Highly enantioselective reduction of β-amino nitroolefins with a simple n-sulfinyl urea as bifunctional catalyst

Article abstract of DOI:10.1002/chem.201201192

Simple but effective: A structurally simple N-sulfinyl urea was found to be a highly efficient bifunctional catalyst, which allows for the development of a novel pathway for the construction of chiral β-amino nitroalkanes through enantioselective reduction of β-amino nitroolefins by trichlorosilane. High yields and excellent enantioselectivities were obtained for a broad range of β-arylamino nitroolefin substrates (see scheme). Copyright

Full text of DOI:10.1002/chem.201201192

COMMUNICATION
DOI: 10.1002/chem.201201192
Highly Enantioselective Reduction of b-Amino Nitroolefins with a Simple
N-Sulfinyl Urea as Bifunctional Catalyst
Xiang-Wei Liu,[a, b] Yan Yan,[a, b] Yong-Qiang Wang,[a, b] Chao Wang,[a] and Jian Sun*[a]
In recent years, bifunctional catalysis has proven to be
a successful concept in asymmetric organocatalysis.[1] In par-
ticular, various highly efficient asymmetric catalytic proto-
cols have been designed and implemented based on this
concept by using (thio)urea-type bifunctional catalysts.[2,3]
The combination of the double hydrogen-donating (thio)ur-
ea group with a Brønsted or Lewis basic group in these cata-
lysts is the key for dual chemical activation. Normally, multi-
ple stereogenic centers and electronically tuning groups plus
certain spacer are installed with these two groups to ensure
high reactivity and stereoselectivity. Thus, a relatively com-
plex molecular structure constitutes a common feature of
these catalysts. Herein, we document that N-sulfinyl ureas 5
(Scheme 1) with a particularly simple structure can also
serve as highly efficient bifunctional catalysts. The unique
feature of this catalyst system is that the simple S-chiral sul-
finyl group plays three critical roles, that is, chirality source,
Lewis base and acidifier, which enables the catalyst struc-
ture to be simplified to minimum. With the use of such cata-
lysts, we developed an unprecedented catalytic pathway for
the highly enantioselective reduction of b-arylamino nitroo-
lefins.
Chiral b-amino nitroalkanes are important intermediates
in organic synthesis, owing to their easy conversion into a va-
riety of useful compounds, such as chiral a-amino acids[4]
and 1,2-diamines.[5] The preparation of this type of com-
pounds mainly relies on asymmetric aza-Henry reactions.[6]
Recently, asymmetric aza-Michael additions have been suc-
Scheme 1. Catalyst structures and proposed activation pattern for the
asymmetric hydrosilylation of b-amino nitroolefins 8.
cessfully developed as highly effective approaches to chiral
b-amino nitroalkanes.[7] In principle, the catalytic reduction
of b-amino nitroolefins should provide an alternative
straightforward pathway to construct chiral b-amino nitroal-
kanes, owing to the easy availability of starting materials.
However, to the best of our knowledge, so far no efficient
method for this transformation has been reported, despite
the development of numerous efficient catalytic methods for
the reduction of many other types of olefins.[8] This stimulat-
ed our strong interest to search for an efficient method to
implement the high enantioselective reduction of b-amino
nitroolefins.
Recently, List and co-workers discovered that Jacobsen-
type thiourea 1 (Scheme 1) as catalyst can activate nitroole-
fins for asymmetric reduction with Hantzsch esters.[9] Mean-
while, Ellman developed a new type of chiral urea catalysts
(2 and 3) for the activation of nitroolefins and nitroalkanes
in asymmetric aza-Henry and Michael reactions.[3f,g] The S-
chiral sulfinyl group in Ellmanꢀs catalysts was used as both
acidifying and chiral-directing element. Such S-chiral sulfinyl
group was also used by Jacobsen in a new design of urea
catalyst 4.[3h,i] In this case, the S-chiral sulfinyl group is not
directly connected with the urea group and should have
[a] X.-W. Liu, Y. Yan, Y.-Q. Wang, C. Wang, Prof. Dr. J. Sun
Natural Products Research Center
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu 610041 (P. R. China)
Fax : (+86)28-85222753
E-mail: sunjian@cib.ac.cn
[b] X.-W. Liu, Y. Yan, Y.-Q. Wang
Graduate University of the Chinese Academy of Sciences
Beijing 100049 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201192.
