Michael addition of active methylene compounds to α, β-unsaturated carbonyl compounds under the influence of molecular sieves in dimethyl sulfoxide

Article abstract of DOI:10.1246/cl.2008.1204

The Michael addition of active methylene compounds to α, β-unsaturated carbonyl compounds in the presence of MS 4A in dimethyl sulfoxide proceeds smoothly to afford the corresponding 1,4-addition products in good to high yields. Copyright

Full text of DOI:10.1246/cl.2008.1204

1204
Chemistry Letters Vol.37, No.12 (2008)
Michael Addition of Active Methylene Compounds to ꢀ,ꢁ-Unsaturated Carbonyl Compounds
under the Influence of Molecular Sieves in Dimethyl Sulfoxide
Tomoko Kakinuma, Ryoichi Chiba, and Takeshi OriyamaÃ
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received September 18, 2008; CL-080894; E-mail: tor@mx.ibaraki.ac.jp)
The Michael addition of active methylene compounds to
ꢀ,ꢁ-unsaturated carbonyl compounds in the presence of MS
4A in dimethyl sulfoxide proceeds smoothly to afford the corre-
sponding 1,4-addition products in good to high yields.
acetonitrile were found to be ineffective for this reaction. The
desired reaction proceeded moderately in DMF and chloroform,
but we discovered that DMSO was the best solvent. The corre-
sponding 1,4-addition product was obtained in a 71% isolated
yield (Entry 7).
Next, we attempted Michael additions in the presence of
various dehydrating agents as additives in DMSO (Table 2).
When the reaction was carried out without an additive, we ob-
tained the desired compound in only 6% yield. On the other
hand, the additions of MS led to dramatic increases in the yield.
In particular, we found MS 4A, MS 13X, and Drierite (CaSO4)
to be extremely effective.9 A longer reaction time (12 h) im-
proved yields of the product as described in Entry 9.
Overall, we detemined the optimal conditions as follows:
the reaction of enones (0.3 mmol) with malononitrile
(0.36 mmol) in the presence of MS 4A (100 mg) in DMSO at
room temperature.10
We examined Michael additions of malononitrile to various
ꢀ,ꢁ-unsaturated carbonyl compounds, as listed in Table 3. The
reactions were uniformly successful for chalcone derivatives
(Entries 1–8). In the case of sterically bulky enone, the desired
compound was obtained in 52% yield (Entry 6). It was found
that ethyl crotonate is also a good Michael acceptor (Entry 10).
When the 1,4-addition to cyclic enone was performed under sim-
ilar reaction conditions, the corresponding product was given in
only 36% yield (Entry 11). In addition, when ꢁ-nitrostyrene was
used as a Michael acceptor, we obtained the desired product in
65% yield (Entry 12).
The Michael addition is an important and useful class of
reactions in organic synthesis, and generally requires a catalyst
such as K2CO3, piperidine or LiI.1,2 On the other hand,
Shirakawa and Shimizu very recently reported that the catalyst-
free Michael addition was efficiently promoted in ethanol by
hydrogen-bonding activation.3 Much attention has been focused
on catalyst-free reactions, because reducing the use of catalyst is
environmentally friendly.
In recent years, dimethyl sulfoxide (DMSO) has received re-
newed attention as a polar solvent and a promoter of efficient or-
ganic reactions.4 We also developed several effective reactions
in DMSO. For example, cyanocarbonation of aldehydes5 and tri-
fluoromethylation of carbonyl compounds6 were documented.
During the course of our research to promote fundamental car-
bon–carbon bond-forming reactions without catalysts in
DMSO,7 a novel Henry reaction was developed successfully in
2007.8 The Henry reaction of various carbonyl compounds with
nitroalkanes proceeded very smoothly to afford the correspond-
ing ꢁ-nitroalcohol without a base catalyst. Furthermore, the 1,4-
addition of nitroalkane to ꢀ,ꢁ-unsaturated ketones was also per-
formed in DMSO. These results suggested that a similar Michael
addition of other active methylene compounds, such as malono-
nitrile and malonate, having larger pKa values than those of
nitroalkanes, could be performed in DMSO.
We also tested various other active methylene compounds
(Table 4). Various malonates yielded successful results (Entries
1–3). Acetylacetone was found to be a good Michael donor, as
First, we chose the reaction of chalcone (0.3 mmol) with ma-
lononitrile (0.36 mmol) in the presence of molecular sieves (MS)
4A (50 mg) as a model case for the optimization of the solvent.
As can be seen in Table 1, toluene, dichloromethane, THF, and
Table 2. Effect of dehydrating agents
Ph
CN
O
Dehydrating agent
DMSO / r t / 2 h
O
CN
CN
NC
+
Ph
Table 1. Effect of solvents
Ph
Ph
