Solvent-free asymmetric conjugate addition of malonates to enones using a diaminomethylenemalononitrile organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2014.05.100

Diaminomethylenemalononitrile organocatalyst 1 efficiently promotes the asymmetric conjugate addition of malonates to α,β-unsaturated ketones to afford the corresponding addition products in high to excellent yields with up to 98% ee.

Full text of DOI:10.1016/j.tetlet.2014.05.100

Tetrahedron Letters 55 (2014) 4334–4337
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free asymmetric conjugate addition of malonates to enones
using a diaminomethylenemalononitrile organocatalyst
Shin-ichi Hirashima a, Takaaki Sakai a, Kosuke Nakashima a, Nana Watanabe a, Yuji Koseki a,
Kanako Mukai b, Yohei Kanada b, Norihiro Tada b, Akichika Itoh b, Tsuyoshi Miura a,
⇑
a Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Diaminomethylenemalononitrile organocatalyst
1
efficiently promotes the asymmetric conjugate
Received 9 April 2014
Revised 21 May 2014
Accepted 26 May 2014
Available online 12 June 2014
addition of malonates to
to excellent yields with up to 98% ee.
a,b-unsaturated ketones to afford the corresponding addition products in high
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Michael addition
Solvent-free
Diaminomethylenemalononitrile
Malonate
Organocatalytic asymmetric conjugate addition is one of the
most efficient and ecofriendly carbonAcarbon bond forming
techniques for obtaining valuable enantiomerically pure building
blocks of use in organic synthesis.1 Among possible Michael donors
and acceptors, the reaction of malonates and enones in the
presence of organocatalysts is quite important, because the
generated products can be readily converted to chiral d-ketoesters,
which are useful synthons following decarboxylation.2 In addition,
malonates can be readily converted to enolates under mild
conditions due to the presence of the two electron-withdrawing
ester groups. In particular, unlike alkyl malonates, such as
dimethyl malonate and diethyl malonate, adducts derived from
dibenzyl malonate can be converted to the corresponding
dicarboxylic acids using not only alkaline conditions, but also via
neutral hydrogenation.3 Several research groups have reported
with the thiourea motif accomplished remarkable development.5
Furthermore, Jacobsen et al. reported that organocatalysts bearing
both thiourea and primary amine groups exhibit excellent catalytic
activity for the asymmetric conjugate additions.6 Recently, we
reported that diaminomethylenemalononitrile (DMM) effectively
serves as an alternative to thiourea groups.7,8 Organocatalyst 1 with
the DMM skeleton promoted the conjugate addition of branched
aldehydes to vinyl sulfone, affording the corresponding adducts in
high yields with excellent stereoselectivities.7 In addition, the
Michael addition of ketones to nitroalkenes using a pyrrolidine–
DMM organocatalyst was also achieved.8 To further demonstrate
the effectiveness of DMM organocatalyst 1, we then attempted to
use this compound as a catalyst for other asymmetric conjugate
additions. Herein, we report efficient conjugate additions of malo-
nates to
a,b-unsaturated ketones using DMM organocatalyst 1
conjugate additions of malonates to
a
,b-unsaturated ketones using
under solvent-free conditions. Solvent-free asymmetric organoca-
talysis has attracted much attention from the green chemistry
viewpoint, because solvent-free reaction conditions provide
pronounced advantages for process chemistry, including easy
work-up procedures, short reaction times, simple apparatus
requirements, and they are environmentally benign.9
organocatalysts;4 however, the successful conjugate addition of
dibenzyl malonate to cyclic enones has rarely been reported.4m
Therefore, the development of a more efficient organocatalyst for
the conjugate addition of malonates is highly desirable in the field
of modern organic chemistry.
Since Takemoto and co-workers reported that the thiourea group
functions as a superior double hydrogen-donor, organocatalysts
First, the optimum reaction conditions for the conjugate
addition of malonates to a,b-unsaturated ketones using catalyst 1
were investigated (Table 1). The reaction between (E)-4-phenyl-
but-3-en-2-one (2a) and dibenzyl malonate (3a) as test reactants
was performed in the presence of a catalytic amount of 1 in various
⇑
Corresponding author. Tel./fax: +81 42 676 4479.
E-mail address: tmiura@toyaku.ac.jp (T. Miura).
http://dx.doi.org/10.1016/j.tetlet.2014.05.100
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Hirashima et al. / Tetrahedron Letters 55 (2014) 4334–4337
4335
Table 1
Optimization of reaction conditions
NC CN
F3C
N
H
N
H
BnO2C CO2Bn
NH2
1
O
CF3
Additive
(0.1 equiv)
Solvent
BnO2C CO2Bn
+
Ph
O
4aa
3a
2a
Entry
Solvent
3a (equiv)
Additive (equiv)
Temp (°C)
