α,α′,α′′-[(NITRILO-N)TRIS(METHYLENE)]TRIS. . . 1

α,α′,α′′-[(Nitrilo-N)tris(methylene)]tris[benzenemethanolato-0](2-propanolato) Titanium

PhN

O TiO

O

Ph

O iPr

Ph

[193023-73-3]InChI = 1/C24H24NO3.C3H7O.Ti/c26-22(19-10-4-1-5-11-19)

16-25(17-23(27)20-12-6-2-7-13-20)18-24(28)21-14-8-3-9-15-21;1-3(2)4;/h1-15,22-24H,16-18H2;3H,1-2H3;/q-3;-1;+4/t22-,23-,24-;;/m0../s1/rC27H31NO4Ti/c1-21(2)29-33-30-25(22-12-6-3-7-13-22)18-28(19-26(31-33)23-14-8-4-9-15-23)20-27(32-33)24-16-10-5-11-17-24/h3-17,21,25-27H,18-20H2,1-2H3/t25-,26-,27-/m0/s1

InChIKey = MBYCOGYZVJDQFG-FGVOIISDBL[191410-20-5] C27H31NO4Ti (MW 481.426)InChI = 1/C24H24NO3.C3H7O.Ti/c26-22(19-10-4-1-5-11-19)

16-25(17-23(27)20-12-6-2-7-13-20)18-24(28)21-14-8-3-9-15-21;1-3(2)4;/h1-15,22-24H,16-18H2;3H,1-2H3;/q-3;-1;+4/t22-,23-,24-;;/m0../s1/rC27H31NO4Ti/c1-21(2)29-33-30-25(22-12-6-3-7-13-22)18-28(19-26(31-33)23-14-8-4-9-15-23)20-27(32-33)24-16-10-5-11-17-24/h3-17,21,25-27H,18-20H2,1-2H3/t25-,26-,27-/m0/s1

InChIKey = MBYCOGYZVJDQFG-FGVOIISDBL

(catalyst for enantioselective sulfoxidation)

Alternate Name: [(R,R,R)-tris(2-alkoxy-2-phenylethyl)amine](2-propanolato) titanium.

Physical Data: mp 156 ◦C dec., [α]25D −217.2◦ (c = 1.0, CH2Cl2).

Solubility: soluble in chlorinated solvents, alcohols, and CH3CN.Form Supplied in: white solid or in situ preparation.Analysis of Reagent Purity: 1H-NMR, ESI–MS.1

Preparative Methods: the preformed catalyst is obtained byreaction of Ti(O-iPr)4 with 1.1 equiv of the enantiopure tri-alkanolamine in anhydrous CH2Cl2 under nitrogen, followedby solvent removal under vacuum and accurate washing cy-cles with CH2Cl2 and hexane. The complex can be prepared insitu in anhydrous CH2Cl2 under nitrogen from stoichiometricprecursors.1

Handling, Storage, and Precaution: stored under nitrogen.

Catalytic Stereoselective Sulfoxidation. The title catalyst be-longs to a family of titanium complexes bearing C3-symmetric tri-alkanolamines ligands, which bind tightly to the Ti(IV) center in atetradentate fashion providing very stable titanatranes.1–3 Thesecomplexes effect the enantioselective oxidation of prostereogenicsulfides in the presence of alkyl hydroperoxides (eq 1).3,4

The active oxidant is a mononuclear alkylperoxo titanium com-plex, which has been characterized by 1H and 13C NMR andESI–MS (eq 1).1,3–6

The effect of parameters, such as the nature of the ligand, thealkyl hydroperoxide, the temperature, or the solvent, on the stere-oselection of the sulfoxidation reaction has been examined in the

oxidation of methyl p-tolyl sulfide, which has been chosen asmodel substrate (Table 1).3,4

