Squaramide-catalyzed enantioselective Michael addition of malononitrile to chalcones

Article abstract of DOI:10.1039/c1ob06302b

A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral quinine-derived squaramide catalyst has been developed. This organocatalytic reaction at a very low catalyst loading (0.5 mol%) led to chiral γ-cyano carbonyl c

Full text of DOI:10.1039/c1ob06302b

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 332
www.rsc.org/obc
PAPER
Squaramide-catalyzed enantioselective Michael addition of malononitrile to
chalcones†
Wen Yang, Yang Jia and Da-Ming Du*
Received 31st July 2011, Accepted 28th September 2011
DOI: 10.1039/c1ob06302b
A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral
quinine-derived squaramide catalyst has been developed. This organocatalytic reaction at a very low
catalyst loading (0.5 mol%) led to chiral g-cyano carbonyl compounds in good yields with high
enantioselectivities (up to 96% ee) under mild reaction conditions.
ric Michael addition,7a–h Friedel–Crafts reaction,7i a-amination of
Introduction
1,3-dicarbonyl compounds,7j Morita–Baylis–Hillman reaction,7k
The conjugate addition of carboanion nucleophiles to electron-
and Aldol reaction.7l Recently, our group also reported chiral
deficient olefins is one of the fundamental carbon–carbon bond
squaramide-catalyzed asymmetric reactions.7e,g Herein, we would
forming reactions in organic synthesis, and it is also a powerful tool
like to describe the highly enantioselective Michael addition
for the construction of highly functionalized carbon skeletons.1,2
of malononitrile to chalcones catalyzed by chiral squaramide
Malononitrile is a valuable source of stabilized carboanion due
organocatalysts.
to the strong electron-withdrawing property of the nitrile group
and its facile transformations to other useful functional groups.3
Results and discussion
However, studies on the asymmetric Michael addition employing
malononitrile are currently limited.4,5 In this context, we were
intrigued to develop an organocatalytic asymmetric Michael
addition of malononitrile to chalcones. To date, only a few efficient
catalytic enantioselective methods to perform this reaction are
reported.5 Wang first reported the asymmetric Michael addition
of malononitrile to trans-chalcone catalyzed by cinchona-derived
thiourea to give the product in 77% yield with 88% ee.5a Recently,
Feng and co-workers developed an efficient quinine-Al(OiPr)3
complex catalytic system to promote this reaction with high yields
and good enantioselectivities.5b Lattanzi and co-workers employed
quinine as an efficient catalyst to achieve good results.5c More
recently, Lattanzi reported a,a-L-diaryl prolinols as promoters,
even though the enantioselectivities obtained were not ideal.5d
Despite these successes, the development of efficient catalytic
systems in pursuit of excellent enantioselectivity, low catalyst
loading, and mild reaction conditions is still challenging and in
great demand.
Initially, the reaction of trans-chalcone 1a with malononitrile 2 was
carried out in the presence of squaramide catalyst I (10% mol) at
room temperature, and the desired product 3a was obtained in 75%
yield with 33% ee. In order to identify a more efficient catalyst,
we prepared a series of chiral squaramide organocatalysts I–VIII
(Fig. 1) and performed a systematic catalyst screening. When
Chiral squaramide is a novel type of good hydrogen bond
donor.6,7 In 2008, Rawal first developed a chiral squaramide
derivative to promote the Michael addition of 1,3-dicarbonyl
compounds to nitroalkenes.7a After the pioneering report, a series
of chiral squaramide organocatalysts were developed and success-
fully applied in various asymmetric reactions,7 including asymmet-
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing, 100081, People’s Republic of China. E-mail: dudm@
bit.edu.cn; Tel: +86 10 68914985
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of Michael addition compounds, and HPLC chromatographs. See
DOI: 10.1039/c1ob06302b
Fig. 1 Screened squaramide catalysts.
332 | Org. Biomol. Chem., 2012, 10, 332–338
This journal is
The Royal Society of Chemistry 2012
©

Table 1 Screening of organocatalysts for the asymmetric Michael addi-
tion of malononitrile to trans-chalconea
Table 2 Optimization of reaction conditions for the asymmetric Michael
addition of malononitrile to trans-chalconea
Entry
Catalyst
Yieldb (%)
eec (%)
Config.
Entry
Solvent
Loading (mol%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
I
75
83
73
78
82
80
68
74
33
59
82
86
81
79
81
79
R
R
S
S
S
S
S
S
1
2
3
4
CH2Cl2
THF
10
10
10
10
10
10
10
10
10
10
5
78
44
37
95
68
76
87
50
79
58
79
82
82
39
67
74
86
61
61
2
II
III
IV
V
VI
VII
VIII
Toluene
MeOH
CH2ClCH2Cl
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
5
74
88
76
86
85
89
89
89
90
91
73
80
6
7d
8e
9f
a Unless noted otherwise, reactions were carried out with trans-chalcone
1a (0.20 mmol) and malononitrile (0.24 mmol) in CH2Cl2 (0.5 mL) at
room temperature for 24 h. b Isolated yields after column chromatography
purification. c Determined by chiral HPLC.
10g
11
12
13
14
15h
16h
1
0.5
0.2
0.5
0.5
quinidine-derived squaramide catalyst II with para-CF3 group
was used, an obvious increase in the enantioselectivity (59% ee)
was observed. To our delight, quinine-derived squaramides III
and IV afforded the corresponding products with the opposite
configuration in good yields with significantly higher enantios-
electivities (82 and 86% ee, respectively). Squaramide catalysts
V–VIII derived from chiral cyclohexane-1,2-diamine were also
tested, but no better results were obtained (Table 1, entries 5–
8). Therefore, squaramide IV was selected as the best catalyst for
further optimization.
a Unless noted otherwise, reactions were carried out with trans-chalcone
1a (0.20 mmol) and malononitrile 2 (0.24 mmol) in the solvent (0.5 mL) at
room temperature for 24 h. b Isolated yields after column chromatography
purification. c Determined by chiral HPLC. d Reaction was performed at
60 ◦C for 12 h. e Reaction was performed at 0 ◦C for 96 h. f 0.25 mL of
CHCl3 was used. g 1.0 mL of CHCl3 was used. h Quinine was used as the
catalyst.
