New organic activators for the enantioselective reduction of aromatic imines with trichlorosilane

Article abstract of DOI:10.1016/j.tetlet.2006.03.122

N-Picolinoyl-(2S)-(diphenylhydroxymethyl)pyrrolidine was found to work as an organic activator in the reduction of aromatic imines to the corresponding amines by Cl₃SiH. The highest selectivity was 80% ee. These are the first data showing that N-formyl group is not always essential as N-protecting group of pyrrolidine derivatives for the reduction of imines by Cl₃SiH.

Full text of DOI:10.1016/j.tetlet.2006.03.122

Tetrahedron Letters 47 (2006) 3751–3754
New organic activators for the enantioselective reduction
of aromatic imines with trichlorosilane
a
a
b
a,
*
Osamu Onomura, Yoshimi Kouchi, Fumiaki Iwasaki and Yoshihiro Matsumura
a
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
b
Tsukuba Research Laboratory, Tokuyama Corporation, 40 Wadai, Tsukuba 300-4247, Japan
Received 21 February 2006; revised 13 March 2006; accepted 17 March 2006
Available online 17 April 2006
Abstract—N-Picolinoyl-(2S)-(diphenylhydroxymethyl)pyrrolidine was found to work as an organic activator in the reduction of
aromatic imines to the corresponding amines by Cl SiH. The highest selectivity was 80% ee. These are the first data showing that
3
N-formyl group is not always essential as N-protecting group of pyrrolidine derivatives for the reduction of imines by Cl
Ó 2006 Elsevier Ltd. All rights reserved.
3
SiH.
1
2
Enantioselective reduction of ketones and imines has
Ph
Ph
Cl SiH (1.5 eq)
N
3
HN
3
been one of the recent topics in asymmetric synthesis.
3
(0.1 eq)
ð1Þ
A variety of reducing reagents have been used in the
reductions but it is still worthwhile to exploit new meth-
ods, which can be carried out using inexpensive reducing
reagents under mild conditions. One of such reagents
may be trichlorosilane (Cl SiH), a liquid material easily
available from silicon industry, though some activator
Ph
Ph
*
CH Cl
0
h
°C → rt
2
2
5
a
4
a
4
A typical reaction was carried out as follows. Cl SiH
0.45 mmol) was added into a solution of 4a (0.3 mmol)
and 3a (0.03 mmol) in CH Cl (1.5 mL), and the result-
ing solution was stirred at room temperature for 4 h.
Then, after usual workup, the products were isolated
by column chromatography. The results obtained using
3
3
(
4
2
2
is necessary for Cl SiH to efficiently reduce ketones
and imines. We already reported chiral N-formylpyr-
3
5
rolidine derivatives 1 as organic activators in the
6
7
enantioselective reduction of ketones and imines with
Cl SiH (Fig. 1). The reduction proceeds smoothly at
3
room temperature with good yields and enantioselectiv-
ity of up to 43% ee for the reduction of ketones and 66%
ee for the reduction of imines. Recently, a new activator
Table 1. Asymmetric reduction of imine 4a with Cl
presence of 1 and 3
3
SiH in the
b
2
for Cl SiH in reducing imines with high enantioselec-
3
Entry
Organic
activator
R
Yield
(%)
ee
(%)
Config.
8
a
tivity (up to 92% ee) was reported (Fig. 2). The notice-
able point in those reductions was that the presence of
N-formyl substituent was essential for those reductions.
c
1
—
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
3f
—
H
18
79
59
91
52
84
83
85
76
96
86
75
—
—
12
55
66
5
—
20
18
25
73
13
—
—
R
R
R
S
c
2
In our continuing effort to exploit new chiral organic
3
2
CO Me
CONHPh
CONHNaph-1
CPh
H
CO
CONHPh
CONHNaph-1
CPh
CHPh
9
c
compounds in place of 1 to activate Cl SiH, we found
4
c
3
N-picolinoylpyrrolidine derivatives 3a–f to also work
as organic activators in the reduction of aromatic imine
5
6
7
8
9
0
1
2
2
OH
—
R
S
4
to amine 5 (Eq. 1). These are the first data showing
2
Me
that N-formyl group is not always essential in the
1
0,11
structure of organic activators for Cl SiH.
3
1
1
1
R
S
2
OH
2
R
Keywords: Organocatalysis; Asymmetric reduction; Imines; Optically
active amines.
a
b
c
Determined by HPLC.
Identified by comparison of the HPLC data with the literature data.
Literature data, see Ref. 7.
*
Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819
476; e-mail: matumura@net.nagasaki-u.ac.jp
2
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.122

