One-pot synthesis of 1,3,4-thiadiazoles using Vilsmeier reagent as a versatile cyclodehydration agent

Article abstract of DOI:10.1016/j.tet.2017.02.042

A simple and efficient synthetic method for the one-pot synthesis of 1,3,4-thiadiazoles utilizing Vilsmeier reagent was developed. In this method carboxylic acids and hydrazine were converted to 1,3,4-thiadiazoles in the presence of Vilsmeier reagent and Lawesson's reagent. The influence of the thionation reagent, solvent, temperature and time, in this reaction was discussed. The developed methodology for 1,3,4-thiadiazole synthesis has the advantage of simplicity, ambient reaction conditions, easy purification and good to excellent yield of products.

Full text of DOI:10.1016/j.tet.2017.02.042

Accepted Manuscript
One-pot synthesis of 1,3,4-thiadiazoles using Vilsmeier reagent as a versatile
cyclodehydration agent
Maaroof Zarei
PII:
S0040-4020(17)30181-3
10.1016/j.tet.2017.02.042
TET 28483
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 December 2016
Revised Date: 10 February 2017
Accepted Date: 20 February 2017
Please cite this article as: Zarei M, One-pot synthesis of 1,3,4-thiadiazoles using Vilsmeier reagent as a
versatile cyclodehydration agent, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.042.
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ACCEPTED MANUSCRIPT
Graphical Abstract
One-pot synthesis of 1,3,4-thiadiazoles using
Vilsmeier reagent as a versatile
cyclodehydration agent
Leave this area blank for abstract info.
Maaroof Zarei

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
One-pot synthesis of 1,3,4-thiadiazoles using Vilsmeier reagent as a versatile
cyclodehydration agent
Maaroof Zarei
Department of Chemistry, Faculty of Sciences, University of Hormozgan, Bandar Abbas 71961, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient synthetic method for the one-pot synthesis of 1,3,4-thiadiazoles utilizing
Vilsmeier reagent was developed. In this method carboxylic acids and hydrazine were converted
to 1,3,4-thiadiazoles in the presence of Vilsmeier reagent and Lawesson’s reagent. The influence
of the thionation reagent, solvent, temperature and time, in this reaction was discussed. The
developed methodology for 1,3,4-thiadiazole synthesis has the advantage of simplicity, ambient
reaction conditions, easy purification and good to excellent yield of products.
Available online
Keywords:
1,3,4-thiadiazoles
Diacylhydrazine
Vilsmeier reagent
Lawesson’s reagent
Acylhydrazine
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
According to their importance, it is not surprising that many
synthetic methods for the preparation of 1,3,4-thiadiazoles have
been reported.3 1,3,4-Thiadiazoles are generally prepared by
conversion of diacylhydrazines to thiahydrazines and then
Thiadiazole is a five membered heterocyclic ring which is an
efficient lead compound for preparation of potent bioactive
agents. There are several isomers of thiadiazole including 1,2,3-
thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-
thiadiazole which a literature survey shows 1,3,4-thiadiazole has
been investigated more than other isomers.1 1,3,4-Thiadiazoles
exhibit a broad spectrum of biological activities2 such as
antimicrobial, anti-inflammatory, anticancer, antituberculosis,
antiparasitic, anticonvulsants, antioxidant, herbicidal and
insecticidal
Acetazolamide (for glaucoma), Furidiazine (antimicrobial) and
Butazolamide (diuretic) are commercially available
1,3,4‐thiadiazole drugs (Fig. 1).
5
cyclization of thiahydrazines. Lawesson’s reagent4 and P2S5 are
usualy used for thionation of diacylhydrazines and source of
sulfur. The cyclization step has been carried out using POCl3,6
8
PCl5,7 FeCl3 and sulfuric acid.9 Recently, application of
propylphosphonic anhydride (T3P)TM as a cyclodehydration
reagent for the one-pot synthesis of 1,3,4-thiadiazoles was
reported.10
properties.
Desaglybuzole
(antidiabetic),
While some of these reagents are expensive, highly toxic and
hazardous materials, and need an excess of reagent or require
high temperature and harsh condition. Other disadvantages are
low yield of products, unnecessary waste and difficult separation
of products.
Though,
chloromethylenedimethylammonium
chloride
(Vilsmeier reagent) 1 has been identified as a formylating
agent,11 the synthetic utility of this reagent as a cyclodehydration
agent and coupling reagent in the synthesis of esters,12 amides,13
acid chlorides,14 β-sultams15 and β-lactams16 has been reported.
To the best of our knowledge, Vilsmeier reagent has not been
studied and utilized as a cyclodehydration reagent for the
synthesis of 1,3,4-thiadiazoles. Hence, based on the
aforementioned, utilizing of Vilsmeier reagent for the synthesis
of 1,3,4-thiadiazoles is reported herein.
