A highly enantioselective Lewis basic organocatalyst for reduction of N-aryl imines with unprecedented substrate spectrum

Article abstract of DOI:10.1021/ol060112g

L-Pipecolinic acid derived formamides have been developed as highly efficient and enantioselective Lewis basic organocatalysts for the reduction of N-aryl imines with trichlorosilane. Catalyst 4b afforded high isolated yields (up to 98%) and enantioselect

Full text of DOI:10.1021/ol060112g

ORGANIC
LETTERS
2006
Vol. 8, No. 5
999-1001
A Highly Enantioselective Lewis Basic
Organocatalyst for Reduction of N-Aryl
Imines with Unprecedented Substrate
Spectrum
Zhouyu Wang,†,‡ Xiaoxia Ye,†,§ Siyu Wei,† Pengcheng Wu,† Anjiang Zhang,†,§ and
Jian Sun*,†
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu, 610041, China, Department of Chemistry, Xihua UniVersity,
Chengdu, 610039, China, Department of Chemistry, Wenzhou UniVersity, Wenzhou,
325035, China, and Graduate School of Chinese Academy of Sciences, China
sunjian@cib.ac.cn
Received January 15, 2006
ABSTRACT
L-Pipecolinic acid derived formamides have been developed as highly efficient and enantioselective Lewis basic organocatalysts for the reduction
of N-aryl imines with trichlorosilane. Catalyst 4b afforded high isolated yields (up to 98%) and enantioselectivities (up to 96%) under mild
conditions with an unprecedented substrate spectrum.
Catalytic enantioselective reduction of imines represents one
of the most important methods for preparing chiral amines,1
a ubiquitous structural motif of natural products, drugs, and
agrochemicals. Since the 1970s, considerable effort has been
devoted to the development of this transformation, and
remarkable progress has been made.1,3 However, compared
with the reduction of alkenes and ketones, relatively limited
numbers of highly enantioselective procedures are currently
available for the reduction of imines, and the development
of efficient catalysts with high enantioselectivity has proven
to be much more difficult. In particular, the highly enantio-
selective catalyst with a satisfactorily broad substrate scope
remains elusive. Factors contributing to the difficulty of this
transformation include the difference in reactivity among
imines containing different nitrogen substituents, the exist-
ence of acyclic imines as inseparable mixtures of E/Z
† Chengdu Institute of Biology.
(3) For examples, see: (a) Moessner, C.; Bolm, C. Angew. Chem., Int.
Ed. 2005, 44, 7564. (b) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 12462. (c) Trifonova, A.; Diesen, J. S.; Chapman,
C. J.; Andersson, P. G. Org. Lett. 2004, 6, 3825. (d) Lipshutz, B. H.;
Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228. (e) Kadyrov, R.;
Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472. (f) Chi, Y.; Zhou,
Y.; Zhang, X. J. Org. Chem. 2003, 68, 4120. (g) Xiao, D.; Zhang, X. Angew.
Chem., Int. Ed. 2001, 40, 3425. (h) Hansen, M. C.; Buchwald, S. L. Org.
Lett. 2000, 2, 713. (i) Nishibayshi, Y.; Takei, I.; Uemura, S.; Hidai, M.
Organometallics 1998, 17, 3420. (j) Verdaguer, X.; Lange, U.; Buchwald,
S. L. Angew. Chem., Int. Ed. 1998, 37, 1103. (k) Schnider, P.; Koch, G.;
Pretot, R.; Wang, G.; Bohnen, F. M.; Kru¨ger, C.; Pfaltz, A. Chem.-Eur. J.
1997, 3, 887. (l) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald,
S. L. J. Am. Chem. Soc. 1996, 118, 6784. (m) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916.
‡ Xihua University.
§ Wenzhou University.
(1) (a) Blaser, H.-U.; Spindler, F. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 1, p 247. (b) Ohkuma, T.; Noyori, R. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 2004; Suppl. 1, p 43.
(2) For recent reviews, see: (a) Taratov, V. I.; Bo¨rner, A. Synlett 2005,
203. (b) Riant, O.; Mostefai, N.; Courmarcel, J. Synthesis 2004, 2943. (c)
Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (d) Blaser, H.-U.; Malan,
C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003,
345, 103. (e) Carpentier, J. F.; Bette, V. Curr. Org. Chem. 2002, 6, 913.
(f) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. (g)
Kobayshi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
10.1021/ol060112g CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/10/2006

