; Bickart, P.; Jacobus, J.; Green, M. M.; Mislow, K. J. Am. Chem. Soc.,

1968, 90, 4835; (4) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley,

J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637 and references cited

therein; (5) Harpp, D. N.; Vines, S. M.; Montillier, J. P.; Chan, T. H. J. Org.

Chem. 1976, 41, 3987; (6) Drabowicz, J.; Bujnicki, B.; Mikołajczyk, M. J. Org.

Chem. 1982, 47, 3325; illustration of enantiomorph crystals: (7) Borchardt-Ott,

W. Kristallographie – eine Einführung für Naturwissenschaftler, 2nd ed.,

- 297 -

Springer Verlag Berlin 1987, 126 – 129; first determination of absolute

configuration by X-ray structure analysis: (8) Bijvoet, J. M.; Peerdeman, A. F.;

van Bommel, A. J. Nature 1951, 168, 271.

[7] For almost classical but still valid general introductions into chiroptical

methods easily transferable to inorganic problems: (1) Charney, E. The

Molecular Basis of Optical Activity: Optical Rotary Dispersion and Circular

Dichroism, John Wiley & Sons New York 1979; (2) Djerassi, C. Optical Rotary

Dispersion, McGraw Hill New York 1960; (3) Optical Rotary Dispersion and

Circular Dichroism in Organic Chemistry; Snatzke, G. (Ed.); Heyden London

1967.

[8] (1) Hegstrom, R. A.; Kondepudi, D. K. Sci. Am. 1990, 262, 98; (2) Gardner, M.

The New Ambidextrous Universe, W. H. Freeman New York 1990; (3)

Stereochemistry and Biological Activity of Drugs; Ariens, E. J.; Soudijin, W.;

Timmermans; P. B. M. W. M. (Eds.); Blackwall Oxford 1983; (4) Borman, S.

Chem. Eng. News 1990, 68, 9; (5) Stinson, S. C. Chem. Eng. News 1992, 70,

46.

[9] (1) Jacques, J.; Colbert, A.; Wilen , S. H. Enantiomers, Racemates and

Resolutions, Wiley Interscience New York 1981 ; (2) Allenmar, S. G.

Chromatographic Enantioseperations: Methods and Applications, Ellis

Horwood Chichester 1988; a hands-on HPLC-handbook including separation

of enantiomers on stationary chiral phases: (3) Aced, G.; Möckel, H. J.

Liquidchromatographie – Apparative, theoretische und methodische

Grundlagen der HPLC, VCH Weinheim 1991; (4) Schurig, V. Angew. Chem.

1984, 96, 733; (5) Seebach, D.; Hungerbühler, E. Mod. Synth. Methods 1980,

2, 91; (6) Henessian, S. Total Synthesis of Natural Products – the Chiron

Approach, Pergamon Press Oxford 1983; (7) Seebach, D.; Imwinkelried, R.;

Weber, T. Mod. Synth. Methods 1986, 4, 125; (8) Ho, T.-L. Enantioselective

Synthesis – Natural Products from Chiral Terpenes, John Wiley & Sons New

York 1992; (9) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis –

Construction of chiral Molecules Using Amino Acids, John Wiley & Sons New

York 1987; (10) Carbohydrates as Raw Materials; Lichtenthaler, W. (Ed.);

- 298 -

VCH Weinheim 1991; (11) Advanced Asymmetric Synthesis; Stephenson, G.

R. (Ed.); Chapman & Hall London 1996; (12) Gawley, R. E.; Aubé, J.

Principles of Asymmetric Synthesis, Pergamon Press Oxford 1996; (13)

Stereocontrolled Asymmetric Synthesis; Trost, B. M. (Ed.); Blackwall Scientific

Oxford 1994; (14) Ager, D. J.; East, M. B. Asymmetric Synthetic Methodology;

CRC Press Boca Raton 1995; (15) Asymmetric Synthesis; Aitken, R. A.;

Kilény, S. N. (Eds.); Chapman & Hall London 1992.

