Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones using a formic acid-triethylamine mixture

Full text of DOI:10.1021/ja954126l

J. Am. Chem. Soc. 1996, 118, 2521-2522
2521
Ruthenium(II)-Catalyzed Asymmetric Transfer
Hydrogenation of Ketones Using a Formic
Acid-Triethylamine Mixture
Akio Fujii, Shohei Hashiguchi, Nobuyuki Uematsu,
Takao Ikariya, and Ryoji Noyori*,†
ERATO Molecular Catalysis Project
Research DeVelopment Corporation of Japan
1247 Yachigusa, Yakusa-cho, Toyota 470-03, Japan
ReceiVed December 7, 1995
Catalytic transfer hydrogenation of ketones to alcohols with
2-propanol sometimes offers an attractive alternative to the
reaction with molecular hydrogen because of the favorable
properties of the organic hydrogen source.1 However, when
the method is applied to the asymmetric version,2-4 it encounters
inherent chemical problems. Even if the reduction proceeds
with excellent kinetic enantioface discrimination, the occurrence
of the reverse process originating from the structural similarity
of the hydrogen donor and product, both being secondary
alcohols, frequently deteriorates the enantiomeric purity of the
chiral product.1-5 In addition, the unfavorable ketone:alcohol
equilibrium ratio often prevents a high conversion. Use of
formic acid6 in place of 2-propanol presents an obvious
possibility to solve these problems. This hydrogen donor,
viewed as an adduct of H2 and CO2, must effect the reaction
irreversibly with truly kinetic enantioselection and, in principle,
100% conversion. However, its use in asymmetric ketone
reduction has remained elusive because of the lack of suitable
transition metal catalysts.7 We have found that Ru(II) com-
plexes modified with an arene and a chiral N-tosylated 1,2-
diamine2 serve as efficient catalysts for the asymmetric reduction
using a 5:2 formic acid-triethylamine azeotropic mixture under
mild conditions.
diamine (TsDPEN), and triethylamine (Ru atom:TsDPEN:
triethylamine molar ratio ) 1:1:2) in 2-propanol at 80 °C for 1
h.2,8 Reaction using a 2 M solution of 1a in a 5:2 formic acid-
triethylamine azeotrope9 containing (S,S)-3 [substrate/catalyst
(S/C) mole ratio ) 200:1, 28 °C, 20 h] gave (S)-2a in 98% ee
and in >99% yield.10 The reaction at 60 °C proceeded 8-10
times faster with a 2% decrease in ee. This reduction can be
conducted even in a 10 M solution (ca. 50% v/v concentration)
and with S/C ) 1000:1. The reactivity and enantioface-
differentiation ability of the Ru complex 3 result from the
compromise between the steric and electronic properties of the
arene ligand and the chiral diamine auxiliary. The reactivity
decreases in the order benzene > p-cymene and mesitylene >
hexamethylbenzene as ligand, while mesitylene or p-cymene
displays a better enantioselection than unsubstituted benzene.
The presence of the NH2 terminus in the TsDPEN auxiliary is
crucially important. The NHCH3 analogue showed a compa-
rable enantioselectivity but with much lower reactivity; the
N(CH3)2 derivative gave very poor reactivity and stereoselec-
tivity.
As shown in Table 1, a range of aromatic ketones can be
reduced to the secondary alcohols with a high chemical yield
and a satisfactory ee. Various acetophenone derivatives, 1b-
d, and the higher analogues, 1e and 1f, as well as acetonaph-
thones (4 and 5) can be used as substrates. The absence of the
reverse process was confirmed by exposure of enantiomerically
pure (S)- and (R)-2a to the reaction conditions with or without
ketone 1b. The irreversibility of the reaction results in a series
of benefits. Enantioselectivity of the reduction using a 2 M
solution of 1a with (S,S)-3 is kept consistently high (S:R ) 99:
1) throughout the reaction until completion. With a 2 M solution
of 1a in 2-propanol, the yield of (S)-2a cannot be high (at most
63%) for thermodynamic reasons, the calculated 2a:1a equi-
librium ratio being ca. 70:30.2 Furthermore, the new reaction
system reduced p-methoxyacetophenone (p-1d), among the most
notorious substrates, to (S)-p-2d in 97% ee and >99% yield,
presenting a significant improvement from the result in 2-pro-
panol (70% ee and 33% yield after 6 h).
