Synergistic effect of ultrasound and deep eutectic solvent choline chloride-urea as versatile catalyst for rapid synthesis of β-functionalized ketonic derivatives

Article abstract of DOI:10.1016/j.molliq.2014.02.016

A green protocol for efficient synthesis of β-functionalized ketonic derivatives is achieved with the combination of ultrasound and the deep eutectic solvent (DES) choline chloride-urea [ChCl:urea (1:2)]. Under optimized conditions, nucleophilic attack of active methylene on α,β- unsaturated ketones gives the conjugate addition product in the short span of 40-50 min an excellent yield of 89-95%. The experimental procedure is very simple, easy to set up, solvent free and completely eliminates the use of any toxic metal catalyst. The use of ChCl:urea as a biodegradable, recyclable and reusable catalyst (up to five cycles) further increases the scope of the developed methodology.

Full text of DOI:10.1016/j.molliq.2014.02.016

Journal of Molecular Liquids 195 (2014) 188–193
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Synergistic effect of ultrasound and deep eutectic solvent choline
chloride–urea as versatile catalyst for rapid synthesis of β-functionalized
ketonic derivatives
⁎
Urmiladevi Narad Yadav, Ganapati Subray Shankarling
Dyestuff Technology Department, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A green protocol for efficient synthesis of β-functionalized ketonic derivatives is achieved with the combination
of ultrasound and the deep eutectic solvent (DES) choline chloride–urea [ChCl:urea (1:2)]. Under optimized con-
ditions, nucleophilic attack of active methylene on α,β-unsaturated ketones gives the conjugate addition product
in the short span of 40–50 min an excellent yield of 89–95%. The experimental procedure is very simple, easy to
set up, solvent free and completely eliminates the use of any toxic metal catalyst. The use of ChCl:urea as a bio-
degradable, recyclable and reusable catalyst (up to five cycles) further increases the scope of the developed
methodology.
Received 16 January 2014
Received in revised form 14 February 2014
Accepted 18 February 2014
Available online 11 March 2014
Keywords:
Conjugate addition
α,β-Unsaturated ketones
Choline chloride–urea
Ultrasonication
© 2014 Elsevier B.V. All rights reserved.
Ionic liquid catalyst
1. Introduction
Suitable modifications have been brought to this field by the use of
eco-friendly catalysts [21–23] and environmentally benign reaction
Carbon–carbon bond forming reactions are considered to be of
immense importance for the synthesis of complex organic molecules
[1–3]. The addition of active methylenes such as ethyl cyanoacetate,
malononitrile and nitromethane to α,β-unsaturated ketones results
in the synthesis of ketonic nitriles and ketonic nitro derivatives
which can be transformed into functionally important hydropyridine
derivatives [4–6]. These addition reactions are usually catalyzed by
inorganic bases [7–12] and organic bases [13–15], and face the prob-
lems of side reactions arising due to auto-condensation, retro-
Michael addition and bis-addition. Remarkable efforts have been
made by researchers to obtain purer products. Various catalysts
have been developed such as transition metal catalyst [16–18],
organocatalysts [19], and phase transfer catalyst [20]. However,
these reactions are complicated by drawbacks related to the use of
expensive catalysts and their efficiency after reuse, high reaction
temperature, tedious multi-step synthesis of a catalyst, stability
and storage of a catalyst, and use of organic solvents. In order to cir-
cumvent this problem, the use of a green approach for conjugate ad-
dition has become a challenging area for the organic chemist.
media [24,25]. Clean and green techniques like microwave [26], ul-
trasound [27], and solvent free conditions [28] are used but there
still remains room for further improvement.
