Synthesis of 1,3,4-thiadiazol-2(3H)-one derivatives via an unexpected intramolecular addition-elimination reaction of 1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.tet.2017.06.006

A new synthesis was developed for 1,3,4-thiadiazol-2(3H)-one derivatives, based on a new arrangement on the thiadiazole ring with an intramolecular addition-elimination reaction. To this end, starting from 5-methyl-1,3,4-thiadiazole-2-thiol (1), derivatives of 3-((un)substituted benzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7a-g) and ((un)substituted phenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (10–15) were synthesized (in yields of 81–88% and 63–71%, respectively). The structures of all synthesized compounds were characterized using IR, ¹H NMR, and ¹³C NMR spectroscopy, and elemental analysis, mass spectroscopy and X-ray diffraction analysis (compounds 3c, 7b-f and 10) techniques. This study presents a new and effective reaction path for the synthesis of 1,3,4-thiadiazol-2(3H)-one derivatives.

Full text of DOI:10.1016/j.tet.2017.06.006

Accepted Manuscript
Synthesis of 1,3,4-thiadiazol-2(3H)-one derivatives via an unexpected intramolecular
addition-elimination reaction of 1,3,4-thiadiazoles
Hakan Tahtaci, Mustafa Er, Tuncay Karakurt, Kemal Sancak
PII:
S0040-4020(17)30625-7
10.1016/j.tet.2017.06.006
TET 28771
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 February 2017
Revised Date: 21 May 2017
Accepted Date: 5 June 2017
Please cite this article as: Tahtaci H, Er M, Karakurt T, Sancak K, Synthesis of 1,3,4-thiadiazol-2(3H)-
one derivatives via an unexpected intramolecular addition-elimination reaction of 1,3,4-thiadiazoles,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.006.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Synthesis of 1,3,4-Thiadiazol-2(3H)-one Derivatives via an Unexpected Intramolecular
Addition-Elimination Reaction of 1,3,4-Thiadiazoles
Hakan Tahtaci a*, Mustafa Er b, Tuncay Karakurt c, Kemal Sancak d
a*Corresponding author
aDepartment of Polymer Engineering, Faculty of Technology, Karabuk University, 78050,
Karabuk, Turkey; Tel: +90 370 433 83 74, Fax: +90 370 433 83 34
E-mail address: hakantahtaci@karabuk.edu.tr
bDepartment of Chemical Engineering, Faculty of Engineering, Karabuk University, 78050,
Karabuk, Turkey
cDepartment of Chemical Engineering, Faculty of Engineering and Architecture, Ahi Evran
University, 40100, Kırşehir, Turkey
dDepartment of Chemistry, Faculty of Sciences, Karadeniz Technical University, 61080
Trabzon, Turkey
1

ACCEPTED MANUSCRIPT
Abstract
A new synthesis was developed for 1,3,4-thiadiazol-2(3H)-one derivatives, based on a new
arrangement on the thiadiazole ring with an intramolecular addition-elimination reaction.
To this end, starting from 5-methyl-1,3,4-thiadiazole-2-thiol (1), derivatives of 3-
((un)substituted benzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7a-g) and ((un)substituted
phenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (10-15) were synthesized (in yields
of 81 to 88% and 63 to 71%, respectively). The structures of all synthesized compounds were
1
13
characterized using IR, H NMR, and C NMR spectroscopy, and elemental analysis, mass
spectroscopy and X-ray diffraction analysis (compounds 3c, 7b-f and 10) techniques.
This study presents a new and effective reaction path for the synthesis of 1,3,4-thiadiazol-
2(3H)-one derivatives.
Keywords: 1,3,4-Thiadiazole; 1,3,4-Thiadiazol-2(3H)-one; Intramolecular Addition-
Elimination Reaction; A Novel Method
2

ACCEPTED MANUSCRIPT
1. Introduction
Heterocyclic molecules are widespread in nature and used in many fields. Among these
molecules, thiadiazoles which have a significant place among 5-member heterorings
containing nitrogen and sulfur are widely used in pharmaceutical chemistry, material science,
and organic syntheses.1,2
1,3,4-Thiadiazole and its derivatives in particular represent a ring which has a broad
spectrum of biological activities such as antimicrobial,3 antifungal,4 antibacterial,5 analgesic,6
anticonvulsant,7
antioxidant,8
anti-inflammatory,9
anticancer,10
antidepressant,11
antihypertensive,12 and antiviral13 activities. Furthermore, 1,3,4-thiadiazole derivatives are
widely used in many fields of agriculture and technology as pesticides, herbicides, fungicides,
insecticides, and bactericides.14,15 Such compounds have various optical and electrochemical
applications due to their thermal and chemical stability.16-18 In this study, (substituted benzyl)-
5-methyl-1,3,4-thiadiazol-2(3H)-one derivatives were synthesized. Very few compounds
containing the 1,3,4-thiadiazole-2(3H)-one nucleus which we synthesized in the current study
can be found in the literature.
In those literature studies, structures containing the 1,3,4-thiadiazole-2(3H)-one nucleus
were synthesized by traditional methods but in low yields.19 It was reported that such
substances inhibit the Protoporphyrinogene oxidase (PPO) enzyme, especially in humans, and
cause cancer cells to die and therefore are used in cancer treatment.20-22 PPO enzymes are also
used for haemoglobin and chlorophyll synthesis.23 Mitochondrial PPO inhibitors inhibit
mitochondrial Protoporphyrin IX (PPIX). As a result of this inhibition, the amount of PPIX in
the mitochondria increases, PPIX enters the cytoplasm by diffusion and is oxidized. Thus,
PPIX causes the circulation in veins from which tumour cells feed to slow down and
eventually tumour cells shrink and die.24,25
3

