A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

Article abstract of DOI:10.1080/00397911.2019.1623257

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2

Full text of DOI:10.1080/00397911.2019.1623257

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A simple and efficient approach for the synthesis
of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-
one derivatives via intramolecular nucleophilic
substitution reaction
Hakan Tahtaci & Gözde Aydın
To cite this article: Hakan Tahtaci & Gözde Aydın (2019): A simple and efficient approach
for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via
intramolecular nucleophilic substitution reaction, Synthetic Communications, DOI:
10.1080/00397911.2019.1623257
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https://doi.org/10.1080/00397911.2019.1623257
A simple and efficient approach for the synthesis of a
novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives
via intramolecular nucleophilic substitution reaction
€
Hakan Tahtaci and Gozde Aydın
Department of Chemistry, Faculty of Science, Karabuk University,Karabuk 78050,Turkey
ABSTRACT
ARTICLE HISTORY
Received 26 January 2019
In this study, we synthesized a new series of substituted aliphatic
1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42
to 70% with an interesting mechanism that involves internal nucleo-
philic substitution followed by an SN2-type nucleophilic substitution.
KEYWORDS
Aliphatic 1,3,4-thiadiazol-
2(3H)-one;intramolecular
nucleophilic substitution
reaction;1,3,4-thiadiazole
derivatives
First,
1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)etha-
none (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadia-
zole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the
presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-
methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a
reduction reaction of this compound using NaBH4. Finally, 5-methyl-
3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the
target compounds, were synthesized from the reaction of this com-
pound (4), which is a secondary alcohol with various alkyl halides
(5a-n) in the presence of sodium hydride (NaH). This study presents
an interesting reaction mechanism related to the synthesis of ali-
phatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in
the literature.
GRAPHICAL ABSTRACT
CONTACT Hakan Tahtaci
hakantahtaci@karabuk.edu.tr
Department of Chemistry, Faculty of Science, Karabuk
University,Karabuk,78050,Turkey
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

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H. TAHTACI AND G. AYDIN
Introduction
Compounds that contain one or more heteroatoms other than carbon and hydrogen,
such as oxygen, nitrogen, or sulfur, and that have the maximum number of conjugated
double bonds are referred to as heterocyclic compounds.[1]
Thiadiazole is a five-membered heterocyclic organic compound. Its molecular formula
is C2H2N2S. Thiadiazoles and their derivatives are commonly used in pharmaceutical
chemistry, materials science, and organic syntheses due to their containing both an elec-
tron-withdrawing (–S) as well as electron-donating group (–C¼N).[2,3] Thiadiazole has
four isomers, including 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-
thiadiazole.[4] The syntheses of 1,3,4-thiadiazole and its derivatives have become the
focus of attention particularly in recent years due to their 2’ and 5’ positions being quite
active against nucleophilic substitution reactions.[5–8]
The two-electron donor nitrogen system (–N¼C–S), the sulfur atom, and the hydro-
gen binding domain in thiadiazole form the part that provides stability and are largely
responsible for biological activity.[9–11] 1,3,4-Thiadiazole and its derivatives are com-
monly used in medicine and pharmacology due to their wide spectrum of biological
and pharmaceutical properties, such as antifungal, antibacterial, antimicrobial, antiviral,
anticancer, antidepressant, antioxidant, anti-inflammatory, anticonvulsant, antitubercu-
losis, antiproliferative, and antihypertensive activities.[12–25]
Nitrogen and sulfur atoms in 1,3,4-thiadiazole contribute to its thermal properties and
play a significant role in conductivity. 1,3,4-Thiadiazole and its derivatives are used for semi-
conductors and coatings in the polymer industry due to their electrical conductivity.[26,27]
There are various methods in the literature used for the synthesis of 1,3,4-thiadiazole
and its derivatives. Some compounds used as the starting compound in the synthesis of
1,3,4-thiadiazole and its derivatives include acylhydrazines, thiohydrazines, 1,3,4-oxadia-
zoles, and azides.[28–34]
In this study, we synthesized compounds containing a 1,3,4-thiadiazole-2(3H)-one
nucleus. Only a limited number of studies in the literature involve such compounds. In
those studies, aryl-substituted 1,3,4-thiadiazole-2(3H)-one compounds were synthesized
using traditional methods, all of which featuring phosgene gas (COCl2), which is a
highly toxic chemical compound.[35–37] However, to the best of our knowledge, there is
no study in the literature involving aliphatic 1,3,4-thiadiazole-2(3H)-one derivatives,
which we synthesized in this study without using phosgene.
In light of the important data mentioned above, the primary purpose of this study is to
synthesize 5-methyl-3-alkyl-1,3,4-thiadiazole-2(3H)-one derivatives (6-24), which are not
found in the literature, using a method that has been used for the first time by our group
through an interesting mechanism. The second purpose is to contribute to the literature
by introducing compounds with new properties by characterizing these compounds using
various analysis methods (1H NMR, 13C NMR, FT-IR, LC-MS, and elemental analysis).
The synthetic pathway for the synthesis of target compounds is shown in Scheme 1.
Results and discussion
In the first part of the study, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazole-2-yl)th-
io)ethanone (3) was synthesized (in yield of 87%) from the reaction of 5-methyl-1,3,4-

