Synthesis and reactions of novel 2,5-disubstituted 1,3,4-thiadiazoles

Article abstract of DOI:10.1080/00397911.2013.846381

The desired 1,3,4-thiadiazole compounds bearing different substituents were obtained by the cyclization of the corresponding thiosemicarbazide followed by the reaction with electrophilic reagents, such as aromatic aldehydes, isatin, phenyl isothiocyanate,

Full text of DOI:10.1080/00397911.2013.846381

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Synthesis and Reactions of Novel 2,5-
Disubstituted 1,3,4-Thiadiazoles
Mahmoud R. Mahmoud a , Sayed A. Shiba b , Ahmed K. El-Ziaty a ,
Fatma S. M. Abu El-Azm a & Mahmoud F. Ismail a
a Chemistry Department, Faculty of Science , Ain Shams University ,
Abbassia , Cairo , Egypt
b Chemistry Department, Faculty of Science and Arts, Sajer , Shaqra
University , Saudia Arabia
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Mahmoud R. Mahmoud , Sayed A. Shiba , Ahmed K. El-Ziaty , Fatma S. M.
Abu El-Azm & Mahmoud F. Ismail (2014) Synthesis and Reactions of Novel 2,5-Disubstituted 1,3,4-
Thiadiazoles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:8, 1094-1102, DOI: 10.1080/00397911.2013.846381
To link to this article: http://dx.doi.org/10.1080/00397911.2013.846381
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Synthetic Communications®, 44: 1094–1102, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.846381
SYNTHESIS AND REACTIONS OF NOVEL
2,5-DISUBSTITUTED 1,3,4-THIADIAZOLES
Mahmoud R. Mahmoud,1 Sayed A. Shiba,2 Ahmed K. El-Ziaty,1
Fatma S. M. Abu El-Azm,1 and Mahmoud F. Ismail1
1Chemistry Department, Faculty of Science, Ain Shams University, Abbassia,
Cairo, Egypt
2Chemistry Department, Faculty of Science and Arts, Sajer, Shaqra
University, Saudia Arabia
GRAPHICAL ABSTRACT
Abstract The desired 1,3,4-thiadiazole compounds bearing different substituents were
obtained by the cyclization of the corresponding thiosemicarbazide followed by the reaction
with electrophilic reagents, such as aromatic aldehydes, isatin, phenyl isothiocyanate, and
carbon disulfide. The newly synthesized 2,5-disubstituted 1,3,4-thiadiazoles were obtained
in good yields and their structures were elucidated by spectral data and elemental analysis.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications® for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords 2,5-Disubstituted 1,3,4-thiadiazoles; ring closure reaction; S-alkylation
INTRODUCTION
Thiadiazoles are important classes of nitrogen–sulphur-containing heterocycles.
They have extensive applications as structural units of various biologically impor-
tant molecules and as useful intermediates in medicinal chemistry. It is well
Received June 29, 2013.
Address correspondence to Fatma Saber Mohamed Abu El-Azm, Chemistry Department, Faculty
of Science, Ain Shams University, Abbassia 11566, Cairo, Egypt. E-mail: ftmsaber@yahoo.com
1094

SYNTHESIS OF NOVEL 1,3,4-THIADIAZOLE DERIVATIVES
1095
established that various 1,3,4-thiadiazole derivatives exhibit a broad spectrum of
pharmacological properties such as antibacterial, antifungal,[1–3] analgesic,[4] anti-
tumor,[5,6] anticonvulsant,[7] anxiolytic,[8] antidiabetic, and anti-inflammatory[9,10]. In
view of the field of biologically active heterocyclic compounds and in continuation of
our work,[11–15] in this article we described the synthesis of some new 2,5-disubstituted
1,3,4-thiadiazoles.
RESULTS AND DISCUSSION
Here in, treatment of lauroyl chloride with ammonium thiocyanate afforded the
lauroyl isothiocyanate 1, which in situ refluxed with cyanoethanoic acid hydrazide in
dioxane to give 1-(2-cyanoacetyl)-4-dodecanoyl thiosemicarbazide 2.
Cyclization of 2 in boiling acetic acid afforded N-[(5-cyanomethyl)-1,3,4-
thiadiazol-2-yl]dodecanamide 3 together with a minor amount of the acetylated
Scheme 1. Acid–base cyclization of 2.

