Aqueous-mediated michael addition of active methylene compounds with nitroalkenes

Article abstract of DOI:10.1002/cjoc.201200228

A simple, atom economical and highly efficient green protocol has been developed for the synthesis of Michael adducts of nitroalkenes and 2-amino-2-chromene derivatives by Michael addition of active methylene compounds (such as malononitrile and ethyl cyanoacetate) to nitroalkenes under aqueous-mediated conditions. This green approach provided the desired products in high yields and the reaction scope proved to be quite broad.

Full text of DOI:10.1002/cjoc.201200228

FULL PAPER
DOI: 10.1002/cjoc.201200228
Aqueous-mediated Michael Addition of Active Methylene
Compounds with Nitroalkenes
Dong, Wenkai(董文凯)
Xu, Dongcheng*(徐东成)
Xie, Jianwu*(谢建武)
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life
Science, Zhejiang Normal University, Jinhua, Zhejiang 321004, China
A simple, atom economical and highly efficient green protocol has been developed for the synthesis of Michael
adducts of nitroalkenes and 2-amino-2-chromene derivatives by Michael addition of active methylene compounds
(such as malononitrile and ethyl cyanoacetate) to nitroalkenes under aqueous-mediated conditions. This green ap-
proach provided the desired products in high yields and the reaction scope proved to be quite broad.
Keywords Michael addition, green chemistry, chromenes, nitroalkenes, domino reaction
Introduction
through hydrogen bonding,[10] we envisage that the nitro
group would also be activated with water through hy-
drogen bonding without any catalyst. Moreover, there
are few reports on conjugate addition of active methy-
lene compounds to nitroalkenes in water without any
catalyst.
As part of our ongoing research work on the devel-
opment of green approaches in organic synthesis,[11]
herein we report an efficient, green route to access Mi-
chael adducts of nitroalkenes and 2-amino-2-chromene
derivatives by aqueous-mediated Michael addition of
active methylene compounds to nitroalkenes.
Environmentally benign reactions have become the
targets of synthetic organic chemists today. In many
synthetic organic processes, organic solvents can cause
significant air pollution, land contamination and water
pollution. Therefore, the development of efficient syn-
thetic methodologies for organic reactions, in the ab-
sence of organic solvents, is an important challenge to-
ward reducing the amount of waste.[1,2] To reduce the
use of ecologically hazardous chemicals, it is advanta-
geous to carry out organic reactions in aqueous media
because water is an environmentally friendly solvent
and exhibits unique reactivity and selectivity, different
from those in conventional organic solvents.[3-6] More-
over, the development of efficient transformations in
water without any catalyst is highly appreciated. Indeed,
great efforts have been implemented in the development
of catalyst-free processes to accomplish greener and
cleaner syntheses, such as ring opening of epoxides by
amines,[7a] Michael addition of thiols or amines to un-
saturated compounds,[7b-7e] N-tert-butyloxy-carbonyla-
tion of amines,[7f] Friedel-Crafts alkylation of naphthols
or indoles with nitroalkenes[7g,7h] and C-alkylation of
2-hydroxy-1,4-naphthoquinone to nitroalkenes.[7i]
Results and Discussion
We started our original studies by screening a range
of solvents for the Michael reaction of malononitrile and
nitroalkenes. As shown in Table 1, when toluene, THF,
and CH2Cl2 were used as solvents, no product was ob-
tained after 12 h at room temperature (Table 1, Entries
1—3). To our delight, Michael addition proceeded in
water without any catalyst or additive, giving the de-
sired product in 9% isolated yield after 12 h (Table 1,
Entry 6). Then different temperatures were screened and
the best yield was obtained when the reaction was car-
ried out at 80 ℃ for 3 h (Table 1, Entry 6). Michael
addition also proceeded smoothly in deionized water
and similar results were obtained. When the reaction
time was extended, the reaction became a little compli-
cated; somewhat low yield was isolated (Table 1, Entry
7). It is worthy of note that catalytic amount of water
could promote the reaction and good yield was obtained.
On the contrary, low yield was obtained when no water
was added (Table 1, Entries 8, 9).
The Michael addition reaction is widely recognized
as one of the most versatile C—C bond forming reac-
tions to construct highly functionalized building blocks
for the total synthesis of natural and biologically active
compounds.[8] Nitroalkenes is a very good Michael ac-
ceptors, and Michael adducts of nitroalkene can be read-
ily transformed into different functionalities.[9] The
electrophilic property of nitroalkene could be increased
when the nitro group is interacted with urea and thiourea