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little acidifying effects on the urea function, but it plays
both Lewis base activating and chiral-directing roles. In-
spired by these works and based on our own work,[10] we en-
visioned that if all the chiral-directing, acidifying, and Lewis
base activating functions of the S-chiral sulfinyl group could
be fully utilized, N-sulfinyl ureas 5 with a relatively simple
structure might serve as efficient catalyst to address the
asymmetric reduction of b-amino nitroolefins through hy-
drosilylation in a new dual-functional activation pattern
(Scheme 1).[11,12]
Thus, we prepared a small set of ureas 5 and tested their
catalytic efficacies in the hydrosilylation of b-amino nitroo-
lefin 8a. Urea 6 and amide 7 were also prepared and tested
for comparison. To our delight, all the ureas 5a–e, regardless
of the different electronic nature of the N’-aryl groups,
could drive the hydrosilylation of 8a to completion in 24 h
and gave the desired b-amino nitroalkane product 9a in
high yield and excellent enantioselectivity (93–99% yield,
95–96% ee, entries 1–5, Table 1). In contrast, urea 6 showed
lyzed hydrosilylation, devoid of which a dramatic loss of re-
activity was observed (entry 8). Other protic additives, such
as acetic acid and isopropanol, were also found to be effec-
tive, affording high yields and slightly lower enantioselectivi-
ties (entries 9 and 10).
We further investigated other parameters of this transfor-
mation. We found that when the reaction temperature was
increased from À40 to À208C, excellent yields remained
(Table 1, entries 11 and 12), but a slight decrease in enantio-
selectivity occurred. Solvent effects were also examined.
Other solvents, including dichloromethane and 1,2-dichloro-
ethane, chloroform, and toluene, all proved to be inferior to
acetonitrile (entries 13–16).
To probe the substrate scope, various b-arylamino nitroal-
kanes 8a–q were subjected to the 5a-catalyzed hydrosilyla-
tion. The results are summarized in Table 2. In general, in
Table 2. Scope of b-amino nitroolefins in the 5a-catalyzed reduction.[a]
Table 1. Effects of catalysts and conditions on the hydrosilylation of
8a.[a]
Entry Substrate
R1
Yield [%][b] ee [%][c] Config.
R2
1
2
3
4
5
6
Ph
PMP
8a
8b
8c
8d
8e
8 f
8g
8h
8i
99
95
94
98
93
94
92
96
94
96
92
95
96
95
94
97
96
95
95
92
93
91
91
88
89
90
82
93
93
92
79
R(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(À)
(+)
(+)
(À)
(À)
(À)
R(À)
4-MeOC6H4 PMP
3-MeOC6H4 PMP
Entry
Catalyst
Solvent
Additive
Yield [%][b]
ee [%][c]
4-MeC6H4
3-MeC6H4
2-naphthyl
4-FC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
4-CF3C6H4
3-CF3C6H4
4-CNC6H4
c-Hex
iPr
Ph
Ph
2-thienyl
2-furyl
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Ph
1
2
3
4
5
6
7
8
9
10
11[d]
12[e]
13
14
15
16
5a
5b
5c
5d
5e
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
H2O
H2O
H2O
H2O
H2O
H2O
H2O
–
AcOH
iPrOH
H2O
H2O
H2O
H2O
H2O
H2O
99
97
96
99
93
<10
63
<10
89
98
95
96
95
96
96
96
–
7
8[d]
9[d]
10
8j
8k
8l
11[e]
12[e]
13[e]
14
7
15
–
5a
5a
5a
5a
5a
5a
5a
5a
5a
8m 94
95
92
94
92
80
53
57
8
8n
8o
8p
97
96
99
84
82
96
15
16
17
18
98
76
68
17
DMP 8q
PMP
PMP
8r
8s
DCE
CHCl3
toluene
19
65
[a] Unless otherwise noted, all reactions were performed with
8
(0.1 mmol), 5a (10 mol%), HSiCl3 (0.3 mmol), and water (1.0 equiv) in
acetonitrile (1.0 mL) at À408C for 24 h. [b] Isolated yield. [c] Determined
by chiral HPLC. [d] Because the substrate solubility is not good, the reac-
tion needed to be run at À308C for 48 h. [e] The catalyst loading was
20 mol%. DMP=2,4-dimethoxyphenyl.
[a] Unless otherwise noted, all reactions were performed with 8a
(0.1 mmol), catalyst (10 mol%), HSiCl3 (0.3 mmol), and additive
(0.1 mmol) in solvent (1.0 mL) at À408C for 24 h. [b] Isolated yield.
[c] Determined by chiral HPLC. The product 9a was determined to be
R-configured in all cases by comparison of the optical rotation with the
literature data. [d] The reaction temperature was À308C. [e] The reaction
temperature was À208C. PMP=para-methoxyphenyl, DCE=1,2-di-
chloroethane.