1096
M. R. MAHMOUD ET AL.
product 4. Compound 3 was obtained as the sole product (66%) in pure form upon
treatment of 2 with concentrated sulfuric acid at 0 °C[16,17] (Scheme 1).
Compelling evidence for the structure 3 was forthcoming from the analyti-
cal and spectroscopic data. The infrared (IR) spectrum of 3 exhibited υNH at 3199,
3124 cm–1, υC-H (CH2,CH3) at 2954, 2922, 2851 cm–1, υC≡N at 2264 cm–1 and υC=O at
1680 cm–1. Moreover, the mass spectrum of compound 3 show the correct molecularion
at m/z=322 (5.3%).
1
Furthermore, HNMR spectrum (CDCl3) revealed the signals from low to
high field at δ (ppm): 12.25 (s, 1H, NH, exchangeable with D2O), 11.0 (s, 1H, NH,
exchangeable with D2O), 4.15 (s, 2H, CH2CN), 2.7 (t, 2H, CH2CO), 1.73 (m, 4H,
CH2CH2), 1.25 (m, 14H), 0.88 (t, 3H, Me), which were completely in accord with the
assigned structure.
The insoluble fraction in toluene was separated and detected as the acetylated
product 4, whose structure was investigated and confirmed using the analytical
and spectroscopic data. Thus, the IR spectrum of compound 4 show the stretching
Scheme 2. Cyclization of 2 using AcOH.

SYNTHESIS OF NOVEL 1,3,4-THIADIAZOLE DERIVATIVES
1097
absorption band for carbonyl group of ester at 1725 cm–1. The electron ionization–
mass spectrometry (EI-MS) spectrum of 4 displayed the radical cation peak at
m/z=384 (M+2, 4.9%) and the cation R-C≡O+ at m/z=183 (46.7%).
The formation of compound 3 and 4 can be visualized as shown in Scheme 2.
In contrast, cyclization of 2 in ethanolic KOH yielded a product with molecular
formula C16H26N4OS (MW=322), which lacked in the IR spectrum the stretching
absorption band for the nitrile group and retained carbonyl stretching band at
1725 cm–1 and weak absorption band for NH at 3165 cm–1. This product was identi-
fied as the pyrazolo [2,3-a]1,3,5-triazine derivative 5 (Scheme 1).
The proclivity of 3 toward some electrophilic reagents such as aromatic
aldehydes, heterocyclic aldehydes, heterocyclic ketone, phenyl isothiocyanate, and
carbon disulfide was investigated. Refluxing compound 3 with salicylaldehyde in
boiling ethanol in the presence of a catalytic amount of piperidine afforded the
2-iminocoumarin derivative 6 as orange crystals[18] (Scheme 3).
The imino coumarin derivative 6 was constructed on the basis of analytical and
spectroscopic data. The IR spectrum of 6 displayed υNH at 3220, 3216 cm–1, υC=O at
1698 cm–1, υC=N at 1669 cm–1 and showed the absence of a stretching absorption band
for nitrile group. Furthermore, the mass spectrum of 6 showed the correct molecular
ion peak characteristic for the molecular formula C23H30N4O2S at m/z=426 (11.7%).
The reaction of 1,3,5-thiadiazole derivative 3 with 1,3-diphenyl pyrazole-
4-carboxaldehyde and/or p-nitrobenzaldehyde in refluxing ethanol in the presence of
piperidine yielded the corresponding condensation products 7a and 7b, respectively.
The structure of compound 7a was confirmed by the analytical and spectro-
scopic data. Thus, the IR spectrum of 7a revealed υNH at 3144cm–1, υC≡N at 2221cm–1,
and υC= O at 1697cm–1. The EI-MS spectrum of 7a showed the correct molecular ion
Scheme 3. Reactions of compound 3 with aromatic aldehydes and heterocyclic ketone.

