An efficient one-pot synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from aldehydes and hydrazides using Lawesson’s reagent

Article abstract of DOI:10.24820/ark.5550190.p010.871

Five-membered heterocyclic-ring systems, such as thiadiazoles, remain an important and prevalent scaffold in the development of novel leads in medicinal chemistry for a variety of therapeutic targets. A two-step, one-pot synthesis of 2,5-disubstituted-1,3,4-thiadiazole derivatives from aryl hydrazides and aryl aldehydes using Lawesson’s reagent is described, yielding 2,5-disubstituted-1,3,4-thiadiazoles in moderate-to-high yields. Based on preliminary biological experiments, some of the newly synthesized thiadiazoles show antioxidant activity.

Full text of DOI:10.24820/ark.5550190.p010.871

The Free Internet Journal
for Organic Chemistry
Review
Archive for
Arkivoc 2019, part iii, 0-0
Organic Chemistry
to be inserted by editorial office
An efficient one-pot synthesis of 2,5-disubstituted-1,3,4-thiadiazoles
from aldehydes and hydrazides using Lawesson’s reagent
Inseok Ko, Soojin Park, Goeun Lee, and Hakwon Kim*
Department of Chemistry and Global Center for Pharmaceutical Ingredient Materials,
Kyung Hee University, Gyonggi-do 1732, Korea
Email: hwkim@khu.ac.kr
This article dedicated to Professor George A. Kraus, in honor of his distinguished career
in synthetic organic chemistry
Received 01-06-2019
Abstract
Accepted 02-10-2019
Published on line 02-13-2019
Five-membered heterocyclic-ring systems, such as thiadiazoles, remain an important and prevalent scaffold in
the development of novel leads in medicinal chemistry for a variety of therapeutic targets. A two-step, one-
pot synthesis of 2,5-disubstituted-1,3,4-thiadiazole derivatives from aryl hydrazides and aryl aldehydes using
Lawesson’s reagent is described, yielding 2,5-disubstituted-1,3,4-thiadiazoles in moderate-to-high yields.
Based on preliminary biological experiments, some of the newly synthesized thiadiazoles show antioxidant
activity.
O
O
Two-step, one-pot reaction
i) ethanol, reflux
R1
R2
NH2
N
H
S
+
H
ii) Lawesson's reagent, DMAP
yield 75-97%
R2
R1
N
N
R1 = H, OCH3, R2 = H, halogen, OCH3, (OCH3)2, Et
2,5-diaryl-1,3,4-thiadiazoles
Keywords: 1,3,4-Thiadiazole, Lawesson’s reagent, N-acylhydrazone, N-aroylhydrazone, dimethylaminopyridine
DOI: https://doi.org/10.24820/ark.5550190.p010.871
Page 1
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
Introduction
Heterocyclic compounds are defined, according to IUPAC (International Union of Pure and Applied Chemistry),
as cyclic compounds including at least two different atoms such as oxygen, sulfur or nitrogen in the ring. These
compounds are important due to their wide range of biological activities. For example, the antiviral Sovaldi
(Gilead Sciences), the antipsychotic Abilify (Otsuka), and the anti-inflammatory Nexium are among the most
popular and widely used drugs worldwide.1
Among the heterocyclic compounds, 1,3,4-thiadiazole has attracted special interest in recent years in
various areas, including pharmaceutical, agricultural, and materials chemistries. 1,3,4-Thiadiazole is a weak
base due to the inductive effect of the sulfur in the ring, and possesses a relatively high aromaticity.2,3,4 In
addition, the ring is electron deficient due to the electron-withdrawing effects of the nitrogen atoms.2 For
these reasons, In the pharmaceutical field, 1,3,4-thiadiazole derivatives are known to exhibit diverse biological
activities, such as antimicrobial5, antiviral6, anticonvulsant7, antifungal,8-10 antitubercular,11-13 anticancer,14 and
immunomodulatory15 activities. Some examples of commercially-available drugs containing the 1,3,4-
thiadiazole ring are Megazol, Acetazolamide (Diamox), Furidiazine, and Desaglybuzole, shown in Figure 1.16,17
N
N
N
N
N
N
N
O
O
N
N
O
O
S
S
N
H
O
N
H
O2N
S
S
S
O
N
S
NH2
H2N
H2N
Megazol
Acetazolamide (Diamox)
Furidiazine
Desaglybuzole
Figure 1. Commercially available 1,3,4-thiadiazole drugs
Synthetic methods to produce 1,3,4-thiadiazoles have been developed and studied over many decades
due to the interest following the discovery of their diverse pharmacological and physiological activities. Well-
known synthetic methods for 1,3,4-thiadiazoles include starting materials such as N,N’-diacylhydrazines,18,19
thiosemicarbazides20 or thiohydrazides,21,22 as well as the transformation of 1,3,4-oxadiazoles.23 Most existing
synthetic methods, however, require harsh conditions, multi-step procedures, and scarce starting materials or
experience difficulty in forming non-symmetric 1,3,4-thiadiazoles. Therefore, it is still necessary to develop a
more efficient synthetic method to produce 1,3,4-thiadiazoles. We, herein, report a highly efficient, two-step,
one-pot synthetic method for 2,5-disubstituted-1,3,4-thiadiazoles from aldehydes and hydrazides in good-to-
excellent yields using a sequence of N-aroylhydrazone formation, thionation, cyclization and oxidation.