Deep eutectics composed of choline chloride and hydrogen bond
donors like urea, malonic acid and oxalic acid form eutectics which
are liquid at room temperature and are commonly called ‘deep
eutectic solvents’ or ‘deep eutectic mixtures’ [29,30]. They are
completely biodegradable, cheap, and superior to ionic liquids as
they are synthesized from readily available raw materials. Thus, in
continuation of our work on utilization of choline based deep eutec-
tics for organic synthesis [31–34], we wish to report the conjugate
addition of active methylenes to α,β-unsaturated ketones using the
environmentally benign catalyst ChCl:urea (1:2) along with use of
ultrasound energy. Use of ultrasound for accelerating chemical reac-
tions in ionic liquid is a well documented fact and is well-known to
facilitate the reaction by forcing the less volatile substrate to under-
go cavitation resulting in a low reaction time [35]. During cavitation,
tiny vapor bubbles undergo sequence-formation, growth and col-
lapse. Implosive collapse of bubbles generates short-lived regions
with temperatures of roughly 5000 °C, pressures of about 1000 atm
as well as heating and cooling rates above 10 billion degrees Celsius
per second [36]. The whole process can be considered as a microreactor
wherein sound energy is transformed into a useful form of chemical en-
ergy, which is to sufficient to activate reactant molecules entering into it
and thereby converting them into reactive intermediates [37]. In this
⁎
Corresponding author at: Department of Dyestuff Technology, Institute of Chemical
Technology, N. P. Marg, Matunga, Mumbai 400 019, India. Tel.: +91 2233612708;
fax: +91 22 33611020.
E-mail addresses: gsshankarling@gmail.com, gs.shankarling@ictmumbai.edu.in
(G.S. Shankarling).
http://dx.doi.org/10.1016/j.molliq.2014.02.016
0167-7322/© 2014 Elsevier B.V. All rights reserved.

U.N. Yadav, G.S. Shankarling / Journal of Molecular Liquids 195 (2014) 188–193
189
R1
R2
O
R1
R2
O
ChCl:Urea
00C
Make: SONICS, USA
Rated output power: 750 W
Operating frequency: 20 kHz
Diameter of titanium steel tip of horn:
13 mm
+
Ar1
Ar2
Ar1
Ar2
8
Intensity: 2.27 × 106 W/m2
Surface area of ultrasound irradiating face:
1.32 × 10−4 m2
Scheme 1. Synthesis of β-functionalized ketonic derivatives using RTIL ChCl:urea (1:2).
2.2. General procedure for synthesis of products (3a–3l) by conventional
heating
paper we have demonstrated the synergistic effect of ultrasound and
the catalytic activity of ChCl:urea (1:2) for carbon–carbon bond forming
reactions (Scheme 1).
To a mixture of (E)-3-(4-fluorophenyl)-1-(phenyl)prop-2-en-1-one
(0.26 g, 1 equiv.) and active methylene (1.2 equiv.), ChCl:urea (1:2) (5
equiv.) was added and the reaction mixture was stirred at 80 °C for an
appropriate time. After completion of the reaction as indicated by TLC,
ethyl acetate was added to the reaction mass. Evaporation of the organic
layer afforded products which were further purified by column chroma-
tography using hexane:ethyl acetate as eluent.
2. Experimental
All common reagent grade chemicals were procured from SD Fine
Chemical Ltd. (Mumbai, India) and were used without further purifica-
tion. The reactions were monitored by thin layered chromatography
using 0.25 mm E-Merck silica gel 60F254 precoated plates, which were
visualized with UV light. 1H spectra were recorded on 400 MHz,
600 MHz and 13C-NMR on a 100 MHz Varian mercury plus spectrome-
ter. Chemical shifts are expressed in δ ppm using TMS as an internal
standard. Mass spectral data were obtained with a micromass-Q-TOF
(YA105) spectrometer. The synthesis of a deep eutectic mixture has
been carried out using a method reported in the literature [31]. It is pre-
pared by mixing choline chloride (100 g, 71 mmol) and urea (86 g,
140 mmol) in a molar ratio of 1:2. The two solids were heated slowly
and maintained at 80 °C for 30 min resulting in the formation of eutectic
solvent with 100% atom economy. The liquid was allowed to cool till it
attains room temperature and was used for synthesis without further
purification.