Fig. 1. Commercially 1,3,4‐thiadiazole drugs
———
Corresponding author. Tel.: +98 76 333 70063; fax: +98 76 333 60716; e-mail: maaroof1357@yahoo.com , mzarei@hormozgan.ac.ir

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and discussion
the presence of Vilsmeier reagent and triethylamine in dry
CH2Cl2 at room temperature gave acylhydrazines 2a-f.
Symmetrical diacylhydrazines 3a-j were directly prepared from
the carboxylic acids via Vilsmeier reagent in dry acetonitrile.
Asymmetrical diacylhydrazines 4a-l were obtained by treatment
of acylhydrazines 2a-f with solution of corresponding carboxylic
acids, triethylamine and reagent 1 in dry acetonitrile (Scheme 1).
Following interest in the use of Vilsmeier reagent for the
synthesis of organic compounds,15-17 a simple protocol for the
one-pot synthesis of acylhydrazines, symmetrical and
asymmetrical diacylhydrazines from carboxylic acids using
Vilsmeier reagent has been reported.18
Reaction of carboxylic acids with excess of hydrazine hydrate in
Scheme 1. Preparation of diacylhydrazines 3a-j and 4a-l
Next, the possibility of using Vilsmeier reagent 1 as a
cyclodehydration reagent for the preparation of 1,3,4-thiadiazoles
from diacylhydrazines was tested. Initially this study started with
the reaction between diacylhydrazine 3a, Vilsmeier reagent 1,
triethylamine and Lawesson’s reagent in CH3CN at room
temperature for 15 h to obtain the desired 1,3,4-thiadiazole 5a
(41%).
thiadiazole 5a was improved to 64% and 81% using P2S5 and
Lawesson’s reagent, respectively, without 1,3,4-oxadiazole 6 as a
by-product. When other solvents such as DMF, toluene, THF and
CH2Cl2 were used in the presence of Lawesson’s reagent at room
temperature for 15 h (Table 1, entries 5–8), the best results were
obtained with THF. Temperature affected the reaction; in fact
nearly identical yields were obtained at high temperature in
shorter time than room temperature (compare Table 1, entry 1
with 3 and entry 7 with 9), but reaction condition at room
temperature is very mild. Finally, it was discovered that the
reaction was completed at room temperature after 15 h with the
highest yield. Then reaction of 1.0 mmol diacylhydrazine,
Vilsmeier reagent (1.0 mmol) and Et3N (3.0 mmol) in the
presence of 2.0 mmol Lawesson’s reagent in dry THF at room
temperature for 15 hours is the best condition (Table 1, entry 7).
In order to improve the yield and find the optimum condition
for the synthesis of 1,3,4-thiadiazole 5a, next, thionation reagent,
solvent, temperature and time of reaction were investigated. All
reactions were monitored by TLC. Of the reagents tested,
Lawesson’s reagent provided the better result than P2S5 (Table 1,
entry 1). Indeed, in the presence of P2S5 at room temperature,
1,3,4-oxadiazole 6 was isolated as a side product in 71% yield;
however, using high temperature for 6 hours the yield of 1,3,4-
Table 1. Reaction condition in the synthesis of 1,3,4-thiadiazole 5a
Entry
Thionation reagent
Temperature (oC)
Solvent
Time (hrs)
Yield (%) 5a:6
1
2
3
4
5
6
7
8
Lawesson’s reagent
P2S5
rt
rt
CH3CN
CH3CN
CH3CN
CH3CN
DMF
15
15
6
63:8
10:71
81:0
Lawesson’s reagent
P2S5
82
82
rt
6
64:0
Lawesson’s reagent
Lawesson’s reagent
Lawesson’s reagent
Lawesson’s reagent
15
15
15
15
19:69
67:0
rt
Toluene
THF
rt
88:0
rt
CH2Cl2
43:11
9
Lawesson’s reagent
Lawesson’s reagent
66
rt
THF
THF
6
79:0
73:0
10
10
11
Lawesson’s reagent
80
DMF
8
28:55
After the optimized reaction condition in hands,
cyclodehydrothionation of various substituted symmetrical
diacylhydrazines 3a-j and asymmetrical diacylhydrazines 4a-l to
corresponding 1,3,4-thiadiazole 5a-v were tested (Scheme 2,
Table 2). The yields were satisfactory in all cases and all
products were supported by spectral data. The IR spectra showed
C=N peak at 1607–1624 cm-1 and disappearance of the NH and
CO peaks of diacylhydrazines. Also, the 13C NMR spectra
showed the C=N peaks at 157.0-164.5 ppm.
Scheme 2.
In the course of this study, cyclodehydrothionation of various
diacylhydrazides to 1,3,4-thiadiazoles using Vilsmeier reagent in
the presence of Lawesson’s reagent with significant yields was
observed that Vilsmeier reagent acts as cyclodehydration reagent.

