A method for the asymmetric hydrosilylation of N-aryl imines

Article abstract of DOI:10.1021/ol005583w

graph presented The asymmetric reduction of N-aryl imines to yield chiral amines with enantiomeric excesses above 90% was achieved. Ethylenebis(η⁵-tetrahydroindenyl)titanium difluoride ((EBTHI)TiF₂,1) was employed as the precatalyst

Full text of DOI:10.1021/ol005583w

ORGANIC
LETTERS
2000
Vol. 2, No. 5
713-715
A Method for the Asymmetric
Hydrosilylation of N-Aryl Imines
Marcus C. Hansen and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received January 25, 2000
ABSTRACT
The asymmetric reduction of N-aryl imines to yield chiral amines with enantiomeric excesses above 90% was achieved. Ethylenebis(η5-
tetrahydroindenyl)titanium difluoride ((EBTHI)TiF , 1) was employed as the precatalyst with polymethylhydrosiloxane (PMHS) as the stoichiometric
2
reducing agent. A variety of N-aryl imines derived from nonaromatic ketones were reduced with high ee.
Despite the importance of chiral secondary amines in the
pharmaceutical industry and as components of natural
products, their preparation by the asymmetric reduction of
ketimines remains a challenge. Although many methods have
been developed to carry out this transformation, none have
proven to be general.1-4 Contributing to the difficulty of this
problem is the existence of most acyclic imines as inseparable
mixtures of E/Z isomers and the difference in reactivity
among imines containing different nitrogen substituents.
Herein we report the first system for the catalytic asymmetric
reduction of a wide variety of N-aryl imines derived from
nonaromatic ketones.
We recently reported that ethylenebis(η5-tetrahydro-
indenyl)titanium difluoride ((EBTHI)TiF2, 1) is an efficient
precatalyst for the asymmetric reduction of a variety of
N-alkyl imines regardless of the initial E/Z ratio of the
starting imine.2 It was found that slow addition of a primary
amine, preferably isobutylamine, to the reaction mixture was
important for promoting catalyst turnover and a high enan-
tiomeric excess.
As part of our ongoing effort to explore the scope of this
protocol, we have been interested in the extension of our
method to the reduction of N-aryl imines. Application of our
protocol to the imine derived from acetophenone and aniline,
4, gave a product with only a 13% ee. We were surprised,
however, to find that N-phenyl cyclohexylmethyl imine, 5,
was reduced to the corresponding amine with 99% ee.
Previous attempts to asymmetrically reduce N-aryl imines
are scarce; to our knowledge, no examples in which
enantiomeric excesses greater than 90% have been reported.3
(1) For reviews, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069-1094. (b) Johansson, A. Contemp. Org. Synth. 1995, 393-408.
(c) Hashiguchi, S.; Uematsu, N.; Noyori, R. J. Synth. Org. Chem., Jpn.
1997, 55, 99-109. (d) Spindler, F.; Blaser, H.-U. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
1998; pp 69-80.
(2) Verdaguer, X.; Lange, U. E. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1998, 37, 1103-1107.
(3) (a) Spindler, F.; Pugin, B.; Blaser, H.-U. Angew. Chem., Int. Ed. Engl.
1990, 29, 558-559. (b) 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) Schnider, P.; Koch, G.; Pre´toˆt, R.; Wang, G.; Bohnen, F. M.;
Kru¨ger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887-892. (d) Kainz, S.;
Brinkmann, A.; Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999, 121, 6421-
6429.
(4) (a) Ringwald, M.; Stu¨rmer, R.; Brintzinger, H. H. J. Am. Chem. Soc.
1999, 121, 1524-1527. (b) Takei, I.; Nishibayashi, Y.; Arikawa, Y.;
Uemura, S.; Hidai, M. Organometallics 1999, 18, 2271-2274. (c) Zhu,
G.; Zhang, X. Tetrahedron: Asymmetry 1998, 2415-2418. (d) Tararov,
V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Bo¨rner, A. Tetrahedron:
Asymmetry 1999, 4009-4015.
10.1021/ol005583w CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/09/2000

Further investigation confirmed that N-aryl imines derived
from nonaromatic ketones could be reduced with excellent
enantioselectivities (Table 1). The N-aryl substrates were less
derived from this class of ketone.2,3a-c,5 In light of this, the
reduction of the imines shown in entries 7 and 8 of Table 1
with ee’s of 88 and 90%, respectively, is noteworthy.
To rationalize the disparity in ee we observed between
the reduction of imines derived from acetophenone and those
from nonaromatic ketones, the reduction of several additional
imines derived from aromatic ketones was examined (Table
2). In contrast to 4 and related substrates which yielded nearly
Table 1. Reduction of N-Aryl Imines Derived from
Nonaromatic Ketones
Table 2. Reduction of N-Aryl Imines Derived from Aromatic
Ketones
racemic amine products, imine 6 was reduced to give a
product with an ee of 97% (entry 3, Table 2).7
An AM1 calculation suggests that in 4 both of the phenyl
groups are perpendicular to the CdN double bond. In the
crystal structure of 6, the CdN double bond and the aromatic
group attached to the carbon atom are coplanar. Possibly,
the difference between the enantioselectivies with which 4
and 6 are reduced is related to this conformational difference.
Although this rationale cannot be used to explain why 5 is
reduced in high ee, it is interesting to note that there are
several examples in the asymmetric reduction of ketones
where aromatic ketones are reduced in high ee and aliphatic
ketones are reduced in lower ee,8 which is opposite to what
reactive than their N-benzyl analogues, necessitating the use
of a slightly higher catalyst loading (2 mol % vs 0.5-1%)
and a slower rate of addition of isobutylamine. Compounds
with meta and para substituents on the N-aryl group are
tolerated while those with ortho substituents failed to react.
The absolute configuration of the amine derived from 5 was
determined; the assignment of the stereocenter as S is in
agreement with our previously described model for N-alkyl
imine reductions.5
Ketones containing only straight-chain alkyl substituents
are difficult to asymmetrically reduce in high ee.6 Few reports
have appeared concerning the asymmetric reduction of imines
(6) See: Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem.,
Int. Ed. 1998, 37, 1100-1103 and references therein.
(7) We have recently discussed the enantiomeric excess difference
between indanone- and tetralone-derived imines. See: Yun, J.; Buchwald
S. L. J. Org. Chem. 2000, 65, 767-774.
(5) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
8952-8959.
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Org. Lett., Vol. 2, No. 5, 2000

we observe here. Studies to further elucidate these intriguing
differences are currently in progress.
unrestricted support was provided by Merck, Novartis, and
Pfizer. Boulder Scientific generously supplied a precursor
to 1. We thank John Kowalski for the preparation of several
imine substrates, Dr. William Davis for the X-ray structural
determination of imine 6, and Jaesook Yun and Joseph Fox
for helpful discussions.
In conclusion, we have developed the first system that
reduces a variety of N-aryl imines in high enantiomeric
excess. Imines derived from nonaromatic ketones or those
derived from indanone are reduced with good to excellent
ee’s.
Supporting Information Available: Detailed experi-
mental procedures and spectral data for the substrates and
products shown in Tables 1 and 2 and full X-ray character-
ization of structure 6. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
National Institutes of Health (GM 46059). Additional
(8) Nishiyama, H. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 267-
287.
OL005583W
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