Highly enantioselective hydrosilylation of N-(1,2-diarylethylidene) arylamines

Article abstract of DOI:10.1039/c2ob26672e

By employing a chiral Lewis base as the catalyst, enantioselective hydrosilylation of N-(1,2-diarylethylidene)arylamines was realized. The reactions proceeded smoothly to afford various chiral 1,2-diarylethanamines with good yields (up to 99%) in good ena

Full text of DOI:10.1039/c2ob26672e

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Highly enantioselective hydrosilylation of
N-(1,2-diarylethylidene)arylamines†
Cite this: DOI: 10.1039/c2ob26672e
Received 24th August 2012,
Yongsheng Zheng,a,b Zhouyang Xue,a,b Lixin Liu,a,b Chang Shu,a,b Weicheng Yuana
and Xiaomei Zhang*a
Accepted 22nd November 2012
DOI: 10.1039/c2ob26672e
www.rsc.org/obc
By employing a chiral Lewis base as the catalyst, enantioselective extensively.13,14 A wide variety of valuable chiral nitrogen-
hydrosilylation of N-(1,2-diarylethylidene)arylamines was realized. containing compounds were prepared via this transformation.
The reactions proceeded smoothly to afford various chiral 1,2-di- As part of our ongoing effort directed toward the development
arylethanamines with good yields (up to 99%) in good enantio- of Lewis base catalyzed asymmetric hydrosilylation of CvN
selectivities (up to 98%). Furthermore, one of the products was double bond compounds,14o–t we have been trying to apply
employed in the synthesis of a pharmaceutical substance.
this methodology in the preparation of various intermediates
of pharmaceutical compounds. Herein we present the highly
enantioselective hydrosilylation of N-(1,2-diarylethylidene)-
arylamines promoted by chiral Lewis bases. The reactions
proceeded smoothly to provide pharmaceutically important
1,2-diarylethanamines in good yields (up to 99%) and good
enantioselectivities (up to 98% ee). Subsequently, one of the
products was employed in the synthesis of a protein kinase B
inhibitor.
Introduction
1,2-Diarylethanamines and their derivatives are important
pharmaceutically or biologically active substances.1 They have
exhibited a wide range of biological activities, including neuro-
protective properties,1 analgesic activity,2 anticonvulsant
activity,3 protein kinase B inhibition,4 human β3 adrenergic
receptor agonistic activity,5 estrogen receptor modulation6 and
other activities.7 1,2-Diarylethanamines were also employed in
construction of various natural products and other physiologi-
cally active molecules.8 Therefore, synthesis of 1,2-diarylethan-
amines is of great significance. Up to now, synthesis of
racemic 1,2-diarylethanamines and their derivatives has been
well developed.9 However, preparation of enantioenriched 1,2-
diarylethanamines has predominantly focused on diastereose-
lective synthesis and resolution.7b,10 As far as we know, catalytic
asymmetric synthesis of enantioenriched 1,2-diarylethan-
amines has seldom been systematically studied. Zhou and
co-workers employed a Rh(I) complex of the chiral spiro phos-
phonite ligand to catalyze enantioselective hydrogenation of
1-(1,2-diarylvinyl)pyrrolidines to provide 1-(1,2-diarylethyl)-
pyrrolidines with excellent ee values.11
Results and discussion
First, chiral Lewis base catalysts 1a–h (Fig. 1) were
evaluated for their ability to promote the hydrosilylation of
N-(1,2-diphenylethylidene)-4-methoxybenzenamine (2a) in
dichloromethane at −10 °C for 24 hours. The results are
summarized in Table 1.
As can be seen in Table 1, all of the catalysts 1a–h (Fig. 1)
catalyzed the hydrosilylation of 2a to provide the product 3a
in good yields. Ephedrine-derived catalyst 1a14o,r gave only
moderate enantioselectivity (Table 1, entry 1). Proline-derived
catalyst 1b14k,p displayed better enantioselection (Table 1, entry
2). When catalysts 1c–e14q,t bearing bulky substituents at the
C4 position of the pyrrolidine ring were tested, remarkable
increases in ee values were observed (Table 1, entries 3–5).
Afterwards, several catalysts 1f,14q,t 1g14q and 1h bearing larger
aryl groups were also screened (Table 1, entries 6–8), in which
1h delivered the highest ee value of 98% (Table 1, entry 8).
Therefore, 1h was determined as the optimal catalyst and
was employed in further investigations. Subsequently, various
solvents were evaluated. Reactions in several chlorinated
solvents resulted in similar yields and ee values (Table 1,
entries 8–10). Good yields and slightly inferior enantio-
selectivities were obtained in toluene and THF (Table 1,
Recently, chiral Lewis base12 promoted asymmetric hydro-
silylation of CvN double bonds has been studied
aKey Laboratory for Asymmetric Synthesis and Chiral technology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
China. E-mail: xmzhang@cioc.ac.cn; Fax: (+86) 28-85257883;
Tel: (+86) 28-85257883
bUniversity of Chinese Academy of Sciences, Beijing, China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c2ob26672e
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Fig. 1 Chiral Lewis base organocatalysts evaluated in this study.
Table 1 Enantioselective hydrosilylation of N-(1,2-diphenylethylidene)-4-meth-
oxybenzenamine 2a promoted by chiral Lewis base catalysts 1a–ha
Table 2 Enantioselective hydrosilylation of N-(1,2-diarylethylidene)arylamines
2a–s promoted by chiral Lewis base catalyst 1ha
Entry
2 (Ar1, Ar2)
Yieldb (%)
eec (%)
Conf.
1
2
3
4
5
6
7
2a (Ph, Ph)
2b (4-MeOC6H4, Ph)
2c (4-MeC6H4, Ph)