3
Table 2 Synthesis of 1,3,4-thiadiazoles 5a-v using Vilsmeier reagent
ACCEPTED MANUSCRIPT
Entry
Diacylhydrazine
R1
R2
Product
Isolated yield (%)
Mp oC (Lit. oC)
136-138 (132)21a
170-172 (172-173)21b
1
2
3a
3b
3c
3d
3e
3f
Ph
Ph
5a
5b
5c
5d
5e
5f
88
86
81
78
85
84
79
82
91
85
88
90
83
80
82
86
81
88
87
91
4-MeOC6H4
4-ClC6H4OCH2
PhthN-CH2
4-MeOC6H4
4-ClC6H4OCH2
PhthN-CH2
3
195-197
4
241-243
5
2-NaphthOCH2
2,4-Cl2C6H3OCH2
3-OHC6H4
2-NaphthOCH2
2,4-Cl2C6H3OCH2
3-OHC6H4
276-278
6
207-209
7
3g
3h
3i
5g
5h
5i
267-269 (273-274)21c
225-227 (224-225)21b
183-185
8
4-ClC6H4
4-ClC6H4
9
2,6-(MeO)2C6H3
MeOCH2
2,6-(MeO)2C6H3
MeOCH2
10
11
12
13
14
15
16
17
18
19
20
3j
5j
128-130
4a
4b
4c
4d
4e
4f
Ph
4-NO2C6H4
5k
5l
265-267 (273-274)21d
262-264 (259-260)21d
202-204
4-MeOC6H4
C6H5OCH2
4-NO2C6H4
4-ClC6H4OCH2
MeOCH2
5m
5n
5o
5p
5q
5r
5s
C6H5OCH2
164-166
2,4-Cl2C6H3OCH2
2,4-Cl2C6H3OCH2
2,4-Cl2C6H3OCH2
2-NaphthOCH2
2-NaphthOCH2
2-NaphthOCH2
C6H5OCH2
180-182
4-ClC6H4OCH2
MeOCH2
179-181
4g
4h
4i
155-157
C6H5OCH2
218-220
4-ClC6H4OCH2
2,4-Cl2C6H3OCH2
234-236
4j
5t
225-227
21
22
4k
4l
2-NaphthOCH2
4-ClC6H4OCH2
MeOCH2
MeOCH2
5u
5v
78
81
171-173
150-152
In the previous work, one-pot synthesis of several
diacylhydrazines from carboxylic acids using Vilsmeier
reagent,18 this reagent acts as coupling reagent. This led to
subsequent studies which a simple route for the one-pot synthesis
of 1,3,4-thiadiazoles from carboxylic acids, wherein, Vilsmeier
reagent works as a coupling and cyclodehydration reagent
together. Direct conversion of benzoic acid to 1,3,4-thiadiazole
5a by reaction of benzoic acid (1.0 mmol) with hydrazine hydrate
(0.3 mmol) in the presence of Vilsmeier reagent 1, Lawesson’s
reagent and triethylamine in dry tetrahydrofuran at room
temperature for 15 hours gave crude 1,3,4-thiadiazole 5a. The
mixture was poured to saturated NaHCO3 solution and extraction
with ethyl acetate was performed. 1,3,4-Thiadiazole 5a was
purified by crystallization from ethanol. The yield was
comparable with previous method from cyclodehydrothionation
of diacylhydrazides. Then, like to this procedure, various pure
1,3,4-thiadiazoles 5a-v were prepared straight from carboxylic
acids (Scheme 3, Table 3).
Scheme 3.
The procedure was mild and practical with moderate to
excellent isolated yields. Further, chromatographic isolation of
the products was not necessary and crystallization from ethanol
after aqueous work up was sufficient to isolate the products with
good purity.
This method was successfully extended to the synthesis of bis-
1,3,4-thiadiazoles. Reaction of terephthalohydrazide 7 with
various carboxylic acids in the presence of Vilsmeier reagent 1,
Lawesson’s reagent and triethylamine in dry THF at room
temperature afforded bis-1,3,4-thiadiazoles 8a-c which were
purified by crystallization from EtOH (Scheme 4). The
synthesized compounds were characterized by IR, H NMR, 13
C
1
NMR and elemental analysis.
