Ruthenium-catalyzed asymmetric transfer hydrogenation of ketones in ethanol

Tetrahedron Letters 52 (2011) 2754–2758

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Ruthenium-catalyzed asymmetric transfer hydrogenation of ketones in ethanol Helena Lundberg, Hans Adolfsson ⇑ Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 18 February 2011 Revised 9 March 2011 Accepted 18 March 2011

A ruthenium catalyst formed in situ by combining [Ru(p-cymene)Cl2]2 and an amino acid hydroxy-amide was found to catalyze efficiently the asymmetric reduction of aryl alkyl ketones under transfer hydrogenation conditions using ethanol as the hydrogen donor. The secondary alcohol products were obtained in moderate to good yields and with good to excellent enantioselectivity (up to 97% ee). Ó 2011 Elsevier Ltd. All rights reserved.

Keywords: Asymmetric catalysis Amino acids Ruthenium Reduction

formed under thermodynamic conditions, and therefore reductions in 2-propanol can result in poor yields of the product due to an unfavorable equilibrium. To circumvent the latter problem, reductions are often performed with low substrate concentrations, typically in the range of 0.1–0.2 M. However, in systems where formic acid or its formate salt are employed as the hydride donor, the reaction is practically irreversible due to the release of carbon dioxide. On the other hand, the downside using formic acid as the hydrogen donor is the limited compatibility with most of the catalysts used in ATH processes.3c A highly interesting alternative to formic acid or 2-propanol as the hydride source in asymmetric reductions is the use of primary alcohols, and in particular ethanol.5 Ethanol is a renewable solvent and energy source, and has attracted much attention for its potential as an alternative to fossil fuels. However, with the exception of the group of Grützmacher,5a,b it has received little attention as a hydrogen source in transfer hydrogenation. The reason for the rare

Enantioselective reductions of polarized organic compounds such as ketones and imines are highly important transformations, since the alcohols and amines formed are often employed as chiral building blocks in the production of a variety of different finechemicals. Methods employing non-hydride reagents as terminal reductants are of particular interest, and an emerging number of catalytic asymmetric protocols have been developed over the last two decades.1 Most catalytic methods rely on the use of chiral transition metal complexes in combination with either molecular hydrogen (hydrogenation)2 or organic hydrogen donors (transfer hydrogenation)3 as reducing agents. In particular, asymmetric transfer hydrogenation (ATH) has emerged as one of the most popular methods for enantioselective ketone and imine reductions, since the use of hazardous reaction conditions are avoided.4 Frequently employed hydrogen donors in ATH of ketones are formic acid and different formate salts, or secondary alcohols such as 2propanol. Transfer hydrogenation processes are reactions per-

a

b O

Ar

[Ru(p-cymene)Cl2]2 (0.25 mol%) Ligand 1 (0.55 mol%)

O

OH

NaOPr i (5 mol%), LiCl (10 mol%) 2-PrOH : THF (1 : 1), [ketone] = 0.2 M

H

Ar O

Li H

Ru O

H3C Scheme 1.

⇑ Corresponding author. E-mail address: [email protected] (H. Adolfsson). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.03.098

OBut CH3

N N

O

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[Ru(p-cymene)Cl2]2 or [RhCp⁄Cl2]2 and the amino acid hydroxyamide ligand 1 as catalysts.7 A vast number of ligands based on various amino acids were screened, and it was found that using a combination of N-Boc alanine and amino-2-propanol resulted in ruthenium catalysts with superior activity and enantioselectivity. Furthermore, during optimization of the reaction conditions for these ATH reductions, we found that the use of lithium 2-propoxide, or a combination of sodium 2-propoxide and lithium chloride, gave significantly better enantioselectivities of the formed products (Scheme 1, a).9 The enhancing effect was traced to participation of the alkali cation in the transfer of the hydride from the catalyst to the substrate. In ATH processes catalyzed by ruthenium– or rhodium–arene complexes, the additional ligand (often a vicinal aminoalcohol, or diamine) serves a dual purpose in (1) controlling the stereochemical outcome of the process and (2) delivering a proton to the substrate oxygen in the reducing step.3d,10 The reaction path is normally referred to as an outersphere type mechanism. However, when amino acid hydroxyamides are employed as ligands, the reaction mechanism is somewhat different. Instead of protonation of the substrate by the ligand, an alkali ion associated with the transition metal hydride complex is transferred to the ketone oxygen simultaneously with the hydride delivery. Hence the overall process can be described as a bimetallic outer-sphere type mechanism (Scheme 1, b).9b In addition, we found that performing the ATH reactions in a mixture of 2-propanol and THF resulted in better overall performance of the catalyst. Based on these findings, we anticipated that the optimized conditions found for the 2-propanol system would also be applicable in other alcohols. In an initial set of experiments, acetophenone (concentration: 0.5 M) was reduced in a 1:1 mixture of THF and four different primary alcohols (Table 1). In order for the reaction to proceed to high conversions, we had to increase the catalyst loading to 1 mol % in comparison to the 2-propanol system. As seen in Table 1, the use of methanol resulted in poor conversion of the substrate (entry 1), whereas in solvent mixtures containing ethanol, 1-propanol, and 1-butanol, respectively, 1-phenylethanol was obtained in moderate to high yields. Most gratifyingly, the reaction performed using ethanol as the hydride donor gave the overall best conversion and the highest enantioselectivity (entry 2), and 1-phenylethanol was formed in 97% ee in favor of the S-isomer. In addition to the desired secondary alcohol, we observed the formation of small amounts of side products which lowered the chemoselectivity to 90%. These additional compounds were found to be condensation products from the reaction between acetophenone and the formed acetaldehyde. Furthermore, monitoring the ATH reaction using NMR, we observed that ethyl acetate was