Results and Discussion
Originally, we thought that the synthesis of 1,3,4-thiadazole (5) could be brought about in a three-step
reaction sequence. In Scheme 1, we illustrate the formation of the aroylhydrazone (3) from the corresponding
hydrazide (1) and aldehyde (2), followed by thionation of 3 with Lawesson’s reagent (LR)24-26 to give a
thiohydrazide intermediate (4). Oxidative cyclization of 4 using an oxidant such as I2, [bis(trifluoro-
acetoxy)iodobenzene] (PIFA) or FeCl3 yields the disubstituted-1,3,4-thiadiazole (5).
Page 2
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
Scheme 1: 1,3,4-thiadiazoles from aryl aldehydes and hydrazides in a three-step sequence
When compound 3 was treated with LR, however, the disubstituted-1,3,4-thiadiazole (5) was formed
directly without oxidant, and with separation of the thiohydrazide (4). Therefore, we studied a two-step, one-
pot synthesis of 2,5-diphenyl-1,3,4-thiadiazole (5a) from benzoylhydrazide (1a) and benzaldehyde (2a) without
isolation of the N-benzoylhydrazone (3a) (Scheme 2). After refluxing for 2 hours, the ethanol was evaporated
in vacuo. To the reaction mixture of crude 3a (0.1 M) in solvent, LR was added, followed by addition of a base.
In other trials, we omitted addition of the base. The resulting mixture was refluxed for 10 hours.
O
O
S
O
NH2
S
Ph
N
Ph
LR, additive
H
ethanol
reflux
+
H
Ph
N
H
N
Ph
N
H
N
solvent
reflux
N
N
3a
4a
1a
2a
5a
Scheme 2. Two-step, one-pot synthesis of 2,5-diphenyl-1,3,4-thiadiazole (5a) from benzoylhydrazide (1a) and
benzaldehyde (2a) without separation of the N-benzoylhydrazone (3a) using LR
To determine the optimal procedure with solvents, thionating agents or additives, this one-pot reaction
was investigated under several conditions (Table 1).
Page 3
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
Table 1. Optimization of the synthesis of 2,5-diphenyl-1,3,4-thiadiazole (5a) from benzoylhydrazide (1a)
and benzaldehyde (2a)a
Entry
1
2
3
4
Thionating reagent [eq]
LR [0.5]
Solvent
Toluene
Toluene
Toluene
THF
Additive [eq]
Yield (%)b
68
-
-
-
LR [0.8]
LR [1.0]
LR [0.8]
79
65
60
-
5
6
7
8
LR [0.8]
LR [0.8]
LR [0.8]
LR [0.8]
LR [0.8]
LR [0.8]
LR [0.8]
LR [0.8]
Ethanol
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
-
73
79
85
77
96
86
70
2,6-lutidine [1.2]
DBU [1.2]
Piperidine [1.2]
Pyridine [1.2]
DMAP [1.2]
DMAP [1.0]
DMAP [1.6]
DMAP [1.2]
DMAP [1.2]
9
10
11
12
13c
14
LR [0.8]
P4S10 [0.8]
70
13
a The reaction was accomplished with a corresponding aldehyde and hydrazide in ethanol at room temperature.
After refluxing for 2 hr, the ethanol was evaporated in vacuo. To a remaining crude 3a, LR and solvent were
added, followed by addition of a base. The resulting mixture was refluxed for 10 hr.
b Isolated yield.
c Two-pot synthesis including separation of 3a.
