A simple, microwave-assisted, and solvent-free synthesis of 2-arylbenzothiazoles by acetic acid-promoted condensation of aldehydes with 2-aminothiophenol in air

Article abstract of DOI:10.1080/10426500802423933

An efficient and simple procedure has been developed for the synthesis of various 2-arylbenzothiazoles by acetic acid-promoted condensation of 2 -aminothiophenol with aromatic aldehydes under microwave irradiation and solvent-free conditions in high yield

Full text of DOI:10.1080/10426500802423933

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A Simple, Microwave-Assisted,
and Solvent-Free Synthesis
of 2-Arylbenzothiazoles
by Acetic Acid–Promoted
Condensation of Aldehydes
with 2-Aminothiophenol in Air
Davood Azarifar a , Behrooz Maleki a & Mehrnaz
Setayeshnazar a
a Faculty of Chemistry, Bu-Ali Sina University,
Hamadan, Iran
Version of record first published: 22 Jul 2009
To cite this article: Davood Azarifar, Behrooz Maleki & Mehrnaz Setayeshnazar (2009):
A Simple, Microwave-Assisted, and Solvent-Free Synthesis of 2-Arylbenzothiazoles
by Acetic Acid–Promoted Condensation of Aldehydes with 2-Aminothiophenol in Air,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:8, 2097-2102
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Phosphorus, Sulfur, and Silicon, 184:2097–2102, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802423933
A Simple, Microwave-Assisted, and Solvent-Free
Synthesis of 2-Arylbenzothiazoles by Acetic
Acid–Promoted Condensation of Aldehydes with
2-Aminothiophenol in Air
Davood Azarifar, Behrooz Maleki, and Mehrnaz
Setayeshnazar
Faculty of Chemistry, Bu-Ali Sina University, Hamadan, Iran
An efficient and simple procedure has been developed for the synthesis of various
2-arylbenzothiazoles by acetic acid–promoted condensation of 2-aminothiophenol
with aromatic aldehydes under microwave irradiation and solvent-free conditions
in high yields.
Keywords Aldehydes; 2-aminothiophenol; 2-arylbenzothiazoles; microwave irradiation
INTRODUCTION
Among various benzazoles, 2-substituted benzothiazoles are an impor-
tant class of biologically active compounds.1–5 The 2-arylbenzothiazole
nucleus exists as the core unit in a myriad of pharmaceutical
agents, including antitumor drugs.5,6 In addition, 2-arylbenzothiazoles
have been used as fluorescent whiting agents7 and photochromic
compounds.8 A number of such compounds play a prominent thera-
peutic role, for example, in the prevention of solid organ transplant
rejection,9 epilepsy,10 amyotrophic lateral sclerosis,11 analgesia,12 and
tuberculosis.13 Benzothiazoles are also useful synthetic intermedi-
ates that are prone to various transformations and transition-metal–
catalyzed cross-coupling reactions, such as Heck,14 Negishi,15 Stille,16
and Sonogashira17 couplings. Thus, synthesis of these heterocyclic
systems is of much interest, and considerable research has been di-
rected towards these compounds.18 Two important methods reported
Received 18 March 2008; accepted 21 August 2008.
We wish to thank the Research Council of Bu-Ali Sina University, Hamedan, Iran, for
financial support to carry out this research.
Address correspondence to Davood Azarifar, Faculty of Chemistry, Bu-Ali Sina Uni-
versity, Hamadan 65178, Iran. E-mail: azarifar@basu.ac.ir
2097

2098
D. Azarifar et al.
for the synthesis of benzothiazoles are (i) condensation of aldehydes
with 2-aminothiophenol19 using DMSO/120◦C,19a ionic liquid 1-phenyl-
3-methylimidazoliumbromide ([pmIm]Br),19b scandium triflate,19c
silica gel,19d MnO2/SiO2,19e molecular iodine,19f molecular oxygen pro-
moted by activated carbon,19g p−TsOH,19h SiO2/graphite,19i elec-
trochemical synthesis in methanol containing sodium acetate as
supporting electrolyte,19j water/110◦C,19k carboxylic acids,20 acid
chlorides,21 or esters22; and (ii) cyclization of thiobenzanilides.23
Several other miscellaneous methods have been reported includ-
ing microwave-mediated reaction of 2-aminothiophenol with β-
chlorocinnamaldehydes,24 palladium-catalyzed Suzuki biaryl coupling
of 2-bromobenzothiazoles with arylboronic acids,25 coupling of ben-
zothiazoles with arylbromides,26 and reaction of thiophenol with
aromatic nitriles.27 However, many of these procedures are sub-
ject to certain disadvantages, such as the use of toxic and/or costly
catalysts18d,18f,19d; hazardous and carcinogenic organic solvents such
as nitrobenzene,18cacetonitrile,26 and dioxane18f ; and multistep process
for reactions.20a,20d To eliminate the harmful effects of these organic
solvents often used in large quantities for organic transformations, se-
rious steps have been recently taken toward alternative green synthetic
procedures.1,2
RESULTS AND DISCUSSION
To make a contribution towards the elimination of the above-mentioned
drawbacks, we were prompted to report here a very simple, be-
nign, and environmentally friendly procedure for the synthesis of 2-
arylsubstituted benzothiazoles. In this report, we have employed a cat-
alytic amount of glacial acetic acid as a very mild, inexpensive, and
nontoxic catalyst when compared with the previously reported strong
and non-green acids, such as p-TsOH,19h to effect the synthesis of a
variety of 2-arylbenzothiazoles (2a–p) by direct and solvent-free con-
densation of arylaldehydes (1a–p) with 2-aminothiophenol under both
microwave irradiation and conventional thermal heating in high yields
(72–96%; Table I, Scheme 1). To obtain the best reaction temperature
SCHEME 1

