CHAPTER

Ytterbium Trifluoromethanesulphonate CatalyzedMichael Addition Reactions of β-Ketoesters and α-Nitroesters with α,β-Unsaturated Ketones in Water1

45

4

1

4.1 Abstract

Michael additions of various β-ketoesters2 and α-nitroesters with α,β-unsaturatedaldehydes and ketones resulted in quantitative conversions into the corresponding 1,4-adducts

when the reactions were carried out in water in the presence of catalytic amounts of ytterbium

trifluoromethanesulphonate (triflate) (Yb(OTf)3) as a water tolerant Lewis acid. The scope and

limitations of the Michael addition reactions of β-ketoesters and α-nitroesters have beeninvestigated.

4.2 Introduction

In the previous chapter it was demonstrated that the copper(II) Schiff base catalyzed

Michael addition of β-ketoesters suffered from ligand-substrate exchange. Therefore, it wasnot possible to perform these Michael additions in an enantioselective manner using chiral

copper(II) Schiff base complexes as water soluble Lewis acids. Furthermore the scope of the

reaction was rather limited. Of the β-ketoesters tested only methyl 1-oxoindanecarboxylategave satisfactory results, whereas for other substrates the Michael addition was still slow also

in the presence of a catalytic amount of copper complex. We therefore searched for a water

stable Lewis acid that could broaden the scope of the Lewis acid catalyzed Michael addition of

β-ketoesters in water. Upon screening the literature, we found that lanthanide triflates wereeffective Lewis acid catalysts for a range of organic reactions in aqueous media, as was first

reported by Kobayashi.3 Although most strong Lewis acids are prepared and employed under

strictly anhydrous conditions, lanthanide triflates are reported to be prepared in aqueous

solution.4 They even maintain their Lewis acidity in aqueous solutions in various organic

reactions. Although the real nature of the catalyst is not always clear, lanthanide triflates have

been used in aqueous solutions for a range of carbon-carbon bond forming reactions. An

1 Part of this work has been published previously: Keller, E., Feringa, B.L. Tetrahedron Lett. 1996, 37,

1879; Keller, E., Feringa, B.L. Synlett 1997, 8422 For a recent review on β-ketoester chemistry, see: Benetti, S., Romagnoli, R., De Risi, C., Spalluto,

G., Zanirato, V. Chem. Rev. 1995, 95, 1065.3 Kobayashi, S. Synlett 1994, 689.4 Forsberg, J.H., Spaziano, V.T., Balasubramanian, T.M., Liu, G.K., Kinsley, S.A., Duckworth, C.A.,

Poteruca, J.J., Brown, P.S., Miller, J.L. J. Org. Chem. 1987, 52, 1017; Collins, S., Hong, Y.Tetrahedron Lett. 1987, 28, 4391; Almasio, M.-C., Arnaud-Nue, F., Schwing-Weill, M.-J. Helv.Chim. Acta 1983, 66, 1296.

Chapter 4

46

overview of the work by Kobayashi and others on Lewis acid catalyzed carbon-carbon bond

formation in aqueous solutions is given in Chapter 2.

4.2.1 Lanthanides

The lanthanides may be classified as 'hard' Lewis acids and therefore preferably bind to

'hard' bases -containing oxygen or fluorine- rather than 'soft' bases with nitrogen, phosphorus

or sulphur donor groups. The strong Lewis acidity of lanthanides in aqueous solutions

originates from this 'hard' character and they show a strong affinity towards carbonyl

oxygens.5 The Lewis acidity of lanthanide complexes has been exploited extensively in their

use as shift reagents for nuclear magnetic resonance studies. A NMR shift is produced by an

interaction between the resonating nucleus and the magnetic field of the unpaired f electrons of

the lanthanide. Lanthanide tris β-diketonates are especially effective NMR shift reagents and

for this purpose a wide range of chiral and achiral β-diketonates has been employed.6,7

Furthermore, several water soluble lanthanide complexes have been used effectively in

aqueous solutions.6,8 Thermodynamic data show that the main driving force for this high

effectivity is the favourable entropy change for the displacement of a number of water

molecules from a strongly hydrated tripositive ion by a polydentate ligand whose donor groups

are forming bonds with the lanthanide ion. In addition, polydentate lanthanide complexes with,

for example, ethylenediamine tetraacetic acid (EDTA) are of course coordinatively

unsaturated in the absence of other ligands. In water, they are hydrated and the water of

hydration may be displaced by other molecules.

Some important of the characteristics of lanthanides are:

a) They are paramagnetic.b) They act as Lewis acids.c) They have vacant coordination sites for Lewis bases.d) Lanthanides commonly adopt coordination numbers greater than 6 (usually 8-9).9

e) They adopt predominantly a +3 oxidation state.f) Polydentate ligands form particularly stable complexes (caused by the 'chelate'

effect).10

g) They form stable diketonate adducts.11

5 Molander, G.A. Chem. Rev. 1992, 92, 29.6 Wenzel, T.J. in NMR Shift reagents CRC Press, Inc., Boca Raton, Florida, 1987.7 Sievers, R.E. in Nuclear Magnetic Resonance Shift Reagents Academic Press, Inc., New York, 1973.8 Hulst, A.J.R.L. New Methods for the Enantiomeric Excess Determination using NMR Ph.D. Thesis,

University of Groningen, 1994, Chapter 2 and references therein.9 Palinek, G.J. Systematics and the Properties of the Lanthanides, Sinha, S.P. Ed., Reidel, Dordrecht,

1983, 153.10 Martell, A.E., Hancock, R.D. in Metal Complexes in Aqueous Solutions Plenum Press, New York,

1996, Chapter 3.11 Wilkinson, G., Gillard, R.D., McCleverty, J.A., in Comprehensive Coordination Chemistry,

Pergamon Press, Oxford, 1987, 1077.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

47

The characteristics described above, particularly the large coordination number, make

lanthanides ideal Lewis acid catalysts for use in aqueous solvents. Although only one

enantioselective Lewis acid catalyzed carbon-carbon bond forming reaction in water has been

reported in the literature so far,12 it can be envisaged that especially the rich coordination

chemistry of these rare earth metals,13,14 can lead to efficient chiral Lewis acid catalysts for use

in enantioselective reactions in water.

4.3 Preliminary investigations

When the reaction of several β-ketoesters with MVK was performed in water withoutthe use of an additional catalyst the addition was very sluggish in almost all cases. Even after

stirring at room temperature for 14 d less then forty percent of the starting material was

converted into the desired Michael adduct. An important observation was, however, that the

reaction proceeded very cleanly and the Michael adduct was formed as the only product. No

trace of by-products, such as polycondensation or cyclized products, which are often found

when the reaction is performed under basic conditions, were observed on working in an

aqueous medium.

O O

OR3R1R2

+

O

R4

OR1

OR3

O

R2

O

R4

4.1

4.24.3OH O

OR3R1R24.4

OR1

OR3

O

R2

O

R4

4.3

OR1

OR3

O

R2

O-

R4

4.5

base

or H2O

H2O

+Tandem Michael adductsor cyclized products

basic conditionsorganic solvent

Scheme 4.1 Michael additions of β-ketoesters in water.

