Asymmetric conjugate addition of aldehydes to vinyl sulfone using a diaminomethylenemalononitrile organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2013.06.141

Diaminomethylenemalononitrile organocatalyst 5 promotes the asymmetric conjugate addition of branched aldehydes to vinyl sulfone to afford the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 91% ee.

Full text of DOI:10.1016/j.tetlet.2013.06.141

Tetrahedron Letters 54 (2013) 4896–4899
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Tetrahedron Letters
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Asymmetric conjugate addition of aldehydes to vinyl sulfone using a
diaminomethylenemalononitrile organocatalyst
Yohei Kanada a, Hiroki Yuasa a, Kosuke Nakashima a, Miho Murahashi a, Norihiro Tada a, Akichika Itoh a,
Yuji Koseki b, Tsuyoshi Miura b,
⇑
a Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
b Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Diaminomethylenemalononitrile organocatalyst 5 promotes the asymmetric conjugate addition of
branched aldehydes to vinyl sulfone to afford the corresponding adducts with all-carbon quaternary ste-
reocenters in excellent yields with up to 91% ee.
Received 17 May 2013
Revised 20 June 2013
Accepted 27 June 2013
Available online 6 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Conjugate addition
Diaminomethylenemalononitrile
Vinyl sulfone
Aldehyde
Chiral thiourea derivatives as hydrogen-bond donors play
important roles in the field of asymmetric organocatalysis. In par-
ticular, Takemoto catalyst 1 and its derivatives are versatile organ-
ocatalysts and promote various important asymmetric reactions
(Fig. 1).1 Two sets of weakly acidic hydrogens in the thiourea group
promote molecular recognition by forming hydrogen bonds with
substrates. Recently, organocatalysts with the squaramide skele-
ton, such as 2, have attracted a great deal of attention because it
can be utilized as an alternative to the thiourea group to afford
excellent catalytic activities in various asymmetric reactions.2,3
Therefore, the development of novel catalysts with a skeleton,
not previously utilized in organocatalysis, is one of the most chal-
lenging research themes in organic chemistry.
All-carbon quaternary stereocenters are ubiquitous and impor-
tant motifs in many natural products and bioactive compounds;
however, relatively harsh conditions are needed for their construc-
tion. Furthermore, possible electrophile–nucleophile combinations
are limited due to their steric hindrance.4 Therefore, stereoselec-
tive formation of carbon–carbon bonds for the construction of
all-carbon quaternary stereocenters is not generally straightfor-
ward, and the development of efficient synthetic methods for their
construction using environmentally benign oraganocatalysts is
highly desirable.5 The conjugate addition of branched aldehydes
to 1,1-bis(benzenesulfonyl)ethylene (6) is one of the most efficient
approaches for stereoselective construction of all-carbon quater-
nary centers; however, the successful conjugate addition of
branched aldehydes to vinyl sulfone 6 for the construction of such
quaternary stereocenters has been rarely reported.6,7 In addition,
high enantioselectivities are obtained only when using organocat-
alysts with the b-aminosulfonamide skeleton.7
We developed an efficient and novel organocatalyst for the con-
jugate addition of branched aldehydes to vinyl sulfone. Herein, we
reported the efficient conjugate addition of branched aldehydes 7
to 6 using a novel organocatalyst 5 having a diaminomethylene-
malononitrile skeleton.
We examined novel diaminomethylenemalononitrile organo-
catalysts 3–5, as shown in Table 1. Among them, 5 was the most
suitable for the conjugate addition to 6. Organocatalyst 5 was pre-
pared as shown in Scheme 1. The treatment of 9, which is prepared
by a reported method,8 with 3,5-bis(trifluoromethyl)benzylamine
(10) and cyclohexane diamine (11) in one pot afforded 5 with
69% yield.9
A study of the optimal solvent conditions for the enantioselec-
tive conjugate addition using 5 is shown in Table 2. The conjugate
addition reactions were conducted with 6 and 2-phenylpropanal
(7a) as test reactants in the presence of a catalytic amount of 5
and trifluoroacetic acid (TFA) at room temperature. Among the
reaction solvents examined, CH2Cl2 was the most suitable (entries
2–12). Notably, when no TFA was added, a significant reduction in
the yield was observed (entry 1). Furthermore, we examined the
effects associated with the presence of other protic acids; however,
⇑
Corresponding author. Tel./fax: +81 42 676 4479.
