Chiral-at-Metal Rh(III) Complex Catalyzed Cascade Reduction-Michael Addition Reaction

Article abstract of DOI:10.1021/acs.joc.9b02243

An enantioselective three-component cascade reduction-Michael addition reaction catalyzed by chiral-at-metal Rh(III) complexes has been developed. With a Hantzsch ester as the hydride source, a number of malononitrile derivatives were prepared in good yie

Full text of DOI:10.1021/acs.joc.9b02243

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Article
Chiral-at-Metal Rh(III) Complex Catalyzed
Cascade Reduction-Michael Addition Reaction
Qian Wan, Shiwu Li, Qiang Kang, Yaofeng Yuan, and Yu Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02243 • Publication Date (Web): 29 Oct 2019
Downloaded from pubs.acs.org on November 2, 2019
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Chiral-at-Metal Rh(III) Complex Catalyzed Cascade
Reduction-Michael Addition Reaction
†
‡
‡
,†
,‡
Qian Wan, Shiwu Li, Qiang Kang, Yaofeng Yuan* and Yu Du*
1
1
1
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1
1
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†College of Chemistry, Fuzhou University, 350108, P. R. China.
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for
Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, 350002, P.
R. China.
Abstract
+
EtO C
CO Et
PF6
2
2
t
Bu
R
O
CN
CN
R2

R3
O
-Rh3 (0.5-2.0 mol %)
N
H
N
R3
N
Rh
N
O
CCl , 50 C or rt
4
NC CN
NCMe
NCMe
N
R1
N
R2
N
27 examples
up to 99% yield, 97% ee
R1
cascade reaction



high enantioselectivity
low catalyst loadings
operational simplicity
tBu
Rh3 R = 3,5-(CF ) C H
2 6 3
R
O

3
An enantioselective three-component cascade reduction-Michael addition reaction
catalyzed by chiral-at-metal Rh(III) complexes has been developed. With a Hantzsch
ester as the hydride source, a number of malononitrile derivatives were prepared in
good yields and excellent enantioselectivities. A model that accounts for the origin
and influence factors of the stereoselectivity has been proposed based on experiments.
Introduction
Malononitrile, which has widely been used as a starting material for producing
many important intermediates or precursors (e.g., 2-amino-4,6-dimethoxy pyrimidine,
2-chloro-4,6-dimethoxy pyrimidine and 2-amino-thiophene, etc.) in medicines,
pesticides and dyes, is a classic equivalent of malonic acid derivatives in organic
1
synthesis. It can serve as a nucleophile with the methylene group tends to lose a
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2
2
2
2
2
2
2
3
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3
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3
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6
proton and form stabilized carbanion to undergo various reactions such as
Knoevenagel condensation,2 Gewald reaction,3 Claisen condensation,4 Michael
5
6
addition and Mannich reaction. In addition, the malononitrile substituent in obtained
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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9
0
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9
0
1
2
3
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
products can undergo further transformation to form carboxylic acid, ester, or amide
7
groups. So far, much progress have been made in catalytic enantioselective
8
construction of malononitrile derivatives via Michael addition of unsubstituted or
substituted8e,9 malononitriles to α,β-unsaturated carbonyl compounds, under
organo-8,10 and metal-complex11 catalysis. In the past few years, multicomponent
reactions involving cascade processes with at least three different simple substrates
1
2
have attracted much attention as an ideal synthetic tool in organic synthesis. In this
context, the asymmetric cascade reduction-Michael addition of in situ reduced
substituted alkylidene malononitriles to α-branched vinyl ketones, which features
α-stereogenic protonation, has been realized by chiral primary amine catalysis13
(Scheme 1a).
Scheme 1. Enantioselective cascade reaction of conjugated malononitriles to
α,β-unsaturated carbonyl compounds
a) Asymmetric cascade reaction of conjugated malononitriles with -branched vinyl ketones
O
O
R2
N
chiral amine
(10 mol %)
R1
R3
EtO2C
CO2Et
R2
R1
NH2
chiral amine

+
CN
N
R3
H

-Rh
+
CN
b) This work
CN EtO2C
NC CN
PF6
t
Bu
R
O

N
Rh
N
Me
CO2Et
R3
C
C
N
N
O
R2

Rh
CN

N
+
(0.5-2.0 mol %)
N
O
R3
H
N
NC CN
Me
R2
N
R1

high enantioselectivity
 low catalyst loading
N
R
O
tBu
R1
Recently, chiral-at-metal complexes have been developed as one kind of chiral
Lewis acid catalyst which can increase the electrophilicity of α,β-unsaturated carbonyl
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compounds, and quite a few reactions under this activation mode have been
successfully achieved with high catalytic efficiency and enantioselectivity.14
However, chiral-at-metal catalysts have rarely been employed in asymmetric cascade
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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4
4
4
5
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
15
reactions. On the basis of our achievements in investigating chiral-at-metal rhodium
complexes catalyzed asymmetric reactions,16 especially catalytic enantioselective
conjugate addition reactions,16a,16g herein an one-pot three-component cascade
reduction-Michael addition reaction catalyzed by chiral-at-metal complexes has been
developed. More specifically, nucleophilic malononitriles generated via hydride
addition from the Hantzsch ester to alkylidene malononitriles, which react with
α,β-unsaturated 2-acyl imidazoles catalyzed by a chiral Rh(III) complex, affording a
variety of malononitrile derivatives in high yields and excellent enantioselectivities
(Scheme 1b).
Results and Discussion
Key results in searching for optimal reaction conditions are shown in Table 1.
Initially, the reaction of α,β-unsaturated 2-acyl imidazole 1a, benzylidene
malononitrile 2a and Hantzsch ester 3 were tested (with a ratio of 1a/2a = 1/2) in the
presence of Λ-Rh1 in THF at 50 °C, the target product 4a was obtained as a racemic
mixture in 77% yield (Table 1, entry 1). A screening of chiral-at-metal complexes
(entries 1-3) showed that the catalyst Ʌ-Rh3 is the superior one in terms of reactivity
and enantioselectivity, resulting in 4a in 68% yield with 36% ee (entry 3). The
background reaction was observed as the addition adduct could be obtained in 26%
yield in the absence of catalyst (entry 4). To our delight, both the yield and
enantioselectivity were significantly improved when we changed the ratio of
substrates 1a and 2a to 2:1, which led to the formation of 4a in 89% yield and 80% ee
(entry 5). Further evaluation of solvents at 50 °C (entries 6-12) revealed that
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1
1
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1
1
2
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2
2
2
2
2
2
2
3
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6
tetrachloromethane (CCl ) was the best choice in terms of both reactivity (82% yield)
4
and enantioselectivity (96% ee) (entry 12). A decrease in reaction temperature led to
the formation of 4a with a prolonged reaction time and significantly reduced yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entry 13).
Table 1. Optimization of the reaction conditionsa
R
PF6
O
tBu

EtO C
CO Et
2
2
N
CN
CN
CH3
C
C
N
N
N
H
O
Ph
Rh
N

2a
-Rh (2 mol %)
Solvent, 50 C
N
3
Ph
CH3
tBu
O
NC CN
N
N
Ph
O
R
4
a
N


-Rh1 R = H
-Rh2 R = 3,5-(CH ) C H
1a
3
2
6
3
-Rh3 R = 3,5-(CF ) C H
3
2 6 3
entry catalyst
ratio of 1a/2a
solvent
THF
THF
THF
THF
THF
time (h)
40
yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
Λ-Rh1
Λ-Rh2
Λ-Rh3
none
1:2
1:2
1:2
1:2
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
77
76
68
26
89
80
89
90
98
90
87
82
48
2
36
0
36
36
--
48
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
Λ-Rh3
48
80
86
10
18
71
88
83
96
95
Toluene
MeOH
MeCN
DCM
DCE
48
48
48
48
48
1
1
1
1
CHCl3
CCl4
48
2
3d
48
CCl4
70
aReaction conditions: entries 1-4, 1a (0.2 mmol), 2a (0.4 mmol), 3 (0.44 mmol) and Λ-Rh (2 mol
to 1a) in 0.5 mL solvent at 50 °C under argon atmosphere; entries 5-13, 1a (0.3 mmol), 2a
0.15 mmol), 3 (0.18 mmol) and Λ-Rh (2 mol % to 2a) in 0.5 mL solvent at 50 °C under argon
%
(
b
c
atmosphere. Isolated yields. Enantiomeric excess, determined via chiral HPLC analysis.
dConducted at room temperature.
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With the optimal conditions (Table 1, entry 12), the scope of this enantioselective
cascade reaction was then examined. We first studied various α,β-unsaturated 2-acyl
imidazoles 1 with benzylidene malononitrile 2a and Hantzsch ester 3 using the
optimal conditions developed above. The results are summarized in Table 2. No
significant difference in enantioselectivity was observed when we changed
substituents on imidazole (e.g., methyl, isopropyl and phenyl, entries 1-3), but
N-isopropyl substituent was more effective to give the highest yield of corresponding
product 4b (96%, entry 2). Then N-isopropyl-substituted substrates 1 with different
β-substituents were evaluated. It was observed that neither the position nor the
electronic nature of groups on β-aryl substituents has an effect on reactivity and
enantioselectivity of the reaction. Excellent yields (up to 98%) and
enantioselectivities (up to 96% ee) were obtained in almost all cases (entries 4-9).
β-Naphthyl-substituted substrate and heteroaryl (e.g., furyl, thienyl) analogues were
also tolerated (entries 10-12). These reactions gave moderate to good yields (57-90%)
and high enantioselectivities (90-93% ee). It should be noted that β-2-furyl substrate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
j could be consumed more quickly at 50 °C, delivering the corresponding adduct 4j
in 93% yield and 59% ee. In contrast, moderate yield (57%) and high
enantioselectivity (93% ee) were obtained when the reaction was performed at room
temperature (entry 10). Furthermore, α,β-unsaturated 2-acyl imidazole 1 with a
β-alkyl substituent (e.g., methyl) also worked well under the optimal reaction
conditions, providing the product 4m with excellent yield and enantioselectivity
(entry 13). The absolute configuration of product 4f was assigned as R-configuration
by a single crystal X-ray analysis.17
Table 2. Substrate scope of α,β-unsaturated 2-acyl imidazolesa
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
5
6
O
O
R2
EtO C
CO Et
2
2
CN

