Enantioselective hydrosilylation of ketimines with trichlorosilane promoted by chiral N-picolinoylaminoalcohols

Article abstract of DOI:10.1016/j.tetlet.2007.09.064

Enantioselective hydrosilylation of N-aryl and N-benzyl ketimines with trichlorosilane catalyzed by readily accessible chiral N-picolinoylaminoalcohols proceeded smoothly furnishing chiral secondary amines in good yields (up to 93%) and moderate to excellent enantioselectivities (up to 95% ee).

Full text of DOI:10.1016/j.tetlet.2007.09.064

Tetrahedron Letters 48 (2007) 7934–7937
Enantioselective hydrosilylation of ketimines with
trichlorosilane promoted by chiral N-picolinoylaminoalcohols
a,b
a
a
a,
*
Hongjie Zheng, Jingen Deng, Wenqing Lin and Xiaomei Zhang
a
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
b
Graduate School of Chinese Academy of Sciences, Beijing 100049, China
Received 23 July 2007; revised 4 September 2007; accepted 11 September 2007
Available online 14 September 2007
Abstract—Enantioselective hydrosilylation of N-aryl and N-benzyl ketimines with trichlorosilane catalyzed by readily accessible chi-
ral N-picolinoylaminoalcohols proceeded smoothly furnishing chiral secondary amines in good yields (up to 93%) and moderate to
excellent enantioselectivities (up to 95% ee).
Ó 2007 Published by Elsevier Ltd.
Chiral amines are versatile building blocks of natural
products and common intermediates in the synthesis
of pharmaceutical drugs and agrochemicals. Enantio-
afforded chiral amines with moderate to good yields
and enantioselectivities. However, there have been only
limited examples of enantioselective hydrosilylation of
1
6
a–c,e,8
selective hydrogenation of ketimines represents one of
the most convenient routes to optically active chiral
amines. Traditional asymmetric high pressure hydro-
N-benzyl ketimines.
Herein, we report our discov-
ery of novel chiral N-picolinoylaminoalcohol derivatives
1–3 (Fig. 1), among which 2a promoted hydrosilylation
of a variety of N-aryl ketimines and N-benzyl ketimines
2
3
genation of ketimines, hydrosilylation of ketimines
4
and transfer hydrogenation of ketimines catalyzed by
chiral transition metal complexes suffer from the
problem of metal leaching. Recently, synthesis of chiral
secondary amines via metal-free asymmetric organocat-
alytic hydrogenation of ketimines received much atten-
tion due to the environmental benignancy of this
with HSiCl in good yields and moderate to excellent
3
enantioselectivities.
First, catalysts 1a–e derived from various aminoalcohols
were evaluated in hydrosilylation of N-(1-phenylethylid-
ene) benzenamine (4a). The structure of the catalyst has
5
,6
method. Biomimetic transfer hydrogenation of keti-
5
mines or reductive amination of ketones with Hantzch
H
esters catalyzed by chiral Brønsted acids proved to be
powerful methods of the synthesis of chiral secondary
amines. On the other hand, asymmetric hydrosilylation
of imines employing trichlorosilane as a hydride source
is also a promising alternative. Since the first asymmetric
hydrosilylation of imines activated by N-formylpyrroli-
R1
R3
N
1
2
N
1
N
N
O
O
R4
HO
R2
HO 2
2
1
3
4
a, R1 = Ph, R = Ph, (1S, 2R)
2
a, R = Me, R = Ph, (1S, 2R)
b, R = Me, R = Ph, (1S, 2S)
c, R = Ph, R = Ph, (1S, 2R)
d, R = Ph, R = Ph, (1S, 2S)
3
4
6
a
6b–i
1
2
dine derivatives, analogous organo-catalysts
and
b, R = Ph, R = Ph, (1S, 2S)
3
4
7
1
2
c, R = Ph, R = H, (1R)
S-chiral sulfinamides were developed to catalyze the
reactions and showed good activities as well as high
enantioselectivities. Besides, N-picolinoylpyrrolidine
3
4
1
2
d, R = i-Pr, R = H, (1R)
3
4
1
2
e, R = Ph, R = H, (1R)
e, R = H, R =Ph, (2R)
8
9
derivatives and 2-pyridyloxazolines which have no
N-formyl unit were employed in the reactions too and
N
Me
Ph
N
3
O
Keywords: Organocatalysis; Hydrosilylation; Imines; Chiral amines.
MeO
*
Corresponding author. Tel.: +86 28 85257883; fax: +86 28
5229250; e-mail: xmzhang@cioc.ac.cn
8
Figure 1. Catalysts evaluated in this study.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.09.064

