Zirconium(IV) oxide chloride and anhydrous copper(II) sulfate mediated synthesis of 2-substituted benzothiazoles

Article abstract of DOI:10.1002/hc.20191

A simple, fast and efficient benign procedure has been developed for one-pot synthesis of 2-substituted benzothiazoles in the presence of zirconium(IV) oxide chloride octahydrate (ZrOCl₂·8H ₂O) and anhydrous copper(II) sulfate. The reaction of 2-aminothiophenol with aldehydes and anhydrides was carried out efficiently in solvent-free conditions with or without microwave irradiation, and adducts were produced in good to excellent yields.

Full text of DOI:10.1002/hc.20191

Heteroatom Chemistry
Volume 17, Number 2, 2006
Z
irconium(IV) Oxide Chloride and Anhydrous
Copper(II) Sulfate Mediated Synthesis of
2-Substituted Benzothiazoles
Firouz Matloubi Moghaddam, Hossein Ismaili,
and Ghasem Rezanejade Bardajee
Department of Chemistry, Sharif University of Technology, PO Box 11365-9516 Tehran, Iran
Received 24 September 2005; revised 26 October 2005
used in industry as antioxidants and vulcanization
ABSTRACT: A simple, fast and efficient benign
accelerators that highlight their synthesis necessity
procedure has been developed for one-pot synthe-
sis of 2-substituted benzothiazoles in the pres-
ence of zirconium(IV) oxide chloride octahydrate
[18].
Organic and medicinal chemists are paying
tremendous attention for the simplification or im-
provement of the existing methods that are widely
used in the manufacture of pharmaceutical and in-
dustrial substances. Reactions under solid support,
chemoenzymatic reactions, and microwave-induced
reactions have already created an enormous impact
in modern science. On the other hand, the develop-
ment of simple synthetic routes for widely used or-
ganic compounds from readily available reagents is
one of the major tasks in organic synthesis.
(
ZrOCl
2
·8H
2
O) and anhydrous copper(II) sulfate. The
reaction of 2-aminothiophenol with aldehydes and
anhydrides was carried out efficiently in solvent-
free conditions with or without microwave irradia-
tion, and adducts were produced in good to excellent
yields. ꢀC 2006 Wiley Periodicals, Inc. Heteroatom Chem
1
7:136–141, 2006; Published online in Wiley InterScience
(
www.interscience.wiley.com). DOI 10.1002/hc.20191
In the literature, it is shown that there are
few methods for the synthesis of benzothiazoles.
The important ones include the reaction of 2-
aminothiophenol with the substituted aromatic
aldeydes and carboxylic acids or its derivatives
in polyphosphate ester [19], polyphosphoric acid
INTRODUCTION
Benzothiazole and their derivatives are very impor-
tant group of heterocyclic bicyclic systems [1], which
play a fundamental role in organic and bioorganic
chemistry. Because of their potent antitumor activ-
ity [2–5] and other important pharmaceutical utili-
ties [6–9] such as their applications for treatment of
autoimmune and inflammatory diseases, prevention
of solid organ transplant rejection, epilepsy, analge-
sia, viral infections, cancer, and tuberculosis [10–16],
there is significant interest in the synthesis of these
compounds in recent years [17]. Also, they can be
[20], or a mixture of methane-sulfonic and phos-
phorous pentoxide [21]; radical cyclization of
phenylthioformamides in the presence of potas-
sium ferricyanide [22] or bromine [23]; Pd-catalyzed
cyclization of 2-bromophenylthioformamides [24];
palladium-catalyzed reaction of aryl halides with
2
-aminothiophenol in the presence of carbon
monoxide [25]; reaction of copper(I) thiobenzoate
and 2-iodoanilines [26]; and the action of se-
lenoamides on 2-aminothiophenol [27]. Most of
these protocols, however, suffer from drawbacks,
namely harsh reaction condition, high thermal
Correspondence to: Firouz Matloubi Moghaddam; e-mail:
matloubi@sharif.edu.
ꢀ
c 2006 Wiley Periodicals, Inc.
1
36

