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Asymmetric transfer hydrogenation of ketones

Petra, D.G.I.

Publication date1999

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Citation for published version (APA):Petra, D. G. I. (1999). Asymmetric transfer hydrogenation of ketones.

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Download date:22 May 2021

Chapter 5

Asymmetric transfer hydrogénation of

functionalised ketones

Danielle G.I. Petra,3 Paul C.J. Kamer,3 Joost N.H. Reek,3 Hans E. Schoemaker,a<b and

Piet W.N.M, van Leeuwen 3

institute of Molecular Chemistry, University of Amsterdam, Amsterdam, The Netherlands bDSM Research, Geleen, The Netherlands

Chapter 5

Abstract

The scope of asymmetric transfer hydrogénation reactions was investigated by the

ruthenium(II)-amino alcohol and iridium(I)-aminosulfide catalysed reduction of

functionalised ketones. Dialkyl ketones 4a-d, a,ß-unsaturated ketones 8 and 10, ethyl

2-oxo-4-phenylbutyrate (12) and 4-phenyl-3-butyn-2-one (15), were reduced using

formic acid or 2-propanol as hydrogen donors.

The transfer hydrogénation reactions proved to be fully chemoselective to the

reduction of the C=0 bond. Moderate enantioselectivities were obtained in the

enantioselective transfer hydrogénation of a,ß-unsaturated ketones, dialkyl ketones,

a-keto esters, whereas enantioselectivitities of up to 98% were obtained in the

reduction of acetylenic ketones.

132

Asymmetrie TH offunctionalised ketones

5.1 Introduction

Asymmetric catalytic transfer hydrogénation using an organic hydrogen source has

proven to be a valuable method for the synthesis of chiral alcohols. The combination

of practical simplicity, mild reaction conditions, relatively non-hazardous reagents

and high enantioselectivities from which this method benefits is unparalleled by

most other processes in synthetic organic chemistry. Many efficient catalytic systems

have been reported containing rhodium, iridium and most commonly ruthenium as

a catalyst precursor using nitrogen donor ligands.1 So far, the catalyst development

has mainly been focussed on the reduction of aryl-alkyl ketones. Substrates of

industrial interest often contain functional groups that, in general, can have a

dramatic effect on both the activity and selectivity of the catalyst. Therefore, it is

worthwhile to study the scope and application of this chiral multiplication method

and develop new catalysts for the transfer hydrogénation of functionalised ketones.

In view of the structural diversity of ketones it is unlikely that a single catalyst will

serve all purposes and therefore different catalytic systems were tested in the

reduction of various functionalised ketones.

Recently, we developed two catalytic systems that proved to be very suitable for the

transfer hydrogénation of aryl-alkyl ketones. A series of new amino alcohol ligands

was synthesised and optimised for the ruthenium(II) catalysed asymmetric transfer

hydrogénation resulting in the most effective chiral amino alcohol ligand (1) so far

for the reduction of acetophenone.2 Enantioselectivities of up to 96% were obtained

in the transfer hydrogénation of aryl-alkyl ketones with 2-propanol as a hydrogen

donor. In a different study a new class of N,S-chelates (e.g. 2 and 3) was developed

for the iridium(I) catalysed reduction of unsymmetrical ketones.3

OH NH

3:R = Ph

133

Chapter 5

Using these iridium(I) catalysts both formic acid and 2-propanol were suitable as

hydrogen donors. Aryl-alkyl ketones were readily reduced resulting in the

corresponding chiral alcohols with enantioselectivities of up to 97%.

Here we present ruthenium(II)-amino alcohol and iridium(I)-aminosulfide catalysed

asymmetric transfer hydrogénation of dialkyl ketones, chloro-substituted ketones,

oc,ß-unsaturated ketones, a-keto esters and acetylenic ketones using formic acid and

2-propanol as hydrogen donors.

The developed catalytic systems produce a variety of functionalised alcohols with

moderate to excellent enantioselectivities, without reducing the CC double and triple

bonds.