With the optimal reaction conditions established, we explored
the scope of this asymmetric Michael addition. The results are
shown in Table 3. The position and the electronic property of
substituent on the aromatic ring have a very limited effect on
the enantioselectivity. A wide array of chalcones bearing electron-
withdrawing or electron-donating substitutions reacted smoothly
with malononitrile 2 to afford the corresponding adducts with
good to high enantioselectivities (entries 2–16). The electronic
property of substituent has a certain effect on the yield. Generally,
those substrates with electron-withdrawing groups gave high
yields, and moderate to good yields were achieved for electron-
rich substrates. Other chalcone analogues were also tested in
the reaction. When substrate 1q derived from 1-naphthlaldehyde
was used as an acceptor, good yield and high enantioselectivity
(74% yield, 89% ee) were obtained (entry 17). Substrate 1r with
a furan ring gave moderate yield and good enantioselectivity
(54% yield, 83% ee) after a prolonged time (entry 18). Aliphatic
enones 1s and 1t were proved to be viable substrates to give
the corresponding products with good enantioselectivities, even
though they exhibited low reactivity (entries 19 and 20).
Further substrate scope was investigated as shown in Scheme
1. (2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one 4 reacted with mal-
ononitrile 2 to afford the 1,4-addition product 5 in moderate
yield with high enantioselectivity. 1-Phenyl-2-buten-1-one as a
substrate was also investigated, but no reaction occurred. Inspired
by Wang’s recent report,9 the reaction of (E)-2-benzylidene-3,4-
dihydronaphthalen-1(2H)-one 6 and malononitrile 2 was carried
out with 1 mol% IV, and the cascade Michael–oxa-Michael–
tautomerization process occurred to give the corresponding
product 7 in moderate yield with high enantioselectivity. To further
With squaramide IV as the optimal catalyst, a simple solvent
screening was first carried out. The screening results were shown in
Table 2. Variation of the solvents had a pronounced effect on the
yields and enantioselectivities. The use of THF and toluene led to
an obvious decrease in the yields and enantioselectivities (entries 2
and 3), while the polar solvent MeOH gave almost racemic product
in excellent yield (entry 4). Other chlorinated solvents were also
screened, and the best result (76% yield, 88% ee) was obtained in
CHCl3 (entries 5 and 6). Subsequently, the effects of temperature
and substrate concentration were investigated. Neither heating
nor cooling the reaction gave a better result (entries 7 and 8).
Variation of substrate concentration affected the enantioselectivity
slightly (entries 9 and 10). Finally, the effect of catalyst loading
was investigated. Interestingly, the yield and enantioselectivity
were slightly improved with a reduced catalyst loading from 10
to 0.5 mol% (entries 1 and 11–13). When the catalyst loading
was reduced to 0.2 mol%, the adduct was obtained with high
enantioselectivity but in low yield (entry 14). The phenomena of
increased enantioselectivity with decreased catalyst loading may
be ascribed to the decreased self-association of this type of catalyst,
as it is known that urea and thiourea based organocatalysts
can form hydrogen-bonded dimmers or aggregates, resulting in
the dependency of enantioselectivity on the concentration.8 For
comparison, a simple catalyst, quinine, was investigated under
identical or similar conditions, with toluene as the best solvent,
and inferior results were obtained (entries 15 and 16). The results
show the superiority of the squaramide-modified quinine catalyst
in a low catalyst loading.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 332–338 | 333
©

Table 3 Scope of the asymmetric Michael addition of malononitrile to
trans-chalcones and other enonesa
changes in yield or enantioselectivity, and the adduct 3a with 97%
ee was obtained after a simple recrystallization.
Based on the absolute configuration of the adduct 3a, a possible
transition-state model for the catalytic reaction of chalcone 1a and
malononitrile 2 is hypothesized and shown in Fig. 2. The chiral
squaramide IV may act as a bifunctional catalyst. Malononitrile 2
is deprotonated by the basic nitrogen atom of the tertiary amine.
Meanwhile, the squaramide moiety as a Brønsted acid activates
chalcone 1a through double hydrogen bonding. The deprotonated
malononitrile attacks the activated chalcone from the Re-face
to afford the S-configured product, which is consistent with the
observed result.
Entry R1
R2
Product Yieldb (%) eec (%)
1
2
C6H5
4-FC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3f
82
77
83
91
96
91
94
79
50
70
79
90
88
60
71
92
74
54
23
35
90 (S)d
96
91
80
86
91
88
90
90
89
89
89
90
91
92
88
89
83
86
88
3
4
5
6
7
8
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
3-BrC6H4
4-MeC6H4
3g
3h
3i
3j
3k
3l
9
4-OMeC6H4 C6H5
2-OMeC6H4 C6H5
C6H5
C6H5
C6H5
10
11
12
13
14
15
16
17
18e
19e
20e
4-FC6H4
4-ClC6H4
4-BrC6H4
3m
C6H5
4-OMeC6H4 3n
4-MeC6H4
4-ClC6H4
1-Naphthyl
2-Furyl
Cyclohexyl
tBu
4-MeC6H4
4-ClC6H4
C6H5
C6H5
C6H5
3o
3p
3q
3r
3s
3t
C6H5
a Unless noted otherwise, reactions were carried out with trans-chalcones
1 (0.20 mmol) and malononitrile 2 (0.24 mmol) in CHCl3 (0.5 mL) at
room temperature for 24 h. b Isolated yields after column chromatography
purification. c Determined by chiral HPLC. d Absolute configuration was
determined by comparison of the optical rotation with literature data.5b,c,10
e Reaction was performed for 48 h.
Fig. 2 Proposed transition state model.
Conclusions
In summary, we have developed a squaramide-catalyzed highly
enantioselective Michael addition of malononitrile to chalcones.
This catalytic reaction at a very low catalyst loading (0.5 mol%)
was effective to give the Michael adducts with high yields and good
enantioselectivities (up to 96% ee) under mild reaction conditions.
Moreover, this catalytic reaction was readily gram-scaled without
significant changes in yield or enantioselectivity. Further studies
on asymmetric reactions catalyzed by squaramides are underway
in our laboratory.
Experimental
Geneal methods
Scheme 1 Further investigation of substrate scope.
Commercially available compounds were used without further
purification, unless otherwise stated. Column chromatography
was carried out with silica gel (200–300 mesh). Melting points were
measured with a XT-4 melting point apparatus without correction.
