L-piperazine-2-carboxylic acid derived N-formamide as a highly enantioselective Lewis basic catalyst for hydrosilylation of N-aryl imines with an unprecedented substrate profile

Article abstract of DOI:10.1021/ol060984i

L-Piperazine-2-carboxylic acid derived N-formamides have been developed as highly enantioselective Lewis basic catalysts for the hydrosilylation of N-aryl imines with trichlorosilane. The arene sulfonyl group on N4 was found to be critical for the high en

Full text of DOI:10.1021/ol060984i

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3045-3048
L
-Piperazine-2-carboxylic Acid Derived
N-Formamide as a Highly
Enantioselective Lewis Basic Catalyst
for Hydrosilylation of N-Aryl Imines with
an Unprecedented Substrate Profile
Zhouyu Wang,†,§ Mounuo Cheng,† Pengcheng Wu,†,‡ Siyu Wei,† and Jian Sun*,†
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu 610041, China, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China, and Department of Chemistry,
Xihua UniVersity, Chengdu 610039, China
sunjian@cib.ac.cn
Received April 25, 2006
ABSTRACT
L-Piperazine-2-carboxylic acid derived N-formamides have been developed as highly enantioselective Lewis basic catalysts for the hydrosilylation
of N-aryl imines with trichlorosilane. The arene sulfonyl group on N4 was found to be critical for the high enantioselectivity of the catalyst.
High isolated yields (up to 99%) and enantioselectivities (up to 97%) were obtained for a broad range of substrates, including aromatic and
aliphatic ketimines, particularly those with R2 as relatively bulky alkyl groups.
Asymmetric Lewis base catalysis has proven to be a powerful
and viable asymmetric synthetic method, of which the most
successful applications have been in allylations and aldol
reactions using trichlorosilylated reagents.1 Recently, asym-
metric reduction of imines, a useful but challenging reaction
for the production of chiral amines,2,3 was also effected by
Lewis base catalysis.4 Matsumura first disclosed that L-
proline derived Lewis basic N-formamide 1 (Figure 1)
catalyzed the reduction of N-aryl ketimines with trichloro-
silane (HSiCl3) in modest enantioselectivity (up to 66% ee).4a
Later, Malkov and Kocovsky reported that L-valine derived
catalyst 2 significantly improved the enantioselectivity (up
to 92% ee).4b,c,5 In our recent publication, we presented a
L-pipecolinic acid derived Lewis basic catalyst (3) that
afforded the highest level of enantioselectivities (up to 96%
ee) with an exceptional substrate spectrum.6 Encouraged by
these results, we continued to search for new highly efficient
(1) 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.
(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.
† Chengdu Institute of Biology.
‡ Chengdu Institute of Organic Chemistry.
§ Xihua University.
10.1021/ol060984i CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/06/2006