Zirconium(IV) Oxide Chloride and Anhydrous Copper(II) Sulfate Mediated Synthesis of 2-Substituted Benzothiazoles 137
conditions, long reaction time, and the use of acid
or base catalysts and toxic metallic compounds that
result in waste streams.
DMSO-d at ambient temperature. The microwave
6
oven used for this work was ETHOS-MR (800 W,
◦
120 C) at 2450 MHz. Melting points were determined
Microwave-assisted reactions in solvent-free
condition have gained popularity because of rapid
reaction rate, cleaner reaction, and ease of ma-
nipulation [28]. Recently, some methods use mi-
crowave heating for the synthesis of 2-substituted
benzothiazoles such as condensation of aromatic or
on a Buchi B540 apparatus.
General Procedure for the Synthesis of
2-Substituted Benzothiazole Compounds in
Solvent-Free Condition
aliphatic aldehydes with 2-aminothiophenol on SiO
2
A mixture of 2-aminothiophenol (1 mmol), aro-
matic aldehyde (1 mmol), and catalytic amount
[29], aromatic aldehydes with 2-aminothiophenol
−
3
in the presence of nitrobenzene/SiO
2
or nitroben-
of zirconium(IV) oxide chloride octahydrate (10
◦
zene/montmorillonite K10 [30], aromatic aldehy-
des with 2-aminothiophenol in an ionic liquid
mmol) was stirred at 70 C (see Table 1) for appro-
priate time as required for completion of the re-
action, which was monitored by TLC. The mixture
was chromatographed over silica gel or PTLC using
petroleum ether: ethyl acetate (4:1) to afford the pure
product.
[
31], ortho-esters with 2-aminothiophenol using KFS
clay [32], benzaldoximes or aromatic aldehydes
with 2-aminothiophenol using Ca(OCl) /Al or
MnO /SiO [33], and Mn(III)-promoted cyclization
2
2
O
3
2
2
of substituted thioformanilides [34].
Zirconium(IV) oxide chloride can function as a
convenient medium as well as a Lewis acid in sol-
vent and/or in solvent-free conditions [35]. Due to
their availability and low toxicity, Zr(IV) salts have
General Procedure for the Synthesis of
2
-Substituted Benzothiazole Compounds in
Microwave-Assisted Solvent-Free Condition
recently attracted much attention [36]. ZrOCl
2
·8H
2
O
A mixture of 2-aminophenol (1 mmol), aldehyde
or anhydride (1 mmol), and anhydrous copper
sulfate(II) (0.6 g) or catalytic amount of zirco-
nium(IV) oxide chloride octahydrate (10 mmol)
was placed in a Teflon flask (∼20 mL) and sub-
jected to microwave irradiation for appropriate time
(see Tables 1 and 2). The reaction mixture was
chromatographed over silica gel or PTLC using
petroleum ether:ethyl acetate (4:1) to afford the pure
product.
is a moisture stable, readily available, and inex-
pensive oxysalt of Zr and thus its handling is eas-
ier in comparison to that of the moisture-sensitive
−
3
ZrCl . On the other hand, various copper salts were
4
used extensively in organic synthesis and recently
we have reported an efficient method for chemose-
lective dithioacetalization of aldehydes either in sol-
vent and/or under solvent-free conditions using an-
hydrous copper sulfate [37].
Herein, we report an efficient, clean, fast, and
mild method for the reaction of 2-aminothiophenol
with various aldehydes and anhydrides in solvent-
free conditions with or without microwave irradi-
ation using anhydrous copper sulfate and zirco-
nium(IV) oxide chloride separately (Scheme 1).
RESULTS AND DISCUSSION
Our investigations showed that 2-aminothiophenol
reacts smoothly with aldehydes and anhydrides in
the presence of zirconium(IV) oxide chloride or an-
hydrous copper sulfate. The corresponding benzoth-
iazoles were obtained in high to excellent yields. At
first, we focused on zirconium(IV) oxide chloride as a
catalyst in various conditions (solvent, solvent-free,
and microwave irradiation). The best results were
obtained in solvent-free conditions with or without
microwave irradiation (see Table 3, entries 4 and 5).
In a typical procedure, 2-aminothiophenol (1 mmol)
with benzaldehyde (1 mmol) in the presence of a
EXPERIMENTAL
The compounds gave all satisfactory spectroscopic
data. IR spectra were taken as thin films for liquid
compounds and as KBr pellets for solids on a Nico-
let spectrometer (Magna 550). A Bruker (DRX-500
1
Avance) NMR was used to record the H NMR spec-
tra. All NMR spectra were determined in CDCl and
3
−3
◦
catalytic amount of ZrOCl
forded the desired 2-substituted benzothiazole in
0% yield. Then the reaction was applied to a va-
2
(10 mmol) at 70 C af-
9
riety of aromatic aldehydes and anhydrides. The re-
sults are summarized in Table 1. Most of these reac-
tions proceeded in relatively short times, and pure
products were obtained by crystallization or PTLC.
SCHEME 1 General reaction.