12 Otto, S., Boccaletti, G., Engberts, J.B.F.N. J. Am. Chem. Soc. 1998, 120, 4238; for a brief discussion

see Chapter 5.13 Ref. 11 p. 1068.14 Cotton, S.A. in Encyclopedia of Inorganic Chemistry King, R.B. Ed., Wiley, Chichester, 1994, Vol.

7, 3595.

Chapter 4

48

The high selectivity is probably due to the fact that the intermediate enolate 4.5 isimmediately protonated when water is used as the solvent, whereas under basic conditions this

enolate can react with another Michael acceptor to give tandem Michael adducts, cyclized

products and other undesired (e.g. aldol type) by-products (Scheme 3.1). These undesired

cyclized products are formed via the well known Robinson annelation.15,16

The uncatalyzed Michael addition of β-ketoesters proceeds via enol 4.4 which as anucleophile attacks the Michael acceptor; the keto-enol equilibrium of β-ketoesters generallylies, however, at the keto side. As already outlined in Chapter 3, in Lewis acid catalyzed

Michael additions of β-dicarbonyl compounds the β-dicarbonyl is proposed to be activated fornucleophilic attack via a metallo-dicarbonyl chelate.17 This is formed on loss of the acidic

hydrogen of the substrate leading to a six membered metallo-chelate. This chelate ring can be

viewed as a metal stabilized nucleophile, in which the charge of the coordinated reagent is

(partly) located on the metal centre. In this sense the Lewis acid catalyzes the formation of the

enolate which then can react as the nucleophile. It is well known that β-diketonates react withlanthanides to give stable lanthanide β-diketonate adducts in which the dicarbonyl is alsocoordinated via a six membered enolate to the metal. Prior to our work Scretti and co-

workers showed that europium triflate could efficiently be employed as Lewis acid catalyst for

the Michael addition of β-dicarbonyl compounds in carbon tetrachloride.18 Since in water, thewater of hydration of the lanthanide may be replaced by other species, lanthanides were

expected to be efficient Lewis acids for the Michael addition of β-ketoesters in water.We therefore decided to investigate the use of lanthanide triflates as Lewis acid

catalysts for the Michael additions of β-ketoesters in water as the solvent. In this chapter thescope and limitations of Yb(OTf)3 catalyzed Michael additions are discussed. Furthermore, the

scope and limitations of such reactions with α-nitroesters were investigated as a furtherelaboration of Lewis acid catalyzed Michael additions. In the next chapter the exploration of

chiral water soluble ligands will be outlined.

4.4 Yb(OTf)3 catalyzed Michael additions of ββ-ketoesters in water

When methyl 1-oxoindanecarboxylate 4.6a was allowed to react with MVK (4.7a) inwater, in the presence of 10 mol% of Yb(OTf)3, the reaction was completed in 48 h, whereas

for the reaction in the absence of catalyst reaction 144 h were required. Although a

heterogeneous system was used, complete conversion of the starting material was found and

the Michael adduct 4.8a was the only product.

15 Jung, M.E. Tetrahedron 1976, 32, 3.16 Gawley, R.E. Synthesis 1976, 777.17 See chapter 3.18 Bonadies, F., Lattanzi, A., Orelli, L.R., Pesci, S., Scretti, A. Tetrahedron Lett. 1993, 34, 7649.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

49

O O

OCH3 +O

Yb(OTf)3

H2O

O O

OCH3

O

4.6a 4.8a4.7a

Scheme 4.2 Yb(OTf)3 catalyzed Michael addition of 4.6a with MVK.

Table 1 Michael additions of β-ketoesters and Methyl vinyl ketone.Entry Michael donor Conditionsa Michael adductb

1 OEt

OO4.6b

Suspension OEt

OO

O

4.8b

2OEt

OO4.6c

Homogeneous OEt

OO

O

4.8 c

3 OEt

OO4.6d

Homogeneous OEt

OO

O

4.8d

H

4OEt

OO4.6e

HomogeneousOEt

OO

O

4.8e

5O

OO4.6f

Suspension

O

OO

O

4.8fa Catalyst Yb(OTf)3 10 mol%, solvent H2O, 5 d.b Isolated yields >98%.

When several other cyclic and acyclic β-ketoesters (4.6 b-f) were employed in thereaction with MVK in water in the presence of 10 mol% of Yb(OTf)3, a much faster reaction

was found, compared to the reaction without Yb(OTf)3. Clean conversions to the Michael

Chapter 4

50

adducts (4.8 b-f) was observed and only the desired Michael adduct was isolated inquantitative yield (Table 1). Although reaction times of 5 d were necessary to reach complete

conversion, the use of Yb(OTf)3 as the catalyst was more effective than the copper (II) Schiff

base catalyst that was discussed in the previous chapter.

In sharp contrast little or no conversion was observed when the same reactions were

performed in organic solvents like THF, 1,4-dioxane or methylene chloride. It is interesting to

note that, although the β-ketoesters in some cases do not give homogeneous reactionmixtures, the solubility of the substrates does not influence the conversion of the Michael

donor in these experiments. For example, in entry 2 the reaction mixture is completely

homogeneous, whereas for the reaction of 4.6a the Michael donor is suspended in the aqueousreaction mixture. It should be emphasized that pure products were obtained using a simple

procedure and in most cases no further purification was needed. In all cases hydrolysis of the

ester functionality was not observed. No side products were found which are usually isolated

when the reactions are performed under basic conditions. It is also important to notice that

polymerization of the Michael acceptor, which is often observed,19,20 did not take place when

the reactions were performed in water. Furthermore the isolated yields were generally higher

than the yields reported for Michael additions catalyzed by other mild Lewis acids in common

organic solvents.21,18

O

R1

O

OR3R2

O

OEt

O

OEt

CN

N

+Yb(OTf)3

H2O

OR1

OOR3

R2

EWG

no reaction

Scheme 4.3 Variation of the Michael acceptor.

When the aqueous Yb(OTf)3 catalyst solution was used repeatedly in the reaction of

4.6b or 4.6c with MVK no loss of Lewis acid activity was observed for two additionalreaction runs. Without isolation of the Yb(OTf)3 again quantitative yields of 4.7b and 4.7cwere obtained. No difficult isolation procedures were required but simply the same aqueous

solution was used again.

19 Perlmutter, P. in Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry

Series, No 9, Pergamon, Oxford, 1992, 65, 121.20 Colapret, J.A., Buonora, P.T. in Encyclopedia of Reagents for Organic Synthesis Paquette, L.A. Ed.,

Wiley, Chichester, 1995, 3637.21 Nelson, J.H., Howells, P.N., DeLullo, G.C., Landen, G.L., J. Org. Chem. 1980, 45, 1246.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

51

O O

OEt +O

Yb(OTf)3

H2O, 5d>98 % O O

OEt

O

O O

OEt +O

Yb(OTf)3

H2O, 5d>98 % O O

OEt

OH

H

O O

OEt +

O

Yb(OTf)3

H2O, 5d>98 % O O

OEt

O

Ph

O O

OEt +Yb(OTf)3

H2O( )nO

n = 0,1

O O

OEt +Yb(OTf)3

H2O

R1

OR24.7 f R1,R2= Me4.7 g R1=Me, R2=H

no reaction

no reaction

4.9b

4.7c

4.9

4.7 d,e

4.8 g

4.8 h

Scheme 4.4 Variation of the Michael acceptor.