3752
O. Onomura et al. / Tetrahedron Letters 47 (2006) 3751–3754
Table 2. Reduction of a variety of imines 4a–h by Cl
3
SiH in the
Config.
presence of 3e
N
N
R
N
Aromatic imines
Yield (%)
86
% ee
73
CHO
O
R
1
a-e
3a-f
N
S
Me
4a
a; R=H
d; R=CONHNaph-1
b; R=CO Me
e; R=CPh OH
2
2
c; R=CONHPh
f; R=CHPh2
OMe
N
Figure 1. Chiral organic activators for Cl
3
SiH.
90
75
71
S
S
Me
4b
NHPh
N
9
7
0
3
N
O
Me
CHO
4c
MeO
2
N
3
Figure 2. Chiral organic activator for reduction of imines by Cl SiH.
71
73
S
Me
Cl
4d
3
a–f as activators are summarized in Table 1, which also
shows the results using 1a–e for comparison (Fig. 1).
N
Although the yield of 5a in the absence of activators was
low (entry 1), the reduction became more efficient by the
addition of a catalytic amount of N-formylpyrrolidines
8
4
S
S
Me 4e
O N
2
1
a–e (entries 2–6). Similarly, compounds 3a–f were
found to work as activators for Cl SiH (entries 7–12).
Also, it was found that the highest enantioselectivity
N
3
4f
67
80
67
(
5
entry 11) in 3a–f was better than that in 1a–e (entry
). The catalytic activity of 3e was also checked in the
reduction of a variety of imines 4b–h and enamine 4i
with almost similar stereoselectivity to that in the reduc-
tion of 4a (Table 2). On the other hand, N-nicotinoyl-
pyrrolidine (3h) and N-(4-pyridylcarbonyl)pyrrolidine
N
a
b
2
8
4
—
Me
4g
Me
O
(
3i) did not activate Cl SiH (Fig. 3), suggesting an
3
important role of a complex in which Si atom coordi-
nates with both a nitrogen atom of picolinoyl group
and a carbonyl oxygen. Little difference of % ee between
N
0
45
41
R
S
CO Me
2
4
h
3
b and d (entries 8–10) also suggests that Si atom does
not coordinate with the carbonyl group of proline ester
b and amides 3c,d, but with both the nitrogen atom of
NH2
3
CO Et
65
2
picolinoyl group and the carbonyl oxygen. Furthermore,
the fact that 3e afforded better result than 3f (Fig. 4) sug-
gests an important role of hydroxyl group of 3e to coor-
4
i
a
N-Phenyl-1-(p-acetylphenyl)ethylamine.
Not determined.
dinate with the Si atom of Cl SiH.
b
3
On the basis of these facts, we propose a mechanism
shown in Figure 5, in which 3e coordinates with both
than transition state B, though the mechanism is a work-
ing hypothesis.
1
2
4
a and Cl SiH, the transition state A being more likely
3
N
N
N
N
N
N
N
N
N
N
Ph
Ph
O
Ph
Ph
O
O
O
O
HO
3
a
3h
3i
3
e
3f
1
2%
21%
13%ee ((R)-5a)
8
3%
73%ee ((S)-5a)
Figure 3. Reduction of 4a with 3a,h,i.
Figure 4. Reduction of 4a with 3e,f.

