Synthesis of Chiral α-Aminosilanes through Palladium-Catalyzed Asymmetric Hydrogenation of Silylimines

Article abstract of DOI:10.1021/acs.orglett.8b04073

The asymmetric hydrogenation of silylimines was first developed by using a palladium complex of a P-stereogenic diphosphine ligand as the catalyst, affording the valuable chiral α-aminosilanes with quantitative conversions and excellent enantioselectiviti

Full text of DOI:10.1021/acs.orglett.8b04073

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral α‑Aminosilanes through Palladium-Catalyzed
Asymmetric Hydrogenation of Silylimines
Dongyang Fan,† Yang Liu,† Jia Jia,‡ Zhenfeng Zhang,*,† Yangang Liu,† and Wanbin Zhang*,†,‡
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, and ‡School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
S
* Supporting Information
ABSTRACT: The asymmetric hydrogenation of silylimines
was first developed by using a palladium complex of a P-
stereogenic diphosphine ligand as the catalyst, affording the
valuable chiral α-aminosilanes with quantitative conversions
and excellent enantioselectivities (up to 99% ee).
Scheme 1. Method for the Synthesis of Chiral α-
Aminosilanes
hiral organosilicon compounds are famous for their
Cunique properties as carbon isosteres in pharmaceutical
chemistry. Among them, chiral α-aminosilanes have been the
most attractive examples for their utilization as mimics of
natural α-amino acids in several protease inhibitors as well as
chiral reagents for the synthesis of various valuable
compounds.1 In view of this, significant progress have been
made for the enantioselective synthesis of chiral α-amino-
silanes. The initial asymmetric methodologies include
lithiation−silylation of cyclic amides,2 reverse aza-Brook
rearrangements of N-silylamines,3 addition of silyl anions to
chiral sulfinimines,4 and MVP-type reduction of silylimines,5
which require stoichiometric chiral reagents. Recently, a
number of copper-catalyzed asymmetric approaches have
been developed, such as silylation of aldimines,6 hydro-
amination of vinylsilanes,7 and addition of Grignard reagents
to arylsilylimines.8 However, uneconomic silicon-, nitrogen-, or
carbon-containing reagents are always needed (Scheme 1).
Thus, an efficient and green method for the construction of
chiral α-aminosilanes is still highly desired.
Among all of the methods for the construction of chiral
compounds, asymmetric hydrogenation (AH) is one of the
most efficient and green technologies.9 The transition-metal-
catalyzed AH of vinyl and acyl silanes have been developed for
the synthesis of chiral unfunctionalized silanes and α-hydroxyl
silanes, respectively.10 However, the asymmetric hydrogenation
of silylimines for the synthesis of chiral α-aminosilanes has not
been solved, probably due to the low reactivity of the
substrates and the instability of the corresponding products.
Along with our continuing research on AH,11 herein we
disclose for the first time the highly efficient asymmetric
hydrogenation of silylimines catalyzed by the palladium
complex of a P-stereogenic diphosphine ligand QuinoxP*
(Scheme 1).
Pd(OCOCF3)2 as the Pd precursor and trifluoroethanol as the
solvent, the desired product 2a was obtained in complete
conversion with moderate enantioselectivity of 65% ee (Table
1, entry 1). Encouraged by this result, more axial-chiral
diphosphine ligands were tested.
(R)-BINAP afforded similar results (entry 2), while the
electron-rich (R)-MeO-BIPHEP and (R)-SegPhos showed
almost no catalytic activity (entries 3 and 4). The ligand
(R)-DTBM-SegPhos bearing t-Bu substituents gave a full
conversion but low enantioselectivity of 33% ee (entry 5). We
then turned our interest to other types of diphosphine ligands
such as (S,S)-ChiraPhos, (R,Sp)-JosiPhos, and (R,R)-Me-
DuPhos (entries 6−8). Only the palladium complex of
Initially, a model substrate 1a, which can be readily prepared
by the reaction of acylsilane with tosylamine in the presence of
triethylamine and TiCl4,5b,10a was tested in Pd-catalyzed
asymmetric hydrogenation using our previously reported
axial-chiral diphosphine ligand (R)-C10-BridgePhos.12 Using
Received: December 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
while Pd(OCOCH3)2 with weakly coordinating anions
provided similar enantioselectivity but lower activity compared
to Pd(OCOCF3)2. Almost no product can be detected using
other solvents such as MeOH, i-PrOH, DCM, and toluene
(entries 15−18).