Scheme 4.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 3 One-pot synthesis of 1,3,4-thiadiazoles 5a-v from carboxylic acids using Vilsmeier reagent
Entry
Carboxylic acid
Acylhydrazine
R1
R2
Product
Isolated yield (%)
1
2
PhCO2H
-
Ph
Ph
5a
5b
5c
5d
5e
5f
85
84
85
71
88
86
81
80
85
87
82
91
86
77
80
87
85
83
85
82
4-MeOC6H4CO2H
4-ClC6H4OCH2CO2H
PhthN-CH2CO2H
2-NaphthOCH2CO2H
2,4-Cl2C6H3OCH2CO2H
3-OHC6H4CO2H
-
4-MeOC6H4
4-ClC6H4OCH2
PhthN-CH2
4-MeOC6H4
4-ClC6H4OCH2
PhthN-CH2
3
-
4
-
5
-
2-NaphthOCH2
2,4-Cl2C6H3OCH2
3-OHC6H4
2-NaphthOCH2
2,4-Cl2C6H3OCH2
3-OHC6H4
6
-
7
-
5g
5h
5i
8
4-ClC6H4CO2H
-
4-ClC6H4
4-ClC6H4
9
2,6-(MeO)2C6H3CO2H
MeOCH2CO2H
-
2,6-(MeO)2C6H3
MeOCH2
2,6-(MeO)2C6H3
MeOCH2
10
11
12
13
14
15
16
17
18
19
20
-
5j
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-ClC6H4OCH2CO2H
MeOCH2CO2H
PhCONHNH2
Ph
4-NO2C6H4
5k
5l
4-MeOC6H4CONHNH2
C6H5OCH2CONHNH2
C6H5OCH2CONHNH2
2,4-Cl2C6H3OCH2CONHNH2
2,4-Cl2C6H3OCH2CONHNH2
2,4-Cl2C6H3OCH2CONHNH2
2-NaphthOCH2CONHNH2
2-NaphthOCH2CONHNH2
2-NaphthOCH2CONHNH2
4-MeOC6H4
C6H5OCH2
4-NO2C6H4
4-ClC6H4OCH2
MeOCH2
5m
5n
5o
5p
5q
5r
5s
C6H5OCH2
C6H5OCH2CO2H
2,4-Cl2C6H3OCH2
2,4-Cl2C6H3OCH2
2,4-Cl2C6H3OCH2
2-NaphthOCH2
2-NaphthOCH2
2-NaphthOCH2
C6H5OCH2
4-ClC6H4OCH2CO2H
MeOCH2CO2H
4-ClC6H4OCH2
MeOCH2
C6H5OCH2CO2H
C6H5OCH2
4-ClC6H4OCH2CO2H
2,4-Cl2C6H3OCH2CO2H
4-ClC6H4OCH2
2,4-Cl2C6H3OCH2
5t
21
22
MeOCH2CO2H
MeOCH2CO2H
2-NaphthOCH2CONHNH2
4-ClC6H4OCH2CONHNH2
2-NaphthOCH2
4-ClC6H4OCH2
MeOCH2
MeOCH2
5u
5v
81
76
According to the reported mechanism in the literature for
carboxylic acids using Vilsmeier reagent, then thionation of the
carbonyl groups by Lawesson’s reagent19 and followed by
cyclization to 1,3,4-thiadiazole using Vilsmeier reagent.
thionation with Lawesson’s reagent19 and for cyclodehydration of
1,2-diacylhydrazine,20 a mechanism was proposed (Scheme 5).
The reaction involves coupling of hydrazine derivatives with
Cl
Me
O
Cl
C N
Me
O
Et3N
O
O
NH2NH2
ꢀ DMF
H
H
Cl
R
O
R
O C NMe2
R
OH
S
R
NHNH2
O
ꢀ Et3NH+
Lawesson's
reagent
H
Cl
O
ꢀ DMF
O
S
S
S
Et3N
ꢀ Et3NH+
R
O C NMe2
RꢀCꢀNHNHꢀCꢀR
RꢀCꢀNNHꢀCꢀR
RꢀCꢀNHNHꢀCꢀR
Cl
Me
C N
Me
H
H
S
Cl
ꢀ Me2NꢀC
Me2N C
Cl
Me2N C
Et3N
N
N
S
S
S
H
S
H
ꢀ Et3NH+
Cl
RꢀC=NNHꢀCꢀR
R
RꢀC=NNꢀCꢀR
R
S
Scheme 5.
3. Conclusion
4. Experimental section
4.1. Chemical reagents
In summary, a simple method for one-pot transformation of
various carboxylic acids to 1,3,4-thiadiazoles using Vilsmeier
reagent in the presence of Lawesson’s reagent has been
developed. The yield of cyclodehydrothionation was good to
excellent, and starting materials were readily available. An
aqueous work up and simple crystallisation was sufficient to
obtain pure products because Vilsmeier reagent produces water-
soluble by-products.
All required chemicals were purchased from Merck, Aldrich
and Acros chemical companies. The melting points were
determined on an Electrothermal 9100 instrument. IR spectra
were measured on a galaxy series FT-IR 5000 spectrometer.