2.3. General procedure for synthesis of products (3a–3l) by using
ultrasound
To a mixture of (E)-3-(4-fluorophenyl)-1-(phenyl)prop-2-en-1-one
(1 equiv.) and active methylene (1.2 equiv.), ChCl:urea (1:2) (5 equiv.)
was added. It was placed under sonication using an ultrasonic horn
(ACE horn, 22 kHz frequency) at 40% amplitude for an appropriate
time with a 5 s on and 5 s off cycle from time t = 0 h. The reaction prog-
ress was monitored on thin layer chromatography (TLC). On completion
of the reaction as indicated on TLC, ethyl acetate was added to the reac-
tion mass. Evaporation of the organic layer afforded products which
were further purified by column chromatography. For recyclability
studies, a deep eutectic mixture was given a wash of ethyl acetate and
was used for the next batch and recycled again.
2.1. Ultrasound set up
2.4. Characterization and spectral data
Ultrasound for sonochemical synthesis is generated with the help of
ultrasonic instrument set-up (horn type). The specification and details
of the set-up, and processing parameters used during the experiments
are:
All the compounds are characterized by mass, FT-IR, 1H and NMR.
1H spectra were recorded on 400 MHz, 600 MHz and 13C-NMR on a
100 MHz Varian Mercury plus spectrometer. Chemical shifts are
Table 1
Comparison of ChCl:urea with various catalysts in the addition of nitromethane to 4-fluorobenzylideneacetophenone.a
Entry
Catalyst
Equiv. of Nitromethane
Solvent
Reaction temp (°C)
Time
10 h
24 h
2 h
6 h
24 h
4 h
Yielda (%)
Ref
1
2
3
4
5
6
7
8
K2CO3, 0.2 mmol
Diethylamine, 5 equiv.
KF/basic alumina
Diethylamine
5.0
5.0
4–8
5.0
1.0
1.0
1.5
Ethanol
80
65
25
60
60
60
80
98
86
94
91
88
80
69
60
74
89
87
70
84
94
94
NR
NR
[38]
[39]
[40]
[41]
[42]
[43]
[25]
Dry methanol
Dry THF
Diethylamine
Dry THF
–
SmI3, 1 equiv.
Rasta resin-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene
[C4mim][C2H5SO4]
ChCl:urea, 1 equiv.
3 equiv.
5 equiv.
7 equiv.
8 h
2 h
2 h
2 h
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
No solvent
1.2
1.2
–
80
2 h
9
Ultrasonication (US)
ChCl:urea, 5 equiv.
50
70
80
90
50
80
60 min
50 min
45 min
45 min
4 h
–
10
No catalyst
5.0
–
–
4 h
a
Isolated yield.

190
U.N. Yadav, G.S. Shankarling / Journal of Molecular Liquids 195 (2014) 188–193
Table 2
Michael addition of active methylene compound to chalcones—advantage of ultrasound over conventional heating.a
Entry
1
Ar1, Ar2
R1, R2
Michael adducts
Conventional heatingb
Time (h), yield (%)
Ultrasonicationc
Time (min), yield (%)d
Ph, 4-FC6H4
2 h, 90%
2.5 h, 84%
3 h, 82%
2.5 h, 90%
4 h, 82%
40 min, 96%
2
3
4
5
4-CH3C6H4, 4-FC6H4
4-OCH3C6H4, 4-FC6H4
4-BrC6H4, 4-FC6H4
Ph, 4-FC6H4
45 min, 86%
45 min, 88%
40 min, 92%
75 min, 82% d.e.p = 33.9%
6
7
8
4-CH3C6H4, 4-FC6H4
4-OCH3C6H4, 4-FC6H4
Ph, 3,4-Cl2C6H3
4 h, 82%
5 h, 81%
6 h, 80%
75 min, 82% d.e.p = 33.9%
90 min, 80% d.e.p = 29.0%
95 min, 82% d.e.p = 30.5%
9
Ph, 4-FC6H4
3 h, 89%
45 min, 96%
55 min, 89%
10
4-OCH3C6H4, 4-FC6H4
4 h, 86%

U.N. Yadav, G.S. Shankarling / Journal of Molecular Liquids 195 (2014) 188–193
191
Table 2 (continued)
Entry
Ar1, Ar2
R1, R2
Michael adducts
Conventional heatingb
Time (h), yield (%)
Ultrasonicationc
Time (min), yield (%)d
11
Ph, 3,4-Cl2C6H3
4 h, 89%
55 min, 93%
12
4-BrC6H4, 4-FC6H4
3.5 h, 91%
45 min, 92%
d.e.p = diastereomeric excess percentage determined by 1H-NMR analyses.
