Highly enantioselective michael addition of malononitrile to vinylogous imine intermediates generated in situ from arylsulfonyl indoles

Article abstract of DOI:10.1002/chem.201001662

(Figure Presented) Malononitrile on rare form: Highly enantioselective Michael addition of malononitrile to vinylogous imine intermediates 2, generated in situ from arylsulfonyl indoles 1, is described (see scheme). This protocol provides easy and conveni

Full text of DOI:10.1002/chem.201001662

COMMUNICATION
DOI: 10.1002/chem.201001662
Highly Enantioselective Michael Addition of Malononitrile to Vinylogous
Imine Intermediates Generated in situ from Arylsulfonyl Indoles
Linhai Jing,[a] Jiangtao Wei,[a] Li Zhou,[a] Zhiyong Huang,[a] Zhengkai Li,[a] Di Wu,[a, b]
Haifeng Xiang,[a] and Xiangge Zhou*[a, b]
The conjugate addition of carbon-based nucleophiles to
activated unsaturated systems represents one of the best es-
tablished and most versatile carbon–carbon bond-forming
reactions in organic chemistry.[1] Malononitrile, a classic
equivalent of a 1,3-dicarbonyl compound, might be a valu-
alkylation product.[8] Since 3-substituted indole frameworks
have been widely found in biologically active compounds,[9]
we wish to demonstrate, herein, the first highly enantioselec-
tive Michael addition of malononitrile to vinylogous imine
intermediates 2, generated in situ from arylsulfonyl indoles
1, catalyzed by chiral thiourea catalysts A–D.[10]
ACHTUNGTRENNUNGable nucleophile, which can then be conveniently trans-
formed into carboxylic acid,[2] ester,[3] amine,[2a,4] or amide
groups.[4b] However, to the best of our knowledge, few stud-
ies of asymmetric Michael additions that use malononitrile
as the nucleophile have been reported.[5]
Arylsulfonyl indoles 1, which bear a good leaving group,
are an effective precursor for vinylogous imine intermedi-
ates 2, which are generated under basic conditions.[6] Re-
cently, several non-asymmetric reactions that use 2 as ac-
ceptors have been carried out.[7] However, compared with
the extensively studied a,b-unsaturated carbonyl compounds
and nitroolefins, the study of the enantioselective conjugate
addition to 2 is still in its infancy and only one asymmetric
example has been reported, in which an aldehyde was react-
ed with a vinylogous imino ion to form the corresponding
Initially, the reaction of 3-[(4-methylphenylsulfonyl)phe-
nylmethyl]-1H-indole and malononitrile was tested in the
presence of catalyst A (Scheme 1).[11] Unfortunately, the re-
action afforded a racemic mixture of product, although in
high yield (93%). This prompted us to investigate the possi-
ble catalytic mechanism of the reaction to improve the re-
sults. Supported by the literature stating that the s-cis/trans
conformations or E/Z configurations of enamines might play
an important role in affecting the diastereo- and enantiose-
lectivities of some asymmetric catalysis,[12] a plausible cata-
lytic mode was proposed (Scheme 2). We hypothesize that
vinylogous imine intermediate 2, generated in situ from aryl-
sulfonyl indole 1, contains E and Z configurations 2-1 and 2-
[a] L. Jing, J. Wei, L. Zhou, Z. Huang, Z. Li, Dr. D. Wu, H. Xiang,
Prof. Dr. X. Zhou
Insitute of Homogeneous Catalysis, College of Chemistry
Sichuan University, Chengdu, 610041 (China)
Fax : (+86)8-8541-2291
E-mail: zhouxiangge@scu.edu.cn
[b] Dr. D. Wu, Prof. Dr. X. Zhou
State Key Laboratory of Coordination Chemistry
Nanjing University, Nanjing, 210093 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001662.
Chem. Eur. J. 2010, 16, 10955 – 10958
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10955