-Rh3 (2 mol %)
N
N
R2
+
+
Ph
CN
CCl4, temperature
N
H
3
NC CN
N
N
R1
R1
2a
1
4
R1
R2
Ph
Ph
Ph
time (h) product
yield (%)b
ee (%)c
96
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
1
2
3
4
5
6
7
8
9
Me
iPr
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
40
44
60
40
40
40
44
44
48
60
48
48
48
4a
4b
4c
4d
4e
4f
82
96
75
86
92
98
98
94
88
57
75
90
99
96
94
4-Me-C H
94
6
4
4-OMe-C H
94
6
4
4-NO -C H
4
96
2
6
4-Cl-C H
4g
4h
4i
91
6
4
4
3-Cl-C H
93
6
2-Me-C H
95
6
4
1
0d
2-furyl
4j
93
11
2-thienyl
4k
4l
90
1
1
2
3
2-naphthyl
92
Me
4m
97
aReaction conditions: 1 (0.3 mmol), 2a (0.15 mmol), 3 (0.18 mmol) and Λ-Rh3 (2 mol %) in 0.5
b
c
mL CCl at 50 °C under argon atmosphere. Isolated yields. Determined via chiral HPLC analysis.
4
dConducted at room temperature.
Pleased to find the reaction applicable to a range of α,β-unsaturated 2-acyl
imidazoles 1, we sought to further examine the scope of the transformation by
exploring the diversity of substitution permitted on conjugated malononitriles 2, with
Michael acceptor 1b and Hantzsch ester 3 using the optimal conditions. The results
are summarized in Table 3. The use of substrates 2 bearing electron-donating (e.g.,
methyl, methoxy) or withdrawing (e.g., chloro, nitro, trifluoromethyl) moieties at the
ortho, meta or para-position of the aryl substituent furnish the corresponding products
4bb–4bg (entries 1-6) in good to excellent yields (70-99%) and excellent
enantioselectivities (up to 97% ee). β-Heteroaryl (e.g., furyl, thienyl) and
naphthyl-substituted substrates worked fine as well, delivering the corresponding
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products 4bh–4bj (entries 7-9) in excellent yields (> 86%) and enantioselectivities
(up to 97% ee). Conjugated malononitriles 2 with β-alkyl substituents (e.g., alkene,
alkyne, cyclopropyl and ethyl) were also well tolerated, affording the corresponding
products 4bk–4bn (entries 10-13) in moderate to good yields (67-85%) and
consistently excellent enantioselectivities (up to 97% ee). Similar trends found in
synthesizing compound 4j (Table 2, entry 10) were also observed for substrate scope
studies of conjugated malononitriles 2 (Table 3). High yields but poor
enantioselectivities were obtained for some cases (4be-4bi, 4bl) conducted at 50 °C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Supporting Information, Table S1). Generally, reducing the reaction temperature
would lead to an improvement of enantioselectivity, but diminished yield.
Table 3. Substrate scope of conjugated malononitrilesa
O
O
Ph
EtO C
CO Et
2
2
N
CN
-Rh3 (2 mol %)
CCl , temperature
N
R3
R3
Ph
+
+
NC CN
N
N
CN
N
H
3
4
2
1
b
4
entry
1
R3
time (h)
product
yield (%)b
ee (%)c
90
2-Me-C H
60
60
60
44
40
40
44
44
60
60
44
48
48
4bb
4bc
4bd
4be
4bf
96
99
78
77
70
78
97
86
94
67
83
85
81
6
4
2
4-Me-C H
96
97
93
91
94
97
97
91
95
91
96
97
6
4
3
4-OMe-C H
6
4
4d
5d
6d
7d
8d
9
3-Cl-C H
6
4
4-NO -C H
4
2
6
4-CF -C H
4bg
4bh
4bi
3
6
4
2-furyl
2-thienyl
2-naphthyl
styryl
4bj
1
1
1
0
1d
4bk
4bl
phenylethynyl
cyclopropyl
Et
2
4bm
4bn
13
aReaction conditions: 1b (0.3 mmol), 2 (0.15 mmol), 3 (0.18 mmol) and Λ-Rh3 (2 mol %) in 0.5
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
c
mL CCl at 50 °C under argon atmosphere. Isolated yields. Determined via chiral HPLC
4
d
analysis. Conducted at room temperature.
Furthermore, a reaction with both substrates 1 and 2 bearing a β-alkyl substituent
has been performed under the optimal conditions, delivering the corresponding
product 4nn in excellent yield (98%) and enantioselectivity (96% ee, Scheme 2).
Scheme 2. Further substrate scope
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
-Rh3
2 mol %)
O
EtO C
CO Et
2
2
CN
(
N
N
Et
CCl , 50 °C
CN
2n, 0.15 mmol
N
4
NC CN
4nn, 60 h
N
N
H
3
, 0.18 mmol
1n, 0.3 mmol
9
8% yield, 96% ee
To check the synthetic viability of our catalytic system, a large-scale reaction of 1b
1.2 g, 5.0 mmol), 2a (385 mg, 2.5 mmol) and 3 (760 mg, 3.0 mmol) was conducted
(
in the presence of 1.0 mol % Λ-Rh3. Gratifyingly, product 4b was obtained in 91%
yield (898 mg) with 95% ee. Notably, by employing as low as 0.5 mol % of Ʌ-Rh3,
the product 4b could be obtained in excellent enantioselectivity (94% ee), albeit with
a prolonged reaction time and diminished yield (Scheme 3a). In order to better
understand the reaction mechanism, two-component reactions were examined
(Scheme 3b). With 2.0 mol % of Λ-Rh3, Michael addition of malononitrile 5 to
substrate 1b worked well at 50 °C in terms of yield (99%), albeit with a low
enantioselectivity (78% ee). In contrast, an improvement in enantioselectivity (97%
ee) and prolonged reaction time were obtained when the reaction was performed at
room temperature. It has already been proven that the reduction of benzylidene
malononitrile 2a by Hantzsch ester 3 could be carried out externally to general
malononitrile 5.18 Based on these evidence and previous investigations, a proposed
mechanism of this three-component cascade reaction and stereoselective control
model is shown in Figure 1.
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Scheme 3. Large-scale and stepwise experiments
a)
O
O
Ph
EtO C
CO Et
2
2
N
CN
CN
2a, 2.5 mmol
N
-Rh3
Ph
Ph
NC CN
N
CCl4, 50 °C
N
N
H
3
, 3 mmol
4b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
3
3
3
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5
5
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
b, 5 mmol
Condition A: -Rh3 (1.0 mol %), 44 h
Condition B: -Rh3 (0.5 mol %), 60 h
4b, 0.9 g, 91% yield, 95% ee
0.7 g, 71% yield, 94% ee
b)
O
O
Ph
N
CN
CN
, 0.15 mmol
N

