Ultrasound promoted efficient and green synthesis of β-amino carbonyl compounds in aqueous hydrotropic medium

Article abstract of DOI:10.1016/j.ultsonch.2011.12.001

Ultrasound promoted synthesis of β-amino carbonyl compounds in aqueous hydrotropic medium at ambient temperature is reported. The remarkable features of the new procedure are shorter reaction time, excellent yields in aqueous medium, cleaner reaction profile and simple experimental and work-up procedure.

Full text of DOI:10.1016/j.ultsonch.2011.12.001

Ultrasonics Sonochemistry 19 (2012) 812–815
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound promoted efficient and green synthesis of b-amino carbonyl
compounds in aqueous hydrotropic medium
⇑
Santosh Kamble, Arjun Kumbhar, Gajanan Rashinkar, Madhuri Barge, Rajashri Salunkhe
Department of Chemistry, Shivaji University, Kolhapur 416004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2011
Received in revised form 6 December 2011
Accepted 10 December 2011
Available online 17 December 2011
Ultrasound promoted synthesis of b-amino carbonyl compounds in aqueous hydrotropic medium at
ambient temperature is reported. The remarkable features of the new procedure are shorter reaction
time, excellent yields in aqueous medium, cleaner reaction profile and simple experimental and work-
up procedure.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Ultrasound
Hydrotrope
Aqueous medium
b-Amino carbonyl compound
1. Introduction
aqueous medium offers many practical and economic advantages
including low cost, safe handling and environmental compatibility
b-Amino carbonyl compounds are valuable synthetic intermedi-
ates for pharmaceutical and natural products [1]. Owing to the
importance as valuable building blocks for the preparation of 1,3-
amino alcohols, b-amino acids as well as for the synthesis of various
bioactive molecules such as the antibiotic nikkomycins and neo-
polyoxines [2–4], several methods have been reported in literature
for the synthesis of b-amino carbonyl compounds. Over the past
few years, various catalysts such as dodecylbenzene sulphonic acid,
polystyrene-SO3H, NbCl5, Re(PFO)3, NaBAr4, SiO2–OAlCl2, etc have
been exploited with various degrees of success [5]. However, most
of the reported methods suffer from serious drawbacks such as use
of large excess of catalyst, expensive reagents, long reaction time,
low yields and ecologically unsafe organic solvents. Thus, an effi-
cient, economical and environmentally benign protocol is highly
desirable for the synthesis of b-amino carbonyl compounds.
Ultrasound irradiation in organic synthesis is considered as a
clean and energy conserving protocol as compared to the tradi-
tional methods and has been established as a versatile technique
in synthetic chemistry [6–9]. It has been well established that
ultrasound, when compared with conventional methods enhance
the rate of reactions and product yields in addition to sometimes
changing the reaction pathway [10].
[11,12]. The term hydrotropes refers to a diverse class of water sol-
uble surface active compounds that enhance the solubilities of or-
ganic reactants in the aqueous phase at higher concentration. They
are capable of increasing the solubilities of organic compounds up
to 200 times in water. Hydrotropes usually comprise of hydrophilic
and hydrophobic moieties, with the latter being typically too small
to induce micelle formation. Their solubilizing power was recog-
nized as early as 1916 by Neuberg [13]. The potential use of hydro-
tropes in industry was stressed in 1946 by McKee [14]. Aqueous
hydrotropic solutions represent the unique alternative reaction
media for organic synthesis. We have recently established the com-
patibility of aqueous hydrotropic solution as safer solvent for micro-
wave assisted reactions [15]. In continuation of our effort to tap the
barely exploited potential of hydrotropes in organic synthesis, we
report herein an efficient synthesis of b-amino carbonyl compounds
in aqueous hydrotropic solution under ultrasonic irradiation.