ACCEPTED MANUSCRIPT
There are various methods used for the synthesis of 1,3,4-thiadiazoles. Azides, hydrazines,
diacyl hydrazines and thiosemicarbazides are the key compounds used in the synthesis of
1,3,4-thiadiazole and derivatives.26-31
In the present study, starting from 5-methyl-1,3,4-thiadiazole-2-thiol (1), derivatives of 3-
((un)substituted benzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7a-g) and ((un)substituted
phenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (10-15) were unexpectedly
obtained by a method not available in the literature. This unexpected result reveals a novel
method for the synthesis of compounds containing the 1,3,4-thiadiazol-2(3H)-one nucleus
(Scheme 1).
4

ACCEPTED MANUSCRIPT
OH
O
O
N N
S
i
ii
R
R
R
+
CH3
HS
S
N
S
N
Br
S
S
3a-d
4a-d
1
2a-d
CH3
CH3
N
N
H; Br; Cl; OCH3
(2a-d, 3a-d, 4a-d)
R:
R1
O
Br
R1
R
S
N
iii
OH
S
N
R2
6
5a-g
R
CH3
S
N
+
S
O
4a-d
Br
O
CH3
N
iii
R2
O
R
8a-f
S
N
S
9
CH3
N
OH
R
Br
R1
+
CH3
R1
N
S
iii
N
S
S
N
4a-d
5a-g
CH3
N
O
7a-g
O
OH
O
Br
R2
CH3
N
S
iii
N
+
R2
S
S
N
4a
8a-f
O
CH3
N
10-15
R2
R1
-H
Comp.
Comp.
-H
Reagents and conditions:
10
11
12
13
14
7a
7b
7c
7d
7e
7f
-Br
-Cl
-F
i : Absolute ethyl alcohol, KOH, reflux, 4-6 h
ii : Absolute ethyl alcohol, NaBH4, 0-5 °C,
30 min. and r.t, 2-3 h
4-Br
4-Cl
4-F
iii: DMF, NaH, r.t, 4-6 h
-CN
4-CF3
-OCH3
2,6-Cl2
15
7g
2-Cl, 6-F
Scheme 1.
5

ACCEPTED MANUSCRIPT
2. Results and discussion
In the first part of the study, 1-(substituted phenyl)-2-((5-methyl-1,3,4-thiadiazol-2-
yl)thio)ethanone derivatives (3a-d) were obtained (in yields of 81 to 88%) from the reaction
of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with phenacyl bromide derivatives (2a-d) in
presence of KOH in absolute ethyl alcohol. Compounds 3a-d have been reported
previously.32,33
Then, 1-(substituted phenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol derivatives (4a-
d), which are alcohol derivatives, were synthesized (in yields of 82 to 91%) by reduction of
compounds 3a-d with NaBH4 in absolute ethyl alcohol.
Our next goal was to synthesize ether derivatives (compound 6) by the reaction of these
alcohol derivatives (4a-d) with various benzyl halides (5a-g) in the presence of NaH in DMF.
However, spectroscopic analyses of the synthesized compounds showed that, contrary to
expectations,
3-((un)substituted
benzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one
(7a-g)
compounds were obtained (in yields of 71 to 82%) by a different mechanism. The resulting
compounds and yields are shown in Figure 1.
6

ACCEPTED MANUSCRIPT
Figure 1.
The reaction is believed to proceed starting from the formation of the benzyloxy group,
which is a quite basic and strong nucleophile, through the deprotonation of secondary alcohol
in compounds 4a-d and then via the formation of a spiro compound following an SNi-type
intramolecular nucleophilic substitution. In the next step, an SN2-type nucleophilic
substitution reaction between the new nucleophilic center formed on nitrogen in the spiro
compound and benzyl bromide derivatives (5a-g) occurs and finally 3-((un)substituted
benzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one derivatives (7a-g) are obtained after the
hydrolysis during work-up. The suggested reaction mechanism is shown in Scheme 2.
7

ACCEPTED MANUSCRIPT
Scheme 2.
In an effort to prove the suggested reaction mechanism, 1-(4-methoxyphenyl)-2-((5-
methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4d) was reacted with NaH in the absence of benzyl
bromide derivatives (5a-g). The resulting compound formed at the intermediate step was
successfully isolated.
Another evidence that the reactions proceed through this proposed mechanism may be
drawn from the following example: we obtained only compound 7a by the reaction of alcohol
derivatives (4a-d) with benzyl bromide (5a). Thus, no matter which alcohol derivative is
used, the result is determined by the benzyl halide derivatives used.
8

ACCEPTED MANUSCRIPT
Furthermore, reactions of 2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)-1-phenylethanol (4a)
with phenacyl bromide derivatives (8a-f) were also carried out to show that the suggested
reaction is possible with other compounds as well and reveal the functionality of the method.
As a result of these reactions, ((un)substituted phenyl)-2-oxoethyl)-5-methyl-1,3,4-
thiadiazol-2(3H)-one (10-15) derivatives were synthesized (in yields of 63 to 71%) via a
similar mechanism. The resulting compounds and yields are shown in Figure 2.
Figure 2.
In conclusion, it is believed that this reaction occurs through SNi-type intramolecular
nucleophilic substitution of the benzyloxy group and involves a 7-substitued phenyl-3-
methyl-6-oxa-4,9-dithia-1,2-diazaspiro[4.4]non-2-ene-1-ide type spiro intermediate step. In
the second step, a nucleophilic substitution reaction occurs between the nitrogen atom of
thiadiazolene in the spiro compound and benzyl bromide (5a-g) and/or phenacyl bromide (8a-
f) derivatives. Finally, the resulting N-benzylated oxathiolan compound undergoes hydrolysis
to the carbonyl group on work-up.
9