The reduction of acetophenone (1a) to 1-phenylethanol (2a)
was selected as the model reaction (eq 1: R1 ) CH3; R2 ) H).
Screening experiments revealed that the catalyst of choice was
the chiral Ru complex, (R)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH-
(C6H5)NH2](η6-mesitylene) [(S,S)-3] or the enantiomer [(R,R)-
3], which was prepared by reacting [RuCl2(η6-mesitylene)]2,
(1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylene-
† Permanent address: Department of Chemistry, Nagoya University,
Chikusa, Nagoya 464-01, Japan.
(1) Reviews: (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV.
1992, 92, 1051-1069. (b) de Graauw, C. F.; Peters, J. A.; van Bekkum,
H.; Huskens, J. Synthesis 1994, 1007-1017.
(2) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562-7563.
(3) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori,
R. J. Chem. Soc., Chem. Commun., in press.
(4) (a) Mu¨ller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. HelV. Chim. Acta
1991, 74, 232-240. (b) Chowdhury, R. L.; Ba¨ckvall, J.-E. J. Chem. Soc.,
Chem. Commun. 1991, 1063-1064. (c) Geneˆt, J.-P.; Ratovelomanana-Vidal,
V.; Pinel, C. Synlett 1993, 478-480. (d) Gamez, P.; Fache, F.; Mangeney,
P.; Lemaire, M. Tetrahedron Lett. 1993, 34, 6897-6898. (e) Gamez, P.;
Dunjic, B.; Fache, F.; Lemaire, M. J. Chem. Soc., Chem. Commun. 1994,
1417-1418. (f) Gamez, P.; Fache, F.; Lemaire, M. Bull. Soc. Chim. Fr.
1994, 131, 600-602. (g) Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron:
Asymmetry 1995, 6, 705-718. (h) Krasik, P.; Alper, H. Tetrahedron 1994,
50, 4347-4354. (i) Yang, H.; Alvarez, M.; Lugan, N.; Mathieu, R. J. Chem.
Soc., Chem. Commun. 1995, 1721-1722.
Although various para-substituted acetophenones are consis-
tently convertible to the alcohols with >90% ee (Table 1), the
(8) (S,S)-3: orange solid; mp 218.6-222.5 °C dec; 1H NMR (CDCl3)
2.24 (s, 3H, CH3), 2.38 (s, 9H, CH3), 3.69 (dd, 1H, J ) 11.2 and 11.2 Hz,
CHNH2), 3.79 (d, 1H, J ) 11.2 Hz, CHNTs), 3.99 (dd, 1H, J ) 9.3 and
11.2 Hz, NH), 4.19 (brd, 1H, J ) 9.3 Hz, NH), 5.30 (s, 3H, arom), 6.65-
6.93 (m, 9H, arom), 7.06-7.15 (m, 3H, arom), 7.35 (d, 2H, J ) 7.8 Hz,
arom). Recrystallization from 99% ethanol afforded crystals of (S,S)-
3‚H2O: mp 220.1-222.3 °C dec; 1H NMR (CDCl3) δ 1.58 (s, H2O), 3.98-
4.12 (br, 2H, NH2). Chemical shifts of other signals were identical with
those of (S,S)-3. The molecular structure determined by single-crystal X-ray
analysis confirms the R configuration at the Ru center2 (see supporting
information).
(9) (a) Wagner, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 50-54. (b)
Narita, K.; Sekiya, M. Chem. Pharm. Bull. 1977, 25, 135-140.
(10) The reaction can conveniently be conducted in an open vessel using
a mixture of [RuCl2(η6-mesitylene)]2 and TsDPEN in a formic acid-
triethylamine mixture without isolating 3.
(5) In certain cases, the reverse process is slow. See: (a) Evans, D. A.;
Nelson, S. G.; Gagne´, M. R.; Muci, A. R. J. Am. Chem. Soc. 1993, 115,
9800-9801. (b) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics, in
press.
(6) (a) Watanabe, Y.; Ohta, T.; Tsuji, Y. Bull. Chem. Soc. Jpn. 1982,
55, 2441-2444. (b) Nakano, T.; Ando, J.; Ishii, Y.; Ogawa, M. Tech. Rep.
