L-Valine derived chiral N-sulfinamides as effective organocatalysts for the asymmetric hydrosilylation of N-alkyl and N-aryl protected ketimines

Article abstract of DOI:10.1039/c4ob01257g

l-Valine derived N-sulfinamides have been developed as efficient enantioselective Lewis basic organocatalysts for the asymmetric reduction of N-aryl and N-alkyl ketimines with trichlorosilane. Catalyst 3c afforded up to 99% yield and 96% ee in the reduction of N-alkyl ketimines and up to 98% yield and 98% ee in the reduction of N-aryl ketimines.

Full text of DOI:10.1039/c4ob01257g

Organic &
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PAPER
L-Valine derived chiral N-sulfinamides as effective
organocatalysts for the asymmetric hydrosilylation
of N-alkyl and N-aryl protected ketimines†
Cite this: Org. Biomol. Chem., 2015,
13, 577
Chao Wang,* Xinjun Wu, Li Zhou and Jian Sun*
Received 17th June 2014,
Accepted 27th October 2014
L-Valine derived N-sulfinamides have been developed as efficient enantioselective Lewis basic organo-
catalysts for the asymmetric reduction of N-aryl and N-alkyl ketimines with trichlorosilane. Catalyst 3c
afforded up to 99% yield and 96% ee in the reduction of N-alkyl ketimines and up to 98% yield and 98%
ee in the reduction of N-aryl ketimines.
DOI: 10.1039/c4ob01257g
www.rsc.org/obc
we thus became interested in incorporating the dual func-
tional chiral sulfinamide group(s) into an amino acid frame-
Introduction
Chiral amines are fundamentally important structural com- work in the hope of obtaining new organocatalysts that have a
ponents of biologically important compounds such as natural broad substrate scope and high yield and enantioselectivity in
products and agrochemicals. Organocatalyst catalyzed enantio- the asymmetric hydrosilylation of ketimines.
selective reduction of prochiral imines or enamines with tri-
We first prepared a set of catalysts 1a–f via incorporating
chlorosilane (HSiCl3) represents one of the most important the tert-butanesulfinamide group into L-proline amide deriva-
methods for preparing chiral amines.1 Formamide,2 picolina- tives. For a wide range of N-alkyl ketimines, high yields and
mide3 and pyridyl-oxazoline4 derivatives have been developed enantioselectivities could be obtained when these catalysts
as efficient Lewis base organocatalysts for the asymmetric were used in the asymmetric hydrosilylation reaction under
hydrosilylation of imines and enamines with trichlorosilane mild conditions.9 Additionally, these catalysts could also be
(HSiCl3). In our earlier study, we found that L-pipecolinic acid5 used in the enantioselective hydrosilylation of a broad range of
and L-piperazine-2-carboxylic acid6 derived N-formamides have N-alkyl β-enamino esters to prepare N-alkyl β-amino acid
an unprecedented substrate scope and high enantioselecti- derivatives with high yields and enantioselectivities.10
vities for the hydrosilylation of N-aryl ketimines. However, Recently, we found that L-phenyl alanine derived new chiral
none of these N-formamide catalysts are tolerant to N-alkyl sulfinamides 2b could also be used as an efficient and highly
ketimines as a substrate for high enantioselectivity.
enantioselective catalyst for activating trichlorosilane in the
Chiral sulfoxides have been well established as efficient and asymmetric reduction of 3-aryl-1,4-benzooxazines to prepare
versatile stereocontrollers and have been extensively used as the corresponding chiral 3-aryl-3,4-dihydro-2H-1,4-benzooxa-
the chirality source of chiral auxiliaries and ligands.7 However, zine products (Fig. 1).11
the development of chiral sulfoxides as Lewis base organocata-
Given the novel performance of L-proline and L-phenyl
lysts has been rarely explored. We reported the first example of alanine derived N-sulfinamides in the asymmetric reduction of
chiral sulfoxides to activate trichlorosilane in the asymmetric imines and enamines with trichlorosilane, it is desirable to
reduction of N-aryl ketimines with high yield and enantio- search other types of amino acid derived N-sulfinamides for a
selectivity.8 The S-chiral center in these catalysts not only plays new catalyst that could be used in the asymmetric hydrosily-
a crucial role similar to the carboxamide groups of N-forma- lation of more practical substrates. As part of our continuing
mide catalysts as a Lewis base for the activation of HSiCl3, but efforts in this field, we have successfully developed catalysts
also serves as a source of chirality that the carboxamide group
lacks for the asymmetric reduction. Encouraged by this result,
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu, 610041, China. E-mail: sunjian@cib.ac.cn, wangchao@cib.ac.cn;
Tel: +86 28 8289 0803
†CCDC 1003514 and 1003515. For crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c4ob01257g
Fig. 1 Previously reported catalysts.