2. Methods
1H NMR and 13C NMR spectra were recorded on a Brucker AC
(300 MHz for 1H NMR and 75 MHz for 13C NMR) spectrometer
using CDCl3 as solvent and tetramethylsilane (TMS) as an internal
standard. Infrared spectra were recorded on a Perkin–Elmer FTIR
spectrometer. The samples were examined as KBr discs. Melting
points were determined with a DBK melting point apparatus and
are uncorrected. All the chemicals were obtained from local suppli-
ers and were used without further purification. The hydrotropes
Organic reactions in aqueous media have attracted increasing
interest because of environmental issues. As a reaction solvent,
⇑
Corresponding author. Tel.: +91 231 260 9240; fax: +91 231 269 2333.
E-mail address: rss234@rediffmail.com (R. Salunkhe).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.12.001

S. Kamble et al. / Ultrasonics Sonochemistry 19 (2012) 812–815
813
were prepared following the literature procedure [16]. Sonication
was performed in SPECTRALAB-UCB-30 ultrasonic bath with a fre-
quency of 40 kHz and a nominal power of 100 W. The reaction flask
was located in the maximum energy area in the water bath. The
temperature of the water bath was maintained at 25–30 °C.
2H), 7.25–7.38 (m, 6H); 13C NMR (75 MHz, CDCl3): 7.5, 7.7, 12.3,
15.9, 26.2, 34.1, 36.7, 52.1, 53.7, 58.9, 59.5, 114.3, 115.2, 118.7,
126.2, 127.4, 127.8, 129.2, 129.8, 141.5, 146.2, 146.7, 213.5.
2-(a
-Anilinobenzyl)cyclohexanone (Table 3, Entry 6a): IR (KBr):
t
3382, 3055, 3026, 2944, 1694, 1603, 1511, 1260, 869 cmÀ1
;
1H
NMR (300 MHz, CDCl3): d 1.63–1.94 (m, 6H, 3 Â CH2), 2.29–2.49
(m, 2H, CH2), 2.76 (d, 1H, CH), 4.62 (d, 0.87 H, anti isomer), 4.79
(d, 0.13 H, syn isomer), 6.54 (d, 2H, Ar–H), 6.65 (d, 1H, Ar–H),
7.02 (s, 2H, Ar–H), 7.18 (d, 1H, Ar–H), 7.27 (s, 2H, Ar–H), 7.48 (s,
2H, Ar–H); 13C NMR (75 MHz, CDCl3): 23.7, 27.7, 31.2, 41.6, 57.3,
58.3, 113.8, 117.8, 127.2,127.2, 128.4, 129.0, 141.9, 147.5, 213.1.
2-[(4-Hydroxy-3-methoxyphenyl)(phenylamino)methyl)]cyclo-
3. General procedure
A mixture of aldehyde (1 mmol), amine (1 mmol) and acetophe-
none
(1 mmol)/cyclohexanone
(1 mmol)/aliphatic
ketone
(1 mmol) in 5–10 mL of aq. 50% hydrotropic solution was stirred
until a clear solution was formed. The mixture was irradiated un-
der ultrasonic waves at ambient temperature. After completion
of reaction, the crude product obtained by addition of cold water
was filtered, washed with water and recystallised from ethanol
to afford pure b-amino carbonyl compound.
hexanone (Table 3, Entry 6d): IR (KBr):
t
3474, 3354, 3052, 2937,
1702, 1606, 1533, 1437, 1265, 1166, 1033, 865, 746 cmÀ1
;
1H
NMR (300 MHz, CDCl3): d 1.66–1.73 (m, 2H), 1.85–1.92 (m, 4H),
2.34–2.44 (m, 2H), 2.68–2.70 (m, 1H), 3.85 (s, 3H), 4.51 (d, 0.96
H, anti isomer), 4.54 (d, 0.14H, syn isomer), 5.53 (s, 1H, NH),
6.52–6.54 (m, 2H), 6.51–6.65 (m, 2H), 6.81–6.84 (m, 3H), 6.90 (s,
1H), 7.03–7.08 (m, 2H); 13C NMR (75 MHz, CDCl3): 23.5, 27.7,
31.0, 55.8, 57.5, 58.1, 109.1, 113.8, 114.0, 117.7, 120.4, 129.0,
133.4, 144.8, 146.7, 147.0, 212.7.