H. Zheng et al. / Tetrahedron Letters 48 (2007) 7934–7937
7935
a remarkable influence on the results of the reaction.
ferred that the methyl group on nitrogen might benefit
to the enantioselectivity of the reaction. In search of
more effective catalysts, we synthesized N-methyl deriv-
atives 2c, 2d, and 2e. As we expected, introduction of
methyl group on nitrogen of catalysts 1a and 1b led to
significant increase in enantioselectivity (Table 1, entries
1–4, vs 17–21). Meanwhile, it resulted in inversion of the
configuration of the product. However, N-methyl deriv-
ative 2e directed the reaction with almost racemic prod-
uct (Table 1, entries 22 and 23). It appears that the effect
of the structure of catalyst on the reaction is rather com-
plicated. Moreover, methylation of the hydroxyl group
of 2a resulted in an obvious drop in enantioselectivity
(Table 1, entry 24). It seems that the H-bonding between
catalyst and substrate also makes an important contri-
(
1
1R,2S)-1,2-Diphenyl-2-aminoethanol derived catalyst
a gave the product with good yields but poor enantio-
selectivities (Table 1, entries 1 and 2). Its diastereomer
b provided the product with slightly higher ee values
Table 1, entries 3 and 4). 1c which has only one chiral
center bonded to amino group gave much better result
Table 1, entry 5) in dichloromethane. However, 1d
1
(
(
which has an isopropyl group on carbon 1 gave only
racemic product (Table 1, entry 8). Catalyst 1e which
has only one chiral center bonded to hydroxy group
gave almost racemic product (Table 1, entry 9). There-
fore, it can be concluded that the chirality of the carbon
bonded to amino group is determinant for the enantio-
selectivity of the reaction.
6
b
bution to enantioselectivity of the reaction.
Then catalysts 2a and 2b derived from ephedrine and
pseudoephedrine were employed in the reaction. Fortu-
nately, we found that 2a resulted in much higher enantio-
selectivities (Table 1, entries 11 and 14) in chloroform.
Its diastereomer 2b was obviously inferior to 2a but
superior to 1a–e (Table 1, entries 15 and 16). We in-
The solvents also show dramatic effect on the reaction.
Generally, chlorinated solvents are advantageous to
the reaction. For most of the catalysts, chloroform is
superior to dichloromethane except for 1c, which
resulted in much higher enantioselectivity in dichloro-
methane than in chloroform (Table 1, entries 5 and 6).
When the reaction was carried out in toluene, both the
reactivity and the enantioselectivity dropped greatly
Table 1. Survey of chiral catalysts for the hydrosilylation of ketimine
4a
(
Table 1, entries 7 and 12). We conjectured that the
Ph
Ph
p–p interaction of catalyst with substrate was blocked
in toluene, which led to low enantioselectivity. The use
of non-protonic polar solvent THF also led to decrease
in enantioselectivity (Table 1, entry 13). Perhaps it is due
to the competitive coordination of THF with
trichlorosilane.
N
HN
*
HSiCl3, Solvent
Cat*
4a
5a
a
b
c
Entry
Catalyst
Solvent
Yield (%)
ee (%)
Afterwards, under the optimal reaction conditions, a
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1c
1d
1e
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
3
CH
CHCl
CH Cl
CHCl
CH Cl
CHCl
Toluene
2
Cl
2
2
2
90
88
85
86
84
91
80
90
76
81
90
40
88
88
82
90
87
89
88
87
87
85
89
5 (S)
20 (S)
31 (S)
30 (S)
65 (S)
18 (S)
0
variety of ketimines 4a–y were reduced with HSiCl in
3
3
CHCl in the presence of 20 mol % 2a at À10 °C (Table
3
2
2). Most of the aromatic ketimines were reduced
smoothly to provide corresponding products in good
yields and enantioselectivities. However, ketimine 4k,
which has a chloro substituent in the ortho position of
the phenyl group of ketone moiety, was reduced in high
yield but poor enantioselectivity (Table 2, entry 11).
Tetralone derived ketimine 4o was reduced in high ee
value (Table 2, entry 15), while reduction of indanone-
derived ketimine 4n gave only moderate enantioselectiv-
ity (Table 2, entry 14). It seems that the conformation
difference between six member ring and five member
ring makes the transition structures of reactions of the
two substrates much different. Meanwhile, a-ketimino
ester 4t was reduced to give protected a-phenylglycine
in good yield and moderate enantioselectivity (Table 2,
entry 20). Furthermore, moderate yields and enantio-
selectivities were afforded in reduction of aliphatic
ketimines (Table 2, entries 24 and 25). In general, higher
enantioselectivities were resulted with N-PMP ketimines
than with N-Ph ketimines. It is noteworthy that
N-benzyl ketimines (Table 2, entries 21–23) could also
be reduced in good yields and enantioselectivities.
3
2
3
CHCl
CHCl
3
0
3
6 (S)
68 (R)
86 (R)
37 (R)
70 (R)
10
11
12
13
14
15
16
17
19
20
21
22
23
24
2 2
CH Cl
CHCl
3
Toluene
THF
d
CHCl
CH Cl
CHCl
CH Cl
CHCl
CH Cl
CHCl
CH Cl
3
92 (R)
2
2
2
2
2
46 (R)
73 (R)
51 (R)
55 (R)
34 (R)
55 (R)
0
3
2
3
2
3
2
CHCl
CHCl
3
5 (R)
70 (R)
3
a
Unless specified otherwise, reactions were carried out with 10 mol %
of catalyst and 2.0 equiv of HSiCl
organic solvent at 0 °C for 16 h.
Isolated yield based on the imine.
3
on 0.2 mmol scale in 2.0 mL of
b
c
The ee values were determined by chiral HPLC. The configuration of
the product was determined by comparison of the HPLC data with
the literature data.
According to the literature,10 N-PMP amines could un-
1
0
6f
8
dergo oxidative deprotection by CAN or TCCA to
give free amines. Furthermore, hydrogenolysis of the
benzyl group of the addition product 5v catalyzed by
d
20 mol % catalyst was used and the reaction was carried out at
À10 °C for 24 h.