[10] (1) Brunner, H. Angew. Chem. Int. Ed. 1969, 8, 382; (2) Brunner, H. Adv.

Organomet. Chem. 1980, 18, 151; (3) Brunner, H.; Langer, M. J. Organomet.

Chem. 1975, 87, 223; (4) Brunner, H. J. Organomet. Chem. 1975, 94, 189; (5)

Brunner, H.; Aclasis, J. A. J. Organomet. Chem. 1976, 104, 347.

[11] Review about chiral recognition by η5-CpRe(III) complexes: (1) Gladysz, J. A.;

Boone, B. J. Angew. Chem. Int. Ed. 1997, 36, 550 and references cited

therein; η5-CpRe(III) σ-acyl complexes: (2) Wong, W. K.; Tam, W.; Strouse, C.

E.; Gladysz, J. A. J. Chem. Soc. Chem. Commun. 1979, 530; (3) Astakhova, I.

S.; Johannson, A. A.; Semion, V. A.; Struchkov, Y. T.; Anibsimov, K. N.;

Kolobova, N. E. J. Chem. Soc. Chem. Commun. 1969, 488; (4) Lukchart, C.

M.; Zeile, J. V. J. Am. Chem. Soc. 1976, 98, 2365.

[12] (1) Davies, S. G. Pure Appl. Chem. 1988, 60, 13 and references cited therein;

(2) Liebeskind, L. S.; Welker, M. E. Tetrahedron Lett. 1984, 25, 4341; (3)

Liebeskind, L. S.; Welker, M. E.; Fengl, R. W. J. Am. Chem. Soc. 1986, 108,

6328; (4) Davies, S. G.; Dordor-Hedgecock, I. M.; Walker, T. C.; Warner, P.

Tetrahedron Lett. 1984, 25, 2709; (5) Davies, S. G.; Dordor, I. M.; Warner, P.

J. Chem. Soc. Chem. Commun. 1984, 956; (6) Ambler, P. W.; Davies, S. G.;

Tetrahedron Lett. 1985, 26, 3075 and 3079; (7) A. D. Cameron, M. C. Baird, J.

Chem. Soc. Dalton Trans., 1985, 2691; (8) Seeman, I. J.; Davies, S. G. J.

Chem. Soc. Dalton Trans. 1985, 2692; (9) Heah, P. C.; Patton, A. T.; Gladysz,

J. A. J. Am. Chem. Soc. 1986, 108, 1185 and references cited therein.

[13] (1) Brunner, H.; Doppelberger, J. Chem. Ber. 1978, 111, 673; (2) Brunner, H.;

Doppelberger, J. Bull. Soc. Chim. Belg. 1975, 84, 923; for the versatility of the

- 299 -

same chiral aminophosphine ligand see: (3) Brunner, H.; Rambold, W. Angew.

Chem. 1973, 85, 1118; (4) Brunner, H.; Steger, W. Z. Naturforsch. 1976, 31b,

1493.

[14] (1) Brunner, H.; Aclasis, J.; Langer, M.; Steger, W. Angew. Chem. Int. Ed.

1974, 13, 810; (2) Brunner, H.; Fisch, K.; Jones, P. G.; Salbeck, J. Angew.

Chem. Int. Ed. 1989, 28, 1521; (3) Brunner, H.; Klankermayer, J.; Zabel, M.

Organometallics 2002, 21, 5746.

[15] (1) Meneghetti, M. R.; Grellier, M.; Pfeffer, M.; Dupont, J.; Fischer, J.

Organometallics 1999, 18, 5560; equilibrium study: (2) Brunner, H.; Zwack, T.

Organometallics 2000, 19, 2423.

[16] (1) Ernst, R. R. scriptum to lecture Physikalische Chemie V – Magnetische

Resonanz, ETH Zürich 1996 and references cited therein; (2) Brunner, H. Eur.