1H NMR spectra were recorded with a Varian Mercury-plus
400 MHz spectrometer. Chemical shifts were reported in ppm
with the internal TMS signal at 0.0 ppm as a standard. The data
are reported as follows: chemical shift (ppm), and multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or
unresolved, br s = broad singlet), coupling constant(s) in Hz, inte-
gration assignment. 13C NMR spectra were recorded at 100 MHz.
Chemical shifts are reported in ppm with the internal chloroform
signal at 77.0 ppm as a standard. Infrared spectra were obtained
with a Perkin Elmer Spectrum One spectrometer. The ESI-MS
evaluate the synthetic potential of the catalytic system, the gram-
scale preparation of 3a was performed. As shown in Scheme 2,
the catalytic reaction was readily gram-scaled without significant
Scheme 2 The gram-scale preparation of 3a.
334 | Org. Biomol. Chem., 2012, 10, 332–338
This journal is
The Royal Society of Chemistry 2012
©

spectra were obtained with a Bruker APEX IV mass spectrometer
or a Varian MS-500 mass spectrometer. Optical rotations were
measured with Kru¨ss P8000 or WZZ-3 polarimeter at the indicated
concentration with units g/100 mL. The enantiomeric excesses of
the products were determined by chiral HPLC using an Agilent
1200 LC instrument with a Daicel Chiralpak IA or AS-H column.
The absolute configurations of the known adducts were assigned
by HPLC and optical rotation comparisons with the reported
data,5b,c,10 and those of other adducts were assigned by analogy.
(t, J = 7.2 Hz, 1H, ArH), 7.51 (t, J = 8.0 Hz, 2H, ArH), 7.44–7.39
(m, 4H, ArH), 4.64 (d, J = 4.8 Hz, 1H, CN-CH), 3.98–3.93 (m,
1H, Ar-CH), 3.73–3.59 (m, 2H, CH2) ppm; MS (ESI): m/z (% rel.
intensity) 308.7 [M - H]+ (28, 37Cl), 306.9 [M - H]+ (100, 35Cl).
Lit.5b [a]2D0 -5.15 (c 0.194, CH2Cl2), 89% ee.
(S)-2-[1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl]malononitrile
(3d). Compound 3d was obtained according to the general
procedure as a white solid (56.0 mg, 91% yield); mp 119–121 ◦C.
Enantiomeric excess was determined by HPLC with a Daicel
Chiralpak AS-H column (n-hexane–2-propanol 90 : 10, flow rate
Preparation of squaramide organocatalysts I–VIII
0.8 mL min-1, detection at 254 nm), minor enantiomer tR
=
38.9 min, major enantiomer tR = 42.4 min, 80% ee; [a]2D0 = +3.6 (c
1.10, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.97 (d, J = 7.6 Hz,
2H, ArH), 7.63 (t, J = 7.2 Hz, 1H, ArH), 7.53–7.47 (m, 4H, ArH),
7.36–7.30 (m, 2H, ArH), 4.68–4.64 (m, 2H, 2CH), 3.81–3.64 (m,
2H, CH2) ppm; MS (ESI): m/z (% rel. intensity) 308.6 [M - H]+
(30, 37Cl), 306.9 (100, 35Cl) [M - H]+. Lit.5c [a]2D2 = +4.0 (c 0.44,
CHCl3), 94% ee.
The squaramide organocatalysts I–VIII were prepared following
the reported procedures.7e,g
General procedure for the enantioselective Michael addition
reaction
Organocatalyst IV (11.3 mg, 0.02 mmol) was added to chloroform
to afford the solution of catalyst IV (10.0 mL, 2.0 mmol L-1). To
a solution of trans-chalcones 1 (0.20 mmol) in the above catalyst
IV solution (0.5 mL, 0.001 mmol, 0.5 mol% catalyst) was added
malononitrile 2 (15.9 mg, 0.24 mmol). The reaction mixture was
stirred at room temperature for 24 h. Then the mixture was directly
purified by silica gel column chromatography (ethyl acetate–
petroleum ether 1 : 15) to give the corresponding adducts 3.
(S)-2-[1-(2,4-Dichlorophenyl)-3-oxo-3-phenylpropyl]malononi-
trile (3e). Compound 3e was obtained according to the general
procedure as a white solid (65.7 mg, 96% yield); mp 123–125 ◦C.
Enantiomeric excess was determined by HPLC with a Daicel
Chiralpak AS-H column (n-hexane–2-propanol 90 : 10, flow rate
0.8 mL min-1, detection at 254 nm), minor enantiomer tR
=
29.5 min, major enantiomer tR = 31.6 min, 86% ee; [a]2D0 = +13.2
(c 1.09, CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.96 (d, J = 8.0
Hz, 2H, ArH), 7.64 (t, J = 7.2 Hz, 1H, ArH), 7.53–7.44 (m, 4H,
ArH), 7.33 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 4.65–4.59 (m, 2H),
3.78–3.63 (m, 2H, CH2) ppm; MS (ESI): m/z (% rel. intensity)
342.7 [M - H]+ (58, 37Cl35Cl), 340.9 [M - H]+ (35Cl35Cl, 100). Lit.5b
[a]2D0 = +10.34 (c 0.232, CH2Cl2), 89% ee.
(S)-2-(3-Oxo-1,3-diphenylpropyl)malononitrile
(3a). Com-
pound 3a was obtained according to the general procedure as a
◦
white solid (44.7 mg, 82% yield); mp 109–111 C. Enantiomeric
excess was determined by HPLC with a Chiralpak IA column
(n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection
at 254 nm), minor enantiomer tR = 14.3 min, major enantiomer
tR = 18.5 min, 90% ee; [a]2D0 -11.6 (c 0.50, CH2Cl2). 1H NMR (400
MHz, CDCl3): d 7.97 (d, J = 7.6 Hz, 2H, ArH), 7.63 (t, J = 7.2
Hz, 1H, ArH), 7.52–7.39 (m, 7H, ArH), 4.66 (d, J = 5.2 Hz, 1H,
CN-CH), 3.98–3.94 (m, 1H, Ar-CH), 3.76–3.62 (m, 2H, CH2)
ppm; MS (ESI): m/z (% rel. intensity) 272.9 [M - H]+ (100). Lit.5b
[a]2D0 -12.59 (c 0.27, CH2Cl2), 89% ee.