Time (h)
Yielda (%)
% eeb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cyclohexane
toluene
CH2Cl2
Et2O
AcOEt
THF
1,4-Dioxane
CH3CN
MeOH
H2O
Brine
Neat
Neat
Neat
Neat
Neat
Neat
Neat
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
2
2
2
2
2
1.5
None
None
None
None
None
None
None
None
None
None
None
None
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
48
48
48
48
47
48
48
48
48
48
48
46
48
48
48
48
50
48
46
48
66
34
9
2
31
16
13
14
10
4
87
92
94
91
96
96
78
93
87
86
91
91
—
96
97
95
96
97
97
97
91
38
9
51
Trifluoroacetic acid (0.1)
4-Nitrobenzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.2)
Benzoic acid (0.05)
None
0c
29
45
58
85
88
88
87
84
50
50
50
50
50
Neat
Neat
Neat
None
a
b
c
Isolated yield.
Determined by HPLC analysis.
Starting material 2a was recovered.
solvents at room temperature. The reactions in typical organic sol-
vents and water afforded low yields; however, high enantioselec-
tivities were observed (entries 1–11). Interestingly, the yield of
adduct 4aa was slightly improved under solvent-free conditions
(entry 12). Next the effect of added protic acids, such as trifluoro-
acetic acid, 4-nitrobenzoic acid, and benzoic acid (entries 13–15),
was examined. Benzoic acid was the most suitable additive and
afforded a higher enantioselectivity (entry 15). To improve the
chemical yield, the conjugate additions were then performed at a
higher temperature (50 °C), and the desired adduct 4aa was
obtained in 85% yield with 96% ee (entry 17). Addition of 0.2 or
0.05 equiv of benzoic acid resulted in similar yields and stereose-
lectivities (entries 18 and 19). However, when no benzoic acid
was added at 50 °C, the Michael addition gave 4aa in 87% yield
with 97% ee (entry 20). Therefore, the optimized reaction condi-
tions were determined to be those used for entries 17 or 20.
With these optimal conditions in hand, the scope and limita-
hindrance. Moreover, cyclic enone cyclohex-2-en-1-one (2h) was
also a good substrate, providing the desired adduct 4ha in 72%
yield with 94% ee (entry 8). To the best of our knowledge, success-
ful organocatalytic conjugate addition of dibenzyl malonates (3a)
to 2h with high enantioselectivity (>90% ee) has been reported
only by Yoshida et al., and their method provided 92% ee.4m
Furthermore, other types of malonates such as dimethyl (3b),
diethyl (3c), and diisopropyl (3d) malonates also afforded the
corresponding products 4ab, 4ac, and 4ad, respectively, in high
yields with high to excellent enantioselectivities (entries 9–11).
The stereochemistry of the addition products 4 was determined
by comparison with the literature chiral-phase HPLC retention
times and the optical rotation data.4o Based on the stereochemistry
of the addition products 4, the Michael additions of malonates to
a,b-unsaturated ketones using DMM organocatalyst 1 is inferred
to proceed via the transition state proposed by Kwiatkowski
et al. (Fig. 1).4p The primary amino group of 1 condenses with
enone 2 to form an iminium intermediate. Next, the two acidic pro-
tons of the DMM skeleton successfully interact with the carbonyl
oxygen of malonates 3 to direct the approach of the malonate eno-
late to the iminium intermediate (attack on the Re face). This tran-
sition state ultimately affords the corresponding addition products
with high stereoselectivity.
tions of the conjugate addition of malonates 3 to a,b-unsaturated
ketones 2 were examined (Table 2).10 Substrates 2b and 2c bearing
bromo and nitro substituents as representative electron-with-
drawing groups on the benzene ring reacted with 3a in the pres-
ence of catalyst 1 to give the corresponding adducts 4ba and 4ca
(entries 2 and 3) in high yields with excellent enantioselectivities,
respectively. The reactions of enones 2d and 2e bearing methyl and
methoxy substituents as electron-donating groups with 3a also
proceeded smoothly, affording the corresponding addition
products 4da and 4ea (entries 4 and 5) with excellent stereoselec-
tivities, respectively. The conjugate additions of 3a to (E)-4-(naph-
thalen-1-yl)but-3-en-2-one (2f) and chalcone (2g) provided
adducts 4fa and 4ga (entries 6 and 7) in 84% and 31% yields with
96% ee and 85% ee, respectively. Longer reaction time was required
for the reactions of substrates 2f and 2g due to their steric
In conclusion, the DMM organocatalyst 1 efficiently catalyzes
the conjugate addition of malonates (3) to a,b-unsaturated ketones
2 at 50 °C under solvent-free conditions to afford the correspond-
ing addition products 4 in high yields with excellent enantioselec-
tivities. In particular, the addition of dibenzyl malonate (3a) to
cyclic enone 2h using catalyst 1 provided excellent stereoselectiv-
ity compared with a previously reported value.4 We are currently
investigating the application of this method to the synthesis of
bioactive compounds.