ACCEPTED MANUSCRIPT
This mechanism is a new method for the synthesis of 5-methyl-1,3,4-thiadiazol-2(3H)-one
derivatives (7a-g and 10-15) with the formation of N-benzylated oxathiolan through two
different substitutions (SNi and SN2)
1
Structures of 7a-g compounds were identified with IR, H NMR, and 13C NMR
spectroscopy, elemental analysis, mass spectroscopy and X-ray diffraction analysis (7b-f)
techniques. Disappearance of –OH absorption peaks observed in the 3340-3269 cm-1 range of
alcohol derivatives (4a-d), and emergence of carbonyl group (C=O) peaks observed in the
1679-1652 cm-1 range are important indicators for the formation of 5-methyl-1,3,4-thiadiazol-
2(3H)-one (7a-g) derivatives.
We did not observe two different methylene (-OCH2 and -SCH2) and aromatic proton
peaks, which are expected for ether derivatives (compound 6), in the 1H NMR spectra of 7a-g
compounds. Instead, we observed methylene peaks corresponding to two protons and proton
peaks belonging to only a single aromatic ring in the 5.26-4.95 ppm range, which supports the
structure that we suggest. Furthermore, the presence of carbonyl group peaks observed in the
170.32-169.36 ppm range in the 13C NMR spectra of these compounds (7a-g) clearly supports
the structure. Mass and elemental analysis results specified in the experimental section clearly
indicates the structures that we suggest.
The fact that two different sharp carbonyl absorption bands were observed in the 1712-
1691 and 1663-1646 cm-1 range in the IR spectra of compounds 10-15 clearly supports the
suggested structures.
Also, two different carbonyl carbon peaks were observed in the 13C NMR spectra of these
compounds (10-15). One of the peaks is the amide carbonyl in the 170.93-170.46 ppm range.
The other belongs to the ketone carbonyl in the 192.78-189.64 ppm range.
13
In C NMR spectra of fluorine containing compounds 7d, 7e, 7g and 13, splittings were
observed due to quite distinct C-F couplings. In coupling constants, it was observed that
10

ACCEPTED MANUSCRIPT
especially the coupling in the 1J CF position was severe and splittings occurred corresponding
to approximately 246-271 Hz range. C-F coupling constants for these compounds are given in
the Experimental section. The spectra of all compounds are given in the Supplementary
Material section.
Finally, the structures of compounds 3c, 7b-f and 10 were also confirmed by X-ray
diffraction analysis. The crystal structures and crystallographic data of compounds 3c, 7b-f
and 10 are given in the Supplementary Material Section. All trials and all spectroscopic data
support the suggested mechanism and structure.
3. Conclusions
In conclusion, this study exhibits a new and effective method to synthesize compounds
containing the 1,3,4-thiadiazol-2(3H)-one nucleus. Not only does this novel method take less
time to perform, but it also costs less and allows the synthesis of the aforementioned
compounds in higher yields. Most importantly, our method is not an alternative to other
methods available in the literature, but a new method for synthesis, which is its most
significant advantage.
4. Experimental section
4.1. General information
1
13
The H NMR and C NMR spectra of the compounds were measured in CDCl3 using an
Agilent NMR VNMRS spectrometer at 400 MHz and 100 MHz, respectively. Chemical shift
values are given in ppm (parts per million) (δ) with tetramethylsilane (TMS) as internal
standard. The peak patterns are indicated as follows: s, singlet; bs, broad singlet; d, doublet; t,
triplet; m, multiplet; dd, doublet of doublets. The coupling constants (J) are given in Hertz
11

ACCEPTED MANUSCRIPT
(Hz). The IR spectra were recorded in a Bruker Optics Alpha FT-IR in ATR. The mass
spectra were measured with a Thermo TSQ Quantum Access Max LC-MS/MS spectrometer.
Elemental analyses were performed on a Truspec Leco Micro CHNS elemental analyzer and
the results were within ± 0.4% of the theoretical values. Melting points were recorded on a
Thermo Scientific IA9000 series apparatus and were uncorrected. For thin layer
chromatography, 60 F254 Aluminum TLC plate were used. Column chromatography was
performed using silica gel (70-230 mesh ASTM). All the chemicals, reagents and solvents
were directly purchased from Sigma-Aldrich (St. Louis, MO) and were used without further
purification, unless mentioned specifically.
4.2. General procedure for the synthesis of 1-((un)substituted phenyl)-2-((5-methyl-1,3,4-
thiadiazol-2-yl)thio)ethanone derivatives (3a-d)
In a two-necked flask, 5-methyl-1,3,4-thiadiazole-2-thiol (1) (0.06 mol; 7.93 g) and KOH
(0.06 mol; 0.336 g) were dissolved in absolute ethanol (100 mL) and the solution was stirred
for 30 minutes at room temperature. Phenacyl bromide derivative (2a-d) (0.06 mol) was
dissolved in absolute ethanol (50 mL) and added dropwise to this solution at room temperature
with the assistance of a dropping funnel. The mixture was then refluxed and stirred for 4-6 h.
The progress of the reaction was monitored by TLC at appropriate time intervals. After
completion of the reaction, the solution was filtered and recrystallized from the ethanol. The
synthesized compounds were dried with P2O5 in a vacuum oven.
4.2.1 .2-((5-Methyl-1,3,4-thiadiazol-2-yl)thio)-1-phenylethanone (3a)32
Yield: 13.21 g (88%), m.p. 86-87 °C (from EtOH). (lit32 m.p. 83-85 °C).
4.2.2. 1-(4-Bromophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3b)33
Yield: 16.79 g (85%), m.p. 111-113 °C (from EtOH) (lit33 m.p. 106-109 °C).
4.2.3. 1-(4-Chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3c)33
12