Synthesis of 2-Arylbenzothiazoles
2099
TABLE I Synthesis of 2-Arylbenzothiazoles (2a–p) by Acetic
Acid–Promoted Condensation of Aldehydes (1a–p) with
2-Aminothiophenol Under Both Microwave Irradiation and
Conventional Heating Conditionsa
Mp (◦C)
Productb
R
Time (min)
Yield (%)c
Found
Reported
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4-MeOC6H4
2-ClC6H4
3-O2NC6H4
2-HOC6H4
C6H5
15 (5)
20 (5)
15 (4)
25 (5)
15 (4)
20 (5)
20 (4)
20 (6)
15 (3)
30 (8)
20 (5)
20 (4)
35 (10)
25 (4)
20 (7)
15 (4)
90 (90)
70 (80)
86 (92)
75 (80)
90 (84)
80 (84)
84 (88)
78 (80)
96 (92)
78 (72)
70 (70)
76 (79)
70 (70)
80 (74)
74 (64)
80 (72)
119–121
81–83
120–12119d
84–8519d
182–184
122–124
110–112
100–103
116–117
99–102
165–166
85–87
227–228
133–135
52–54
129–131
98–100
84–86
181–18219f
125–12619d
112–11319d
103–10419d
115–11719d
101–10319d
162–16419i
84–8619d
2-Furyl
4-ClC6H4
2-MeO C6H4
4-NCC6H4
4-MeC6H4
4-HOC6H4
2-O2NC6H4
2-MeC6H4
4-BrC6H4
4-FC6H4
225–22619d
135–13619d
53–5419d
130–13119i
101–10319f
84–8619i
3-BrC6H4
aThe reaction times and yields under microwave irradaiation condition are shown in
the parenthesis.
bProducts were characterized by their physical properties, comparison with
authentic samples, and by their spectral (1H-NMR, 13C-NMR, IR) analysis.
cIsolated yields.
for thermal reactions or the best power level for microwave-irradiated
reactions, optimization was carried out, for example, for the reaction
of 4-methoxybenzaldehyde with 2-aminothiophenol at various temper-
atures or different power levels. It was noticed that 70◦C was the best
temperature for thermal reactions (15 min, 90%), and also the most
convenient power level found to produce the highest yield in short-
est time was 60%. It is noticed that the application of the microwave
(MW) irradiation technique has a profound effect on the acceleration
of these reactions, providing short reaction times without any consid-
erable change in the yields of the products. The rate-enhancing role
of microwave irradiation is now believed to be presumably due to the
selective absorption of MW energy by polar molecules such as acetic
acid or polar intermediates formed in the course of the reactions.28 It is
important to mention that when these reactions are carried out under

2100
D. Azarifar et al.
conventional heating conditions (70◦C), much longer periods of time
(15–35 min) are required.
When these reactions are run at room temperature, only a trace
amount of benzothiazoles are formed, and the reactions are mainly
ended with the formation of imines, as reported by others.19b,19e This
implies that the mechanism of the reaction most likely involves the
prior formation of an intermediate imine that undergoes cyclization
with the –SH group under reflux conditions or microwave irradiation
followed by dehydrative oxidation in air to yield benzothiazole.
In conclusion, the present work offers a simple procedure promoted
by inexpensive and nontoxic glacial acetic acid as an efficient method-
ology for the synthesis of 2-substituted benzothiazoles through both
thermal heating and microwave-assisted condensation of aromatic
aldehydes with 2-aminothiophenol. The significant advantages of
this procedure are (a) very fast reaction (3–10 min), (b) mild reaction
conditions compatible with a variety of sensitive groups, (c) high yields,
(d) low cost of AcOH as the catalyst, and (e) green aspects avoiding
hazardous solvents, toxic catalysts, and waste.
EXPERIMENTAL
General Procedure for the Synthesis of 2-Arylbenzothiozoles
Microwave Irradiation
2-Aminothiophenol (1 mmol), aldehydes 1a–p (1 mmol), and a cat-
alytic amount of acetic acid (2 mmol) were thoroughly mixed in an
open glass tube. The tube was placed in an alumina bath in a domestic
microwave oven (model: Black & Decker, MX30PG 1000 watt) and irra-
diated for an appropriate time (3–10 min) (Table I) at power level of 60%
with intermittent cooling after each 30 sec of irradiation. The progress
of the reactions was monitored by TLC (n−hexane:ethyl acetate, 2:8),
and the products were recrystallized from EtOH (96%) following their
extraction from the reaction mixture (Table I).
Thermal Heating Condition
2-Aminothiophenol (1 mmol), aldehydes 1a–p (1 mmol), and a cat-
alytic amount of acetic acid (2 mmol) were thoroughly mixed in an open
glass tube. The tube was placed in a water bath at 70◦C for 15–35 min
(Table I). After complete conversion of the substrates (as monitored by
TLC using n-hexane:ethyl acetate, 2:8), the products 2a–p were pu-
rified by recrystallization from EtOH (96%) following their extraction
from the reaction mixture (Table I).

Synthesis of 2-Arylbenzothiazoles
2101
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