J. Inorg. Chem. 2001, 905; (3) Loza, M. L.; Parr, J.; Slawin, A. M. Z.

Polyhedron 1997, 16, 2321; equilibrium study resp. confirmation see: (4)

Brunner, H.; Köllnberger, A.; Burgemeister, T.; Zabel, M. Polyhedron 2000, 19,

1519; (5) Brunner, H.; Wallner, G. Chem. Ber. 1976, 109, 69 ; (2) Brunner, H.;

Fisch, K.; Jones, P. G.; Salbeck , J. Angew. Chem. Int. Ed. 1989, 28, 1521.

[17] Applications of metal catalyzed transfer hydrogenation reactions see: (1)

Gladiali, S.; Menstroni, G. in Transition Metals for Organic Synthesis; Bolm,

C.; Beller, M. (Eds); John-Wiley-VCH Weinheim 1998, 2, 81; formic acid /

amine complexes as reducing agents: (2) Wagner, K. Angew. Chem. 1970,

82, 73; reductive amination and related reactions: (3) Leuckart, R. Ber. Dtsch.

Chem. Ges. 1885, 18, 2341; (4) Moore, M. L. Org. React. 1949, 5, 301; (5)

Lukasiewicz, A. Tetrahedron 1963, 19, 1789; Meerwein-Ponndorf-Verley-

Reduction: (6) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925,

444, 221; (7) Ponndorf, W. Angew. Chem. 1926, 39, 138; (8) Verley, A. Bull.

Soc. Chim. 1925, 37, 537; (9) Wilds, A. L. Org. React. 1944, 2, 178; (10)

Oppenauer, R. V. Recl. Trav. Chim. Pays-Bas 1937, 56, 137; (11) Djerassi, C.

Org React. 1951, 6, 207; (12) Okano, T.; Matsuoka, M.; Konishi, H.; Kiji, J.

Chem. Lett. 1987, 181.

- 300 -

[18] (1) Johnson, F. Chem. Rev. 1968, 375; (2) Hoffmann, R. W. Chem. Rev. 1989,

89, 1841; (3) Broeker, J. L.; Hoffmann, R. W.; Houk, K. N. J. Am. Chem. Soc.

1977, 3, 139; (4) Bürgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.

[19] (1) Woodward, R. B.; Hoffmann, R. Die Erhaltung der Orbitalsymmetrie,

Verlag Chemie Weinheim 1970; (2) Fleming, I. Grenzorbitale und Reaktionen

organischer Verbindungen, VCH Weinheim 1990; metalla six-membered chair-

like pericyclic transition states in carbonyl reactions: (3) Seebach, D. lecture

Organische Chemie III – Stereochemie, ETH Zürich 1994 / 95; (4) Corey, E.

J.; Helal, C. J. Angew. Chem. 1998, 110, 2092; (5) Yamakawa, M.; Noyori, R.

J. Am. Chem. Soc. 1995, 117, 6327; (6) Yamakawa, M.; Noyori, R.

Organometallics 1999, 18, 128; (7) Matteson, D. S. Organomet. Chem. Rev. A

1969, 4, 263; (8) Evans, D. A. Science 1988, 240, 420; (9) Corey, E. J.; Yuen,

P.-W.; Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55, 784; (10)

Steinhagen, H.; Helmchen, G. Angew. Chem. 1996, 108, 2489; (11)

Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma, K. J. Am. Chem. Soc.

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87; Pd(0)-catalyzed crosscoupling of zinc organyls: (9) Negishi, E.-i.; Luo, F.-

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(12) Pedersen, H. L.; Johannsen, M. J. Org. Chem. 2002, 67, 7982;

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W. J. Chem. Soc. Dalton Trans. 2001, 2989.

[54] Although inverse titration of alkyllithium reagents with cheap and non

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1976, 41, 1879.