Figure 1. Structures of the catalysts reported previously.
Figure 2. Structures of the catalysts evaluated in this study.
isomers, and the ease of interconversion between these two
isomers in solution. Therefore, the search for efficient
catalysts for highly enantioselective reduction of imines still
remains a challenging task.
commercially available L-pipecolinic acid as the template.
In our initial practice, we observed that compound 4a (Figure
2) exhibited significantly higher reactivity and selectivity than
its congener 1a in the reduction of imine 5a with HSiCl3
(entries 1 and 2, Table 1). This observation prompted us to
Currently available chemical catalysts for the enantiose-
lective reduction of imines are mostly limited to chiral
transition metal complexes, which often require elevated
pressures and/or additives to afford high yields and ee
values.2,3 Recently, some attention has been turned to the
development of chiral organocatalysts.2-6 Effective catalysts
reported thus far in the literature include the Lewis bases
14a and 24b (Figure 1) for the hydrosilation with trichlorosi-
lane (HSiCl3) and the Brønsted acids 3a5a and 3b5b for the
transfer hydrogenation with Hantzch esters. High enantiose-
lectivities have been obtained with 2 and 3b in the reduction
of a few N-aryl ketimines.4b,5b However, the generality of
these catalysts is far less than satisfactory.7 Herein, we report
our discovery of the novel Lewis basic organocatalyst 4b
(Figure 2) that promotes the reduction of N-aryl ketimines
with HSiCl3 in high yield and excellent enantioselectivity
with an unprecedented substrate spectrum.
Table 1. Asymmetric Reductions of Ketimine 5aa
entry catalyst
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
temp (°C) yield (%)b ee (%)c
1
1a
4a
4b
4c
4d
4b
4b
4b
4b
4b
4b
4b
0
75d
94
97
97
71
97
91
81
97
71
87
61
59d
73
94
93
47
92
94
94
90
95
94
85
2
3
4
5
0
0
0
0
0
0
0
Recently, great progress has been made in the development
of highly enantioselective Lewis basic organocatalysts for
the nucleophilic reactions of trichlorosilyl derivatives.8 We
are particularly interested to design novel formamide-based
Lewis basic catalysts for the relatively less advanced
asymmetric hydrosilation of imines with HSiCl3 using the
6
7
8
9
rt
-20
0
10
11e
12f
0
(4) (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki,
T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525. (b) Malkov, A. V.;
Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6, 2253.
(5) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M.
Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 7424.
(6) For organocatalysis, see leading reviews: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) List, B. Tetrahedron 2002,
58, 5573. (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. Two major
journals have recently dedicated special issues to organocatalysis. See: (e)
Acc. Chem. Res. 2004, 37 (8), 487. (f) AdV. Synth. Catal. 2004, 346 (9-
10), 1007.
(7) At the time of the submission of this manuscript, an analogue of 3
(R ) SiPh3) was reported to catalyze the reduction of in situ prepared imines
with Hantzch esters in high enantioselectivity with broad substrate
spectrum: Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, W. C. J. Am.
Chem. Soc. 2006, 128, 84.
(8) For recent reviews, see: (a) Denmark, S. E.; Heemstra, J. R.; Beutner,
G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (b) Rendler, S.; Oestreich,
M. Synthesis 2005, 1727. (c) Koboyashi, S.; Sugiura, M.; Ogawa, C. AdV.
Synth. Catal. 2004, 346, 1023. (d) Denmark, S. E.; Fu, J. Chem. ReV. 2003,
103, 2763. (e) Denmark, S. E.; Fu, J. Chem. Commun. 2003, 167. (f)
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
a Unless specified otherwise, reactions were carried out with 10 mol %
catalyst and 2.0 equiv of HSiCl3 on a 0.2 mmol scale in 1.0 mL of solvent
for 16 h. b Isolated yield based on the imine. c The ee values were
determined using chiral HPLC. d The yield and ee at room temperature
reported in ref 4a are 97 and 55%, respectively. e 5 mol % of catalyst was
used. f 1 mol % catalyst was used.
prepare compounds 4b-d, starting from L-pipecolinic acid
and corresponding chiral 2-amino-1,2-diphenylethanols (see
Supporting Information), and we examined their catalytic
efficiencies (Table 1). In the testing reaction of imine 5a in
the presence of 10 mol % catalyst in CH2Cl2 at 0 °C for 16
h, 4b afforded the highest yield and ee (97% yield and 94%
ee, entry 3).9 Its diastereomer 4c gave the same yield and
marginally lower ee (entries 3 and 4), indicating that the
(9) The analogous L-proline derivative gave 71% yield and 75% ee under
identical conditions.
1000
Org. Lett., Vol. 8, No. 5, 2006