4.4.1 Substrate variation, scope and limitations

Next, various common Michael acceptors were tested. However, when acrylonitrile,

ethyl acrylate, ethyl propynate or vinyl pyridine were used, only starting materials were

recovered in all cases using both cyclic and acyclic β-ketoesters, even after prolonged reactiontimes (Scheme 4.3). Furthermore nitroalkenes could not be employed since these compounds,

contrary to enones, rapidly polymerize in the presence of water.22 Of the Michael acceptors

tested bearing alternative electron withdrawing groups only acrolein gave the desired Michael

adduct 4.8h, again in quantitative yield (a typical example is given in Scheme 4.4, reaction b).

Since the addition of various β-ketoesters proceeded smoothly with MVK, several ofα,β-unsaturated enones bearing different substituents at the β or the α' position were tested

22 Yamani, T., Kato, M., Yoshikoshi, A. J. Chem. Soc., Chem. Commun. 1975, 726; Singleton, D.A., in

Encyclopedia of Reagents for Organic Synthesis Paquette, L.A. Ed., Wiley, Chichester, 1995, 3769.

Chapter 4

52

(Scheme 4.4). From the results in scheme 4.4 it can be concluded that again effective Michael

addition takes place when β-unsubstituted enones are employed. Although no decrease inreactivity for α,β-unsaturated enones with a substituent at the α'-position was observed,substituents at the β-position were not allowed. Cyclic enones (4.7d, 4.7e), mesityl oxide(4.7f) or 3-penten-2-one (4.7g) only gave starting materials with, for example, ethyl 2-oxocyclopentanonoate in water in the presence of 10 mol% of Yb(OTf)3, even after prolonged

reaction times. Also chalcone (4.7h) and benzalacetone (4.7i) were not reactive under theseconditions.

Ph

O

Ph Ph

O

4.7h 4.7i

Figure 4.1

The reduced reactivity is not unexpected, since β-dicarbonyl compounds are softnucleophiles and they often require more drastic reaction conditions to react in conjugate

addition reactions with more sterically demanding substrates.23 In an attempt to exploit this

difference in reactivity between β-substituted and β-unsubstituted enones, 4.6c was added to4.7j under the standard reaction conditions. However, probably due to the less effectivepolarization of the carbon-carbon double bond, no reaction took place using this substrate

(Scheme 4.5).24

O O

OEt +Yb(OTf)3

H2Ono reactionO

4.7j4.6c

Scheme 4.5

4.4.2 Brönsted acid versus Yb(OTf)3 catalysis

Since the reaction mixtures of the reactions described above are acidic due to the

presence of both Yb(OTf)3 and the β-ketoester and because Michael additions can also bepromoted by Brönsted acids, there is a possibility that the reactions are not Yb(OTf)3catalyzed but the catalysis is simply caused by the presence of acid. Therefore control

experiments were performed in buffered aqueous solutions. The reaction of 4.6c with MVKwas performed in Tritisol® buffer solutions in the presence and absence of Yb(OTf)3. The

reaction mixture was extracted after 24 h and the conversion was determined by GC analysis

(Table 2). Since in the absence of Lewis acid no reaction had occurred it was concluded that

23 Krief, A. Tetrahedron 1980, 36, 2531.24 Morris, I.G., Pinder, A.R. J. Chem. Soc. 1963, 1841.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

53

the catalysis observed in the presence of Yb(OTf)3 was not simply Brönsted acid catalysis and

that Yb(OTf)3 was indeed responsible.

Table 2 Yb(OTf)3 catalyzed Michael addition of 4.6c with MVK in buffered solutions.PH Yb(OTf)3 (mol%) Conversion (%)

a

4 0 < 2

4 10 60a monitored by GC analysis25

4.4.3 Base catalyzed Michael additions in water

When water is used as the solvent in the Michael addition of β-ketoesters with β-unsubstituted enones in the presence of a catalytic amount of Yb(OTf)3, both the chemical

yield of the reaction and the purity of the products could be improved compared to traditional

methods in organic solvents. However, the reaction times still need to be improved. Recently,

Ballini and Bosica used amphiphilic molecules to influences the reactivity of the conjugate

addition of nitroalkanes with α,β-unsaturated enones. In fact, cetyltrimethylammoniumchloride (CTACl) as a cationic surfactant promoted the Michael reaction of various

nitroalkanes with α,β-unsaturated enones using a sodium hydroxide solution (0.025 M).26

Later on it was reported that also the additions to α,β-unsaturated esters, sulfones and nitrileswere effectively performed using these conditions.27,28 Since the reactions were fast compared

to the Yb(OTf)3 catalyzed reactions in water and because the authors claimed that no

polymerisation or polycondensation took place under their reaction conditions,27 we

investigated the Michael addition of 4.6b and 4.6c with MVK under the conditions reportedby Ballini and Bosica26 (Scheme 4.6). Although these authors found no polycondensation

products in the Michael additions of nitroalkanes, in our hands the reaction of 4.6b and 4.6cafforded 4.8b and 4.8c in 63% and 56%, respectively, after column chromatography. In sharpcontrast with the results obtained by Ballini and Bosica with nitroalkanes, the yield in the

Michael addition of β-ketoesters with MVK is drastically reduced compared to that in theYb(OTf)3 catalyzed reactions in water by the formation of polycondensation products.

Although the starting β-ketoester was converted within 3 h and these dilute basic conditionsare thus superior with respect to reaction times, it is evident that with respect to isolated yield

the Yb(OTf)3 catalyzed reaction in water is to be preferred.

25 HP-1, cross linked methylsilicon gum, 15m x 0.35 mm, oven temperature: 170 °C, injection

tr 4.6c = 1.39, tr 4.8c = 5.13.26 Ballini, R., Bosica, G. Tetrahedron Lett. 1996, 37, 8027.27 Ballini, R., Bosica, G. Eur. J. Org. Chem. 1998, 355.28 Also nitroaldol reactions were successfully performed using these dilute basic conditions: Ballini, R.,

Bosica, G. J. Org. Chem. 1997, 62, 425.

Chapter 4

54

( )n

O O

OEt +O

0.025 M NaOH (aq)

CTAB, RT2-3 h ( )n

O O

OEt

O

+ polycondensation

4.6b n = 14.6c n = 0

4.8b n = 0 63 %4.8c n = 0 56 %

Scheme 4.6 Base catalyzed Michael additions in water.

4.5 Michael additions of dialkyl malonates in water

Another important class of synthetically useful β-dicarbonyl compounds are thedialkylmalonates (4.10).29 Although it was known from the literature that the Michael additionof dialkylmalonates is readily promoted by various Lewis acids,21 no reaction was observed

when, for example, diethyl malonate (4.10a) or substituted diethyl malonates (4.10b,c) werestirred in a 0.01 M aqueous Yb(OTf)3 solution with MVK or for example cyclohexenone

(4.7e). Even after longer reaction times no trace of the desired Michael adduct was found butonly starting material was recovered. These results are in sharp contrast with the results

obtained with the Yb(OTf)3 catalyzed Michael addition of β-ketoesters in water.