a
Reaction conditions: chalcone (1 mmol), active methylene (1 mmol), ChCl:urea (1:2) 5 equiv., temperature 80 °C.
Isolated yield obtained using conventional heating method.
b
c
Isolated yield obtained using ultrasound.
d
All the compounds are characterized by mass, FT-IR and 1H-NMR.
expressed in δ ppm using TMS as an internal standard. Mass spectral
2.4.5. Product 3e
data were obtained with a micromass-Q-TOF (YA105) spectrometer.
Ethyl 2-cyano-3-(4-fluorophenyl)-5-oxo-5-phenylpentanoate.
d.e.p = 33.9%. Major isomer: 1H-NMR (600 MHz, CDCl3, Me4Si): δ =
1.12 (t, J = 7.4 Hz, 3H), 3.50 (dd, J = 5.2, 13.3 Hz, 1H), 3.68 (dd, J =
4.2 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 4.13–4.18 (m, J = 3.1, 6.2 Hz,
1H), 4.32 (d, J = 5.1 Hz, 1H), 6.99–7.59 (m, Ar–H, 7H), 7.95 (d, J =
8.2 Hz, 2H). Minor isomer: 1H-NMR (600 MHz, CDCl3, Me4Si): δ = 1.20
(t, J = 7.2 Hz, 3H), 3.61 (dd, J = 8.2 Hz, 1H), 3.65 (dd, J = 5.1, 9.2 Hz),
3.89 (d, J = 5.1 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 6.99–7.59 (m, Ar–H,
7H), 7.92 (d, J = 8.2 Hz, 2H). IR (neat, cm−1): 3436, 2953, 2345, 1724,
1692, 1510, 1221, 1038. EIMS m/z (%) = 338.1 (M+ + 1). C20H18FNO3
calculated m/z 339.36.
2.4.1. Product 3a
3-(4-Fluorophenyl)-4-nitro-1-phenylbutan-1-one. 1H-NMR (300 MHz,
CDCl3, Me4Si): δ = 3.40 (dd, J = 2.43, 4.5, 7.31 Hz, 1H), 3.43 (dd, J =
2.43, 4.5, 6.33 Hz, 1H), 4.16–4.26 (br, quintet, J = 7.3 Hz, 1H), 4.64
(dd, J = 7.8, 8.3 Hz, 1H), 4.80 (dd, J = 6.3 Hz, 1H), 6.99 (t, J =
8.3 Hz, 2H), 7.25 (dd, J = 6.8, 3.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H)
7.56 (t, J = 7.3 Hz, 1H), 7.88 (d, 2H, J = 7.8 Hz, 2H). 13C-NMR
(100 MHz, CDCl3, Me4Si); δ = 38.6, 41.5, 79.5, 115.8, 116.0, 128.0,
128.7, 129.1, 129.2, 133.6, 134.8, 134.9, 136.2, 160.5, 163.7, 196.6.
IR (neat, cm−1): 2969, 1738, 1681, 1552, 1353, 1216.