(S)-2-[1-(4-Bromophenyl)-3-oxo-3-phenylpropyl]malononitrile
(3f)5d,11
. Compound 3f was obtained according to the gen-
eral proc◦edure as a white solid (60.8 mg, 91% yield); mp
127–129 C. Lit.11 mp 126–127 ◦C (racemate). Enantiomeric
excess was determined by HPLC with a Chiralpak IA col-
umn (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 18.0 min, ma-
jor enantiomer tR = 27.3 min, 91% ee; [a]2D0 -23.4 (c 0.35,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.96 (d, J = 8.0
Hz, 2H, ArH), 7.64 (t, J = 7.2 Hz, 1H, ArH), 7.57 (d, J =
8.4 Hz, 2H, ArH), 7.51 (t, J = 7.6 Hz, 1H, ArH), 7.34 (d, J =
8.4 Hz, 2H, ArH), 4.63 (d, J = 5.2 Hz, 1H, CN-CH), 3.96–3.91
(m, 1H, Ar-CH), 3.72–3.58 (m, 2H, CH2) ppm; MS (ESI): m/z (%
rel. intensity) 352.7 [M - H]+ (100, 81Br), 350.9 [M - H]+ (98, 79Br).
(S)-2-[1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl]malononitrile
(3b). Compound 3b was obtained according to the general
procedure as a white solid (45.1 mg, 77% yield); mp 103–104 ◦C.
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 15.4 min, major
enantiomer tR = 22.2 min, 96% ee; [a]2D0 -6.0 (c 1.44, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 7.97 (d, J = 8.0 Hz, 2H, ArH), 7.64
(t, J = 7.2 Hz, 1H, ArH), 7.51 (t, J = 7.6 Hz, 2H, ArH), 7.46–7.43
(m, 2H, ArH), 3.99–3.94 (m, 1H, Ar-CH), 3.73–3.59 (m, 2H, CH2)
ppm; MS (ESI): m/z (% rel. intensity) 290.9 [M - H]+ (100). Lit.5b
[a]2D0 -5.56 (c 0.288, CH2Cl2), 89% ee.
(S)-2-[1-(3-Bromophenyl)-3-oxo-3-phenylpropyl]malononitrile
(3g). Compound 3g was obtained according to the general
procedure as a white semi-solid (66.6 mg, 94% yield). Enantiomeric
excess was determined by HPLC with a Chiralpak IA column (n-
hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection at
254 nm), minor enantiomer tR = 14.6 min, major enantiomer tR =
18.0 min, 88% ee; [a]D20 -6.0 (c 1.47, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 7.96 (d, J = 7.2 Hz, 2H, ArH), 7.63–7.28 (m, 7H, ArH),
4.63 (d, J = 4.8 Hz, 1H, CN-CH), 3.94–3.92 (m, 1H, Ar-CH),
3.72–3.58 (m, 2H, CH2) ppm. 13C NMR (100 MHz, CDCl3): d
196.1, 138.6, 135.4, 134.2, 132.3, 131.0, 130.8, 128.9, 128.0, 126.7,
123.2, 111.5, 111.4, 40.6, 39.8, 28.5 ppm. IR (KBr): n 3031, 2921,
(S)-2-[1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl]malononitrile
(3c). Compound 3c was obtained according to the general
procedure as a white solid (51.0 mg, 83% yield); mp 132–133 ◦C.
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 16.9 min, major
enantiomer tR = 25.1 min, 91% ee; [a]2D0 -2.4 (c 1.08, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 7.97 (d, J = 7.2 Hz, 2H, ArH), 7.64
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 332–338 | 335
©

2255, 1721, 1679, 1608, 1573, 1516, 1450, 1410, 1368, 1291, 1276,
1223, 1207, 1183, 1121, 1001, 811, 728, 577 cm-1. HRMS (ESI):
m/z calc. for C18H14BrN2O [M + H]+ 353.02840, found 353.02826.
(S)-2-[3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl]malononitrile
(3l). Compound 3l was obtained according to the general
procedure as a white solid (55.2 mg, 90% yield); mp 124–126 ◦C.
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 18.6 min, major
enantiomer tR = 22.5 min, 89% ee; [a]2D0 = +11.5 (c 1.08, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 7.90 (d, J = 8.4 Hz, 2H, ArH),
7.48–7.41 (m, 7H, ArH), 4.62 (d, J = 5.2 Hz, 1H, CN-CH), 3.97–
3.93 (m, 1H, Ar-CH), 3.71–3.58 (m, 2H, CH2) ppm; MS (ESI):
m/z (% rel. intensity) 308.8 [M - H]+ (40, 37Cl), 306.8 [M - H]+
(100, 35Cl). Lit.5b [a]2D0 = +7.87 (c 0.254, CH2Cl2), 80% ee.
(S)-2-[1-(4-Methylphenyl)-3-oxo-3-phenylpropyl]malononitrile
(3h). Compound 3h was obtained according to the general
procedure as a colorless oil (45.5 mg, 79% yield). Enantiomeric
excess was determined by HPLC with a Chiralpak IA column
(n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection
at 254 nm), minor enantiomer tR = 13.8 min, major enantiomer
tR = 19.2 min, 90% ee; [a]2D0 -7.3 (c 1.10, CH2Cl2). 1H NMR (400
MHz, CDCl3): d 7.96 (d, J = 7.6 Hz, 2H, ArH), 7.62 (t, J =
7.2 Hz, 1H, ArH), 7.49 (t, J = 8.0 Hz, 2H, ArH), 7.33 (d, J
= 8.0 Hz, 2H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH), 4.61 (d,
J = 5.2 Hz, 1H, CN-CH), 3.94–3.90 (m, 1H, Ar-CH), 3.72–3.59
(m, 2H, CH2), 2.36 (s, 3H, CH3) ppm; MS (ESI): m/z (% rel.
intensity) 286.9 [M - H]+ (100). Lit.5b [a]D20 -2.41 (c 0.166, CH2Cl2),
87% ee.
(S)-2-[3-(4-Bromophenyl)-3-oxo-1-phenylpropyl]malononitrile
(3m). Compound 3m was obtained according to the general
procedure as a white solid (62.1 mg, 88% yield); mp 146–147 ◦C.
