NHC-copper-catalyzed asymmetric conjugate silylation of access chiral α-aminosilanes

Article abstract of DOI:10.1016/j.tetlet.2019.03.072

Chiral α-aminosilane and its derivatives have found potential applications in pharmaceuticals. Yet there are rare examples have been reported for the synthesis of these molecules. Herein we report a catalytic asymmetric conjugate silylation reactions of β-amido-acrylonitriles and β-amido-acrylates for the first time in the presence of catalytic amount of chiral N-heterocyclic carbene (NHC)/Copper(I) complex. A variety of functionalized chiral α-aminosilanes were obtained at room temperature in good yields with high enantioselectivities in the presence of NHC (10 mol%), CuCl (10 mol%), NaOtBu or NaOMe (20 mol%), and MeOH (2 equivalents).

Full text of DOI:10.1016/j.tetlet.2019.03.072

Accepted Manuscript
NHC-Copper-Catalyzed Asymmetric Conjugate Silylation of Access Chiral α-
Aminosilanes
Yajuan Zhang, Min Tong, Qian Gao, Panke Zhang, Senmiao Xu
PII:
S0040-4039(19)30310-7
https://doi.org/10.1016/j.tetlet.2019.03.072
TETL 50713
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
15 February 2019
27 March 2019
29 March 2019
Please cite this article as: Zhang, Y., Tong, M., Gao, Q., Zhang, P., Xu, S., NHC-Copper-Catalyzed Asymmetric
Conjugate Silylation of Access Chiral α-Aminosilanes, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.03.072
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Tetrahedron Letters
NHC-Copper-Catalyzed Asymmetric Conjugate Silylation of Access Chiral -
Aminosilanes
Yajuan Zhanga,b, Min Tongb, Qian Gao,b Panke Zhang,a, and Senmiao Xub,
aCollege of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Centre for Excellence in Molecular Synthesis, Suzhou Research Institute , Lanzhou Institute of
Chemical Physics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lanzhou 730000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Chiral -aminosilane and its derivatives have found potential applications in pharmaceuticals.
Yet there are rare examples have been reported for the synthesis of these molecules. Herein we
report a catalytic asymmetric conjugate silylation reactions of -amido-acrylonitriles and -
amido-acrylates for the first time in the presence of catalytic amount of chiral N-heterocyclic
carbene (NHC)/Copper(I) complex. A variety of functionalized chiral -aminosilanes were
obtained at room temperature in good yields with high enantioselectivities in the presence of
NHC (10 mol%), CuCl (10 mol%), NaOtBu or NaOMe (20 mol%), and MeOH (2 equivalents).
Available online
Keywords:
Oganosilanes
2009 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Chiral -aminosilanes
Synthetic methods
unexplored,6-8 which hamper further applications of these
methods. Thus, it is still appealing to develop efficient methods
Introduction
to prepare -aminosilanes with multiple functionalities.
Optically active Organosilane compounds have found widespread
applications in both synthetic and medicinal chemistry.1,2 Among
these, chiral -aminosilanes have gained increasing attention
because they have shown significant bioactivities and served as
the key constituents of peptidomimetics.2,3 Accordingly, many
methods have been developed in the synthesis of these
structures.4,5 However, only a few examples have been reported
for their asymmetric synthesis. The traditional diastereoselective
synthesis requires organolithium reagents, which usually suffers
from limitations such as narrow functional group tolerance and
harsh reaction conditions. In this context, examples include
reverse aza-Brook rearrangement6-8 and the addition of
silyllithium reagents to the chiral aldimines.3,9-13 On the other
hand, copper-catalyzed asymmetric transformations provide mild
and straightforward approaches to access these structures with
wide functional group compatibility. Examples in this aspect
include silyl addition to the aldimines,14 addition of Grignard
reagents to the aromatic silyl ketimines,15 hydroamination and
aminoboration of vinyl silanes.16 However, there are still some
limitations. For examples, reactions of aldimines or silyl
ketimines are restricted to aryl substrates; hydroamination of
vinylsilanes requires expensive silanes as hydride source and
instable aminating reagents. In addition, catalytic methods to
synthesizing chiral -aminosilanes with functional groups such
Scheme 1. Strategies to synthesis of Chiral -aminosilanes
via asymmetric catalysis.
Transition-metal-catalyzed -silylation of ,-unsaturated
compounds have received considerable attention in synthesizing
optically active chiral -silanes.17-22 In particular, inexpensive
copper complexes are able to efficiently give silyl transfer to
cyclic and acyclic ,-unsaturated carbonyl compounds with
high enantioinduction.20-22 However, none of them have been
used to -heteroatom substituted substrates. The deficiency of
research is probably caused by deactivation of substrates through
as ester, cyanide, amide, and halogens remain virtually
———
 Corresponding author. e-mail: pkzhang@zzu.edu.cn
 Corresponding author. e-mail: senmiaoxu@licp.cas.cn