2.4.6. Product 3f
Ethyl 2-cyano-3-(4-fluorophenyl)-5-oxo-5-(p-tolyl)pentanoate.
d.e.p = 29.0%. Major isomer: 1H-NMR (600 MHz, CDCl3, Me4Si): δ =
1.13 (t, J = 6.3 Hz, 3H), 2.41 (s, 3H), 3.45 (dd, J = 5.1 Hz, 1H), 3.66 (d,
J = 8.9 Hz, 1H), 3.61–3.63 (m, J = 7.3 Hz, 8.1 Hz), 4.10 (q, J = 7.2 Hz,
2H), 4.32 (d, J = 5.1 Hz, 1H), 7.00–7.40 (m, 6H), 7.86 (d, J = 8.1 Hz,
2H). Minor isomer: 1H-NMR (600 MHz, CDCl3, Me4Si): δ = 1.21 (t, J =
6.3 Hz, 3H), 2.40 (s, 3H), 3.87 (d, J = 5.1 Hz, 1H), 3.48 (d, J = 5.1 Hz,
1H), 4.12–4.19 (m, 2H), 4.27 (q, J = 7.3, 6.8 Hz, 2H), 7.00–7.40 (m,
6H), 7.83 (d, J = 8.1 Hz, 2H). 13C-NMR (100 MHz, CDCl3, Me4Si); δ =
13.0, 13.1, 13.2, 20.7, 23.7, 23.9, 24.0, 38.8, 39.7, 39.8, 40.7, 42.9, 43.0,
43.3, 61.9, 62.2, 113.2, 114.6, 114.9, 115.1, 115.4, 126.5, 127.5, 128.7,
128.8, 129.1, 129.2, 129.3, 129.4, 129.5, 133.2, 133.3, 134.0, 134.7,
143.7, 143.9, 159.9, 160.0, 162.8, 163.1, 163.3, 164.5, 195.4, 195.8.
IR (neat, cm−1): 2985, 2355, 1674, 1467, 1240, 1065, 1028. EIMS
m/z (%) = 354.0 (M+ + 1). C21H20FNO3 calculated m/z 353.39.
2.4.2. Product 3b
3-(4-Fluorophenyl)-4-nitro-1-(p-tolyl)butan-1-one. 1H-NMR (400 MHz,
CDCl3, Me4Si): δ = 1.58 (s, 3H), 3.42 (dd, J = 8.2 Hz, 1H), 3.44 (dd, J =
6.8 Hz, 1H), 4.20–4.24 (m, 1H), 4.66 (dd, J = 20.3 Hz, 1H), 4.82 (dd, J =
16.2 Hz, 1H), 6.99–7.05 (m, 2H), 7.23–7.42 (m, 4H), 7.874–7.819 (d,
2H, J = 8 Hz). IR (neat, cm−1) 2359, 1682, 1552, 1508, 1384, 1353,
1218. EIMS m/z (%) = 318.0 (M+ + 1), C17H16FNO4 calculated m/z
317.31.
2.4.3. Product 3c
3-(4-Fluorophenyl)-1-(4-methoxyphenyl)-4-nitrobutan-1-one.
1H-NMR (300 MHz, CDCl3, Me4Si): δ = 3.31–3.40 (m, J = 7.0,
8.2 Hz, 2H), 3.86 (s, 3H), 4.18–4.23 (br, quintet, J = 7.2 Hz, 1H),
4.64 (dd, J = 8.2, 9.2 Hz, 1H), 4.80 (dd, J = 6.2, 7.2 Hz, 1H), 6.92 (d,
J = 9.0 Hz, 2H), 7.00 (t, J = 8.2, 2H), 7.25 (dd, J = 3.0, 5.1, 13.3 Hz,
2H), 7.89 (d, 2H, J = 9.2 Hz, 2H). IR (neat, cm−1): 2960, 1670,
1577, 1260, 1169. EIMS m/z (%) = 301.9 (M+ + 1), C17H16FNO3 cal-
culated m/z 301.0.
