Henry reaction and 1,4-addition of nitroalkanes to α,β- unsaturated carbonyl compounds under the influence of MS 4 A in DMSO

Article abstract of DOI:10.1246/cl.2007.612

In the presence of MS 4 A in DMSO (dimethyl sulfoxide), Henry reaction with various carbonyl compounds and nitroalkanes proceeded smoothly to give the corresponding β-nitroalcohol without a base catalyst. Moreover, 1,4-additon of nitroalkane to α,β-unsaturated ketones was also performed in DMSO. Copyright

Full text of DOI:10.1246/cl.2007.612

612
Chemistry Letters Vol.36, No.5 (2007)
Henry Reaction and 1,4-Addition of Nitroalkanes
to ꢀ,ꢁ-Unsaturated Carbonyl Compounds under the Influence of MS 4 A in DMSO
˚
Takeshi Oriyama,Ã Masaru Aoyagi, and Katsuyuki Iwanami
Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512
(Received February 13, 2007; CL-070170; E-mail: tor@mx.ibaraki.ac.jp)
˚
In the presence of MS 4 A in DMSO (dimethyl sulfoxide),
˚
(MS) 4 A (50 mg) proceeded very smoothly to afford the desired
product in 88% yield (Run 2). When the reaction was performed
˚
in the presence of MS 3 A and 13X, the yield was slightly
decreased (Runs 9 and 11). It was also demonstrated that DMSO
is the most suitable solvent for this transformation as shown in
Table 1. Although use of DMF as a solvent afforded the desired
product in 52% yield, MeCN, CH2Cl2, hexane, and THF were
not effective for this reaction (Runs 3–7). As a whole, we found
Henry reaction with various carbonyl compounds and nitroal-
kanes proceeded smoothly to give the corresponding ꢀ-nitroal-
cohol without a base catalyst. Moreover, 1,4-additon of nitroal-
kane to ꢁ,ꢀ-unsaturated ketones was also performed in DMSO.
Our recent investigations documented the silylation of
alcohols with trialkylsilyl chloride in DMSO–hexane without a
catalyst,1 cyanobenzoylation of aldehydes with benzoyl cyanide
in DMSO,2 and cyanocarbonylation of aldehydes with cyanofor-
mate in DMSO.3 And more recently, we have discovered a tri-
fluoromethylation of carbonyl compounds using TMSCF3 in
DMSO without a catalyst.4 On the basis of this background in
the papers, we would like to report another new DMSO-promot-
ed efficient reaction, Henry reaction of aldehydes in DMSO.
The Henry reaction is a fundamental carbon–carbon bond-
forming reaction in synthetic organic chemistry.5 The continu-
ous discovery of new and efficient Henry reactions is one of
the key steps in the development of simpler, cheaper, and more
environment-friendly synthesis of complex molecules.6 A cata-
lytic Henry reaction is especially very important, because it
leads to the benign creation of new chemical bonds.7–9
˚
that a reaction using MS 4 A in DMSO gave the product in 91%
yield.
