Indium-mediated Michael addition of methyl (Z)-2-(Bromomethyl)-3- phenylacrylate to arylidenemalononitriles in aqueous medium

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Indium-mediated Michael
Addition of Methyl (Z)-2-
(Bromomethyl)-3-phenylacrylate to
Arylidenemalononitriles in Aqueous
Medium
Warjeet S. Laitonjam a , Bhavna Thingom a & Soniya D. Moirangthem
a
a Department of Chemistry , Manipur University , Canchipur , 795
003 , Manipur , India
To cite this article: Warjeet S. Laitonjam , Bhavna Thingom & Soniya D. Moirangthem (2013)
Indium-mediated Michael Addition of Methyl (Z)-2-(Bromomethyl)-3-phenylacrylate to
Arylidenemalononitriles in Aqueous Medium, Organic Preparations and Procedures International: The
New Journal for Organic Synthesis, 45:3, 246-251, DOI: 10.1080/00304948.2013.786587
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Organic Preparations and Procedures International, 45:246–251, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.786587
OPPI BRIEF
Indium-mediated Michael Addition of Methyl
(Z)-2-(Bromomethyl)-3-phenylacrylate to
Arylidenemalononitriles in Aqueous Medium
Warjeet S. Laitonjam, Bhavna Thingom,
and Soniya D. Moirangthem
Department of Chemistry, Manipur University Canchipur–795 003,
Manipur, India
The Michael addition reaction is one of the most general and versatile methods for forma-
tion of C–C bonds.1 The development of metal-catalysis reactions based on green chemistry
protocols has received much attention. The allylation reaction of carbonyl compounds with
allyl halides to afford the homoallylic alcohols is probably the most widely used of the many
indium-mediated reactions in synthesis.2 Recently, organic reactions that can be carried out
in aqueous media have become one of the most challenging areas due to environmentally
favorable effects of water on organic transformations.3 The use of indium in aqueous media
has been of current interest because of its exceptional stability to air and water as compared
to other metals.4,5 A large proportion of this work has focussed on the use of stoichiometric
organoindium reagents to promote organic reactions in aqueous media. It is known that
organoindium compounds are less reactive than alkyllithiums and Grignard reagents. How-
ever, indium metal can react with organic substrates to generate an organoindium species in
situ, thus avoiding the use of sensitive, toxic or expensive other organometallics. Therefore,
allylation, cyclopropanation and Reformatsky reactions can be effected using indium metal
and corresponding allyl halides, methylene dibromides and α-haloesters.6–9 The recent
emergence of indium(III) complexes as efficient Lewis acid catalysis presents new and
exciting opportunities for organoindium chemistry.10 Although comparatively weak Lewis
acid compared to their aluminium and boron counterparts, indium(III) salts are stable to
water. It has been reported a catalytic amount of indium(III) chloride can effectively pro-
mote the Michael reaction between amines and α, β-ethylenic compounds in water and
under mild conditions.11 Examples on the indium-mediated Michael addition of allyl bro-
mide to 1,1-dicyano-2-arylethenes in aqueous media have also been reported.12 Recently,
Submitted by April 20, 2012.
Address correspondence to Warjeet S. Laitonjam, Department of Chemistry, Manipur University
Canchipur–795 003, Manipur, India. E-mail: warjeet@yahoo.com
246

Indium-Mediated Michael Addition
247
Ar1
CN
O
CN
CN
Ar1
H
H
In
Ar
OMe
CN
+
THF-H2O
Ar
CO2CH3
Br
1
2
3
a) Ar = Ar 1 = C6H5; b) Ar = C 6H5; Ar 1 = p-ClC6H4; c) Ar = C 6H5; Ar 1 = p-CH3OC6H4;
d) Ar = C 6H5; Ar 1 = p-CH3C6H4; e) Ar = C 6H5; Ar 1 = p-HOC6H4
Scheme 1
indium-mediated Barbier type reaction of Morita-Baylis-Hillman bromide with aldehydes
for the synthesis of γ -alkylidenebutenolides was developed.13 The indium-mediated alky-
lation reactions of imine derivatives based on the alkyl radical addition to carbon-nitrogen
double bond were also reported.14 The reactions of allyl and benzyl bromides with α,
β-unsaturated nitriles in the presence of indium(I) iodide under sonication to produce the
corresponding allylated and conjugated imines were reported.15
When α,β-unsaturated carbonyl compounds react with Grignard reagents or
Reformatsky reagents under anhydrous conditions, generally 1,2-addition products
predominate.16 However, for α,β-unsaturated dinitriles, the carbon–nitrogen triple bonds
are not as reactive as carbonyl group towards nucleophilic attack, so that only Michael
1,4-addition products are formed. In most of the indium-mediated organic synthesis, it
was found that the cyano groups in the substrate 2 remain unchanged.17,18 We report
herein the indium-mediated Michael addition reaction of methyl (Z)-2-(bromomethyl)-
3-phenylacrylate (1)19–22 to various substituted arylidenemalononitriles (2)23 in aqueous
media (Scheme 1).
Methyl (Z)-2-(bromomethyl)-3-phenylacrylate was prepared by bromination (NBS) of
methyl 3-hydroxy-2-methylene-3-phenylbutanoate which was obtained by condensation of
benzaldehyde with methyl acrylate in presence of DABCO at 0◦C.19–22
Treatment of benzylidenemalononitrile (1 equiv.) (2) with methyl (Z)-2-
(bromomethyl)-3-phenylacrylate (2 equiv.) (1) in presence of indium powder (1.2 equiv.)
in various solvents at room temperature was first investigated. The yields of the Michael
addition products differed significantly in various solvents. Very little reaction occurred
after 24 h of stirring at RT (25◦C) in aprotic solvents such as dichloromethane (DCM) and
tetrahydrofuran (THF). When more polar aprotic solvents such as MeCN and DMF were
used, the reaction was very slow. Even in protic solvents such as DMSO and water, the
product (3) was formed in only low yields. When organic solvents such as DMSO, MeCN,
DMF, and THF were combined with water, the yield of the Michael adducts increased, but
in general, the reaction proceeded more rapidly in THF-H2O mixture. To our gratification,
the yield was significantly improved by about 85% when a 4:1THF:H2O mixtures were
employed.