2.4.7. Product 3g
Ethyl
2-cyano-3-(4-fluorophenyl)-5-(4-methoxyphenyl)-5-
oxopentanoate. d.e.p = 30.5%. Major isomer: 1H-NMR (600 MHz,
CDCl3, Me4Si): δ = 1.12 (t, J = 7.2 Hz, 3H), 3.45 (d, J = 5.1 Hz,
1H), 3.86 (s, 3H) 4.09 (q, J = 7.2 Hz, 2H), 4.12–4.18 (m, J = 6.0,
4.7 Hz, 2H) 4.33 (d, J = 5.5 Hz, 1H), 6.913–7.40 (m, ArH, 6H),
7.94 (d, J = 9.0 Hz, 2H). Minor isomer: δ = 1.20 (t, J = 7.2 Hz,
3H), 3.42 (d, J = 4.7 Hz, 1H), 3.85 (s, 3H), 3.58 (d, J = 7.2 Hz),
3.60–3.63 (m, J = 8.0, 09.8 Hz, 2H), 6.91–7.40 (m, ArH, 6H), 7.91
(d, J = 8.6 Hz, 2H). 13C-NMR (100 MHz, CDCl3, Me4Si); δ = 13.9,
39.5, 40.2, 40.2, 41.2, 43.4, 44.1, 55.5, 62.7, 63.0, 113.9, 113.9,
115.6, 113.7, 115.9, 116.0, 129.3, 129.3, 129.5, 129.8, 129.0, 130.4,
134.2, 135.0, 160.6, 160.8, 163.9, 164.0, 164.9, 165.0, 194.8, 195.3.
EIMS m/z (%) = 370.0 (M+ + 1). C16H13BrFNO3 calculated m/z
369.39.
2.4.4. Product 3d
1-(4-Bromophenyl)-3-(4-fluorophenyl)-4-nitrobutan-1-one. 1H-NMR
(300 MHz, CDCl3, Me4Si): δ = 3.34 (dd, J = 2.9, 4.4 Hz, 1H), 3.36 (dd,
J = 2.2, 4.4 Hz, 1H), 4.16–4.21 (br, quintet, 1H), 4.61 (dd, J = 6.2 Hz,
1H), 4.75 (dd, J = 6.2 Hz, 1H), 6.89–6.95 (t, J = 8.7 Hz, 2H), 7.164–
7.256 (m, 4H), 7.76–7.79 (d, J = 8.0 Hz, 2H). 13C-NMR (100 MHz,
CDCl3, Me4Si); δ = 38.2, 38.3, 40.9, 79.0, 79.2, 79.4, 115.1, 115.3,
115.4, 115.6, 127.7, 128.9, 133.5, 135.0, 135.0, 144.1, 160.0, 163.2,
196.0. IR (neat, cm−1) 2915, 2320, 1668, 1605, 1551, 1509, 1407,
1362. EIMS m/z (%) = 367.9 (M+ + 1). C16H13BrFNO3 calculated m/z
366.18.

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U.N. Yadav, G.S. Shankarling / Journal of Molecular Liquids 195 (2014) 188–193
2.4.8. Product 3h
1007. EIMS m/z (%) = 371.0 [(M+,100]. C18H12BrFN2O calculated m/z
371.20.
Ethyl 2-cyano-3-(3,4-dichlorophenyl)-5-oxo-5-phenylpentanoate.
d.e.p = 26.7%. Major isomer: 1H-NMR (400 MHz, CDCl3, Me4Si): δ =
1.18 (t, J = 7.1 Hz, 3H), 3.52 (d, J = 5.2 Hz, 1H), 3.89 (d, J = 5.1 Hz,
1H), 4.22 (q, J = 7.2 Hz, 2H), 4.31 (d, J = 5.3 Hz, 1H), 4.11–4.16
(m, J = 7.1, 6.5 Hz, 1H), 7.15–7.98 (m, 8H, ArH). Minor isomer: δ =
1.24 (t, J = 7.1 Hz, 3H), 3.48 (d, J = 5.2 Hz, 1H), 3.60 (d, J = 7.9 Hz,
1H), 4.22 (q, J = 7.2 Hz, 2H), 4.31 (d, J = 5.3 Hz, 1H), 4.11–4.16
3. Results and discussion
In order to optimize the reaction condition, conjugate addition of
nitromethane (1.5 mmol) to 4-fluorobenzylideneacetophenone
(1 mmol) was taken as a model reaction. The reaction was carried
out in varying equivalents of ChCl:urea (1:2) and in different sets
of reaction conditions. Among the various tested solvents such as
methanol, ethanol, tetrahydrofuran (THF), diethylamine, solvent
free conditions, ionic liquid [C4mim][C2H5SO4] and various catalysts
(K2CO3, KF, SmI3, LiNO3, diethylamine), the addition was best cata-
lyzed by 5 equiv. of ChCl:urea (1:2) giving a good yield of 89% within
2 h (Table 1).
