Eco-friendly one-pot synthesis of 2,4-disubstituted thiazoles by grinding under catalyst- and solvent-free conditions

Article abstract of DOI:10.1080/10426507.2010.492366

Chemical Equation Presented An efficient and facile synthesis of 2,4-disubstituted thiazoles is achieved by a one-pot reaction of aldehydes and α-bromoketones with thiosemicarbazide by grinding under catalyst- and solvent-free conditions. This method has notable advantages in terms of simple workup, neat conditions, high yield, reasonably rapid reaction rate, and environmental friendliness. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.492366

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Eco-Friendly One-Pot Synthesis of 2,4-
Disubstituted Thiazoles by Grinding
Under Catalyst- and Solvent-Free
Conditions
Quansehng Ding a , Dongjian Zhu a , Huile Jin a , Jiuxi Chen a ,
Jinchang Ding a & Huayue Wu a
a College of Chemistry and Materials Engineering , Wenzhou
University , Wenzhou, PR China
Published online: 19 Feb 2011.
To cite this article: Quansehng Ding , Dongjian Zhu , Huile Jin , Jiuxi Chen , Jinchang Ding & Huayue
Wu (2011) Eco-Friendly One-Pot Synthesis of 2,4-Disubstituted Thiazoles by Grinding Under Catalyst-
and Solvent-Free Conditions, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:2,
220-224, DOI: 10.1080/10426507.2010.492366
To link to this article: http://dx.doi.org/10.1080/10426507.2010.492366
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Phosphorus, Sulfur, and Silicon, 186:220–224, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.492366
ECO-FRIENDLY ONE-POT SYNTHESIS OF
2,4-DISUBSTITUTED THIAZOLES BY GRINDING UNDER
CATALYST- AND SOLVENT-FREE CONDITIONS
Quansehng Ding, Dongjian Zhu, Huile Jin, Jiuxi Chen,
Jinchang Ding, and Huayue Wu
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
PR China
GRAPHICAL ABSTRACT
S
S
O
catalyst-free grinding
neat, rt, 5 min
Ar
N
R
+
+
RCHO
N
N
H2N
Br
N
NH2
H
Ar
H
3 (88%-93% yields)
1
2
Abstract An efficient and facile synthesis of 2,4-disubstituted thiazoles is achieved by a one-pot
reaction of aldehydes and α-bromoketones with thiosemicarbazide by grinding under catalyst-
and solvent-free conditions. This method has notable advantages in terms of simple workup,
neat conditions, high yield, reasonably rapid reaction rate, and environmental friendliness.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Catalyst-free; grinding; one-pot; solvent-free; thiazoles
INTRODUCTION
Thiazolederivatives have become increasingly important in the past few years because
they have been found to be associated with various biological properties such as antibac-
terial,1 antifungal,2 and anti-inflammatory activities.3 A number of synthetic methods to
prepare these compounds have been described in the past few years.4 The typical procedure
for the synthesis of thiazoles involves the reaction of readily available α-haloketones with
thioureas or thioamides in the presence of various promoting agents, such as ammonium
12-molybdophosphate,5 cyclodextrin,6 iodine,7 and [bbim]BF4,8 and silica chloride,9 and
with the aid of microwaves.10 In spite of their potential utility, however, the use of high
temperatures, an excess of organic solvents and catalysts that are harmful to environment,
longer reaction times, unsatisfactory yields, and cumbersome product isolation procedures
Received 15 April 2010; accepted 7 May 2010.
We are grateful to the National Key Technology R&D Program (No. 2007BAI34B00) and the Natural
Science Foundation of Zhejiang Province (No. Y4080107) for financial support.
Address correspondence to Jiuxi Chen, College of Chemistry and Materials Engineering, Wenzhou Univer-
sity, Wenzhou 325027, PR China. E-mail: jiuxichen@wzu.edu.cn
220

SYNTHESIS OF 2,4-DISUBSTITUTED THIAZOLES
221
limit the use of these methods. Therefore, a search for better methods for the synthesis of
thiazole derivatives is still desirable.
Recently, a series of 2-thiazolylhydrazone derivatives has been investigated for the
ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO)
selectively.11 Moreover, the results demonstrate that not only the thiazole ring but the aryl
ring has a contribution to the antioxidant activities.12
In recent years, significant articles have reported solid-state reactions by grinding.13
Most of these reactions are carried out at room temperature in an absolutely solvent-free
environment using only a mortar and pestle, and therefore the common merits of these
processes is that they are efficient, economical, and environmentally friendly.
In continuation of our interest in the synthesis of sulfur-containing compounds,14
we describe in this article a green, simple, and practical method that we developed for
the synthesis of 2,4-disubstituted thiazoles by grinding under catalyst- and solvent-free
conditions.
RESULTS AND DISCUSSION
At the onset of the research, we investigated the reaction of thiosemicarbazide with
α-bromoacetophenone by grinding; no reaction was observed. However, when the reaction
was performed smoothly in the presence of benzaldehyde, 2-(2-benzylidenehydrazinyl)-
4-phenylthiazole 3a was obtained in good yield (Scheme 1). Therefore, we examined
the one-pot reactions of aldehydes and α-bromoketones with thiosemicarbazide in the
subsequent study.
S
O
S
NH2
H2N
S
Br +
H2N
Ph
(1)
(2)
N
N
NH2
Ph
N
H
H
S
O
Ph
N
+
+
PhCHO
Ph
Br
N
H
N
N
H
NH2
Ph
3a
Scheme 1 One-pot reactions of aldehydes and α-bromoketones with thiosemicarbazide.
A model reaction of α-bromoacetophenone (1a) and benzaldehyde (2a) with
thiosemicarbazide was conducted to screen the optimal reaction conditions. First, the
reaction were stirred at room temperature in H2O and ethanol as solvents. After 2 h, the
desired product 3a was obtained in 38% and 46% yields, respectively. To keep this method
economical, all reactants were taken in a glass mortar and ground well under catalyst-
and solvent-free conditions at room temperature. It was observed that the mixture, which
was initially in a partial liquid state, solidified during the process of grinding to a white
solid mass, and thin layer chromatography (TLC), at this moment, indicated the complete
conversion to the desired product. The solid mass was washed with ethyl acetate (3 ×
10 mL). The combined organic solvent was removed under vacuum to obtain the crude
solid product. The crude product was further purified by silica gel column chromatography
using ethyl acetate/petroleum ether (1:3) as eluent to afford 3a in 90% yield.