E-mail address: tmiura@toyaku.ac.jp (T. Miura).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.141

Y. Kanada et al. / Tetrahedron Letters 54 (2013) 4896–4899
4897
Table 2
Study of solvents
H
O
O
CF3
F3C
N
H
TFA
S
N
H
HN
(0.1 equiv)
F3C
N
N
H
CHO
Ph
7a
(2 equiv)
catalyst 5
H
SO2Ph
SO2Ph
6
NMe2
CF3
SO2Ph
SO2Ph
Ph
+
(0.1 equiv)
1
N
2
OHC
solvent, rt
8a
NC CN
NC CN
Entry
Solvent
Time (h)
Yielda (%)
% eeb
R
F3C
1c
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
Toluene
Et2O
EtOAc
THF
MeCN
EtOH
24
24
24
24
21
48
24
24
26
48
24
24
19
90
97
94
83
95
90
2
89
61
78
91
—
89
79
82
64
N
H
N
H
N
H
N
H
NH2
NH2
CF3
3: R = Ph
4: R = Bn
5
66
Figure 1. Structure of organocatalysts.
ꢀ8d
20
ꢀ30d
ꢀ37d
2
Table 1
10
11
12
Selection of organocatalysts
H2O
Neat
TFA
17
(0.1 equiv)
a
b
c
CHO
Ph
7a
(2 equiv)
Isolated yield.
Determined by HPLC analysis.
Without TFA.
catalyst
SO2Ph
SO2Ph
6
SO2Ph
SO2Ph
Ph
OHC
+
(0.1 equiv)
CH2Cl2, rt
d
Product with the opposite absolute configuration (R-isomer) was predomi-
8a
nantly obtained.
Entry
Catalyst
Time (h)
Yielda (%)
% eeb
(entry 10), whereas 5 promoted the reaction of 2-methoxy-2-phe-
nylacetaldehyde (7k) with 6 to yield the corresponding adduct 8k
with high enantioselectivity (80% ee) (entry 11). The stereochemis-
try of the addition products 8a–k obtained using 5 was determined
by comparison with reported chiral-phase HPLC retention times
and optical rotation data.7
1
2
3
3
4
5
21
48
24
93
88
88
64
78
89
a
Isolated yield.
Determined by HPLC analysis.
b
We propose that the conjugate addition of aldehydes with 6
using 5 proceeds via a plausible transition state, as shown in
Figure 2, on the basis of the stereochemistry of addition products
8a–i. In this mechanism, the primary amino group of 5 condenses
with 7a to generate the E-enamine intermediates. Then, the two
acidic protons of the diaminomethylenemalononitrile group suc-
cessfully interact with the oxygen of vinyl sulfone to direct the ap-
proach of vinyl sulfone to the Si face of the enamine intermediates.
This ultimately affords the corresponding addition products with
high stereoselectivity. We speculate that the acidity of the two
N–H groups is enhanced by the electron-withdrawing effect of
the two cyano groups enabling them to strongly coordinate to
vinyl sulfone and stabilize the rigid transition states during the
F3C
NH2
NC CN
H2N
NH2
11
F3C
CF3
N
H
N
H
NC CN
10
NH2
THF, reflux,
24 h
THF, reflux,
18 h
MeS SMe
CF3
5
69%
9
Scheme 1. Preparation of organocatalyst 5.
TFA was found to be the most suitable additive (Table 3). The addi-
tion of 0.2 or 0.05 equiv of TFA resulted in a slight reduction in the
enantioselectivity (entries 6 and 7). When the reaction was con-
ducted at 0 °C, a reduction in both yield and stereoselectivity was
observed (entry 8). Therefore, the optimal conditions were deter-
mined to be 0.1 equiv of 5 and 0.1 equiv of TFA in CH2Cl2 at room
temperature (entry 1).