ACCEPTED MANUSCRIPT
Yield: 14.52 g (85%), m.p. 115-116 °C (from EtOH) (lit33 m.p. 112-115 °C).
4.2.4. 1-(4-Methoxyphenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3d)33
Yield: 13.63 g (81%), m.p. 105-106 °C (from EtOH) (lit33 m.p. 106-108 °C).
4.3. General procedure for the synthesis of 1-((un)substituted phenyl)-2-((5-methyl-1,3,4-
thiadiazol-2-yl)thio)ethanol derivatives (4a-d)
In a two-necked flask, ketone derivatives (3a-d) (0.03 mol) were dissolved in absolute
ethanol (100 mL) and cooled to 0-5 °C. Sodium borohydride (NaBH4) (0.06 mol,; 2.27 g )
was dissolved in absolute ethanol (20 mL) and added dropwise to this solution with the
assistance of a dropping funnel. The mixture was stirred for 30 minutes at 0-5 °C. Then, the
mixture was stirred for 2-3 h at room temperature. The progress of the reaction was monitored
by TLC at appropriate time intervals. At the end of this period, the solvent was removed
under reduced pressure. The crude residue was suspended in water and extracted with
chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and then
evaporated to dryness. The solid was recrystallized from the benzene/petroleum ether (2:1).
The synthesized compounds were dried with P2O5 in a vacuum oven.
4.3.1. 2-((5-Methyl-1,3,4-thiadiazol-2-yl)thio)-1-phenylethanol (4a)
Light yellow oil, yield: 6.89 g (91%). IR (ATR, cm-1): 3274 (OH), 3066 (Ar-CH), 2922
(Aliph. CH), 1608 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.67 (s, 3H, -CH3), 3.44 (dd,
J=7.6 Hz, J=7.2 Hz, 1H, -CH2 (A)), 3.67 (dd, J=7.6 Hz, J=7.2 Hz, 1H, -CH2 (B)), 4.41 (d,
J=2.0 Hz, 1H, OH), 5.09 (t, J=4.0 Hz, 1H, -CH-), 7.26 (t, J=6.4 Hz, 1H), 7.32 (t, J=7.2 Hz,
2H), 7.40 (d, J=8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ ppm): 15.6 (-CH3), 42.7 (-CH2),
72.9 (-CH), 125.8 (CH), 127.9 (CH), 128.5 (CH), 142.4 (C), 165.4 (C), 166.2 (C). MS: m/z
13

ACCEPTED MANUSCRIPT
252.72 (M+, 100). Anal. Calcd. for C11H12N2OS2: C, 52.35; H, 4.79; N, 11.10. Found: C,
52.29; H, 4.76; N, 11.01.
4.3.2. 1-(4-Bromophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4b)
White solid, yield: 8.94 g (90%), m.p. 82-83 °C (from benzene-petroleum ether, 2:1). IR
(ATR, cm-1): 3340 (OH), 3046 (Ar-CH), 2918 (Aliph. CH), 1579 (C=N). 1H NMR (400 MHz,
CDCl3) δ (ppm): 2.74 (s, 3H, -CH3), 3.41 (dd, J=8.4 Hz, J=8.0 Hz, 1H, -CH2 (A)), 3.69 (dd,
J=3.6 Hz, J=2.8 Hz, 1H, -CH2 (B)), 4.22 (d, J=2.0 Hz, 1H, OH), 5.13 (t, J=4.0 Hz, 1H, -CH-),
7.32 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ ppm): 15.6 (-
CH3), 42.5 (-CH2), 72.4 (-CH), 121.7 (C), 127.6 (CH), 131.6 (CH), 141.4 (C), 165.6 (C),
166.1 (C). MS: m/z 331.24 (M+, 100), 333.14 (M+2, 97). Anal. Calcd. for C11H11BrN2OS2: C,
39.88; H, 3.35; N, 8.46. Found: C, 39.75; H, 3.31; N, 8.39.
4.3.3. 1-(4-Chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4c)
White solid, yield: 7.05 g (82%), m.p. 80-81 °C (from benzene-petroleum ether, 2:1). IR
(ATR, cm-1): 3313 (OH), 3058 (Ar-CH), 2976 (Aliph. CH), 1586 (C=N). 1H NMR (400 MHz,
CDCl3) δ (ppm): 2.73 (s, 3H, -CH3), 3.35 (dd, J=8.4 Hz, J=8.0 Hz, 1H, -CH2 (A)), 3.69 (dd,
J=3.6 Hz, J=3.2 Hz, 1H, -CH2 (B)), 4.24 (bs, 1H, OH), 5.14 (dd, J=3.2 Hz, J=2.8 Hz, 1H, -
13
CH-), 7.32 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm):
15.6 (-CH3), 42.6 (-CH2), 72.5 (-CH), 127.2 (CH), 128.6 (CH), 133.6 (C), 140.9 (C), 165.5
(C), 166.1 (C). MS: m/z 286.81 (M+, 100). Anal. Calcd. for C11H11ClN2OS2: C, 46.07; H,
3.87; N, 9.76. Found: C, 46.01; H, 3.92; N, 9.84.
4.3.4. 1-(4-Methoxyphenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4d)
White solid, yield: 7.21 g (85%), m.p. 71-72 °C (from benzene-petroleum ether, 2:1). IR
(ATR, cm-1): 3269 (OH), 3009 (Ar-CH), 2961 (Aliph. CH), 1609 (C=N), 1238-1057 (-OCH3).
1H NMR (400 MHz, CDCl3) δ (ppm): 2.73 (s, 3H, -CH3), 3.46 (dd, J=8.4 Hz, J=8.0 Hz, 1H, -
CH2 (A)), 3.68 (dd, J=3.2 Hz, J=3.2 Hz, 1H, -CH2 (B)), 3.77 (d, J=3.6 Hz, 1H, OH), 3.88 (s,
14