-Rh3 (2 mol %)
Ph
Ph
CCl4, temperature
N
NC CN
N
5
1
b, 0.3 mmol
Condition A: 50 °C, 40 h 4b, 99% yield, 78% ee
Condition B: rt, 60 h 99% yield, 97% ee
The Hantzsch ester works as the reductant to react with benzylidene malononitrile
a to generate an α-proton acidic malononitrile 5 or a nucleophilic anionic
2
intermediate A, and compound 5 could be equilibrated to anion A without base. On
the other hand, the α,β-unsaturated 2-acyl imidazole can be activated by the rhodium
catalyst through bidentate N,O-coordination.11e The Si-face of the coordinated
substrate B is effectively shielded by one of the tert-butyl groups. Then malononitrile
derived anion A can undergo a 1,4-addition in a highly selective approach from the
Re-face of the coordinated substrate, leading to the desired product after final
protonation with β-(R) configuration, which is consistent with the observed absolute
configuration of 4f determined by X-ray crystallographic analysis.17 The rate and
enantioselectivity of this cascade reaction are closely related to the concentration of
anion A. For some cases, especially reactions employing active conjugated
malononitriles, if the reaction was performed at 50 °C (Supporting Information, Table
S1), the generation of anion A and subsequent Michael addition would be too fast to
be well stereo-controlled, the competitive background reaction without catalyst led to
a poor enantioselectivity (Table 1, entry 4).
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1
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2
2
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2
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2
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4
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5
5
5
5
5
5
5
5
6
R
O
NC
Si-face blocked
N
Rh
N
2
a
N
NC
N
i-Pr
B
b)
Hantzsch a)
ester
O
0
1
2
3
4
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9
0
1
2
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0
1
2
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5
6
7
8
9
0
Ph
NC
H
NC
NC
O
tBu
R
H+
5
NC
A
Re-face approach
Figure 1. Proposed mechanism and stereoselective control model
Conclusion
In conclusion, we have successfully developed a chiral-at-metal Rh(III) complex
catalyzed cascade reduction-Michael addition reaction of conjugated malononitriles to
α,β-unsaturated 2-acyl imidazoles, affording the corresponding adducts in good yields
with excellent enantioselectivities. This protocol features wide substrate scope, mild
reaction conditions and an operationally simple procedure. The catalyst exhibits
remarkable reactivity and enantioselectivity for the reaction, given the fact that the
title reaction can be conducted on a large scale by using as low as 0.5 mol % of
Λ-Rh3 as catalyst with comparable enantioselectivity. The mechanism of the
asymmetric induction and three-component reaction process has been preliminarily
investigated.
EXPERIMENTAL SECTION
All reactions were performed in Schlenk tubes under an atmosphere of argon using
oven-dried glassware. For reactions that require heating, oil bath was used as the heat
source. Commercially obtained reagents were used without further purification, unless
otherwise noted. Chloroform was distilled over P O and stored over 3Å type
2
5
molecular sieves. THF and toluene were distilled freshly before use over sodium and
benzophenone. Acetonitrile (MeCN), dichloromethane (DCM) and 1,2-dichloroethane
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(
DCE) were distilled from CaH . Reactions were checked for completion by TLC
2
analysis and plates were visualized with short-wave UV light (254 nm). Products
were purified by flash column chromatography performed on a huanghai 200−300
mesh silica gel 60. The column dimensions are 17 mm outer diameter, 13.4 mm inner
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
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2
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4
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0
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2
3
4
5
6
7
8
9
0
1
13
diameter and approximate 16 cm long. Unless otherwise noted, the H, C NMR and
1
9
F spectra were obtained in CDCl using a Bruker-BioSpin AVANCE III HD NMR
3
1
spectrometer at 400, 100 and 376.4 MHz, respectively. The H spectra of substrates
2
e-2m were obtained in CDCl using a JEOL ECZ600S NMR spectrometer at 600
3
MHz. Chemical shifts are reported in parts per million (δ value) calibrated against the
residual solvent peak. Signal patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. Coupling constants (J) are given in hertz (Hz). HPLC
analyses of the compounds were done on chiralcel IA-IF and ADH columns using
hexane and isopropanol as eluent. The infrared spectra were recorded on a Bruker
VERTEX 70 IR spectrometer as KBr pellets, with absorption reported in cm-1.
High-resolution mass spectra were recorded on a Bruker Impact II UHR TOF LC/MS
Mass Spectrometry. Crystal structure data were collected on a SuperNova, Dual, Cu
at zero, Atlas diffractometer.
Synthesis of catalysts: Racemic rhodium catalyst rac-Rh3 and chiral catalysts
Λ-Rh1, Λ-Rh2, Λ-Rh3 were prepared according to reported procedures.11e,16c,19
Synthesis of ,β-unsaturated 2-acyl imidazoles: ,β-Unsaturated 2-acylimidazoles
1
6c
20
1
a-1l , 1m-1n were prepared according to reported procedures.
Synthesis of conjugated malononitriles: Conjugated malononitriles 2a-2l were
prepared according to the previously reported procedure with some modifications.21-26
To a 100 mL round-bottom flask equipped with a magnetic stir bar was added
malononitrile (10.0 mmol, 1.0 equiv), ammonium acetate (0.23 g, 3.0 mmol, 0.3
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2
2
2
2
2
2
2
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3
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4
4
4
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5
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5
5
5
5
5
5
5
6
equiv), the corresponding aldehyde (11 mmol, 1.1 equiv), acetic acid (0.3 ml), and
toluene (1.0 M of malononitrile, 10 ml). The round-bottom was attached to a
Dean-Stark apparatus and heated to reflux for 2 h until water was obtained. After
cooling to room temperature, the reaction mixture was washed with a solution of
saturated NaCl (3 × 10 mL). The organic layer was dried over anhydrous Na SO ,
0
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5
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9
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0
2
4
filtered and concentrated in vacuo. The resulting solid was recrystallized in EtOH for
two times. Alkylidene malononitriles 2m-2n were prepared according to a published
procedure.27-28
Characterization of substrates 2a-2l
2-benzylidenemalononitrile (2a)21-23 was obtained as white solid, 1.20 g, 78% yield,
22
1
mp: 83-85 °C (lit. 83-84 °C) . H NMR (400 MHz, CDCl ): δ = 7.91 (d, J = 7.7 Hz,
3
2
H), 7.79 (s, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H).
2-(2-methylbenzylidene)malononitrile (2b)21-23 was obtained as white solid, 1.23 g,
24
1
7
3% yield, mp: 106-108 °C (lit. 107-109 °C) . H NMR (400 MHz, CDCl ): δ =
3
8
.14-8.06 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.41-7.29 (m, 2H), 2.45 (s, 3H).