The substrate scope of this reaction was examined and the
successful results are summarized in Table 2.10 Good to high
yield of Henry reaction products was achieved for many aromat-
ic aldehydes containing different substituents on the benzene
ring and several aliphatic aldehydes. The reaction of aliphatic
aldehydes proceeded in shorter reaction time as compared to ar-
omatic aldehydes (Runs 15 and 16). Even in the case of sterically
hindered aliphatic aldehyde, the desired product was obtained
in 61% yield (Run 17). Additionally, the reaction of ethyl
pyruvate with nitromethane was similarly performed to give
Table 2. Henry reaction with various carbonyl compoundsa
OH
O
MS 4 Å, DMSO
rt, 24 h
In the first place, we tried the reaction of benzaldehyde
(0.3 mmol) with 5 equiv. of nitromethane in DMSO. The reac-
tion mixture was stirred at room temperature for 24 h. The usual
work-up afforded the corresponding product, 1-phenyl-2-nitro-
ethanol, in 10% isolated yield (Table 1, Run 1). On the other
hand, a similar reaction in the presence of molecular sieves
R1
NO2
MeNO2
+
R1
R2
R2
Run
Substrate
PhCHO
Yield/%b
1
2
91
84
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
2,4,6-Me3C6H2CHO
4-MeOC6H4CHO
4-BrC6H4CHO
4-NCC6H4CHO
4-MeO2CC6H4CHO
4-AcC6H4CHO
1-Naphthaldehyde
2-Naphthaldehyde
PhCH2CH2CHO
PhCH2CH2CHO
PhCH2CH2CHO
cyclo-C6H11CHO
BnOCH2C(CH3)2CHO
AcCO2Et
3
4
88
83
Table 1. Optimization of the reaction conditionsa
5
6
38
67
OH
DMSO
PhCHO + MeNO2
NO2
Ph
7
8
91
82
rt, 24 h
Molecular sieves
none
Run
Solvent
Yield/%b
9
93
64
1
2
3
DMSO
DMSO
DMF
10
88
52
10
11
12
13
14
15
16
17
18
˚
4 A (50 mg)
90
89
˚
4 A (50 mg)
˚
35c
tracec,d
79e
93e
61
4
5
6
7
8
9
10
11
MeCN
CH2Cl2
Hexane
THF
DMSO
DMSO
DMSO
DMSO
4 A (50 mg)
trace
0
trace
trace
91
88
28
84
˚
4 A (50 mg)
˚
4 A (50 mg)
˚
4 A (50 mg)
˚
4 A (60 mg)
˚
3 A (60 mg)
84
˚
5 A (60 mg)
13X (60 mg)
aAll reactions were performed using benzaldehyde (0.3
mmol) and nitromethane (1.5 mmol) in DMSO (2 mL) in
aAll reactions were performed using benzaldehyde (0.3
mmol) and nitromethane (1.5 mmol) in DMSO (2 mL).
bYield of isolated product after chromatographic purification.
the presence of MS 4 A (60 mg). Yield of isolated product
b
˚
c
˚
after chromato-graphic purification. Without MS 4 A.
dH2O (100 mL) was added. eThe reaction time was 6 h.
Copyright ꢀ 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.5 (2007)
613
Table 3. Henry reaction with various nitroalkanesa
chalcone and the various substituted chalcones gave the desired
products in high yields. However, the reaction of sterically
hindered chalcone (Run 6) or p-methoxy-substituted chalcone
on the ꢀ-phenyl group (Run 7) provided poor results. In addition,
the reaction of chalcone with nitroethane also gave the corre-
sponding 1,4-adduct in moderate yield (Run 13).
While the mechanism of this new reaction is still being
investigated, we have developed an efficient and convenient
method for the Henry reaction in DMSO. This reaction has the
following synthetic advantages: (1) in contrast to the known
Henry reaction, the present reaction does not need an additional
base as an activator, (2) a broad range of carbonyl compounds
including sterically hindered aldehydes and ꢁ-keto ester can
be applied, (3) 1,4-addition of nitroalkanes to various ꢁ,ꢀ-unsat-
urated carbonyl compounds also proceeds smoothly. Further
studies for the development of DMSO-promoted benign
reactions are currently underway in our laboratory.
OH
MS 4 Å, DMSO
rt, 24 h
R''
NO2
+
RCHO
R
R' NO2
R' R''
Run
Substrate
PhCHO
PhCH2CH2CHO
PhCHO
PhCH2CH2CHO
PhCHO
PhCH2CH2CHO
Nitroalkane
Yield/%b
1
2
3
4
5
6
MeNO2
MeNO2
EtNO2
EtNO2
i-PrNO2
i-PrNO2
91
79c
84d
88c,e
2
53
aAll reactions were performed using benzaldehyde (0.3
mmol) and nitroalkane (1.5 mmol) in DMSO (2 mL) in the
b
˚
presence of MS 4 A (60 mg). Yield of isolated product after
chromatographic purification. cThe reaction time was 6 h.
dThe ratio of diastereomers was 2:3. eThe ratio of diastereom-
ers was 1:1.
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,
Culture, Sports, Science and Technology, Japan.