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Table 1 Asymmetric reduction of ketimine 7aa
Entry
Catalyst
Solvent
T [°C]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
3a
4a
3b
4b
3c
4c
5a
6a
5b
6b
5c
6c
3c
3c
3c
3c
3c
7c
3c
5a
5a
5a
3c
3c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−40
−20
−20
−40
−40
−40
95
62
70
60
80
80
91
80
91
90
93
85
50
80
45
50
80
65
80
65
40
70
95
60
75
15
79
9
82
5
Fig. 2 Catalysts evaluated in this study.
89
87
90
80
83
81
52
88
85
83
90
65
93
23
15
71
93
78
3–6 derived from L-valine and L-pipecolinic acid that could be
used in the asymmetric hydrosilylation of both N-alkyl and
N-aryl ketimines with high yields and enantioselectivities.
Herein, we wish to report the results (Fig. 2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24e
Toluene
CHCl3
DCE
Results and discussion
CCl4
Kočovský and coworkers proved that the N-methyl L-valine
derived N-formamide catalysts are superior to those prepared
from proline in the catalytic reduction of imines with trichloro-
silane. However, they reported that the N-methyl L-valine
derived tert-butanesulfinamide catalyst is less efficient for acti-
vating HSiCl3 in the asymmetric reduction of ketimines, and
no more than 50% ee could be obtained.12 We thought that
this problem may be caused by the mismatch between the
S-chiral center and the C-chiral center of the catalyst since
catalysts 1 and 2 show dramatically different performance in
enantioselectivity when the R/S chiral tert-butanesulfinamide
group was incorporated into the amino acid backbones,
CH3CN
Toluene
Toluene
CCl4
CH2Cl2
Toluene
Toluene
a Reactions were carried out with 2.0 equiv. of HSiCl3 on a 0.1 mmol
scale in 0.5 mL of solvent for 24 h. b Isolated yield based on the imine.
c The ee values were determined using chiral HPLC. d The reaction
time is 48 h. e The catalyst loading is 10 mol%.
respectively. In order to verify our hypotheses, catalysts 3a and temperature to −40 °C (entry 19, Table 1). In contrast, for cata-
4a have been prepared according to a reported procedure. We lyst 5a, the ee fell to 23% from 89% when the solvent was
observed that catalyst 3a exhibited significantly higher reactiv- changed from dichloromethane to toluene under the testing
ity and selectivity than 4a in the reduction of N-benzyl keti- reaction conditions (entries 7 and 20, Table 1). The ee
mine 7a with HSiCl3. This observation prompted us to prepare decreases to 71% as the reaction temperature goes down to
compounds 3–6. Starting from L-valine and L-pipecolinic acid, −40 °C in dichloromethane (entry 22, Table 1). The obvious
compounds 3b, 3c, 5a–c and their diastereomers 4b, 4c and difference in enantioselectivity between catalysts 3c and 5a
6a–c were easily synthesized as a mixture which could be sepa- under identical reaction conditions indicates the pivotal role
rated by column chromatography. The stereochemistry of the of the amino acid framework in the transition state to furnish
chiral sulfur centers in 3c and 4c was determined by single- the asymmetric reaction of imine 7a.
crystal X-ray diffraction analysis.13 For the other catalysts, the
stereochemistry on the sulphur atom was established from a strate scope of catalyst 3c was explored. A wide range of aro-
clear analogy of their 1H NMR profiles to those of 3c and 4c.
