An environmentally benign procedure for the synthesis of substituted 2-thiobenzothiazoles, 2-thiobenzoxazoles, 2-thiobenzimidazoles, and 1,3-oxazolopyridine-2-thiols

Article abstract of DOI:10.1007/s00706-011-0551-1

An improved environmentally benign procedure for the synthesis of substituted 2-thio-benzothia(oxa)zoles, 2-thiobenzimidazoles, and 1,3-oxazolopyridine-2-thiols by cyclization of 2-aminophenols, 2-aminothiophenols, 1,2-phenylenediamines, or 2-amino-3-hydroxypyridines with potassium O-ethyldithiocarbonate in PEG 400 or glycerol under directed microwave irradiation is described. The method can be applied to the synthesis of a variety of derivatives. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0551-1

Monatsh Chem (2011) 142:895–899
DOI 10.1007/s00706-011-0551-1
ORIGINAL PAPER
An environmentally benign procedure for the synthesis
of substituted 2-thiobenzothiazoles, 2-thiobenzoxazoles,
2-thiobenzimidazoles, and 1,3-oxazolopyridine-2-thiols
•
Todor G. Deligeorgiev Stefka S. Kaloyanova
•
•
Nedyalko Y. Lesev Juan J. Vaquero
Received: 11 November 2010 / Accepted: 8 June 2011 / Published online: 13 July 2011
Ó Springer-Verlag 2011
Abstract An improved environmentally benign procedure
for the synthesis of substituted 2-thio-benzothia(oxa)zoles,
2-thiobenzimidazoles, and 1,3-oxazolopyridine-2-thiols
by cyclization of 2-aminophenols, 2-aminothiophenols,
1,2-phenylenediamines, or 2-amino-3-hydroxypyridines
with potassium O-ethyldithiocarbonate in PEG 400 or
glycerol under directed microwave irradiation is described.
The method can be applied to the synthesis of a variety of
derivatives.
fungicides, and bactericides [8, 9]. Furthermore, certain
compounds that contain the benzothiazolyl structural
moiety have in vitro antitumor properties [10].
One of the most important applications of heterocyclic
2-thiones, which are of particular interest to us, is their use
as intermediates [11] in the synthesis of monomethine
cyanine dyes. Their structural diversity and the ability to
modify this type of structure can produce dyes superior to
those currently used [12, 13]. Typically, the main part of
the synthetic steps for obtaining dye structures involves the
preparation of starting materials. The proposed procedure
greatly facilitates the synthesis of such important
intermediates.
Keywords 2-Thiobenzothiazoles ꢀ 2-Thiobenzoxazoles ꢀ
2-Thiobenzimidazoles ꢀ 1,3-Oxazolopyridine-2-thiols ꢀ
Microwave synthesis ꢀ Green chemistry
The known synthetic procedures for obtaining
2-thiobenzoxazoles, 2-thiobenzothiazoles, and 2-thiobenz-
imidazoles from the corresponding 2-aminophenols,
2-aminothiophenols, and 1,2-phenylenediamines are based
on the direct use of toxic and hazardous reagents such as
carbon disulfide [1, 14–16]. A solvent-free synthetic meth-
odology to obtain 2-mercaptobenzimidazoles is also known
[17]; however, the experimental conditions in this case
involve relatively long reaction times (4–24 h), high reac-
tion temperatures, heating under an inert atmosphere, and
laborious procedures are usually required for the isolation of
the products, which are often obtained in 60–70% yields.
The reported methods that involve the use of 2-amino-3-
hydroxypyridine as the starting material include heating
under reflux with carbon disulfide in the presence of base or
direct reaction with potassium O-ethyldithiocarbonate in an
appropriate solvent [16, 18]. The synthesis of 2-thiobenz-
oxazoles, 2-thiobenzothiazoles, 2-thiobenzimidazoles, and
1,3-oxazolopyridine-2-thiols from the corresponding
2-aminophenols, 2-aminothiophenols, 1,2-phenylenediam-
ines, and 2-amino-3-hydroxypyridine under directed micro-
wave irradiation has not been reported.
Introduction
Heterocyclic 2-thiones are an important group of com-
pounds with numerous applications as starting materials in
the synthesis of various intermediates and final products [1,
2], many of which show a wide range of biological activ-
ities [3–6], e.g., as highly effective herbicides [7],
´
Dedicated to Professor Julio Alvarez-Builla on the occasion of his
65th birthday.
T. G. Deligeorgiev (&) ꢀ S. S. Kaloyanova ꢀ N. Y. Lesev
Faculty of Chemistry, University of Sofia,
1 James Bourchier Avenue, 1164 Sofia, Bulgaria
e-mail: toddel@chem.uni-sofia.bg
J. J. Vaquero
Facultad de Farmacia, Universidad de Alcala,
28871 Alcala de Henares, Madrid, Spain
123