4. Spectral data of representative compounds
3-Anilino-1,3-diphenylpropan-1-one (Table 2, Entry 4a): IR
(KBr):
t ;
3385, 3025, 2917, 1669, 1600, 1509, 1291, 861 cmÀ1 1H
NMR (300 MHz, CDCl3): d 3.41–3.58 (m, 2H, CH2), 5.00–5.04 (dd,
1H, CH), 6.57 (d, 2H, Ar–H), 6.60–6.71 (m, 1H, Ar–H), 7.01–7.10
(m, 2H, Ar–H), 7.22–7.64 (m, 1H, Ar–H), 7.43 (t, 2H, Ar–H), 7.53
(t, 4H, Ar–H), 7.55 (d, 1H, Ar–H), 7.90 (d, 2H, Ar–H); 13C NMR
(75 MHz, CDCl3): 46.1, 55.0, 114.0, 118.0, 126.3, 127.3, 128.1,
128.6, 128.7, 129.0, 133.2; DEPT of CH2 at 46.1.
5. Results and discussion
We initially focused our attention on the selection of appropri-
ate hydrotrope for the present work. The different hydrotropes
such as sodium benzene sulphonate (NaBS), sodium p-xylene sul-
phonate (NaXS) and sodium p-toluene sulphonate (NaPTS) were
selected for this purpose. We opted to use 50% (w/v) aqueous solu-
tions of selected hydrotropes as a solvent, since this concentration
was suitable for the maximum solubilization of organic com-
pounds. Our next task was to assess the efficiency of the aqueous
hydrotropic solutions in the synthesis of b-amino carbonyl com-
pounds. Accordingly, a model reaction between acetophenone,
benzaldehyde and aniline in 50% of aq. NaBS, NaXS and NaPTS
was carried at ambient temperature under ultrasound irradiation.
On the completion of reaction as monitored by thin layer chroma-
tography (TLC), the reaction mixture was diluted with cold water
during which the product separated. The filtration of reaction mix-
ture followed by recrystallization afforded the corresponding prod-
uct of a high purity, which gave correct spectral analysis. The
3-(4-Chlorophenylamino)-3-(4-methoxyphenyl)-1-phenylpro-
pane-1-one (Table 2, Entry 4e): IR (KBr):
t 3383, 3062, 2929, 1668,
1603, 1505, 1256, 808 cmÀ1 1H NMR (300 MHz, CDCl3): d 3.33 (s,
;
3H, OCH3), 3.49 (dd, 1H, CH2), 3.78 (dd, 1H, CH2), 4.90 (s, 1H, NH),
6.45 (t, Ar–H, 2H), 6.85 (d, Ar–H, 2H), 7-04 (t, Ar–H, 2H), 7.32 (t, Ar–
H, 2H), 7.47 (t, Ar–H, 2H), 7.59 (s, Ar–H, 1H), 7.91 (d, Ar–H, 2H); 13
C
NMR (75 MHz, CDCl3): 46.0, 54.6, 55.1, 96.1, 114.2, 115.2, 127.3,
128.1, 128.6, 128.9, 133.3, 136.7, 145.2, 158.9, 197.9; DEPT of
CH2 at 46.0.