matic N-benzyl ketimines (7a–n) were reduced with HSiCl3 in
With the optimized reaction conditions in hand, the sub-
With the catalysts in hand, their ability to catalyse the asym- the presence of 20 mol% catalyst 3c in toluene at −40 °C for
metric hydrosilylation of ketimines was evaluated. We found 48 h. As illustrated in Table 2, all the tested methyl ketimines
that L-pipecolinic acid derivatives 5 and 6 showed higher 7 could be reduced to the corresponding products. Both the
stereoselectivity and activity than L-valine derivatives 3 and 4 electron rich and electron deficient aromatic methyl ketimines
in the testing reaction. Up to 91% yield and 90% ee could be 7a–h reacted well to give the corresponding products 8 in mod-
obtained when catalyst 5b was used in the reduction of imine erate to good yields and high enantioselectivities (40–95%
7a in the presence of 20 mol% catalyst in dichloromethane at yield, 90–96% ee). However, for some substrates higher
−20 °C for 24 h (entry 9, Table 1). Interestingly, 88% ee could enantioselectivities and yields could be obtained on switching
be reached for catalyst 3c when the reaction solvent was the solvent from toluene to dichloromethane. The steric hin-
changed from dichloromethane to toluene under the testing drance of the aromatic groups of the ketimines played a
reaction conditions (entry 14, Table 1). The ee of the reaction pivotal role in the reaction activity; only 20–30% yields could
could be further increased to 95% by decreasing the reaction be obtained when substrates 7i and 7j were reduced using the
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Table 2 Asymmetric reduction of N-Bn ketimines 7 with catalyst 3ca
Table 3 Asymmetric reduction of N-alkyl ketimines 9 with catalyst 3ca
Yieldb
[%]
eec
[%]
Yieldb
[%]
eec
[%]
Entry
Ketimine
X =
Entry
Ketimine
X =
1
2
3
4d
5
6
7
8
9a
9b
9c
9d
9e
9f
H
Me
Cl
99
90
84
84
91
60
83
92
94
95
90
95
93
93
93
92
1
7a
7b
7c
7d
7e
7f
H
Me
Cl
95
60
85
82
40
80
80
80
93
95
93
93
92
92
94
93
2
3d
4d
5
Br
Br
OMe
CF3
F
OMe
CF3
F
6d
7
9g
9h
7g
7h
8d
NO2
NO2
9
10
9i
9j
H
OMe
50
85
90
89
9
10
7i
7j
H
OMe
20
30
91
92
11
7k
—
89
77
11
9k
—
55
77
12
13
7l
7m
Br
Cl
85
50
90
84
12
13
9l
9m
Br
Cl
92
90
90
89
14
7n
—
20
57
14
9n
—
90
71
a Reactions were carried out with 20 mol% catalyst 3c and with 2.0
equiv. of HSiCl3 on a 0.1 mmol scale in 0.5 mL of solvent at −40 °C for
48 h. b Isolated yield based on the imine. c The ee values were
determined using chiral HPLC. d Reaction was carried out in
dichloromethane.
15
16
9o
9p
Me
Et
85
60
94
79
a Reactions were carried out with 20 mol% catalyst 3c and with 2.0
equiv. of HSiCl3 on a 0.1 mmol scale in 0.5 mL of solvent at −40 °C for
48 h. b Isolated yield based on the imine. c The ee values were
determined using chiral HPLC. d Reaction was carried out in
dichloromethane.
current system. The stereoselectivity of the reaction is sensitive
to both the position of the substituents on the aromatic group
and the steric hindrance of R2 (entries 9–14, Table 2).