O. Onomura et al. / Tetrahedron Letters 47 (2006) 3751–3754
3753
Me
Me
N
N
H-bonding
H-bonding
H
H
H
H
O
O
N
N
N
N
Cl
Si
O
Cl
Si
O
Cl
Cl
Cl
Cl
A
B
(
S)-5a
(R)-5a
8
6.5%
13.5%
Figure 5. A plausible reaction mechanism for reduction of 4a with 3e.
Acknowledgements
M. T.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 6784–
789; (e) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am.
6
Chem. Soc. 2005, 127, 12462–12463; Hydrogen transfer
reactions: (f) Uematsu, N.; Fujii, A.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–
This study was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas, (No. 420: Reaction
Control of Dynamic Complexes) from the Ministry of
Education, Science, Sports and Culture, Japan, and by
the Tokuyama Science Foundation.
4
917; (g) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841–843;
Hydrogenation: (h) Levi, A.; Modena, G.; Scorrano, G.
J. Chem. Soc., Chem. Commun. 1975, 6–7; (i) Burk, M. J.;
Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266–6267; (j)
Willoughpy, C. A.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 8952–8965; (k) Trifonova, A.; Diesen, J. S.;
Chapman, C. J.; Abdersson, P. G. Org. Lett. 2004, 6,
3825–3827; (l) Solinas, M.; Pfaltz, A.; Cozzi, P. G.; Leiner,
W. J. Am. Chem. Soc. 2004, 126, 16142–16147; (m)
Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44,
7564–7567.
References and notes
1
. Representative literatures, borane-hydride reagents: (a)
Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem.
Soc., Chem. Commun. 1983, 469–470; (b) Corey, E. J.;
Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5
551–5553; (c) Yamada, T.; Nagata, T.; Sugi, K. D.;
3. Some recent reviews, see: (a) Noyori, R.; Hashiguchi, S.
Acc. Chem. Res. 1997, 30, 97–102; (b) Corey, E. J.; Helal,
C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012; (c)
Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40,
40–73; (d) Carpentier, J.-F.; Bette, V. Curr. Org. Chem.
2002, 6, 913–936; (e) Riant, O.; Mostefai, N.; Courmarcel,
J. Synthesis 2004, 2943–2958; (f) Tararov, V. I.; B o¨ rner, A.
Synlett 2005, 203–211; (g) Weinreb, S. M.; Orr, R. K.
Synthesis 2005, 1205–1227.
4. (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42,
2781–2782; (b) Benkeser, R. A.; Snyder, D. C. J.
Oganomet. Chem. 1982, 225, 107–115; (c) Akutagawa,
S. J. Synth. Org. Chem. Jpn. 1986, 44, 513–518; (d)
Okamoto, H.; Kato, S. Bull. Chem. Soc. Jpn. 1991, 64,
2128–2130; (e) Zulehler, W.; Neure, B.; Rau, G. In
Ullmann’s Encyclopedia of Industrial Chemistry; VCH:
Weinheim, 1993; Vol. A23; pp 721–741; (f) Chong, P. Y.;
Janicki, S. Z.; Petillo, P. A. J. Org. Chem. 1998, 63,
8515–8521; (g) Enholm, E. J.; Schulte, J. P., II. J. Org.
Chem. 1999, 64, 2610–2611; (h) Iwasaki, K.; Nozawa, S.
J. Synth. Org. Chem. Jpn. 2000, 58, 62–64; (i) Hayashi,
T.; Hirata, S.; Kitayama, K.; Tsuji, H.; Torii, A.;
Uozumi, Y. J. Org. Chem. 2001, 66, 1441–1449; (j)
Cheng, C.-H.; Shih, H.-H.; Shih, H.-T. Org. Lett. 2001,
3, 811–814; (k) Choi, S.-B.; Kim, B.-K.; Boudjouk, P.;
Grier, D. G. J. Am. Chem. Soc. 2001, 123, 8117–8118;
Yorozu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.;
Mukaiyama, T. Chem. Eur. J. 2003, 9, 4485–4509;
Aluminium-hydride reagents: (d) Yamaguchi, S.; Mosher,
H. S. J. Org. Chem. 1973, 38, 1870–1877; (e) Noyori, R.;
Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709–6716; Hydrogen transfer reactions:
(
f) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563; (g)
Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522;
Hydrogenation: (h) Ohkuma, T.; Ooka, H.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
2
675–2676; (i) Ohkuma, T.; Koizumi, M.; Doucet, H.;
Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.;
Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 13529–13530; (j) Ohkuma, T.; Sandoval,
C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Muniz, K.; Noyori,
R. J. Am. Chem. Soc. 2005, 127, 8288–8289.
2
. Representative literatures, hydride reagents: (a) Langlois,
N.; Dang, T.-P.; Kagan, H. B. Tetrahedron Lett. 1973,
4
865–4868; (b) Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.;
Owa, M.; Kanda, N.; Nakahama, S. J. Chem. Soc., Perkin.
Trans. 1 1985, 2615–2619; (c) Becker, R.; Brunner, H.;
Mahboobi, S.; Wiegrebe, W. Angew. Chem., Int. Ed. 1985,
2
4, 995–996; (d) Verdaguer, X.; Lange, U. E. W.; Reding,