EtOR

O O

OEt+

O

4.10a R = H4.10b R = Me4.10c R = Et

O

orYb(OTf)3

H2O

no reaction

Scheme 4.7 Michael additions of dialkyl malonates in water.

4.6 Michael additions of αα-nitroesters

Nitroacetic acid derivatives 4.11 are valuable synthetic intermediates for the preparationof many nitro and amine containing compounds.30,31 The Michael additions of 4.11 to enones

open a very attractive route towards functionalized (α-alkylated) α-aminoacids 4.13 andsubstituted proline derivatives 4.14 via subsequent reductive cyclization of the 5-oxo-

nitroesters 4.12 (Scheme 4.8).32 Although alkylations and Michael additions of α-nitroesters

29 Stowell, J.C. in Carbanions in Organic Synthesis John Wiley & Sons, New York, 1979, 191.30 Shipchandler, M.T. Synthesis 1979, 666.31 Zen, S., Kaji, E. Bull. Chem. Soc. Jpn. 1970, 43, 2277; ibid 1973, 46, 337.32 Osugi, K. J. Pharm. Soc. Jpn. 1957, 77, 630.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

55

under basic conditions often suffer from polycondensations and O-alkylations,33 several

methods have been developed for the Michael addition of these compounds.34

R2

R1O2C

O2N+

O

R4R1O2C

O2N

R2

O

R4R3

R3

R1O2C

O2N

R2

R5

R4

R3NH

R2

R4

CO2R1R3or

4.114.12

4.13 4.14

Scheme 4.18 Michael additions of α-nitroesters.

Only one example of a Lewis acid catalyzed Michael addition of α-nitroesters hasappeared in the literature.35 Rather drastic conditions were, however, required in this reaction

catalyzed by copper(II) acetate in refluxing 1,4-dioxane and reaction times of six days were

needed. The results obtained in the Yb(OTf)3 Michael addition of β-ketoesters with β-unsubstituted enones prompted us to use of lanthanide triflates as reusable catalysts in Michael

additions of α-nitroesters in water as the solvent.

4.7 Yb(OTf)3 catalyzed Michael additions of αα-nitroesters in water

When the reaction of methyl nitroacetoacetate 4.11a with excess MVK was performedin water at room temperature in the presence of 10 mol% of Yb(OTf)3, under the standard

conditions that were used for the reaction of β-ketoesters, bis-Michael adduct 4.15 wasisolated in quantitative yield as the only product. With exactly one equivalent of MVK the

mono Michael adduct 4.12a was found exclusively (Table 3). α-Nitroesters bearing an alkylsubstituent at the α-position also gave the corresponding Michael adducts 4.12b-d inquantitative yield in the reaction with MVK in water as the solvent in the presence of 10 mol%

of Yb(OTf)3. In the absence of Yb(OTf)3 the reaction was much slower, resulting in a low

conversion to the desired Michael adduct even after prolonged reaction times. Although the

reactions with α-nitroesters bearing an alkyl substituent at the α-position gave desired productin quantitative yield when methyl 2-nitro-3-phenylpropionate was employed, only traces of the

desired Michael adduct were formed and mainly starting material was recovered, even when

the mixture was stirred for 14 d at room temperature.

33 Díez-Barra, E., de la Hoz, A., Moreno, A. Synth. Commun. 1994, 24, 1817; Gogte, V.N., Natu, A.A.,

Pore, V.S. Synth. Commun. 1987, 17, 1421.34 Niyazymbetov, M.E., Evans, D.H. J. Org. Chem. 1993, 58, 779; Lalonde, J.J., Bergbreiter, D.E.,

Wong, C.-H. J. Org. Chem. 1988, 53, 2323. Fiandanese, V., Naso, F., Scilimati, A. Tetrahedron Lett.1984, 25, 1187.

35 Coda, A.C., Desimoni, G., Invernizzi, A.G., Righetti, P.P., Seneci, P.F., Tacconi, P. Gazz. Chim. Ital.1985, 115, 457.

Chapter 4

56

Table 3 Michael addition of α-nitroesters 4.11a-d and MVK

R2

R1O2C

O2N+

O

R1O2C

O2N

R2

O4.11 4.12

10 mol% Yb(OTf)3

H2O, RT

Entry Michael donora Michael adduct Yield (%)

1

MeO2C

O2N4.11a

MeO2C

O2N

4.15

O

O

99

2 MeO2C

O2N4.11a

MeO2C

O2N

O

4.12a

98

3 EtO2C

O2N4.11b

EtO2C

O2N

O

4.12b

99

4 EtO2C

O2N4.11c

EtO2C

O2N

O

4.12c

98

5

MeO2C

O2N4.11d

MeO2C

O2N

O

4.12d

96

a Catalyst Yb(OTf)3, solvent H2O, Michael acceptor MVK, RT.

It should be emphasised that single products were obtained using this simple procedure

and in most cases no further purification was necessary. The Michael addition was not

accompanied by undesired O-alkylation, polycondensation or hydrolysis of the ester

functionality.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

57

4.7.1 Substrate variation, scope and limitations

Next, various common Michael acceptors were tested. Similar to the results obtained in

the Michael addition of β-ketoesters only starting materials were recovered in all cases when4.11b was stirred at room temperature with acrylonitrile, ethyl acrylate, or ethyl propionate inwater in the presence of 10 mol% of catalyst. However, when the reactions were performed

with α,β-unsaturated enones bearing various substituents at the α′-position again the desiredMichael adducts 4.12 were obtained in quantitative yield after 5 d (Scheme 4.9). Cyclic (4.7d,

4.7e) or β-substituted α,β-unsaturated enones (4.7f, 4.7g) were not reactive under theseconditions. With the Michael acceptors bearing an alternative electron withdrawing group only

acrolein gave the desired Michael adduct 4.16a in nearly quantitative yield. However, in thiscase also polymerization of the Michael acceptor was found. Still the Michael addition did not

suffer from polycondensation. This trend in reactivity of α-nitroesters in water was alsoobserved for β-ketoesters.

+O

REtO2C

O2NO

R4.11b

4.12e R=Et4.12f R=Ph4.16a R=H

Yb(OTf)3

H2O, RT

4.7b R=Et4.7c R=Ph

Scheme 4.9 Variation of the Michael acceptor.

In order to study the effect of substituents at the α-position of the Michael acceptor,methacrolein 4.17 was allowed to react with 4.11b. The adducts could be isolated in 72 %yield after flash chromatography. Although the reaction afforded Michael adducts 4.16b and4.16c as a one to one mixture of inseparable diastereoisomers, a reaction time of 170 h wasrequired to obtain nearly complete conversion of the starting materials due to the lowerreactivity of 4.17.

+O

HEtO2C

O2NO

H4.11b

Yb(OTf)3

H2O, RT

EtO2C

O2NO

H

4.17 4.16b 4.16c

Scheme 4.10 Michael addition of 4.11b to methacrolein.

