1,3,4-Thiadiazoles and 1,3-thiazoles from one-pot reaction of bisthioureas with 2-(bis(methylthio)methylene)malononitrile and ethyl 2-cyano-3,3-bis(methylthio)acrylate

Article abstract of DOI:10.1080/17415993.2016.1237637

Bisthioureas reacted with either 2-(bis(methylthio)methylene)malononitrile or ethyl 2-cyano-3,3-bis(methylthio)acrylate to give 1,3,4-thiadiazoles and 1,3-thiazoles. Only, the reactive allyl derivative of bisthioureas reacted with the bis(methylthio)methy

Full text of DOI:10.1080/17415993.2016.1237637

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
1,3,4-Thiadiazoles and 1,3-thiazoles from
one-pot reaction of bisthioureas with 2-
(bis(methylthio)methylene)malononitrile and ethyl
2-cyano-3,3-bis(methylthio)acrylate
Ashraf A. Aly, Alaa A. Hassan, Stefan Bräse, Mahmoud A. A. Ibrahim, El-
Shimaa S. M. Abd Al-Latif, Eduard Spuling & Martin Nieger
To cite this article: Ashraf A. Aly, Alaa A. Hassan, Stefan Bräse, Mahmoud A. A. Ibrahim, El-
Shimaa S. M. Abd Al-Latif, Eduard Spuling & Martin Nieger (2016): 1,3,4-Thiadiazoles and 1,3-
thiazoles from one-pot reaction of bisthioureas with 2-(bis(methylthio)methylene)malononitrile
and ethyl 2-cyano-3,3-bis(methylthio)acrylate, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2016.1237637
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Date: 01 October 2016, At: 14:27