membered cyclic backbones. We envisioned that the piper-
azinyl backbone could be a good replacement of the
piperidinyl backbone of 3 considering that the secondary
amino group on the 4-position (N4) of the former should
provide an excellent open site for introducing diversity
elements and thus fine tuning the catalytic properties. On
the other hand, it should be interesting to see if the chiral
2-acetoxy-1,2-diphenylethyl amide group of 3, which was
shown to be critical for the high enantioselectivity,6 is still
favorable in the PCA-based new catalyst system. Thus, we
prepared a set of new N-formamide catalysts (4a-e and 5a-
e, Figure 2) starting from the commercially available L-PCA
(see Supporting Information) and tested their catalytic effects
in the model reaction of 6a with HSiCl3 in the presence of
10 mol % of catalyst in CH2Cl2 at 0 °C.
Figure 1. Structures of the catalysts reported previously.
and enantioselective Lewis basic N-formamide catalysts with
structural diversity. Herein, we report our discovery of the
L-piperazine-2-carboxylic acid (PCA) derived new catalyst
4e (Figure 2) that has a relatively simple structure and
As shown in Table 1, catalyst 4a with an alkyl group (Bn)
on N4 gave only a moderate yield and ee value (entry 1).
Table 1. Asymmetric Hydrosilylation of Ketimine 6aa
entry
catalyst
temp (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13d
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
4e
4e
4e
0
0
0
0
0
0
0
0
0
65
64
77
82
97
92
68
80
71
63
95
30
30
40
<5
74
77
80
73
56
36
5
71
89
89
88
Figure 2. Structures of the catalysts evaluated in this study.
0
-20
-40
-20
exhibits high enantioselectivity in the hydrosilylation of
N-aryl ketimines with an unprecedented substrate profile.
Given the outstanding performance of 3,6 we were
interested to design new catalysts bearing analogous six-
a Unless specified otherwise, reactions were carried out with 10 mol %
of catalyst and 2.0 equiv of HSiCl3 on a 0.2 mmol scale in 1.0 mL of CH2Cl2
for 48 h. b Isolated yield based on the imine. c The ee values were
determined using chiral HPLC. d 5 mol % of catalyst was used.
(3) For selected recent examples, see: (a) Lipshutz, B. H.; Frieman, B.
A.; Tomaso, A. E., Jr. Angew. Chem., Int. Ed. 2006, 45, 1259. (b) Storer,
R. I.; Carrera, D. E.; Ni, Y.; MacMillan, W. C. J. Am. Chem. Soc. 2006,
128, 84. (c) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44, 7424. (d) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (e) Moessner, C.; Bolm, C. Angew.
Chem., Int. Ed. 2005, 44, 7564. (f) Nolin, K. A.; Ahn, R. W.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 12462. (g) Trifonova, A.; Diesen, J. S.;
Chapman, C. J.; Andersson, P. G. Org. Lett. 2004, 6, 3825. (h) Lipshutz,
B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228. (i) Kadyrov,
R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472. (j) Chi, Y.;
Zhou, Y.; Zhang, X. J. Org. Chem. 2003, 68, 4120. (k) Xiao, D.; Zhang,
X. Angew. Chem., Int. Ed. 2001, 40, 3425. (l) Hansen, M. C.; Buchwald,
S. L. Org. Lett. 2000, 2, 713.
(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.
(c) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.; McGeoch,
G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264.
(5) (a) Very recently, modest to high ee values were also achieved with
chiral Brønsted basic organocatalysts; see: (a) Malkov, A. V.; Liddon, A.;
Ramirez-Lopez, P.; Bendova, L.; Haigh, D.; Kocovsky, P. Angew. Chem.,
Int. Ed. 2006, 45, 1432. (b) Onomura, O.; Kouchi, Y.; Iwasaki, F.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751.
Surprisingly, when this group was changed to methane-
sulfonyl, the resulted catalyst 4b totally lost the selectivity
(entry 2). It seems plausible to ascribe this to the competitive
nonstereoselective binding of the sulfonyl oxygen with the
central silicon atom of HSiCl3. However, the switch of the
aliphatic methanesulfonyl group to the aromatic benzene-
sulfonyl group enables catalyst 4c to recover the selectivity
(74% ee, entry 3). Moreover, the addition of an alkyl group
to the para position of the benzene ring was found to be
beneficial to both the reactivity and the selectivity. 4d with
a para-methyl gave 82% yield and 77% ee (entry 4), and 4e
with a bulky para-tert-butyl resulted in 97% yield and 80%
ee (entry 5).
(6) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 8, 999.
3046
Org. Lett., Vol. 8, No. 14, 2006