The reaction of cyclic α-nitroesters could in principle also lead to the correspondingMichael adducts. The synthesis of the cyclic analogs of 4.11 was, however, without precedentin the literature. Unfortunately the attempted synthesis of these compounds starting from the

corresponding bromides, which is known to be successful for a range of acyclic analogs,41 did

not afford the desired compounds (Scheme 4.11). No trace of the starting materials was

Chapter 4

58

recovered and multiple attempts to synthesize these compounds failed under several reaction

conditions. A possible explanation is the hydrolysis of the cyclic ester functionality.

O O

NO2

O O

Br phloroglucinol

DMF or DMSONaNO2

Scheme 4.11 Attempted synthesis of cyclic α-nitroesters.

4.8 Reduction of αα-nitroester Michael adducts

As an example of the synthetic potential of α-nitroester Michael adducts, Desimoni35

described the reductive cyclization of 4.12a (Scheme 4.12). The reductive cyclization of 4.12aafforded 5-alkylated proline ester 4.20 as a ca 10:1 mixture of cis- and trans-isomers.

Because the Yb(OTf)3 catalyzed Michael addition of α-nitroesters provides an efficient routeto α-substituted Michael adducts 4.12 and the reduction of for example 4.12b would inprinciple afford 2,5-alkylated proline esters,36 the catalytic hydrogenation of 4.12b wasinvestigated. First 4.12b was stirred overnight, under hydrogen atmosphere using palladium oncoal in ethanol, in the presence of anhydrous sodium sulfate to trap the water that is released

upon the cyclization.37 To our surprise not the expected 2,5-disubstituted proline ester 4.18was isolated but the reaction gave 2,5-disubstituted nitrone 4.19b as an oil in 92 % yield(Scheme 4.13). These results are in sharp contrast with the results reported by Desimoni with

4.12a.

MeO2C

O2NO

H2 1 atm 5% Pd-C

EtOHNa2SO4

NO

OMe

4.12a 4.20

HN

O

OMe

H

+

Scheme 4.12 Reduction of 4.12a according to Desimoni.35

EtO2C

O2NO

1 atm H2 5% Pd-CEtOH

Na2SO4N+

O- O

OEt

4.12b 4.19b

NO

OEt

4.18

1 atm H2 5% Pd-CEtOH

Na2SO4H

Scheme 4.13 Hydrogenation of 4.12b at atmospheric pressure.

The methyl substituent at the α position of 4.12b apparently has a dramatic effect onthe outcome of the reaction. When the reaction was performed at higher pressure (2.5 atm for

72 h), again not the expected 2,5-disubstituted proline was isolated but the reaction afforded

36 van der Werf, A., Kellogg, R.M. Tetrahedron Lett. 1991, 32, 3727.37 Stevens, R.V., Lee, A.W.M. J. Chem. Soc., Chem. Commun. 1982, 102.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

59

N-hydroxy-2,5-dimethyl proline ester 4.21 as a 7:3 mixture of cis- and trans-isomers as theirHCl-salts (Scheme 4.14). The major isomer 4.21a could be isolated after crystallisation fromethanol:ether and was unambiguously assigned the cis-geometry by COSY and NOESY NMR

experiments. This stereochemistry was expected if hydrogenation occurs from the least

hindered side.

EtO2C

O2NO

1) H2 2.5 atm 5% Pd-C EtOH,Na2SO4

2) Et2O,HClNOH O

OEt

4.12b 4.21a

NOH O

OEt+

.HCl .HCl

4.21b

Scheme 4.14 Reduction of 4.12b at elevated hydrogen pressure.

For an explanation of the formation of 4.2138 we have to look at the reaction sequenceof the reductive cyclization (Scheme 4.15). Under the reductive conditions the Michael adduct

4.12 is first converted into the corresponding hydroxylamine 4.22, which then loses oneequivalent of water upon cyclization, to afford the corresponding nitrones 4.19. When thereaction is performed with 4.12a (R = H) at 1 atm hydrogen pressure, nitrone 4.19a is furtherreduced to give 4.23a. For 4.12b (R = Me), however, higher hydrogen pressure is required toachieve effective reduction of 4.19b, and the reaction can be stopped in the nitrone stepprobably due to steric reasons.

EtO2C

O2N

R

O

N+

O-

R

O

OEt

4.12a R=H4.12b R=Me

4.19a R=H4.19b R=Me

EtO2C

NH

R

O

HO

4.22a R=H4.22b R=Me

-H2O

NOH

R

O

OEt

4.23a R=H4.23b R=Me

R=H-H2O

NO

OEt

4.24

H2 H2N

O

OEt

H

4.20

R=Me

H2, Pd-CEtOH

Na2SO4

Scheme 4.15 Reductive cyclization of Michael adducts 4.12.

38 For a review on N-hydroxy-α-amino acids see: Zeegers, H.J.M. Hydroxamic Acids Derived from N-

Hydroxy-α-aminoacids: Synthesis and Applications, Ph.D. Thesis, University of Nijmegen, TheNetherlands, 1989, Chapters 1 and 2.

Chapter 4

60

Subsequently, 4.23a loses another equivalent of water, because of the presence of the

acidic α-proton, to provide imine 4.24, which again is reduced to afford 4.20. For 4.23b thereaction, however, stops since no acidic α-proton is present in this molecule and N-hydroxy-2,5-dimethyl proline ethyl ester 4.21 can be isolated as the HCl-salt. Since the final step of theformation of 4.20 is the reduction of imine 4.24, whereas 4.23b is formed after reduction ofnitrone 4.19b, the difference in selectivity of the final step cannot be explained simply by stericeffects of the presence or absence of a methyl substituent in either reaction sequence. It should

be noted that any selectivity in the reduction of 4.19a into 4.23a is lost in the dehydration stepand the observed selectivity comes from the final reduction of imine 4.24 to 4.20.

4.9 ConclusionsThe Yb(OTf)3 catalyzed Michael addition of β-ketoesters and α-nitroesters in water

with β-unsubstituted enones and enals furnishes the Michael addition products under very mildconditions. By performing these reactions in water, undesired side reactions such as

polymerisation, polycondensation and O-alkylation are not observed and single products are

isolated in nearly quantitative yield. Yb(OTf)3 can be reused for at least two times without loss

of activity. In this way the yields and selectivity of the reaction could considerably be

improved compared to traditional methods using organic solvents.

The reductive cyclization of 4.12b yields, depending on the conditions, 2,5-alkylated

nitrone 4.19b or N-hydroxy-proline ethylester 4.23b. The alkyl substituent at the α-positionprevents complete reduction into the 2,5-alkylated proline ethyl ester.

4.10 Experimental section

MaterialsEthyl acetoacetate, ethyl 2-methylacetoacetate, ethyl 2-oxocyclopentanoate, ethyl 2-

oxocyclohexanoate and 3-acetyl-butyrolactone were commercial products (Aldrich, Janssen,

Acros or Fluka) and were used without further purification. Methyl vinyl ketone (lachrymator,

highly toxic)20, ethyl vinyl ketone (lachrymator, highly toxic), acrolein (lachrymator, highly

toxic), methacrolein (lachrymator, highly toxic), mesityl oxide (lachrymator, highly toxic), 3-

penten-2-one (lachrymator, highly toxic), ethyl acrylate (lachrymator, highly toxic)

cyclopentenone, and cyclohexenone were commercial products (Aldrich, Janssen, Acros or

Fluka) and were distilled directly prior to use. Phenyl vinyl ketone,39 methyl 2-nitroacetate,40

ethyl 2-nitropropionate,41 ethyl 2-nitrobutyrate41 and methyl 2-nitropentenoate42 were

prepared according to literature procedures.