Ph O
0.3 mmol
0.36 mmol
MS 4A (50 mg)
O
CN
CN
NC
+
Yield/%a
Ph
Entry
Dehydrating agent
None
Solvent (2 mL)
r t / 2 h
Ph
Ph
CN
1
2
3
4
5
6
7
8
9
6
60
71
30
70
72
34
73
92b
0.3 mmol
0.36 mmol
MS 3A (50 mg)
MS 4A (50 mg)
MS 5A (50 mg)
MS 13X (50 mg)
Drierite (50 mg)
MgSO4 (50 mg)
MS 4A (100 mg)
MS 4A (100 mg)
Entry
Solvent
Yield/%a
1
2
3
4
5
6
7
Toluene
CH2Cl2
THF
CH3CN
DMF
0
1
1
0
46
59
71
CHCl3
DMSO
aIsolated yield of purified product. bThe reaction was
carried out for 12 h.
aIsolated yield of purified product.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
1205
Table 3. Michael addition to various ꢀ,ꢁ-unsaturated carbonyl
compounds
atom economy is extremely high, consuming almost all reagents
under very mild reaction conditions. Further studies on the de-
velopment of DMSO-promoted benign reactions are currently
in progress in our laboratory.
R
O
MS 4A (100 mg)
DMSO (1 mL) / r t
O
CN
CN
NC
NC
+
X
R
X
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘‘Advanced Molecular Transforma-
tions of Carbon Resources’’ from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
0.3 mmol
0.36 mmol
Time
/h
Yield
/%a
Entry
R
X
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
12
12
4
12
12
12
2
12
10
24
12
8
93
91
91
98
89
52
92
96
48
65
36
65b
References and Notes
1
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2,4,6-Me3C6H2
For reviews, see: E. D. Bergman, D. Ginsberg, R. Rappo, Org.
React. 1959, 10, 179.
2
a) H. O. House, W. L. Roelofs, B. M. Trost, J. Org. Chem. 1966,
31, 646. b) R. Antonioletti, F. Bonadies, E. S. Monteagudo, A.
Screttri, Tetrahedron Lett. 1991, 32, 5373. c) P. Victory, J. I.
Borrell, A. Vidal-Ferran, Tetrahedron Lett. 1991, 32, 5375. d)
B. C. Ranu, S. Bhar, Tetrahedron 1992, 48, 1327. e) H. Kotsuki,
K. Arimura, T. Ohisi, R. Maruzawa, J. Org. Chem. 1999, 64,
3770. f) Y. Mori, K. Kakumoto, K. Manabe, S. Kobayashi, Tet-
rahedron Lett. 2000, 41, 3107. g) K. Shibatomi, T. Nakahashi,
Y. Uozumi, Synlett 2000, 1643. h) D. Bensa, J.-M. Brunel, G.
Buono, J. Rodriguez, Synlett 2001, 715. i) Z. Zhang, Y.-W.
Dang, G.-W. Wang, K. Komatsu, Synlett 2004, 61. j) B. C.
Ranu, S. Banerjee, R. Jana, Tetrahedron 2007, 63, 776.
S. Shirakawa, S. Shimizu, Synlett 2007, 3160.
Ph
Ph
Me
Me
4-ClC6H4
4-MeOC6H4
4-MeC6H4O
OEt
10
11
12
2-Cyclohexenone
ꢁ-Nitrostyrene
aIsolated yield of purified product. bThe reaction was carried
out with DMSO (0.3 equiv) in hexane (2 mL).
3
4
´
a) Y. Genisson, L. Gorrichon, Tetrahedron Lett. 2000, 41, 4881.
Table 4. Michael addition of various active methylene com-
pounds
b) W. Li, J. Li, M. Lin, S. Wacharasindhu, K. Tabei, T. S.
Mansour, J. Org. Chem. 2007, 72, 6016. c) W. Li, J. Li, Z.-K.
Wan, J. Wu, W. Massefski, Org. Lett. 2007, 9, 4607.
K. Iwanami, Y. Hinakubo, T. Oriyama, Tetrahedron Lett. 2005,
46, 5881.
R
O
Ph
O
O
MS 4A (100 mg)
DMSO (1 mL) / r t
+
CH2(COR)2
O
Ph
5
Cl
Cl
R
0.3 mmol
0.36 mmol
6
7
K. Iwanami, T. Oriyama, Synlett 2006, 112.
Yield/%a
For other catalyst-free reactions in DMSO developed by our
group, see: a) T. Watahiki, M. Matsuzaki, T. Oriyama, Green
Chem. 2003, 5, 82. b) T. Watahiki, S. Ohba, T. Oriyama, Org.
Lett. 2003, 5, 2679.
Entry
R
Time/h
1
2
3
4
OMe
OEt
OBn
Me
12
24
36
24
92
88
73
65
8
9
T. Oriyama, M. Aoyagi, K. Iwanami, Chem. Lett. 2007, 36, 612.
For MS-promoted reactions see: a) S. E. Sen, S. M. Smith, K. A.
Sullivan, Tetrahedron 1999, 55, 12657. b) T. Matsuura, J. W.
Bode, Y. Hachisu, K. Suzuki, Synlett 2003, 1746. c) M. M.
aIsolated yield of purified product.
´
Sa, L. Meier, Synlett 2006, 3474.
evident from Entry 4. Although the detailed reaction mechanism
has not been clarified yet, MS 4A played a very important role in
promoting the Michael addition.
In conclusion, we have developed a convenient Michael ad-
dition of various active methylene compounds to various enones
in DMSO under the influence of MS 4A. It should be noted that
this very efficient reaction is simpler, cheaper, and more environ-
ment-friendly than other available methods. This reaction is very
attractive from the standpoint of green chemistry, because the
10 Typical experimental procedure is as follows: A mixture of
chalcone (62.5 mg, 0.3 mmol) and malononitrile (23.8 mg,
0.36 mmol) in DMSO (1 mL) in the presence of MS 4A
(100 mg) was stirred at room temperature under an argon atmo-
sphere. After 12 h, the reaction mixture was quenched with a
phosphate buffer (pH 7, 20 mL). The organic materials were ex-
tracted with AcOEt and dried over anhydrous MgSO4. 4-Oxo-
2,4-diphenylbutane-1,1-dicarbonitrile (76.8 mg, 92%) was iso-
lated by TLC on silica gel.
Published on the web (Advance View) November 1, 2008; doi:10.1246/cl.2008.1204