Asymmetric transfer hydrogenation of imines

Full text of DOI:10.1021/ja960364k

4916
J. Am. Chem. Soc. 1996, 118, 4916-4917
first time that suitably designed chiral Ru(II) complexes catalyze
efficiently the asymmetric reduction of imines with an inex-
pensive, well-behaving formic acid-triethylamine mixture under
mild conditions.
Asymmetric Transfer Hydrogenation of Imines
Nobuyuki Uematsu, Akio Fujii, Shohei Hashiguchi,
Takao Ikariya, and Ryoji Noyori*,†
In this investigation, we selected as the model reaction the
reduction of the imine 1a to salsolidine 2a in the presence of
Ru(II) catalysts 3.9-11,13 Screening experiments revealed that
asymmetric reduction of 1a was best effected with a 5:2 formic
acid-triethylamine azeotropic mixture14 in acetonitrile contain-
ing (S,S)-3a at 28 °C (S/C ) 200, HCO2H/1a ) 6, [1a] ) 0.5
M, 3 h), leading to (R)-2a in 95% ee and in >99% yield. The
reaction was conducted equally well in various aprotic polar
solvents including DMF, DMSO, and CH2Cl2, but not in ethereal
or alcoholic media; the reaction in a neat formic acid-
triethylamine mixture11 was very slow.
ERATO Molecular Catalysis Project
Research DeVelopment Corporation of Japan
1247 Yachigusa, Yakusa-cho, Toyota 470-03, Japan
ReceiVed February 5, 1996
The cardinal significance of chiral amines in pharmaceutical
and agrochemical substances demands the development of an
efficient catalytic asymmetric reduction of imines. Certain
imines were hydrogenated by chiral phosphine-Rh or -Ir
catalysts with a substrate/catalyst molar ratio (S/C) of 100-
1000 at 10-100 atm to give secondary amines in a fair to good
ee1 and by a chiral ansa-titanocene catalyst (S/C ) 20, 6-140
atm) with 95-100% enantioselection.2,3 Hydrosilylation with
chiral phosphine-Rh complexes (S/C ) 50-100)4 or hydrobo-
ration with chiral oxazaborolidines (S/C ) 10)5,6 also effect the
asymmetric reduction with 60-70% optical yield. These
procedures, though viable, can still be improved for practical
use in organic synthesis. Transfer hydrogenation using stable
organic hydrogen donors is an attractive alternative in view of
the less hazardous properties of the reducing agents and
operational simplicity, as well as possible high overall cost
performance. Although such reductions have emerged as a
convenient method for asymmetric saturation of CdC7 and
CdO linkages,8-12 its usage for enantioselective CdN reduction
has remained totally undeveloped. Here we disclose for the
† Permanent address: Department of Chemistry, Nagoya University,
Chikusa, Nagoya 464-01, Japan.
The rate and enantioselectivity of the reaction are delicately
influenced by the η6-arene and 1,2-diamine ligands in 3. The
high efficiency attained with (S,S)-3a relies on not only the
chirality of the N-tosylated 1,2-diamine but also the presence
of the polar functional groups as well as the alkyl substituents
on the p-cymene ligand. The NH2 (not N(CH3)2) and ArSO2
(not CF3SO2, C6H5CO, or CH3CO) groups play crucial roles
for the high reactivity, while the structure of the Ar group and
the substitution pattern of the η6-arene ligand may be fine-tuned
depending on the imine substrates. The same result was
obtained using the Ru complex 3 in situ formed from [RuCl2-
(η6-arene)]2 and the N-sulfonylated diamine in triethylamine
without isolating the pure compound. The reaction was
normally performed with an S/C ratio of 200, but the ratio could
be as high as 1000.
(1) (a) Rh, S/C )100, 73% ee: Bakos, J.; To´th, I.; Heil, B.; Marko´, L.
J. Organomet. Chem. 1985, 279, 23-29. (b) Rh, S/C ) 100, 71-91% ee:
Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kang, G.-J.;
Rettig, S. J. Inorg. Chem. 1991, 30, 5002-5008. (c) Rh, S/C ) 100, 89-
96% ee: Bakos, J.; Orosz, AÄ .; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou,
D. J. Chem. Soc., Chem. Commun. 1991, 1684-1685. (d) Ir, S/C >1000,
40-80% ee: Chan, Y. Ng C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112,
9400-9401. (e) Ir, S/C ) 100, 79-93% ee: Morimoto, T.; Achiwa, K.
Tetrahedron: Asymmetry 1995, 6, 2661-2664. (f) Ir, S/C ) 100, 70-90%
ee: Tani, K.; Onouchi, J.; Yamagata, T.; Kataoka, Y. Chem. Lett. 1995,
955-956.
(2) (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1992,
114, 7562-7564. (b) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 8952-8965. (c) Willoughby, C. A.; Buchwald, S. L. J.
Am. Chem. Soc. 1994, 116, 11703-11714.