39 Mannich, C., Heilner G. Chem. Ber. 1922, 55, 359.40 Zen, S., Koyama, M., Koto, S. Organic Synthesis, Wiley, New York, 1976, 55, 77.41 Kornblum, N.; Blackwood, R.K. Organic Synthesis, Wiley, New York, 1963, Collect. Vol. 4, 454.42 Ferroud, P., Genet, J.P., Muzart, J. Tetrahedron Lett. 1984, 25, 4379.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

61

Methyl 2-nitropentenoate42

1H NMR (CDCl3, 200 MHz) δ = 2.88-3.08 (m, 2H), 3.82 (s, 3H), 5.11-5.27 (m, 3H), 5.63-5.84 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ = 30.05 (t), 53.41 (q), 87.05 (d), 120.32 (t),129.96 (d), 164.41 (s).

General procedure for Yb(OTf)3 catalyzed Michael additions in water

In a typical procedure 1.0 mmol of β-ketoester or α-nitroester was added to a vigorouslystirred 0.01 M aqueous solution of Yb(OTf)3 (10.0 mL). To this mixture were added 3.0 equiv

of freshly distilled Michael acceptor and the mixture was stirred at room temperature until

complete conversion (followed by GC or TLC). The volatile components (excess Michael

acceptor) were evaporated under reduced pressure and the remaining aqueous solution was

extracted with methylene chloride (3 x 10 mL). The combined organic fractions were filtered,

the solvent evaporated under reduced pressure and to the residual colorless oil was added

toluene (10 mL) and the toluene evaporated to give the pure Michael adducts in nearly

quantitative yield. When non-volatile Michael acceptors were used, the products could be

isolated in nearly quantitative yield after filtration over SiO2 (ethyl acetate : hexanes = 1 : 9).

All compounds were characterized by NMR spectroscopy, NMR data are given below.

Methyl 1-oxo-2-(3-oxo-butyl)-indan-2-carboxylate (4.8a)

According to the general procedure 4.8a was obtained as a colourless oil, starting from methyl1-oxo-indan-2-carboxylate and methyl vinyl ketone in quantitative yield. 1H-NMR (CDCl3,

200 MHz) δ = 2.13 (s, 3H), 2.2-2.3 (m, 2H), 2.4-2.8 (m, 2H), 3.04 (d, J = 17.5 Hz, 1H), 3.67(d, 17.5 Hz, 1H), 3.70 (s, 3H), 7.38-7.80 (m, 4H, Ar); 13C-NMR (CDCl3, 50 MHz) δ = 28.57(t), 29.92 (q), 37.86 (t), 38.78 (t) 52.74 (q), 59.08 (t), 124.86 (d), 126.39 (d), 127.96 (d),

135.02 (s), 135.53 (d) 152.49 (s), 171.56 (s), 202.21 (s), 207.42 (s).

Ethyl 2-oxo-1-(3-oxo-butyl)-cyclohexanoate (4.8b)43

According to the general procedure 4.8b was obtained as a colourless oil, starting from ethyl2-oxocyclohexanoate and methyl vinyl ketone in quantitative yield. 1H NMR (CDCl3, 200

MHz) δ = 1.29 (t, J = 7.3 Hz, 3H), 1.56-2.59 (m, 12H), 2.14 (s, 3H), 4.21 (q, J = 7.3 Hz,2H); 13C-NMR (CDCl3, 50 MHz) δ = 13.80 (q), 22.20 (t), 27.19 (t), 28.04 (t), 29.61 (q),36.34 (t), 38.47 (t), 40.71 (t), 59.66 (s), 61.14 (s), 171.89 (s), 207.84 (s), 207.99 (s).

43 Dreiding, T., Tomasewski, A.J. J. Am. Chem. Soc. 1955, 77, 411.

Chapter 4

62

Ethyl 2-oxo-1-(3-oxo-butyl)-cyclopentanoate (4.8c)46

According to the general procedure 4.8c was obtained as a colourless oil, starting from ethyl2-oxocyclopentanoate and methyl vinyl ketone in quantitative yield. 1H NMR (CDCl3, 200

MHz) δ = 1.25 (t, J = 7.1 Hz, 3H), 1.84-2.55 (m, 9H), 2.14 (s, 3H), 2.64-2.77 (m, 1H), 4.13(q, J = 7.1 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ = 14.06 (q), 19.56 (t), 26.96 (t), 29.89 (q),34.40 (t), 37.97 (t), 38.86 (t), 58.91 (s), 61,41 (t), 171.38 (s), 207.03 (s), 215.92 (s).

Ethyl 2-acetyl-5-oxohexanoate (4.8d)44

According to the general procedure 4.8d was obtained as a colourless oil, starting from ethyl

acetoacetate and methyl vinyl ketone in quantitative yield. 1H NMR (CDCl3, 200 MHz) δ =1.29 (t, J = 7.3 Hz, 3H), 2.10 (dd, J1 = J2 = 7.3 Hz, 2H), 2.15 (s, 3H), 2.25 (s, 3H), 2.51 (t, J

= 7.3 Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H), 4.21 (q, J = 7.3 Hz, 2H); 13C NMR (CDCl3, 50 MHz)

δ = 14.00 (q), 21.58 (t), 28.91 (q), 29.86 (q), 40.37 (t), 58.14 (d), 61.41 (t), 169.43 (s),202.78 (s), 207.38 (s).

Ethyl 2-acetyl-2-methyl-5-oxohexanoate (4.8e) 45

According to the general procedure 4.8e was obtained as a colourless oil, starting from ethyl2-methylacetoacetate and methyl vinyl ketone in quantitative yield. 1H NMR (CDCl3, 200

MHz) δ = 1.26 (t, J = 7.1 Hz, 3H), 1.33 (s, 3H), 1.80-2.61 (m, 4H), 2.11 (s, 3H), 2.13 (s,3H), 4.15 (q, J = 7.1 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ = 13.86 (q), 21.94 (q), 26.20 (t),26.80 (q), 29.73 (q), 40.35 (t), 55.46 (s), 61.67 (t), 172.39 (s), 204.33 (s), 208.5 (s).

3-Acetyl-3-(3-oxo-butyl)-dihydro-furan-2-one (4.8f)46

According to the general procedure 4.8f was obtained as a colourless oil, starting from 3-acetyl-butyrolactone and methyl vinyl ketone in quantitative yield. 1H NMR (CDCl3, 200

MHz) δ = 1.94-2.48 (m,5H), 2.16 (s, 3H), 2.33 (s, 3H), 2.83 (m, 1H), 4.11-4.37 (m, 2H); 13CNMR (CDCl3, 50 MHz) δ = 25.64 (q), 27.38 (t), 29.75 (t), 29.86 (q), 38.27 (t), 60.10 (s),66.00 (t), 175.37 (s), 202.56 (s), 206.40 (s).