Initially, the reaction was started with 0.5 equivalent of LR, since, stoichiometrically, one equivalent of LR
produces two equivalents of dithiophosphine ylides to thionate a carbonyl group.24-26 When 0.5 equivalent of
LR was used, 2,5-diphenyl-1,3,4-thiadiazole (5a) was produced in 68% yield (Table 1, entry 1). The amount of
LR was gradually increased to 0.8 or 1.0 equivalent (Table 1, entries 2-3). The highest yield (79%) was obtained
using 0.8 equivalent of LR (Table 1, entry 2). When tetrahydrofuran (THF), which is more polar than toluene,
was used, the yield was only 60%. No reaction occurred when ethanol was used (Table 1, entry 5). Next, the
base-additive effect was investigated by adding various bases, while maintaining the amount of LR at 0.8
equivalent in refluxing toluene as described above. When using bases such as 2,6-lutidine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), piperidine, pyridine, and dimethylaminopyridine (DMAP), the number
of byproducts were lower, and the yields were similar or higher than those in the trials omitting the bases. The
highest yield (96%) was obtained when 1.2 equivalents of DMAP were used (Table 1, entry 10), and was
superior compared to 1.0 equivalent or 1.6 equivalents of DMAP (Table 1, entries 11-12). On the other hand,
the two-step synthesis involving separation of N-aroylhydrazone (3) showed a lower overall yield of 70% than
the one-pot synthesis (Table 1, entry 13). Using another thionating reagent, P4S10, yielded only 13% of the
desired product (Table 1, entry 14).
Based on the previous experimental results and the literature,27 the mechanism of this reaction can be
proposed as shown in Scheme 3. Following formation of the N-aroylhydrazone intermediate (3), it would react
with LR to give the thiohydrazone (4). It is believed that dihydrothiadiazole (4'), which is the preferred
Page 4
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
tautomeric form of the thiohydrazone (4), is readily oxidized to produce the disubstituted-1,3,4-thiadiazole
(5).
S
O
O
O
S
Ar2
Ar2
Ar
P
-H2O
NH2
LR
Ar1
Ar2
Ar1
Ar1
S
N
+
H
N
N
N
N
H
H
H
2
1
3
4
Ar1, Ar2 = aryl
R1
R2
S
Ar1
Ar2
H
SH
[O]
Ar2
S
Ar1
-H2
N
N
N
N
N
N
H
4'
5
Scheme 3. Proposed mechanism for formation of the 1,3,4-thiadiazoles.
To clarify the mechanism of this reaction, we needed to prove formation of intermediate 4 and/or 4’.
Therefore, we synthesized compounds 4 and 4’ by the known literature method.27-29 After the reaction of the
phenyl thiohydrazide (9) with benzaldehyde (2a), the ring tautomer dihydrothiadiazole (4’) was obtained,
1
rather than the thiohydrazone (4) (Scheme 4). This was confirmed by analyzing H and 13C NMR spectra
compared with the spectral data from a previous study.29 During our one-pot reaction, a TLC spot of
dihydrothiadiazole (4’) was also observed below the spot of 2,5-diphenyl-1,3,4-thiadiazole (5a). In addition, a
small amount of 4’ was isolated and its structure confirmed. As a result, it is suggested that the
dihydrothiadiazole intermediate (4’) is directly formed from 3, and immediately oxidized under the reaction
conditions to produce 2,5-diphenyl-1,3,4-thiadiazole (5a).
S
S
S
S
Ph
Ph
H
CS2
PhCHO (2a)
N2H4.H2O
Ph
OH
NH2
PhMgBr
Ph
S
Ph
N
then
chloroacetic acid
Ph
N
H
N
N
N
EtOH
O
H
7
H
8
9
4
4'
Scheme 4. Results of literature method for synthesis of intermediates 4 and/or 4’
As mentioned above, the use of a base is, presumably, to inhibit the reverse reaction of N-acylhydrazones
(3) to aldehydes (2) and hydrazides (1), and, thereby, improve the overall yield of the reaction. Also, according
to the literature, pyridine has been reported to stabilize and activate the phosphine ylide by forming stable
complexes with P4S1030 and Woollins reagents (WR),31 which has a structure similar to LR. LR is known to be in
equilibrium with its dithiophosphine ylide in solution (Figure 2). This ylide is said to be the reactive
intermediate in the thionation processes with LR.24-26 Therefore, we hypothesized that DMAP would protect
the inverse-hydrolysis reaction of N-acylhydrazone (3), stabilize and activate LR by forming a stable DMAP-
dithiophosphine complex like pyridine.
Page 5
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
S
P
S
P
S
P
Ar
Ar
Ar
DMAP
S
S
S
S
Ar
P
S
Ar
N
2
2
S
N
Lawesson's reagent (LR)
P
S
Ar = p-methoxyphenyl
LR-DMAP complex
Se
S
S
S
P
S
Se
P
N
N
P
N
S
P4S10-Py complex
WR-Py complex
Figure 2. Proposed structures of DMAP-LR, P4S10-Py, and WR-Py complexes
To extend the one-pot synthetic method to various 1,3,4-thiadiazoles (5), different combinations of
aroylhydrazides (1a-n) and benzaldehydes (2a-n) were reacted under the same conditions as 5a. First, the
same amounts of aldehyde and hydrazide were reacted in refluxing ethanol for two hours. After the ethanol
was evaporated, the remaining crude thiahydrazone (3) in the reaction vessel was reacted in toluene, refluxing
with 0.8 equivalent of LR and 1.2 equivalents of DMAP for 12 hours as shown in Scheme 5.