Additionally, we found that the aforementioned reduction
system could also be used in the asymmetric hydrosilylation of to good yields. In the testing reduction of 11a in the presence
other aromatic N-alkyl ketimines 9. Good to high yields and of 20 mol% catalyst 3c at −20 °C, 96% ee could be achieved
enantioselectivities could be obtained when N-allyl ketimines when dichloromethane was used as the reaction solvent.
were reduced and the reaction activity and the stereoselectivity However, the ee dropped to 93% when toluene was used
were not sensitive to the electronic properties of the substitute (entries 1 and 2, Table 2). Thus a broad range of N-aryl keti-
group in the aromatic ring (entries 1–8, Table 3). Toluene was mines were reduced with HSiCl3 in dichloromethane. As
the appropriate solvent for most of the substrates. Only one shown in Table 4, ketimines with relatively bulky R, including
substrate could afford higher ee on switching the solvent from Et, nPr were all found to be good substrates for catalyst 3c,
toluene to dichloromethane (entry 4, Table 3). Again we found affording excellent enantioselectivities (entries 2–4, Table 4).
that the steric hindrance of the R1 and R2 groups was impor- More significantly, ketimines 11d–f with both electron rich
tant both for the reactivity and the stereoselectivity of the reac- and electron deficient anilines reacted well to give the desired
tion. Increasing the steric hindrance of R1 or R2 would cause a products in moderate yields and high enantioselectivities
lower yield and ee.
(entries 5–7, Table 4). Furthermore, 95–98% ee could be
Moreover, the catalyst 3c could be used in the reduction of achieved for those ketimines derived from o-methoxyaniline
N-aryl ketimines with high enantioselectivities and moderate (entries 8–14, Table 4). To the best of our knowledge, such a
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Table 4 Asymmetric reduction of N-aryl ketimines 11 with catalyst 3ca
Yieldb
[%]
eec
[%]
Entry
Ketimine
X =
1d
2
3
11a
11a
11b
11c
Me
Me
Et
92
90
40
40
93
96
96
95
4
n-Pr
5
6
7
11d
11e
11f
p-NO2
p-OMe
p-Cl
56
95
60
92
96
96
Scheme 1 General procedure for the synthesis of 3 and 4.
anhydrous Na2SO4. The solvent was evaporated under vacuum
to give compound 14.
8
9
10
11
12
13
11g
11h
11i
11j
11k
11l
H
p-Cl
p-NO2
p-OMe
p-F
98
90
75
45
92
43
97
97
95
98
97
96
To a stirred solution of tert-butyl sulfinyl chloride14 (3.16 g,
22.5 mmol) in THF (80 mL) were added triethylamine (3.1 mL,
22.5 mmol) and 14 (1.49 g, 6.8 mmol) at 0 °C. The mixture was
stirred at room temperature for 12 h, and then concentrated
under vacuum. The residue was diluted with EtOAc, washed
with saturated NaHCO3 and brine, and then dried over anhy-
drous Na2SO4. Solvents were evaporated under vacuum. The
residue was purified by column chromatography (silica gel,
hexane–EtOAc = 5 : 1) to give pure 3 and 4 (Scheme 1).
p-Me
14
11m
—
62
97
(3a): White solid; yield: 25%; [α]2D0 = −50 (c = 0.10, CHCl3);
mp 147–148 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.02
(s, 1H), 7.57 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.9 Hz, 2H), 7.04
(t, J = 7.4 Hz, 1H), 3.70 (d, J = 8.0 Hz, 1H), 2.68 (s, 3H), 2.5–2.45
(m, 1H), l.30 (s, 9H), 1.05 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ (ppm) 168.1, 138.0, 128.8,
124.2, 119.8, 75.5, 59.7, 28.8, 28.5, 24.3, 21.1, 19.8; ESI HRMS
exact mass calcd for (C16H26N2O2S1 + Na)+ requires m/z
333.1607, found m/z 333.1611.
a Reactions were carried out with 20 mol% catalyst 3c and with 2.0
equiv. of HSiCl3 on a 0.1 mmol scale in 0.5 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. d Reaction was carried out in toluene.
substrate profile has not been reported previously in the asym-
metric hydrosilylation of N-protected ketimines.
