First chemo- and stereoselective reduction of imines using trichlorosilane activated with N-formylpyrrolidine derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00219-2

Trichlorosilane activated with N-formylpyrrolidine derivatives was found to be an effective reagent for reduction of imines to amines. The reagent showed much higher selectivity toward imino groups than carbonyl groups. The reduction of imines using trichlorosilane activated with optically active N-formylproline derivatives gave enantiomerically enriched amines in moderate optical yields (up to 66% ee).

Full text of DOI:10.1016/S0040-4039(01)00219-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2525–2527
First chemo- and stereoselective reduction of imines using
trichlorosilane activated with N-formylpyrrolidine derivatives
a
b
b
b
b
Fumiaki Iwasaki, Osamu Onomura, Katsuhiko Mishima, Takefumi Kanematsu, Toshihide Maki
b,
and Yoshihiro Matsumura *
a
Tsukuba Research Laboratory, Tokuyama Corporation, 40 Wadai, Tsukuba 300-4247, Japan
b
Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 17 January 2001; accepted 2 February 2001
Abstract—Trichlorosilane activated with N-formylpyrrolidine derivatives was found to be an effective reagent for reduction of
imines to amines. The reagent showed much higher selectivity toward imino groups than carbonyl groups. The reduction of imines
using trichlorosilane activated with optically active N-formylproline derivatives gave enantiomerically enriched amines in
moderate optical yields (up to 66% ee). © 2001 Elsevier Science Ltd. All rights reserved.
Chemo- and stereoselective reduction of imines is very
useful for the preparation of functionalized amino com-
pounds. Although there have been a variety of solid
well as the requirement of HMPA as a ligand, while the
latter liquid reagent might be useful for industrial use
because of the relatively easy handling in operation and
1
6
reducing reagents, most of them prefer the reduction
low cost. However, there has been little information on
7
of a carbonyl group to that of an imino group due to
selectivity of the reagent 1 toward an imino group. In
2
the lower electrophilicity of an imino group. Recently
our continuing exploration of the versatility of 1 acti-
3
8
developed dibutylchlorotin hydride and trichlorosilane
vated with N-formylpyrrolidine derivatives, we have
4
,5
(
1)
can also reduce an imino group. The former
found the first chemo-, stereo-, and enantioselective
reduction of imino compounds using 1 activated with a
catalytic amount of N-formylpyrrolidines 2a,b.
reducing reagent is not suitable from the viewpoint of
green chemistry because of its non-catalytic nature, as
NPh
NHPh
Me
Cl SiH 1 (1.5 mmol)
3
Z
Ph
Me
Ph
N
in CH Cl , rt, 6 h
2
2
3a
4a
CHO
(1.0 mmol)
no N-formyl compound
a (0.2 mmol)
b (0.2 mmol)
18%
79%
67%
43%
Z=H
2a
2b
(1)
2
2
Z=CONHPh
DMF (0.2 mmol)
1
(1.0 mmol)
NPh
Me
O
NHPh
Me
OH
+
+
in CH Cl , rt, 6 h
Ph
Ph
Me
2
2
Ph
Ph
Me
3a
5
4a
6
(1.0 mmol)
(1.0 mmol)
2a (0.2 mmol)
80%
0%
(2)
LiAlH4
DIBAL
NaBH4
43%
0%
49%
42%
21%
9%
70%
77%
NaBH CN
3
Keywords: amines; imines; reduction; silicon halides.
*
Corresponding author. Tel./fax: +81-95-843-2442; e-mail: matumura@net.nagasaki-u.ac.jp
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00219-2