*
E-mail: xjw@zjnu.cn; Tel./Fax: 0086-0579-82282610
Received March 8, 2012; accepted April 5, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200228 or from the author.
Chin. J. Chem. 2012, XX, 1—4
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Dong, Xu & Xie
FULL PAPER
Table 1 Reaction of nitroalkene 1a and malononitrile under
different conditionsa
Table 2 Reaction of different nitroalkenes 1a—1m and malono-
nitrilea
NC
Ar
CN
NO2
NC
CN
NO2
H2O
80 oC, 3 h
NO2
+
NC
CN
NO2
Ar
Solvent
12 h
1
2a
NC
CN
+
3
1a
2a
3aa
Entry
1
Ar
Ph (1a)
3
Yieldb/%
81
Yieldb/%
Trace
Trace
Trace
9
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
Entry
Solvent
Temp./℃
2
p-CH3OC6H4 (1b)
p-CH3C6H4 (1c)
p-FC6H4 (1d)
p-ClC6H4 (1e)
o-ClC6H4 (1f)
m-ClC6H4 (1g)
p-BrC6H4 (1h)
o-BrC6H4 (1i)
p-NO2C6H4 (1j)
o-NO2C6H4 (1k)
Furyl (1l)
88
1
Toluene
THF
CH2Cl2
H2Oc
H2Oc
H2Oc
H2Oc
—
25
25
25
25
60
80
80
80
80
3
89
2
4
91
3
5
87
4
6
86
5
31
6d
7e
8
81
7
90
8
89
70
9
88
11
9f
—
73
10
11
12
13
92
a Unless noted otherwise, reactions performed with 0.50 mmol of
1a, 0.60 mmol of malononitrile in 2 mL solvent. Isolated yield.
c Tap water. 3 h. e 4 h. Catalytic amount of water (0.1 mmol)
94
b
70
d
f
Thienyl (1m)
85
was added.
a Unless noted otherwise, reactions performed with 0.50 mmol of
1, 0.60 mmol of malononitrile in 2 mL water at 80 ℃. b Isolated
yield.
Consequently, an array of various substituted nitro-
alkenes 1 was explored in the reactions with malononi-
trile to establish the general utility of this new method-
ology (Table 2). Several points are noteworthy: (1) In
general, the desired product can be prepared in good to
excellent yields under standard conditions from the cor-
responding nitroalkenes and malononitrile. Nitroalkenes
with electron withdrawing substituents on the ortho,
meta or para positions have a little effect on the yields
(Table 2, Entries 5—7). (2) It turned out that the sub-
stituents on the phenyl group of nitroalkenes had a little
influence on the yields under the optimized conditions
(Table 2, Entries 2—11). Excellent yields were obtained
when there were strong electron-withdrawing groups on
the phenyl group of nitroalkenes (Table 2, Entries 10,
11). (3) For the reactions of malononitrile, good yields
were achieved with nitroalkenes bearing various het-
eroaryl substitutions (Table 2, Entries 12, 13). Unfortu-
nately, no product was observed when other Michael
acceptors (such as α,β-unsaturated ketones, esters and
cinnamonitrile) were used, as well as other Michael do-
nors (such as ethyl cyanoacetate 2b, acetylacetone and
malonates) were used.
Chromene derivatives are an important class of het-
erocycles, widely present in plants, including edible
vegetables and fruits.[12] And they are of considerable
interest as they possess a wide range of biological prop-
erties.[13] Different approaches towards the synthesis of
2-amino-2-chromene derivatives have been reported.[14]
Having succeeded in synthesizing Michael adducts, we
turned our attention to the possible synthesis of
Chromenes. Gratifyingly, the domino Michael addi-
tion/intramolecular cyclization reaction of functional-
ized nitroalkenes with malononitrile proceeded smooth-
ly in water without any catalyst or additive at 40 ℃ for
12 h, and 2-amino-2-chromene derivatives were ob-
tained with good to excellent yields. As summarized in
Table 3, high yields were obtained in the domino reac-
tions of 2a and electron-withdrawing substituent on aryl
ring of functionalized nitroalkenes 1q—1s (Table 3,
Entries 4—6). On the contrary, an electron-donating
substituent on aryl ring of functionalized nitroalkenes
1o—1p tended to decrease the reactivity (Table 3, En-
tries 2, 3). The reactions of ethyl cyanoacetate 2b with
functionalized nitroalkenes also found to be successful
while the reaction temperature should be increased, and
2-amino-2-chromene derivatives were obtained with
moderate to good yields (Table 3, Entries 7—9). No
product was observed when other Michael donors (such
as acetylacetone and malonates) were used in this reac-
tion.
A plausible mechanistic proposal considering all data
obtained is shown in Scheme 1. The reaction proceeds
faster in water than that in organic solvents without
catalyst (Table 1, Entries 1—10), since hydrogen atom
of water could activate nitroalkenes by the hydrogen-
bond between water and oxygen atom of the nitroolefin,
increasing electrophilic property of the β-carbon,
whereas the hydrogen bond between water and hydro-
gen atom of the active methylene compounds increases
the nucleophilic property of active methylene com-
pounds.[15] Thus, water could activate both donors and
acceptors to increase reactivity simultaneously through
hydrogen bond formation.
2
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Chin. J. Chem. 2012, XX, 1—4