Table 1. Condition Optimization
With the optimized conditions, the effect of silyl and sulfonyl
groups was examined (Scheme 2). The substrates 1a−d
bearing different silyl groups were converted to 2a−d in good
to excellent enantioselectivities. The substrate 1b bearing a
bulky tert-butyldimethylsilyl (TBS) substituent gave the
product 2b with highest enantioselectivity (99% ee). Further
exploration of the sulfonyl groups showed an obvious influence
a
Scheme 2. Substrate Scope
a
b
c
entry
ligand
solvent
conv (%)
ee (%)
1
2
C10-BridgePhos
BINAP
TFE
TFE
99
99
65
58
3
4
5
6
MeO-BIPHEP
SegPhos
DTBM-SegPhos
ChiraPhos
JosiPhos
TFE
TFE
TFE
TFE
NR
trace
99
trace
99
33
18
7
TFE
8
9
10
11
12
13
14
15
16
17
18
Me-DuPhos
DuanPhos
BipheP*
TFE
TFE
THF
TFE
TFE
TFE
TFE
MeOH
iPrOH
DCM
toluene
NR
NR
99
99
99
NR
70
<10
NR
NR
NR
67
84
84
BenzP*
QuinoxP*
QuinoxP*
QuinoxP*
QuinoxP*
QuinoxP*
QuinoxP*
QuinoxP*
d
e
85
a
Conditions: 1a (0.1 mmol), ligand (0.0022 mmol), Pd(OCOCF3)2
(0.002 mmol), H2 (40 atm), solvent (2 mL), rt, 10 h, unless otherwise
b
c
noted. The conversions were calculated from 1H NMR spectra. The
d
ee’s were determined by HPLC using chiral columns. PdCl2 was
used instead of Pd(OCOCF3)2. Pd(OCOCH3)2 was used instead of
e
Pd(OCOCF3)2.
JosiPhos showed catalytic activity and obtained the hydro-
genated product with 18% ee (entry 7). Some P-stereogenic
diphosphine ligands were chosen and evaluated in this reaction
(entries 9−11). No product was detected when the hydro-
genation was catalyzed by the palladium complex of (R,SP)-
DuanPhos (entry 9). The ligand (RP,RP,Sa)-BipheP* recently
developed in our group13 showed high activity and good
enantioselectivity (entry 10). To our delight, the palladium
complex of (R,R)-BenzP* and (R,R)-QuinoxP*14 promoted
the hydrogenation to obtain product 2a with better
enantioselectivities (entries 11 and 12). The more stable and
available ligand QuinoxP* was chosen for the further
optimization. We then turned our attention to examine the
effect of Pd precursor on reactivity and enantioselectivity
(entries 13 and 14). PdCl2 showed almost no catalytic activity,
a
Conditions: 1 (0.1 mmol), (R,R)-QuinoxP* (0.0022 mmol),
Pd(OCOCF3)2 (0.002 mmol), H2 (40 atm), TFE (2 mL), rt, 10 h.
Isolated yields were recorded. The ee’s were determined by HPLC
using chiral columns.
B
DOI: 10.1021/acs.orglett.8b04073
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
on the reaction. High yields and enantioselectivities were
obtained for the substrates 1e,f possessing phenylsulfonyl or 4-
methoxyphenylsulfonyl groups, while no hydrogenated product
was obtained for substrate possessing a 4-(trifluoromethyl)-
phenylsulfonyl group. When the hydrogen pressure was
reduced from 40 to 15, 5, and even 1 atm, all of the
hydrogenation of 1b could be finished in 10 h with a slightly
decreasing enantioselectivity from 99.6% ee to 99.4%, 98.9%,
and 98.5% ee.