2
-(4-methylbenzylidene)malononitrile (2c)21-23 was obtained as gray solid, 0.99 g,
2
2 1
5
9% yield, mp: 133-135 °C (lit. 133-134 °C) . H NMR (400 MHz, CDCl ): δ = 7.81
3
(d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H).
2
-(4-methoxybenzylidene)malononitrile (2d)21-23 was obtained as yellow solid,
2
2 1
1.23 g, 67% yield, mp: 114-116 °C (lit. 110-112 °C) . H NMR (400 MHz, CDCl ): δ
3
=
7.92 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H).
-(3-chlorobenzylidene)malononitrile (2e)21-23 was obtained as white solid, 1.50 g,
2
2
2 1
80% yield, mp: 113-115 °C (lit. 113-115 °C) . H NMR (600 MHz, CDCl ): δ =
3
7
.87-7.82 (m, 2H), 7.73 (s, 1H), 7.63-7.58 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H).
2
-(4-nitrobenzylidene)malononitrile (2f)21-23 was obtained as red solid, 1.39 g, 70%
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yield, mp: 160-162 °C (lit. 161-162 °C) . H NMR (600 MHz, CDCl ): δ = 8.40 (d, J
3
=
9.0 Hz, 2H), 8.08 (d, J = 9.0 Hz, 2H), 7.89 (s, 1H).
2-(4-(trifluoromethyl)benzylidene)malononitrile (2g) was obtained as white solid,
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23 1
1
8
.89 g, 85% yield, mp: 107-109 °C (lit. 110 °C) . H NMR (600 MHz, CDCl ): δ =
3
.01 (d, J = 8.0 Hz, 2H), 7.89-7.76 (m, 3H).
2
2
2
-(furan-2-ylmethylene)malononitrile (2h) was obtained as yellow solid, 1.17 g,
2
2 1
8
1% yield, mp: 67-69 °C (lit. 69-70 °C) . H NMR (600 MHz, CDCl ): δ = 7.82 (d, J
3
=
1.8 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J = 3.6 Hz, 1H), 6.73 (dd, J = 3.6, 1.8 Hz, 1H).
2
2
2
-(thiophen-2-ylmethylene)malononitrile (2i) was obtained as white solid, 0.83 g,
2
2 1
52% yield, mp: 110-112 °C (lit. 110-112 °C) . H NMR (600 MHz, CDCl ): δ =
3
7
.93-7.86 (m, 2H), 7.84-7.79 (m, 1H), 7.28 (dd, J = 5.4, 4.2 Hz, 1H).
-(naphthalen-2-ylmethylene)malononitrile (2j)24 was obtained as white solid,
2
2
4
1
1.12 g, 55% yield, mp: 143-145 °C (lit. 145.5-146.5 °C) . H NMR (600 MHz,
CDCl ): δ = 8.33-8.23 (m, 1H), 8.07 (dd, J = 8.4, 1.8 Hz, 1H), 7.95 (dd, J = 8.4, 4.2
3
Hz, 2H), 7.92-7.86 (m, 2H), 7.68 (ddd, J = 8.4, 6.6, 1.2 Hz, 1H), 7.61 (ddd, J = 8.4,
6
.6, 1.2 Hz, 1H).
E)-2-(3-phenylallylidene)malononitrile (2k) was obtained as yellow solid, 1.06
2
5
(
2
2 1
g, 59% yield, mp: 125-127 °C (lit. 126-127 °C) . H NMR (600 MHz, CDCl ): δ =
3
7
.64-7.56 (m, 3H), 7.52-7.42 (m, 3H), 7.32-7.23 (m, 2H).
2
5
2-(3-phenylprop-2-yn-1-ylidene)malononitrile (2l) was obtained as yellow solid,
25
1
0
7
.71 g, 40% yield, mp: 86-88 °C (lit. 87-88 °C) . H NMR (600 MHz, CDCl ): δ =
3
.65-7.60 (m, 2H), 7.53 (tt, J = 7.8, 1.2 Hz, 1H), 7.46-7.41 (m, 2H), 7.17 (s, 1H).
2
6
2-(cyclopropylmethylene)malononitrile (2m) was obtained as colorless oil, 0.66 g,
1
5
6% yield. H NMR (600 MHz, CDCl ): δ = 6.63 (d, J = 11.4 Hz, 1H), 2.16 (ddt, J =
3
1
5.6, 7.8, 3.6 Hz, 1H), 1.48-1.42 (m, 2H), 1.09-1.04 (m, 2H).
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2
-propylidenemalononitrile (2n)27-28 was obtained as colorless oil, 0.61 g, 58%
1
yield. H NMR (400 MHz, CDCl ): δ = 7.34 (t, J = 8.0 Hz, 1H), 2.63 (p, J = 8.0 Hz,
3
2H), 1.21 (t, J = 6.8 Hz, 3H).
0
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General Procedure for chiral-at-metal Rh(III) complex catalyzed cascade
reduction-Michael addition reaction: To an oven-dried 25 mL Schlenk tube
equipped with a magnetic stir bar, Λ-Rh3 (3.9 mg, 2 mol %) was added along with
α,β-unsaturated 2-acyl imidazole 1 (0.3 mmol, 2.0 equiv), conjugated malononitrile 2
(
0.15 mmol, 1.0 equiv), Hantzsch ester 3 (0.18 mmol, 1.2 equiv) and CCl (0.3 M of
4
2
, 0.5 mL). The reaction was stirred at 50 °C under argon atmosphere until
consumption of the malononitrile as monitored by thin layer chromatography. After
cooling to room temperature, the solution was purified by flash column
chromatography on silica gel (EtOAc/Petroleum ether = 1:5) to afford the desired
adduct 4.
General procedure for gram-scale experiments:
Condition A: To an oven-dried 25 mL Schlenk tube equipped with a stir bar,
Λ-Rh3 (31.4 mg, 1 mol %) was added along with α,β-unsaturated 2-acyl imidazole 1b
(
1.2 g, 5 mmol), conjugated malononitrile 2a (385 mg, 2.5 mmol), Hantzsch ester 3
(
760 mg, 3 mmol) and CCl (8 mL). The reaction was stirred at 50 °C under argon
4
atmosphere for 48 h. After removing the solvent, the crude product was purified by
flash column chromatography on silica gel (EtOAc/Petroleum ether = 1:5) to afford
the desired adduct 4b.
Condition B: To an oven-dried 25 mL Schlenk tube equipped with a stir bar,
Λ-Rh3 (15.7 mg, 0.5 mol %) was added along with α,β-unsaturated 2-acyl imidazole
1
3
b (1.2 g, 5 mmol), conjugated malononitrile 2a (385 mg, 2.5 mmol), Hantzsch ester
(760 mg, 3 mmol) and CCl (8 mL). The reaction was stirred at 50 °C under argon
4
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atmosphere for 48 h. After removing the solvent, the crude product was purified by
flash column chromatography on silica gel (EtOAc/Petroleum ether = 1:5) to afford
the desired adduct 4b.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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Characterization of compounds 4:
(R)-2-benzyl-2-(3-(1-methyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)malononitri
le (4a). With α,β-unsaturated 2-acyl imidazole 1a (64 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and Λ-Rh3
(
3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4a (45 mg, 82% yield) as yellow solid. mp:
4
7
5-76 °C, 96% ee, [α]D25 = +28.6 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
1
tmajor = 11.35 min, tminor = 14.24 min). H NMR (400 MHz, CDCl ): δ = 7.55-7.48 (d,
3
J = m, 2H), 7.44-7.28 (m, 8H), 7.17 (s, 1H), 7.02 (s, 1H), 4.37 (dd, J = 17.2, 10.4 Hz,
1H), 4.08 (dd, J = 10.4, 3.6 Hz, 1H), 3.87 (s, 3H), 3.81 (dd, J = 17.2, 3.6 Hz, 1H),
3
.09 (d, J = 13.6 Hz, 1H), 2.91 (d, J = 13.6 Hz, 1H). 13C NMR {1H} (100 MHz,
CDCl ): δ = 187.6, 142.4, 135.5, 132.3, 130.2, 129.5, 129.3, 129.1, 129.0, 128.9,
3
-
1
1
2
28.7, 127.6, 115.1, 114.2, 47.3, 45.4, 42.1, 41.3, 36.1. IR (KBr): ν (cm ) 3033, 2925,
361, 2341, 1679, 1497, 1456, 1409, 1290, 1156, 1090, 1002, 974, 915, 766, 702, 667.
+
HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 391.1529, found: 391.1530.
2
3
20
4
(R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)malononi
trile (4b). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and Λ-Rh3
(
3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4b (57 mg, 96% yield) as yellow solid. mp:
4
39-41 °C, 96% ee, [α]D25 = +17.3 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
1
tmajor = 9.27 min, tminor = 14.06 min). H NMR (400 MHz, CDCl ): δ = 7.54-7.46 (m,
3
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H), 7.44-7.28 (m, 8H), 7.24 (s, 1H), 7.20 (s, 1H), 5.40-5.25 (m, 1H), 4.34 (dd, J =
7.2, 10.4 Hz, 1H), 4.08 (dd, J = 10.4, 4.0 Hz, 1H), 3.85 (dd, J = 17.2, 4.0 Hz, 1H),
3.10 (d, J = 13.6 Hz, 1H), 2.92 (d, J = 13.6 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.29 (d,
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2
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0
13
J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.8, 141.7, 135.6, 132.3,
3
1
4
1
30.2, 130.0, 129.3, 129.1, 129.0, 128.9, 128.7, 121.8, 115.1, 114.3, 49.3, 47.5, 45.4,