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Scheme 1. Synthetic pathway for the synthesis of 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one deriva-
tives (6-24).
thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of
potassium hydroxide in absolute ethyl alcohol.
Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazole-2-yl)thio)ethanol (4) was
synthesized (in yield of 86%) as a result of reduction reaction of this compound (3)
with NaBH4 in absolute ethyl alcohol. The starting materials (compounds 3 and 4)
were prepared in accordance with the existing methods.[38–40]
Finally, 5-methyl-3-alkyl-1,3,4-thiadiazole-2(3H)-one derivatives (6-24) were obtained
from the reaction of this alcohol compound (4) with various alkyl halides (5a-n) in the
presence of sodium hydride (NaH) in DMF, which is a polar aprotic solvent, with mod-
erate-to-good yields (in yields of 42% to 70%). The target compounds and the yields are
shown in Figure 1.

4
H. TAHTACI AND G. AYDIN
Figure 1. Structures of the target compounds (6-24) (yields are given in parentheses).
This reaction works with the formation of the benzyloxy group, which is quite a basic
and strong nucleophile, through the deprotonation of the secondary alcohol (compound
4). Then this benzyloxy group leads to an SNi-type intramolecular nucleophilic substitu-
tion reaction and forms a spiro intermediate A.
Subsequently intermediate B forms as a result of the SN2-type nucleophilic substitu-
tion of the new nucleophilic center on the nitrogen atom of this spiro intermediate A
formed in the intermediate step with alkyl halides (5a-n).
Finally, this compound (intermediate B) is converted to 5-methyl-3-alkyl-1,3,4-thia-
diazole-2(3H)-one derivatives (6-24), the target compounds, with hydrolysis during
work-up. This reaction involves two intermediate steps and appears to be an interesting
mechanism. The suggested reaction mechanism related to the synthesis is shown in
Scheme 2.
In a similar study previously conducted by our group, benzyl halides and phenacyl
bromide derivatives were used instead of alkyl halides in this reaction. Substituted ben-
zyl-5-methyl-1,3,4-thiadiazole-2(3H)-one derivatives were obtained through the same
mechanism as a result of these reactions.[39] In this study, the secondary alcohol (com-
pound 4) was react with NaH without any benzyl bromide or phenacyl bromide deriva-
tives in the reaction environment in order to prove that the reaction occurs through the
suggested mechanism.
Thus, spiro intermediate A compound formed in the intermediate step and was iso-
lated. The reaction mechanism shown in Scheme 2 was suggested based on
this formation.
This study proves that the suggested reaction mechanism occurs in different deriva-
tives (alkyl halides) other than benzyl halides and phenacyl bromide derivatives.
The suggested reaction mechanism shows that the target compounds are determined
by the alkyl halides regardless of which alcohol derivative (4) with a similar principal
structure is used at the beginning; this is shown in Figure 2.
This reaction mechanism involves an interesting reaction whereby exocyclic oxygen
had transferred to the thiadiazole ring via two different substitution reactions (SNi and