248
Laitonjam et al.
Table 1
Yields, Time and Combustions Analyses of Compounds 3 and 5
Entry
1
Product
Yield (%)
85
Time (h)
4.0
Anal. Calcd. Value
Found
3a
C, 76.34; H, 5.49;
N, 8.48
C, 76.29; H, 5.38;
N, 8.36
2
3
4
5
6
7
8
3b
3c
3d
3e
5a
5b
5c
85
82
76
78
75
80
88
5.0
5.0
4.0
4.5
4.0
4.5
5.0
C, 69.14; H, 4.70;
N, 7.68
C, 73.32; H, 5.59;
N, 7.77
C, 76.72; H, 5.85;
N, 8.13
C, 72.82; H, 5.24;
N, 8.09
C, 76.12; H, 5.17;
N, 4.23
C, 68.95; H, 4.41;
N, 3.83
C, 76.50; H, 5.54;
N, 4.06
C, 69.03; H, 4.50;
N, 7.58
C, 73.28; H, 5.52;
N, 7.67
C, 76.67; H, 5.68,
N, 8.12
C, 72.78; H, 5.19;
N, 8.02
C, 76.07; H, 5.10;
N, 4.17
C, 68.89; H, 4.39;
N, 3.78
C, 76.45; H, 5.44;
N, 4.01
With the optimal reaction conditions determined, the Michael reaction was examined
to a variety of substituted arylidenesmalononitrile and methyl (Z)-2-(bromomethyl)-3-
phenylacrylate in presence of indium powder in THF-H2O (4:1) at room temperature.
Thus, stirring a mixture of metallic indium powder (2.2 mmols) with 1 mmol of aryliden-
emalononitriles and 2 mmols of methyl (Z)-2-(bromomethyl)-3-phenylacrylate led to the
desired products (3) with 76–85% overall yields based on arylidenemalononitriles (Table
1). α-Methylcinnamates were not detected in these reactions.
However, when ethyl benzylidenecyanoacetate (1 mmol) (4a),24 which was obtained
by condensation of benzaldehyde with ethyl cyanoacetate, was allowed to react with
methyl (Z)-2-(bromomethyl)-3-phenylacrylate (2 mmol) (1) in presence of indium powder
(1.2 mmol), under the same reaction conditions, the product obtained is (5a) (Scheme 2) in
moderate yields (75%). The results are summarized in Table 1.
CN
O
Ar1
Ar
O
CN
Ar1
In
Ar
OMe
+
THF-H2O
H
COOMe
COOEt
Br
1
4
5
a) Ar = Ar1 = C6H5; b) Ar = C6H5; Ar1 = p-ClC6H5; c) Ar = C6H5; Ar1 = p-CH3C6H5
Scheme 2