absolute configuration of Câ (see 4b for labeling) has little
impact on the reactivity and selectivity. In contrast, 4d was
found to be much less selective and reactive than 4b and
4c, affording only 71% yield and 47% ee under identical
conditions (entry 5). Thus an (S)-configuration proved to be
distinctly preferred for the CR.
Table 2. Asymmetric Reduction of Ketimines 5 with Catalyst
4ba
We also examined the influences of different reaction
parameters on the performance of 4b in the reduction of 5a
(entries 6-12, Table 1). Chloroform, dichloroethane, and
toluene were all found to afford the same high level of
enantioselectivities as dichloromethane (entries 6-8). Low-
ering the reaction temperature to -20 °C had little effect on
the selectivity (entry 10), but the reactivity was significantly
decreased. The lowest effective catalyst loading was found
to be 10 mol %. The ee value remained at the same level
with 5 mol % of 4b, but the reaction slowed to some extent
(entry 11). Further decrease of the catalyst loading to 1 mol
% caused an unacceptable loss of reactivity and selectivity
(entry 12).
To probe the generality of catalyst 4b, a broad range of
N-aryl ketimines (5a-s) was reduced with HSiCl3 under
optimal conditions. As illustrated in Table 2, for the aromatic
N-Ph and N-p-MeOPh ketimines 5a-i, the desired products
6a-i were obtained in very good yields (82-98%, entries
1-9) with excellent ee values (90-96%). The sterically
hindered N-o-MeOPh imines 5k and 5q (entries 11 and 17)
and imines 5l-o with electron-withdrawing -Cl and -Br
groups on the arene of R5 (entries 12-15) all reacted well
to give high ee values of 87-95% and yields of 75-98%.
Furthermore, catalyst 4b also exhibited high enantioselec-
tivities for the challenging aliphatic ketimines 5o-r despite
that all the imines were used as E/Z isomeric mixtures,
affording 87-95% ee values with 75-86% yields (entries
15-18). Additionally, in the presence of catalyst 4b, R,â-
unsaturated imine 5s (E/Z ) 2/1) was chemo- and enanti-
oselectively reduced to afford allylic amine 6s in 81% yield
and 87% ee. Overall, the high enantioselectivity of 4b proved
to be remarkably general for N-aryl ketimines, which is
unprecedented in catalytic asymmetric reduction of imines.
a Unless specified otherwise, reactions were carried out with 2.0 equiv
of HSiCl3 on a 0.2 mmol scale in 1.0 mL of solvent at 0 °C for 16 h.
b Isolated yield based on the imine. c The ee values were determined using
chiral HPLC. d The reaction time is 48 h.
aspects and the full application scope of this catalytic system
are under exploration and will be reported in due course.
Acknowledgment. We are grateful for financial support
from the Chinese Academy of Sciences (Hundreds of Talents
Program) and from the National Science Foundation of China
(20402014).
In summary, we have developed a highly efficient Lewis
basic organocatalyst (4b) for the enantioselective reduction
of N-aryl imines with trichlorosilane. This catalyst, easily
prepared from the commercially available L-pipecolinic acid,
promoted the reduction of a broad range of N-aryl imines in
high yields and excellent ee values under mild conditions.
The broad substrate spectrum of this catalyst is unprecedented
in asymmetric imine reduction catalysis. The mechanistic
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060112G
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