the presence of 10 mol% catalyst, the reactions with sub-
strates bearing a b-aryl group went to completion in 24 h
and the desired products were obtained in excellent yields
(92–99%) and enantioselectivities (91–97% ee, entries 1–
10). Substrates bearing a relatively electron-deficient b-aryl
group 8k–m tended to be less reactive and required
a higher catalyst loading (20 mol%) to drive the reaction to
completion in 24 h in satisfying yields (entries 11–13). In
these cases, slightly lower enantioselectivities (88–91% ee)
were observed. Notably, the b-alkyl-type substrates 8n and
almost no reactivity (entry 6), implying that the strong
Lewis basicity of the sulfinyl group is critical for the chemi-
cal activation.[13] On the other hand, amide 7 retained mod-
erate reactivity, but gave poor enantioselectivity (entry 7),
suggesting that the urea motif is also important for both the
reactivity and the stereoselectivity. Notably, one equivalent
of water proved to be a crucial additive for the urea-cata-
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Organocatalytic Enantioselective Reduction of b-Amino Nitroolefins
COMMUNICATION
8o also smoothly underwent hydrosilylation under the opti-
mal conditions and afforded the desired aliphatic b-amino
nitroalkane product in high yield and good enantioselectivi-
ty (entries 14 and 15). Moreover, substrates 8p and 8q, de-
rived from arylamines other than para-methoxyaniline, were
also well tolerated in the present catalytic reaction system
(entries 16 and 17). In addition, good results were obtained
with heterocyclic substrates 8r and 8s (entries 18 and 19).
To illustrate the synthetic utility of the present method,
the conversion of the resulting product 9a into 1,2-diamine
and amino acid derivatives were conducted by known nitro-
reduction[14] and Nef oxidation[15] methods, respectively
(Scheme 2a). The corresponding products 10a and 12 were
Scheme 3. Deuterium-labeling experiments and proposed reaction path-
way.
In conclusion, we have developed a novel method for the
asymmetric reduction of b-amino nitroolefins by using struc-
turally simple S-chiral N-sulfinyl ureas as bifunctional cata-
lyst and trichlorosilane as reducing agent. A broad range of
substrates was reduced in high yield and excellent enantiose-
lectivity. The product can easily be transformed into practi-
cally useful diamine and amino acid derivatives. Not only
does this method provide a new approach to chiral b-amino
nitroalkanes, but it also offers a new strategy for the design
and implementation of efficient bifunctional catalysts, par-
ticularly for the asymmetric reduction through hydrosilyla-
tion.
Scheme 2. a) Conversion of the b-amino nitroalkane product 9a into dia-
mine and amino acid derivatives and b) gram-scale reduction of 8a.
Experimental Section
obtained in good yields with complete preservation of the
enantiopurity. Moreover, a gram-scale reaction for the re-
duction of 8a was performed, which retained the excellent
yield and enantioselectivity (Scheme 2b).
General procedure: Trichlorosilane (30 mL, 0.3 mmol) was added drop-
wise to a stirred solution of 8 (0.1 mmol), catalyst 5a (0.01 mmol), and
water (1.8 mL, 0.1 mmol) in anhydrous acetonitrile (1.0m) at À408C
under an argon atmosphere. The mixture was stirred at the same temper-
ature for 24 h. Then, the reaction was quenched by addition of water and
extracted with ethyl acetate. The combined organic phases were washed
with brine, dried over anhydrous magnesium sulfate, and concentrated
under vacuum. The crude product was further purified by column chro-
matography (silica gel, hexane/EtOAc) to afford the desired pure b-
amino nitroalkanes 9.
To obtain insights into the reaction mechanism of the
present catalytic system, we conducted deuterium-labeling
experiments in the 5a-catalyzed reduction of 8a by using
deuterated water as additive (Scheme 3). Interestingly, both
a-hydrogen atoms in product 9a were partially labeled, and
no labeling of the amino group occurred at all. Moreover,
the labeling percentage of both hydrogen atoms rose by
over 20% when the amount of deuterated water was in-
creased from 1.0 to 2.0 equivalents. These results clearly
suggest that the reaction should prefer path c to other possi-
ble paths, such as a and b (Scheme 3). The acid, generated
from the reaction of water with trichlorosilane, first proto-
nates C1 of 8 to form iminium intermediate C, which is then
subjected to the reduction by trichlorosilane in the presence
of the catalyst. The deuterium labeling of the second hydro-
gen on C1 is due to the fast equilibrium between intermedi-
ate C and 8.
Acknowledgements
We are grateful for financial supports from the National Natural Science
Foundation of China (Project Nos. 20972152 and 91013006).
Keywords: amino nitroolefins
· asymmetric catalysis ·
bifunctional catalyst · hydrosilylation · reduction · sulfinyl
ureas
Chem. Eur. J. 2012, 00, 0 – 0
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Received: April 8, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Organocatalytic Enantioselective Reduction of b-Amino Nitroolefins
COMMUNICATION
Simple but effective: A structurally
simple N-sulfinyl urea was found to be
a highly efficient bifunctional catalyst,
which allows for the development of
a novel pathway for the construction
of chiral b-amino nitroalkanes through
enantioselective reduction of b-amino
nitroolefins by trichlorosilane. High
yields and excellent enantioselectivities
were obtained for a broad range of b-
arylamino nitroolefin substrates (see
scheme).
Organocatalysis
X.-W. Liu, Y. Yan, Y.-Q. Wang,
C. Wang, J. Sun* ............. &&&& — &&&&
Highly Enantioselective Reduction of
b-Amino Nitroolefins with a Simple N-
Sulfinyl Urea as Bifunctional Catalyst
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!