Microwave-assisted efficient synthesis of azlactone derivatives using TsCl/DMF under solvent-free conditions

Article abstract of DOI:10.1016/j.crci.2011.11.011

A simple and efficient procedure for the synthesis of azlactones employing condensation reaction of aromatic aldehydes with hippuric acid has been developed by using the tosyl chloride (TsCl) and dimethylformamide (DMF) system as condensing agent in the absence of solvents under microwave irradiation. The present protocol is operationally simple and offers several advantages such as high yields, short reaction time, and simple workup.

Full text of DOI:10.1016/j.crci.2011.11.011

C. R. Chimie 15 (2012) 346–349
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Full paper/Memoire
Microwave-assisted efficient synthesis of azlactone derivatives using
TsCl/DMF under solvent-free conditions
b
c
Hassan Moghanian a, , Meisam Shabanian , Hadi Jafari
*
a Department of Chemistry, Dezful Branch, Islamic Azad University, Dezful, Iran
b Young Researchers Club, Arak Branch, Islamic Azad University, Arak, Iran
c Department of Chemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple and efficient procedure for the synthesis of azlactones employing condensation
reaction of aromatic aldehydes with hippuric acid has been developed by using the tosyl
chloride (TsCl) and dimethylformamide (DMF) system as condensing agent in the absence
of solvents under microwave irradiation. The present protocol is operationally simple and
offers several advantages such as high yields, short reaction time, and simple workup.
ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Received 17 June 2011
Accepted after revision 15 November 2011
Available online 28 December 2011
Keywords:
Azlactone
Hippuric acid
Tosyl chloride
Microwave irradiation
Solvent-free
1. Introduction
such as Al2O3 [14], Bi(OAc)3 [15], Bi(OTf)3 [16], silica-
supported heteropolyacids [17], Yb(OTf)3 [18], Ca(OAc)2
Azlactones, or 2,4-substituted oxazolin-5-ones, are
interesting intermediates for the synthesis of a variety of
bioactive compounds, including aminoacids [1], peptides
[2], heterocycles [3], N-substituted pyrroles [4], biosensors
[5] and antitumor [6] or anticancer [7] compounds. The
usual procedure for azlactone synthesis is the Erlenmeyer
and Justus method [8], which involves the condensation
reactions of different aryl aldehydes with hippuric acid in
acetic anhydride as dehydrating agent and anhydrous
sodiumacetateasa homogeneousbasiccatalyst. A literature
search revealed that different reagents have been used for
the synthesis of azlactones involving perchloric acid [9],
polyphosphoric acid [10], carbodiimides [11], POCl3 [12]
and SO3 in dimethylformamide [13]. Other reported routes
for the synthesis of azlactones by condensation reaction of
aldehydes with hippuric acid in acetic anhydride as
dehydrating agent are in the presence of various catalysts
[19], supported KF [20] and anhydrous zinc chloride[21].
Most of the methods are suitable; however, some of these
procedures needhightemperature(refluxtemperature)and
are difficult to handle. The presence of acetic anhydride may
cause side reactions such as esterification or acylation.
Therefore, replacement of acetic anhydride by other
reagents is required.
Microwave irradiation is a well-known technique to
promote the synthesis of a variety of compounds, where
chemical reactions are accelerated because of the selective
absorption of microwaves by polar molecules [22]. The use
of this technique in organic synthesis [23–26] has attracted
attention in recent years due to enhanced reaction rates,
high yields, improved purity and ease of work up after the
reaction.
2. Results and discussion
As a continuation of our recent studies, devoted to the
development of practical, safe and environmentally
friendly procedures for some important transformations
* Corresponding author.
E-mail address: moghanian@gmail.com (H. Moghanian).
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2011.11.011