NMR spectra were recorded in DMSO-d6 using a Bruker
spectrophotometer (1H NMR 300 MHz, 13C NMR 75 MHz) using
tetramethylsilane as an internal standard and coupling constants

5
were given in cycles per second (Hz). Elemental analyses were
Calcd for C H N O S: C, 41.37; H, 5.79; N, 16.08. Found: C,
ACCEPTED MANUSCRI1P0 T
6
2
2
run on
a Vario EL III elemental analyzer. Thin-layer
41.50; H, 5.94; N, 16.16.
4.2.7. 2-({4-Chlorophenoxy}methyl)-5-(phenoxymethyl)-1,3,4-
thiadiazole (5m): Yield: 0.267 g (83%); Off-white needles
chromatography was carried out on silica gel 254 analytical
sheets obtained from Fluka.
1
4.2. General procedure for the conversion
diacylhydrazines to 1,3,4-thiadiazoles 5a-v
of
crystal. mp 202
5.09, 5.22 (2 CH2, 2s, 4H), 6.74
–
204 oC. IR (KBr) cm-1: 1615 (C=N). H NMR δ
–
6.92 (ArH, m, 5H), 7.19–7.25
(ArH, m, 4H). 13C NMR δ 56.9, 59.3 (CH2), 110.4, 116.0, 121.5,
127.1, 129.3, 129.5, 154.1, 156.7 (aromatic carbons), 159.6,
161.8 (C=N). Anal. Calcd for C16H13ClN2O2S: C, 57.74; H, 3.94;
N, 8.42. Found: C, 57.81; H, 4.03; N, 8.37.
A solution of diacylhydrazines 3a-j or 4a-l (1.0 mmol),
Vilsmeier reagent (1.0 mmol), Lawesson’s reagent (2.0 mmol),
and Et3N (3.0 mmol) in dry THF (20 mL) was stirred at room
temperature for 15 h. Water (20 mL) was added and the mixture
was extracted with EtOAc (3×20 mL). The organic layer was
washed with brine (20 mL), dried (Na2SO4), filtered and the
solvent was removed under reduced pressure to give the crude
products. The crude residues were purified by crystallization
from 95% ethanol. Spectral data for 5a-b, 5g-h and 5k-l have
been previously reported.21a-d
4.2.8.
2-(Methoxymethyl)-5-(phenoxymethyl)-1,3,4-thiadiazole
o
(5n): Yield: 0.189 g (80%); Off-white solid. mp 164
–
166 C. IR
(KBr) cm-1: 1614 (C=N). H NMR δ 3.42 (OMe, s, 3H), 4.61,
1
5.06 (2 CH2, 2s, 4H), 6.85–6.96 (ArH, m, 3H). 7.22–7.27 (ArH,
m, 2H). 13C NMR δ 56.0 (OMe), 58.8, 61.3 (CH2), 112.8, 121.5,
129.5, 153.8 (aromatic carbons), 157.5, 162.6 (C=N). Anal.
Calcd for C11H12N2O2S: C, 55.92; H, 5.12; N, 11.86. Found: C,
56.03; H, 5.27; N, 11.90.
4.2.1. 2,5-Bis({4-chlorophenoxy}methyl)-1,3,4-thiadiazole (5c):
Yield: 0.297 g (81%); Colorless needles crystal. mp 195–
197 oC.
IR (KBr) cm-1: 1608 (C=N). 1H NMR δ 5.11 (2 CH2, s, 4H), 6.71
(ArH, d, 4H, J = 8.0), 7.23 (ArH, d, 4H, J = 8.0). 13C NMR δ
57.2 (CH2), 112.9, 127.1, 129.3, 155.6 (aromatic carbons), 161.0
(C=N). Anal. Calcd for C16H12Cl2N2O2S: C, 52.33; H, 3.29; N,
7.63. Found: C, 52.45; H, 3.44; N, 7.69.
4.2.9.
2-({2,4-Dichlorophenoxy}methyl)-5-(phenoxymethyl)-
1,3,4-thiadiazole (5o): Yield: 0.300 g (82%); White solid. mp
o
1
180
(2 CH2, 2s, 4H), 6.75
–
182 C. IR (KBr) cm-1: 1607 (C=N). H NMR δ 5.15, 5.23
–
6.94 (ArH, m, 4H), 7.19–7.31 (ArH, m,
4H). 13C NMR δ 61.5, 61.7 (CH2), 115.7, 117.2, 121.5, 125.7,
128.5, 128.6, 129.5, 130.1, 143.7, 155.1 (aromatic carbons),
157.8, 159.1 (C=N). Anal. Calcd for C16H12Cl2N2O2S: C, 52.33;
H, 3.29; N, 7.63. Found: C, 52.39; H, 3.39; N, 7.58.
