Synthesis of aza-Henry products and enamines in water by Michael addition of amines or thiols to activated unsaturated compounds

Article abstract of DOI:10.1016/j.tetlet.2007.12.042

Nitroamines and nitrothiols were synthesized in high yields by the Michael addition of amines and thiols to nitroolefins without using any catalyst. Also, the reaction of amines with dimethylacetylene dicarboxylate (DMAD) in water afforded the corresponding enamines.

Full text of DOI:10.1016/j.tetlet.2007.12.042

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1244–1248
Synthesis of aza-Henry products and enamines in water
by Michael addition of amines or thiols to activated
unsaturated compounds
Azim Ziyaei-Halimehjani, Mohammad R. Saidi *
Department of Chemistry, Sharif University of Technology, PO Box 11465-9516 Tehran, Iran
Received 17 October 2007; revised 26 November 2007; accepted 6 December 2007
Available online 14 December 2007
Abstract
Nitroamines and nitrothiols were synthesized in high yields by the Michael addition of amines and thiols to nitroolefins without using
any catalyst. Also, the reaction of amines with dimethylacetylene dicarboxylate (DMAD) in water afforded the corresponding enamines.
Ó 2007 Elsevier Ltd. All rights reserved.
The use of water as a solvent for organic reactions has
attracted much attention in synthetic organic chemistry in
recent years, not only because water is an environmentally
friendly solvent, but also because it exhibits unique reacti-
vity and selectivity, different from those in conventional
organic solvents. Thus, the development of novel reactivity
and selectivity that cannot be attained in conventional
organic solvents is one of the challenging goals of aqueous
chemistry.1
There are a few reports in the literature on reactions cata-
lyzed by water without using any catalyst, such as the
Michael addition of thiols to unsaturated compounds,2 ring
opening of epoxides by amines,3 the synthesis of dithiocar-
bamate,4 and N-tert-butyloxy-carbonylation of amines.5
Recently, Ranu and Banerjee investigated the Michael addi-
tion of amines to a,b-unsaturated alkenes in water.6 They
showed that the reaction of aliphatic amines with activated
unsaturated double bonds was accelerated in water to give
high yields of products in short reaction times. They also
showed that the reaction of aromatic amines with unsatu-
rated double bonds did not give any product in water.
Herein, we report a direct method for the Michael addi-
tion of aromatic amines to nitroolefins in water without
using any catalyst. 1,2-Nitroamines are important inter-
mediates for the synthesis of many organic compounds.7
They can be transformed into 1,2-diamines8 by reduction,9
and into a-amino acids by Nef oxidation.10 1,2-Nitro-
amines are typically synthesized by aza-Henry reaction
through the addition of nitro compounds to an azomethine
function (Scheme 1, path A).
The use of nitroalkenes as Michael acceptors11 has
attracted significant interest in recent years, because of
the activating effect of the nitro group, as well as its easy
transformation to a number of functional groups. They
are also useful starting materials for the synthesis of com-
plex molecules.12 There are a few reports on the direct
addition reaction of amines to nitro-olefins in the literature
(Scheme 1, path B).13,14
Worrall reported the reaction of aniline with nitro-
olefins under solvent-free conditions,15 and showed that
R1
N
Path A
CH3NO2
R1
R
H
NH
NO2
R
Path B
NO2
R1NH2
R
*
Corresponding author. Tel.: +98 21 6600 5718; fax: +98 21 66012983.
Scheme 1. Methods for the synthesis of aza-Henry products.
E-mail address: saidi@sharif.edu (M. R. Saidi).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.042