[55] (1) International Tables for Crystallography; Wilson, A. J. C. (Ed.); C, Kluwer

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- 313 -

222), 4.2.4.2 (193 - 199); (2) Flack, H. D.; Acta Cryst. 1983, A39, 876; (3)

Coppens, P. in Crystallographic Computing; Ahmed (Ed.), F. R.; S. R. Hall &

C. P. Huber Copenhagen (Munksgaard) 1970, 255 - 270; following computer

programs were used: (4) COLLECT Bruker-Nonius, 2002 for data collection;

(5) EvalCCD, Bruker-Nonius 2002 for data reduction; (6) SADABS 2.06,

Bruker-AXS 2002 for absorption correction; (7) SHELXTL NT 6.12, Bruker

AXS 2002 for structure determination; (8): SHELXTL NT 6.12, Bruker AXS

2002 for refinement; (9) SHELXTL NT 6.12, Bruker AXS 2002 for molecule

projection.

- 314 -

Mein persönlicher Dank gebührt….

... wiederum den Herren Prof. Walter Bauer, Dr. Frank Heinemann und Dr. Ralph

Puchta für die großartige Hilfe bei der Gliederung, der inhaltlichen Gestaltung und

der Korrektur meiner Dissertation. Sie als auch Herr Prof. Hans H. Brand mit seiner

Vorlesung "Quantenelektronische Grundlagen des Lasers" boten mir darüber hinaus

auch ein intellektuelles Zuhause in Erlangen.

Meinen Arbeitskreiskollegen Dr. Guido Marconi und Dr. Martin Hofmann bin ich

freundschaftlich verbunden. Die Sonntagsbrunchs im Teehaus mit Guido und seiner

Frau Laura gehören zu meinen entspannten Momenten in Erlangen. Die Touren auf

Moffs "Moto-Guzzi-Bestie“ durch die Fränkische Schweiz bleiben unvergeßlich. A mi

compañero de trabajo Sergi Huguet Torrell por su camaradería en el grupo y por su

reconfortable temperamento catalán. En este sentido agradezco también a Frau Dr.

“Diabolina” Maribel Carrizo-Salfner y a todo el grupo de trabajo del Prof. Nickel por

los agradables momentos vividos, la excelente e informal cooperación y como no, las

divertidas fiestas durante el semestre. Nunca olvidare como a veces, cuando

nuestros laboratorios aun estaban enfrente, una simple sonrisa nos daba la

motivación mutua para ir hacia delante. Son estos pequeños momentos los que a

veces te hacen la vida más llevadera.

Chciałbym bardzo serdecznie podziękować moim Koleżankom i Kolegom: Radimowi

Berankowi, dr Kindze Hein, dr Ivanie Ivanović-Burmazović, Agnieszce Nawara, Ewie

Pasgreta, Vesselinie Popovej, „mamie“ Joannie i Sławomirowi Procelewskim z

małym Phillipem…. Dziękuję Wam za serdecznie koleżeńskie, moralne i solidarne

poparcie w wielu bardzo trudnych sytuacjach i przede wszystkim za adaptację do

polsko-słowiańskiej społeczności. Miałem przyjemność rozkoszować się

spontanicznością i szarmanckością polskiej kultury, wciąż z łezką w oku wspominam

wiele naszych wspólnych spotkań. Chciałbym jeszcze dodać, dzięki inicjatywie

„mamy” przeprowadziłem pomiary kinetyczne 31P-NMR ( Rozdział 4), za co również

bardzo dziękuję. Nigdy Was nie zapomnę …. !!!

- 315 -

Herrn Dr. Jörg Sutter gebührt großer Dank für seine vielen "Feuerwehreinsätze“ bei

EDV-Unfällen und anderen Problemen jeglicher Art. Die angenehme Labor-

nachbarschaft und exzellente logistische und informative Zusammenarbeit mit Dr.

Alexander Czaja, Sina Kasper und Dr. Frank Lauderbach werde ich stets in guter

Erinnerung behalten.

Ohne mir eine nicht gebührende Autorität anmaßen zu wollen danke ich Herrn Dr.