The favored and disfavored transition states are shown
(Figure 1). According to the single-crystal structure of 1b, the
A wide range of arylsilylimines bearing Ts and TBS
substituents were tested (Scheme 2). Substrates with
electron-donating (1g−k) or electron-withdrawing (1l−o)
substituents on the para-position of the aryl groups can be
successfully hydrogenated to give the corresponding amines
2g−o with excellent ee’s. Electron-withdrawing substituents
reduced the enantioselectivities slightly as shown on substrates
2m−o. Changing the substituents from the para-position to
the meta-position on the aryl groups has almost no effect on
the enantioselectivities as shown for the products 2p−r
compared to 2h, 2m, and 2n. However, substrate 2s with a
strong electron-withdrawing fluoro substituent in the ortho-
position was obtained in a slightly lower ee of 91%. The
substrates 1t,u bearing dimethyl or difluoro substitutents on
the meta- and para-positions were all fully reduced to 2t,u with
satisfactory enantioselectivities. Furthermore, the substrates
processing other aryl groups such as naphthyl and thienyl (1v−
w) were also applicable in this system to afford 2v−w
quantitatively with 99% and 98% ee’s, respectively. A
benzylsilylimine has also been synthesized and hydrogenated
under the above conditions. However, no product was
detected. Substrate 1v was also completely hydrogenated in
20 h using higher S/C (200/1) with no decrease in
enantioselectivity. Further reducing the S/C to 500/1 was
accomplished by using BenzP* with a slight decrease in
enantioselectivity (98% ee).
Deprotection of tosyl group produces the free α-amino-
silanes and ensures the further applications of this method-
ology. To the best of our knowledge, there is no report
concerning on the cleavage of Ts−N bond bearing a fragile C−
Si bond.6,8 We also encountered difficulties with this reaction
after many failures using the common reagents such as base,
acid, sodium naphthalide, thioanisole, and SmI2. Fortunately,
we finally found an indirect way to solve this problem. The
Ts−N bond was activated after introduction of a Boc group on
the N atom and was smoothly disconnected by treatment with
Mg/MeOH reagent. After removal of the Boc group, the free
α-aminosilanes was obtained in high yield and with retained
optical purity (Scheme 3).
Figure 1. Proposed stereochemical model for the Pd-catalyzed
asymmetric hydrogenation of 1b. The red imine is positioned on top
of the blue Pd complex.
Ts group is located opposite to the more bulky TBS group
(compared to the Ph group). In the favored transition state,
the more steric hindered Ts group (compared to the lone pair
electrons) and TBS group (compared to Ph) on the substrate
is adjacent to the smaller Me group (compared to t-Bu) on the
ligand. In the disfavored transition state, the more bulky t-Bu
groups on the ligand becomes their adjacent groups, which
leads to higher energy barrier for the approach of substrate to
the catalyst. Thus, the product 2b was predicted to be (S)-
configuration, which was consistent with the results of X-ray
crystallography.
In summary, asymmetric hydrogenation of a new kind of
substrate, N-sulfonyl arylsilylimines, was realized for the first
time. Catalyzed by the palladium complex of a P-stereogenic
diphosphine ligand QuinoxP*, the chiral α-aminosilanes, as the
mimics of natural α-amino acids, were obtained in high yields
and with excellent enantioselectivities. A challenging depro-
tection of tosyl group was developed to produce the free α-
aminosilanes and ensure the further applications of this
methodology.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04073.
Synthetic details for substrates, procedures for hydro-
genation reactions, and spectra of NMR and HPLC data
(PDF)
Accession Codes
CCDC 1448051 and 1502280 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 3. Deprotection of Tosyl Group
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanbin@sjtu.edu.cn.
*E-mail: zhenfeng@sjtu.edu.cn.
ORCID
Zhenfeng Zhang: 0000-0003-3295-6966
C
DOI: 10.1021/acs.orglett.8b04073
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Rev. 2012, 112, 2557. (c) Chen, Q.-A.; Ye, Z.-S.; Duan, Y.;
Wanbin Zhang: 0000-0002-4788-4195
Notes
̀
Zhou, Y.-G. Chem. Soc. Rev. 2013, 42, 497. (d) Verendel, J. J.; Pamies,
́
O.; Dieguez, M.; Andersson, P. G. Chem. Rev. 2014, 114, 2130.
The authors declare no competing financial interest.
(e) Zhang, Z.; Butt, N. A.; Zhang, W. Chem. Rev. 2016, 116, 14769.
(f) Zhang, Z.; Butt, N. A.; Zhou, M.; Liu, D.; Zhang, W. Chin. J.
Chem. 2018, 36, 443. Recent representative papers: (g) Friedfeld, M.
R.; Zhong, H.; Ruck, R. T.; Shevlin, M.; Chirik, P. J. Science 2018,
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21572131, 21620102003, and
21831005) and Shanghai Municipal Education Commission
(201701070002E00030). We also thank the Instrumental
Analysis Center of SJTU for characterization.
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