A. Ziyaei-Halimehjani, M. R. Saidi / Tetrahedron Letters 49 (2008) 1244–1248
1245
Table 1
Michael addition of amines and thiols with nitroolefins in water without using any catalyst
Nu
H2O
NO2
Nucleophile
R
NO2
R
NO2
OMe
NO2
NO2
O2N
NO2
NO2
NO2
Cl
S
NO2
1
2
3
4
5
6
Entry
1
Nucleophile
Nitroolefin
Yielda,b (%)
Entry
Nucleophile
Nitroolefin
1
Yielda,b (%)
8213
1
8515
21
MeO
NH2
NH2
2
3
4
5
6
2
3
4
5
6
95
93
98
95
84
22
23
24
25
26
2
3
4
5
6
9513
8413
9313
9013
6513
7
1
8815 (H2O)
27
1
20
Cl
NH2
O2N
NH2
8
9
80 (THF)
74 (CH2Cl2)
80 (Hexane)
90 (Toluene)
28
29
30
1
2
3
981
SH
10
11
9717
10017
12
2
96
31
5
901
13
14
3
4
88
90
32
33
34
1
2
3
100
99
SH
15
5
92
74
16
17
6
1
70
35
36
5
1
100
100
40c
NH2
SH
NH2
18
19
1
1
45c
37
38
5
6
92
88
H
3815
N
20
23 (CH2Cl2)
a
Yields based on nitroolefin.
References are given for known compounds.
The yield of imine as reaction product.
b
c
p-chloroaniline and N-methylaniline do not react with
nitrostyrene. This method is not suitable for the prepara-
tion of 1,2-nitroamines when the amines and nitroolefins
are solids, which is a drawback of this procedure.
As part of our ongoing research devoted to the develop-
ment of green organic chemistry using water as the reaction
medium,16 we report an efficient, novel, and green proce-
dure for the Michael-type addition of aromatic amines
and thiols to activated unsaturated bonds in water without
using any catalyst at room temperature in excellent yields.
We initially examined the Michael addition of 4-chloro-
aniline to nitrostyrene in different solvents. As shown in

1246
A. Ziyaei-Halimehjani, M. R. Saidi / Tetrahedron Letters 49 (2008) 1244–1248
solvents in yields of about 80%. To the best of our knowl-
R1
R
H2O
R1SH
S
edge, there is no report on the synthesis of 1,2-nitrothiols in
water. Our study showed that the reaction of thiols with
nitroolefins in water gave excellent yields for both aromatic
and aliphatic thiols, Scheme 2.
NO2
NO2
R
Scheme 2. Addition of thiols to nitroolefins in water.
We also investigated the reaction of amines with acti-
vated unsaturated bonds in water. Various aliphatic and
aromatic amines were reacted with dimethyl acetylenedi-
carboxylate (DMAD) in water to give the corresponding
enamines. The prepared enamines are valuable synthetic
intermediates,18 which are found in a variety of biologically
active compounds such as the inhibitor U6751 found in rat
liver.19
Table 1 (entries 7–11) the yield in water was as high as that
in toluene.
We next examined the scope and limitation of this reac-
tion using various aliphatic and aromatic amines with
nitroolefins in water. We found that the reaction of aro-
matic amines with nitroolefins afforded the desired prod-
ucts in excellent yields at room temperature in aqueous
medium. Although electron-donating and electron-with-
drawing substituents on the phenyl group of nitrostyrene
did not have any effect on the yields of the reaction, the
Michael reaction of an aniline with a strong electron-with-
drawing group, such as nitro, gave a low yield of the
adduct (Table 1, entry 27).
When aliphatic amines, such as benzyl amine and sec-
butyl amine were used as nucleophiles, the imine was the
major product (ca. 40%). For secondary aliphatic amines,
such as pyrrolidine and piperidine, we did not obtain any
of the desired products. It seems that due to the high basi-
city of the primary and secondary aliphatic amines, decom-
position of the nitroolefin to an aldehyde and nitromethane
or decomposition of the products occurred. N-Methyl-
aniline showed lower reactivity than aniline toward nitro-
olefins due to steric hindrance, and the yield was 38% in
water compared to 23% in CH2Cl2.
We also attempted the synthesis of an aza-Henry prod-
uct on large scale (10 g of nitrostyrene and aniline in
100 mL of water). The reaction proceeded well without
using any organic solvents for extraction of the product,
simply decanting the water gave the crude product in high
purity. Further purification by recrystallization from etha-
nol gave an 86% isolated yield of product.
Reactions of thiols with nitroolefins were studied by
Cason and coworkers17 for the preparation of 1,2-nitro-
thiol compounds using piperidine as a catalyst in organic
Although there are only a few reports on the addition of
amines to DMAD,18 most used anhydrous methanol, dry
ether, or THF as solvent with long reaction times
(12–24 h). We found that the reaction of primary and
secondary aliphatic and aromatic amines with DMAD
was complete in less than 2 h in aqueous medium. The
products were stable in aqueous medium. For aromatic
amines with different substituents on the phenyl ring, and
also N-methyaniline, we obtained high yields of products.
As shown in Table 2, 2-thionaphthol and 2-butanethiol
reacted with DMAD to give products in quantitative
yields. In the case of secondary aliphatic amines and aniline
1
derivatives, the H NMR spectra showed only one signal
for the hydrogen attached to the double bond18d,e
(4.7 ppm for aliphatic and 5.2 ppm for aniline derivatives
1
in the H NMR; 85 ppm for aliphatic amines and 94 ppm
for aniline derivatives in 13C NMR). These data indicate
that only E isomers were formed in these cases which is
in complete agreement with the NMR data reported by
1
Dolfini.20 In the case of primary amines and thiols, H
NMR spectra showed two singlets at 5.15 and 4.7 ppm
for the hydrogen attached to the double bond, which indi-
cated that mixtures of E and Z isomers were formed (e.g.,
for benzyl amine the E/Z ratio was 2.7), Scheme 3. In the
case of thiols, the E isomer was the major product and
the E/Z ratio for thionaphthol was 0.67 compared to
2-butanethiol with an E/Z ratio of 0.1.
Table 2
Reaction of aliphatic and aromatic amines and thiols with DMAD in water
COOMe
COOMe
COOMe
H2O
Nu
Nu
Nucleophile
COOMe
COOMe
COOMe
E
Z
Entry
1
2
3
4
5
6
7
8
9
10
NH2
11
12
13
14
NHMe
NH2
CH3
NH2
NH2
NH2
SH
NH2
NH2
SH
NH
NH
NH
Nucleophile
NH
O
OH
Cl
Cl
OMe
Yielda,b (%) 8518
10018
E
10018
E
10018
E
10021
E
10019
2.7
10019
1
9921
E
9721
E
10021
E
8421
E
10022
0.1
10022
0.67
10021
3.8
E/Z
E
a
Isolated yield.
References are given for known compounds.
b