-1
2.1, 41.9, 23.6, 23.3. IR (KBr): ν (cm ) 3033, 2981, 2933, 2360, 2340, 1679, 1497,
456, 1396, 1255, 1089, 971, 916, 767, 702. HRMS (ESI, m/z) calcd for
+
C H N NaO [M+Na] : 419.1842, found: 419.1840.
2
5
24
4
(R)-2-benzyl-2-(3-oxo-1-phenyl-3-(1-phenyl-1H-imidazol-2-yl)propyl)malononitri
le (4c). With α,β-unsaturated 2-acyl imidazole 1c (82 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and Λ-Rh3
(3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4c (48 mg, 75% yield) as white solid. mp:
4
50-52 °C, 94% ee, [α]D25 = -15.6 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
1
tmajor = 8.99 min, tminor = 12.64 min). H NMR (400 MHz, CDCl ): δ = 7.50-7.45 (m,
3
2
1
H), 7.44-7.28 (m, 12H), 7.16 (s, 1H), 7.06-6.95 (m, 2H), 4.31 (dd, J = 17.2, 10.4 Hz,
H), 4.03 (dd, J = 10.4, 4.0 Hz, 1H), 3.85 (dd, J = 17.2, 4.0 Hz, 1H), 3.06 (d, J = 13.6
1
3
Hz, 1H), 2.89 (d, J = 13.6 Hz, 1H). C NMR {1H} (100 MHz, CDCl ): δ = 186.3,
3
1
42.3, 137.8, 135.4, 132.2, 130.2, 130.0, 129.5, 129.1, 129.0, 128.9, 128.7, 127.6,
-1
125.6, 115.0, 114.2, 47.3, 45.4, 42.1, 41.6. IR (KBr): ν (cm ) 3063, 3033, 2924, 2361,
2
341, 1687, 1494, 1456, 1406, 1305, 1150, 1092, 959, 914, 761, 702. HRMS (ESI,
+
m/z) calcd for C H N NaO [M+Na] : 453.1686, found: 453.1684.
2
8
22
4
(R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-(p-tolyl)propyl)malono
nitrile (4d). With α,β-unsaturated 2-acyl imidazole 1d (76 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and Λ-Rh3
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(
3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4d (53 mg, 86% yield) as white solid. mp:
4
1
08-110 °C, 94% ee, [α]D25 = +5.7 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
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tmajor = 8.47 min, tminor = 10.44 min). 13C NMR {1H} (100 MHz, CDCl ): δ =
3
7
1
3
3
1
.41-7.29 (m, 7H), 7.24 (s, 1H), 7.21-7.14 (m, 3H), 5.43-5.25 (m, 1H), 4.31 (dd, J =
7.2, 10.4 Hz, 1H), 4.05 (dd, J = 10.4, 3.6 Hz, 1H), 3.83 (dd, J = 17.2, 3.6 Hz, 1H),
.09 (d, J = 13.6 Hz, 1H), 2.93 (d, J = 13.6 Hz, 1H), 2.33 (s, 3H), 1.33 (d, J = 6.8 Hz,
1
3
H), 1.30 (d, J = 6.4 Hz, 3H). C NMR (100 MHz, CDCl ): δ = 187.9, 141.7, 138.8,
3
32.5, 132.4, 130.3, 130.0, 129.7, 129.2, 128.8, 128.7, 121.7, 115.2, 114.4, 49.2, 47.2,
-1
45.5, 42.1, 41.9, 23.6, 23.3, 21.2. IR (KBr): ν (cm ) 3033, 2982, 2931, 2361, 2341,
1
678, 1516, 1456, 1396, 1254, 1088, 971, 916, 767, 703. HRMS (ESI, m/z) calcd for
+
C H N NaO [M+Na] : 433.1999, found: 433.1998.
2
6
26
4
(R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-1-(4-methoxyphenyl)-3-oxoprop
yl)malononitrile (4e). With α,β-unsaturated 2-acyl imidazole 1e (81 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol)
and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4e (59 mg, 92% yield) as yellow
4
solid. mp: 99-101 °C, 94% ee, [α]D25 = +6.6 (c = 0.5, CHCl ); The ee was determined
3
by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0
1
mL/min, tmajor = 10.64 min, tminor = 15.42 min). H NMR (400 MHz, CDCl ): δ = 7.42
3
(d, J = 8.7 Hz, 2H), 7.39-7.30 (m, 5H), 7.25 (s, 1H), 7.20 (s, 1H), 6.90 (d, J = 8.8 Hz,
2
H), 5.40-5.25 (m, 1H), 4.31 (dd, J = 17.2, 10.4 Hz, 1H), 4.04 (dd, J = 10.4, 3.6 Hz,
H), 3.81 (dd, J = 17.2, 3.6 Hz, 1H), 3.79 (s, 3H), 3.09 (d, J = 13.6 Hz, 1H), 2.94 (d, J
1
1
3
= 13.6 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H). C NMR {1H}
(
100 MHz, CDCl ): δ = 187.9, 159.9, 141.7, 132.4, 130.5, 130.2, 130.0, 128.9, 128.7,
3
1
27.4, 121.8, 115.2, 114.4, 55.3, 49.3, 46.9, 45.6, 42.0, 41.9, 23.6, 23.3. IR (KBr): ν
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(
cm ) 2969, 2934, 2838, 2360, 2341, 1678, 1610, 1515, 1456, 1396, 1254, 1181,
+
1
088, 1032, 971, 916, 768, 703. HRMS (ESI, m/z) calcd for C H N NaO [M+Na] :
2
6
26
4
2
449.1948, found: 449.1948.
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(
R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-1-(4-nitrophenyl)-3-oxopropyl)
malononitrile (4f). With α,β-unsaturated 2-acyl imidazole 1f (86 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol)
and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4f (65 mg, 98% yield) as white
4
solid. mp: 179-180 °C, 96% ee, [α]D25 = +5.1 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column IC, λ = 254 nm, hexane/i-PrOH = 85/15,
1
flow rate 0.8 mL/min, tmajor = 25.66 min, tminor = 23.75 min). H NMR (400 MHz,
CDCl ): δ = 8.25 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.44-7.31 (m, 5H),
3
7
.28 (s, 1H), 7.22 (s, 1H), 5.40-5.20 (m, 1H), 4.38 (dd, J = 17.2, 10.8 Hz, 1H), 4.17
(dd, J = 10.8, 3.6 Hz, 1H), 3.89 (dd, J = 17.2, 3.6 Hz, 1H), 3.21 (d, J = 13.6 Hz, 1H),
13
2
{
1
.99 (d, J = 13.6 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H). C NMR
1H} (100 MHz, CDCl ): δ = 186.9, 148.2, 143.1, 141.3, 131.6, 130.4, 130.3, 130.2,
3
29.1, 124.2, 122.3, 114.4, 113.8, 49.4, 47.0, 45.0, 42.1, 41.3, 23.6, 23.3. IR (KBr): ν
-1
(
cm ) 3032, 2984, 2931, 2361, 2341, 1673, 1607, 1523, 1456, 1397, 1351, 1253,
162, 1113, 1088, 974, 916, 860, 776, 705. HRMS (ESI, m/z) calcd for C H N O
1
2
5
24
5
3
+
[
M+H] : 442.1874, found: 442.1876.
(R)-2-benzyl-2-(1-(4-chlorophenyl)-3-(1-isopropyl-1H-imidazol-2-yl)-3-oxopropyl)m
alononitrile (4g). With α,β-unsaturated 2-acyl imidazole 1g (83 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol)
and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4g (64 mg, 98% yield) as yellow
4
solid. mp: 115-116 °C, 91% ee, [α]D25 = +14.1 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
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flow rate 1.0 mL/min, tmajor = 8.794 min, tminor = 11.859 min). H NMR (400 MHz,
CDCl ): δ = 7.45 (d, J = 8.4 Hz, 2H), 7.42-7.29 (m, 7H), 7.26 (s, 1H), 7.20 (s, 1H),
3
5.42-5.22 (m, 1H), 4.31 (dd, J = 17.2, 10.8 Hz, 1H), 4.05 (dd, J = 10.8, 3.6 Hz, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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7
8
9
0
1
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4
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8
9
0
1
2
3
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5
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7
8
9
0
3
1
.82 (dd, J = 17.2, 3.6 Hz, 1H), 3.12 (d, J = 13.6 Hz, 1H), 2.95 (d, J = 13.6 Hz, 1H),
1
3
.35 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H). C NMR {1H} (100 MHz, CDCl ):
3
δ = 187.4, 141.6, 135.0, 134.1, 132.0, 130.7, 130.2, 130.1, 129.3, 128.9, 128.8, 122.0,
-1
1
14.8, 114.1, 49.3, 46.9, 45.3, 42.0, 41.6, 23.6, 23.3. IR (KBr): ν (cm ) 3033, 2982,
2
933, 2361, 2341, 1678, 1495, 1456, 1396, 1254, 1164, 1092, 1014, 972, 916, 768,
+
7
03. HRMS (ESI, m/z) calcd for C H ClN NaO [M+Na] : 453.1453, found:
25 23
4
453.1454.
(
R)-2-benzyl-2-(1-(3-chlorophenyl)-3-(1-isopropyl-1H-imidazol-2-yl)-3-oxopropyl)m
alononitrile (4h). With α,β-unsaturated 2-acyl imidazole 1h (83 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4h (61 mg, 94% yield) as
4
white solid. mp: 87-89 °C, 93% ee, [α]D25 = +6.7 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column IE, λ = 254 nm, hexane/i-PrOH = 90/10,
1
flow rate 1.0 mL/min, tmajor = 12.62 min, tminor = 14.50 min). H NMR (400 MHz,
CDCl ): δ =7.49-7.41 (m, 2H), 7.41-7.30 (m, 7H), 7.26 (s, 1H), 7.21 (s, 1H),
3
5