R2
R1
O
O
LR (0.8 eq), DMAP (1.2 eq)
toluene, reflux
NH2
S
N
H
+
H
R2
R1
N
N
1
2
5
Scheme 5. Synthesis of 2,5-diphenyl-1,3,4-thiadiazole derivatives (5). Note: Benzaldehyde (1.0 mmol) and
benzoylhydrazide (1.0 mmol) were refluxed in ethanol for 2 hr, evaporated in vacuo, and then reacted with LR and
DMAP in refluxing toluene.
A series of 2,5-disubstituted-1,3,4-thiadiazoles (5a-m) were prepared in moderate-to-high yields (75% to
97%) from hydrazides (1a-n) and aldehydes (2a-n), the results of which are summarized in Table 2.
Page 6
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
Table 2: Results of reactions of hydrazides (1) and benzaldehydes (2) to yield 2,5-disubstituted-1,3,4-
thiadiazole compounds (5)
Yield
Entry
z
Product
Entry
8
Product
Yield (%)a
89
(%)a
S
MeO
S
96
N
S
N
5a
N
N
5e
F
97
93
87
93
85
80
80
85
84
78
75
85
2
3
4
5
6
7
N
N
N
N
9
5b
Cl
S
MeO
Cl
Br
S
N
10
11
12
13
14
5c
N
N
5i
Br
S
MeO
S
5d
N
5j
N
N
OMe
S
MeO
OMe
S
N
N
5e
N
N
5k
OMe
OMe
MeO
S
S
OMe
N
N
5f
OMe
N
N
5l
S
MeO
S
N
N
5g
5m
N
N
a Isolated yield by flash column chromatography.
In summary, a two-step, one-pot reaction was accomplished in refluxing ethanol using the same amounts
of hydrazide 1 and aldehyde 2 without separating the hydrazine intermediate 3, and in the absence of added
oxidant.
Conclusions
In conclusion, we have developed a highly efficient, two-step, one-pot synthesis of 2,5-disubstituted-1,3,4-
thiadiazoles in moderate-to-high yields from benzaldehydes and hydrazines using LR in the absence of an
Page 7
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
additional oxidant. Based on the confirmation of the formation of thiadiazoline intermediate, a reaction
mechanism has been proposed and the role of the base additives in this reaction has been suggested.
According to preliminary biological experiments, some of the newly synthesized thiadiazoles show antioxidant
activity. These results will be presented in a future study.
Experimental Section
General.
1
Melting points were determined using a Barnstead Electrothermal 9100 melting point apparatus. H NMR and
13C NMR spectra were recorded on a JEOL 300 MHz spectrometer and JEOL 75MHz spectrometer, respectively.
Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hertz (Hz). The
following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br s = broad singlet. High resolution mass spectrometry (HRMS) was performed using a JEOL
JMS-700 M station mass spectrometer and electron impact ionization (EI-magnetic sector) mass spectrometer.
General procedure for synthesis of compounds 5a-5m
In a round bottom flask, corresponding aldehyde (2) (1.0 mmol) and hydrazide (1) (1.0 mmol) were added in
ethanol (5.0 ml) at room temperature. The reaction mixture was refluxed for 2 hr. The ethanol was evaporated
in vacuo. To the resulting crude product (3), Lawesson’s reagent (0.8 mmol, 0.8 eq) and toluene (10 ml) were
added, followed by 4-(dimethylamino)pyridine (1.2 mmol, 1.2 eq). The resulting mixture was refluxed for 10 to
15 hr until 2,5-diphenyl-2,3-dihydro-1,3,4-thiadiazole was not detected by TLC. After evaporation of toluene,
the residue was purified by flash-column chromatography.