4.2.2. 2,2'-({1,3,4-Thiadiazole-2,5-diyl}bis[methylene])bis(isoin-
doline-1,3-dione) (5d): Yield: 0.315 g (78%); Pale-yellow solid.
o
mp 241
–
243 C. IR (KBr) cm-1: 1614 (C=N), 1739, 1771 (CO,
Phth). 1H NMR δ 4.95 (2 CH2, s, 4H), 7.55 (ArH, d, 4H, J = 8.6),
7.71 (ArH, d, 4H, J = 8.6). 13C NMR δ 51.9 (CH2), 119.6, 132.0,
132.5 (aromatic carbons), 163.2 (C=N), 166.0 (CO, phth) Anal.
Calcd for C20H12N4O4S: C, 59.40; H, 2.99; N, 13.85. Found: C,
59.51; H, 3.13; N, 13.79.
4.2.10. 2-({4-Chlorophenoxy}methyl)-5-({2,4-dichlorophenoxy}
methyl)-1,3,4-thiadiazole (5p): Yield: 0.345 g (86%); Colorless
1
needles crystal. mp 179
NMR δ 5.12, 5.16 (2 CH2, 2s, 4H), 6.74
(ArH, d, 1H, J = 7.4), 7.22
–
181 oC. IR (KBr) cm-1: 1622 (C=N). H
–
6.81 (ArH, m, 3H), 7.12
7.30 (ArH, m, 2H), 7.31 (ArH, s,
–
1H). 13C NMR δ 58.1, 58.8 (CH2), 115.6, 116.9, 125.4, 126.9,
128.1, 128.8, 129.6, 131.0, 144.9, 155.1 (aromatic carbons),
158.9, 159.2 (C=N). Anal. Calcd for C16H11Cl3N2O2S: C, 47.84;
H, 2.76; N, 6.97. Found: C, 47.77; H, 2.67; N, 6.92.
4.2.3.
2,5-Bis({naphthalen-2-yloxy}methyl)-1,3,4-thiadiazole
(5e): Yield: 0.340 g (85%); Off-white needles crystal. mp 276
–
278 C. IR (KBr) cm-1: 1612 (C=N). 1H NMR δ 5.21 (2 CH2, s,
4H), 6.92 (ArH, s, 2H), 7.29-7.38 (ArH, m, 6H), 7.53-7.56 (ArH,
m, 2H), 7.66-7.69 (ArH, m, 4H). 13C NMR δ 58.7 (CH2), 108.6,
117.6, 123.9, 127.2, 127.3, 128.7, 129.4, 131.1, 138.1, 157.4
(aromatic carbons), 163.4 (C=N). Anal. Calcd for C24H18N2O2S:
C, 72.34; H, 4.55; N, 7.03. Found: C, 72.29; H, 4.50; N, 6.97.
o
4.2.11.
1,3,4-thiadiazole (5q): Yield: 0.247 g (81%); Colorless solid. mp
155
157 oC. IR (KBr) cm-1: 1616 (C=N). 1H NMR δ 3.41 (OMe,
2-({2,4-Dichlorophenoxy}methyl)-5-(methoxymethyl)-
–
s, 3H), 4.62, 5.07 (2 CH2, 2s, 4H), 6.78 (ArH, d, 1H, J = 7.6),
7.15 (ArH, d, 1H, J = 7.6), 7.33 (ArH, s, 1H). 13C NMR δ 55.8
(OMe), 56.8, 61.5 (CH2), 114.0, 125.9, 127.9, 128.3, 134.1, 153.5
(aromatic carbons), 159.5, 163.8 (C=N). Anal. Calcd for
C11H10Cl2N2O2S: C, 43.29; H, 3.30; N, 9.18. Found: C, 43.41; H,
3.44; N, 9.11.
4.2.4.
2,5-Bis({2,4-dichlorophenoxy}methyl)-1,3,4-thiadiazole
209 oC. IR
(5f): Yield: 0.366 g (84%); Off-white plates. mp 207
–
(KBr) cm-1: 1609 (C=N). 1H NMR δ 5.13 (2 CH2, s, 4H), 6.75
(ArH, d, 2H, J = 7.5), 7.13 (ArH, d, 2H, J = 7.5), 7.36 (ArH, s,
2H). 13C NMR δ 59.4 (CH2), 110.8, 125.7, 128.5, 128.6, 130.7,
158.2 (aromatic carbons), 162.7 (C=N). Anal. Calcd for
C16H10Cl4N2O2S: C, 44.06; H, 2.31; N, 6.42. Found: C, 44.16; H,
2.44; N, 6.49.
4.2.12.