As observed with the previously reported N-formamide
catalysts,4,6 the amide group also has profound impacts on
both the reactivity and selectivity of this series of PCA-based
new catalysts. Although catalyst 5a bearing a para-methoxy-
phenyl amide group led to a slightly lowered yield and ee
value, a significantly decreased yield and ee value were
achieved with 5b bearing a 2-naphthyl amide group. More-
over, the (1S,2S)-2-acetoxy-1,2-diphenylethyl amide group,
a critical structural motif of 3,6 was found to be unfavorable
in this catalyst system. 5c catalyzed the reaction with only
36% ee (entry 8). To check if the absolute stereochemistries
in this amide group could make any big difference, the
diastereomers 5d and 5e were examined. In agreement with
the observation in the case of 3, an (S)-configuration is
distinctly preferred for C1′ (see 5c for labeling). 5d with an
(R)-C1′ afforded a nearly racemic product (entry 9). Interest-
ingly, although the absolute configuration of C2′ has marginal
influence on the selectivity of 3, 5e with an (R)-C2′ exhibited
much higher selectivity than 5d with an (S)-C2′ (entries 9
and 10). Thus, catalyst 5e with the (1S,2R)-2-acetoxy-1,2-
diphenylethyl amide group has the best-match stereochem-
istries. Nevertheless, the performance of 5e is still not as
good as that of 4e (entries 5 and 10). Hence, catalyst 4e was
selected for further studies.
Table 2. Asymmetric Hydrosilylation of Ketimines 6 with
Catalyst 4ea
We next examined the influences of some other reaction
parameters on the performance of 4e in the hydrosilylation
of 6a. When the reaction temperature was lowered from 0
to -20 °C, the ee value of product 7a was lifted to 89%
and the yield was almost unchanged (entries 5 and 11).
Further lowering the temperature to -40 °C had no effect
on the selectivity but caused an unacceptable loss of reactivity
(entry 12). When the catalyst loading was reduced from 10
to 5 mol %, the ee value of the product remained in the
same level, whereas only 30% yield was obtained because
of low conversion (entry 13).
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 -20 °C for 48 h.
b Isolated yield based on the imine. c The ee values were determined using
chiral HPLC; the data in parentheses are for catalyst 3.
95%),6 only low to moderate enantioselectivities (entries 8,
9, and 15-19; data in parentheses) were attained for 6h, 6i,
and 6o-s, with only one exception of 92% ee for 6q with
R6 as cyclopropanyl (entry 17).
We also investigated some other ketimines with different
N-substituents (Scheme 1). Unfortunately, with the catalysis
Having established the optimal reaction conditions, we
next explored the application scope of 4e. A broad range of
N-phenyl ketimines (6a-s) were reduced with HSiCl3 in the
presence of 10 mol % of catalyst in CH2Cl2 at -20 °C. As
illustrated in Table 2, regular electron-rich and electron-
deficient aromatic methyl ketimines 6a-f (R6 ) Me) reacted
well to give the desired products 7a-f in high yield and
enantioselectivity (63-99% yield, 85-90% ee, entries 1-6).
The hydrosilylation of the aliphatic cyclohexyl methyl
ketimine 6g also proceeded well with 86% yield and 82%
ee (entry 7). More significantly, ketimines 6h-s with a
relatively bulky R6, including Et, nPr, iPr, c-Pr, nBu, and iBu,
were all found to be good substrates for catalyst 4e, affording
high yields (75-92%) and excellent enantioselectivities (84-
97%, mostly 90-97%). Furthermore, consistently higher ee
values were obtained for these ketimines bearing a relatively
bulky R6 than the corresponding methyl ketimines (84-97%
vs 82-90% ee, entries 8-19 vs 1-7). To the best of our
knowledge, such a substrate profile has not been previously
reported for the asymmetric reduction of N-aryl ketimines.
As a matter of fact, when 3 was used as the catalyst, a
dramatically different scenario was observed: whereas 6a-g
were previously shown to afford excellent ee values (90-
Scheme 1
of 4e, the ketimines with a substituted N-phenyl group were
found to give significantly lowered ee values compared with
the corresponding N-phenyl ketimines. The N-benzyl ketimines
were also proven to be unsuitable substrates for the catalyst.
In summary, we have developed the first L-pipecolinic acid
based chiral Lewis basic N-formamide catalyst (4e) that
Org. Lett., Vol. 8, No. 14, 2006
3047

promotes the enantioselective reduction of N-aryl ketimines
with trichlorosilane in high yield and enantioselectivity.
Compared with the L-pipecolinic acid based catalyst 3 that
we previously developed, the most remarkable features of
this catalyst include (a) its structural simplicity given that
the bulky and costly chiral amide fragment needed in 3 for
ensuring high enantioselectivity is not needed, (b) its high
enantioselectivity for both methyl ketimines and ketimines
with a relative bulky R6, and (c) its consistently higher
enantioselectivity for the latter substrates than for the former,
which is so far unprecedented in organocatalytic asymmetric
reduction of imines. The mechanistic aspects of the special
substrate profile and the full application scope of this catalyst
system are currently under investigation. The results will be
reported in due course.
Acknowledgment. We are grateful for financial support
from the Chinese Academy of Sciences (Hundreds of Talents
Program).
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for the products
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060984I
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Org. Lett., Vol. 8, No. 14, 2006