Further, we carried out the above addition reaction under
ultrasonication. It was observed that ultrasonic time and tempera-
ture had a great influence on the reaction time. When the reaction
temperature was at 50 °C the yield of the product was only 70%; an
increase in temperature to 80 °C gave an excellent yield of 92% with-
in a short time of 45 min. However, a further increase in temperature
gave a lower yield indicating by-product formation (Table 1, entry
10). Rate of reaction was faster under ultrasound compared to con-
ventional heating. This is attributed to the cavitation phenomena oc-
curring during sonication. Cavitation results in formation and
adiabatic collapse of microbubbles resulting in the generation of
local hotspots. These hotspots generate high temperature and pres-
sures of several thousand atmospheres which cause the reaction to
proceed rapidly.
In order to explore the versatility of the synergistic effect of DES
ChCl:urea (1:2) and ultrasound, different substrates were used. Aro-
matic α,β-unsaturated ketones with different substituents such as
\CH3, \OCH3, \Cl, \Br and \F were treated with various active meth-
ylenes like nitromethane, ethyl cyanoacetate and malononitrile. Addi-
tion of nitromethane to α,β-unsaturated ketones gave the desired
product in high yields and in short reaction times (Table 2). Electron do-
nating moiety in α,β-unsaturated ketones like methyl (Table 2, entries
2 & 6) and methoxy (Table 2, entries 3, 7 & 10) required longer reaction
times to produce comparable yields than those of their simple and
electron-withdrawing counterparts. The rate of reaction was found to
be slow for ethyl cyanoacetate (70–95 min) as compared to nitrometh-
ane (40–45 min) and malononitrile (45–55 min), which is attributed to
steric hindrance offered due to bulky substituents and to some extent to
their acidities. Conjugate addition of α,β-unsaturated ketones with
ethyl cyanoacetate, resulted in diastereomer formation. It is difficult to
separate the individual diastereomer as the members of the diastereo-
meric mixture have very close Rf values (Table 2, entries 5, 6, 7 & 8)
(m, J = 7.1, 6.5 Hz, 1H), 7.15–7.98 (m, 8H, ArH) IR (neat cm−1
)
2923, 2252, 1743, 1683, 1596, 1366, 1251, 1210, 1029. EIMS m/z
(%) = 390.1 (M+ + 1). C20H17Cl2NO3 calculated m/z 390.36.
2.4.9. Product 3i
2-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)malononitrile. 1H-NMR
(600 MHz, CDCl3, Me4Si): δ = 3.61 (dd, J = 5.1, 5.2 Hz, 1H), 3.68 (dd,
J = 8.2, 9.2 Hz, 1H), 3.95–3.98 (br, quintet, J = 4.1, 5.1 Hz, 1H), 4.62
(d, J = 5.1 Hz, 1H), 7.12 (t, J = 8.2 Hz, 2H), 7.44 (dd, J = 5.1, 6.1 Hz,
2H), 7.50 (t, J = 7.1 Hz, 2H), 7.63 (t, J = 7.2, 2H), 7.96 (d, J = 7.2 Hz,
2H). EIMS m/z (%) = 292 (M+). IR (neat, cm−1): 3062, 2916,
2256,1676, 1600, 1229, 453. C20H17Cl2NO3 calculated m/z 292.31.