(4a): White solid; yield: 30%; [α]2D0 = −94 (c = 0.10, CHCl3);
mp 205–208 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.41
(s, 1H), 7.61–7.57 (m, 2H), 7.33–7.26 (m, 2H), 7.11–7.06
(m, 1H), 3.64 (d, J = 10.4 Hz, 1H), 2.77 (s, 3H), 2.58–2.50
Experimental section
To
a
stirred solution of N-Me-N-Boc-L-valine (2.31 g, (m, 1H), l.26 (s, 9H), 1.08 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.5 Hz,
10.0 mmol) in DCM (50 mL) were added aniline (1.1 mL, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) 168.0, 138.1, 128.9,
12.0 mmol), HOBt (1.62 g, 12.0 mmol), DIEA (4.0 mL, 128.8, 124.0, 119.6, 119.5, 59.2, 26.5, 22.8, 19.9, 19.5; ESI
24.0 mmol), and EDCI (2.35 g, 12.0 mmol) at 0 °C. The reac- HRMS exact mass calcd for (C16H26N2O2S1 + Na)+ requires m/z
tion mixture was stirred at room temperature for 12 h, and 333.1607, found m/z 333.1595.
then concentrated under vacuum. The residue was diluted
(3b): White solid; yield: 32%; [α]2D0 = −65 (c = 0.10, CHCl3);
with EtOAc (200 mL), washed with 1 N aqueous HCl, saturated mp 158–160 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.82
aqueous NaHCO3 (15 mL) and brine, and then dried over anhy- (s, 1H), 7.24 (s, 2H), 6.73 (s, 1H), 3.73 (d, J = 7.6 Hz, 1H), 2.67
drous MgSO4. Solvents were evaporated under vacuum. The (s, 3H), 2.53–2.46 (m, 1H), 2.28 (s, 6H), 1.26 (s, 9H), l.07 (d, J =
residue was purified by column chromatography (silica gel, 6.6 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
hexane–EtOAc = 10 : 1) to give compound 13.
CDCl3): δ (ppm) 168.1, 138.5, 137.9, 125.9, 117.4, 75.4, 59.7,
Compound 13 (2.30 g, 7.2 mmol) was charged in a 50 mL 28.9, 28.6, 24.3, 21.3, 21.1, 19.8; ESI HRMS exact mass calcd
round flask. A solution of HCl–EtOAc (4 mol L−1, 10 mL) was for (C18H30N2O2S1 + Na)+ requires m/z 361.1920, found m/z
then added. The mixture was stirred at room temperature until 361.1904.
13 disappeared completely. The volatiles were removed under
(4b): White solid; yield: 35%; [α]2D0 = −103 (c = 0.10, CHCl3);
vacuum. The residue was diluted with EtOAc, washed with mp 181–183 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.27
saturated aqueous NaHCO3 and brine, and then dried over (s, 1H), 7.24 (s, 2H), 6.73 (s, 1H), 3.61 (d, J = 10.3 Hz, 1H), 2.76
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(s, 3H), 2.57–2.49 (m, 1H), 2.28 (s, 6H), 1.26 (s, 9H), l.07 (d, J =
(5b): White solid; yield: 36%; [α]2D0 = −170 (c = 0.10, CHCl3);
6.4 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 10.02 (s, 1H), 7.28 (s, 2H),
δ (ppm) 167.9, 138.6, 138.0, 125.7, 117.2, 66.2, 59.2, 26.6, 22.8, 21.3, 6.72 (s, 1H), 4.37–4.35 (m, 1H), 3.25–3.20 (m, 2H), 2.43–2.22
20.5, 20.0; ESI HRMS exact mass calcd for (C18H30N2O2S1 + Na)+ (m, 7H), 1.90–1.51 (m, 5H), 1.30 (s, 9H); 13C NMR (75 MHz,
requires m/z 361.1920, found m/z 361.1904.
CDCl3): δ (ppm) 168.4, 138.5, 138.4, 125.5, 116.2, 59.0, 56.1,
(3c): White solid; yield: 30%; [α]2D0 = −71 (c = 0.10, CHCl3); 48.9, 25.7, 25.5, 23.4, 21.3, 20.7; ESI HRMS exact mass calcd for
mp 154–156 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.45 (C18H28N2O2S1 + Na)+ requires m/z 359.1761, found m/z 359.1775.