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–isopropanol 90 : 10 v/v, flow rate 1.0 mL
min-1, detection at 254 nm), minor enantiomer tR = 20.9 min,
major enantiomer tR = 25.0 min, 90% ee; [a]2D0 = +12.6 (c 1.38,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 7.82 (d, J = 8.4 Hz, 2H,
ArH), 7.63 (d, J = 8.4 Hz, 2H, ArH), 7.44–7.40 (m, 5H, ArH), 4.61
(d, J = 5.2 Hz, 1H, CN-CH), 3.97–3.92 (m, 1H, Ar-CH), 3.70–3.57
(m, 2H, CH2) ppm; MS (ESI): m/z (% rel. intensity) = 352.7 [M
- H]+ (100, 81Br), 350.7 [M - H]+ (99, 79Br). Lit.12 [a]2D0 = +30.1 (c
0.19, ethyl acetate), 81% ee.
(S)-2-[1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl]malononitrile
(3i). Compound 3i was obtained according to the general
procedure as a colorless oil (30.7 mg, 50% yield). Enantiomeric
excess was determined by HPLC with a Chiralpak IA column (n-
hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection at
254 nm), minor enantiomer tR = 20.1 min, major enantiomer tR =
31.0 min, 90% ee; [a]D20 -5.6 (c 1.15, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 7.97 (d, J = 8.0 Hz, 2H, ArH), 7.63 (t, J = 7.2 Hz, 1H,
ArH), 7.50 (t, J = 7.6 Hz, 2H, ArH), 7.38 (d, J = 8.8 Hz, 2H, ArH),
6.94 (d, J = 8.8 Hz, 2H, ArH), 4.62 (d, J = 5.2 Hz, 1H, CN-CH),
3.94–3.90 (m, 2H, Ar-CH), 3.82 (s, 3H, CH3), 3.74–3.58 (m, 2H,
CH2) ppm; MS (ESI): m/z (% rel. intensity) 302.9 [M - H]+ (100).
Lit.4g [a]2D5 -11.0 (c 0.21, CHCl3), 87% ee.
(S)-2-[3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl]malononitrile
(3n). Compound 3n was obtained according to the general
procedure as a white semi-solid (36.5 mg, 60% yield). Enantiomeric
excess was determined by HPLC with a Chiralpak IA column (n-
hexane–2-propanol 90 : 10 v/v, flow rate 1.0 mL min-1, detection
at 254 nm), minor enantiomer tR = 30.6 min, major enantiomer
1
tR = 41.9 min, 91% ee; [a]2D0 = +12.2 (c 1.21, CH2Cl2). H NMR
(S)-2-[1-(2-Methoxyphenyl)-3-oxo-3-phenylpropyl]malononitrile
(3j). Compound 3j was obtained according to the general
procedure as a white solid (42.5 mg, 70% yield); mp 116–118 ◦C.
Enantiomeric excess was determined by HPLC with a Daicel
Chiralpak AS-H column (n-hexane–2-propanol 90 : 10, flow rate
(400 MHz, CDCl3): d 7.93 (d, J = 8.8 Hz, 2H, ArH), 7.45–7.37
(m, 5H, ArH), 6.93 (d, J = 8.8 Hz, 2H, ArH), 4.66 (d, J = 4.8
Hz, 1H, CN-CH), 3.95–3.90 (m, 1H, Ar-CH), 3.85 (s, 3H, CH3),
3.67–3.53 (m, 2H, CH2) ppm; MS (ESI): m/z (% rel. intensity)
302.8 [M - H]+ (100). Lit.4g [a]D25 = +11.0 (c 0.1, CHCl3), 87% ee.
1.0 mL min-1, detection at 254 nm), minor enantiomer tR
=
32.5 min, major enantiomer tR = 45.2 min, 89% ee; [a]2D0 -5.8 (c
(S)-2-[1,3-Bis(4-methylphenyl)-3-oxopropyl]malononitrile (3o).
Compound 3o was obtained according to the general procedure
as a colorless oil (43.0 mg, 71% yield). Enantiomeric excess was
determined by HPLC with a Chiralpak IA column (n-hexane–2-
propanol 90 : 10, flow rate 1.0 mL min-1, detection at 254 nm), mi-
nor enantiomer tR = 16.9 min, major enantiomer tR = 25.9 min, 92%
ee; [a]2D0 = +8.4 (c 1.10, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.86 (d, J = 8.0 Hz, 2H, ArH), 7.35–7.22 (m, 6H, ArH), 4.65 (d, J =
4.8 Hz, 1H, CN-CH), 3.93–3.88 (m, 1H, Ar-CH), 3.70–3.55 (m,
2H, CH2), 2.43 (s, 3H, CH3), 2.37 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d 196.3, 145.2, 139.0, 133.5, 133.3, 129.9,
129.5, 128.2, 127.8, 112.0, 111.7, 40.8, 39.9, 28.9, 21.7, 21.1 ppm.
IR (KBr): n 3063, 2910, 2256, 1683, 1597, 1570, 1477, 1449, 1432,
1368, 1307, 1212, 1076, 998, 756, 689 cm-1. HRMS (ESI): m/z
calc. for C20H18N2NaO [M + Na]+ 325.13113, found 325.13097.
1
1.06, CH2Cl2). H NMR (400 MHz, CDCl3): d 7.96 (d, J = 6.8
Hz, 2H, ArH), 7.61 (t, J = 7.2 Hz, 1H, ArH), 7.49 (t, J = 7.6 Hz,
2H, ArH), 7.36–7.31 (m, 2H, ArH), 7.00–6.93 (m, 2H, ArH), 4.68
(d, J = 6.4 Hz, 1H, CN-CH), 4.46 (q, J = 6.8 Hz, 1H, Ar-CH),
3.90 (s, 3H, CH3), 3.80–3.61 (m, 2H, CH2) ppm; MS (ESI): m/z
(% rel. intensity) 302.9 [M - H]+ (100). Lit.5b [a]D20 = +24.22 (c
0.194 in CH2Cl2), 87% ee.
(S)-2-[3-(4-Fluorophenyl)-3-oxo-1-phenylpropyl]malononitrile
(3k)12. Compound 3k was obtained according to the general
procedure as a colorless oil (46.4 mg, 79% yield). Enantiomeric
excess was determined by HPLC with a Chiralpak IA column (n-
hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection at
254 nm), minor enantiomer tR = 15.7 min, major enantiomer tR =
18.4 min, 89% ee; [a]D20 -6.3 (c 0.76, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 8.02–7.98 (m, 2H, ArH), 7.44–7.40 (m, 5H, ArH), 7.16
(t, J = 8.4 Hz, 2H, ArH), 4.63 (d, J = 5.2 Hz, 1H, CN-CH), 3.98–
3.93 (m, 1H, Ar-CH), 3.71–3.58 (m, 2H, CH2) ppm; MS (ESI):
m/z (% rel. intensity) 290.9 [M - H]+ (100). Lit.12 [a]D20 = +10.5 (c
0.48, ethyl acetate), 75% ee.