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Scheme 2. The reaction mechanism for the formation of the target compounds (6-24).
SN2). The progress of this reaction mechanism, where the SNi and SN2 reactions shown
in Scheme 2 occur successively, relies on the alkoxide anion being a strong nucleophile
as well as a strong base. This allows for the intramolecular nucleophilic substitution
reaction (SNi). The suggested reaction mechanism appears to be a novel and interesting
method for the synthesis of 5-methyl-3-alkyl-1,3,4-thiadiazole-2(3H)-one derivatives
(6-24).
In this mechanism, first 7-(4-chlorophenyl)-3-methyl-6-oxa-4,9-dithia-1,2-diazaspir-
o[4.4]non-2-en-1-ide (spiro intermediate A) forms through the SNi-type intramolecular
nucleophilic substitution reaction of the benzyloxy group. This compound is believed to
then turn into the carbonyl group through the SN2-type nucleophilic substitution reac-
tion of the compound with various alkyl halides, and finally with the hydrolysis of this
N-alkylated oxathiolane compound (intermediate B).
The 5-methyl-3-alkyl-1,3,4-thiadiazole-2(3H)-one derivatives (6-24) synthesized in
this study are not found in the literature, similar compounds were synthesized with
known methods,[35–37] which in turn makes our study unique.
The structures of the target compounds (6-24) synthesized in this study were eluci-
1
dated using the H NMR, 13C NMR, FT-IR, elemental analysis, and mass spectroscopy.

6
H. TAHTACI AND G. AYDIN
Figure 2. Synthetic route for the formation of the target compounds (6-24).
The broad ꢀOH absorption band belonging to compound 4, which was used as the
starting compound, disappeared in the FT-IR spectra of the target compounds (6-24).
The carbonyl group (C¼O) peaks appeared in the 1679–1651 cmꢀ1 range, which consti-
tutes strong evidence for the formation of these compounds. Furthermore, aromatic
–CH peaks were not observed in the 3100–3050 cmꢀ1 range in the target compounds,
which in turn supports the suggested structures.
1
The H NMR spectra of the target compounds contained considerable evidence for
the formation of these compounds. The AB system observed at 3.69 and 3.35 ppm in
the starting compound and the broad singlet peak belonging to OH observed at
4.24 ppm in the starting compound disappeared, and this indicates the formation of the
target compounds.
No peak was observed in the domain belonging to the aromatic structures in the
7.5–8.0 ppm range. Instead, peaks belonging to the aliphatic groups were observed in
the 1–3 ppm range depending on the compound structure, which is the most significant
1
evidence for the formation of the target compounds. It can be said that the H NMR
spectra of the target compounds were similar. The main difference was the increased
integration value of the protons belonging to the aliphatic –CH2 groups in the
1.39–1.18 ppm range with the elongation of the aliphatic chain.
1
Detailed data related to the H NMR spectra can be found in the experimental sec-
tion together with the coupling constants, and the relevant spectra are given in the
Supporting Information.
The presence of peaks belonging to the carbonyl group carbon observed in the
170.43–169.92 ppm range in the 13C NMR spectra of the target compounds (6-24) sup-
ports the structures that we suggest. These values are very consistent with the litera-
ture.[39,41] The data related to the 13C NMR spectra can be found in the experimental
section, while all the spectra are given in the Supporting Information.