Matthias Moll diesem Sinne persönlich für seinen unermüdlichen und

organisatorischen Einsatz für unser Institut. Ohne ihn hätten wohl für uns alle die

drastischen Mittelkürzungen weitaus gravierendere Folgen als nur so manchen

temporären Mangel an Chemikalien, Lösemitteln und Schutzhandschuhen bedeutet.

Daher bedanke ich mich auch herzlich bei den vielen Kollegen in anderen

Arbeitskreisen für die solidarische Zusammenarbeit über Institutsgrenzen hinaus.

Bei meinen Studentinnen und Studenten im Mitarbeiterteil des Fortgeschrittenen-

Praktikum bedanke für mich für die angefertigten Präparate. Es war schön, ihre

kontinuierliche Entwicklung in Erinnerung an meine eigene Studienzeit zu

beobachten. Weiterhin kann ich sie in ihrer Eigenständigkeit des reflektierenden

Denkens, Lernen und Handelns nur bestärken. Lehren bedeutet auch Lernen. Ich

wünsche ihnen für ihren professionellen und persönlichen Werdegang alles Gute und

besonders das dafür notwendige Durchstehvermögen - fortiter in re, dulce in modo!

In diesem Sinne hoffe ich auch meinen Nachfolgern eine Arbeit hinterlassen zu

haben, die ihnen eine möglichst schnelle, umfassende, selbstständige aber auch

Übersicht schaffende Einarbeitung in das Gebiet der enantioselektiven Katalyse und

insbesondere der Transferhydrierung von Carbonylverbindungen ermöglicht. Ich

wünsche Ihnen dabei und bei der notwendig eigenständigen Verwirklichung ihrer

Ideen viel Erfolg!

But most I am indebted to my family and to the closest circle of my friends all over the

world. During rough seas and in troubled waters they were my lighthouse, pilots and

life raft. Honor et virtus, amicitia fides!

- 316 -

- 317 -

Lebenslauf

31.03.1970 Ich, Immo Weber, wurde in Tübingen als erster von drei Söhnen von

Dr. med. Volker Weber und Dr. med. Christa Weber, geb. Nickolay

geboren; Deutscher, ledig.

28.05.1990 Abitur am Gymnasium Aloisiuskolleg Bonn-Bad Godesberg.

1990 – 1994 Studium der Chemie an der Eberhard-Karls-Universität Tübingen,

Vordiplom 29.03.1993, Sommer 1993 Austauschsemester am Barnett

Institute der Northeastern University, Boston (Mass., USA).

1995 – 1998 Hauptstudium an der Eidgenössischen Technischen Hochschule

Zürich, Dipl. Chem. ETH 03.12.1998, Diplomarbeit "C3-symmetrische

Dendrimere der ersten und zweiten Generation mit terminalen PN-

Ferrocenyl-Ligandeneinheiten - Anwendungen in der enantioselektiven

Katalyse" unter der Anleitung von Prof. Dr. A. Togni, Laboratorium für

Anorganische Chemie; Sommer 1996 Praktikum in der F&E-Abteilung

bei der AGFA AG Leverkusen, Sommer 1995 Assistent am Institut de

Microtechnique der Université Neuchâtel.

1999 – 2001 Barnett Institute der Northeastern University; Arbeiten über planar

chirale Tricarbonylchrom(0)-η6-Arenliganden für Pd-katalysierte enan-

tioselektive Reaktionen; Cumulative Examinations und "Award for

Academic Excellence" Frühjahr 1999.

01.01.2002 Beginn der Dissertation am Institut für Anorganische Chemie II der

Friedrich-Alexander-Universität Erlangen-Nürnberg unter der Anleitung

von Prof. Dr. Ulrich Zenneck.

2005 Ab Januar Teilzeitanstellung bei der Kunststoff- und Metallwarenfabrik

Erlangen (KUM) GmbH & Co. KG als direkt der Geschäftsleitung

unterstellter Projektleiter Forschung und Entwicklung.