1
38 Matloubi Moghaddam, Ismaili, and Rezanejade Bardajee
TABLE 1 Synthesis of 2-Substituted Benzothiazoles Catalyzed by ZrOCl ·8H O in Various Solvent-Free Conditions
2
2
Aldehyde or
Anhydride
Entry
Product
Yield a,b (%)
Yield a,c (%)
1
PhCHO
90
90 [31]
2
3
4
5
88
88
72
75
90 [31]
87 [31]
81 [31]
80 [29]
6
7
8
65
76
60
76 [31]
82 [31]
64 [31]
9
71
60
92
63 [29]
62 [31]
92 [34]
1
1
0
1
1
1
2
3
74
92
76 [8]
90
aAll yields refer to isolated products and the products were characterized by mp, IR, 1H-NMR, and their physical data were similar to those
reported in the literature.
b
c
◦
The reactions were carried out at 70 C without microwave irradiation for 3 h.
The reactions were carried out in microwave-assisted solvent-free condition for 4 min.
These reactions were also repeated in solvent-free
conditions and under microwave irradiation. In this
case similar yields were obtained in shorter reaction
times.
Anhydrous copper sulfate as a good and cheap
medium has also been used for this reaction. Af-
ter optimization of the reaction conditions (solvent,
solvent-free, and microwave irradiation), the best
choice was found, microwave-assisted solvent-free
conditions (see Table 3, entry 10). Aliphatic and
aromatic aldehydes and anhydrides efficiently re-
acted with 2-aminothiophenol in the presence of

Zirconium(IV) Oxide Chloride and Anhydrous Copper(II) Sulfate Mediated Synthesis of 2-Substituted Benzothiazoles 139
TABLE 2 Anhydrous Copper(II) Sulfate Mediated Synthesis of 2-Substituted Benzothiazoles from 2-Aminothiophenol under
Microwave Irradiation
Aldehyde or
Anhydride
Entry
Product
Time (min)
Yield a (%)
1
PhCHO
3
90
2
3
4
5
3
3
4
4
94
90
73
76
6
7
8
3
3
3
67
77
60
9
3
3
3
72
56
94
1
1
0
1
1
1
1
1
1
1
2
3
4
5
6
7
5
5
5
5
5
3
75
54 [29]
55 [29]
54
54
91
aAll yields refer to isolated products and the products were characterized by mp, IR, 1H-NMR, and their physical data were similar to those
reported in the literature.

1
40 Matloubi Moghaddam, Ismaili, and Rezanejade Bardajee
TABLE 3 Condensation of 2-Aminothiophenol and Benzaldehyde under Different Conditions
Entry
Solvent
Condition
Lewis Acid
Time
Isolated Yield (%)
1
2
3
4
5
6
7
8
9
EtOH
Reflux
Reflux
Reflux
70 C
MW
Zirconium(IV) oxide chloride
Zirconium(IV) oxide chloride
Zirconium(IV) oxide chloride
Zirconium(IV) oxide chloride
Zirconium(IV) oxide chloride
Anhydrous copper(II) sulfate
Anhydrous copper(II) sulfate
Anhydrous copper(II) sulfate
Anhydrous copper(II) sulfate
Anhydrous copper(II) sulfate
3 h
3 h
3 h
3 h
3 min
3 h
3 h
3 h
3 h
3 min
85
25
62
90
90
84
77
79
88
90
CH Cl
2
2
CH CN
3
◦
Solvent free
Solvent free
EtOH
Reflux
Reflux
Reflux
CH Cl
2
2
CH CN
3
◦
Solvent free
Solvent free
100 C
10
MW
with a variety of aldehydes and anhydrides. Further-
more, the use of microwave irradiation considerably
decreases the time of the reaction.
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