2
Tetrahedron Letters
the interaction of a lone pair of electrons of the heteroatom with
79% ee). The use of a more sterically congested 2,6-2,6-
diethylphenyl group substituted ligand L3 could improve
enantioselectivity further (Table 1, entry 3, 81%). To further
enhance the enantioselectivity of the current reaction, we turned
our attention from C1-symmetric ligands L1-L3 to C2-symmetric
ones L4 and L5. Pleasingly, 88% ee was obtained albeit with
moderate isolated yield in the presence of ligand L4 bearing two
2-naphthyl groups . 3,5-Dimethylphenyl substituted ligand
L5provided 2a in 92% yield and 94% ee. With optimized ligand
L5 in hand, we then investigated other reaction conditions such
as solvent and base as shown in Table 1 (entries 6-11). The
results showed that reaction conditions in entry 5 were optimal.
the conjugated -system of the olefin moiety.23 Moreover, the
heteroatoms are usually good leaving groups, which would cause
the elimination of heteroatoms.24 Despite these problematic
issues, the reaction of ,-unsaturated compounds containing a
-nitrogen substituent with silyl reagent may provide an
alternative approach to provide chiral -aminosilanes. We
envisioned that the deactivation and deamination could be
minimized by judicious choice of substituents on nitrogen.
Herein, we report a copper-catalyzed asymmetric -silylation of
-amidoacrylonitriles and -amidoacylate esters under mild
reaction conditions, providing functionalized chiral -
aminosilanes in good to excellent enantioselectivities.
With optimized reaction conditions in hand, we then turned
our attention to the substrate scope of the current reaction
(Scheme 2). Substituents of benzoate groups have negligible
effects on enantioselectivities, giving products with uniformly
excellent enanatioselectivities (2a-e, 92-94% ee). And most of
them were obtained in high yields (2a-d, 86-92%). Ortho-methyl
benzoate substituted substrate gave the silylated product (2e) in
moderate yield (62%) probably due to steric encumbrance. Next,
we examined alkyl substituents on the nitrogen. Again, all of
them provided consistently excellent enantioselectivities (2f-i,
93-94% ee). The low yield of 2h (28%) probably arose from
relatively bulky benzyl group. Interestingly, the reaction is
compatible with the alkenyl group (1i) which is usually sensitive
to silyl copper species. The untouched olefin motif of 2i allows it
to undergo further functionalization. Switching benzoyl to
naphthoyl could also result in products 2j and 2k in good yields
(75% and 78%, respectively) and excellent enantioselectivities
(92% ees). The reaction could also applicable to substrates
bearing lactams at -position, giving products 2l and 2m in
superior yields (both 98%) with excellent levels of
Results and Discussion
Table 1 Optimization of Copper-Catalyzed Asymmetric
Conjugate Silylation of -Amido-acryonitrile 1a.
Entry
L
Base
Solvent
THF
yield/%a
94
ee/%b
75
1
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
KOt-Bu
LiOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
stereoselectivities (94% and 92%, respectively).
2
THF
94
79
3
THF
95
81
4
THF
64
88
5
THF
92
94
6
THF
87
94
7
THF
36
90
8
Toluene
CH2Cl2
CH3CN
88
94
9
Trace
94
81
10
11
83
n-Hexane 91
92
a Isolated yields. b Determined by Chiral HPLC.
Recently, we reported a copper-catalyzed borylation of -
amido-acrylonitriles and -amido-acrylates using chiral
phosphines as ligands.24 However, when we applied this protocol
to the silylation, only a trace amount of product was observed.
The reason is probably due to less nucleophilicity of silylcopper
species than its boryl analog. Therefore, a ligand with the strong
 donating ability (such as N-heterocyclic carbene (NHC)) is a
necessity to force this reaction to happen. Gratifyingly, the
reaction of -amido-acrylonitrile 1a with PhMe2Si-Bpin (2.0
equivalents) in the presence of MeOH (2 equivalents), 10 mol%
CuCl, 10 mol% C1-symmetric imidazolinium L1 and 20 mol%
NaOt-Bu in THF at room temperature underwent smoothly,
affording corresponding silylated product 2a in 94% yield with
75% ee within 24 h (Table 1, entry 1). The reaction did not
complete when reducing the amount of PhMe2Si-Bpin. Notably,
no product was observed without MeOH, L1 or NaOt-Bu. We
then focused on the effects of N-aryl substituents on chiral
induction. Replacement of a phenyl group of L1 with 2-naphthyl
group (L2) slightly enhanced enantioselectivity (Table 1, entry 2,
Scheme 2. Copper-Catalyzed Asymmetric Conjugate
Silylation of -Amido-acryonitriles 1.
Scheme 3. Copper-Catalyzed Asymmetric Conjugate
Silylation of -Amido-acrylates 3.