896
T. G. Deligeorgiev et al.
In recent years, a wide range of practical applications have
cyclization has been reported [1, 19]. We envisaged that
these processes could be carried out in green solvents, with
simple equipment and an easy work-up to provide an
environmentally benign approach.
been identified for microwave irradiation in organic synthesis.
These applications are attractive as a result of considerable
advantages such as the perceptible reduction of the reaction
time and the reliable, simple, highly reproducible synthetic
procedures that have, in most cases, reduced environmental
impact and ensure higher yields of the desired products.
The improved synthetic procedure to obtain substituted
hetaryl thiols involves the use of a Biotage microwave
system (Initiatior 2.5) with directed microwave irradiation.
The cyclization was carried out at low microwave power
without a catalyst and in glycerol or PEG 400, which have
been confirmed as eco-friendly solvents [20, 21]. In this
way the use of toxic solvents was avoided. The application
of PEGs and glycerol [22] in synthetic organic chemistry as
eco-friendly reaction media represents both an opportunity
and a challenge, and the wide availability of these solvents
at low cost may give such processes a promising future in
green chemistry [21, 23].
Results and discussion
It was of particular interest to us to study the application of
directed microwave irradiation to the cyclization reaction
of 1,2-phenylenediamine, 2-amino-3-hydroxypyridines,
2-aminophenols, or 2-aminothiophenols with potassium
O-ethyldithiocarbonate (Scheme 1). The mechanism of this
nucleophilic aromatic substitution reaction and subsequent
On the basis of previously reported results [18] as well
as our own experimental data, optimization of the reaction
conditions was investigated (Table 1). The best yields for
shorter reaction times were obtained when 2.2–2.5 molar
equivalents of potassium O-ethyldithiocarbonate was used.
The best yields of 3b and 3e were obtained on irradi-
ating the reaction mixture for 5 min at 30 W (Table 1,
entry 1) or for 2 min at 45 W (Table 1, entry 13) in the
presence of glycerol or PEG 400. Complete consumption
of the starting materials (i.e., they were no longer detected
by TLC) was considered to represent the end of the
R
Z
S
S
R
R
X
N
H
Z
2
KS
OC2H5
SH
PEG-400
N
Y
NH2
Y
O
N
or
1a-1k
glycerol
3a-3k
S
N
H
X = OH, SH, NH2
Y = CH, N
Z = S, N, O
R = H, Cl, CH3, NO2, COPh
Scheme 1
Table 1 Optimization of
reaction conditions for
compounds 3b and 3e in the
Biotage microwave system
Entry
1
Compound
Solvent
Power/W
30
Irradiation
time/min
Final temperature
reached/°C
Isolated
yield/%
3b
Glycerol
5
140
94
S
N
SH
2
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
PEG 400
Glycerol
Glycerol
Glycerol
PEG 400
Glycerol
Glycerol
Glycerol
Glycerol
Glycerol
PEG 400
30
40
40
45
45
50
60
70
80
90
30
5
127
155
185
163
165
170
175
185
230
277
130
78
81
90
79
86
64
92
93
89
3
3
4
4
5
2
6
2
7
2
8
1.5
1
9
10
11
12
1
a
1
–
3e
5
80
Cl
O
SH
N
13
14
15
16
3e
3e
3e
3e
PEG 400
Glycerol
PEG 400
PEG 400
45
45
70
80
2
2
1
1
165
167
200
228
92
89
85
83
a
Reaction overheated
123

An environmentally benign procedure
897
Table 2 Starting compounds, reaction conditions, and isolated yields for products 3a–3 k
Starting compound
Product
Biotage microwave system
m.p./°C
Irradiation
Time/min
Power/W
Final reached
temperature/°C
Yield/%
81
Solvent
m.p. reported/°C
5
5
3
3
2
3
3
3
3
30
142
140
152
155
165
153
155
152
153
Glycerol
241–243
243 [25]
OH
O
SH
SH
N
N
N
NH2
3a
1a
1b
1c
1d
1e
1f
30
40
40
45
40
40
40
40
94
83
91
92
87
89
75
78
Glycerol
PEG 400
Glycerol
PEG 400
PEG 400
Glycerol
PEG 400
PEG 400
174–176
167 [26]
SH
S
N
3b
NH2
204–205
PhOC
SH
PhOC
S
SH
N
NH2
3c
193–195
191 [26]
OH
O
SH
N
3d
NH2
222–225
Cl
OH
NH2
Cl
O
N
224–225 [27]
SH
3e
3f
208–210/
PhOC
OH
NH2
PhOC
H3C
O2N
O
N
210–212 [28]
SH
207–209/
209 [29]
H3C
OH
O
SH
N
NH2
3g
3h
1g
1h
1i
215–216/
O2N
OH
O
N
216–217 [30]
SH
SH
NH2
242–244/
OH
O
N
244–245 [31]
O2N
O2N
NH2
3i
123