5.2 Results and discussion

The performance of the ruthenium(II) catalyst with amino alcohol ligand 1 and two

different iridium(I) catalysts with amino sulfides 2 and 3 were tested in the

asymmetric transfer hydrogénation of various functionalised ketones.

On using 2-propanol as a hydrogen donor the typical catalysis experiments were

carried out using a solution of ketone (0.1 M in dry 2-propanol), the catalyst

precursor (i.e. [RuCl2(p-cymene)]2 or [IrCl(COD)]2, 0.5 mol%), the chiral ligand (1

mol%) and fBuOK (2.5 mol%) which were stirred at room temperature under argon.

On using formic acid as a hydrogen donor the standard conditions comprised of the

use of 0.5 mol% [IrCl(COD)]2 as the catalyst precursor and 2.5 mol% ligand in a 5/2

azeotropic mixture of formic acid / triethyl amine at 60 °C. Conversions and

enantioselectivities were monitored during the reaction by GC, HPLC and/or *H

NMR.

134

Asymmetrie TH offunctionalised ketones

Transfer hydrogénation of dialkyl ketones

Asymmetrie reduction of simple dialkyl ketones generally proceeds with low

enantioselectivity with only a few exceptions. The reduction of cyclohexyl methyl

ketone using a combination of Ru(II) and a phosphinooxazoline4 or an

oxazolinylferrocenylphosphine5 gave rise to enantioselectivities of 66%. On using an

in situ Rh-PennPhos catalyst enantioselectivities of up to 92% were recently obtained

in the reduction of tbutyl methyl ketone.6

The results of the ruthenium(II) and iridium(I) catalysed asymmetric reduction of

dialkyl ketones 4a-d (Scheme 5.1) are shown in Table 5.1. Both the ruthenium and

iridium catalysed transfer hydrogénation of dialkyl ketones 4a-4d only gave rise to

low enantioselectivities.

0

A Ri CH3

OH

R-i CH3

0

A Ri CH3

OH

R-i CH3

4a R-i = n-butyl 5a R-i = n-butyl

4b R, = /-butyl 5b R-i = /-butyl

4c R! = /-propyl 5c R-i = /-propyl

4d R-i = c-hexyl

Scheme 5.1

5d R, = c-hexyl

135

Chapter 5

Table 5.1 Hydrogen Transfer Reduction of Dialkyl Ketones 4a-d

Entry Metal Ligand H-donor Ketone Conv. [%]c (3h) Ee [%]d

1 [Ru(p-Cy)Cl2]2 1 ;PrOHa 4a 65 25

2 [IrCl(COD)]2 2 zPrOHa 4a 41 14

3 [IrCl(COD)]2 3 HCOOHb 4a 53 13

4 [Ru(p-Cy)Cl2]2 1 zPrOHa 4b 25 33

5 [IrCl(COD)]2 2 zPrOHa 4b 12 9

6 [IrCl(COD)]2 3 HCOOHb 4b 41 19

7 [Ru(p-Cy)Cl2]2 1 zPrOHa 4c 30 23

8 [IrCl(COD)]2 2 zPrOHa 4c 16 6

9 [IrCl(COD)]2 3 HCOOHb 4c 38 21

10 [Ru(p-Cy)Cl2]2 1 zPrOHa 4d 58 23e

11 [IrCl(COD)]2 2 zPrOHa 4d 58 33e

12 [IrCl(COD)]2 3 HCOOHb 4d 68 7e

aThe reaction was carried out at room temperature using a 0.1 M solution (5 mmol) in propan-2-ol. Substrate : [M]

: ligand : BuOK = 400 : 1 : 5 : 12.5. bThe reaction was carried out at 60 °C using 4 mmol substrate in a 3 ml

formic acid / triethylammonium formate (5/2) solution. Substrate : [lrCI(COD)]2 : Ligand = 400 : 1 : 5. Conversions

were determined by GLC analysis, determined by capillary GLC analysis using a Chiraldex-GTA column.

determined as the trifluoroacetic anhydride derivative.