(S) - 2 - [1,3 - Bis(4 - chlorophenyl) - 3 - oxopropyl]malononitrile
(3p)13. Compound 3p was obtained according to the general
procedure as a white solid (63.0 mg, 92% yield); mp 90–91 ◦C. Lit.13
mp 81–82 ◦C (racemate). Enantiomeric excess was determined by
HPLC with a Chiralpak IA column (n-hexane–2-propanol 90 : 10,
336 | Org. Biomol. Chem., 2012, 10, 332–338
This journal is
The Royal Society of Chemistry 2012
©

flow rate 1.0 mL min-1, detection at 254 nm), minor enantiomer
(S)-2-(2, 2-Methyl-5-oxo-5-phenylpentyl)malononitrile (3t).
Compound 3t was obtained according to the general procedure
as a colorless oil (17.8 mg, 35% yield). Enantiomeric excess was
determined by HPLC with a Chiralpak IA column (n-hexane/2-
propanol 95 : 5, flow rate 1.0 mL min-1, detection at 254 nm),
major enantiomer tR = 12.0 min, minor enantiomer tR = 14.4
min, 88% ee; [a]2D5 = +25.6 (c 0.50, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 8.02 (d, J = 7.6 Hz, 2H, ArH), 7.63 (t, J = 7.2 Hz, 1H,
ArH), 7.51 (t, J = 8.0 Hz, 2H, ArH), 4.10 (d, J = 2.8 Hz, 1H,
CN-CH), 3.41 (dd, J1 = 18.4 Hz, J2 = 4.4 Hz, 1H, CH2), 3.19 (dd,
J1 = 18.4 Hz, J2 = 7.2 Hz, 1H, CH2), 2.95–2.92 (m, 1H, tBu-CH),
1.10 (s, 9H, CH3) ppm; MS (ESI): m/z (% rel. intensity) 252.9 [M -
H]+ (100). Lit.5b [a]D20 = +38.10 (c 0.042, CH2Cl2), 93% ee.
tR = 21.8 min, major enantiomer tR = 30.9 min, 88% ee; [a]D20
=
1
+13.4 (c 1.03, CH2Cl2). H NMR (400 MHz, CDCl3): d 7.90 (d,
J = 8.4 Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.42–7.37
(m, 4H, ArH), 4.60 (d, J = 5.2 Hz, 1H, CN-CH), 3.96–3.92 (m,
1H, Ar-CH), 3.68–3.55 (m, 2H, CH2) ppm; MS (ESI): m/z (%
rel. intensity) = 344.6 [M - H]+ (14, 37Cl37Cl), 342.6 [M - H]+ (51,
35Cl37Cl), 340.9 [M - H]+) (100, 35Cl35Cl).
(S)-2-[1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl]malononitrile
(3q). Compound 3q was obtained according to the general
procedure as a white solid (48.2 mg, 74% yield); mp 167–169 ◦C.
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 16.1 min, major
enantiomer tR = 18.4 min, 89% ee; [a]2D0 = +13.0 (c 1.34, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 8.12 (d, J = 8.4 Hz, 1H, ArH),
7.98–7.86 (m, 4H, ArH), 7.68 (d, J = 7.2 Hz, 1H, ArH), 7.65–
7.46 (m, 6H, ArH), 5.02 (q, J = 6.0 Hz, 1H, Ar-CH), 4.70 (d,
J = 4.8 Hz, 1H, CN-CH), 3.90–3.77 (m, 2H, CH2) ppm; 13C
NMR (100 MHz, CDCl3): d 196.3, 135.7, 134.1, 132.5, 130.9,
130.7, 129.5, 128.9, 128.1, 127.3, 126.3, 125.3, 124.3, 121.7, 112.1,
111.6, 40.5, 28.0 ppm. IR (KBr): n 3049, 2906, 2256, 1679, 1596,
1514, 1449, 1356, 1230, 1002, 796, 775, 763, 689 cm-1. HRMS
(ESI): m/z calc. for C22H16N2NaO [M + Na]+ 347.11548, found
347.11548.
(R,E)-2-(5-Oxo-1,5-diphenylpent-1-en-3-yl)malononitrile (5).
To a solution of catalyst IV (2.3 mg, 0.004 mmol) in chloroform
(0.5 mL) was added ((1E,3E)-4-nitrobuta-1,3-dienyl)benzene 4
(93.7 mg, 0.40 mmol) and malononitrile 2 (31.7 mg, 0.48 mmol).
The reaction mixture was stirred for 4 days at room temperature.
Then the mixture was concentrated and purified by silica gel
column chromatography (ethyl acetate–petroleum ether 1 : 30)
to afford the product 5 as a colorless oil (62.4 mg, 52% yield).
Enantiomeric excess was determined by HPLC with a Chiralpak
IA column (n-hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1,
detection at 254 nm), minor enantiomer tR = 14.3 min, major
enantiomer tR = 19.5 min, 90% ee; [a]2D0 -25.0 (c 2.00, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 7.97 (d, J = 7.6 Hz, 2H, ArH), 7.63
(t, J = 7.2 Hz, 1H, ArH), 7.50 (t, J = 8.0 Hz, 2H, ArH), 7.42 (d, J =
7.2 Hz, 2H, ArH), 7.36–7.30 (m, 3H, ArH), 6.79 (d, J = 8.0 Hz,
1H, CH ), 6.23 (dd, J1 = 8.8 Hz, J2 = 16.0 Hz, 1H, CH ), 4.57
(d, J = 4.8 Hz, 1H, CN-CH), 3.59–3.52 (m, 1H, CH), 3.51–3.39
(m, 2H, CH2) ppm; MS (ESI): m/z (% rel. intensity) = 298.9 [M -
H]+ (100). Lit.5c [a]D21 -14.4 (c 0.3, CHCl3), 89% ee.
(S)-2-[1-(Furan-2-yl)-3-oxo-3-phenylpropyl]malononitrile (3r).