ACCEPTED MANUSCRIPT
3H, -OCH3), 5.09 (t, J=4.0 Hz, 1H, -CH-), 6.89 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H). 13C
NMR (100 MHz, CDCl3, δ ppm): 15.6 (-CH3), 42.7 (-CH2), 55.2 (-OCH3), 72.7 (-CH), 113.9
(CH), 127.1 (CH), 134.5 (C), 159.3 (C), 165.3 (C), 166.1 (C). MS: m/z 282.75 (M+, 100).
Anal. Calcd. for C12H14N2O2S2: C, 51.04; H, 5.00; N, 9.92. Found: C, 51.11; H, 4.93; N, 9.85.
4.4. General procedure for the synthesis of 3-((un)substituted benzyl)-5-methyl-1,3,4-
thiadiazol-2(3H)-one (7a-g)
In a round-bottomed flask, alcohol derivatives (4a-d) (3.5 mmol) were dissolved in DMF
(6ml). NaH (60% mineral oil dispersion, 5.25 mmol; 0.126 g) was added in small fractions to
prevent any heating. The appropriate benzyl halides (5a-g) (3.5 mmol) were dissolved in
DMF (4ml) and added dropwise to this solution. The mixture was stirred at room temperature
for 4-6 h. The progress of the reaction was monitored by TLC at appropriate time intervals.
After completion of the reaction, the excess hydride was decomposed with a small amount of
methyl alcohol, then the solvent was removed under reduced pressure. The crude residue was
suspended in water and extracted with chloroform. The organic layer was dried over
anhydrous sodium sulfate, filtered and then evaporated to dryness. The crude residue was
purified by column chromatography on a silica-gel column using chloroform as the eluent to
obtain target compounds (7a-g). The synthesized compounds were dried with P2O5 in a
vacuum oven.
4.4.1. 3-Benzyl-5-methyl-1,3,4-thiadiazol-2(3H)-one (7a)34
Yellowish oil, yield: 0.55 g (77%), Rf = 0.64 (CHCl3/MeOH 90:10). IR (ATR, cm-1): 3033
(Ar-CH), 2925 (Aliph. CH), 1668 (C=O), 1562 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm):
13
2.36 (s, 3H, -CH3), 5.01 (s, 2H, -CH2), 7.34 (s, 5H). C NMR (100 MHz, CDCl3, δ ppm):
18.1 (-CH3), 50.5 (-CH2), 128.0 (CH), 128.2 (CH), 128.7 (CH), 135.8 (C), 148.6 (C), 170.3
15

ACCEPTED MANUSCRIPT
(C=O). MS: m/z 206.84 (M+, 100). Anal. Calcd. for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58.
Found: C, 58.15; H, 4.81; N, 13.49.
4.4.2. 3-(4-Bromobenzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7b)
Colorless crystals, yield: 0.78 g (78%), m.p. 89-91 °C (from chloroform); Rf = 0.62
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3053 (Ar-CH), 2949 (Aliph. CH), 1652 (C=O), 1563
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.37 (s, 3H, -CH3), 4.95 (s, 2H, -CH2), 7.22 (d,
13
J=7.6 Hz, 2H), 7.47 (d, J=7.2 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm): 18.1 (-CH3),
49.8 (-CH2), 122.1 (C), 130.1 (CH), 131.8 (CH), 134.7 (C), 148.8 (C), 170.2 (C=O). MS: m/z
286.24 (M+1, 100). Anal. Calcd. for C10H9BrN2OS: C, 42.12; H, 3.18; N, 9.82. Found: C,
42.05; H, 3.22; N, 9.76.
4.4.3. 3-(4-Chlorobenzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7c)
Colorless crystals, yield: 0.69 g (82%), m.p. 80-82 °C (from chloroform); Rf = 0.67
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3055 (Ar-CH), 2932 (Aliph. CH), 1657 (C=O), 1563
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.37 (s, 3H, -CH3), 4.97 (s, 2H, -CH2), 7.28 (d,
13
J=8.4 Hz, 2H), 7.31 (d, J=6.8 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm): 18.1 (-CH3),
49.8 (-CH2), 128.9 (CH), 129.7 (CH), 130.0 (C), 134.2 (C), 148.8 (C), 170.2 (C=O). MS: m/z
241.05 (M+1, 100). Anal. Calcd. for C10H9ClN2OS: C, 49.90; H, 3.77; N, 11.64. Found: C,
49.81; H, 3.68; N, 11.58.
4.4.4. 3-(4-Fluorobenzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7d)
Light yellow crystals, yield: 0.61 g (78%), m.p. 76-78 °C (from chloroform); Rf = 0.67
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3081 (Ar-CH), 2960 (Aliph. CH), 1660 (C=O), 1559
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.36 (s, 3H, -CH3), 4.97 (s, 2H, -CH2), 7.02 (t,
J=7.6 Hz, 2H), 7.33 (t, J=6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ ppm): 18.1 (-CH3),
16