2
Tetrahedron Letters
To further demonstrate the generality of the current protocol, we next examined the reaction of ethyl -aminoacylates 3
(Scheme 3). Gratifyingly, the use of same ligand L5 could also provide efficient silyl transfer with good enantioinduction when
NaOMe was used as the base instead of NaOtBu. N-alkyl substituted substrates provided products in high yields (4a, 4c, and 4d, 90-
98%) with good ee values (84-87%). Interestingly, the substrate 3b bearing a free N-H group could also be compatible with the
reaction conditions, giving 4b in 72% yield with good enantioselectivity (88%). The free N-H group allows it to undergo further
diversifications.
Figure 1. Plausible reaction mechanism.
Giving the importance of MeOH in promoting the reaction, we believed the reaction has a similar mechanism with other copper-
catalyzed -silylation of ,-unsaturated compounds. Thus, a plausible mechanism is elucidated as shown in Figure 1. The reaction
of in-situ generated copper alkoxide NHC-CuOR A with borylsilane via -bond metathesis gives silylcopper intermediate B.25
Coordination of B with the carbon-carbon -bond of 1a followed by 3,4-addition would provide the complex D bearing a C-Cu
bond.26 Subsequent protonation of C-Cu bond results in the silylated product with the concurrent regeneration of species A.
Conclusion
In summary, we have developed an NHC-copper-catalyzed enantioselective -silylation of -amido acrylonitriles and -
amidoacrylates under mild reaction conditions for the first time. The reaction provides corresponding chiral -aminosilanes in good
yields with good to excellent enantioselectivities (84-94% ees). Application of silylated products and development of other
asymmetric silylation reactions are currently underway in our laboratory.
Acknowledgments
This work was supported by a Start-up Grant from Lanzhou Institute of Chemical Physics, National Natural Science Foundation of
China (21573262, 21502175, 21801246), Natural Science Foundation of Jiangsu Province (BK20161259, BK20170422) and
Outstanding Young Talent Research Found of Zhengzhou University (NO. 1621316005).
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Supplementary Material
Supplementary material including experimental procedures and characterization data to this article can be found online.

4
Tetrahedron Letters
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NHC-Copper-Catalyzed Asymmetric
Conjugate Silylation of Access Chiral -
Aminosilanes
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Yajuan Zhang, Min Tong, Qian Gao, Panke Zhang, and Senmiao Xu

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Highlights



In situ formed inexpensive copper(I) complexes were
used as catalysts.
The reaction proceeded with high enantioselectivities
under mild conditions.
A series of potentially useful functionalized chiral -
aminosilanes were prepared.