222
Q. DING ET AL.
Table 1 Synthesis of 2,4-disubstituted thiazoles by grinding under catalyst- and solvent-free conditionsa
S
O
S
Catalyst-free
neat, rt, 5 min
H2N
Ar
Br
N
R
+
+
R CHO
N
NH2
N
Ar
N
H
H
1
2
3
Entry
Ar
R
Product
Yield (%)b
Found mp (◦C) (lit.)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
90
92
88
92
89
90
93
88
89
92
90
89
92
88
191–193
221–223
199–200
p-CF3-C6H4
p-Br-C6H4
p-Me-C6H4
o-MeO-C6H4
C6H5CH2CH2
C6H5
p-CF3-C6H4
p-Me-C6H4
o-MeO-C6H4
C6H5CH2CH2
C6H5
193–195 (195–196)12
186–187
111–113
209–210
204–205
228–230
161–163
135–136
194–195
225–227
p-CF3-C6H4
p-Me-C6H4
201–202
aReaction conditions: thiosemicarbazide (1.0 mmol), α-bromoketone (1.0 mmol), aldehyde (1.0 mmol) by
grinding at room temperature for 5 min.
bIsolated total yield.
Next, the reactions of thiosemicarbazide with different α-bromoketones 1 and various
aldehydes 2 were examined to explore the scope and generality of this method, and the
results are summarized in Table 1.
As shown in Table 1, a variety of α-bromoacetophenone bearing either electron-
withdrawing (Table 1, entries 7–11) or electron-donating (Table 1, entries 12–14) groups on
the aromatic ring underwent smooth transformation to the corresponding 2,4-disubstituted
thiazoles in excellent yields. In addition, a series of substituted aromatic aldehydes with
electron-withdrawing or electron-donating groups attaching to aromatic ring was also in-
vestigated. The substitution group on the aromatic ring of the aldehyde did not make any
difference in the reaction. The substituents at the ortho position have no obvious differ-
ence (Table 1, entries 5 and 10). Moreover, the reaction of aliphatic aldehydes proceeded
smoothly and the desired products were obtained with excellent yields (Table 1, entries 6
and 11).
To elucidate the working mechanism, we further investigated the reaction of thiosemi-
carbazide with benzaldehyde in the absence of α-bromoketones by grinding; however, the
product 2-benzylidenehydrazinecarbothioamide (4a) was obtained with 82% yield. Sub-
sequently, 3a could be formed by the reaction of α-bromoacetophenone with 4a. Thus,
we have formulated a working mechanism as outlined in Scheme 2 based on experiment
results and the previously proposed mechanism.8,13 The first step may involve the reaction
of thiosemicarbazide with aldehydes, and then 2,4-disubstituted thiazole derivatives could
be produced by condensation-cyclization reaction.
The structures of the isolated known products were confirmed by elemental analyses,
from spectral data (mass, 1H, and 13C NMR spectra), and by comparison of their melting

SYNTHESIS OF 2,4-DISUBSTITUTED THIAZOLES
223
S
S
Grinding
H2N
Ph
Ph
N
+
PhCHO
N
NH2
N
H
4a
NH2
rt
H
O
S
Ph
Grinding
rt
N
Br
4a
+
Ph
N
N
H
3a
Scheme 2 Working mechanism.
point values with those of authentic samples (see the Supplemental Materials, available
online).
In conclusion, the combination of simple experimental procedures and ease of recov-
ery and reuse of this novel reaction media is expected to contribute to the development of
a green strategy for the preparation of 2,4-disubstituted thiazoles. Compared to previously
reported methodologies, the procedure offers simple experimental procedure, short reaction
time, no need for catalysts or solvents, low cost, efficient yield, and mild reaction condi-
tions, which makes this method a useful and attractive strategy in view of economic and
environmental advantages. Currently, studies on the extension of this protocol are ongoing
in our laboratory.
EXPERIMENTAL
All products were known compounds and were identified by comparison with au-
thentic samples. Melting points were measured on a Digital Melting Point Apparatus
WRS-1B and are uncorrected. IR spectra were recorded on an Avatar 370 FI-Infrared spec-
trophotometer. All 1H and 13C NMR spectra were recorded on a Bruker Avance 300 MHz
spectrophotometer in CDCl3 or DMSO-d6 as a solvent with TMS as the internal standard.
J values are given in Hz.
General Procedure for the Preparation of 2,4-Disubstituted Thiazoles
A mixture of thiosemicarbazide (1 mmol), α-bromoketones (1) (1 mmol), and alde-
hyde (2) (1 mmol) was ground at room temperature with a glass pestle in a glass mortar.
The progress of the reaction was monitored by TLC. After completion of the reaction, the
product was washed with dehydrated alcohol or ethyl acetate (3 × 10 mL). The combined
organic solvent was removed under vacuum to obtain the crude solid product. The crude
product was purified by silica gel column chromatography using ethyl acetate/petroleum
ether (1:3) as eluent to afford the pure product 3.
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