(3) For selected asymmetric hydrogenations of functionalized CdN
bonds, see: (a) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli,
G. Tetrahedron Lett. 1990, 31, 4117-4120. (b) Burk, M. J.; Feaster, J. E.
J. Am. Chem. Soc. 1992, 114, 6266-6267. (c) Burk, M. J.; Martinez, J. P.;
Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399-4428.
(4) (a) Kagan, H. B.; Langlois, N.; Dang, T. P. J. Organomet. Chem.
1975, 90, 353-365. (b) Brunner, H.; Becker, R; Gauder, S. Organometallics
1986, 5, 739-746.
Triethylamine is necessary; attempted reaction of 1a with
formic acid in acetonitrile containing 3a failed to produce 2a.
Ru(II) complexes are known to catalyze the reversible process,
HCO2H h H2 + CO2,15 and 3a indeed catalyzes the decom-
position of formic acid under the above described reaction
conditions. However, the asymmetric reduction of the imine
is a result of transfer hydrogenation by formic acid, and
molecular hydrogen does not intervene. The reaction of 1a in
acetonitrile under a D2 atmosphere (1a/(S,S)-3a ) 200, D2 60
atm, D2:HCO2H molar ratio ) 24:1) under otherwise identical
conditions gave (R)-2a in 93% ee and in >99% yield without
(5) (a) Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1992, 3, 1583-
1590. (b) Bolm, C.; Felder, M. Synlett 1994, 655-656. (c) Sakai, T.; Yan,
F.; Uneyama, K. Synlett 1995, 753-754. (d) Shimizu, M.; Kamei, M.;
Fujisawa, T. Tetrahedron Lett. 1995, 36, 8607-8610.
(6) For highly enantioselective stoichiometric reductions, see: (a)
Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin Trans. 1 1983,
265-270. (b) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.;
Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985, 2039-2044.
(c) Hutchins, R. O.; Abdel-Magid, A.; Stercho, Y. P.; Wambsgans, A. J.
Org. Chem. 1987, 52, 702-704. (d) Sakito, Y.; Yoneyoshi, Y.; Suzukamo,
G. Tetrahedron Lett. 1988, 29, 223-224. (e) Itsuno, S.; Sakurai, Y.;
Shimizu, K.; Ito, K. J. Chem. Soc., Perkin Trans. 1 1990, 1859-1863.
(7) (a) Brunner, H.; Leitner, W. Angew. Chem., Int. Ed. Engl. 1988, 27,
1180-1181. (b) Saburi, M.; Ohnuki, M.; Ogasawara, M.; Takahashi, T.;
Uchida, Y. Tetrahedron Lett. 1992, 33, 5783-5786.
2
deuterium incorporation at C(1) (1H and H NMR analysis).
(12) (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. (c) Evans, D. A.; Nelson, S. G.;
Gagne´, M. R.; Muci, A. R. J. Am. Chem. Soc. 1993, 115, 9800-9801.
(13) Molecular structure of the 3a was determined by single-crystal X-ray
analysis (see supporting information). See also refs 9 and 11.
(14) (a) Wagner, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 50-54. (b)
Narita, K.; Sekiya, M. Chem. Pharm. Bull. 1977, 25, 135-140.
(15) (a) Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. ReV. 1995, 95, 259-
272. (b) Laine, R. M.; Rinker, R. G.; Ford, P. C. J. Am. Chem. Soc. 1977,
99, 252-253.
(8) Gao, J.-X.; Ikariya, T.; Noyori R. Organometallics 1996, 15, 1087-
1089.
(9) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562-7563.
(10) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori,
R. J. Chem. Soc., Chem. Commun. 1996, 233-234.
(11) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522.
S0002-7863(96)00364-2 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4917
Table 1. Asymmetric Transfer Hydrogenation of Imines Catalyzed
this method allows a convenient preparation of the chiral amines,
(S)-9a and (S)-9b, which serve as intermediates for the synthesis
of MK-0417, a carbonic anhydrase inhibitor.17
by Chiral Ru(II) Complexesa
amine
The general sense of asymmetric induction with this catalytic
system is schematically illustrated in Figure 1. In the stereo-
determining hydrogen-transfer step, the chiral Ru species,
probably a hydride, formally discriminates the enantiofaces at
the sp2 nitrogen atom of the cyclic and acyclic imine, generating
a stereogenic sp3 carbon (R control according to the latent
trigonal center rule).18 With acyclic imines, the difficulty in
obtaining the geometrically pure compound as well as configu-
rational instability,2,19 causing syn-anti isomerization, tends to
lower the extent of enantioselectivity.