o
2,5-Diphenyl-1,3,4-thiadiazole (5a)32, 33 [CAS No. 1456-21-9]. White solid; Yield: 96%; mp 134-135 C (Lit. 140
or 132 oC); 1H NMR (300 MHz, CDCl3) δ (ppm) 7.47-7.56 (m, 4H), 7.98-8.07 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 127.98, 129.23, 130.24, 131.15, 168.23 (thiadiazole C)
2-(4-Fluorophenyl)-5-phenyl-1,3,4-thiadiazole (5b)33 [CAS No. 16020385-48-9]. White solid; Yield: 97%; mp
o
o
174-175 C (Lit. 173 C) 1H NMR (300 MHz, CDCl3) δ (ppm) 7.21 (t, J 8.5 Hz, 2 H), 7.48-7.55 (m, 3 H), 7.98-8.07
(m, 4 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 116.27, 116.56, 127.97, 129.25, 130.01, 131.23, 162.83, 166.17 (F-
Phenyl-4-C), 166.99 (thiadiazole C), 168.28 (thiadiazole C)
2-(4-Chlorophenyl)-5-phenyl-1,3,4-thiadiazole (5c)32 [CAS No. 17453-22-4]: White solid; Yield: 93%; mp 177-
o
o
1
178 C (Lit. 180 C). H NMR (300 MHz, CDCl3) δ (ppm) 7.41-7.56 (m, 5 H), 7.89-8.06 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ (ppm) 128.01, 128.71, 129.11, 129.28, 129.53, 130.05, 131.32, 137.28, 166.98 (thiadiazole C),
168.49 (thiadiazole C)
2-(4-Bromophenyl)-5-phenyl-1,3,4-thiadiazole (5d)33 [CAS No. 17453-23-5]. White solid; Yield: 87%; mp 153-
o
o
154 C (Lit. 152 C). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.51-7.53 (m, 3 H), 7.65 (d, J 8.6 Hz, 2 H), 7.90 (d, J 8.6
Hz, 2 H), 8.02 (dd, J 6.6, 2.9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 125.77, 128.18, 129.31, 129.46, 130.20,
131.50, 132.66, 167.24 (thiadiazole C), 168.69 (thiadiazole C)
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-thiadiazole (5e)33 [CAS No. 1456-67-3]. White solid; Yield: 93% from
phenylhydrazide and 4-methoxybenzaldehyde, 89% from 4-methoxybenzohydrazide and benzaldehyde;
mp137-138 oC (Lit. 136 oC). 1H NMR (300 MHz, CDCl3) δ (ppm) 3.85 (s, 3 H), 6.96-7.05 (m, 2 H), 7.43-7.54 (m, 3
H), 7.91-8.05 (m, 4 H) ; 13C NMR (75 MHz, CDCl3) δ (ppm) 55.60, 114.77, 123.13, 128.08, 129.37, 129.73,
130.58, 131.15, 162.22 (MeO-Phenyl-4-C), 167.62 (thiadiazole C), 168.19 (thiadiazole C)
Page 8
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
o
1
2-(3,5-Dimethoxyphenyl)-5-phenyl-1,3,4-thiadiazole (5f). White solid; Yield: 85%; mp 144-145 C. H NMR
(300 MHz, CDCl3) δ (ppm) 3.88 (s, 6 H), 6.60 (t, J 2.2 Hz, 1 H), 7.18 (d, J 2.2 Hz, 2 H), 7.47-7.55 (m, 3 H), 8.01
(dd, J 6.6, 2.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 55.73, 103.56, 106.02, 128.14, 129.39, 130.35, 131.36,
131.97, 161.42, 168.36 (thiadiazole C), 168.48 (thiadiazole C); HRMS (EI+): m/z Calcd. for C16H14N2O2S+:
298.0776; found: 298.0764
o
1
2-(4-Ethylphenyl)-5-phenyl-1,3,4-thiadiazole (5g). White solid; Yield: 80%; mp 90-91 C. H NMR (300 MHz,
CDCl3) δ (ppm) 1.28 (t, J 7.6 Hz, 3 H), 2.72 (q, J 7.7 Hz, 2 H), 7.33 (d, J 8.3 Hz, 2 H), 7.44-7.57 (m, 3 H), 7.93 (d, J
8.3 Hz, 2 H), 7.97-8.06 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 15.18, 28.75, 127.74, 127.96, 128.02,
128.75, 129.21, 130.35, 131.05, 147.94, 167.84 (thiadiazole C), 168.38 (thiadiazole C) ; HRMS (EI+): m/z Calcd.