Table 1 Ruthenium-catalyzed asymmetric reduction of acetophenone with various alcohols as hydrogen donorsa Entry

Alcohol

Time (h)

Conversionb (%)

Selectivityb (%)

eec (%)

1 2 3 4

MeOH EtOH 1-PrOH 1-BuOH

6 2 6 6

3 83 63 65

100 90 66 64

>99 97 96 90

a The reactions were carried out under an N2 atmosphere under anhydrous conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl2]2 (0.5 mol %), ligand 1 (1.1 mol %) and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 alcohol/THF. b Conversion and selectivity were determined by GLC analysis. c Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).

use of ethanol in ATH reactions can be traced to its ability to form stable carbonyl complexes with the catalysts used for the process.6 In addition, there is an obvious risk of forming condensation products between acetaldehyde and the ketone substrate, when the ATH reaction is performed under basic conditions. Nevertheless, the catalyst compatibility of ethanol should be similar to that of 2-propanol, and the sometimes disfavored equilibria obtained with the latter hydride donor could possibly be circumvented due to the lower boiling point of acetaldehyde as compared to acetone. Therefore, ATH reactions performed in ethanol would be expected to reach higher conversions, since the formed acetaldehyde has a chance of escaping the reaction vessel, and thereby help push the equilibrium towards the product. Moreover, the initially formed acetaldehyde can react further to generate ethyl acetate via dehydration of the intermediate hemiacetal.5a,b From an environmental perspective, it would be possible to perform the reactions with a significantly higher substrate concentration and thereby reduce effectively the amount of solvent used. We have previously developed highly efficient and selective ruthenium and rhodium catalysts for the asymmetric transfer hydrogenation of ketones in 2-propanol.7 These half-sandwich Ru- or Rh-complexes were chirally-modified using different N-carbamate protected a-amino acid derivatives as ligands, and depending on the choice of derivative, we were able to obtain both isomers of the alcohol products in high yields and enantioselectivity.8 The above catalyst system proved to be incompatible with formic acid or formate as hydride donors, and we were therefore interested to investigate if the scope could be expanded towards other alcohols. Herein we report on an efficient and enantioselective method for the asymmetric transfer hydrogenation of aryl alkyl ketones in ethanol. We have previously demonstrated that aryl alkyl ketones can be reduced enantioselectively in 2-propanol using a combination of

O

O N H

NH

N H OH

1

Boc

NH 2

NH

OH 3

Boc

O

O N H

Boc

N H

OH

Boc

S

NH

O

4

N H Boc

NH

5

OH

N H NH Boc

OH 6

Figure 1. Amino acid based ligands for asymmetric transfer hydrogenation with ruthenium and/or rhodium.

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Table 2 Ruthenium-catalyzed asymmetric reduction of acetophenone with various ligandsa Entry

Metal

Ligand

Conversionb (%)

Selectivityb (%)

eec (%)

1 2 3 4 5 6 7 8

Ru Ru Ru Ru Ru Rh Rh Ru

1 2 2 3 3 4 5 6

83 46 93 77 98 82 90 98

90 78 90 68 95 96 96 80

97 93 92 92 88 77 90 80

d

d d d d

(S) (S) (S) (S) (S) (R) (S) (R)

a The reactions were carried out under an N2 atmosphere under anhydrous conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl2]2 or [Rh(Cp*)Cl2]2 (0.5 mol %), the corresponding ligand (1.1 mol %) and LiCl (10 mol %) at 40 °C over 2 h in a 0.5 M solution with 1:1 EtOH (99%)/THF. b Conversion and selectivity were determined by GLC analysis. c Enantiomeric excess was determined using GLC (CP Chirasil DEX CB). d 1 mol % metal precursor and 2.2 mol % ligand.

generated in the reaction mixture. This observation is in agreement with the studies presented by Grützmacher.5a,b Having established that the ATH process could be efficiently performed in ethanol, we screened a number of previously developed and successfully employed amino acid based ligands (Fig. 1)7,8 in the Ru- and Rh-catalyzed reduction of acetophenone (Table 2). The catalyst based on ligand 1 in combination with

Table 3 Ruthenium-catalyzed asymmetric reduction of acetophenone with various substrate concentrationsa Entry

Acetophenone (M)

Time (h)

Conversionb (%)

Selectivity (%)b

eec (%)

1 2 3

0.5 1 2

2 3 2

83 82 69

90 85 81

97 96 95

a The reactions were carried out under an N2 atmosphere under anhydrous conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl2]2 (0.5 mol %), ligand 1 (1.1 mol %) and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 EtOH (99%)/ THF. b Conversion and selectivity were determined by GLC analysis. c Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).