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The mass spectra belonging to the target compounds were also observed as expected
with molecular ion peaks.
Conclusions
In summary, this study presents an interesting mechanism where exocyclic oxygen
transferred to the thiadiazole ring via two different substitution reactions. In this study,
aliphatic 1,3,4-thiadiazole-2(3H)-one derivatives, which were not previously recorded in
the literature, were synthesized and characterized using various analysis techniques.
The advantages and novelties of this study include synthesizing aliphatic 1,3,4-thiadia-
zole-2(3H)-one derivatives under mild conditions with simple synthetic procedures, and
obtaining them without using phosgene (COCl2).
We further believe that the novel compounds synthesized, and the interesting reac-
tion mechanism suggested in this study, may pave the way for other study groups syn-
thesizing novel heterocyclic compounds.
Experimental section
Materials and methods
1
The H NMR and 13C NMR spectra were recorded on an Agilent NMR VNMRS spec-
trometer at 400 and 100 MHz, respectively in CDCl3 with tetramethylsilane as internal
reference. Chemical shift values are provided in ppm (parts per million) (d) and the
designation of signals were as follows: s, singlet; bs, broad singlet; d, doublet; t, triplet;
q, quartet; and m, multiplet. The IR spectra were measured in ATR with a Bruker
Optics Alpha FT-IR. A Thermo TSQ Quantum Access Max LC-MS/MS spectrometer
was used for the measurement of the mass spectra. It was Truspec Leco Micro CHNS
elemental analyzer on which elemental analyses were carried out and the results were
within 0.4% of the theoretical values. A Thermo Scientific IA9000 series apparatus was
utilized for recording the melting points (uncorrected). Thin layer chromatography
(TLC) was carried out on the glass backed silica-gel sheets (Silica Gel 60 F254 Aluminum
TLC plate) and imaged in UV light (254 nm and 365 nm). Silica gel (70–230 mesh
ASTM) eluting with chloroform was used to carry out column chromatography.
General procedure for the synthesis of 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one
derivatives (6-24)
The compound (4) (3.48 mmol) was dissolved in DMF (about 5 mL) in a round-bot-
tomed flask. NaH (60% mineral oil dispersion, 5.23 mmol; 0.2092 g) was added in small
fractions. The alkyl halides (5a-n) (3.48 mmol) were dissolved in DMF (about 3 mL)
and added drop by drop into this solution. For a period of about 6 h, the reaction mix-
ture was stirred at room temperature. TLC was used to observe the progress of the reac-
tion at appropriate time intervals. After the reaction was ended, the excess sodium
hydride was decomposed with methyl alcohol (5 mL), and then the solvent was evapo-
rated with rotary evaporator. The residue of the crude was suspended in brine and
extracted with chloroform (ꢁ3). The organic portion was dried over anhydrous sodium