for C16H14N2S+: 266.0878; found: 266.0872
o
1
2-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5h). White solid; Yield: 80%; mp 160-161 C. H
NMR (300 MHz, CDCl3) δ (ppm) 3.89 (s, 3 H) 7.01 (d, J 9.0 Hz, 2 H), 7.19 (t, J 8.6 Hz, 2 H), 7.95 (d, J 8.8 Hz, 2 H),
8.00 (dd, J 8.8, 5.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 55.52, 114.72, 116.32, 116.62, 122.89, 126.77,
126.81, 129.64, 129.90, 130.02, 162.19, 162.84, 166.17, 166.30 (thiadiazole C), 168.18 (thiadiazole C); HRMS
(EI+): m/z Calcd. For C15H11FN2OS+: 286.0576; Found: 286.0576
2-(4-Chlorophenyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5i).34 [CAS No. 17572-63-3]: White solid; Yield:
o
o
1
85%; mp190-191 C (Lit. 186-187 C]. H NMR (300 MHz, CDCl3) δ (ppm) 3.89 (s, 3 H) 7.01 (d, J 8.8 Hz, 2 H),
7.48 (d, J 8.6 Hz, 2 H), 7.95 (dd, J 8.8, 2.9 Hz, 4 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 55.59, 114.80, 122.91,
129.04, 129.20, 129.64, 129.75, 137.22, 162.31, 166.33 (thiadiazole C), 168.43 (thiadiazole C)
o
1
2-(4-bromophenyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5j). White solid; Yield: 83% ; mp 215 C; H NMR
(300MHz, CDCl3) δ (ppm) 3.89 (s, 3 H) 7.01 (d, J 8.6 Hz, 2 H), 7.63 (d, J 8.4 Hz, 2 H), 7.88 (d, J 8.4 Hz, 2 H), 7.96
(d, J 8.6 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 55.59, 114.77, 122.85, 125.52, 129.36, 129.73, 132.59,
162.28, 166.41 (thiadiazole C), 168.45 (thiadiazole C); HRMS (EI+): m/z Calcd. For: C15H11BrN2OS+: 345.9775;
Found: 345.9764
2,5-Bis-(4-methoxyphenyl)-1,3,4-thiadiazole (5k)35 [CAS No. 17453-03-1]. White solid; Yield: 78%; mp 167-169
oC[Lit. 170-172 oC]. 1H NMR (300 MHz, CDCl3) δ (ppm) 3.88 (s, 6 H), 7.00 (d, J 8.8 Hz, 4 H), 7.94 (d, J 8.8 Hz, 4 H);
13C NMR (75 MHz, CDCl3) δ (ppm) 55.58, 114.72, 123.28, 129.61, 162.06, 167.40 (thiadiazole C)
2-(3,5-Dimethoxyphenyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5l). Light beige solid; Yield: 75%; mp 134-
o
135 C. 1H NMR (300 MHz, CDCl3) δ (ppm) 3.88 (s, 6 H), 3.89 (s, 3 H), 6.59 (t, J 2.3 Hz, 1 H), 7.01 (d, J 8.8 Hz, 2
H), 7.16 (d, J 2.3 Hz, 2 H), 7.95 (d, J 8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ (ppm) 55.57, 55.72, 103.42, 105.94,
114.74, 123.05, 129.69, 132.13, 161.41, 162.22, 167.56 (thiadiazole C), 168.25 (thiadiazole C); HRMS (EI+): m/z
Calcd. for C17H16N2O3S+: 328.0882; Found: 328.0869
o
1
2-(4-Ethylphenyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5m). White solid; Yield: 85%; mp 101-102 C. H
NMR (300 MHz, CDCl3) δ (ppm) 1.28 (t, J 7.6 Hz, 3 H), 2.72 (q, J 7.5 Hz, 2 H), 3.89 (s, 3 H), 7.01 (d, J 9.0 Hz, 2 H),
7.32 (d, J 8.3 Hz, 2 H), 7.96 (d, J 9.0 Hz, 2 H), 7.92 (d, J 8.3 Hz, 2 H) ; 13C NMR (75 MHz, CDCl3) δ (ppm) 15.35,
28.88, 55.56, 114.68, 123.16, 127.99, 128.07, 128.84, 129.63, 147.85, 162.06, 167.72 (thiadiazole C), 167.76
(thiadiazole C); HRMS (EI+): m/z Calcd. For C17H16N2OS+: 296.0983; Found: 296.1002
Procedure for synthesis of compound (8)27,28
In a round-bottom flask, following flame drying, 40 ml of 1M phenylmagnesium bromide (40 mmol) in THF was
added. It was then cooled to 0 °C, and 2.42 ml of carbon disulfide (40 mmol) was slowly introduced dropwise.
It was stirred at room temperature for 12 hr and then poured into 100 g of ice water and 3.78 g of chloroacetic
o
acid (40 mmol). Anhydrous sodium carbonate 3.36g (20 mmol) was added and stirred for 24 hr at 90 C. The
liquid was adjusted to pH 2 with concentrated hydrochloric acid, and a red solid was obtained by
recrystallization in a mixture of ethyl acetate and hexane.
Page 9
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
o
o
2-(Phenylcarbonothionylthio)acetic acid (8) [CAS No. 942-91-6]. Yield: 72% ; mp 125-126 C [Lit. 123-125 C].
1H NMR (300 MHz, CDCl3) δ (ppm) 4.28 (s, 2 H), 7.41 (t, J 7.7 Hz, 2 H), 7.57 (t, J 7.5 Hz, 1 H), 8.03 (d, J 7.9 Hz, 2
H), 10.52 (br. s., 1 H) ; 13C NMR (75 MHz, CDCl3) δ (ppm) 38.76, 127.23, 128.69, 133.18, 144.20, 173.86, 225.89.