7
936
H. Zheng et al. / Tetrahedron Letters 48 (2007) 7934–7937
Bn
Table 2. Reduction of ketimines 4 with trichlorosilane catalyzed by 2a
Ac
HN
a
b
c
HN
Entry
Ketimines
Yield ee
1) 10% Pd/C, H
MeOH, RT, 2 h
2
(
%)
(%)
R
N
2) Ac
2
O, Et
3
N
MeO
MeO
o
5
0 C, 2 h
1
2
4a R = Ph
4b R = PMP
88
90
92
93
d
6 (R, 70%, 82% eea)
5v (R, 82% ee)
R
N
a
3
4
4c R = Ph
4d R = PMP
91
82
89
92
(>99)
Determined by GC using a chiral column (Chirasil-DEX CB).
Scheme 1. Hydrogenolysis of the benzyl group of 5v and following
protection with acetic group.
MeO
R
N
1
0% Pd/C gave the free amine smoothly without
5
6
4e R = Ph
4f R = PMP
92
90
87
92
racemization (Scheme 1). Thus, the methodology is well
established to synthesize optically active amines via
organo-catalytic asymmetric hydrosilylation of N-PMP
and N-benzyl ketimines.
Br
Cl
7
8
9
0
1
4g p-Cl R = Ph
90
84
88
90
91
90
91
85
88
43
R
N
4h p-Cl, R = PMP
4i m-Cl, R = Ph
4j m-Cl, R = PMP
4k o-Cl, R = PMP
In conclusion, we have developed a highly efficient me-
tal-free catalyst, easily prepared from 2-picolinic acid
and (1R,2S)-ephedrine, for the reduction of a variety
of N-aryl ketimines and N-benzyl ketimines with trichlo-
rosilane in high yields (<93%) and moderate to excellent
ee values (<95%) under mild conditions. However, at
present, we cannot provide a reasonable mechanism to
explain the effect of the structure of catalyst on the reac-
tion, especially, the configuration of the product. The
mechanistic aspects and the further application of the
present catalyst to other reactions are under investiga-
tion, and will be reported in due course.
1
1
R
N
1
1
1
1
2
3
4l R = Ph
4m R = PMP
85
80
76
88
2
O N
PMP
N
1
1
4
5
4n n = 1
4o n = 2
90
85
68
95
n
R
N
Acknowledgments
1
6
7
4p R = Ph
93
86
90
99)
90
(
We are grateful for financial support from the National
Natural Science Foundation of China (20572109) and
Sichuan Youth Science and Technology Foundation.
1
4q R = PMP
R
N
N
1
1
8
9
4r R = Ph
4s R = PMP
91
88
76
84
References and notes
PMP
1. Blaser, H. U.; Spindler, F.. In Comprehensive Asymmetric
Catalysis; Springer: Berlin, 1999; Vol. 1, p 247; Ohkuma,
T.; Noyori, R. In Comprehensive Asymmetric Catalysis;
Springer: New York, 2004; p 43, Suppl. 1.
20
4t
85
65
2
CO Et
2
. For reviews, see: (a) Blaser, H. U.; Malan, C.; Pugin, B.;
Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal.
2003, 345, 103–151; (b) Tang, W.; Zhang, X. Chem. Rev.
Bn
21
22
23
4u Ar = Ph
4v Ar = PMP
4w Ar = 2-naphthyl 80
85
85
80
82
82
96)
N
2
003, 103, 3029–3070; (c) Tararov, V. I.; B o¨ rner, A.
Ar
Synlett 2005, 203–211.
(
3
. (a) Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2,
713–715; (b) Nishikori, H.; Yoshihara, R.; Hosomi, A.
Synlett 2003, 561–563; (c) Lipshutz, B. H.; Shimizu, H.
Angew. Chem., Int. Ed. 2004, 43, 2228–2230; (d) Nolin, K.
A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
R
N
2
2
4
5
4x R = Ph
4y R = PMP
70
71
67
61
1
2462–12463.
a
Unless specified otherwise, reactions were carried out with 20 mol %
4. (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917; (b)
Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed.
2003, 42, 5472–5474; (c) Samec, J. S. M.; Backvall, J. E.
Chem. Eur. J. 2002, 8, 2955–2961.
3
of catalyst and 2.0 equiv of HSiCl on 0.2 mmol scale in 2.0 mL
chloroform at À10 °C for 24 h.
b
c
Isolated yield based on the ketimines.
The ee values were determined by chiral HPLC, the data in paren-
theses were obtained after a single recrystallization.
PMP = p-methoxyphenyl.
5. (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781–3783; (b) Hoffmann, S.;
d