Compound 3r was obtained according to the general procedure
as a pale yellow oil (28.3 mg, 54% yield). Enantiomeric excess was
determined by HPLC with a Chiralpak IA column (n-hexane–2-
propanol 90 : 10, flow rate 1.0 mL min-1, detection at 254 nm),
minor enantiomer tR = 18.0 min, major enantiomer tR = 20.5
min, 83% ee; [a]2D0 = +13.5 (c 1.45, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 7.98 (d, J = 8.0 Hz, 2H, ArH), 7.63 (t, J = 7.2 Hz, 1H,
ArH), 7.50 (t, J = 7.6 Hz, 2H, ArH), 7.45 (s, 1H, CH), 6.44 (d,
J = 3.2 Hz, 1H, CH), 6.39 (s, 1H, CH), 4.60 (d, J = 4.8 Hz, 1H,
CN-CH), 4.18–4.13 (m, 1H, Ar-CH), 3.72–3.59 (m, 2H, CH2)
ppm; 13C NMR (100 MHz, CDCl3): d 196.0, 149.4, 143.4, 135.5,
134.2, 128.9, 128.1, 111.5, 111.2, 110.8, 109.1, 38.5, 35.6, 27.1
ppm. IR (KBr): n 3124, 3063, 2917, 2257, 1683, 1597, 1581, 1504,
1450, 1414, 1364, 1216, 1183, 1015, 1002, 908, 760, 689, 598 cm-1.
HRMS (ESI): m/z calc. for C16H22N2NaO2 [M + Na]+ 287.07910,
found 287.07923.
(S)-2-Amino-4-phenyl-5,6-dihydro-4H-benzo[h]chromene-3-
carbonitrile (7)9. To a solution of catalyst IV (2.3 mg, 0.004
mmol) in chloroform (0.5 mL) was added (E)-2-benzylidene-
3,4-dihydronaphthalen-1(2H)-one 6 (93.7 mg, 0.40 mmol) and
malononitrile 2 (31.7 mg, 0.48 mmol). The reaction mixture was
stirred for 4 days at room temperature. Then the mixture was
concentrated and purified by silica gel column chromatography
(ethyl acetate–petroleum ether 1 : 20) to afford the product 7 as a
yellow solid (48.1 mg, 40% yield); mp 206–208 ◦C. Enantiomeric
excess was determined by HPLC with a Chiralpak IA column (n-
hexane–2-propanol 90 : 10, flow rate 1.0 mL min-1, detection at
254 nm), minor enantiomer tR = 9.6 min, major enantiomer tR =
13.2 min, 91% ee; [a]3D0 -55.2 (c 0.33, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.47 (d, J = 7.2 Hz, 1H, ArH), 7.35–7.20 (m, 7H, ArH),
7.12 (d, J = 6.8 Hz, 1H, ArH), 4.56 (s, 2H, NH2), 4.08 (s, 1H, CH),
2.83–2.66 (m, 2H, CH2), 2.22–2.14 (m, 1H, CH2), 2.10–2.02 (m,
1H, CH2) ppm; MS (ESI): m/z (%) = 322.9 [M + Na]+ (100), 301.0
[M + H]+ (25). Lit.9 [a]D20 -39.5 (c 0.45, CHCl3), 80% ee.
(R)-2-(1-Cyclohexyl-3-oxo-3-phenylpropyl)malononitrile (3s).
Compound 3s was obtained according to the general procedure
as a colorless oil (13.0 mg, 23% yield). Enantiomeric excess was
determined by HPLC with a Chiralpak IA column (n-hexane–2-
propanol 95 : 5, flow rate 1.0 mL min-1, detection at 254 nm), minor
enantiomer tR = 12.2 min, major enantiomer tR = 13.4 min, 86%
ee; [a]2D0 = +44.0 (c 0.65, CH2Cl2). 1H NMR (400 MHz, CDCl3): d
7.97 (d, J = 8.4 Hz, 2H, ArH), 7.63–7.59 (m, 1H, ArH), 7.49 (t, J =
7.6 Hz, 2H, ArH), 4.36 (d, J = 4.8 Hz, 1H, CN-CH), 3.35 (dd,
J1 = 18.4 Hz, J2 = 4.8 Hz, 1H, CH2), 3.16 (dd, J1 = 18.4 Hz, J2 =
8.0 Hz, 1H, CH2), 2.76–2.70 (m, 1H, cyclohexyl-CH), 1.86–1.69
(m, 6H, cyclohexyl), 1.37–1.05 (m, 5H, cyclohexyl) ppm. MS
The gram-scale preparation of 3a
To a solution of trans-chalcone 1a (10.0 mmol, 2.08 g) and
catalyst IV (0.05 mmol, 28.2 mg) was added malononitrile 2
(12.0 mmol, 0.79 g). The reaction mixture was stirred at room
temperature for 24 h. Then the mixture was directly purified
by silica gel column chromatography (ethyl acetate–petroleum
(ESI): m/z (% rel. intensity) 278.9 [M - H]+ (100). Lit.5c [a]2D6
+34.7 (c 0.33, CHCl3), 95% ee.
=
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 332–338 | 337
©

ether 1 : 15) to give the corresponding adduct 3a as a white solid
(2.19 g, 80% yield). Enantiomeric excess (89% ee, 97% ee after a
simple recrystallization with ethyl acetate–petroleum ether) was
determined by HPLC with a Chiralpak IA column.
Zhong, Y. C. Chen, J. Liao, J. Zhu and J. G. Deng, Org. Biomol. Chem.,
2008, 6, 349; (h) S.-L. Zhao, C.-W. Zheng and G. Zhao, Tetrahedron:
Asymmetry, 2009, 20, 1046; (i) L. H. Jing, J. T. Wei, L. Zhou, Z. Y.
Huang, Z. K. Li, D. Wu, H. F. Xiang and X. G. Zhou, Chem.–Eur. J.,
2010, 16, 10955; (j) X. Huang, P. Li, X.-S. Li, D.-C. Xu and J.-W. Xie,
Org. Biomol. Chem., 2010, 8, 4527; (k) C. G. Oliva, A. M. S. Silva, D. I.
S. P. Resende, F. A. A. Paz and J. A. S. Cavaleiro,, Eur. J. Org. Chem.,
2010, 3449; (l) X.-M. Li, B. Wang, J. M. Zhang and M. Yan, Org. Lett.,
2011, 13, 374; (m) Z.-P. Hu, C.-L. Lou, J.-J. Wang, C.-X. Chen and M.