4336
S. Hirashima et al. / Tetrahedron Letters 55 (2014) 4334–4337
Table 2
Conjugate additions using organocatalyst 1
NC CN
F3C
R3O2C CO2R3
R1
N
H
N
H
NH2
O
R3O2C CO2R3
1
R2
CF3
R1
+
(0.1 equiv)
neat, 50 o
R2
Product 4
O
3
2
C
(2 equiv)
Entry
1
Enone
Malonate
Time (h)
Product
Yielda (%)
87
% eeb
97
O
BnO2C CO2Bn
BnO2C CO2Bn
3a
48
62
2a
O
4aa
O
BnO2C CO2Bn
BnO2C CO2Bn
3a
2c
3c
4
87
86
88
91
84
95
89
98
94
96
Br
2b
Br
O
4ba
O
BnO2C CO2Bn
BnO2C CO2Bn
3a
48
O2N
2c
O2N
O
4ca
BnO2C CO2Bn
O
BnO2C CO2Bn
3a
82
Me
2d
Me
O
4da
O
BnO2C CO2Bn
BnO2C CO2Bn
3a
5c
65
MeO
2e
MeO
O
4ea
BnO2C CO2Bn
BnO2C CO2Bn
O
3a
6c,d
192
2f
O
4fa
O
BnO2C CO2Bn
BnO2C CO2Bn
3a
7c
476
31
85
2g
O
4ga
O
BnO2C CO2Bn
O
3a
8c
22
94
72
85
97
85
94
97
95
98
CO2Bn
CO2Bn
2h
4ha
O
MeO2C CO2Me
MeO2C CO2Me
3b
9c
2a
2a
O
4ab
O
O
EtO2C CO2Et
EtO2C CO2Et
3c
10c
94
O
4ac
iPrO2C CO2iPr
iPrO2C CO2iPr
3d
11c
161
2a
O
4ad
a
b
c
Isolated yield.
Determined by HPLC analysis.
Benzoic acid (0.1 equiv) was added.
The reaction was carried out at rt.
d

S. Hirashima et al. / Tetrahedron Letters 55 (2014) 4334–4337
4337
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NC
CN
F3C
N
H
N
H
N
O
OR
H
H
O
CF3
Ar
RO
Re face attack
Figure 1. Plausible transition state model.
Acknowledgment
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The authors would like to thank Enago (www.enago.jp) for the
English language review.
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10. Atypical procedurefor the conjugateadditions using1 isas follows:Dibenzylmalonate
(3a, 102 lL, 0.42 mmol) was added to a mixture of organocatalyst 1 (9.0 mg,
0.021 mmol) and 2a (31 mg, 0.21 mmol) at room temperature. After stirring at
50 °C for 48 h, the reaction mixture was directly purified by flash column
chromatography on silica gel with hexane and acetone (gradually 16:1–8:1) to
afford the pure 4aa (79 mg, 87%)asawhitepowder.Enantiomeric excess of4aawas
determined by HPLC with Chiralpak AS-H column (hexane/2-propanol = 70:30),
flow rate = 0.5 mL/min; k = 254 nm; tmajor = 16.5 min, tminor = 18.6 min.