44 Frejaville, C., Jullien, R. Tetrahedron Lett. 1974, 1021.45 Pleininger, H., Suehiro, T. Chem. Ber. 1956, 2789.46 Wijnberg, H. and Helder, R. Tetrahedron Lett. 1975, 4057.

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

63

Ethyl 2-oxo-1-(3-oxo-pentyl)-cyclopentanoate (4.8g)

According to the general procedure 4.8g was obtained as a colourless oil, starting from ethyl2-oxocyclopentanoate and ethyl vinyl ketone in quantitative yield. 1H-NMR (CDCl3, 200

MHz) δ = 1.00 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.3 Hz, 3H), 1.49-2.71 (m, 12H), 4.12 (q, J =7.3 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ = 7.48 (q), 13.78 (q),19.30 (t), 26.76 (t), 34.03(t), 35.63 (t), 37.25 (t), 37.72 (t), 58.84 (s), 61.20 (t), 171.32 (s), 210.70 (s), 215.01 (s).

Ethyl 2-oxo-1-(3-oxo-propyl)-cyclopentanoate (4.8h)47

According to the general procedure 4.8h was obtained as a colourless oil, starting from ethyl2-oxocyclopentanoate and freshly distilled acrolein in quantitative yield. 1H-NMR (CDCl3, 200

MHz) δ = 1.21 (t, J = 7.2 Hz, 3H), 1.45 -2.85 (m, 10 H), 4.14 (q, J = 7.2 Hz, 2H), 9.73 (s,1H) ); 13C NMR (CDCl3, 50 MHz) δ = 13.78 (q), 19.28 (t), 25.11 (t), 33.84 (t), 37.68 (t),39.22 (t), 59.64 (s), 61.17 (t), 171.06 (s), 201.17 (d), 214.69 (s).

Ethyl 2-oxo-1-(3-oxo-3-phenylpropyl)-cyclopentanoate (4.8i)48

According to the general procedure 4.8i was obtained as a colourless oil, starting from ethyl2-oxocyclopentanoate and phenyl vinyl ketone in 96 % yield after column chromatography

(SiO2: hexanes: ethyl acetate = 7:3). 1H-NMR (CDCl3, 200 MHz) δ = 1.26 (t, J = 7.4 Hz,

3H), 1.74-2.62 (m, 6H), 2.92-3.08 (m, 2H), 3.17-3.34 (m, 2H), 4.19 (q, J = 7.4 Hz, 2H),

7.41-7.56 (m, Ar, 3H), 7.95 (dd, J1 = 6.9 Hz, J2 = 1.7 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ

= 13.84 (q), 19.38 (t), 27.45 (t), 33.80 (t), 34,17 (t), 37.79 (t), 58.98 (s), 61.28 (t), 127.97

(d), 128.45 (d), 132.99 (d), 136.54 (s), 171.40 (s), 199.45 (s), 214,95 (s).

Methyl 2-nitro-5-oxohexanoate (4.12a)35

According to the general procedure 4.12a was obtained as a nearly colourless oil, startingfrom methyl 2-nitroacetate and 1 equiv of methyl vinyl ketone in 98 % yield. 1H-NMR

(CDCl3, 200 MHz) δ = 2.15 (s, 3H), 2.41-2.64 (m, 4H), 3.82 (s, 3H), 5.25 (t, 7.1 Hz, 1H);13C NMR (CDCl3, 50 MHz) δ = 23.76 (t), 29.67 (q), 38.00 (t), 53.41 (q), 86.34 (d), 164.67(s), 206.01 (s).

47 Shono, T., Kise, N., Fujimoto, T., Yamanami, A., Nomura, R. J. Org. Chem. 1994, 59, 1730.48 Austin, E.M., Brown, H.L., Buchanan, G.L. Tetrahedron 1969, 25, 5509.

Chapter 4

64

Ethyl 2-methyl-2-nitro-5-oxohexanoate (4.12b)46

According to the general procedure 4.12b was obtained as a nearly colourless oil, startingfrom ethyl 2-nitropropionate and methyl vinyl ketone in 99 % yield. 1H-NMR (CDCl3, 300

MHz) δ = 1.19 (t, J = 7.3 Hz, 3H), 1.67 (s, 3H), 2.06 (s, 3H), 2.31-2.48 (m, 4H), 4.16 (q, J =7.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ = 13.52 (q), 21.76 (q), 29.69 (q), 29.94 (t), 37.63(t), 62.74 (t), 91.64 (s), 166.97 (s), 205.73 (s).

Ethyl 2-ethyl-2-nitro-5-oxohexanoate (4.12c)

According to the general procedure 4.12c was obtained as a nearly colourless oil, startingfrom ethyl 2-nitrobutyrate and methyl vinyl ketone in 98 % yield. 1H-NMR (CDCl3, 200 MHz)

δ = 0.91 (t, J = 7,4 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 2.15 (s, 3H), 2.17-2.29 (m, 2H), 2.40-2.51 (m, 4H), 4.26 (q, J = 7.2 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ = 7.77 (q), 13.60 (t),26.97 (t), 28.00 (t), 29.72 (q), 37.50 (t), 62.55 (t), 95.55 (s), 166.50 (s), 205.84 (s). MS(CI)

249 [M++NH4+].

Methyl 2-nitro-2-(3-oxo-butyl)-pent-4-enoate (4.12d)

According to the general procedure 4.12d was obtained as a nearly colourless oil, startingfrom methyl 2-nitropentenoate and methyl vinyl ketone in 96 % yield. 1H-NMR (CDCl3, 200

MHz) δ = 1.56 (s, 3H), 2.39-2.55 (m, 4H), 2.91 (m, 2H), 3.78 (s, 3H), 5.15-5.21 (m, 2H),5.53-5.64 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ = 27.42 (t), 29.67 (q), 37.41 (t), 39.39 (t),53.29 (q), 94.49 (s), 121.57 (t), 128.98 (d), 166.06 (s), 205.65 (s); MS(CI) 247 [M++NH4

+].

Ethyl 2-methyl-2-nitro-5-oxoheptanoate (4.12e)

According to the general procedure 4.12e was obtained as a nearly colourless oil, startingfrom ethyl 2-nitropropionate and ethyl vinyl ketone in 96 % yield. 1H-NMR (CDCl3, 200

MHz) δ = 1.05 (t, J = 7.3 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.76 (s, 3H), 2.37-2.54 (m, 4H),4.25 (q, J = 7.3 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ = 7.47 (q), 13.54 (q), 21.71 (q), 30.02(t), 35.75 (t), 36.27 (t), 62.72 (t), 91.73 (s), 167.02 (s), 208.62 (s); MS(CI) 249 [M++NH4

+].