(s, 1H), 7.65–7.63 (m, 1H), 7.18–7.13 (m, 1H), 7.00–6.97
(6b): White solid; yield: 32%; [α]2D0 = −72 (c = 0.07, CHCl3);
(m, 1H), 3.71–3.67 (m, 1H), 2.69 (s, 3H), 2.48–2.41 (m, 1H), 1H NMR (300 MHz, CDCl3): δ (ppm) 8.94 (s, 1H), 7.28 (s, 2H),
1.34 (s, 9H), l.05–1.00 (m, 6H); 13C NMR (75 MHz, CDCl3): 6.76 (s, 1H), 4.19–4.17 (m, 1H), 3.46–3.43 (m, 1H), 3.06–2.97
δ (ppm) 168.1, 149.7 (dd, J = 244, 13 Hz), 146.7 (dd, J = 243.1, (m, 1H), 2.56–2.52 (m, 1H), 2.30 (s, 6H), 1.76–1.56 (m, 2H),
12.7 Hz), 134.8, 116.7 (d, J = 17.9 Hz), 115.1, 109.1 (d, J = 1.39–1.19 (m, 3H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3):
21.8 Hz), 75.8, 59.8, 28.5, 28.2, 24.5, 20.7, 19.8; ESI HRMS δ (ppm) 168.8, 138.6, 137.7, 126.0, 117.1, 60.2, 58.8, 44.5, 26.8,
exact mass calcd for (C16H24F2N2O2S1 + Na)+ requires m/z 24.6, 23.3, 21.3, 20.6; ESI HRMS exact mass calcd for
369.1419, found m/z 369.1410.
(C18H28N2O2S1 + Na)+ requires m/z 359.1764, found m/z 359.1766.
(5c): White solid; yield: 35%; [α]2D0 = −102 (c = 0.08, CHCl3);
(4c): White solid; yield: 33%; [α]2D0 = −108 (c = 0.10, CHCl3);
mp 176–178 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 9.76 1H NMR (300 MHz, CDCl3): δ (ppm) 10.55 (s, 1H), 7.77–7.70
(s, 1H), 7.72–7.65 (m, 1H), 7.14–7.03 (m, 2H), 3.64 (d, J = 10.4 (m, 1H), 7.18–7.04 (m, 2H), 4.38–4.36 (m, 1H), 3.32–3.14
Hz, 1H), 2.76 (s, 3H), 2.56–2.48 (m, 1H), 1.26 (s, 9H), l.07 (m, 2H), 2.41–2.36 (m, 1H), 1.88–1.52 (m, 5H), 1.30 (s, 9H);
(d, J = 7.0 Hz, 3H), l.02 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, 13C NMR (75 MHz, CDCl3): δ (ppm) 168.7, 150.0 (dd, J = 244.6,
CDCl3): δ (ppm) 168.0, 150.1 (dd, J = 244.5, 13.0 Hz), 146.7 13.0 Hz), 146.4 (dd, J = 242.7, 12.8 Hz), 135.2, 116.9 (d, J =
(dd, J = 243.1, 12.7 Hz), 134.8, 117.0 (d, J = 17.9 Hz), 115.1, 17.9 Hz), 114.7, 108.7 (d, J = 21.7 Hz), 59.1, 55.8, 49.4, 25.7, 25.4,
109.1 (d, J = 21.5 Hz), 65.5, 59.3, 35.3, 26.5, 24.3, 22.7, 20.6, 23.4, 20.6; ESI HRMS exact mass calcd for (C16H22F2N2O2S1 + Na)+
19.8; ESI HRMS exact mass calcd for (C16H24F2N2O2S1 + Na)+ requires m/z 367.1262, found m/z 367.1262.
requires m/z 369.1419, found m/z 369.1409.