Table 4. 1,4-Addition of nitroalkanes to various ꢁ,ꢀ-unsaturat-
ed carbonyl compoundsa
R1
O
MS 4 Å, DMSO
O
References and Notes
1
MeNO2
+
R1
Run
R2
O2N
R2
T. Watahiki, M. Matsuzaki, T. Oriyama, Green Chem. 2003, 5,
82.
rt, 24 h
R1
R2
Yield/%b
2
3
T. Watahiki, S. Ohba, T. Oriyama, Org. Lett. 2003, 5, 2679.
K. Iwanami, Y. Hinakubo, T. Oriyama, Tetrahedron Lett.
2005, 46, 5881.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
Ph
Me
Ph
Ph
Ph
26
92
85
84
83
26
45
84
65
88
83
46
74c
6d
4
5
K. Iwanami, T. Oriyama, Synlett 2006, 112.
a) L. Henry, Bull. Soc. Chim. Fr. 1895, 13, 999. b) F. A.
Luzzio, Tetrahedron 2001, 57, 915.
2-MeC6H4
3-MeC6H4
4-MeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
6
7
a) E. J. Corey, F.-Y. Zhang, Angew. Chem., Int. Ed. 1999, 38,
1931. b) M. Shibasaki, H. Sasai, T. Arai, Angew. Chem., Int.
Ed. Engl. 1997, 36, 1236.
2,4,6-Me3C6H2
4-MeOC6H4
4-BrC6H4
1-Naphthyl
2-Naphthyl
Ph
For Henry reaction using inorganic bases, see: a) G. Rossini,
R. Ballini, P. Sorrenti, Synthesis 1983, 1014. b) R. Ballini,
G. Bosica, J. Org. Chem. 1997, 62, 425. c) I. Kudyba, J.
Raczko, J. Jurczak, Helv. Chim. Acta 2004, 87, 1724.
For Henry reaction using organic bases, see: a) D. Simoni,
R. Rondanin, M. Morini, R. Baruchello, F. P. Invidiata, Tetra-
hedron Lett. 2000, 41, 1607. b) R. Ballini, D. Fiorini, M. V.
Gil, A. Palmieri, Tetrahedron 2004, 60, 2799.
For Henry reaction using rare earth metals, see: a) H. Sasai, S.
Arai, M. Shibasaki, J. Org. Chem. 1994, 59, 2661. b) J. M.
Concellon, H. Rodriguez-Solla, C. Concellon, J. Org. Chem.
2006, 71, 7919.
4-ClC6H4
8
9
Diethyl benzylidenemalonate
Ph
Ph
Ph
Ph
aAll reactions were performed using enone (0.3 mmol) and
nitroalkane (1.5 mmol) in DMSO (2 mL) in the presence of
b
˚
MS 4 A (30 mg). Yield of isolated product after chromato-
graphic purification. cNitroethane was used. The ratio of
diastereomers was 1:1. d2-Nitropropane was used.
10 Typical experimental procedure is as follows: A solution of
benzaldehyde (30 mL, 0.30 mmol) and CH3NO2 (81 mL,
1.5 mmol) in DMSO (2 mL) in the presence of powdered MS
the corresponding 1,2-addition product of a carbonyl group (Run
˚
18). At the present time, the role of MS 4 A is supposed to be a
˚
4 A (60 mg) was stirred at room temperature under an argon
dehydrating agent, because the reaction with a small amount of
11
atmosphere. After 24 h, the reaction mixture was quenched
with a phosphate buffer (pH 7, 20 mL). The organic materials
were extracted with AcOEt, and dried over anhydrous MgSO4.
2-Nitro-1-phenylethanol (45.5 mg, 91%) was isolated by TLC
on silica gel.
˚
water in the absence of MS 4 A has scarcely occurred (Run 14).
In order to determine the scope and limitation of this reac-
tion, the Henry reaction was tested using other nitroalkanes.
The reaction of aldehydes with nitroethane gave the desired
products in good yields (Table 3, Runs 3 and 4). In contrast,
the reaction with rather sterically bulky, 2-nitropropane, afford-
ed lower yield of products (Runs 5 and 6).
The reaction also occurred with ꢁ,ꢀ-unsaturated ketones.12
1,4-Addition products were uniformly obtained in moderate to
high yields as shown in Table 4. Especially, the reaction of
11 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. Sa, L. Meier, Synlett 2006, 3474.
12 R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini,
Chem. Rev. 2005, 105, 933.
Published on the web (Advance View) March 31, 2007; doi:10.1246/cl.2007.612