A. Ziyaei-Halimehjani, M. R. Saidi / Tetrahedron Letters 49 (2008) 1244–1248
1247
MeOOC
N
COOMe
COOMe
E 100%
COOMe
COOMe
H2O
NH
N
COOMe
Z 0%
COOMe
COOMe
COOMe
COOMe
NH2
MeOOC
NH
H2O
NH
COOMe
73%
E
Z 27%
Scheme 3. Synthesis of enamines by the addition of amines to DMAD.
5. Sunay, V.; Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006,
8, 3259–3262.
In summary, we have developed a highly efficient and
environmentally friendly Michael addition reaction of
amines and thiols with nitroolefins for the preparation of
aza-Henry products and nitrothiol compounds under aque-
ous conditions. Also, the reaction of amines with DMAD
has been investigated in water yielding the corresponding
enamines. The metal-free and nonhazardous experimental
conditions, room-temperature operation, ease of reaction,
short reaction times, and high yields are advantages of this
method.
6. Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141–143.
7. For recent reviews, see: (a) Volkmann, R. A. In Nucleophilic Addition
to Imines and Imine Derivatives in Comprehensive Organic Synthesis;
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9. See, for instance O’Brien, P. M.; Sliskovic, D. R.; Blankley, C. J.;
Roth, B. D.; Wilson, M. W.; Hamelehle, K. L.; Krause, B. R.;
Stanfield, R. L. J. Med. Chem. 1994, 37, 1810–1822.
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General procedure for the conjugate addition of amines
and thiols to nitroolefins and DMAD: In a round bottom
flask equipped with a magnetic stirrer, nucleophile (amine
or thiol) (6 mmol), nitroolefin or DMAD (5 mmol), and
water (20 mL) were charged. Then the reaction mixture
was stirred vigorously at room temperature (2 h for
DMAD and 4 h for nitroolefins). Extraction of the product
with ethyl acetate or CH2Cl2 gave the crude product after
evaporation. Further purification was achieved by crystal-
lization from ethanol or by column chromatography using
ethyl acetate/petroleum ether gradient. It is notable that on
large scale no solvent was required for extraction with
decanting being sufficient.
12. Ballini, R. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19, p 117.
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We are grateful to the Research Council of Sharif Uni-
versity of Technology for financial support.
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