H. Zheng et al. / Tetrahedron Letters 48 (2007) 7934–7937
7937
Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
424–7427; (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86;
d) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc.
7. Pei, D.; Wang, Z. Y.; Wei, S. Y.; Zhang, Y.; Sun, J. Org.
Lett. 2006, 8, 5913–5915.
8. Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y.
Tetrahedron Lett. 2006, 47, 3751–3754.
7
(
2
2
007, 129, 5830–5831; (e) You, S. L. Chem. Asian. J. 2007,
, 820–827; (f) Kang, Q.; Zhao, Z. A.; You, S. L. Adv.
9. Malkov, A. V.; Liddon, A. J. P. S.; Ramirez-Lopez, P.;
Bendova, L.; Haigh, D.; Ko cˇ ovsk y´ , P. Angew. Chem., Int.
Ed. 2006, 45, 1432–1435.
Synth. Catal. 2007, 349, 1657–1660.
6
. (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu,
T.; Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42,
10. Chi, Y.; Zhou, Y. G.; Zhang, X. J. Org. Chem. 2003, 68,
4120–4122.
2
525–2527; (b) Malkov, A. V.; Mariani, A.; MacDougall,
11. Typical experimental procedure for the catalytic enan-
tioselective hydrosilylation of ketimine 4 with catalyst
2a: under an argon atmosphere, trichlorosilane (60 lL,
0.6 mmol) was introduced to a stirred solution of imine
4 (0.30 mmol) and catalyst 2a (16.2 mg, 0.02 mmol) in
K. N.; Ko cˇ ovsk y´ , P. Org. Lett. 2004, 6, 2253–2256; (c)
Malkov, A. V.; Ston cˇ ius, S.; MacDougall, K. N.; Mariani,
A.; McGeoch, G. D.; Ko cˇ ovsk y´ , P. Tetrahedron 2006, 62,
2
64–284; (d) Wang, Z. Y.; Ye, X. X.; Wei, S. Y.; Wu, P.
C.; Zhang, A. J.; Sun, J. Org. Lett. 2006, 8, 999–1001; (e)
Wang, Z. Y.; Cheng, M.; Wu, P. C.; Wei, S. Y.; Sun, J.
Org. Lett. 2006, 8, 3045–3048; (f) Malkov, A. V.; Ston cˇ ius,
S.; Ko cˇ ovsk y´ , P. Angew. Chem., Int. Ed. 2007, 46, 3722–
anhydrous CHCl
allowed to stir at À10 °C for 24 h. The reaction was
quenched with saturated aqueous solution of NaHCO
and extracted with EtOAc. The combined organic
extract was washed with brine and dried over anhy-
3
(2 mL) at À10 °C. The mixture was
3
3
724; (g) Malkov, A. V.; Figlus, M.; Ston cˇ ius, S.;
Ko cˇ ovsk y´ , P. J. Org. Chem. 2007, 72, 1315–1325; (h)
Wang, Z. Y.; Wei, S. Y.; Wang, C.; Sun, J. Tetrahedron:
Asymmetry 2007, 18, 705–709; (i) Zhou, L.; Wang, Z. Y.;
Wei, S. Y.; Sun, J. Chem. Commun. 2007, 2977–2979; (j)
Baudequin, C.; Chatrvedi, D.; Tsogoeva, S. B. Eur. J. Org.
Chem. 2007, 2623–2629.
4
drous MgSO , filtered and evaporated. Purification by
chromatography (silica gel, hexane/EtOAc) afforded
pure amine 5. The ee values were determined using
established HPLC techniques with chiral stationary
phases.