With these optimal conditions, the scope and limitations of the
conjugate addition of branched aldehydes 7 to 6 were examined
(Table 4).10 We selected methyl and methoxy substituents as rep-
resentative electron-donating group and halogen substituents as
electron-withdrawing groups on the benzene ring. The reactions
of branched aldehydes 7b–g with 6 smoothly proceeded and re-
sulted in the corresponding adducts in excellent yields (84–99%)
with 82–91% ee (entries 2–7). Moreover, we examined the reac-
tions between 6 and branched aldehydes 7h and 7i possessing a
naphthalene skeleton. Although 6 smoothly reacted with 7h to af-
ford the corresponding adduct 8h in excellent yield (95%) with 87%
ee, the reaction with 7i afforded the adduct 8i only in low yield
Table 3
Optimization of reaction conditions
additive
CHO
5
catalyst
SO2Ph
SO2Ph
6
SO2Ph
SO2Ph
8a
Ph
OHC
+
Ph
7a
(2 equiv)
(0.1 equiv)
CH2Cl2, rt
Entry
Additive (equiv)
Time (h)
Yielda (%)
% eeb
1
2
3
4
5
6
7
8c
TFA (0.1)
24
48
48
48
48
24
48
46
90
91
90
47
48
98
88
57
89
52
61
50
45
83
83
67
PhCO2H (0.1)
4-NO2C6H4CO2H (0.1)
AcOH (0.1)
4-MeOC6H4CO2H (0.1)
TFA (0.2)
TFA (0.05)
TFA (0.1)
a
b
c
Isolated yield.
Determined by HPLC analysis.
The reaction was carried out at 0 °C.
(37%) (entries 8 and 9). The conjugate addition of N-Boc
ophenylacetaldehyde (7j) to 6 gave the corresponding adduct 8j
in excellent yield (97%) but with low enantioselectivity (26% ee)
a-amin-

4898
Y. Kanada et al. / Tetrahedron Letters 54 (2013) 4896–4899
NC
CN
Table 4
Conjugate additions using organocatalyst 5
F3C
TFA
(0.1 equiv)
N
H
N
H
HN
Me
CHO
5
catalyst
SO2Ph
SO2Ph
6
O
O
SO Ph
SO2Ph
R
2
Ar
OHC
+
Ar
(0.1 equiv)
CH2Cl2, rt
CF3
R
Ph
S
Ph
7
(2 equiv)
8
PhO2S
Entry
1
Product
Time (h)
Yielda (%)
% eeb
89
Figure 2. Plausuble transition state model for conjugate additions.
SO2Ph
SO2Ph
Ph
OHC
24
24
90
8a
Br
yields with high enantioselectivities. The superior performance is
probably due to the diaminomethylenemalononitrile skeleton of
5. This report is the first example applying this unit as a framework
for organocatalysts. Further application of this catalyst in the syn-
thesis of bioactive compounds is currently being investigated in
our laboratory.
SO2Ph
SO2Ph
2
3
4
99
97
96
89
83
82
OHC
F
8b
SO2Ph
SO2Ph
48
48
OHC
Me
8c
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific
Research (C) (No. 22590007) from the Japan Society for the Promo-
tion of Science.
SO2Ph
SO2Ph
OHC
8d
SO2Ph
SO2Ph
MeO
5
6
24
48
84
97
91
89
References and notes
OHC
OMe
8e
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SO2Ph
SO2Ph
OHC
Br
8f
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Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem. Eur. J. 2010,
16, 4177–4180; (h) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450–5453; (i) Yang,
W.; Du, D.-M. Adv. Synth. Catal. 2011, 353, 1241–1246; (j) Lee, H. J.; Kang, S. H.;
Kim, D. Y. Synlett 2011, 1559–1562; (k) Marcos, V.; Alemán, J.; Ruano, J. L. G.;
Marini, F.; Tiecco, M. Org. Lett. 2011, 13, 3052–3055; (l) Bae, H. Y.; Some, S.; Lee,
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2011, 9, 7983–7985; (n) Dai, L.; Yang, H.; Niu, J.; Chen, F.-E. Synlett 2012, 314–
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SO2Ph
7
24
88
85
OHC
SO2Ph
8g
SO2Ph
SO2Ph
8
9
48
48
95
37
87
82
OHC
8h
SO2Ph
SO2Ph
OHC
8i
SO Ph
Ph
2
BocHN
OHC
10
11
48
48
97
69
26
80
SO2Ph
8j
SO Ph
Ph
2
MeO
OHC
SO2Ph
8k
a
Isolated yield.
b
Determined by HPLC analysis.