1098
M. R. MAHMOUD ET AL.
peak at m/z=552 (48.4%), which after lossing the acyl radical yielded the cation at
m/z=370 (93.5%).
The structure of 7b was deduced from the analytical and spectroscopic data. IR
spectrum of compound 7b exhibited υNH at 3244, 3202 cm–1, υC≡N at 2228 cm–1 and
υ
C= O at 1687 cm–1. Moreover, the mass spectrum of 7b show the correct molecular ion
peak at m/z=455 (5.8%) together with the peaks at m/z=273 and 183 characteristic for
the radical cations [M-RCO] and [RC≡O+], respectively.
Similarly, isatin easily condensed with the active methylene group in compound
3 upon refluxing with ethanol in the presence of piperidine to give 8 in good yield as
red crystals (Scheme 3). The structure 8 was substantiated from the microanalytical
and spectroscopic data.
When compound 3 was allowed to react with α-cyano-3,4-dimethoxy cinna-
monitrile in refluxing ethanol with catalytic amount of piperidine, it afforded N-(5-
(1-cyano-2-(3,4-dimethoxyphenyl)vinyl)-1,3,4-thiadiazol-2-yl)dodecanamide 9.
The carbanion derived from 3 was added via Michael addition to the β-carbon
of the arylidene malononitrile to give the Michael adduct, which eliminates malon-
onitrile to give 9 via E1CB mechanism (Scheme 4).
Scheme 4. A plausible mechanism for conversion of 3 to 9.

SYNTHESIS OF NOVEL 1,3,4-THIADIAZOLE DERIVATIVES
1099
The structure 9 was confirmed by the study of IR, 1HNMR, and mass spectra.
The reaction of 3 with phenyl isothiocyanate in the presence of elemental
sulfur in boiling ethanol and triethyl amine gave N-(5-(4-amino-3-phenyl-2-thioxo-2,
3-dihydrothiazol-5-yl)-1,3,4-thiadiazol-2-yl)dodecanamide 10 (Scheme 5).
The IR spectrum of 10 displayed the coupling bands for NH2 group at 3270,
3160 cm–1, υC=O at 1692 cm–1, and υC=N at 1622 cm–1 and lacked the stretching absorp-
tion band for the nitrile group. Moreover, 1HNMR spectrum (DMSO-d6) revealed
the signals characterstic for deshielded one NH proton at δ 12.44 ppm, multiplet
integrated for 3H at δ 7.67 ppm, doublet for 2H at δ 7.43–7.40 ppm corresponding
to five aromatic protons, broad singlet for 2H representing the NH2 group, and the
signals upfield characteristic for the dodecanyl protons. Furthermore, the EI-MS of
10 detected the presence of a molecular ion peak at m/z=489 (79%) together with
the base peak at m/z=307 (100%) characteristic for the radical cation [M-RCO.]. The
formation of 10 could be visualized as shown in Scheme 6.
Scheme 5. Reaction of thiadiazole derivative 3 with CS2 and PhNCS.