.42-5.24 (m, 1H), 4.29 (dd, J = 17.2, 10.4 Hz, 1H), 4.04 (dd, J = 10.4, 3.6 Hz, 1H),
3.85 (dd, J = 17.2, 3.6 Hz, 1H), 3.12 (d, J = 13.6 Hz, 1H), 2.95 (d, J = 13.6 Hz, 1H),
13
1
.36 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ):
3
δ = 187.3, 141.5, 137.7, 134.9, 132.0, 130.4, 130.2, 130.1, 129.7, 129.3, 128.9, 128.8,
-1
127.2, 122.0, 114.8, 114.0, 49.3, 47.0, 45.1, 42.1, 41.8, 23.6, 23.3. IR (KBr): ν (cm )
3
033, 2982, 2933, 2360, 2341, 1678, 1574, 1456, 1396, 1254, 1087, 973, 916, 767,
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+
7
4
02. HRMS (ESI, m/z) calcd for C H ClN NaO [M+Na] : 453.1453, found:
25 23 4
53.1453.
(R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-(o-tolyl)propyl)malono
0
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nitrile (4i). With α,β-unsaturated 2-acyl imidazole 1i (76 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and Λ-Rh3
(
3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4i (54 mg, 88% yield) as yellow oil, 95% ee,
4
[
α]D25 = -9.1 (c = 0.5, CHCl ); The ee was determined by HPLC (Chiralpak column
3
ADH, λ = 254 nm, hexane/i-PrOH = 80/20, flow rate 1.0 mL/min, tmajor = 5.52 min,
1
tminor = 8.63 min). H NMR (400 MHz, CDCl ): δ = 7.67 (d, J = 7.6 Hz, 1H),
3
7.30-7.43 (m, 5H), 7.29-7.14 (m, 5H), 5.21-5.39 (m, 1H), 4.45 (dd, J = 10.7, 3.5 Hz,
1
1
H), 4.31 (dd, J = 16.7, 10.7 Hz, 1H), 3.83 (dd, J = 16.7, 3.5 Hz, 1H), 3.23 (d, J =
3.5 Hz, 1H), 2.98 (d, J = 13.5 Hz, 1H), 2.43 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H), 1.28 (d,
1
3
J = 6.7 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.9, 141.6, 137.9, 134.7,
3
1
4
2
32.2, 131.0, 130.4, 129.9, 128.9, 128.8, 128.5, 127.0, 126.9, 121.7, 115.3, 114.2,
-
1
9.2, 45.6, 42.7, 41.4, 41.2, 23.6, 23.2, 20.3. IR (KBr): ν (cm ) 3032, 2979, 2933,
360, 2341, 1680, 1496, 1456, 1397, 1254, 1088, 973, 916, 767, 732, 703. HRMS
+
(
ESI, m/z) calcd for C H N O [M+H] : 411.2179, found: 411.2180.
2
6
27
4
(
S)-2-benzyl-2-(1-(furan-2-yl)-3-(1-isopropyl-1H-imidazol-2-yl)-3-oxopropyl)mal
ononitrile (4j). With α,β-unsaturated 2-acyl imidazole 1j (69 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4j (33 mg, 57% yield) as
4
yellow oil, 93% ee, [α]D25 = +30.7 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
1
tmajor = 8.39 min, tminor = 14.41 min). H NMR (400 MHz, CDCl ): δ = 7.46 (d, J = 1.2
3
Hz, 1H), 7.38 (s, 5H), 7.29 (s, 1H), 7.22 (s, 1H), 6.53 (d, J = 3.6 Hz, 1H), 6.40 (dd, J
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=
3.6, 2.0 Hz, 1H), 5.52-5.28 (m, 1H), 4.29 (dd, J = 24.0, 10.4 Hz, 2H), 3.76 (dd, J =
2
4.0, 10.4Hz, 1H), 3.16 (d, J = 13.6 Hz, 1H), 3.03 (d, J = 13.6 Hz, 1H), 1.39 (d, J =
6.8 Hz, 6H). 13C NMR {1H} (100 MHz, CDCl ): δ = 187.2, 149.3, 143.3, 141.5,
3
1
1
1
1
1
1
1
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1
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32.2, 130.3, 130.1, 128.9, 128.8, 121.9, 114.6, 114.0, 111.0, 110.2, 49.4, 44.7, 41.4,
-1
1.1, 40.4, 23.6, 23.4. IR (KBr): ν (cm ) 3033, 2983, 2935, 2360, 2341, 1681, 1499,
456, 1397, 1254, 1150, 1088, 1015, 974, 916, 768, 745, 703. HRMS (ESI, m/z) calcd
+
for C H N O [M+H] : 387.1816, found: 387.1817.
2
3
23
4
2
(S)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-(thiophen-2-yl)propyl)
malononitrile (4k). With α,β-unsaturated 2-acyl imidazole 1k (74 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4k (45 mg, 75% yield) as
4
yellow oil, 90% ee, [α]D25 = +23.9 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0 mL/min,
1
tmajor = 9.82 min, tminor = 17.47 min). H NMR (400 MHz, CDCl ): δ = 7.37 (s, 5H),
3
7
5
3
1
1
.30 (d, J = 5.1 Hz, 1H), 7.27 (s, 2H), 7.21 (s, 1H), 7.03 (dd, J = 4.8, 3.6 Hz, 1H),
.48-5.26 (m, 1H), 4.42 (dd, J = 10.4, 3.6 Hz, 1H), 4.29 (dd, J = 17.2, 10.4 Hz, 1H),
.85 (dd, J = 17.2, 3.6 Hz, 1H), 3.15 (d, J = 13.6 Hz, 1H), 3.06 (d, J = 13.6 Hz, 1H),
1
3
.35 (d, J = 6.8 Hz, 6H). C NMR {1H} (100 MHz, CDCl ): δ = 187.1, 141.5, 137.6,
3
32.2, 130.3, 130.1, 128.9, 128.8, 128.1, 127.5, 126.2, 121.9, 114.8, 114.1, 49.3, 45.7,
-1
43.5, 43.0, 41.9, 23.6, 23.3. IR (KBr): ν (cm ) 3033, 2981, 2932, 2361, 2341, 1680,
456, 1396, 1254, 1088, 967, 916, 768, 703. HRMS (ESI, m/z) calcd for C H N OS
1
2
3
23
4
+
[M+H] : 403.1587, found: 403.1581.
(R)-2-benzyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-1-(naphthalen-2-yl)-3-oxopropy
l)malononitrile (4l). With α,β-unsaturated 2-acyl imidazole 1l (87 mg, 0.3 mmol),
conjugated malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
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mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4l (60 mg, 90% yield) as
4
white solid. mp: 167-169 °C, 92% ee, [α]D25 = -6.4 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
0
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2
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0
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2
3
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7
8
9
0
1
flow rate 1.0 mL/min, tmajor = 10.02 min, tminor = 14.19 min). H NMR (400 MHz,
CDCl ): δ = 7.97 (s, 1H), 7.92-7.78 (m, 3H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 7.56-7.46
3
(m, 2H), 7.42-7.28 (m, 5H), 7.21 (d, J = 5.6 Hz, 2H), 5.40-5.15 (m, 1H), 4.50 (dd, J =
1
3
7.2, 10.4 Hz, 1H), 4.25 (dd, J = 10.8, 3.6 Hz, 1H), 3.92 (dd, J = 17.2, 3.6 Hz, 1H),
.15 (d, J = 13.6 Hz, 1H), 2.95 (d, J = 13.6 Hz, 1H), 1.30 (d, J = 6.4 Hz, 3H), 1.23 (d,
1
3
J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.7, 141.7, 133.4, 133.2,
3
133.0, 132.3, 130.3, 130.0, 128.9, 128.9, 128.7, 128.3, 127.7, 126.8, 126.7, 126.6,
-1
1
2
21.8, 115.2, 114.3, 49.2, 47.6, 45.4, 42.2, 42.1, 23.6, 23.2. IR (KBr): ν (cm ) 3032,
981, 2931, 2361, 2341, 1677, 1456, 1396, 1253, 1088, 975, 916, 820, 768, 702, 479.
+
HRMS (ESI, m/z) calcd for C H N O [M+H] : 447.2179, found: 447.2183.
2
9
27
4
(S)-2-benzyl-2-(4-(1-isopropyl-1H-imidazol-2-yl)-4-oxobutan-2-yl)malononitrile
(4m). With α,β-unsaturated 2-acyl imidazole 1m (87 mg, 0.3 mmol), conjugated
malononitrile 2a (23 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol) and
Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4m (50 mg, 99% yield) as colorless
4
oil, 97% ee, [α]D25 = -6.6 (c = 0.5, CHCl ); The ee was determined by HPLC
3
(Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 95/5, flow rate 0.8 mL/min,
1
tmajor = 27.56 min, tminor = 24.88 min). H NMR (400 MHz, CDCl ): δ = 7.47-7.35 (m,
3
5
1
H), 7.32 (s, 1H), 7.22 (s, 1H), 5.60-5.42 (m, 1H), 3.62-3.44 (m, 2H), 3.23 (dd, J =
8.8, 13.6 Hz, 2H), 3.02-2.87 (m, 1H), 1.47 (d, J = 5.2 Hz, 6H), 1.38 (d, J = 6.8 Hz,
1
3
3H). C NMR {1H} (100 MHz, CDCl ): δ = 188.7, 141.8, 132.4, 130.2, 130.0, 129.0,
3
28.8, 122.0, 114.6, 114.6, 49.5, 45.2, 42.4, 40.7, 36.3, 23.6, 16.6. IR (KBr): ν (cm-1)
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981, 2935, 2360, 2341, 1677, 1456, 1397, 1255, 1089, 995, 973, 916, 767, 703.
+
HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 357.1686, found: 357.1684.
2
0
22
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(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(2-methylbenzyl)m
alononitrile (4bb). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2b (25 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
1
1