[Ru(p-cymene)Cl2]2 proved to be superior to all other combinations evaluated (Table 2, entry 1). One particular benefit from performing the reactions in ethanol is the theoretical possibility of using higher substrate concentrations. As seen in Table 3, the increase of [acetophenone] to 1 M gave similar results with respect to conversion and enantioselectivity as those obtained with a 0.5 M substrate concentration (Table 3, entry 2). However, we observed a larger amount of byproducts formed in addition to the desired alcohol, which favor the use of the lower concentration. Further increase of the concen-

Table 4 Ruthenium-catalyzed asymmetric reduction of various aryl alkyl ketonesa Entry

Substrate

Time (h)

Conversionb (%)

Selectivityb (%)

eec (%)

2

83

90

97 (S)

23

40

100

95 (S)

4

15

97

94 (S)

4

74

87

97 (S)

4

53

100

94 (S)

4

86

94

96 (S)

1

>99

94

93 (S)

3

98

77

89 (S)

O 1

O 2

O 3

O 4

O 5

MeO O 6

MeO

O 7

F 3C O 8

F3 C

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H. Lundberg, H. Adolfsson / Tetrahedron Letters 52 (2011) 2754–2758 Table 4 (continued) Entry

Substrate

Time (h)

Conversionb (%)

Selectivityb (%)

eec (%)

3

89

88

94 (S)

3

95

90

91 (S)

6

35

63

96 (S)

3

86

88

93 (S)

22

89

88

94 (R)

5

59

92

95 (R)

O

9

O O

O 10

Br O 11

O 12

O MeO 13d

MeO OMe OMe O 14d

MeO

MeO a

The reactions were carried out under an N2 atmosphere under anhydrous conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl2]2 (0.5 mol %), ligand 1 (1.1 mol %) and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 EtOH (99%)/THF. b Conversion and selectivity were determined by GLC analysis. c Enantiomeric excess was determined using GLC (CP Chirasil DEX CB). d Ligand ent-1 (1.1 mol %) was employed.

tration resulted in lower conversion, selectivity and ee. The lower conversion obtained at higher substrate concentration is somewhat contradictory, and can possibly be explained by lower catalyst solubility in the reaction medium. From the above optimizations we concluded that the overall best reaction conditions for the ATH of acetophenone in ethanol were: 40 °C using 1 mol % catalyst in a 1:1 mixture of ethanol and THF, at a substrate concentration of 0.5 M.11 Employing these reaction conditions, we evaluated a series of other aryl alkyl ketones and the results are presented in Table 4. In most of the reactions the secondary alcohol products were formed in moderate to good yields, and with good to excellent enantioselectivity. The chemoselectivity was in most cases >87% with 30 -trifluoromethylacetophenone and 40 -methylacetophenone being the exceptions (Table 4, entries 8 and 11). We have previously observed that substrates possessing potential sterically hindering groups on the alkyl chain of ketones, result in poor conversions when the ATH reaction is performed in 2-propanol. The same trend is valid for reactions carried out in ethanol as seen by the poor conversion obtained in the reduction of 2-methylpropiophenone (Table 4, entry 3). In conclusion, we have demonstrated that the combination of [Ru(p-cymene)Cl2]2 and amino acid hydroxy-amide 1 efficiently catalyzes the reduction of aryl alkyl ketones in a solvent mixture of THF and ethanol, where the latter solvent also acts as the reduc-

ing agent (hydride donor). A series of differently substituted ketones were subjected to the optimized reaction conditions, and the corresponding secondary alcohols were formed in moderate to good yields and in enantioselectivities ranging from 89% to 97%. The successful switch from 2-propanol to ethanol should allow for further use of this renewable hydride source in other reduction reactions. General procedure for the ATH of aryl alkyl ketones. To a 10 ml vial equipped with a septum and stirring bar, [Ru(p-cymene)Cl2)2 (0.0024 g, 0.004 mmol), ligand 1 (0.0028 g, 0.0088 mmol), and LiCl (0.0034 g, 0.08 mmol) were added. The vial was sealed and the atmosphere exchanged via 3  vacuum/N2 cycles. The vial was placed in an oil bath at 40 °C and dry THF (0.8 ml), 99% EtOH (0.4 ml) and the substrate (0.8 mmol) were added. The mixture was allowed to stir for 20 min, after which NaOtBu (0.0046 g, 0.048 mmol) dissolved in 99% EtOH (0.4 ml) was added. Aliquots were removed and filtered through a small plug of silica before analysis on chiral GC. Solid substrates were added to the vial at the same time as the metal precursor and the ligand. Acknowledgments We are grateful for financial support from the Swedish Research Council, the Carl Trygger Foundation, and the K & A Wallenberg Foundation.

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