therefore, results in the formation of a racemic product mix-
ture.
Further experiments supported the likelihood of this
mechanism. As shown in Table 1, the ee value was dramati-
cally increased to 54% when R1 was changed from a proton
Scheme 1. The reaction between malononitrile and 3-[(4-methylphenyl-
Table 1. Optimization of the reaction conditions.[a]
sulfonyl)phenylmethyl]-1H-indole; Tol=4-methylphenyl.
Entry
Catalyst
Base
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
22[f]
A
B
C
KF/alumina
KF/alumina
KF/alumina
KF/alumina
KF
Na2CO3
K2CO3
NaHCO3
NaOAc
K3PO4
Na2HPO4
DIPEA
DMAP
Et3N
K3PO4
K3PO4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
MeCN
THF
DMF
toluene
toluene
toluene
toluene
92
90
90
89
80
82
88
78
70
87
84
78
79
75
60
77
75
72
91
90
72
55
54
À53
À52
50
46
36
77
31
32
80
52
–
–
–
–
–
–
–
91
91
46
30
D
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
[a] Unless otherwise noted, the reactions were carried out with malononi-
trile (0.1 mmol), catalyst (0.02 mmol), 1a (0.11 mmol), and base
(0.11 mmol) in solvent (2.0 mL) at 308C for 24 h. DIPEA=N,N-diisopro-
pylethylamine; DMAP=4-dimethylaminopyridine. [b] Isolated yield.
[c] Enantioselective excess was determined by chiral HPLC analysis.
[d] 10 mol% of catalyst was used. [e] 5 mol% of catalyst was used. [f] 2
mol% of catalyst was used.
Scheme 2. Proposed catalytic mode through double activation.
to a methyl group, under the same catalytic conditions
(Table 1, entry 1). Furthermore, the other three thiourea cat-
alysts (B–D) gave almost the same results (Table 1, en-
tries 2–4). Reaction conditions were then optimized; K3PO4
afforded the best ee (80%), although racemic products were
obtained when organic bases, including DIPEA, DMAP, or
Et3N, were used (Table 1, entries 5–14). This is probably due
to a loss of hydrogen bonding interactions between catalyst
A and the substrates. The influence of other solvents was
also examined. Protic solvents (EtOH) and polar solvents
(MeCN, THF, DMF) gave inferior results (Table 1, en-
tries 15–18), whereas a nonpolar solvent (toluene) efficiently
promoted the reaction in excellent yield (91%) and high
enantioselectivity (91%; Table 1, entry 19). Finally, the cata-
lyst loading was investigated and it was observed that the
catalyst loading could be decreased to 10 mol% without loss
of enantioselectivity (Table 1, entry 20).
2, as shown in Scheme 2. The thiourea moiety of catalyst A
acts as a Brønsted acid and interacts with the nitrogen atom
of 2 through hydrogen bonding, enhancing the electrophilici-
ty.[10e,13] Meanwhile, the aliphatic tertiary amine unit in A
acts as a Brønsted base to deproACTHNUGRTNEUNGtonate and activate malono-
nitrile by forming a hydrogen bond with its anion,[5e–h,14] gen-
erating ternary-complex transition states 4-1 and 4-2, respec-
tively. Consequently, nucleophilic attack to 2-1 and 2-2 af-
fords the correspondingly configured products 3-1 and 3-2,
respectively. Thus, the formation of hydrogen bonds, as well
as the ratio of E/Z configurations of the exocyclic double
bond, are important factors in determining the ultimate
enantioselectivity. During the reaction shown in Scheme 1,
the lack of steric effects in vinylogous imine 2 (R1 =H)
might induce the ratio of E/Z isomers to be around 1:1 and,
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Enantioselective Michael Addition
COMMUNICATION
With the optimized reaction conditions in hand, we then
screened a series of arylsulfonyl indoles 1a–m. As portrayed
in Table 2, various arylsulfonyl indoles underwent the reac-
Table 2. Asymmetric conjugate addition of malononitrile to arylsulfonyl
indoles 1.[a]
Figure 1. X-ray structure of enantiomerically pure 3h. Thermal ellipsoids
are set at 30% probability.
Entry
1
R