Kansai UniV. 1987, 29, 69-76.
(7) For the use for asymmetric saturation of olefinic substrates, see: (a)
Brunner, H.; Kunz, M. Chem. Ber. 1986, 119, 2868-2873. (b) Brown, J.
M.; Brunner, H.; Leitner, W.; Rose, M. Tetrahedron: Asymmetry 1991, 2,
331-334. (c) Leitner, W.; Brown, J. M.; Brunner, H. J. Am. Chem. Soc.
1993, 115, 152-159. (d) Saburi, M.; Ohnuki, M.; Ogasawara, M.;
Takahashi, T.; Uchida, Y. Tetrahedron Lett. 1992, 33, 5783-5786.
0002-7863/96/1518-2521$12.00/0 © 1996 American Chemical Society

2522 J. Am. Chem. Soc., Vol. 118, No. 10, 1996
Communications to the Editor
notable enantiomeric bias corresponding to ∆∆Gq) 0.95 kcal/
mol. The absolute configuration of the major enantiomer was
determined by X-ray crystallographic analysis after condensation
with (R)-1-(1-naphthyl)ethyl isocyanate. Thus, the enantiomeric
bias of the asymmetric reduction appears to be generated by
both steric and electronic factors.
Asymmetric reduction of 1-indanone (7) and 1-tetralone (8)
is now best effected by this method to give 1-indanol and
1-tetralol in 99% ee and >99% yield. Furthermore, the 2-furyl
ketone 10 and oxacyclic ketone 11 were reduced to the
corresponding alcohol12 with a high ee. The reaction of the
sulfur-containing ketones 12 and 13 in the presence of (R,R)-3
led to the R alcohols in >98% ee, which serve as key
intermediates for the synthesis of MK-0417, an excellent
carbonic anhydrase inhibitor.13
This transfer hydrogenation is selective for a keto function.7
The reduction of the multifunctionalized ketone 14 catalyzed
by (R,R)-3 gave the desired R benzylic alcohol, an intermediate
in the synthesis of L-699,392 (LTD4 antagonist),14 in 92% ee
without affecting the olefinic bond, halogen atom, quinoline ring,
and ester function.
Under the catalytic conditions, formic acid decomposes into
H2 and CO2 to a substantial extent. However, gaseous hydrogen
participates little in the alcohol formation. First, an attempted
reaction of 1a with hydrogen gas in a 2:1 mixture of acetic
acid (a nonreducing formic acid analogue) and triethylamine
under otherwise identical conditions (20 atm, [1a] ) 2 M, S/C
) 200, 28 °C, 20 h) gave (S)-2a in only 75% ee and 5% yield.
The presence of formic acid (10 equiv with respect to Ru) did
not show any marked effect. Furthermore, reaction of 1a with
a 5:2 formic acid-triethylamine mixture under a D2 atmosphere
(65 atm, HCO2H:D2 mole ratio ) 1:29, S/C ) 200, 28 °C, 40
h) formed (S)-2a in 98% ee and 99% yield, in which 0.08D
and 0.18D (0.06D/hydrogen) were incorporated at the C(1) and
C(2) positions (2H NMR analysis).
Table 1. Asymmetric Transfer Hydrogenation of Ketones in a
Formic Acid-Triethylamine Mixture Catalyzed by a Chiral Ru(II)
Complexa
alcohol
ketone
3, catalyst
time, h
% yieldb
% eec
configd
1a
1a
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
S,S
R,R
R,R
R,R
20
1.5f
60
21
24
14
50
60
60
90
60
22
60
48
48
6f
>99
>99
>99
>99
>99
>99
>99
>99
96
99
93
>99
54
98e
96e
98e
97e
95e
90h
98
S
S
S
S
S
S
S
S
1ag
m-1b
p-1b
p-1c
m-1d
p-1d
1e
97
97
S
1f
4
95i
83
S j
S
5
96k
66k
99
S
6l
Sm
S
7
8
8
9
>99
>99
>99
70
99
S
S
S
S
98
80
36
40
40
65
72
82n
98e
97k
99
10
>99
11l
12
47
S
95o
Rp
R
R
13q
14l,q
95r
98
68s
92k
a The reaction was carried out at 28 °C using a ketone (5.0 mmol)
in a formic acid-triethylamine mixture (5:2, 2.5 mL) with S/C ) 200.