2d (4-ClC6H4, Ph)
2e (4-BrC6H4, Ph)
2f (3,4-Me2C6H3, Ph)
2g (3,4,5-Me3C6H2, Ph)
2h (2-thienyl, Ph)
2i (2-furanyl, Ph)
2i (2-furanyl, Ph)
2j (Ph, 4-PhC6H4)
2k (Ph, 4-FC6H4)
2l (Ph, 2-ClC6H4)
2m (4-MeC6H4, 2,4,5-F3C6H2)
2n (4-MeC6H4, 2-naphthyl)
2o (4-MeC6H4, 4-BrC6H4)
2p (4-MeC6H4, 4-MeOC6H4)
2q (4-BrC6H4, 4-ClC6H4)
2r (4-BrC6H4, 4-BrC6H4)
2s (4-MeC6H4, 4-ClC6H4)
99
97
99
99
97
99
99
97
97
17
95
95
98
87
92
99
98
99
95
97
98
97
96
97
96
97
96
93
69
—
98
98
95
98
97
97
96
97
93
97
(+)
(+)
(+)
S (+)d
(+)
(+)
(+)
(+)
(−)
—
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
Entry
Cat*
Solvent
T (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1h
1h
1h
1h
1h
1h
1h
1h
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
Cl3CCH3
Toluene
THF
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
0
97
94
99
97
98
90
95
99
98
97
96
97
66
99
93
85
71
82
97
92
97
95
96
98
97
96
95
95
94
95
98
97
8e
9e
10f
11
12
13
14
15
16
17
18
19
20
9
10
11
12
13
14d
15e
16f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−20
−10
−10
a Unless specified otherwise, reactions were carried out with the
catalyst 1h (10 mol%) and HSiCl3 (2.0 equiv.) on a 0.2 mmol scale in
CH2Cl2 (3.0 mL) at −10 °C for 24 hours. b Isolated yield based on 2.
c The ee values were determined by using chiral HPLC. d The absolute
configuration of 3d was determined by comparison of the optical
rotation value with the literature datum after being converted into a
known compound.10a e The reactions proceeded for 18 hours. f The
reaction was performed in the absence of the catalyst for 24 hours.
a Unless specified otherwise, reactions were carried out with the
catalyst (10 mol%) and HSiCl3 (2.0 equiv.) on a 0.2 mmol scale in the
appropriate solvent (3.0 mL) for 24 hours. b Isolated yield based on 2a.
c The ee values were determined by using chiral HPLC. d The reaction
was carried out for 36 hours. e 5 mol% of 1h was used. f 2.5 mol% of
1h was used.
in Table 2. Generally, when Ar2 was phenyl, for Ar1, phenyl
groups bearing substituents in the para or meta position gave
entries 11 and 12). Thus dichloromethane was selected as the
most favourable solvent for the reaction. When the reaction
was conducted at 0 °C, only 66% of the desired product was high yields as well as high ee values (Table 2, entries 1–7). The
achieved because a lot of the substrate decomposed (Table 1,
entry 13). Lowering the temperature to −20 °C did not benefit
electronic nature of the substituents had little influence on the
results. When Ar1 was 1-thienyl, the reaction also provided
the enantioselection (Table 1, entry 14). When 5 mol% or good yield and good enantioselectivity (Table 2, entry 8).
However, when Ar1 was 1-furanyl, the reaction exhibited rather
2.5 mol% of the catalyst was employed, the ee value kept the
same level, however, the yield dropped evidently and decompo-
sition of the substrate was observed (Table 1, entries 14 and 1-furanyl substrate 2i was conducted in the absence of the
low enantioselection (Table 2, entry 9). When the reaction of
15). Therefore, 10 mol% of the catalyst was employed in the
following study.
catalyst, 17% of the product was obtained (Table 2, entry 10).
Thus the lower ee value of 2i could be ascribed to the back-
Having established the optimal conditions, the enantio- ground reaction. On the Ar2 side, almost all of the substrates
with Ar2 bearing substituents in the para, meta or ortho posi-
selective hydrosilylation was expanded to a wide variety of
N-(1,2-diarylethylidene)arylamines. The results are summarized
tion afforded high yields as well as high ee values (Table 2,
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Scheme 1 Synthesis of protein kinase B inhibitor 7.
entries 11–13, 15–20), except 2m which gave the product with 21172217) and the National Basic Research Program of China
obviously lower yield perhaps due to the instability of the tri- (973 Program) (2010CB833300).
fluoro substituted phenyl group (Table 2, entry 14).
To further illustrate the synthetic utility of this method-
ology, the product 3d was employed in synthesis of a protein
Notes and references
kinase B inhibitor 74 (Scheme 1). First, 3d was treated with per-
iodic acid to remove the PMP group to generate free amine 4.
The absolute configuration of 4 was determined as S by com-
parison of the optical rotation value with the literature
datum.10a Then amine 4 was subjected to condensation with
acid 5 to afford amide 6. Finally, deprotection of 6 with hydro-
chloric acid accomplished the preparation of 7 in good yield.
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Conclusions
In conclusion, we have demonstrated an efficient enantioselec-
tive hydrosilylation of N-(1,2-diarylethylidene)arylamines pro-
moted by chiral Lewis bases. The reactions proceeded smoothly
to provide the corresponding 1,2-diarylethanamines in good
yields (up to 99%) and good enantioselectivities (up to 98% ee).
In addition, product 3d was deprotected to give free amine 4
which is a known compound. Thus the absolute configuration
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rotation value of 4 with the literature datum. Subsequently, 4
was converted to a protein kinase B inhibitor 7 successfully.
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Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (20972155 and
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