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
90
88
93
93
90
92
90
95
82
82
78
70
75
91
81
82
83
91
4-Br-C6H4
4-F-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-Me-C6H4
4-OMe-C6H4
3-OMe-C6H4
1-Np
bond play important roles in the enantioselectivity during
catalysis. Overall, we believe this approach will be an impor-
tant complementary reaction to the Friedel–Crafts alkyla-
tion of indoles.[16] Further investigations to broaden the
scope of this type of transformation and find evidence for
the mechanism are currently ongoing in our laboratory.
84
80
>99[d]
81
1j
1k
1l
2-NO2-C6H4
Bn
tBu
3j
3k
3l
65
86
96
90
Experimental Section
1m
iBu
3m
General experimental procedure: Catalyst A (0.01 mmol), malononitrile
(0.1 mmol), arylsulfonyl indole 1 (0.11 mmol), K3PO4 (0.11 mmol), and
toluene (2 mL) were mixed in an ordinary test tube equipped with a mag-
netic stirring bar and then sealed in air. After being stirred at 308C for
24 h, the reaction mixture was purified by flash column chromatography
on silica gel (ethyl acetate/petroleum ether 1:6–1:10) to afford product 3.
The enantiomeric excess was determined by HPLC analysis on a chiral
column. Further experimental details can be found in the Supporting In-
formation.
[a] The reactions were carried out with malononitrile (0.1 mmol) and 1
(0.11 mmol). Np=naphthyl; Bn=benzyl. [b] Isolated yield. [c] The ee
value was determined by HPLC analysis on an AD-H, AS-H, or OD-H
column. [d] The absolute configuration of 3h was determined to be S by
X-ray crystal structure analysis (Figure 1).[15] The absolute configuration
of other products was assigned by analogy.
tion smoothly and gave the corresponding products with
good to excellent results. A para substituent had little influ-
ence on the enantioselectivity of the reaction (Table 2, en-
tries 2–4, 6, and 7). An ortho or meta substituent, on the
other hand, seemed to be beneficial to the reaction. For ex-
ample, the use of 2-Cl-substituted 1e gave 91% ee, whereas
83% ee was obtained in the case of 4-Cl-substituted 1d
(Table 2, entries 4 and 5). The highest ee (more than 99%)
was obtained when 3-OMe-substituted 1h was used to form
product 3h (Table 2, entry 8). Its absolute configuration was
further confirmed by single crystal structure determination
(Figure 1). However, a relatively low ee was observed for
the reaction between 2-NO2-substituted 1j and malononi-
trile (Table 2, entry 10), possibly due to an interaction be-
tween the nitro group and catalyst A. Finally, sulfonyl in-
doles with aliphatic substituents could also be employed and
good yields and high enantioselectivities, ranging from 86 to
96%, were obtained (Table 2, entries 11–13).
In conclusion, we have developed the first highly enantio-
selective Michael addition of malononitrile to vinylogous
imine intermediates 2, generated in situ from arylsulfonyl in-
doles 1, catalyzed by a chiral thiourea catalyst. This organo-
catalytic approach provides easy and convenient access to
valuable 3-indolyl derivatives 3 in high yields and enantiose-
lectivities. We have proposed that the ratio of E/Z configu-
rations in the intermediate and the formation of a hydrogen
Acknowledgements
We thank the Natural Science Foundation of China (Nos. 20672075,
20771076, and 20901052), the Sichuan Provincial Foundation (08ZQ026-
041), and the Ministry of Education of China (NCET-10-0581) for finan-
cial support and the Analytical & Testing Centre of Sichuan University
for NMR analysis.
Keywords: asymmetric catalysis · imines · indoles · Michael
addition · organocatalysis
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Received: June 11, 2010
Published online: August 16, 2010
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Chem. Eur. J. 2010, 16, 10955 – 10958