Transfer hydrogénation of functionalised ketones

Substituted substrates such as 2-chloroacetophenone (6) and 2-chloropropiophenone

(7) are valuable substrates for asymmetric reduction, since their products may be

converted to chiral epoxides and other valuable synthetic intermediates. On using a

polymer supported version of Noyori's TsDPEN with the formic acid /

triethylamine system, this process has been used to prepare (R)-2-chloro-l-

phenylethanol in 95% ee (TsDPEN = N-(p-tolylsulfonyl)-l,2-diphenyl-

ethylenediamine).7 However, the polymer supported catalyst generally requires

reaction times of 15 hours or more in order to obtain the product alcohols in high

yields.

136

Asymmetrie TH offiinctionalised ketones

Unfortunately, neither ruthenium(II) nor iridium(I) catalysed transfer hydrogénation

of substrates 6 and 7 resulted in formation of the product alcohol. This might be due

to catalyst deactivation as a result of oxidative addition of the alkyl chlorides.

O Q

" "a

7

Transfer hydrogénation of a,ß-unsaturated ketones

The enantioselective reduction of simple a,ß-unsaturated ketones has remained

difficult because of the conformational flexibility of the substrates as well as the

sensitivity to basic conditions. Recently, Noyori and coworkers reported the

asymmetric hydrogénation of a,ß-unsaturated ketones using a RuCl2(xylbinap)(l,2-

diamine) catalyst.8 Enantioselectivities of over 90% were obtained. In order to obtain

high yields the reaction times were around 15 hours or more at 8-10 atmosphere

hydrogen pressure.

Here we present the ruthenium(II) and iridium(I) catalysed transfer hydrogénation

of the ot, ß-unsaturated ketones 8 and 10, which are relatively insensitive to basic

conditions (Scheme 5.2). Table 5.2 shows that 8 and 10 are successfully reduced into

the corresponding chiral alcohols, without reduction of the C=C bond. The

reduction of 8 resulted in enantioselectivities of up to 35%, whereas the reduction of

the more rigid substrate 10 resulted in enantioselectivities of up to 71%.

137

Chapter 5

XK OH

C H ,

10 11

Scheme 5.2

Table 5.2 Hydrogen Transfer Reduction of a,ß-Unsaturated Ketones 8 and 10

Entry Metal Ligand H-donor Ketone Conv. [%]c Ee [%]d

1 [Ru(p- 1 zPrOH* 8 79(5) 35 (R)

2 [IrCl(COD)]2 2 fPrOHa 8 40(5) 25 (R)

3 [IrCl(COD)]2 3 HCOOHb 8 54(5) 14 (S)

4 [Ru(p- 1 z'PrOH3 10 44 (16) 42 (R)

5 [IrCl(COD)]2 2 iPrOHa 10 78 (16) 71 (R)

6 [IrCl(COD)]2 3 HCOOHb 10 98 (16) 33 (S) aThe reaction was carried out at room temperature using a 0.1 M solution (5 mmol) in propan-2-ol. Substrate : [M]

: ligand : fBuOK = 400 : 1 : 5 : 12.5. bThe reaction was carried out at 60 °C using 4 mmol substrate in a 3 ml

formic acid / triethylammonium formate (5/2) solution. Substrate : [lrCI(COD)]2 : Ligand = 400 : 1 : 5. Conversions

were determined by GLC analysis, determined by capillary GLC analysis using a chiral cycloSil-B column.

138

Asymmetrie TH offunctionalised ketones

Transfer hydrogénation of a-keto esters

Enantiomerically pure a-hydroxy acid derivatives are important building blocks for

the synthesis of a wide variety of natural products and biologically active molecules.