1-Anilino-1-phenylpentan-3-one (Table 2, Entry 4t): IR (KBr):
3427, 3350, 3042, 2914, 1687, 1652, 1560, 1227, 1144, 1028,
885 cmÀ1 1H NMR (300 MHz, CDCl3): d 0.97–0.99 (m, 2H), 2.31–
t
;
2.35 (m, 2H), 2.90–2.92 (m, 2H), 4.70 (brs, 1H, NH), 4.79–4.83
(m, 1H), 6.52–6.55 (m, 2H), 6.60–6.63 (m, 1H), 7.07–7.10 (m,
Table 2
Ultrasound promoted synthesis of b-amino carbonyl compounds in 50% aq.NaPTS solutiona
Entry
R1
R2
R3
Time (h)
Yieldb (%)
M.P. (°C)
Lit. M.P. [18,19] (°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
0.75
1.70
1.10
2.00
1.10
1.70
1.75
1.30
1.70
2.25
1.50
2.00
2.50
1.70
2.25
2
91
87
86
90
93
95
90
89
91
92
92
92
88
85
83
81
82
81
70
82
167–168
138–140
162–165
187–188
113–115
117–119
136–138
114–117
149–152
156–158
110–112
138–140
116–119
135–137
126–127
90–92
169–170
140–142
167–168
190–192
116–118
118–119
142–143
118–119
153–155
159–160
114–115
141–143
119–120
141–142
130–132
87–88
3-NO2
4-CH3
4-COOH
4-Cl
4-Cl
H
4-CH3
4-Cl
4-COOH
H
4-Cl
H
4-CH3
4-Cl
H
4-OCH3
4-Cl
4-OCH3
4-Cl
3-NO2
4-Cl
4-Cl
3-NO2
H
H
H
H
H
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-Cl C6H4
n-C3H7
n-C3H7
n-C3H7
n-C3H7
C5H9O
4-CH3
4-Cl
4-NO2
H
2
2
3.5
2
96–98
88–90
104–106
114–116
97–98
85–86
101–103
118–119
H
H
H
4s
4t
a
All products were characterized by IR, 1H NMR and 13C NMR spectroscopy.
Isolated yields after recrystallization.
b

814
S. Kamble et al. / Ultrasonics Sonochemistry 19 (2012) 812–815
Table 1
Screening of various hydrotropes for synthesis of b-amino carbonyl compound.
O
NH2
CHO
O
HN
50 % aq. hydrotropic solution
+
+
Entry
Hydrotrope
With US
Silent
Time (h)
Yield (%)a
Time (h)
Yield (%)a
1
2
3
Sodium p-toluene sulphonate (NaPTS)
Sodium p-xylene sulphonate (NaXS)
Sodium benzene sulphonate (NaBS)
0.75
0.75
0.75
90
65
48
5
5
5
75
57
43
a
Isolated yield.
for this new methodology. In order to show the generality and
scope of the new protocol, the reactions of different aliphatic and
cyclic ketones were carried out under the same conditions. Several
aliphatic ketones underwent reactions yielding corresponding b-
amino carbonyl compounds in satisfactorily yield (Table 2, Entry
4p–4t). The reactions of cyclohexanone (Scheme 2) accomplished
with anti regioselectivity which was confirmed by 1H NMR spec-
troscopy (Table 3). The identity of all the compounds was ascer-
tained on the basis of IR, 1H NMR and 13C NMR spectroscopy. The
physical and spectroscopic data are in harmony with the proposed
structures.
Recycling of hydrotrope is important for large scale operations
and industrial point of view. To check the possibility of the hydro-
trope recycling, the model reaction was carried out in 50% aq.
NaPTS solution under ultrasound irradiation at ambient tempera-
ture. After completion of the reaction, the product was separated
out from the reaction mixture and the resultant aqueous hydrotro-
pic solution was concentrated and reused for the subsequent reac-
tions. As shown in Fig. 2, the aq. NaPTS solution could be reused for
at least five times with modest change in yield of the product.