Procedure for synthesis of compound 928
Compound 8 (2.0 g, 9.4 mmol) was dissolved in 1 M NaOH (10 mL, 1 eq) and H2O (10 ml). Upon addition of
hydrazine hydrate (1.7 g, 55%, 18.8 mmol), the orange color disappeared. After consumption of the starting
material, the reaction mixture was acidified to pH 5-6 with dilute HCl (aq) and stirred for 1 hr while cooling in
an ice bath. A white solid was filtered and recrystallized from water to produce benzothiohydrazide (9) as
white crystals.
o
o
1
Benzothiohydrazide (9) [CAS No. 20605-40-7]. White solid; Yield: 60%; mp 80-82 C[Lit. 78-80 C]. H NMR
(300 MHz, CDCl3) δ (ppm) 6.25 (br. s., 1 H), 7.37-7.46 (m, 3 H), 7.70 (d, J 7.0 Hz, 2 H), 12.13 (br. s., 1 H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 127.82, 129.63, 129.69, 131.64, 167.97.
Procedure for synthesis of compound (4’)29
In a round-bottom flask, benzaldehyde (0.5 mmol) and 9 (0.5 mmol) were added in ethanol (5 ml) for 2 hr at
room temperature. After the reaction was complete, the ethanol was evaporated under vacuum, and the
product was obtained by recrystallization in a mixture of ethyl acetate and hexane.
o
o
2,5-Diphenyl-2,3-dihydro-1,3,4-thiadiazole (4’) [CAS No. 82243-06-9]. Yield: 92%; mp 78-79 C[Lit. 76-78 C].
1H NMR (300 MHz, CDCl3) δ (ppm) 6.36 (s, 1 H, C-5 H), 7.29-7.42 (m, 6 H), 7.43-7.53 (m, 2 H), 7.61-7.75 (m, 2
H); 13C NMR (75 MHz, CDCl3) δ (ppm) 74.72 (C-5), 126.65, 127.21, 128.69, 129.12, 129.25, 129.81, 131.37,
140.93, 146.65.
Acknowledgements
This work was supported by the GRRC program of Gyeonggi province. [GRRCkyunghee2018-B04]
References
1. Martins, P.; Jesus, J.; Santos, S.; Raposo, L. R.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R.
Molecules 2015, 20, 16852
https://doi.org/10.3390/molecules200916852
2. Hu, Y.; Li, C.Y.; Wang, X.M.; Yang, Y. H.; Zhu, H.L. Chem. Rev. 2014, 114, 5572
https://doi.org/10.1021/cr400131u
3. Balaban, A.T.; Oniciu, D.C.; Katritzky, A.R. Chem. Rev. 2004, 104, 2777
https://doi.org/10.1021/cr0306790
4. Glossman-Mitnik, D. J. Mol. Struct.: THEOCHEM 2001, 549, 285
https://doi.org/10.1016/S0166-1280(01)00550-4
5. Alamajan, G.L.; Barbucescu, S-F.; Baricescu, G.; Saramet, I. Saramet, G.; Draghici, C. Eur. J. Med. Chem.
2010, 45, 6139
6. Al-Soud, Y.A.; Al-Masoudi, N.A.; Loddo, R.; La Colla, P. Arch. Pharm. Chem. Life Sci. 2008, 341, 365
https://doi.org/10.1002/ardp.200700272
7. Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J.P. Eur. J. Med. Chem. 2008, 43, 1945
https://doi.org/10.1016/j.ejmech.2007.12.003
Page 10
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
8. Liu, F.; Luo, X.Q.; Song, B. A.; Bhadury, P.S.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y. Bioorg. Med. Chem. 2008,