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mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bb (59 mg, 96% yield)
4
as white solid. mp: 148-150 °C, 89% ee, [α]D25 = +13.8 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
1
flow rate 1.0 mL/min, tmajor = 7.89 min, tminor = 10.29 min). H NMR (400 MHz,
CDCl ): δ = 7.53 (d, J = 6.9 Hz, 2H), 7.45-7.31 (m, 4H), 7.26-7.12 (m, 5H), 5.44-5.23
3
(m, 1H), 4.37 (dd, J = 17.2, 10.4 Hz, 1H), 4.13 (dd, J = 10.4, 3.6 Hz, 1H), 3.87 (dd, J
=
17.2, 3.6 Hz, 1H), 3.16 (d, J = 14.0 Hz, 1H), 3.00 (d, J = 14.0 Hz, 1H), 2.21 (s, 3H),
1
3
1.34 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ):
3
δ = 187.8, 141.7, 137.4, 135.6, 131.1, 130.9, 130.6, 130.0, 129.4, 129.0, 129.0, 128.6,
1
26.4, 121.8, 115.4, 114.4, 49.3, 48.0, 44.5, 41.9, 38.2, 23.6, 23.3, 19.6. IR (KBr): ν
-1
(cm ) 2981, 2932, 2360, 2342, 1679, 1496, 1456, 1396, 1255, 1163, 1089, 968, 916,
+
7
4
72, 745, 702. HRMS (ESI, m/z) calcd for C H N O [M+H] : 411.2179, found:
2
6
27
4
11.2179.
R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(4-methylbenzyl)m
(
alononitrile (4bc). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2c (25 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bc (61 mg, 99% yield)
4
as yellow solid. mp: 39-40 °C, 96% ee, [α]D25 = +10.5 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
1
flow rate 1.0 mL/min, tmajor = 8.81 min, tminor = 11.10 min). H NMR (400 MHz,
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CDCl ): δ = 7.49 (d, J = 6.8 Hz, 2H), 7.42-7.30 (m, 3H), 7.26-7.11 (m, 6H), 5.41-5.32
3
(m, 1H), 4.34 (dd, J = 17.2, 10.4 Hz, 1H), 4.07 (dd, J = 10.4, 3.6 Hz, 1H), 3.84 (dd, J
= 17.2, 3.6 Hz, 1H), 3.07 (d, J = 13.6 Hz, 1H), 2.89 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H),
0
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2
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2
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8
9
0
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2
3
4
5
6
7
8
9
0
13
1
.33 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ):
3
δ = 187.8, 141.7, 138.5, 135.6, 130.1, 130.0, 129.6, 129.3, 129.2, 129.0, 128.9, 121.8,
-
1
1
2
7
15.2, 114.4, 49.2, 47.4, 45.6, 41.9, 41.8, 23.6, 23.3, 21.2. IR (KBr): ν (cm ) 3032,
982, 2929, 2361, 2341, 1679, 1517, 1456, 1396, 1255, 1089, 970, 916, 816, 777,
+
02. HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 433.1999, found: 433.1999.
26
26
4
(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(4-methoxybenz
yl)malononitrile (4bd). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2d (28 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bd (50 mg, 78% yield)
4
as white solid. mp: 45-46 °C, 97% ee, [α]D25 = +10.5 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
1
flow rate 1.0 mL/min, tmajor = 12.27 min, tminor = 14.12 min). H NMR (400 MHz,
CDCl ): δ = 7.49 (d, J = 6.8 Hz, 2H), 7.43-7.30 (m, 3H), 7.27 (s, 1H), 7.24 (s, 2H),
3
7.20 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 5.43-5.23 (m, 1H), 4.33 (dd, J = 17.2, 10.4 Hz,
1H), 4.06 (dd, J = 10.4, 3.6 Hz, 1H), 3.84 (dd, J = 17.2, 3.6 Hz, 1H), 3.80 (s, 3H),
3.06 (d, J = 13.6 Hz, 1H), 2.89 (d, J = 13.6 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3H), 1.29 (d,
1
3
J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.8, 159.9, 141.7, 135.6,
3
1
4
31.4, 129.9, 129.3, 129.0, 128.9, 124.2, 121.8, 115.2, 114.4, 114.2, 55.3, 49.3, 47.3,
-1
5.7, 41.9, 41.5, 23.6, 23.3. IR (KBr): ν (cm ) 3035, 2968, 2934, 2838, 2361, 2341,
1679, 1612, 1515, 1456, 1396, 1253, 1180, 1032, 916, 827, 777, 753, 702, 522.
+
HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 449.1948, found: 449.1949.
2
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(
R)-2-(3-chlorobenzyl)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)m
alononitrile (4be). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2e (28 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
1
1
1
1
1
1
1
1
1
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2
3
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8
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0
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4be (50 mg, 77% yield)
4
as yellow oil, 93% ee, [α]D25 = +7.0 (c = 0.5, CHCl ); The ee was determined by
3
HPLC (Chiralpak column IC, λ = 254 nm, hexane/i-PrOH = 80/20, flow rate 1.0
1
mL/min, tmajor = 10.47 min, tminor = 6.36 min). H NMR (400 MHz, CDCl ): δ = 7.49
3
(
d, J = 6.8 Hz, 2H), 7.44-7.27 (m, 6H), 7.26-7.17 (m, 3H), 5.40-5.24 (m, 1H), 4.32
dd, J = 17.2, 10.4 Hz, 1H), 4.08 (dd, J = 10.4, 3.6 Hz, 1H), 3.85 (dd, J = 17.2, 3.6 Hz,
(
1H), 3.06 (d, J = 13.6 Hz, 1H), 2.89 (d, J = 13.6 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H),
13
1
1
.29 (d, J = 6.4 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.6, 141.6, 135.3,
3
34.6, 134.2, 130.3, 130.2, 130.0, 129.3, 129.1, 129.1, 129.0, 128.4, 121.9, 114.9,
-1
114.0, 49.3, 47.6, 45.0, 41.9, 41.6, 23.6, 23.3. IR (KBr): ν (cm ) 2982, 2933, 2361,
2
342, 1679, 1478, 1456, 1396, 1255, 1085, 1000, 971, 916, 777, 703. HRMS (ESI,
+
m/z) calcd for C H ClN NaO [M+H] : 453.1453, found: 453.1449.
2
5
23
4
(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(4-nitrobenzyl)
malononitrile (4bf). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2f (30 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18 mmol)
and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bf (46 mg, 70% yield) as
4
yellow solid. mp: 98-99 °C, 91% ee, [α]D25 = +10.3 (c = 0.5, CHCl ); The ee was
3
determined by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25,
1
flow rate 1.0 mL/min, tmajor = 15.01 min, tminor = 23.35 min). H NMR (400 MHz,
CDCl ): δ = 8.24 (d, J = 8.8 Hz, 2H), 7.58-7.45 (m, 4H), 7.45-7.32 (m, 3H), 7.27 (s,
3
1
H), 7.21 (s, 1H), 5.39-5.26 (m, 1H), 4.33 (dd, J = 16.8, 10.4 Hz, 1H), 4.13 (dd, J =
0.4, 4.0 Hz, 1H), 3.87 (dd, J = 16.8, 4.0 Hz, 1H), 3.20 (d, J = 13.6 Hz, 1H), 3.01 (d,
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13
J = 13.6 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H). C NMR {1H}
(
100 MHz, CDCl ): δ = 187.4, 148.2, 141.5, 139.5, 135.1, 131.4, 130.1, 129.3, 124.0,
3
-1
122.0, 114.6, 113.7, 49.3, 47.7, 44.8, 41.9, 41.6, 23.5, 23.3. IR (KBr): ν (cm ) 2982,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
1
2
3
4
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7
8
9
0
1
2
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4
5
6
7
8
9
0
2
932, 2361, 2342, 1681, 1524, 1456, 1396, 1348, 1254, 971, 916, 856, 776, 704.
+
HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 464.1693, found: 464.1692.
2
5
23
5
3
(
R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(4-(trifluoromet
hyl)benzyl)malononitrile (4bg). With α,β-unsaturated 2-acyl imidazole 1b (72 mg,
0
.3 mmol), conjugated malononitrile 2g (34 mg, 0.15mmol), Hantzsch ester 3 (46 mg,
.18 mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bg (54 mg, 78%
0
4
yield) as yellow oil, 94% ee, [α]D25 = +12.1 (c = 0.5, CHCl ); The ee was determined
3
by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0
1
mL/min, tmajor = 10.00 min, tminor = 13.01 min). H NMR (400 MHz, CDCl ): δ = 7.63
3
(d, J = 8.4 Hz, 2H), 7.54-7.44 (m, 4H), 7.44-7.32 (m, 3H), 7.26 (s, 1H), 7.22 (s, 1H),
5
3
1
.40-5.25 (m, 1H), 4.35 (dd, J = 17.2, 10.4 Hz, 1H), 4.12 (dd, J = 10.4, 4.0 Hz, 1H),