In order to illustrate the role of hydrotrope, the model reaction
was carried out using pure water. The reaction did not give quan-
titative yield of corresponding product indicating that the use of
NaPTS is crucial. NaPTS is short chain organic compound with a po-
lar group that serves as agent to dissolve poorly water soluble sub-
stances or organic compounds in water, if added in high
concentration. Cooperative aggregation is absent because the
hydrophobic moieties are too small for hydrophobic interactions
to overcome electrostatic repulsion. Lack of aggregation results in
Table 3
Ultrasound promoted synthesis b-amino carbonyl compounds from cyclohexanone in
50% aq. NaPTS.a
Entry R2
R3
H
Time
(h)
Yieldb
(%)
M.P.
(°C)
Lit. M.P.
[20] (°C)
Anti/Syn
[17]
6a
6b
6c
6d
6e
H
H
H
2.50
2.70
1.50
2.10
2.30
90
91
86
82
82
135–
136
138–
140
114–
116
144–
145
139–140
137–138
116–117
146–147
134–135
87:13
65:35
87:13
96:14
77:23
4-
Cl
4-
CH3
H
3-OCH3,
4-OH
H
2-
Cl
132–
133
a
All products were characterized by IR, 1H NMR and 13C NMR spectroscopy.
Isolated yields after recrystallization.
b
results are summarized in Table 1. It is noteworthy that the same
reactions in absence of sonication showed significant rate retarda-
tion resulting in considerably lower yields of product (Table 1). The
plausible reason for the significant rate enhancement observed un-
der sonication can be accounted on the basis of process of acoustic
cavitation: the formation, growth and implosive collapse of bub-
bles in liquid. Cavitation and the subsequent sonochemistry pri-
marily depend on the chemical properties of the fluid medium
used. Aqueous hydrotropic solutions provide an interesting ap-
proach to control the chemical contents of bubble due to a combi-
nation of the low vapour pressure and increased viscosity of the
aqueous hydrotropic solutions relative to pure water. Chemical
control of the vapour content of the collapsing bubble allows for
a stronger collapse that leads to greater compressional heating of
reactants leading to reaction rate acceleration.
As excellent results were obtained for NaPTS, we employed this
particular hydrotrope for subsequent studies. We have also studied
the effect of concentration of aq. NaPTS. The efficiency of model
reaction varied dramatically with respect to concentration of
hydrotrope and was maximum when 50% of aq. NaPTS was used
as a reaction medium (Fig. 1).
After the selection of appropriate hydrotrope and optimized
conditions, a series of b-amino carbonyl compounds was synthe-
sized by reacting various acetophenones with differently substi-
tuted benzaldehydes and anilines (Scheme 1). In all cases, the
reactions proceeded smoothly affording the corresponding prod-
ucts in high yields (Table 2). The acetophenones and benzalde-
hydes with electron withdrawing substituents gave slightly
higher yields than those bearing electron-donating substituents.
Aromatic amines bearing variety of substituents were all suitable
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
Hydrotrope Concentration
Fig. 1. Effect of NaPTS concentration on the yield of b-amino carbonyl compound.

S. Kamble et al. / Ultrasonics Sonochemistry 19 (2012) 812–815
815
R
3
CHO
NH2
O
O
HN
50 % aq. NaPTS
))))))
+
+
R
R
1
1
R
R
2
3
R
2
1
4
2
a-t
3
Scheme 1. Synthesis of b-amino carbonyl compounds in 50% aq. NaPTS.
R
R
3
3
CHO
O
NH2
O
HN
O
HN
50 % aq. NaPTS
))))))
+
+
+
R
R
3
2
R
R
2
2
6
6
Syn
2
3
5
Anti
Scheme 2. Synthesis of b-amino carbonyl compounds from cyclohexanone in 50% aq. NaPTS.
References
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Fig. 2. Recyclability performance of aq. 50% NaPTS in b-amino carbonyl compound
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In summary, a simple, efficient and green protocol for the syn-
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solution under ultrasound irradiation is described. The significant
aspects of methodology are efficiency, generality, high yield, short
reaction time, low cost, greener reaction profile, ease of product
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We gratefully acknowledge the financial support from the
Department of Science Technology and University Grants Commis-
sion for FIST and SAP respectively.