One of the most direct routes to enantiomerically enriched a-hydroxy acid

derivatives is through asymmetric hydrogénation of corresponding a-keto acid

compounds. Several enantioselective catalysts have been developed for this purpose

giving rise to enantioselectivities of up to 93%.9-11

To the best of our knowledge the transfer hydrogénation of a-keto-esters has never

been investigated. The product of a-keto-ester 12 (i.e. 13) is a potential building block

for an ACE inhibitor.12-13 The iridium(I) catalysed transfer hydrogénation of a-keto-

ester 12 using amino sulfide 3 as ligand and formic acid as hydrogen donor gave rise

to a very fast reaction (Scheme 5.3). After one hour more than 99% conversion into

13 was obtained, unfortunately, with a low enantioselectivity of 24%.14 In the

iridium or ruthenium catalysed transfer hydrogénation using 2-propanol as a

hydrogen donor, surprisingly, no chiral alcohol was formed (Scheme 5.3). Instead,

dimerisation of the substrate occurred under these basic reaction conditions and

ethoxide was eliminated to form 14. This condensation reaction was apparently

faster than the formation of 13 and also took place without catalyst.

^

O

O

O ^ / lr(l), ligand 3 *-

HCOOH 12

OH

° ^ O

13

O

12

° ^ ^ KOH

2-propanol

Et02C o.

Scheme 5.3

139

Chapter 5

Transfer hydrogénation of acetylenic ketones

Chiral propargylic alcohols are useful building blocks for the synthesis of various

biologically active and structurally interesting compounds.15 The most

straightforward approach to synthesise these compounds would be asymmetric

hydrogénation, however, none of the currently available catalyst systems can

convert oc,ß-acetylenic ketones to propargylic alcohols both in a chemoselective and

enantioselective manner. Other methods that have been used to prepare this class of

compounds include reduction of acetylenic ketones by metal hydrides, reductive

cleavage of chiral acetylenic acetals, enantioselective alkynylation of aldehydes,

enzymatic transformations and hydroboration of a,ß-ynones.15

Recently, Noyori and coworkers described the first asymmetric transfer

hydrogénation of acetylenic ketones using chiral Ru(II) catalysts and 2-propanol as

the hydrogen donor. This method allowed the highly selective reduction of

structurally diverse acetylenic ketones to propargylic alcohols with enantiomeric

excesses of over 95% leaving the CC triple bond intact.15

Table 5.3 shows the performance of the ruthenium(II) and iridium(I) catalysed

transfer hydrogénation of 4-phenyl-3-butyn-2-one (15) using ligands 1-2 (Scheme

5.4).

Scheme 5.4

The ruthenium(II) amino alcohol catalyst gave rise to a very high enantioselectivity

of 98%, whereas the use of the iridium(I) catalysed reaction resulted in 90% ee. The

reductions proved to be fully chemoselective towards the reduction of the C=0

bond. When formic acid was used as a hydrogen donor in the iridium(I)-amino

sulfide catalysed reaction many byproducts were formed.

140

Asymmetrie TH c if'functionalised ketones

Table 5.3 Hydrogen Transfer Reduction of 4-phenyl-3-butyn-2-onea

Entry Metal Ligand H-donor Conv. [%]b Ee[%]c Confign

1 [Ru(p-Cy)Cl2]2 1 i'PrOH 74(16)

2 [IrCl(COD)]2 2 iPrOH 63(16)

98 (S)

90 (S) aThe reaction was carried out at room temperature using a 0.1 M solution (5 mmol) in propan-2-ol. Substrate : [M]

: ligand : /BuOK = 400 : 1 : 5 : 12.5. Conversions were determined by 300 MHz 1H NMR analysis, determined

using chiral HPLC with a Chiracel OD column.

5.3 Concluding remarks

The ruthenium(II)-arnino alcohol and iridium(I)-amino sulfide catalysts gave rise to

moderate enantioselectivities in the reduction of dialkyl ketones, a-keto esters, and

oc,ß-unsaturated ketones, whereas enantioselectivitities of up to 98% were obtained

in the reduction of acetylenic ketones. The transfer hydrogénation reactions proved

to be fully chemoselective to the reduction of the C=0 bond, since no reduction of

CC double and triple bonds was observed.