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H. TAHTACI AND G. AYDIN
sulfate, filtered, and then evaporated by using rotary evaporator. The crude residue was
purified using column chromatography on a silica-gel column with chloroform as the
eluent to obtain target compounds (6-24). The pure matter was dried with phosphorus
pentoxide in a vacuum oven.
Selected characterization data
3-Ethyl-5-methyl-1,3,4-thiadiazol-2(3H)-one (6)s
Yellowish oil, yield: 0.348 g (69%), Rf ¼ 0.60 (CHCl3). IR (ATR, cmꢀ1): 2929 (Aliph.
CH), 1667 (C¼O), 1563 (C¼N). 1H NMR (400 MHz, CDCl3) d (ppm): 1.28 (t,
J ¼ 8.0 Hz, 3H, –CH3), 2.34 (s, 3H, –CH3), 3.86 (q, J ¼ 8.0 Hz, 2H, –CH2). 13C NMR
(100 MHz, CDCl3, d ppm): 13.8 (–CH3), 18.0 (–CH3), 42.0 (–CH2), 148.15 (Thiadiazole-
C), 169.9 (C¼O). MS: m/z 144.86 (Mþ, 100). Anal. Calcd. for C5H8N2OS: C, 41.65; H,
5.59; N, 19.43. Found: C, 41.54; H, 5.49; N, 19.38.
5-Methyl-3-propyl-1,3,4-thiadiazol-2(3H)-one (7)
Light oil, yield: 0.376 g (68%), Rf ¼ 0.61 (CHCl3). IR (ATR, cmꢀ1): 2941 (Aliph. CH),
1
1670 (C¼O), 1563 (C¼N). H NMR (400 MHz, CDCl3) d (ppm): 0.89 (t, J ¼ 8.0 Hz, 3H,
–CH3), 1.73–1.71 (m, 2H, –CH2), 2.34 (s, 3H, –CH3), 3.76 (t, J ¼ 8.0 Hz, 2H, –CH2).
13C NMR (100 MHz, CDCl3, d ppm): 10.9 (–CH3), 18.0 (–CH3), 21.9 (–CH2), 48.5
(–CH2), 147.9 (Thiadiazole-C), 170.2 (C¼O). MS: m/z 158.79 (Mþ, 100). Anal. Calcd.
for C6H10N2OS: C, 45.55; H, 6.37; N, 17.71. Found: C, 45.50; H, 6.45; N, 17.59.
3-Butyl-5-methyl-1,3,4-thiadiazol-2(3H)-one (8)
Light oil, yield: 0.386 g (64%), Rf ¼ 0.62 (CHCl3). IR (ATR, cmꢀ1): 2943 (Aliph. CH),
1
1670 (C¼O), 1562 (C¼N). H NMR (400 MHz, CDCl3) d (ppm): 0.91 (t, J ¼ 4.0 Hz, 3H,
–CH3), 1.34–1.32 (m, 2H, –CH2), 1.72–1.68 (m, 2H, –CH2), 2.36 (s, 3H, -CH3), 3.82 (t,
J ¼ 4.0 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3, d ppm): 13.5 (–CH3), 18.0 (–CH3),
19.6 (–CH2), 30.6 (–CH2), 46.7 (–CH2), 147.9 (Thiadiazole-C), 170.1 (C¼O). MS: m/z
172.93 (Mþ, 100). Anal. Calcd. for C7H12N2OS: C, 48.81; H, 7.02; N, 16.26. Found: C,
48.76; H, 6.91; N, 16.34.
5-Methyl-3-pentyl-1,3,4-thiadiazol-2(3H)-one (9)
Light oil, yield: 0.39 g (60%), Rf ¼ 0.64 (CHCl3). IR (ATR, cmꢀ1): 2936 (Aliph. CH),
1
1673 (C¼O), 1563 (C¼N). H NMR (400 MHz, CDCl3) d (ppm): 0.88 (t, J ¼ 8.0 Hz, 3H,
–CH3), 1.37–1.30 (m, 4H, –CH2), 1.72–1.68 (m, 2H, –CH2), 2.37 (s, 3H, –CH3), 3.81 (t,
J ¼ 4.0 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3, d ppm): 13.8 (–CH3), 18.0 (–CH3),
22.1 (–CH2), 28.3 (–CH2), 28.5 (–CH2), 47.0 (–CH2), 147.9 (Thiadiazole-C), 170.1
(C¼O). MS: m/z 187.00 (M þ 1100). Anal. Calcd. for C8H14N2OS: C, 51.58; H, 7.58; N,
15.04. Found: C, 51.45; H, 7.65; N, 15.00.

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3-Hexyl-5-methyl-1,3,4-thiadiazol-2(3H)-one (10)
Light oil, yield: 0.367 g (52%), Rf ¼ 0.67 (CHCl3). IR (ATR, cmꢀ1): 2931 (Aliph. CH),
1
1674 (C¼O), 1563 (C¼N). H NMR (400 MHz, CDCl3) d (ppm): 0.85 (t, J ¼ 4.0 Hz, 3H,
–CH3), 1.28–1.25 (m, 6H, –CH2), 1.72–1.68 (m, 2H, –CH2), 2.36 (s, 3H, –CH3), 3.80 (t,
J ¼ 8.0 Hz, 2H, –CH2). 13C NMR (100 MHz, CDCl3, d ppm): 13.9 (–CH3), 18.0 (–CH3),
22.4 (–CH2), 26.1 (–CH2), 28.5 (–CH2), 31.2 (–CH2), 47.0 (–CH2), 147.9 (Thiadiazole-
C), 170.1 (C¼O). MS: m/z 200.98 (Mþ, 100). Anal. Calcd. for C9H16N2OS: C, 53.97; H,
8.05; N, 13.99. Found: C, 53.89; H, 7.98; N, 13.87.
Funding
€
The financial support by the Karabuk University (Project ID Number: KBUBAP-18-YL-167) is
gratefully acknowledged.
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