(6c): White solid; yield: 30%; [α]2D0 = −99 (c = 0.10, CHCl3);
(5a): White solid; yield: 25%; [α]2D0 = −223 (c = 0.10, CHCl3); 1H NMR (300 MHz, CDCl3): δ (ppm) 9.37 (s, 1H), 7.81–7.74 (m,
mp 134–137 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 10.1 1H), 7.19–7.07 (m, 2H), 4.19–4.18 (m, 1H), 3.46–3.45 (m, 1H),
(s, 1H), 7.63–7.60 (m, 2H), 7.31–7.26 (m, 2H), 7.07–7.03 3.01–2.92 (m, 1H), 2.55–2.51 (m, 1H), 1.78–1.52 (m, 5H), 1.30
(m, 1H), 4.36 (s, 1H), 3.27–3.16 (m, 2H), 2.42–2.38 (m, 1H), (s, 9H); 13C NMR (75 MHz, CDCl3): δ (ppm) 169.2, 149.9(dd, J =
1.88–1.56 (m, 5H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3): 245.9, 13.1 Hz), 146.9 (dd, J = 244.5, 11.8 Hz), 135.2, 117.0
δ (ppm) 168.5, 138.5, 128.7, 123.6, 119.1, 59.0, 56.1, 48.9, 25.6, 25.5, (d, J = 17.9 Hz), 115.1, 109.2 (d, J = 21.8 Hz), 61.1, 58.9, 43.9,
23.4, 20.7; ESI HRMS exact mass calcd for (C16H24N2O2S1 + Na)+ 27.1, 24.6, 23.5, 22.3, 20.6; ESI HRMS exact mass calcd for
requires m/z 331.1451, found m/z 331.1457 (Scheme 2).
(6a): White solid; yield: 40%; [α]2D0 = −66 (c = 0.10, CHCl3);
mp 120–123 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 10.12
(C16H22F2N2O2S1 + Na)+ requires m/z 367.1262, found m/z 367.1264.
General procedure for the catalytic reduction of imines
(s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.56 Hz, 2H), 7.06 Under an argon atmosphere, trichlorosilane (20 μL, 0.24 mmol)
(t, J = 7.38 Hz, 1H), 4.38–4.37 (m, 1H), 3.29–3.21 (m, 2H), 2.39 was added dropwise to a stirred solution of imines 7, 9 and 11
(m, 1H), 1.78–1.54 (m, 7H), 1.30 (s, 9H); 13C NMR (75 MHz, (0.10 mmol), catalyst 3c (3.22 mg, 0.01 mmol) in anhydrous
CDCl3): δ (ppm) 168.6, 138.6, 128.8, 123.7, 119.2, 59.0, 56.1, toluene or DCM at −40 or −20 °C. The mixture was allowed to
48.9, 25.7, 25.5, 23.4, 20.7; ESI HRMS exact mass calcd for stir at the same temperature for 24 h. The reaction was
(C16H24N2O2S1 + Na)+ requires m/z 331.1451, found m/z quenched with a saturated aqueous solution of NaHCO3 (5 mL)
331.1434.
and was extracted with EtOAc. The combined extracts were
washed with brine and dried over anhydrous MgSO4 and the
solvents were evaporated under vacuum. Purification by column
chromatography (silica gel, hexane–EtOAc or DCM–MeOH)
afforded pure amines 8, 10 and 12. The ee values were deter-
mined using established HPLC techniques with chiral station-
ary phases.
General procedure for the acylation of 10
To a stirred solution of amine 10 in dichloromethane (2 mL)
was added an acylating reagent (2.0 equiv.) at 0 °C. The mixture
was stirred at room temperature for 10 h, and was then concen-
trated under vacuum. The residue was purified by column
chromatography (silica gel, hexane–EtOAc = 20 : 1) to give the
pure acylated amine, which was used for chiral HPLC analyses.
Scheme 2 General procedure for the synthesis of 5 and 6.
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Paper
Organic & Biomolecular Chemistry
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In summary, we have developed a highly efficient Lewis basic
organocatalyst 3c for the enantioselective reduction of both
N-alkyl and N-aryl ketimines with trichlorosilane in high enantio-
selectivity and moderate to good yields. The broad substrate
scope of this catalyst is unprecedented in asymmetric imine
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Acknowledgements
We are grateful for financial support from the Western Light
Talents Training Program of the Chinese Academy of Sciences
and the National Natural Science Foundation of China (project
no. 21272227 and 21402185).
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