The developed catalytic systems exhibit a wide scope since they are capable of

producing a variety of functionalised alcohols. As yet, enantioselectivities need to be

improved to realise the demands of fine chemical industries.

5.4 Acknowledgements

The Innovation Oriented Research Programme (IOP-Katalyse) is gratefully

acknowledged for their financial support of this research. We thank Wim de Lange

for measuring the HPLC data. M. Boesten and J. Mommers (DSM Research) are

acknowledged for measuring the GC data in Table 5.1.

141

Chapter 5

5.5 Experimental Section

Ruthenium(II) catalysed enantioselective reduction of ketones

A solution of (arene)ruthenium(II) chloride dimer (0.0125 mmol) and amino alcohol ligand 1

(0.030 mmol) in dry propan-2-ol (5 ml) was heated at 80 °C for 1 h under argon. After cooling

the mixture to room temperature, it was diluted with propan-2-ol (44.25 ml) and the ketone

(5 mmol) and rBuOK (0.75 ml, 0.1M in propan-2-ol, 0.075 mmol) were added. The reaction

was run at room temperature under argon for the time indicated and monitored by GC,

NMR and/or HPLC.

Iridium(l) catalysed enantioselective reduction of ketones using 2-propanol as a

hydrogen donor

A solution of [IrCl(COD)]2 (0.01 mmol, 6.7 mg) and the amino sulfide ligand (2 or 3) (0.05

mmol) in dry propan-2-ol (5 ml) was heated at 80 °C for 30 min under argon. After cooling

the mixture to room temperature, it was diluted with propan-2-ol (33.75 ml) and the ketone

(4 mmol) and rBuOK (1.25 ml, 0.1M in propan-2-ol, 0.125 mmol) were added. The reaction

was run at room temperature under argon for the time indicated and monitored by GC,

NMR and/or HPLC.

Iridium(l) catalysed enantioselective reduction of ketones using formic acid as a

hydrogen donor

A solution of [IrCl(COD)]2 (0.01 mmol, 6.7 mg) and the amino sulf(ox)ide as a ligand (0.05

mmol) in ketone (4 mmol) was heated at 65 °C for 30 min under argon. The argon inlet was

removed and the azeotropic mixture of formic acid / triethyl amine (5/2) (3 ml) was added

in air. The reaction was run at 60 °C in an open vessel for the time indicated and monitored

by GC, NMR and/or HPLC.

3-benzyl-4-hydroxy-5-oxo-2-phenylethyl-2,5-dihydro-furan-2-carboxylic acid ethyl ester

(14)

Ethyl 2-oxo-4-phenylbutyrate (5 mmol, 0.95 ml) was added to a solution of KOH (5 mmol,

280.6 mg) in 2-propanol (10 ml). After stirring the reaction mixture for 3 h at room

142

Asymmetrie TH of fiinctionalised ketones

temperature, the salts were filtered and the solvent was removed in vacuo. The compound

was purified by crystallisation from diethyl ether / hexane. Yield: 1.6 g (90%), white solid. IR

(neat): v (cm"1) = 3333, 3063, 3028, 2980, 2935, 1749. *H NMR (CDCI3): 5 = 1.15 (3H, d, ƒ = 7.1

Hz, CH3), 2.05-2.50 (4H, m, 2 CH2), 3.67 (2H, s, CH2), 3.95 (2H, q, ƒ = 7.1 Hz, CH2 in ester),

6.96-7.29 (10H, m, 2 C6H5). 13C NMR (CDCI3): 5 = 14.03 (CH3), 29.30, 30.19, 36.08, 62.71 (4

CH2), 87.44 (Cq), 126.37, 127.15, 128.61, 128.88, 129.21 (5 CHa rom), 131.87, 136.57, 139.86,

140.45 (5 Cq), 169.92,168.17 (2 Cq, carbonyl). GC-MS (E.I.): m/z calcd for C21H22O3 [M-C02]+:

322. Found: 322. HRMS (FAB+): m/z calcd for C22H23O5 [M+H]+: 367.1545. Found: 367.1553.

Anal. Calcd for C22H22O5: C, 72.12; H, 6.05. Found: C, 71.91; H, 6.15.