3754
O. Onomura et al. / Tetrahedron Letters 47 (2006) 3751–3754
(
l) Iwasaki, F. Oda J. Synth. Org. Chem. Jpn. 2001, 59,
005–1007.
. Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996,
07–408.
. Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507–7511.
. Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.;
Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42,
1
5
6
7
4
O
N
Ph
N
6
2525–2527.
8
. Malkov, A. V.; Ston cˇ ius, S.; MacDougall, K. N.; Mariani,
A.; McGeoch, G. D.; Ko cˇ ovsk y´ , P. Tetrahedron Lett.
11. Some recent literatures concerning organic activators for
other trichlorosilanes, see: (a) Nakajima, M.; Saito, M.;
Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120,
6419–6420; (b) Denmark, S. E.; Su, X.; Nishigaichi, Y. J.
Am. Chem. Soc. 1998, 120, 12990–12991; (c) Shimada, T.;
Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799–
2801; (d) Denmark, S.; Fan, Y. J. Am. Chem. Soc. 2002,
124, 4233–4235; (e) Wong, W.-L.; Lee, C.-S.; Leung,
H.-K.; Kwong, H.-L. Org. Biomol. Chem. 2004, 2, 1967–
1969; (f) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew.
Chem., Int. Ed. 2004, 43, 6491–6493; (g) Nakajima, M.;
Kotani, S.; Ishiduka, T.; Hashimoto, S. Tetrahedron Lett.
2005, 46, 157–159.
2006, 62, 264–284.
9
. Pyridine catalyzed hydrosilylation of unsaturated carbon–
carbon bonds with Cl SiH, see: (a) Nozakura, S.;
3
Konotsune, S. Bull. Chem. Soc. Jpn. 1956, 29, 322–326;
(
b) Pike, R. A. J. Org. Chem. 1962, 27, 2186–2190; Also
pyridine promoted reduction of phosphine oxides with
Cl SiH, see: (c) Horner, L.; Balzer, W. D. Tetrahedron
3
Lett. 1965, 1157–1162; Reductive silylation of carbonyl
compounds proceeded using Cl SiH–tertiary amine affor-
3
ded not alcohols but alkylsilanes, see: (d) Benkeser,
R. A.; Smith, W. E. J. Am. Chem. Soc. 1969, 91, 1556–
1
557.
12. Intermediates such as one involving a Si–O bond cannot
be ruled out.
1
0. Recently, we disclosed that using N-picolinoyl-L-proline
derivative 3b as an activator for Cl SiH reduced ketones to
chiral alcohols with good optical purities, see Ref. 13. And
more recently, the other group reported that 2-pyridylox-
azoline 6 worked well as an efficient activator for Cl SiH
3
to reduce ketones and imines, see Ref. 14.
13. Matsumura, Y.; Onomura, O.; Iwasaki, F. Jpn. Kokai
Tokkyo Koho 2005; JP 2005029503: CA 142:176534, 2005.
14. Malkov, A. V.; Stewart Liddon, A. J. P.; Ram ´ı rez-L o´ pez,
P.; Bendov a´ , L.; Haigh, D.; Ko cˇ ovsk y´ , P. Angew. Chem.,
Int. Ed. 2006, 45, 1432–1435.
3