1100
M. R. MAHMOUD ET AL.
Scheme 6. The expected mechanism for the formation of compound 10.
On the other hand, the reaction of 3 with phenyl isothiocyanate in ethanolic
potassium hydroxide afforded after acidification the thiadiazole derivative 11 via the
formation of intermediate B (Scheme 5). The structure 11 was confirmed by IR and
mass spectra beside the correct elemental analysis. Thus, the IR spectrum displayed
υ
NH at 3203 cm–1, υC≡N at 2191 cm–1, υC= O at 1695 cm–1 and υC= S at 1322 cm–1. The
EI-MS of 11 show the parent peak at m/z=457 (37.3%).
Treatment of 3 with carbon disulfide and potassium hydroxide in dimethyl for-
mamide (DMF) yielded the dipotassium salt C which in situ undergo alkylation with
1,2-dibromoethane to give the dithiolan derivative 12 (Scheme 5).
The structure 12 was confirmed from IR and MS spectra. Thus, the IR spec-
trum of compound 12 revealed υNH (br) at 3153cm–1, υC≡N at 2201cm–1, and υC= O at
1696 cm–1. The mass spectrum of 12 displayed the correct molecular ion at m/z=424
(14.6%) and the radical cation of m/z=242 (68.3%) obtained upon loss of R-C.=O
radical followed by H-abstraction.
Refluxing compound 3 with thioglycollic acid in pyridine afforded the thiazoli-
dinone derivative 13 (Scheme 7).
Compound 13 showed the disappearance of the stretching absorption band for
the nitrile group and displayed a new carbonyl band at 1730cm–1 for thiazolidinone
beside the carbonyl group for dodecanoyl group at 1690cm–1. Furthermore, the mass
spectrum of 13 showed the correct molecular ion peak at m/z=396 (23.4%) together
with the base peak at m/z=214 (100%) characteristic for the radical cation [M+-R-CO].
Scheme 7. Reaction of thiadiazole derivative 3 with thioglycollic acid.

SYNTHESIS OF NOVEL 1,3,4-THIADIAZOLE DERIVATIVES
1101
CONCLUSION
Novel 2,5-disubstituted 1,3,4-thiadiazoles were prepared via cyclization of the
corresponding thiosemicarbazide followed by the reaction with some electrophilic
reagents. The synthesized compounds were obtained in good yields.
EXPERIMENTAL
All reagents were obtained from commercial sources and used without
further purification. Melting-points are uncorrected and were measured by
an electric melting-point apparatus (G-K). The IR spectra were recorded on a
Pye-Unicam SP1200 spectrophotometer using the KBr Wafer technique. The
1HNMR spectra were determined on a Varian Gemini 300-MHz NMR spectro-
photometer using CDCl3 or dinethylsulfoxide (DMSO-d6) as solvent with tetra-
methylsilane (TMS) as an internal standard. All chemical shifts are in parts per
million (ppm) downfield from TMS. The elemental analyses were carried out in
Faculty of Science, Ain Shams University. Mass spectra (MS) were recorded on
a Shimadzu GC-MS QP1000EX instrument in the Microanalytical Laboratory,
Cairo University. Monitoring of the progress of all reactions was carried out by
thin-layer chromatography (TLC).
Synthesis of 1-(2-Cyanoacetyl)-4-dodecanoylthiosemicarbazide 2
Cyanoacetohydrazide (0.99g, 0.01mol) in boiling dioxane was added to a
mixture of lauroyl chloride (2.3mL, 0.01mol) and ammonium thiocyanate (0.76g,
0.01mol) in dioxane (20mL) and then the whole mixture was refluxed for 30 min. The
colorless solid deposited while hot was collected by filtration and then recrystallized
from toluene to give 2 as colorless crystals;
Selected Data
Mp: 109–110 ºC, yield 67%. Anal. calcd. for C16H28N4O2S (340.48): C, 56.44; H,
8.29; N, 16.46; S, 9.42. Found: C, 56.27; H, 8.51; N, 16.52; S, 9.38. IR (υ/cm–1): 3265,
3208 (NH), 2955, 2922, 2885 (CH3,CH2), 2269 (C≡N), 1702 (C = O). MS m/z (%):
340 (M+; 2.5), 257 (6.0), 183 (29.8), 157 (2.8), 99 (39.0), 57 (100). 1HNMR
(DMSO-d6) δ (ppm): 12.88 (s, 1H, NH, exchangeable with D2O), 9.55 (s, 1H, NH,
exchangeable with D2O), 8.614 (s, 1H, NH, exchangeable with D2O), 3.56 (s, 2H,
CH2CN), 2.38 (t, 2H, CH2CO), 1.645 (m, 4H, CH2CH2-), 1.26 (m, 14H, (CH2)7),
0.88 (t, 3H, Me).
SUPPORTING INFORMATION
Full experimental details and spectroscopic data for compounds 3–13 can be
found via the Supplementary Content section of this article’s Web page.

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M. R. MAHMOUD ET AL.
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