b Determined by GLC or 400-MHz 1H NMR analysis. c HPLC analysis
using a Daicel Chiralcel OB column unless otherwise specified. Details
are described in the supporting information. d Determined by the sign
of rotation of the isolated product. e Capillary GLC analysis using a
chiral Chrompack CP-cyclodextrin-â-236-M-19 column. f Reaction at
60 °C. g Reaction using a 10 M solution of the ketone (25 mmol) in a
formic acid-triethylamine mixture (2:1, 2.7 mL, 25 mmol) with S/C
) 1000. After 12 h, the reducing agent (0.4 mL, 10 mmol) was
renewed. h Chiralcel OJ column. i Chiralcel OD column. j Determined
after conversion to (S)-6-phenyltetrahydro-2H-pyran-2-one. k Chiralpak
AS column. l THF (1 mL) was added to dissolve the ketonic substrate.
m Determined by X-ray analysis after condensation with (R)-1-(1-
naphthyl)ethyl isocyanate. n Chiralpak AD column. o (R)-5,6-Dihydro-
4H-thieno[2,3-b]thiopyran-4-ol. p Determined after oxidation to the
sulfone. q Reaction using 1.0 mmol of ketone in 0.5 mL of a 5:2 formic
acid-triethylamine mixture. r (R)-5,6-Dihydro-4H-thieno[2,3-b]thiopy-
ran-4-ol 7,7-dioxide. s (R,E)-Methyl 2-[3-[3-[2-(7-chloro-2-quinoli-
nyl)ethenyl]phenyl]-3-hydroxypropyl]benzoate.
In summary, this work presents the first successful use of a
formic acid-triethylamine mixture for asymmetric transfer
hydrogenation of ketones. This method overwhelms the
energetic requirement of the reduction process, where an
unfavorable thermodynamic balance is expected with 2-propanol
as the hydrogen source. Thus, the asymmetric reaction proceeds
under truly kinetic control to completion with a much higher
substrate concentration (2-10 M) than in 2-propanol (<0.1 M).
Acknowledgment. We thank Professor Shin-ichi Inoue of Aichi
Institute of Technology and Professor Masashi Yamakawa of Kinjo
Gakuin University for valuable discussions, Professor Masafumi Hirano
of Tokyo University of Agriculture and Technology for analysis of
gas in the reaction mixture, and Miss Mieko Kunieda of JRDC for
skillful analytical assistance.
Supporting Information Available: Experimental procedures for
the transfer hydrogenation, HPLC or GLC behavior, and [R]D values
of the products and data of single-crystal X-ray analysis of (S,S)-3‚H2O
and (S)-(p-methoxyphenyl)(p′-cyanophenyl)methyl (R)-N-1-(1-naph-
thyl)ethylcarbamate (39 pages). This material is contained in many
libraries on microfiche, immediately follows this article in the microfilm
version of the journal, can be ordered from the ACS, and can be
downloaded from the Internet; see any current masthead page for
ordering information and Internet access instructions.
JA954126L
electron-withdrawing substituents tend to slightly decrease the
enantioselectivity. A benzophenone derivative 6, with electron-
accepting and -donating substituents at the para positions, was
(12) Majeric´, M.; Gelo-Pujic´, M.; Sˇunjic´, V.; Le´vai, A.; Sebo¨k, P.; Tima`r,
T. Tetrahedron: Asymmetry 1995, 6, 937-944.
(13) Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre,
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E. J. J. J. Org. Chem. 1991, 56, 763-769.
reduced to (S)-p-methoxy-p′-cyanobenzhydrol in 66% ee,11
a
(11) For asymmetric hydrosilylation and hydroboration of benzophenone
derivatives, see: (a) Peyronel, J.-F.; Fiaud, J.-C.; Kagan, H. B. J. Chem.
Res. Miniprint 1980, 4057-4080. (b) Corey, E. J.; Helal, C. J. Tetrahedron
Lett. 1995, 36, 9153-9156.
(14) King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J.; Xiang, Y. B.; Belley, M.; Leblanc, Y.;
Labelle, M.; Prasit, P.; Zamboni, R. J. J. Org. Chem. 1993, 58, 3731-
3735.