Yan, J. Org. Chem., 2011, 76, 3797; (n) C. De Fusco and A. Lattanzi,
Eur. J. Org. Chem., 2011, 3728.
5 For examples of asymmetric Michael addition of malononitrile to
chalcones, see: (a) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie, W. Duan and
W. Wa n g , J. Am. Chem. Soc., 2006, 128, 12652; (b) J. Shi, M. Wang, L.
He, K. Zheng, X. H. Liu, L. L. Lin and X. M. Feng, Chem. Commun.,
2009, 4711; (c) A. Russo, A. Perfetto and A. Lattanzi, Adv. Synth.
Catal., 2009, 351, 3067; (d) A. Russo, A. Capobianco, A. Perfetto, A.
Lattanzi and A. Peluso, Eur. J. Org. Chem., 2011, 1922.
Acknowledgements
We are grateful for financial support from the National Nat-
ural Science Foundation of China (Grant No. 21072020),
the Science and Technology Innovation Program of Bei-
jing Institute of Technology (Grant Nos. 2011CX01008 and
2011CX03037) and the Development Program for Distinguished
Young and Middle-aged Teachers of Beijing Institute of Tech-
nology.
6 For reviews of squaramides, see: (a) J. Alema´n, A. Parra, H. Jiang and
K. A. Jørgensen, Chem.–Eur. J., 2011, 17, 6890; (b) R. I. Storer, C.
Aciro and L. H. Jones, Chem. Soc. Rev., 2011, 40, 2330.
Notes and references
7 (a) J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem. Soc.,
2008, 130, 14416; (b) Y. Zhu, J. P. Malerich and V. H. Rawal, Angew.
Chem., Int. Ed., 2010, 49, 153; (c) D. Q. Xu, Y.-F. Wang, W. Zhang, S.-P.
Luo, A.-G. Zhong, A.-B. Xia and Z.-Y. Xu, Chem.–Eur. J., 2010, 16,
4177; (d) L. Dai, S.-X. Wang and F.-E. Chen, Adv. Synth. Catal., 2010,
352, 2137; (e) W. Yang and D.-M. Du, Org. Lett., 2010, 12, 5450; (f) H.
Jiang, M. W. Paixao, D. Monge and K. A. Jørgensen, J. Am. Chem.
Soc., 2010, 132, 2775; (g) W. Yang and D.-M. Du, Adv. Synth. Catal.,
2011, 353, 1241; (h) Y.-F. Wang, W. Zhang, S.-P. Luo, G.-C. Zhang,
A.-B. Xia, X.-S. Xu and D.-Q. Xu, Eur. J. Org. Chem., 2010, 4981;
(i) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J. Zhao and V. H. Rawal, Chem.
Commun., 2010, 46, 3004; (j) H. Konishi, T. Y. Lam, J. P. Malerich and
V. H . Rawa l , Org. Lett., 2010, 12, 2028; (k) H.-L. Song, K. Yuan and
X.-Y. Wu, Chem. Commun., 2011, 47, 1012; (l) S. V. Pansare and E. K.
Paul, Chem. Commun., 2011, 47, 1027.
8 (a) H. S. Rho, S. H. Oh, J. W. Lee, J. Y. Lee, J. Chin and C. E. Song,
Chem. Commun., 2008, 1208; (b) G. Ta´rka´nyi, P. Kira´ly, S. Varga, B.
Vakulya and T. Soo´s, Chem.–Eur. J., 2008, 14, 6078.
9 Q. Ren, Y. J. Gao and J. Wang, Chem.–Eur. J., 2010, 16, 13594.
10 K. Yasuda, M. Shindo and K. Koga, Tetrahedron Lett., 1996, 37, 6343.
11 D. Shi, N. Wu and Q. Zhuang, Chin. J. Chem., 2009, 27, 169.
12 L. Yue, W. Du, Y.-K. Liu and Y.-C. Chen, Tetrahedron Lett., 2008, 49,
3881.
1 P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992.
2 For selected reviews of asymmetric Michael additions, see: (a) O. M.
Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877;
(b) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701; (c) J. Christoffers,
G. Koripelly, A. Rosiak and M. Ro¨ssle, Synthesis, 2007, 1279; (d) S.
Sulzer-Mosse´ and A. Alexakis, Chem. Commun., 2007, 3123; (e) J. L.
Vicario, D. Bad´ıa and L. Carrillo, Synthesis, 2007, 2065; (f) D. Almasi,
D. A. Alonso and C. Na´jera, Tetrahedron: Asymmetry, 2007, 18, 299.
3 (a) F. J. Weiberth and S. S. Hall, J. Org. Chem., 1987, 52, 3901; (b) Y.-C.
Chen, D. Xue, J.-G. Deng, X. Cui, J. Zhu and Y.-Z. Jiang, Tetrahedron
Lett., 2004, 45, 1555; (c) H. Burtod and P. F. Hu, J. Chem. Soc., 1948,
601; (d) T. van Es and B. Staskun, Org. Synth., 1971, 51, 20; (e) J.
Mueller, C. Wuertele, O. Walter and S. Schindler, Angew. Chem., Int.
Ed., 2007, 46, 7775; (f) D. M. Zhu, H. Ankati, C. Mukherjee, Y. Yang,
E. R. Biehl and L. Hua, Org. Lett., 2007, 9, 2561.
4 For selected examples of asymmetric Michael additions of malononi-
trile, see: (a) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2003,
125, 11204; (b) K. Itoh, Y. Oderaotoshi and S. Kanemasa, Tetrahedron:
Asymmetry, 2003, 14, 635; (c) Y. Hoash, T. Okino and Y. Takemoto,
Angew. Chem., Int. Ed., 2005, 44, 4032; (d) M. S. Taylor, D. N. Zalatan,
A. M. Lerchner and E. N. Jacobsen, J. Am. Chem. Soc., 2005, 127,
1313; (e) T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2006, 128, 9413; (f) H. Yanagita, K. Kodama and S. Kanegamoto,
Tetrahedron Lett., 2006, 47, 9353; (g) X. F. Li, L. F. Cun, C. X. Lian, L.
13 D.-P. Liang, X. Xin, H. Gao, H.-F. Duan and Y.-J. Lin, Chem. Res.
Chin. Univ., 2009, 25, 169.
338 | Org. Biomol. Chem., 2012, 10, 332–338
This journal is
The Royal Society of Chemistry 2012
©