2.4.10. Product 3j
2-(1-(4-Fluorophenyl)-3-(4-methoxyphenyl)-3-oxopropyl)
malononitrile. 1H-NMR (600 MHz, CDCl3, Me4Si): δ = 3.54 (dd, J =
4.1,5.1 Hz, 1H), 3.63 (dd, J = 8.2, 9.3 Hz, 1H), 3.88 (t, 3H), 3.92–3.95
(br, quintet, J = 4.1, 5.1 Hz, 1H), 4.65 (d, J = 5.1 Hz, 1H), 6.66 (d, J =
5.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 7.12 (t, J = 5.1 Hz, 2H), 7.44 (dd,
J = 3.1, 5.1 Hz, 2H), 7.94 (d, J = 9.2 Hz, 2H). IR (neat, cm−1): 3372,
2913, 2251, 1667, 1600, 1513, 1237. EIMS m/z (%) = 322.0 (M+).
C19H15FN2O2 calculated m/z 322.33.
2.4.11. Product 3k
2-(1-(3,4-Dichlorophenyl)-3-oxo-3-phenylpropyl)malononitrile. 1H-
NMR (400 MHz, CDCl3, Me4Si): δ = 4.13–4.18 (m, J = 6.6, 8.3 Hz,
2H), 4.65 (d, J = 2.9 Hz, 1H), 5.12 (d, J = 6.6 Hz, 1H), 7.10–7.80 (m,
8H, Ar–H). 13C-NMR (100 MHz, CDCl3, Me4Si); δ = 40.6, 45.2, 45.3,
48.2, 49.3, 49.4, 51.4, 51.5, 74.5, 115.6, 115.8, 116.1, 124.5, 128.0,
128.2, 128.7, 130.6, 131.2, 133.0, 143.5, 161.3, 161.4, 164.6, 164.7,
203.8. IR (neat, cm−1) 2969.84, 2359.48, 1741.41, 1448.28, 1371.14,
1229.4, 1215.9; EIMS m/z (%) = 344.0 (M+ + 1,100). C18H12Cl2N2O cal-
culated m/z 343.1.
2.4.12. Product 3l
2-(3-(4-Bromophenyl)-1-(4-fluorophenyl)-3-oxopropyl)
malononitrile. 1H-NMR (400 MHz, CDCl3, Me4Si): δ = 4.13–4.18 (m, J =
6.6, 8.3 Hz, 2H), 4.65 (d, J = 2.9 Hz, 1H), 5.12 (d, J = 6.6 Hz, 1H), 7.10–
7.80 (m, 8H, Ar–H). IR (neat cm−1): 3428, 2359, 1644, 1509, 1397, 1226,
O
H
H
H
R1
R2
H
N
N+
H
Cl-
OH
HH
O
N
H
H
H
N
OH R44
N+
N
O
Cl-
1
,4-conjugate
N
R1
H
R3
Proto
bstraction
n
H
H
H
additio
n
N
H
N
H
a
+
OHH
R2
ChCl:Urea
O- R4
O
R4
O
R1
R1
R3
R3
Product
Ar1
Ar2
R2
Intermediate
R2
A
t
ctivation of unsaturated carbonyl compound
hrough hydrogen bonding with ChCl:Urea
Scheme 2. Mechanistic pathway for conjugate addition reaction catalyzed by ChCl:urea.

U.N. Yadav, G.S. Shankarling / Journal of Molecular Liquids 195 (2014) 188–193
193
Appendix A. Supplementary data
File contains characterization data of all compounds. Supplementary
data to this article can be found online at http://dx.doi.org/10.1016/j.
molliq.2014.02.016.
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4. Conclusion
In summary, the present work represents an expedient and clear-cut
protocol for facile synthesis of β-substituted ketonic derivatives using
biodegradable eutectic of ChCl:urea (1:2) as a versatile catalyst.
The current process is advantageous over conventional methods as
it completely avoids strongly basic or acidic conditions, expensive
catalysts, and toxic solvents. In regard to synthetic improvements re-
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(1:2) as solvent and catalyst demonstrates many advantages such as:
re-use of the catalyst, short reaction times, high yields and an easy
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Acknowledgements
Authors are thankful to UGC-CAS for providing financial assistance
and to the Institute of Chemical Technology, SAIF IIT-Bombay for record-
ing mass spectra and TIFR Mumbai for recording 1H-NMR spectra.
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