ACCEPTED MANUSCRIPT
49.7 (-CH2), 115.5-115.7 (CH) 3J CF=21.0 Hz, 130.1-130.2 (CH) 2J CF=8.3 Hz, 131.6-131.7
(C) 4J CF=3.1 Hz, 148.7 (C), 161.2-163.7 (C) 1J CF=246.0 Hz, 170.2 (C=O). MS: m/z 224.83
(M+, 100). Anal. Calcd. for C10H9FN2OS: C, 53.56; H, 4.05; N, 12.49. Found: C, 53.49; H,
4.00; N, 12.57.
4.4.5. 5-Methyl-3-(4-(trifluoromethyl)benzyl)-1,3,4-thiadiazol-2(3H)-one (7e)
Light yellow crystals, yield: 0.73 g (76%), m.p. 50-52 °C (from chloroform); Rf = 0.69
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3078 (Ar-CH), 2946 (Aliph. CH), 1667 (C=O), 1558
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 3H, -CH3), 5.06 (s, 2H, -CH2), 7.45 (d,
13
J=7.2 Hz, 2H), 7.60 (d, J=7.2 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm): 18.1 (-CH3),
1
3
49.9 (-CH2), 119.9-122.6 (CF3) J CF=271.0 Hz, 125.3 (CH), 125.6-125.7 (CH) J CF=4.0
3
1
2
Hz, 125.8-125.9 (CH) J CF=4.0 Hz, 128.0-128.5 (CH) J CF=51.0 Hz, 129.8-130.1 (C) J
2
CF=35.0 Hz, 130.4-130.7 (C) J CF=32.0 Hz, 139.6 (C), 149.1 (C), 170.3 (C=O). MS: m/z
274.83 (M+, 100). Anal. Calcd. for C11H9F3N2OS: C, 48.17; H, 3.31; N, 10.21. Found: C,
48.11; H, 3.26; N, 10.11.
4.4.6. 3-(2,6-Dichlorobenzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7f)
Colorless crystals, yield: 0.72 g (75%), m.p. 130-132 °C (from chloroform); Rf = 0.70
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3076 (Ar-CH), 2959 (Aliph. CH), 1679 (C=O), 1561
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.29 (s, 3H, -CH3), 5.26 (s, 2H, -CH2), 7.22 (t,
13
J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm): 18.2 (-CH3),
45.4 (-CH2), 128.4 (CH), 130.0 (CH), 131.0 (C), 136.7 (C), 148.3 (C), 169.9 (C=O). MS: m/z
274.69 (M-1, 100), 276.79 (M+1, 74). Anal. Calcd. for C10H8Cl2N2OS: C, 43.65; H, 2.93; N,
10.18. Found: C, 43.54; H, 2.85; N, 10.15.
4.4.7. 3-(2-Chloro-6-fluorobenzyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (7g)
Light yellow crystals, yield: 0.64 g (71%), m.p. 84-85 °C (from chloroform); Rf = 0.65
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3093 (Ar-CH), 2958 (Aliph. CH), 1665 (C=O), 1569
17

ACCEPTED MANUSCRIPT
(C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.28 (s, 3H, -CH3), 5.06 (s, 2H, -CH2), 7.26 (t,
13
J=9.2 Hz, 1H), 7.34 (d, J=9.2 Hz, 1H), 7.45-7.40 (m, 1H). C NMR (100 MHz, CDCl3, δ
ppm): 18.2 (-CH3), 41.4-41.5 (-CH2) 4J CF=4.6 Hz, 115.0-115.2 (CH) 3J CF=22.0 Hz, 121.6-
121.8 (CH) 4J CF=17.5 Hz, 126.0-126.1 (CH) 2J CF=3.8 Hz, 131.6-131.7 (C) 3J CF=9.8 Hz,
3
1
135.1-135.2 (C) J CF=5.3 Hz, 149.2 (C), 160.6-163.3 (C) J CF=270.0 Hz, 169.3 (C=O).
MS: m/z 260.88 (M+2, 100). Anal. Calcd. for C10H8ClFN2OS: C, 46.43; H, 3.12; N, 10.83.
Found: C, 46.38; H, 3.04; N, 10.76.
4.5. General procedure for the synthesis of ((un)substituted phenyl)-2-oxoethyl)-5-methyl-
1,3,4-thiadiazol-2(3H)-one (10-15)
In a round-bottomed flask, 2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)-1-phenylethanol (4a)
(3.5 mmol; 0.88 g) was dissolved in DMF (6ml). NaH (60% mineral oil dispersion, 5.25
mmol; 0.126 g) was added in small fractions to prevent any heating. The appropriate phenacyl
bromide derivatives (8a-f) (3.5 mmol) were dissolved in DMF (4ml) and added dropwise to
this solution. The mixture was stirred at room temperature for 4-6 h. The progress of the
reaction was monitored by TLC at appropriate time intervals. After completion of the
reaction, the excess hydride was decomposed with a small amount of methyl alcohol, then the
solvent was removed under reduced pressure. The crude residue was suspended in water and
extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate,
filtered and then evaporated to dryness. The crude residue was purified by column
chromatography on a silica-gel column using chloroform as the eluent to obtain target
compounds (10-15). The synthesized compounds were dried with P2O5 in a vacuum oven.
4.5.1. 5-Methyl-3-(2-oxo-2-phenylethyl)-1,3,4-thiadiazol-2(3H)-one (10)
18