time,
h
%
%
imine catalyst S/C
1a (S,S)-3a 200 CH3CN
1ae (S,S)-3a 1000 CH3CN
solvent
yieldb eec configd
3
12
7
12
8
12
5
>99 95
97 94
90 95
99 92
99 84
>99 84
86 97
89 93
83 96
72 77h
90 89i
82 85
84 88
R
R
S
1b
1c
1d
1e
4a
(R,R)-3b 200 (CH3)2NCHO
(R,R)-3b 200 CH2Cl2
S
(S,S)-3d
(R,R)-3d 100 CH2Cl2
(S,S)-3a 200 (CH3)2NCHO
200 CH2Cl2
Rf
S
R
R
Rf
S
4ae (S,S)-3a 1000 (CH3)2NCHO 12
4b
6g
7
8a
8b
(S,S)-3a
(S,S)-3c
(S,S)-3d
(S,S)-3d
(S,S)-3d
200 (CH3)2NCHO
200 CH2Cl2
100 CH2Cl2
100 CH3CN
100 CH3CN
5
36
6
12
5
Sj
Sk
S
a A 5:2 formic acid-triethylamine azeotropic mixture (2.5 mL) was
added to a solution of an imine (5 mmol) and a preformed Ru catalyst
(0.02 mmol) in solvent (8 mL), and the mixture was stirred at 28 °C.
b Isolated yield after flash chromatography on silica gel. c HPLC analysis
using a Daicel Chiralcel OD column. d Determined by sign of the
isolated product unless otherwise noted. e A 20 mmol scale reaction.
f Determined by X-ray analysis of the (S)- or (R)-R-methoxy-R-
(trifluoromethyl)phenylacetyl derivative. g With a 3:2 formic acid-
triethylamine mixture. h Sumichiral OA-4100. i Chiralcel OB column.
j Determined after conversion to (S)-1,2,3,4-tetrahydro-1-naphthylamine.
k Determined after oxidation to the sulfone.
Figure 1. General sense of asymmetric transfer hydrogenation
catalyzed by the Ru complex 3.
Among the most notable feature of this reduction is the
eminent functional group selectivity. Although the chiral Ru
complex 3 does catalyze transfer hydrogenation of ketones in a
formic acid-triethylamine mixture,11 imines are more reactive
under the present catalytic conditions. For example, the imine
1a can be reduced eVen in acetone that contains (S,S)-3a (S/C
) 200, [1a] ) 0.5 M, 1a:CH3COCH3 molar ratio ) 1:5.4, 28
°C, 3 h) to give (R)-2a in >99% yield and in 95% ee
accompanied with only 3% conversion of the solvent to
2-propanol. A competitive experiment using a 1:5 mixture of
1a and structurally related 3,4-dimethoxyacetophenone in ac-
etonitrile indicated that the ketimine is >1000 times more
reactive than the ketone. The CdN/CdO chemoselectivity1d
is superior to that observed in the stoichiometric reduction using
NaBH3CN (98:1).20 Simple olefinic substrates such as R-meth-
ylstyrene are inert to this reduction condition. The successful
reaction with the 1-aryl derivatives 1d, 1e, and 4b clearly
excludes the possibility of the reaction pathway involving an
imine-enamine isomerization.
Experiments using 2-propanol-2-d with formic acid or acetic
acid in triethylamine revealed that 2-propanol cannot serve as
a hydrogen source.
This catalytic method is particularly useful for the enantio-
selective reduction of cyclic imines to the amines with an ee
value ranging from 90% to 97%, as illustrated in Table 1.
Various substrates of type 1 with an alkyl, benzyl, or aryl
substituent can be used, opening a new, general way to
isoquinoline alkaloids.16 N-methylation of (S)-2b, (S)-2c, and
(S)-2e gives naturally occurring laudanosine, homolaudanosine,
and cryptostyline II, respectively. Furthermore, this asymmetric
reaction can be extended to the synthesis of optically active
indoles 5 from 4. Since most products are crystalline com-
pounds, the enantiomeric purities are readily increased by
recrystallization. Although the reaction of acyclic imines such
as 6 (anti:syn ) 94:6), 7, and 8 is somewhat less stereoselective,
Acknowledgment. We thank Professor Shin-ichi Inoue of Aichi
Institute of Technology and Dr. Karl-Josef Haack of JRDC for helpful
discussions and Miss Mieko Kunieda of JRDC for skillful analytical
assistance.
Supporting Information Available: Structural assignment of 8a
and 8b, procedures for catalyst preparation and X-ray analysis of (S,S)-
3a, experimental procedure of transfer hydrogenation and [R]D values
of the products, X-ray analyses of the (S)-R-methoxy-R-(trifluoro-
methyl)phenylacetyl derivative of (R)-2d and the (R)-R-methoxy-R-
(trifluoromethyl)phenylacetyl derivative of (R)-5b (60 pages). Ordering
information is given on any current masthead page.
JA960364K
(16) For asymmetric synthesis of isoquinoline alkaloids using BINAP-
Ru catalyzed hydrogenation, see: Kitamura, M.; Hsiao, Y.; Ohta, M.;
Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59,
297-310.
(17) Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre,
D. J.; Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.; Grabowski,
E. J. J. J. Org. Chem. 1991, 56, 763-769.
(18) Duhamel, P.; Duhamel, L. C. R. Acad. Sci., Ser. IIb 1995, 320,
689-694.
(19) McCarty, C. G. In The Chemistry of the Carbon-Nitrogen Double
Bond; Patai, S., Ed.; John Wiley & Sons: New York, 1970; Chapter 9, pp
363-464.
(20) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897-2904.