N

OOO

Ti

O

RR

OR1

R

NHO

OH

R OH

R RTi(i-PrO)4

ArSR

ArSOR

N

OOO

Ti

O-iPr

RR

R

R1OOHR=Me, Ph, t-Bu

ee=40−84%

(1)

Table 1 Effect of ligand [N(CH2CHROH)3] and of the hydroperoxide(R′OOH, 0.05 M) on the titanium catalyzed asymmetric oxidation of p-TolSMe(0.1 M) to p-TolSOMe (SO) and p-TolSO2Me (SO2) in CH2ClCH2Cl at−20 ◦C (catalyst 10%)3

R (Absolute R′ Time (h) Yield (%) SO/SO2 eeSO (%)Configuration)

Me, (S,S,S) t-Bu 240 82 86:14 11 (R)Me, (S,S,S) PhCMe2 75 100 76:24 19 (R)Me, (S,S,S) Ph3C 1320 100 76:24 13 (R)Ph, (R,R,R) t-Bu 45 100 89:11 29 (S)Ph, (R,R,R) PhCMe2 40 100 84:16 36 (S)Ph, (R,R,R) Ph3C 256 98 87:13 35 (S)t-Bu, (R,R,R) t-Bu 115 91 90:10 3 (R)t-Bu, (R,R,R) PhCMe2 64 100 89:11 29 (S)t-Bu, (R,R,R) Ph3C 1800 75 96:4 10 (S)

The best results were obtained by using the title catalyst with(R,R,R)-tris-(2-phenylethanol)amine as ligand and cumyl hydro-peroxide (CHP) as primary oxidant in chlorinated solvents at−20 ◦C. The system yields sulfoxides with S absolute configura-tion, which is opposite to the absolute configuration of the chiralligand employed. The robust nature of this Ti(IV) complex allowsasymmetric oxidation of the substrate to be carried to completionusing as little as 0.1% of the catalyst. The scope of the catalyticstereoselective sulfoxidation was examined with different sulfides(Table 2).3,4

The highest enantioselectivities were obtained with the benzyland tert-butyl phenyl sulfides (ee’s = 84% and 60%, respectively).Lower ee’s were obtained with the other alkyl aryl sulfides and inthis case neither the presence of aromatic substituents with differ-ent electronic character nor the elongation of the alkyl chain signif-icantly affect the enantioselection of the process (ee’s = 38–45%).On the contrary, very low ee values have been obtained in theoxidation of dialkyl sulfides. Interestingly, the highest enantiose-lectivities are obtained with substrates that lack a significant stericdifferentiation between the two sulfur atom substituents.3,4

In all oxidations, a significant amount of sulfone is formed fromthe over-oxidation of sulfoxide. Kinetic evidence in the oxidationof methyl p-tolyl sulfide shows the occurrence of two consecutivereactions, namely the stereoselective oxidation to methyl p-tolylsulfoxide and its kinetic resolution via further oxidation to sulfone.

Avoid Skin Contact with All Reagents

2 α,α′,α′′-[(NITRILO-N)TRIS(METHYLENE)]TRIS. . .

Table 2 Asymmetric oxidation of RSR′ (0.1 M) to RSOR′ (SO) andRSO2R′ (SO2) by cumyl hydroperoxide (0.1 M) catalyzed by (R,R,R)-Ti(O-iPr)(OCH(Ph)CH2)3N (10%) in CH2ClCH2Cl at 0 ◦C3,4

R R′ Yield (%) SO/SO2 eeSO (%) AbsoluteConfigurationSO

p-Tol Me 98 62:38 45 S2-Napt Me 86 60:40 38 Sp-MeOC6H4 Me 94 68:32 41 Sp-Tol Et 99 64:36 38 Sp-Tol n-Bu 99 58:42 44 SPh t-Bu 98 60:40 60 SPh Bn 94 77:23 84 SBn Me 99 78:22 5 Sn-Oct Me 95 83:16 5 S