Aqueous-mediated Michael Addition of Active Methylene Compounds with Nitroalkenes
Table 3 Reaction of functionalized nitroalkenes 1n—1r and
column chromatography using Qingdao silica gel
active methylene compoundsa
(200—300 mesh). Analytical thin-layer chromatography
(TLC) was performed on silica gel GF254 (Qingdao,
China) with ethyl acetate and petroleum ether (60—90
℃) and detected by UV light or iodine vapor. Melting
points were recorded on an Elemental digital melting
O2N
6
1
NO2
5
H2O
EWG
NH2
2
OH
+
4
NC
EWG
40 oC, 12 h
R
3
O
R
2a: EWG = CN
2b: EWG = COOEt
1
1
points apparatus and were uncorrected. The H NMR
3
and 13C NMR spectra were recorded on Bruker DRX
400 spectrometer, using CDCl3 or DMSO as solvent and
TMS as internal reference, IR spectra were recorded
using a Perkin-Elmer 1600 Series FTIR. ESI-HRMS
spectrometer was measured with a Finnigan LCQDECA
ion trap mass spectrometer.
Entry
1
R
2
3
Yieldb/%
81
H (1n)
5-Me (1o)
2a
2a
3na
3oa
3pa
3qa
3ra
3sa
3nb
3ob
3sb
2
79
3
4-MeO (1p)
5-F (1q)
5-Cl (1r)
5-Br (1s)
H (1n)
2a
2a
2a
2a
2b
2b
2b
72
4
89
5
87
General procedure for Michael addition of malono-
nitrile to nitroalkenes
6
85
7 c
8 c, d
9 c
84
A mixture of malononitrile (0.6 mmol) and
β-nitroalkene (0.5 mmol) was suspended in 2 mL of
water, and the reaction mixture was heated at 80 ℃ for
3 h. The reaction mixture was extracted with ethyl ace-
tate (5 mL×3). The organic layer was separated, dried
over anhydrous sodium sulfate, and concentrated to ob-
tain crude product. Further purification was achieved by
column chromatography using ethyl acetate/petroleum
ether as eluent to furnish the products 3aa—3ma.
5-Me (1o)
54
5-Br (1s)
85
a Unless noted otherwise, reactions performed with 0.50 mmol of
b
1, 0.60 mmol of 2 in 2 mL water at 40 ℃. Isolated yield. c 80
℃, 3h. d 24 h.
Conclusions
In summary, we have developed a facile and effi-
cient synthesis of Michael adducts of nitroalkenes by
Michael addition of malononitrile with nitroalkenes.
The reaction scope proved to be quite broad. Notably,
this methodology aslo provides facile access to various
multifunctional 2-amino-2-chromene derivatives which
may serve as a platform for further manipulation leading
to structurally unique chromenes and other pharmaceu-
tically intriguing compounds. Additionally, the reaction
can be carried out in water as a cheap and environmen-
tally benign solvent and can be conducted on a larger
scale at low cost making it an ideal alternative to exist-
ing methods.
General procedure for synthesis of 2-amino-2-
chromene derivatives
A mixture of active methylene compounds (0.6
mmol) and (E)-2-(2-nitrovinyl)phenol (0.5 mmol) was
suspended in 2 mL of water, and the reaction mixture
was heated. The progress of the reaction was monitored
by TLC. After completion of the reaction, the reaction
mixture was cooled, diluted with water (10 mL) and
filtered. Further purification was achieved by column
chromatography using ethyl acetate/petroleum ether as
eluent to furnish the products 3na—3sb.
Acknowledgement
Experimental
We are grateful for the financial support from the
National Natural Science Foundation of China (No.
20902083) and the Program for Changjiang Scholars
and Innovative Research Team in Chinese Universities
(No. IRT0980).
All commercial reagents were used as received
unless otherwise mentioned. Various substituted nitro-
alkenes were synthesized by aldehyde and CH3NO2.
Purification of reaction products was carried out by
Scheme 1 Proposed mechanism of Michael addition of active methylene compounds with nitroalkenes
H
H
O
O
O
O
O
O
O
H
H
N
N
O
H
O
R
O
H2O
H
H
H
N
H
H
GWE
EWG
GWE
EWG
R
R
H
O
O
O
OH
H
O
O
O
O
N
N
H
EWG
N
EWG
H
EWG
EWG
EWG
R
R
GWE
R
Chin. J. Chem. 2012, XX, 1—4
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3

Dong, Xu & Xie
FULL PAPER
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