Methyl 2-nitro-5-oxo-2-(3-oxo-butyl)-hexanoate (4.15)36

According to the general procedure 4.15 was obtained as a nearly colourless oil, starting frommethyl 2-nitroacetate and 3 equiv of methyl vinyl ketone in 98 % yield. 1H-NMR (CDCl3, 200

MHz) δ = 2.14 (s, 6H), 2.41-2.52 (m, 8H), 3.79 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ =28.20 (t), 29.69 (q), 37.41 (t), 53.36 (q), 94.21 (s), 166.704 (s), 205.57 (s).

Ytterbium Trifluoromethanesulphonate Catalyzed Michael Addition Reactions in Water.

65

Ethyl 2-methyl-2-nitro-5-oxopentanoate (4.16a)49

According to the general procedure 4.16a was obtained as a nearly colourless oil, startingfrom ethyl 2-nitropropionate and freshly distilled acrolein in quantitative yield. 1H-NMR

(CDCl3, 200 MHz) δ = 1.28 (t, J = 7.3 Hz, 3H), 1.78 (s, 3H), 2.47-2.64 (m, 4H), 4.26 (q, J =7.3 Hz, 2H), 9.76 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ = 13.27 (q), 21.39 (q), 28.15 (t),37.99 (t), 62.61 (t), 91.7 (s), 166.56 (s), 198.77 (d).

Ethyl 2,4-dimethyl-2-nitro-5-oxopentanoate (4.16b, 4.16c)

According to the general procedure 4.16b and 4.16c were obtained as an inseparable mixtureof diastereoisomers as a nearly colourless oil in 72 % yield after column chromatography

(SiO2, hexanes:ethyl acetate = 4:1, Rf = 0.37) starting from ethyl-2-nitropropionate and

methacrolein. 1H-NMR (CDCl3, 300 MHz) δ = 1.09 ( 2d, J1 = 7.3 Hz, J2 = 7.7 Hz, 3H), 1.19(t, J = 7.3 Hz, 3H), 1.65 and 1.70 (2s, 3H), 1.95-2.08 (m, 1H), 2.38-2.53 (m, 1H), 2.72-2.79

(m, 1H), 4.10-4.23 (m, 2H), 9.46 and 9.48 (2d, J1 = J2 = 1.1 Hz, 1H); 13C NMR (CDCl3, 75

MHz) δ = 13.44 (q) 15.03 (q), 15.11 (q), 21.43 (q), 22.54 (q), 35.71 (t), 35.95 (t), 41.86 (d),41.98 (d), 62.83 (t), 91.67 (s), 166.79 (s), 201.75 (s). MS(CI): 235 [M++NH4

+], 190 [M+-

NO2+NH4+];

Dilute base catalyzed Michael addition in water in the presence of CTAB; generalprocedure26

To a mixture of β-ketoester 4.6c or 4.6d (5.0 mmol) and MVK (15.0 mmol) in 0.025 MNaOH (15 mL) was added cetyltrimethylammonium bromide (CTAB, 0.5 mmol). The solution

was stirred at RT for 3 h, then saturated with NaCl and extracted with ether (3 x 15 mL). The

solvent was evaporated, toluene was added and the solvent was evaporated again. The

residual oil was purified by column chromatography (SiO2, hexanes : ethyl acetate = 9:1) to

give the desired products 4.8b and 4.8c in 56 % and 63 % yield, respectively, as colourlessoils. NMR data were in accordance with the products obtained in the Yb(OTf)3 catalyzed

reactions.

Ethyl 2,5-dimethyl-∆∆5-pyrroline-1-oxide-2-carboxylate (4.19b)

A mixture of ethyl 2-nitro-2-methyl-5-oxo-hexanoate (4.12b, 0.384 g, 1.77 mmol), Na2SO4(0.150 g) and palladium on carbon (10%, 0.075 g) in 5.0 mL anhydrous ethanol was

vigorously stirred under H2 atmosphere for 40 h. After filtration over celite the solvent was

evaporated in vacuo and the residual oil was purified by flash chromatography (SiO2:

49 Bonnet, R., Brown, R.F.C., Clark, V.M., Sutherland, I.O., Todd, A. J. Chem. Soc. 1959, 2094.

Chapter 4

66

CHCl3:MeOH = 97:3, Rf = 0.88) to give 0.26 g (1.62 mmol) of 4.19b as a colourless oil. 1H-

NMR (CDCl3, 300 MHz) δ = 1.41 (t, J = 7.2 Hz, 3H), 1.83 (s, 3H), 2.08-2.18 (m, 1H), 2.23(s, 3H), 2.51-2.63 (m, 1H), 2.73-2.98 (m, 2H), 4.36 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ =12.88 (q), 13.77 (q), 20.76 (q), 30.15 (t), 30,26 (t), 61.90 (t), 78.51 (s), 145.54 (s), 170.23

(s); HRMS calcd for C7H15NO3 = 185.105; found 185.105.

Ethyl N-hydroxy-2,5-dimethyl-pyrrolidin-2-carboxylate (4.21)

A mixture of ethyl-2-nitro-2-methyl-5-oxo-hexanoate (4.12b, 1.0 g, 4.99 mmol), Na2SO4 (0.5g) and palladium on carbon (10 %, 0.25 g) in 25.0 mL anhydrous ethanol was shaken in a Parr

apparatus for 72 h at 2.5 atm (35-40 psi) H2 pressure. After filtration over celite, the solvent

was removed in vacuo and the residual colourless oil was dissolved in 100 mL dry diethyl

ether. Hydrogen chloride gas was bubbled through the solution for 30 min during which the

HCl-salt of the hydroxy pyrrolidine (7:3 mixture of cis and trans isomers, 1H-NMR)

crystallized as a white powder (0.754 g, 3.4 mmol, 69 %). To the mixture of HCl-salts in a

small amount of ethanol, ether was added upon which the (major) cis isomer (determined by

COSY and NOESY) crystallized as the single compound. Cis isomer: 1H-NMR (DMSO-d6,

300 MHz, 100 °C) δ 1.20 (t, J = 7.2 Hz, 3H), 1.39 (d, J =6.4 Hz, 3 H), 1.45 (s, 3H), 1.48-1.62 (m, 1H), 1.82-1.92 (m, 1H), 2.02-2.13 (m, 1H), 2.29-2.38 (m, 1H), 3.63-3.72 (m, 1H),

4.14 (dq, J = 0.2 Hz, J = 7.2 Hz, 2 H); 13C-NMR (DMSO-d6, 75 MHz, 100 °C) δ 13.23 (q),14.83 (q), 18.13 (q), 25.60 (t), 30.91 (t), singlet missing: under DMSO resonance, 61.00 (t),

62.58 (d), 132.2 (s). Trans isomer 1H-NMR (DMSO-d6, 300 MHz, 100 °C) δ 1.20 (t, , J = 7.2Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1.61 (s, 3H), 1.54-1.63 (m, 1H), 1.85- 2.39 (m, 3H), 3.82

(m, 1H), 4.24 (q, J = 7.2 Hz, 2H); 13C-NMR (DMSO-d6, 75 MHz, 100 °C) δ 16.65 (q), 19.78(q), 21.20 (q), 29.65 (t), 35.60 (t), singlet missing: under DMSO resonance, 54.38 (d), 71.73

(t), 170.34 (s); MS(CI): 187 [M+- HCl]; MS (ES) 188 [M+ + 1 - HCl].