2-({Naphthalen-2-yloxy}methyl)-5-(phenoxymethyl)-
1,3,4-thiadiazole (5r): Yield: 0.306 g (88%); Off-white solid. mp
o
1
218
(2 CH2, 2s, 4H), 6.84-6.90 (ArH, m, 3H), 6.92 (ArH, s, 1H),
–
220 C. IR (KBr) cm-1: 1611 (C=N). H NMR δ 4.96, 5.17
4.2.5. 2,5-Bis(2,6-dimethoxyphenyl)-1,3,4-thiadiazole (5i): Yield:
o
0.326 g (91%); Colorless needles crystal. mp 183
–
185 C. IR
7.03–7.38 (ArH, m, 5H), 7.58 (ArH, d, 1H, J = 7.5), 7.70–7.75
(KBr) cm-1: 1621 (C=N). H NMR δ 3.59 (4 OMe, s, 12H), 6.70
(ArH, d, 4H, J = 8.1), 7.35 (ArH, t, 2H, J = 8.1). 13C NMR δ 55.7
(OMe), 109.4, 115.7, 130.4, 158.8 (aromatic carbons), 162.1
(C=N). Anal. Calcd for C18H18N2O4S: C, 60.32; H, 5.06; N, 7.82.
Found: C, 60.41; H, 5.17; N, 7.87.
1
(ArH, m, 2H). 13C NMR δ 55.0, 56.9 (CH2), 115.8, 117.7, 122.0,
124.1, 127.2, 127.3, 128.4, 129.0, 129.3, 131.5, 135.3, 141.7,
151.0, 155.3 (aromatic carbons), 158.3, 159.1 (C=N). Anal.
Calcd for C20H16N2O2S: C, 68.95; H, 4.63; N, 8.04. Found: C,
69.07; H, 4.79; N, 8.11.
4.2.6. 2,5-Bis(methoxymethyl)-1,3,4-thiadiazole (5j): Yield: 0.148
4.2.13.
methyl)-1,3,4-thiadiazole (5s): Yield: 0.332 g (87%); Off-white
needles crystal. solid. mp 234
236 oC. IR (KBr) cm-1: 1618
(C=N). H NMR δ 5.11, 5.17 (2 CH2, 2s, 4H), 6.81 (ArH, d, 2H,
2-({4-Chlorophenoxy}methyl)-5-({naphthalen-2-yloxy}
g (85%); Colorless needles crystal. mp 128–
130 oC. IR (KBr) cm-
1
1: 1617 (C=N). H NMR δ 3.43 (2 OMe, s, 6H), 4.66 (2 CH2, s,
–
4H). 13C NMR δ 56.4 (OMe), 61.7 (CH2), 164.5 (C=N). Anal.
1

6
Tetrahedron
reduced pressure to give the crude products. The crude residues
J = 7.9), 7.02 (ArH, s, 1H), 7.22
–7.41 (ArH, m, 5H), 7.56–7.60
ACCEPTED MANUSCRIPT
7.74 (ArH, m, 2H). 13C NMR δ 55.5, 58.3
were purified by crystallization from 95% ethanol.
(ArH, m, 1H), 7.68
–
(CH2), 106.8, 115.4, 118.4, 124.6, 126.9, 127.3, 127.5, 128.9,
129.6, 129.7, 132.0, 141.0, 152.9, 155.7 (aromatic carbons),
157.9, 161.3 (C=N). Anal. Calcd for C20H15ClN2O2S: C, 62.74;
H, 3.95; N, 7.32. Found: C, 62.78; H, 4.02; N, 7.35.
4.5. General procedure for one-pot synthesis of bis-1,3,4-
thiadiazoles 8a-c
Terephthalohydrazide 7 (1.0 mmol) was added to a solution of
corresponding carboxylic acid (2.2 mmol), Vilsmeier reagent (2.2
mmol) and Et3N (5.0 mmol) in dry THF (25 mL) at room
temperature. After 2 h Vilsmeier reagent (2.0 mmol) Et3N (4.0
mmol) and Lawesson’s reagent (4.0 mmol) was added and the
mixture was stirred at room temperature 18 h. Saturated NaHCO3
(25 mL) was added and the mixture was extracted with EtOAc
(3×25 mL). The organic layer was washed with brine (25 mL),
dried (Na2SO4), filtered and the solvent was removed under
reduced pressure to give the crude products. The crude residues
were purified by crystallization from 95% ethanol. Spectral data
for 8a has been previously reported.21d
4.2.14.
2-({2,4-Dichlorophenoxy}methyl)-5-({naphthalen-2-
yloxy}methyl)-1,3,4-thiadiazole (5t): Yield: 0.379 g (91%);
o
Colorless needles crystal. mp 225-227 C. IR (KBr) cm-1: 1624
1
(C=N). H NMR δ 5.03, 5.09 (2 CH2, 2s, 4H), 6.75 (ArH, d, 1H,
J = 8.1), 7.09
(ArH, d, 1H, J = 8.1), 7.78
–
7.15 (ArH, m, 3H), 7.38
–7.43 (ArH, m, 3H), 7.55
–
7.80 (ArH, m, 2H). 13C NMR δ 56.3,
57.0 (CH2), 108.9, 111.6, 116.4, 124.1, 125.4, 127.0, 127.1,
128.6, 128.8, 128.9, 129.5, 130.4, 131.3, 135.0, 149.6, 154.5
(aromatic carbons), 158.2, 160.3 (C=N). Anal. Calcd for
C20H14Cl2N2O2S: C, 57.56; H, 3.38; N, 6.71. Found: C, 57.67; H,
3.52; N, 6.65.