ACCEPTED MANUSCRIPT
White crystals, yield: 0.52 g (63%), m.p. 102-103 °C (from chloroform); Rf = 0.38
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3057 (Ar-CH), 2937 (Aliph. CH), 1702 (C=O), 1651
(C=O), 1595 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.40 (s, 3H, -CH3), 5.51 (s, 2H, -
13
CH2), 7.56 (t, J=7.8 Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H). C NMR (100
MHz, CDCl3, δ ppm): 18.1 (-CH3), 53.6 (-CH2), 128.6 (CH), 129.4 (CH), 134.5 (CH), 134.6
(C), 149.0 (C), 170.4 (C=O), 192.7 (C=O). MS: m/z 235.57 (M+1, 100). Anal. Calcd. for
C11H10N2O2S: C, 56.39; H, 4.30; N, 11.96. Found: C, 56.29; H, 4.27; N, 11.92.
4.5.2. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (11)
Yellowish solid, yield: 0.72 g (66%), m.p. 99-101 °C (from chloroform); Rf = 0.41
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3062 (Ar-CH), 2985 (Aliph. CH), 1703 (C=O), 1662
(C=O), 1587 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.42 (s, 3H, -CH3), 5.26 (s, 2H, -
13
CH2), 7.65 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm):
18.2 (-CH3), 52.6 (-CH2), 129.4 (C), 129.5 (CH), 132.3 (CH), 133.0 (C), 149.2 (C), 170.8
(C=O), 190.4 (C=O). MS: m/z 314.28 (M+1, 100). Anal. Calcd. for C11H9BrN2O2S: C, 42.19;
H, 2.90; N, 8.95. Found: C, 42.11; H, 2.88; N, 8.91.
4.5.3. 3-(2-(4-Chlorophenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (12)
Yellow solid, yield: 0.61 g (65%), m.p. 90-91 °C (from chloroform); Rf = 0.40
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3043 (Ar-CH), 2986 (Aliph. CH), 1703 (C=O), 1663
(C=O), 1589 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.41 (s, 3H, -CH3), 5.26 (s, 2H, -
13
CH2), 7.47 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.8 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm):
18.2 (-CH3), 52.6 (-CH2), 129.3 (CH), 129.4 (CH), 132.6 (C), 140.6 (C), 149.2 (C), 170.8
(C=O), 190.2 (C=O). MS: m/z 268.11 (M+, 100). Anal. Calcd. for C11H9ClN2O2S: C, 49.17;
H, 3.38; N, 10.42. Found: C, 49.11; H, 3.32; N, 10.45.
4.5.4. 3-(2-(4-Fluorophenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (13)
19

ACCEPTED MANUSCRIPT
Yellow solid, yield: 0.57 g (65%), m.p. 92-93 °C (from chloroform); Rf = 0.43
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3071 (Ar-CH), 2942 (Aliph. CH), 1703 (C=O), 1663
(C=O), 1598 (C=N). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.42 (s, 3H, -CH3), 5.27 (s, 2H, -
13
CH2), 7.17 (t, J=8.4 Hz, 2H), 7.99 (t, J=8.4 Hz, 2H). C NMR (100 MHz, CDCl3, δ ppm):
3
2
18.2 (-CH3), 52.6 (-CH2), 116.1-116.3 (CH) J CF=22.0 Hz, 130.7-130.8 (C) J CF=9.1 Hz,
4
1
131.3-132.4 (C) J CF=3.1 Hz, 149.2 (C), 164.9-167.5 (C) J CF=255.0 Hz, 170.9 (C=O),
189.7 (C=O). MS: m/z 253.16 (M+1, 100). Anal. Calcd. for C11H9FN2O2S: C, 52.37; H, 3.60;
N, 11.10. Found: C, 52.33; H, 3.52 ; N, 11.02.
4.5.5. 4-(2-(5-Methyl-2-oxo-1,3,4-thiadiazol-3(2H)-yl)acetyl)benzonitrile (14)
Yellow solid, yield: 0.63 g (70%), m.p. 133-135 °C (from chloroform); Rf = 0.38
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3079 (Ar-CH), 2981 (Aliph. CH), 2233 (C≡N), 1712
1
(C=O), 1660 (C=O), 1563 (C=N). H NMR (400 MHz, CDCl3) δ (ppm): 2.41 (s, 3H, -CH3),
5.28 (s, 2H, -CH2), 7.80 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3, δ ppm): 18.2 (-CH3), 52.8 (-CH2), 117.3 (C≡N), 128.5 (CH), 129.5 (CH), 132.3 (C),
137.2 (C), 149.5 (C), 170.8 (C=O), 190.4 (C=O). MS: m/z 260.83 (M+1, 100). Anal. Calcd.
for C12H9N3O2S: C, 55.59; H, 3.50; N, 16.21. Found: C, 55.48; H, 3.43; N, 16.33.
4.5.6. 3-(2-(4-Methoxyphenyl)-2-oxoethyl)-5-methyl-1,3,4-thiadiazol-2(3H)-one (15)
Yellow solid, yield: 0.66 g (71%), m.p. 70-72 °C (from chloroform); Rf = 0.36
(CHCl3/MeOH 90:10). IR (ATR, cm-1): 3063 (Ar-CH), 2942 (Aliph. CH), 1691 (C=O), 1646
(C=O), 1597 (C=N), 1181, 1118 (-OCH3). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.40 (s, 3H,
-CH3), 3.86 (s, 3H, -OCH3), 5.25 (s, 2H, -CH2), 6.95 (d, J=8.8 Hz, 2H), 7.92 (d, J=9.2 Hz,
2H). 13C NMR (100 MHz, CDCl3, δ ppm): 18.2 (-CH3), 52.4 (-CH2), 55.5 (-OCH3), 114.1
(CH), 127.3 (C), 130.3 (CH), 149.9 (C), 164.1 (C), 170.9 (C=O), 189.6 (C=O). MS: m/z
265.90 (M+1, 100). Anal. Calcd. for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found: C,
54.46; H, 4.51; N, 10.50.
20

ACCEPTED MANUSCRIPT
Acknowledgments
The financial support under the contract (KBÜ-BAP-15/1-DS-021 and KBÜ-BAP-17-BM-
132) from Karabük University is gratefully acknowledged.
Supporting Information
1H NMR, 13C NMR, FT-IR, Mass and Elemental analysis spectra copies of all compounds and
X-Ray crystallographic data of compounds 3c, 7b-f and 10 are given in Supporting
Information.
CCDC Numbers: for compound 3c: 1528417, for compound 7b: 1528421, for compound 7c:
1528418, for compound 7d: 1528422, for compound 7e: 1528419, for compound 7f:
1528420, for compound 10: 1528423.
References
1. Sayed AR. Tetrahedron. 2012; 68:2784.
2. Shahcheragh SM, Habibi A, Khosravi S. Tetrahedron Lett. 2017; 58:855.
3. El-Gohary NS, Shaaban MI. Eur J Med Chem. 2013; 63:185.
4. Zoumpoulakis P, Camoutsis C, Pairas G, Soković M, Glamočlija J, Potamitis C, Pitsas A.
Bioorg Med Chem. 2012; 20:1569.
5. Li P, Shi L, Gao M-N, Yang X, Xue W, Jin LH, Hu D-Y, Song B-A. Bioorg Med Chem
Lett. 2015; 25:481.
6. Ragab FA, Heiba HI, El-Gazzar MG, Abou-Seri SM, El-Sabbagh WA, El-Hazek RM. J
Photochem Photobiol B: Biol. 2016; 166:285.
7. Luszczki JJ, Karpinska M, Matysiak J, Niewiadomy A. Pharmacol Rep. 2015; 67:588.
21