16, 3632
https://doi.org/10.1016/j.bmc.2008.02.006
9. Liu, X. H.; Shi, Y.X.; Ma, Y.; Zhang, C.Y.; Dong, W.L.; Pan, L.; Wang, B.L.; Li, B. J.; Li, Z.M. Eur. J. Med. Chem.
2009, 44, 2782
https://doi.org/10.1016/j.ejmech.2009.01.012
10. Zoumpoulakis, P.; Camoutsis, C.; Pairas, G.; Sokovic, M.; Glamoclija, J.; Potamitis, C.; Pitsas, A. Bioorg. Med.
Chem. 2012, 20, 1569
https://doi.org/10.1016/j.bmc.2011.12.031
11. Foroumadi, A.; Mirzaei, M.; Shafiee, A. Farmaco 2001, 56, 621
https://doi.org/10.1016/S0014-827X(01)01099-0
12. Karakus, S.; Rollas, S. Farmaco 2002, 57, 577
https://doi.org/10.1016/S0014-827X(02)01252-1
13. Talath, S.; Gadad, A.K. Eur. J. Med. Chem. 2006, 41, 918
https://doi.org/10.1016/j.ejmech.2006.03.027
14. Kumar, D.; Kumar, N.M.; Chang, K.H.; Shah, K. Eur. J. Med. Chem. 2010, 45, 4664
https://doi.org/10.1016/j.ejmech.2010.07.023
15. Sasikumar, P.G.N.; Ramaachandra, M.; Naremaddepalli, S.S. PCT Int. Appl. 033301, 2015
16. Carvalho, S.A.; Lopes, F.A.S.; Salomão, K; Romeiro, N.C.; Wardell, S.M.S.V.; de Castro, S.L.; da Silva, E.F.;
Fraga, C.A.M. Bioorg. Med. Chem. 2008, 16, 413
https://doi.org/10.1016/j.bmc.2007.09.027
17. Ali, T.E.S.; El-Kazak, A.M. Eur. J. Chem. 2010, 1, 6
https://doi.org/10.5155/eurjchem.1.1.6-11.12
18. Selvarasu, C.; Kannan, P. J. Chem. Sci. 2015, 127, 1831
https://doi.org/10.1007/s12039-015-0949-0
19. Pathak, S.K.; Nath, S.; De, J.; Pal, S.K.; Achalkumar, A.S. New J. Chem. 2017, 41, 4680
https://doi.org/10.1039/C7NJ00911A
20. Epishina, M.A.; Kulikov, A.S.; Ignat’ev, N.V.; Schulte, M. Mendeleev Commun. 2011, 21, 331
https://doi.org/10.1016/j.mencom.2011.11.013
21. Farrar, J.M.; Patel, M.K.; Kaszynski, P.; Young, V.G. J. Org. Chem. 2000, 65, 931
https://doi.org/10.1021/jo991126l
22. Shahcheragh, S.M.; Habbi, A.; Khosravi, S. Tetrahedron Lett. 2017, 855
https://doi.org/10.1016/j.tetlet.2017.01.057
23. Linganna, N.; Lokanatha Rai, K.M. Synth. Commun. 1998, 28, 4611
https://doi.org/10.1080/00397919808004526
24. Lecher, H.Z.; Greenwood, R.A.; Whitehouse, K.C.; Chao, T.H. J. Am. Chem. Soc. 1956, 78, 5018
https://doi.org/10.1021/ja01600a058
25. Rauchfuss, T.B.; Zank, G.A. Tetrahedron Lett. 1986, 27, 3445
https://doi.org/10.1016/S0040-4039(00)84818-2
26. Jesberger, M.; Davis, T.P.; Barner, L. Synthesis, 2003, 1929
27. Lu, J-T.; Chen, S-S.; Du, M.; Tang, L-F. Appl. Organometal. Chem. 2006, 20, 448
https://doi.org/10.1002/aoc.1087
28. Liu, H.Q.; Wang, D.C.; Wu, F.; Tang, W.; Ouyang, P.K. Chin. Chem. Lett. 2013, 24, 929
https://doi.org/10.1002/aoc.1087
Page 11
©ARKAT USA, Inc

Arkivoc 2019, iii, 0-0
Ko, I. S. et al.
29. Evans, D.M.; Taylor, D.R. J. Chem. Soc., Chem. Commun. 1982, 3, 188
https://doi.org/10.1039/C39820000188
30. Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P.H. J. Org. Chem. 2011, 76, 1546
https://doi.org/10.1021/jo101865y
31. Ascherl, L.; Nordheider, A.; Athukorala Arachchige, K.S.; Cordes, D.B.; Karaghiosoff, K.; Bűhl, M.; Slawina,
A.M.Z.; Woollins, J.D. Chem. Commun. 2014, 50, 6214
https://doi.org/10.1039/C4CC01073F
32. Srivastava, V.; Singh, P.K.; Singh, P.P. Croat. Chem. Acta 2015, 88, 59
https://doi.org/10.5562/cca2520
33. Kumar, D.; Pilania, M.; Arun, V.; Pooniya, S. Org. Biomol. Chem. 2014, 12, 6340
https://doi.org/10.1039/C4OB01061B
34. Siegrist, A.E.; Maeder, E.; Duennenberger, M.; Liechti, P. Patentschrift (Switz) 1967, CH426828 19670630;
Chem. Abstr. 1968, 69002
35. Zarei, M. Tetrahedron 2017, 73, 1867.
https://doi.org/10.1016/j.tet.2017.02.042
Page 12
©ARKAT USA, Inc