4.5.1. 1,4-Bis(5-{4-chlorophenyl}-1,3,4-thiadiazol-2-yl)benzene
(8b): Yield: 0.382 g (82%); Pale-yellow needles crystal. mp:
4.2.15. 2-(Methoxymethyl)-5-({naphthalen-2-yloxy}methyl)-1,3,4-
o
1
286
–
288 C. IR (KBr) cm-1: 1617 (C=N). H NMR δ 7.39 (ArH,
thiadiazole (5u): Yield: 0.209 g (78%); Colorless solid. mp 171
–
d, 4H, J = 7.6), 7.48 (ArH, d, 4H, J = 7.6), 7.78 (ArH, s, 4H). 13
C
o
1
173 C. IR (KBr) cm-1: 1613 (C=N). H NMR δ 3.40 (OMe, s,
3H), 4.64, 5.19 (2 CH2, 2s, 4H), 6.92 (ArH, s, 1H), 7.32 7.39
7.72 (ArH, m, 2H).
NMR δ 116.7, 122.2, 122.6, 128.9, 132.6, 145.2 (aromatic
carbons), 164.9, 168.4 (C=N). Anal. Calcd for C22H12Cl2N4S2: C,
56.54; H, 2.59; N, 11.99. Found: C, 56.68; H, 2.65; N, 12.07.
–
(ArH, m, 3H), 7.55–7.58 (ArH, m, 1H), 7.67–
13C NMR δ 55.1 (OMe), 58.4, 61.7 (CH2), 107.3, 118.1, 124.1,
128.7, 129.1, 130.0, 131.3, 132.6, 144.2, 155.6 (aromatic
carbons), 159.0, 164.1 (C=N). Anal. Calcd for C15H14N2O2S: C,
62.92; H, 4.93; N, 9.78. Found: C, 63.02; H, 5.06; N, 9.84.
4.5.2. 1,4-Bis(5-{4-methoxyphenyl}-1,3,4-thiadiazol-2-yl)benzene
o
(8c): Yield: 0.408 g (89%); Yellow solid. mp: 297
–299 C. IR
(KBr) cm-1: 1612 (C=N). H NMR δ 3.74 (2 OMe, s, 6H), 7.19
(ArH, d, 4H, J = 7.8), 7.55 (ArH, d, 4H, J = 7.8), 7.76 (ArH, s,
4H). 13C NMR δ 55.5 (OMe), 111.3, 120.8, 126.8, 127.2, 135.7,
157.4 (aromatic carbons), 166.0, 169.8 (C=N). Anal. Calcd for
C24H18N4O2S2: C, 62.86; H, 3.96; N, 12.22. Found: C, 62.95; H,
4.09; N, 12.19.
1
4.2.16. 2-({4-Chlorophenoxy}methyl)-5-(methoxymethyl)-1,3,4-
thiadiazole (5v): Yield: 0.219 g (81%); Gray solid. mp 150–152
1
oC. IR (KBr) cm-1: 1610 (C=N). H NMR δ 3.49 (OMe, s, 3H),
4.56, 5.07 (2 CH2, 2s, 4H), 7.17 (ArH, d, 2H, J = 7.8), 7.50 (ArH,
d, 2H, J = 7.8). 13C NMR δ 56.3 (OMe), 57.5, 61.9 (CH2), 113.8,
128.7, 131.4, 156.2 (aromatic carbons), 159.2, 163.6 (C=N).
Anal. Calcd for C11H11ClN2O3: C, 48.80; H, 4.10; N, 10.35.
Found: C, 48.75; H, 4.17; N, 10.32.
Acknowledgments
Thanks are due to University of Hormozgan Research Council
for the financial support of this study.
4.3. General procedure for one-pot synthesis of symmetrical
1,3,4-thiadiazoles 5a-j
References and notes
Hydrazine hydrate (0.3 mmol) was added to a solution of
carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and
Et3N (2.0 mmol) in dry THF (20 mL) at room temperature. After
2 h Vilsmeier reagent (0.4 mmol), Et3N (1.0 mmol) and
Lawesson’s reagent (0.8 mmol) was added and the mixture was
stirred at room temperature 13 h. Saturated NaHCO3 (20 mL)
was added and the mixture was extracted with EtOAc (3×20
mL). The organic layer was washed with brine (20 mL), dried
(Na2SO4), filtered and the solvent was removed under reduced
pressure to give the crude products. The crude residues were
purified by crystallization from 95% ethanol.
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