H. Moghanian et al. / C. R. Chimie 15 (2012) 346–349
347
O
O
O
TsCl/DMF
N
H
COOH
N
ArCHO
Ar
+
MW
3
1
2
Scheme 1. Synthesis of azlactone derivatives.
[27–31], we wish to report an efficient, convenient and
facile procedure for the condensation of aromatic alde-
hydes with hippuric acid to the corresponding azlactones,
in the presence of inexpensively available tosyl chloride
(TsCl) and dimethylformamide (DMF) system as condens-
ing agent in the absence of solvents under microwave
irradiation (Scheme 1).
synthesis of azlactones were studied (Table 2). The
reaction of hippuric acid with various aromatic aldehydes
bearing electron-withdrawing groups (such as nitro and
halides), electron-donating groups (such as methyl and
methoxy), was carried out under optimized conditions. In
all cases, the corresponding products were obtained in
good to high yields (Table 2).
First, to evaluate the synthetic potential of the proposed
procedure and to optimize the reaction conditions, the
reaction of benzaldehyde and hippuric acid was examined
in the presence of TsCl and different bases such as sodium
acetate, pyridine, triethylamine and dimethyl formamide
under microwave irradiation. As can be seen from Table 1,
the best result was obtained when the reaction was carried
out in the presence of TsCl/DMF and in the absence of
solvents under microwave irradiation.
Aliphatic aldehydes such as acetaldehyde or propio-
naldehyde and ketones such as ethyl methyl ketone or
cyclohexanone were also examined under the same
conditions, but the corresponding products were isolated
only in trace amounts.
A
possible mechanism for this transformation is
proposed in Scheme 2. The reaction of hippuric acid (III)
with TsCl (I) and DMF (II) produced the Vilsmeier adduct
as proposed by Higashi et al. for the activation of
carboxylic acids [33]. This intermediate (IV), upon an
intermolecular cyclization, yielded the azlactone (V) that
supported by good evidence in Erlenmeyer synthesis [34].
Then, azlactone derivatives (VI) can be obtained from
aldol condensation of azlactone (V) and carbonyl com-
pounds.
To evaluate the generality of the process, several
examples illustrating the present procedure for the
Table 1
Optimization of reaction conditions.
Yield (%)a
The results obtained from the condensation reaction of
benzaldehyde, 4-methoxybenzaldehyde and 4-nitroben-
zaldehyde with hippuric acid under optimized conditions
were compared to the best ones published so far for this
reaction using inorganic or organic catalysts, the data
listed in Table 3. It showed that the TsCl/DMF system was a
fairly good reagent for this reaction in terms of short
reaction time and simplified conditions.
Entry
Regent
Conditions
Time
1
2
3
4
5
6
7
TsCl
MW (300 W)
MW (300 W)
MW (300 W)
MW (300 W)
MW (300 W)
80 8C
2.5
2.5
2.5
2.5
2.5
2.5
2.5
<10
53
77
70
TsCl/NaOAc
TsCl/pyridine
TsCl/triethylamine
TsCl/DMF
91
75
88
TsCl/DMF
TsCl/DMF
MW (450 W)
a
Isolated yields.
Table 2
Synthesis of azlactones with the use of TsCl/DMF system.
a
Entry
Aldehyde (Ar)
Time (min)
Yield (%)
Azlactone
M.P. (8 C)
Found
Reported [lit.]
1
2
C6H5
2.5
2.5
4
91
90
89
90
92
91
88
87
93
86
85
91
53
3a
3b
3c
3d
3e
3f
166–167
141–143
160–161
156–157
182–183
169–170
140–141
100–102
210–211
160–161
155–156
234–236
170–171
167–168 [14]
143–144 [14]
162–163 [18]
155–157 [18]
183–185 [14]
166–167 [18]
141–143 [32]
99–102 [14]
212–214 [32]
162–163[32]
156–157 [14]
237–139 [32]
174–175 [14]
4-Me C6H4
2,4-Cl2 C6H3
4-MeO C6H4
4-F C6H4
3
4
4
5
2.5
2.5
3
6
3-NO2 C6H4
2-Br C6H4
7
3g
3h
3i
8
3-MeO C6H4
4-(Me2N) C6H4
2-Cl C6H4
3
9
3
10
11
12
13
3
3j
2-MeO C6H4
4-NO2 C6H4
2-Thiophene
3.5
2
3k
3l
2
3m
a
Isolated yields.