Indium-Mediated Michael Addition
249
Table 2
IR, 1H and 13C-NMR Data of Compounds 3 and 5
13C NMR (CDCl3,
Entry Product
IR (cm−1
)
1H NMR (CDCl3, 300 MHz, δ)
75 MHz, δ)
1
3a
3028,2950,
2370,1720,
1589,1200,
1026
3.85(s, 3H, OCH3), 4.47–4.50 (m,
–CH(CN)2), 7.85(m, –CH–Ph),
7.24 (m, –CH2 CH), 7.27–7.50
(m, 10H, Ph)
52.24, 57.96,
126.56,128.46–130.83,
134.48, 142.70
2
3b
3120–2950,
2355,1715,
1595,1113,
1016
3.59 (s, 3H, OCH3), 3.68–3.72 (d,
CH (CN)2), 5.57–5.84
(–CH CH2), 6.25–6.34
(–CH–Ph), 7.23–7.39 (m, (9H)
Ph)
51.92, 52.00, 73.05,
126.57–13.51,140.51,
140.79, 166.92
3
4
3c
2953, 2363,
1718,1443,
1149–1020
3.82 (s, 3H, OCH3), 4.49
(CH–(CN)2) 6.88–6.95
(-CH CH2), 7.22–7.47 (m, 9H,
Ph), 7.84 (–Ch–Ph)
2.43 (s, 3H, CH3), 3.87 (s, 3H,
OCH3), 4.50 (s, 2H, CH2),
7.26–7.52 (m, 9H, Ph), 7.84 (s,
3H, CH3), 7.98 (CH CH2),
8.00 (CH–Ph)
50.01,51.40, 55.29,
57.95,114.37, 115.13,
126.56–130.84,142.68,
168.46
21.76, 52.47,
58.08,126.24–130.81,
144.49, 134.47,168.49
3d
2920, 2300,
1720,1578,
1020–1200
5
6
7
8
3e
5a
5b
5c
3300, 2951,
2330,1717,
1493, 1109
3.87 (s, 3H, OCH3), 4.95 (–CH
(CN)2), 4.94 (s,
52.24, 57.96,
128.62,128.72,
128.62–130.83,134.48,
142.69,168.47
29.70, 51.99, 73.30,
125.84–
129.59,141.20,
141.89,166.80
51.93, 73.27, 126.57,
128.01–129.2, 141.87,
141.20, 166.79
OH),7.27(CH CH2), 7.38–7.67
(m, 9H, Ph), 7.84 (–CH–Ph)
3.73 (s, 3H, OCH3), 5.57
(–CH–CN), 5.84 (–CH C–),
6.34 (–CH–Ph), 7.29–7.39 (m,
10 H, Ar)
3.72 (s, 3H, OCH3), 5.61 (m,
–CH–CN–), 5.82 (CH C), 6.34
(m, CH–Ph), 7.03–7.64 (m, 9H,
Ar)
2951, 2361,
1710,1630,
1198–1018
3029, 2951,
2359,1722,
1628,
1149–1043
3029, 2951,
2357,1722,
1629,
1.63 (s, 3H, –CH3), 3.73 (s, 3H,
–OCH3), 5.57 (–CH–CN), 5.82
(–C CH), 6.35 (–CH–Ph),
7.19–7.39 (m, 9H, Ar)
29.70, 52.00, 73.33,
126.25–129.19,
141.86, 166.80
1196–1045
In conclusion, we have developed a convenient method for the synthesis of Michael-
type addition products in aqueous media by using indium. The reaction of arylidene-
malononitriles and methyl (Z)-2-(bromomethyl)-3-phenylacrylate in presence of indium
powder in THF-H2O (4:1) at room temperature yielded the corresponding Michael adducts.
Experimental Section
All commercially available reagents were used without further purification. Infrared (IR)
Spectra were recorded on Shimadzu FT-IR spectrophotometer in the range of 200 cm−1
to 4000 cm−1. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on

250
Laitonjam et al.
BRUKER-ACF-300 (300 MHz). Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on BRUKER-ACF-300 (75 MHz). Compounds were purified by column
chromatography using Merck silica gel 60 (0.040–0.063). All reactions were carried out in
oven-dried glassware.
Reaction of Methyl (Z)-2-(Bromomethyl)-3-phenylacrylate (1) and
Benzylidenemalononitrile (2a).Typical Procedure
Indium powder (0.138 g, 1.2 mmol), 100 mesh), benzylidenemalononitrile (2a, 0.154 g,
1 mmol), methyl (Z)-2-(bromomethyl)-3-phenylacrylate (1, 0.51 g, 2 mmol), THF (4 ml)
and water (1 ml) were placed in a reaction flask. The mixture was stirred at room temperature
for 3 h until the indium powder was nearly consumed and the solution became turbid. Then
2 ml of hydrochloric acid (0.5 N) was added to quench the reaction and the mixture was
extracted with ether (2 × 20 ml). The ethereal extracts were washed with brine, dried over
anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the crude
product, which was then purified by column chromatography on silica gel, (petroleum
ether/ethyl acetate as the eluent) to give the pure product, 3a as oil. The characteristic
data of the product were given in Table 2. The reaction using 2.04 g bromoacylate gave
essentially the same yield.
Acknowledgments
We thank the Council of Scientific and Industrial Research (CSIR), New Delhi and De-
partment of Science and Technology (DST), New Delhi for financial assistance. We also
acknowledge the Indian Institute of Technology (IIT), Guwahati and Sophisticated Analyt-
ical Instrumental Facility (SAIF), NEHU, Shillong for the spectral data.
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