898
T. G. Deligeorgiev et al.
Table 2 continued
Starting compound
Product
Biotage microwave system
m.p./°C
Irradiation
Time/min
Power/W
Final reached
temperature/°C
Yield/%
84
Solvent
m.p. reported/°C
2
45
163
PEG 400
298–301/
NH2
H
N
301–303 [32]
SH
NH2
N
1j
3j
3
40
155
81
PEG 400
289–291/
H3C
NH2
NH2
H
N
H3C
290–92 [17]
SH
N
1k
3k
reaction. Irradiation at power levels below 30 W did not
lead to a sufficiently high temperature for the starting
compounds to react and in these cases longer irradiation
times were needed. Irradiation at power levels higher than
80 W led to overheating of the reaction mixture (entry
11—temperature in the reaction mixture reached about
260 °C) and a decrease in the yield (Table 1, entry 10).
Furthermore, a high pressure resulted when the reaction
was carried out in a closed vial at higher power.
Experimental
All products were characterized and/or compared with
reported data. Melting points were obtained on a Gal-
lenkamp apparatus and are corrected. H NMR and 13C
1
NMR spectra of the compounds not reported previously
were recorded on a Varian 200 MHz spectrometer in
DMSO-d6 as solvent. Elemental analyses were performed
on a Vario III instrument. The reactions were carried out in
a Biotage microwave system (Initiator 2.5). Experiments
were performed in power-control mode and the tempera-
ture was monitored using the built-in calibrated IR sensor.
The progress of the reactions was monitored by TLC
(Merck F 254 silica gel; dichloromethane/n-heptane 4:1).
All starting materials and solvents were commercial
products from Sigma-Aldrich, except for compounds 1c,
1f, and 1g which were synthesized by known procedures
[29, 33, 34]. Analytical samples of the reaction prod-
ucts were obtained by recrystallization from methanol or
ethanol.
The experiments carried out for the optimization of the
reaction conditions did not highlight which solvent—
glycerol or PEG 400—was better in terms of the product
yield or the rate of the reaction. Both solvents are suitable
for obtaining the products in good to excellent yields.
Glycerol has more advantages from an economical and
environmental point of view [22–24].
These conditions were extended to the synthesis of dif-
ferent hetaryl thiols with various substituents (Table 2). The
reaction was found to be generally applicable to various
2-aminophenols, 2-aminothiophenols, 1,2-phenylenediam-
ines, and 2-amino-3-hydroxypyridines, regardless of the
substituents in the aromatic nucleus (products 3a–3k).
In conclusion, we have demonstrated that heterocyclic
2-thioles can be synthesized from various 2-amino-3-
hydroxypyridines, 2-aminophenols, 1,2-phenylene-dia-
mine, or 2-aminothiophenols under green mild reaction
conditions with directed microwave irradiation (Table 2)
ensuring energy efficiency. The demonstrated approach is
highly reproducible and can be applied to the synthesis of a
variety of 2-thiohetaryl derivatives with different substit-
uents in the aromatic nucleus and gives products with high
purity and in short reaction times. Green solvents were
used and the reaction procedure ensures the easy isolation
of the products and solvent recyclability.
General procedure for preparation of compounds
in the Biotage microwave system
The starting compounds 1a–1k (0.001 mol) and potassium
O-ethyldithiocarbonate (2, 0.0025 mol) were mixed in a
2- to 5-cm3 microwave vial with 2–3 cm3 of the appro-
priate solvent (PEG 400 or glycerol). The reaction mixture
was homogenized and pre-stirred for 4 min and irradiated
at 30–45 W for a time ranging between 2 and 5 min
(Table 2). The product (3a–3k) was dissolved in 1–2 cm3
of ethanol and precipitated by dilution with water
(50 cm3), acidified to pH 3–4 with CH3COOH, filtered,
and air-dried.
123

An environmentally benign procedure
899
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6-Benzoylbenzothiazole-2-thiol (3c, C14H9NOS2)
M.p.: 204–205 °C; 1H NMR (200 MHz, DMSO-d6):
d = 14.42 (s, 1H, SH), 8.52 (s, 1H, ArH), 7.82 (d, 2H,
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