2
526
F. Iwasaki et al. / Tetrahedron Letters 42 (2001) 2525–2527
NPh
O
NHPh
OMe
1
(1.5 mmol)
OMe
+
7
Ph
1
Ph
in CH2Cl2, rt, 24 h
O
(3)
8
7
.0 mmol
no N-formyl compound
60%
37%
2a (0.2 mmol)
0%
92%
NHPh
OH
NaBH4 (0.3 mmol)
in CH3OH, rt, 18h
7
7
+
8
+
Ph
1
.0 mmol
(4)
74%
20%
9
6%
A typical reaction is exemplified by the reduction of
imine 3a (Eq. (1)). Although 3a was reduced in low
yields by 1 in the absence of N-formylpyrrolidines 2a,b,
the reduction was found to become much more effec-
tive in the presence of a catalytic amount of 2a,b,
suggesting that 2a,b played the role of efficient activa-
NCH2Ph
Me
NHCH2Ph
Me
1
(1.5 mmol)
in CH Cl , rt, 6 h
2
2
(5)
10
11
1
.0 mmol
cis/trans
5
tors for 1. DMF was less effective than 2a,b.
2a (0.2 mmol)
85%
82%
70%
84%
98/2
64/36
83/17
97/3
NaBH CN
3
A reducing reagent 1 activated with N-formylpyrro-
lidine 2a also presented high imino-selectivity in a
9-BBN
Superhydride
competitive reduction between 3a and a ketone 5 (Eq.
9
(
2)). A comparison of the selectivity with those using
NHR
NR
1 (1.5 mmol)
3
conventional reducing reagents makes the characteris-
tic of 1 activated with 2a as an imino-selective reducing
reagent much clearer.
Ar
Me
*
Ar
Me
a-e
.0 mmol
(S)-2b,c
(6)
in CH2Cl2, rt, 24h
3
4a-e
1
Furthermore, 1 activated with 2a was used in a selective
reduction of imino ester 7 to give amino ester 8 in high
(
S)-2b,c as activators (Eq. (6)). The enantio ratios (ees)
yield (Eq. (3)), while the reduction of 7 by NaBH4
of the product 4a–e were moderate, as shown in Table
1
12
resulted in a recovery of 7 with a small amount of 8
contaminated with amino alcohol 9 (Eq. (4)).
.
The fact that (S)-2b,c gave (R)-enriched amines (R)-
4a,b (entries 1, 2, and 6) suggested that the reduction
predominantly proceeds through a pathway involving a
transition state A rather than the other transition state
B (Fig. 1). Although the ees of product 4 were still
moderate in most cases, a relatively high ee (66% ee)
was obtained in a case using 1-naphthylamides (S)-2c
Excellent stereoselectivity in the reduction of imine 10
10
using 1 activated with 2a was also observed (Eq. (5)).
The high cis-selectivity in the reduction was compara-
ble to that of superhydride and is much higher than the
11
results obtained using other reducing reagents.
13
Finally, our system was applied to a preparation of
optically active amines. The reduction of aromatic
imines 3a–e by 1 was carried out in the presence of
(entry 6).
In summary, we have presented a new finding that
trichlorosilane (1) activated with N-formylpyrrolidine
optically active N-formyl-
L
-proline aromatic amides
Table 1. Asymmetric reduction of 3 with optically active 2 as activators
Entry
Activator (mmol)
Substrate
Ar
R
Yield of 4 (%)
% Eea
R or S
1
2
3
4
5
6
(S)-2b (0.1)
(S)-2b (0.1)
(S)-2b (0.2)
(S)-2b (0.2)
(S)-2b (0.2)
3a
3b
3c
3d
3e
3a
Ph
Ph
4-NO Ph
4-ClPh
2-Naph
Ph
Ph
Bn
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4a
91
97
\99
95
56
52
55
55
49
54
49
66
R
R
b
–
–
–
2
b
b
R
CONH-1-Naph
N
CHO
(S)-2c (0.1)
a
Determined by Chiralcel OD.
Not determined.
b

F. Iwasaki et al. / Tetrahedron Letters 42 (2001) 2525–2527
2527
Me
C
Me
C
N
N
H
H
Ph
N
O
N
O
Ph
Si+
C
N
Si+
H
H
C
N
Cl-
Cl
Cl-
Cl
O
C
O
C
H
Cl
Cl
H
(
R)-4a
(S)-4a
B
A
Figure 1. Working hypothesis for asymmetric reduction of 3a by Cl SiH (1) activated with (S)-2b.
3
derivatives 2 is an effective reagent for the reduction of
imines which was not affected by the presence of car-
bonyl groups. In addition, we qualified this method
using 1 with optically active N-formylproline deriva-
tives 2b,c as a new enantioselective reduction method of
imines. Further study on the mechanistic aspect and the
improvement of the ees is currently under way.
H.; Kohra, S.; Tominaga, Y. J. Chem. Soc., Chem.
Commun. 1986, 1411–1412; (b) Hojo, M.; Murakami, C.;
Fujii, A.; Hosomi, A. Tetrahedron Lett. 1999, 40, 911–
914.
8. This reducing reagent was highly effective for the reduc-
tion of ketones to alcohol. See: Iwasaki, F.; Onomura,
O.; Mishima, K.; Maki, T.; Matsumura, Y. Tetrahedron
Lett. 1999, 40, 7507–7511.
9
. Similar high imino-selectivity has been observed in alkyl-
ation of imines in the presence of aldehydes. Allylation:
Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem.
Soc. 1996, 118, 6641–6647. Enolate addition: Kobayashi,
S.; Nagayama, S. J. Org. Chem. 1997, 62, 232–233.
Acknowledgements
This study was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (B), No. 706 (Dynamic
control of Stereochemistry) from the Ministry of Edu-
cation, Science, Sports and Culture, Japan, and by a
Grant-in-Aid for Scientific Research (C) (No.
10. The reduction of 10 by 1 without any activator afforded
11 in good yields. This phenomenon can be explained in
terms of the difference in reactivity between aromatic
imine 3a and aliphatic imine 10. The details will be
published as a full paper.
1
2650855) from Japan Society for the Promotion of
Science.
1
1
1. Wrobel, J. E.; Ganem, B. Tetrahedron Lett. 1981, 22,
3447–3450.
2. A typical experimental procedure for the reduction of 3:
To 3a (1.0 mmol) and (S)-2b (0.1 mmol) in CH Cl (5
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4
5
1
(
R)-isomer].
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2
2
presence of hypervalent silicates (Ref. 14). 1: −9.4 ppm;
1–2a (1:1): −41.5 and −185.4 ppm; 1–2a (1:2): −185.3
ppm. 1–2b (1:1): −9.4 and −18.8 ppm; 1–2b (1:2): −18.8,
−181.3, and −184.1 ppm.
6
7
7
21–741.
−
. The hypervalent silicate reagent ([(MeO) SiH] from
4
−
(
MeO) SiH with OMe ) was effective for the reduction of
14. Williams, E. A. In The Chemistry of Organic Silicon
Compounds; Patai, S.; Rappoport, Z., Ed.; John Wiley &
Sons: New York, 1989; Chapter 8.
3
carbonyl compounds, while the reagent did not reduce
imines except tosylimine. See: (a) Hosomi, A.; Hayashida,
.
.