HPLC and GLC analysis of transfer hydrogénation products

4-phenyl-3-buten-2-ol (9)

Conversions were determined by GLC (BPX 35 (SGE) column, 120 °C, He (60 kPa), alcohol

6.72 min, ketone 7.09 min). Ee's were determined by GLC (CycloSil-B column, 140 °C, He (80

kPa), (S)-isomer 26.0 min, (R)-isomer 26.3 min).

1 -(2-methyl-cyclopent-1 -enyl)-ethanol (11)

Conversions were determined by GLC (BPX 35 (SGE) column, 100 °C, He (60 kPa), alcohol

3.97 min, ketone 4.72 min). Ee's were determined by GLC (CycloSil-B column, 120 °C, He (80

kPa), (S)-isomer 22.0 min, (R)-isomer 22.9 min).

ethyl 2-ol-4-phenylbutyrate (13)

99% conversion by !H NMR. 24% ee by GLC (CycloSil-B column, 160 °C, He (80 kPa), (R)-

isomer 36.7 min, (S)-isomer 37.5 min).

4-phenyl-3-butyn-2-ol (16)

Conversions were determined by *H NMR. Ee's were determined by HPLC (Chiracel OD

column, 2-propanol : hexane = 5 : 95 (0.5 ml/min), (R)-isomer 12.7 min, (S)-isomer 21.9 min).

143

Chapter 5

5.6 References and Notes

1. M.J. Palmer, M. Wills, Tetrahedron: Asymmetry 1999,10, 2045-2061.

2. D.G.I. Petra, P.C.J. Kamer, P.W.N.M. van Leeuwen, K. Goubitz, A.M. van Loon, J.G. de

Vries, H.E. Schoemaker, Eur. J. Inorg. Chem., in press.

3. D.G.I. Petra, P.C.J. Kamer, P.W.N.M. van Leeuwen, H.E. Schoemaker, submitted.

4. T. Langer, G. Helmchen, Tetrahedron Lett. 1996, 37,1381.

5. Y. Nishibayashi, I. Takei, S. Uemura, M. Hidai, Organometallics 1999,18, 2293.

6. Y. Jiang, Q. Jiang, G. Zhu, X. Zhang, Tetrahedron Lett. 1997, 38, 215.

7. D.J. Bayston, C.B. Travers, M.E.C. Polywka, Tetrahedron: Asymmetry 1998, 9, 2015.

8. T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama, T.

Yokozawa, T. Ikariya, R. Noyori, ƒ. Am. Chem. Soc. 1998,120,13529-13530.

9. K. Mashima, K. Kusano, N. Sato, Y. Matsumura, K. Nozaki, H. Kumobayashi, N. Sayo, Y.

Hori, T. Ishizaki, S. Akutagawa, H. Takaya, J. Org. Chem. 1994, 59, 3064-3076.

10. F. Hapiot, F. Agbossou, A. Mortreux, Tetrahedron: Asymmetry 1995, 6, (1), 11-14 and

references therein.

11. J.-F. Carpentier, A. Mortreux, Tetrahedron: Asymmetry 1997, 8, (7), 1083-1099 and

references therein.

12. F. Spindler, U. Pittelkow, H.-U. Blaser, Chirality 1991, 3, 370.

13. H.-U. Blaser, H.-P. Jalett, F. Spindler,/. Mol Catal. 1996,107, 85.

14. The reaction was carried out at 60 "C using 4 mmol substrate in a 3 ml formic acid /

triethylammonium formate (5/2) solution. Substrate : [IrCl(COD)]2 : Ligand = 400 : 1 : 5. The

conversion was determined by ]H NMR. The enantioselectivity was determined by capillary

GLC analysis using a chiral cycloSil-B column.

15. K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, }. Am. Chem. Soc. 1997,119, 8738-8739

and references therein.

144