Both processes cooperate in building up the same enantiomer asrevealed by the increase of the ee during the course of the reaction.Such behavior has been directly observed in the kinetic resolutionof the (±)-methyl p-tolyl sulfoxide (eq 2).3,4

SMe

O

pTol pTolS

Me

OO+

pTolSOMe

ee(S)=34%, 50% conversion

CHP, CH2ClCH2Cl−20 °C

(R,R,R)-Ti(O-iPr)(OCH(Ph)CH2)3N

(±)

(2)

The rates of the two consecutive oxidations are comparable(kS/kSO = 3.2), which stands in contrast with the classical reac-tivity exhibited by do transition metal peroxides and in generalby electrophilic oxidants (kS/kSO = 100).4,7 The reason for thisselectivity loss is the biphilic nature of the titanatrane perox-ide, behaving as a classical electrophilic oxidant towards sul-fides, while being able to activate a nucleophilic pathway in theoxidation of sulfoxides.4,7 Considering the oxidation of para-substituted thioanisoles, the title catalyst shows higher reactivityfor the electron-rich sulfides, while in the second oxygen transferstep electron-poor sulfoxides are the most reactive. This umpolungof the reactivity is triggered by the coordination of the sulfoxideto the metal center, which promotes the switch of the electroniccharacter of the peroxide functionality (Figure 1).4,7

Figure 1

A close relative of the title catalyst is the partially hydrolyzedZr(IV) complex bearing the same enantiopure (R,R,R)-tris-(2-phenylethanol)amine as ligand.4,8 Under analogous reactionconditions, the Zr(IV) catalyst affords sulfoxides with ee’sup to 91%. The ee’s are higher compared with the analogousTi(IV) catalyzed process, both in the stereoselective oxidationto sulfoxide and in the kinetic resolution. It is worthy to noticethat in the zirconium mediated oxidation, the (R)-sulfoxide ispreferentially obtained when the (R,R,R)-trialkanolamine is usedas chiral ligand, with an opposite stereochemical outcome of theoxygen transfer with respect to the Ti(IV) catalyzed process.4,8

Therefore, both enantiomeric sulfoxides can be prepared by usingthe same chiral ligand simply by switching the metal ion fromTi(IV) to Zr(IV) in the catalytic protocol.

Related Reagents. Titanium(IV)(triethanolaminato)isoprop-oxide (TYZOR®) TE Organic Titanate [74665-17-1]; Tita-nium(IV) (triisopropanolaminato)isopropoxide [156191-27-4].

1. Bonchio, M.; Licini, G.; Modena, G.; Bortolini, O.; Moro, S.; Nugent, W.A., J. Am. Chem. Soc. 1999, 121, 6258.

2. Nugent, W. A.; Harlow, R. L., J. Am. Chem. Soc. 1994, 116, 6142.

3. Di Furia, F.; Licini, G.; Modena, G.; Motterle, R.; Nugent, W. A., J. Org.Chem. 1996, 61, 5175.

4. Licini, G.; Bonchio, M.; Modena, G.; Nugent, W. A., Pure Appl. Chem.1999, 71, 463.

5. Bonchio, M.; Licini, G.; Modena, G.; Moro, S.; Bortolini, O.; Traldi, P.;Nugent, W. A., Chem. Commun. 1997, 869.

6. Nugent, W. A.; Licini, G.; Bonchio, M.; Bortolini, O.; Finn, M. G.;McCleland, B. W., Pure Appl. Chem. 1998, 70, 1041.

7. Bonchio, M.; Calloni, S.; Di Furia, F.; Licini, G.; Modena, G.; Moro S.;Nugent, W. A., J. Am. Chem. Soc. 1997, 119, 6935.

8. Bonchio, M.; Licini, G.; Di Furia, F.; Mantovani, S.; Modena, G.; Nugent,W. A., J. Org. Chem. 1999, 64, 1326.

Giulia Licini & Marcella BonchioUniversity of Padova, Padova, Italy

A list of General Abbreviations appears on the front Endpapers