348
H. Moghanian et al. / C. R. Chimie 15 (2012) 346–349
O
O
N
H
COOH
III
O
S
O
S
O
O
Cl
O
CH3
CH3
O
Cl
N
+
H
CH3
N
H3C
H3C
-TsOH
O
CH3
I
II
O
O
CH3
N
ArCHO
DMF
O
O
N
H
CH3
N
-DMF
-HCl
N
Ar
O
IV
Cl
VI
V
Scheme 2. The most probable mechanism for the synthesis of azlactone derivatives.
Table 3
Preparation of azlactone 3a, 3d and 3l under different conditions.
Entry
Regent
Conditions
Time (min)/Yield (%)a
Ref.
3a
3d
3l
1
2
3
4
5
6
7
TsCl/DMF
MW (300 W)
80–95 8C
40 8C
Toluene/reflux
Reflux
2.5/91
90/90
4/90
2/91
–
Polyphosphoric acid
Ac2O/Yb(OTf)3
90/90
–
[10]
[18]
[17]
[20]
[12]
[15]
30/82
30/84
60/83
–
Ac2O/Silica-supported heteropolyacids
Ac2O/KF-Al2O3
60/95, 96
60/81.2
20/86
60/93, 94
60/74.4
10/73
60/72.6
15/90
–
POCl3
Reflux
Ac2O/Bi(OAc)3
Reflux
60/88
60/56
a
Isolated yields.
3. Conclusion
(1 mmol) was added and the reaction mixture was
irradiated using the microwave oven for the appropriate
time according to Table 2. The progress of the reaction was
monitored by TLC. Upon completion of the reactions, a
mixture of EtOH–H2O (2:1.5 mL) was added to it, the
suspension was stirred for 5 min and the precipitate
filtered. The crude products were purified by recrystalli-
zation from EtOH.
In summary, we have developed a new, microwave
assisted protocol for the synthesis of azlactone derivatives
from condensation of aromatic aldehydes with hippuric
acid using TsCl/DMF system as a condensing agent. In
addition to the efficiency and simplicity, high yields, short
reaction time and the ease of workup make the method
advantageous.
4.3. Representative spectral data
4. Experimental
3a: IR (KBr) (nmax): 3070, 1786, 1649, 1450, 1301, 1158,
4.1. General
760, 657 cmÀ1. 1H NMR (300 MHz, CDCl3)
7.42–7.63 (m, 6 H), 8.18–8.21 (m, 4H).
d = 2.27 (s, 1 H),
Products are known compounds and were character-
ized by comparison of their spectral data (1H NMR, IR) and
melting points with those reported in the literature. IR
spectra were recorded as KBr disc on a galaxy series FT-IR
5000 spectrometer. NMR spectra were recorded on a
brucker spectrometer in CDCl3 with TMS as an internal
standard. Microwave irradiation was carried out in a
National Microwave Oven, Model No. NN-K571MF
(2450 MHz).
3b: IR (KBr) (
1160, 981, 858, 764 cmÀ1
= 2.41 (s, 3 H), 7.21–7.34 (m, 3 H), 7.50–7.62 (m, 3H),
8.11–8.19 (m, 4H).
3g: IR (KBr) (
11650, 860, 761 cmÀ1. 1H NMR (300 MHz, CDCl3)
n
max): 3065, 1793, 1649, 1602, 1490, 1301,
.
1H NMR (300 MHz, CDCl3)
d
n
max): 3058, 1793, 1650, 1550, 1323,
= 7.35–
d
7.65,(m, 6 H), 7.77 (s, 1H), 8.21 (d, J = 7.4, 2H), 8.95 (d,
J = 7.7, 1H).
Acknowledgment
4.2. General procedure
We gratefully acknowledge the financial support from
the Research Council of Islamic Azad University, Dezful
Branch.
To a mixture of aromatic aldehydes (1 mmol), hippuric
acid (1.1 mmol) and tosyl chloride (1 mmol), DMF

H. Moghanian et al. / C. R. Chimie 15 (2012) 346–349
349
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