.88 (dd, J = 17.2, 4.0 Hz, 1H), 3.15 (d, J = 13.6 Hz, 1H), 2.99 (d, J = 13.6 Hz, 1H),
1
3
.34 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ):
3
δ = 187.5, 141.6, 136.3, 135.2, 131.0 (q, J = 32.6 Hz), 130.7, 130.0, 129.3, 129.2,
1
4
29.2, 125.8 (q, J = 3.6 Hz), 123.9 (q, J = 270.6 Hz), 121.9, 114.8, 113.9, 49.3, 47.7,
1
9
5.0, 41.9, 41.7, 23.5, 23.3. F NMR {1H} (376 MHz, CDCl ): δ = -62.73. IR (KBr):
3
-1
ν (cm ) 2985, 2937, 2360, 2341, 1681, 1456, 1397, 1325, 1255, 1168, 1118, 1068,
1
019, 970, 916, 854, 775, 702, 672. HRMS (ESI, m/z) calcd for C H F N NaO
2
6
23
3
4
+
[
M+Na] : 487.1716, found: 487.1716.
(R)-2-(furan-2-ylmethyl)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylprop
yl)malononitrile (4bh). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2h (22 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
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mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bh (56 mg, 97% yield)
4
as yellow oil, 97% ee, [α]D25 = +22.6 (c = 0.5, CHCl ); The ee was determined by
3
HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mL/min, tmajor = 8.34 min, tminor = 14.92 min). H NMR (400 MHz, CDCl ): δ = 7.49
3
(d, J = 6.8 Hz, 2H), 7.46-7.42 (m, 1H), 7.42-7.31 (m, 3H), 7.24 (s, 1H), 7.19 (s, 1H),
6
1
.47-6.34 (m, 2H), 5.40-5.23 (m, 1H), 4.34 (dd, J = 17.2, 10.8 Hz, 1H), 4.02 (dd, J =
0.8, 3.6 Hz, 1H), 3.79 (dd, J = 17.2, 3.6 Hz, 1H), 3.23 (d, J = 15.2 Hz, 1H), 3.12 (d,
1
3
J = 14.8 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H). C NMR {1H}
(
100 MHz, CDCl ): δ = 187.7, 146.3, 143.5, 141.7, 135.2, 130.0, 129.4, 129.0, 129.0,
3
121.8, 114.9, 114.2, 110.9, 110.7, 49.2, 46.4, 43.2, 41.6, 35.0, 23.6, 23.3. IR (KBr): ν
-1
(
cm ) 2983, 2934, 2361, 2341, 1679, 1498, 1456, 1397, 1255, 1148, 1088, 1014, 972,
+
9
16, 777, 747, 703. HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 409.1635,
2
3
22
4
2
found: 409.1628.
(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(thiophen-2-yl
methyl)malononitrile (4bi). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3
mmol), conjugated malononitrile 2i (24 mg, 0.15mmol), Hantzsch ester 3 (46 mg,
0
.18 mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bi (52 mg, 86%
4
yield) as yellow oil, 97% ee, [α]D25 = +17.6 (c = 0.5, CHCl ); The ee was determined
3
by HPLC (Chiralpak column IC, λ = 254 nm, hexane/i-PrOH = 80/20, flow rate 1.0
1
mL/min, tmajor = 10.66 min, tminor = 8.05 min). H NMR (400 MHz, CDCl ): δ = 7.49
3
(d, J = 6.8 Hz, 2H), 7.42-7.28 (m, 4H), 7.24 (s, 1H), 7.19 (s, 1H), 7.13 (d, J = 3.2 Hz,
1
H), 7.02 (dd, J = 5.2, 3.6 Hz, 1H), 5.40-5.21 (m, 1H), 4.34 (dd, J = 17.2, 10.8 Hz,
1H), 4.07 (dd, J = 10.8, 3.6Hz, 1H), 3.82 (dd, J = 17.2, 3.6 Hz, 1H), 3.37 (d, J = 14.8
Hz, 1H), 3.21 (d, J = 14.8 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H).
1
3
C NMR {1H} (100 MHz, CDCl ): δ = 187.6, 141.7, 135.3, 133.1, 130.0, 129.3,
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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1
2
29.2, 129.1, 129.0, 127.5, 126.6, 121.8, 115.1, 114.3, 49.2, 46.9, 45.5, 41.8, 36.6,
-1
3.6, 23.3. IR (KBr): ν (cm ) 2981, 2932, 2361, 2341, 1678, 1456, 1396, 1324, 1255,
1163, 1089, 1069, 971, 916, 776, 702. HRMS (ESI, m/z) calcd for C H N NaOS
2
3
22
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[M+Na] : 425.1407, found: 425.1407.
(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(naphthalen-2-
ylmethyl)malononitrile (4bj). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3
mmol), conjugated malononitrile 2j (31 mg, 0.15mmol), Hantzsch ester 3 (46 mg,
0
.18 mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bj (63 mg, 94%
4
yield) as yellow oil, 91% ee, [α] 2 = +8.4 (c = 0.5, CHCl ); The ee was determined
5
D
3
by HPLC (Chiralpak column IC, λ = 254 nm, hexane/i-PrOH = 80/20, flow rate 1.0
1
mL/min, tmajor = 18.89 min, tminor = 7.98 min). H NMR (400 MHz, CDCl ): δ =
3
7
.90-7.77 (m, 4H), 7.57-7.33 (m, 8H), 7.24 (s, 1H), 7.21 (s, 1H), 5.41-5.24 (m, 1H),
4.37 (dd, J = 17.2, 10.4 Hz, 1H), 4.14 (dd, J = 10.4, 4.0 Hz, 1H), 3.89 (dd, J = 17.2,
4
3
1
1
.0 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.10 (d, J = 13.6 Hz, 1H), 1.33 (d, J = 6.8 Hz,
1
3
H), 1.29 (d, J = 6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.7, 141.7,
3
35.6, 133.2, 133.2, 130.0, 129.8, 129.7, 129.4, 129.1, 129.0, 128.7, 128.1, 127.7,
27.6, 126.6, 126.5, 121.8, 115.2, 114.3, 49.3, 47.6, 45.4, 42.3, 41.9, 23.6, 23.3. IR
-1
(KBr): ν (cm ) 2980, 2931, 2361, 2341, 1678, 1456, 1396, 1254, 1088, 972, 916, 820,
+
7
53, 702, 477. HRMS (ESI, m/z) calcd for C H N NaO [M+Na] : 469.1999, found:
29 26
4
469.1997.
(R)-2-cinnamyl-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)malon
onitrile (4bk). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3 mmol),
conjugated malononitrile 2k (27 mg, 0.15mmol), Hantzsch ester 3 (46 mg, 0.18
mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bk (42 mg, 67% yield)
4
as yellow oil, 95% ee, [α]D25 = +24.2 (c = 0.5, CHCl ); The ee was determined by
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HPLC (Chiralpak column IC, λ = 254 nm, hexane/i-PrOH = 80/20, flow rate 1.0
1
mL/min, tmajor = 9.39 min, tminor = 6.95 min). H NMR (400 MHz, CDCl ): δ = 7.47 (d,
3
J = 6.8 Hz, 2H), 7.43-7.26 (m, 8H), 7.24 (s, 1H), 7.20 (s, 1H), 6.62 (d, J = 15.6 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
=
H), 6.24 (dt, J = 15.2, 7.2 Hz, 1H), 5.38-5.23 (m, 1H), 4.30 (dd, J = 17.2, 10.4 Hz,
H), 4.02 (dd, J = 10.4, 3.6 Hz, 1H), 3.81 (dd, J = 17.2, 3.6 Hz, 1H), 2.74 (dd, J =
4.0, 7.6 Hz, 1H), 2.67 (dd, J = 14.0, 7.2 Hz, 1H),, 1.32 (d, J = 6.8 Hz, 3H), 1.28 (d, J
1
3
6.8 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.7, 141.6, 137.8, 135.9,
3
1
4
35.4, 129.9, 129.3, 129.0, 129.0, 128.7, 128.4, 126.7, 121.8, 119.4, 115.2, 114.2,
-1
9.3, 46.4, 43.6, 41.8, 39.8, 23. 6, 23.3. IR (KBr): ν (cm ) 2980, 2928, 2361, 2341,
1681, 1456, 1396, 1254, 1089, 969, 916, 777, 752, 701. HRMS (ESI, m/z) calcd for
+
C H N NaO [M+Na] : 445.1999, found: 445.2000.
2
7
26
4
(R)-2-(3-(1-isopropyl-1H-imidazol-2-yl)-3-oxo-1-phenylpropyl)-2-(3-phenylprop-
2-yn-1-yl)malononitrile (4bl). With α,β-unsaturated 2-acyl imidazole 1b (72 mg, 0.3
mmol), conjugated malononitrile 2l (27 mg, 0.15mmol), Hantzsch ester 3 (46 mg,
0
.18 mmol) and Λ-Rh3 (3.9 mg, 2 mol %) in CCl (0.5 mL) gave 4bl (52 mg, 83%
4
yield) as yellow oil, 91% ee, [α]D25 = +82.9 (c = 0.5, CHCl ); The ee was determined
3
by HPLC (Chiralpak column ADH, λ = 254 nm, hexane/i-PrOH = 75/25, flow rate 1.0
1
mL/min, tmajor = 6.53 min, tminor = 9.37 min). H NMR (400 MHz, CDCl ): δ =
3
7
.58-7.45 (m, 4H), 7.43-7.28 (m, 6H), 7.24 (s, 1H), 7.20 (s, 1H), 5.40-5.23 (m, 1H),
4.39 (dd, J = 17.2, 10.8 Hz, 1H), 4.26 (dd, J = 10.8, 3.6 Hz, 1H), 3.81 (dd, J = 17.2,
3
3
.6 Hz, 1H), 3.07 (d, J = 16.8 Hz, 1H), 2.84 (d, J = 16.8 Hz, 1H), 1.33 (d, J = 6.8 Hz,
1
3
H), 1.28 (d, J = 6.4 Hz, 3H). C NMR {1H} (100 MHz, CDCl ): δ = 187.58, 141.66,
3
134.74, 132.02, 129.96, 129.18, 129.09, 128.99, 128.41, 121.86, 121.78, 114.73,
14.01, 87.29, 79.94, 49.23, 45.46, 42.48, 41.62, 28.38, 23.57, 23.26. IR (KBr): ν
1
-1
(
cm ) 2982, 2932, 2361, 2341, 1679, 1491, 1456, 1396, 1319, 1255, 1088, 983, 916,
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