ACCEPTED MANUSCRIPT
8. Gür M, Muğlu H, Çavuş MS, Güder A, Sayıner HS, Kandemirli F. J Mol Struct. 2017;
1134:40.
9. Kadi AA, Al-Abdullah ES, Shehata IA, Habib EE, Ibrahim TM, El-Emam AA. Eur J Med
Chem. 2010; 45:5006.
10. Polkam N, Rayam P, Anireddy JS, Yennam S, Anantaraju HS, Dharmarajan S, Perumal
Y, Kotapalli SS, Ummanni R, Balasubramanian S. Bioorg Med Chem Lett. 2015; 25:1398.
11. Yusuf M, Khan RA, Ahmed B. Bioorg Med Chem. 2008; 16:8029.
12. Turner S, Myers M, Gadie B, Nelson AJ, Pape R, Saville JF, Doxey JC, Berridge TL. J
Med Chem. 1988; 31:902.
13. Chen Z, Xu W, Liu K, Yang S, Fan H, Bhadury PS, Huang D-Y, Zhang Y. Molecules.
2010; 15:9046.
14. Zarei M. Tetrahedron. 2017; 73:1867.
15. Zou X-J, Lai L-H, Jin G-Y, Zhang Z-X. J Agric Food Chem. 2002; 50:3757.
16. Grykien R, Luszczynska B, Glowacki I, Kurach E, Rybakiewicz R, Kotwica K, Zagorska
M, Pron A, Tassini P, Maglione MG. Opt Mater. 2014; 37:193.
17. Gündüz B, Turan N, Kaya E. Polym Bull. 2014; 71:2945.
18. Kurowska A, Kostyuchenko AS, Zassowski P, Skorka L, Yurpalov VL, Fisyuk AS, Pron
A, Domagala W. J Phys Chem C. 2014; 118:25176.
19. Zuo Y, Yang S-G, Jiang L-L, Hao G-F, Wang Z-F, Wu Q-Y, Xi Z, Yang G-F. Bioorg
Med Chem. 2012; 20:296.
20. Marks GS. The Botanical Review. 1966; 32:56.
21. Poulson R, Polglase, W. J Biol Chem. 1975, 250, 1269.
22. Poulson, R. J Biol Chem. 1976; 251:3730.
23. Jiang L-L, Tan Y, Zhu X-L, Wang Z-F, Zuo Y, Chen Q, Xi Z, Yang G-F. J Agric Food
Chem. 2009; 58:2643.
22

ACCEPTED MANUSCRIPT
24. Duke SO, Rebeiz CA. In ACS Symposium Series; American Chemical
Society:Washington, DC, 1994; Vol. 559, p 71.
25. Fingar VH, Wieman TJ, McMahon KS, Haydon PS, Halling BP, Yuhas DA, Winkelman
JW. Cancer Res. 1997; 57:4551.
26. Augustine JK , Vairaperumal V, Narasimhan S, Alagarsamy P, Radhakrishnan A.
Tetrahedron. 2009; 65:9989.
27. Clark J, English J, Winnek P, Marson H, Cole Q, Clapp J. J Am Chem Soc. 1946; 68:96.
28. Coburn RA, Bhooshan B, Glennon RA. J Org Chem. 1973; 38:3947.
29. Er M, Isildak G, Tahtaci H, Karakurt T. J Mol Struct. 2016; 1110:102.
30. Er M, Ergüven B, Tahtaci H, Onaran A, Karakurt T, Ece A. Med Chem Res. 2017; 26:615.
31. Oruç EE, Rollas S, Kandemirli F, Shvets N, Dimoglo AS. J Med Chem. 2004; 47:6760.
32. Siddaraju Y, Prabhu KR. Org Lett. 2016; 18:6090.
33. Pradaux-Caggiano F, Caggiano FP, Su X, Vicker N, Thomas MP, Smithen D, Halem HA,
Culler MD, Potter VL. Med Chem Commun. 2012; 3:1117.
34. Kishi M, Ishitobi H, Nagata W, Tsuji T. Heterocycles. 1979; 13:197.
Figure and Scheme Captions
23

ACCEPTED MANUSCRIPT
Scheme 1. Synthetic route for the synthesis of ((un)substituted benzyl)-5-methyl-1,3,4-
thiadiazol-2(3H)-one derivatives (7a-g) and ((un)substituted phenyl)-2-oxoethyl)-5-methyl-
1,3,4-thiadiazol-2(3H)-one derivatives (10-15).
Scheme 2. A plausible mechanism for the formation of compounds (7a-g) and (10-15).
Figure 1. Structures of the compounds 7a-g (yields are given in the parentheses).
Figure 2. Structures of the compounds 10-15 (yields are given in the parentheses).
24

ACCEPTED MANUSCRIPT
Highlights
•
•
•
•
This study exhibits a new and effective method to synthesize target compounds.
A new method of synthesis was developed for 1,3,4-thiadiazol-2(3H)-one derivatives.
Not only this method takes less time to perform, but it also costs less.
The synthesized compounds were characterized by different spectroscopic techniques.