4. For reviews, see: (a) Fuji, K. Chem. Rev. 1993, 93, 2037–2066; (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401; (c) Christoffers, J.;
Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–4597; (d) Christoffers, J.; Baro, A.
Angew. Chem., Int. Ed. 2003, 42, 1688–1690; (e) Douglas, C. J.; Overman, L. E.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367; (f) Christoffers, J.; Baro, A. Adv.
Synth. Catal. 2005, 347, 1473–1482; (g) Trost, B. M.; Jiang, C. Synthesis 2006,
369–396; (h) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969–5994; (i) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683–1691; (j) Riant,
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Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575–2600.
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Alexakis, A. Eur. J. Org. Chem. 2010, 927–936.
conjugate addition. However, the stereochemistry of 8j and 8k ob-
tained had the opposite absolute configuration to those of 8a–i,
and the reason is not clear.
In conclusion, the novel organocatalyst 5, which is based on the
diaminomethylenemalononitrile skeleton, can be easily prepared
from 2-[bis(methylthio)methylene]malononitrile (9) in one pot.
Organocatalyst 5, which is a relatively simple structure, efficiently
catalyzes the conjugate addition of various branched aldehydes to
6 at room temperature to afford the corresponding addition prod-
ucts featuring all-carbon quaternary stereocenters in excellent

Y. Kanada et al. / Tetrahedron Letters 54 (2013) 4896–4899
4899
7. (a) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 46, 2235–2237; (b) Moteki, S. A.; Xu, S.;
Arimitsu, S.; Maruoka, K. J. Am. Chem. Soc. 2010, 132, 17074–17076; (c) Miura,
T.; Yuasa, H.; Murahashi, M.; Ina, M.; Nakashima, K.; Tada, N.; Itoh, A. Synlett
2012, 2385–2388.
10. A typical procedure of the conjugate additions using 5 is as follows: To a
solution of (35.8 mg, 0.116 mmol) and organocatalyst (5.0 mg,
0.0116 mmol) in 1.0 mL of CH2Cl2 was added 2-phenylpropanal (7a, 31.1 L,
0.232 mmol) and trifluoroacetic acid (0.9 L, 0.0116 mmol) at room
6
5
l
l
8. Tominaga, Y.; Kohra, S.; Honkawa, H.; Hosomi, A. Heterocycles 1989, 29, 1409–
1429.
temperature. After stirring at room temperature for 24 h, the reaction
mixture was directly purified by flash column chromatography on silica gel
with a 3:1 mixture of hexane and AcOEt to afford the pure 8a7 (46.2 mg, 90%)
as a colorless powder. 1H NMR (400 MHz, CDCl3): d = 1.46 (s, 3H), 2.82 (dd,
J = 5.8, 16.4 Hz, 1H), 2.95 (dd, J = 3.4, 16.4 Hz, 1H), 4.42 (dd, J = 3.4, 5.8 Hz, 1H),
9. Organocatalyst 5: colorless powder; mp = 128 °C; ½a D24
ꢁ
+ 16.6 (c 0.99, MeOH);
1H NMR (500 MHz, CD3OD): d = 1.15–1.36 (m, 4H), 1.73 (m, 2H), 1.87 (m, 1H),
1.93–1.95 (m, 1H), 2.53–2.58 (m, 1H), 3.28 (m, 1H), 4.75 (s, 2H), 7.93 (s, 1H),
7.96 (s, 2H); 13C NMR (500 MHz, CD3OD): d = 25.8, 26.0, 33.4, 33.7, 35.3, 47.5,
7.26–7.29 (m, 2H), 7.36–7.73 (m, 11H), 7.87 (d, J = 8.2 Hz, 2H), 9.60 (s, 1H); 13
C
1
55.6, 62.3, 120.1, 122.5, 124.8 (q, JCꢀF = 272 Hz), 129.0, 133.0 (q,
NMR (125 MHz, CDCl3): d = 19.6, 30.9, 53.1, 80.2, 127.6, 128.1, 129.1, 129.3,
129.7, 129.8, 134.6, 137.3, 137.8, 138.3, 201.4.
2JCꢀF = 33.6 Hz), 142.5; Anal. Calcd for C19H19F6N5: C, 52.90; H, 4.44; N, 16.23.
Found: C, 52.83; H, 4.26; N, 16.13.