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1237637
1,3,4-Thiadiazoles and 1,3-thiazoles from one-pot reaction of
bisthioureas with 2-(bis(methylthio)methylene)malononitrile
and ethyl 2-cyano-3,3-bis(methylthio)acrylate
Ashraf A. Alya, Alaa A. Hassana, Stefan Bräseb, Mahmoud A. A. Ibrahima,
El-Shimaa S. M. Abd Al-Latifa, Eduard Spulingb and Martin Niegerc
aChemistry Department, Faculty of Science, Minia University, El-Minia, Egypt; bInstitute of Organic Chemistry,
Karlsruhe Institute of Technology, Karlsruhe, Germany; cLaboratory of Inorganic Chemistry, Department of
Chemistry, University of Helsinki, Helsinki, Finland
ABSTRACT
ARTICLE HISTORY
Received 21 July 2016
Accepted 13 September 2016
Bisthioureas reacted with either 2-(bis(methylthio)methylene)malo-
nonitrile or ethyl 2-cyano-3,3-bis(methylthio)acrylate to give 1,3,4-
thiadiazoles and 1,3-thiazoles. Only, the reactive allyl derivative of
bisthioureas reacted with the bis(methylthio)methylene compounds
to give 1,3-thiazoles. The mechanism was discussed. The structures
of products were proved by MS, IR, NMR and elemental analyses and
X-ray structure analysis.
KEYWORDS
Bisthioureas;
bis(methylthio)malononitrile;
bis(methylthio)acrylate;
1,3,4-thiadiazoles;
1,3-thiazoles; X-ray
1. Introduction
1,3,4-Thiadiazole derivatives have demonstrated a broad spectrum of biological proper-
ties in both pharmaceutical and agrochemical fields. They are known to exhibit diverse
biological activities such as in vitro inhibition of cyclooxygenase and 5-lipoxygenase
activities [1]. Acylated substituted 5-thio-β-D-glucopyranosylimino-1,3,4-thiadiazoles
have been tested in vitro for antiviral activity against HIV-1, HIV-2 and human
cytomegalo virus [2]. Recently, 1,3,4-thiadiazole cores have received much attention
in material science due to their interesting electronic and optical properties [3]. Var-
ious methodologies that exist in the literature [4] for their synthesis are associated
CONTACT Ashraf A Aly
ashrafaly63@yahoo.com
Chemistry Department, Faculty of Science, Minia University,
61519El-Minia, Egypt
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1237637
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
A. A. ALY ET AL.
with the number of drawbacks that impedes their applicability in the long run. How-
ever, 1,3,4-thiadiazoles are commercially available antibiotic and anticancer drugs in
the market, such as Acetazolamide, Methazolamide, Tebuthiuron, Megazol, Sulfamethi-
zole, Filanesib, Cefazedone and Cefazolin [5]. On the other hand, the thiazole nucleus
is found in many biologically active compounds that makes it one of the most exten-
sively studied heterocycles [6]. Thiazoles play a pivotal role in many drug structures
[7]. For example, Ritonavir (anti-HIV drug) [8], Dasatinib and Tiazofurin (antineoplas-
tic agents) [9], Fanetizole, Fentiazac and Meloxicam (anti-inflammatory agents) [10],
Nizatidine (antiulcer agent) [11], Ravuconazole (antifungal agent) [12] and Nitazox-
anide (antiparasitic agent) [13]. Inspired by these interesting previous biologically active
compounds, we envisioned that treatment of 2-hydrazinocarbothioyl-N-substituted-
hydrazinecarbothioamides 1a–d with 2-(bis(methylthio)methylene)malononitrile (2a)
and ethyl 2-cyano-3,3-bis(methylthio)acrylate (2b) would form 1,3,4-thiadiazole and/or
1,3-thiazole derivatives.
2. Results and discussion
Equimolar amounts of 2-(hydrazinocarbonothioyl)-N-substituted-hydrazinecarbothio-
amides 1a–d and 2-(bis(methylthio)methylene)malononitrile (2) were stirred in tetrahy-
drofuran (THF) with catalytic amounts of trimethylamine (Et3N) at refluxing temperature
for 1 h and at room temperature for 1–3 h. Bisthioureas 1a–c provided excellent to moder-
ate yields of the respective diaminothiadiazoles. For the bis-arylthioureas having electron-
donating substituent like 1b, the yield of 3b (84%) was superior to 3c (80%, Scheme 1). In
general, 1,3,4-thiazole derivatives 3a–c were precipitated as colorless solids and as the sole
products in 75–84% yields (Scheme 1). In the case of 1d reacting with 2a and/or 2b, 1,3-
thiazole derivatives were obtained in a different manner (Scheme 1). The mass spectrum
and elemental analysis proved the molecular formula of 3a as C14H12N4S. The phenyl pro-
tons in the 1H NMR spectrum of 3a appeared as two triplets at δ = 6.94 (J = 7.6 Hz, 2H)
H
and 7.27 (J = 7.6 Hz, 4H) and a doublet at δ = 7.54 (d, J = 7.6 Hz, 4H). The NH protons
H
were absorbed as broad singlet at δ = 9.38. The 13C NMR spectrum indicated the ring
H
of 1,3,4-thiadiazole ring structure, by revealing the C=N carbon signal at δ = 156.3.
C
All spectroscopic and analytical data are in a good agreement with the structure of 3a
[14]. Similarly, compound 1b reacted with 2 to produce 3b [15]. The structure proof of 3b
was unambiguously supported by X-ray structure analysis (Figure 1). In the same man-
ner, 1,3,4-thiadaizole-2,5-diamine derivative 3c [14]. was obtained in 80% yield from the
Scheme 1. Reactions of bisthioureas 1a–d with π-deficient compounds 2a,b.

JOURNAL OF SULFUR CHEMISTRY
3
Figure 1. Molecular structure analysis of N,N’-bis(4ꢀ-methylphenyl)-1,3,4-thiadiazole-2,5-diamine (3b)
with crystallographic C2-symmetry (displacement parameters are drawn at 50% probability level).
reaction of 1c with 2 (Scheme 1). The newly prepared thiazolidine-1-carbothioamide 4a
was obtained as pale red crystals in 90% yield (Scheme 1).
The results of combustion analyses and spectroscopic data suggested that the molecular
weight of the products results from the sum of the two reactants 1d with 2a accompa-
nied by loss of a HCN molecule (see Section 4). The IR spectrum showed the amino
and nitrile groups at ν
= 3230 and 2210 cm−1. The thiocarbonyl group absorbed in
max
1
the IR spectra at ν
= 1225 cm−1. The H NMR spectrum revealed the SMe pro-
max
tons as a singlet at δ = 2.60. The two allyl-CH2N protons appeared as two broad
H
singlets in different regions at δ = 4.28 and 3.90 (see Section 4). Allyl-CH= and allyl-
H
CH2 = protons resonated as two multiplets and appeared at δ = 5.80−5.72 (2H) and
H
5.20–5.14 (4H). The 13C NMR spectrum of 4a supported the allylic structure of 4a
and exhibited peaks at δ =133.0, 130.8 (allyl-CH=), 118.2, 116.1 (allyl−CH2 =) and
C
44.0, 42.6 (CH2). Moreover, the exo-azomethine carbon (thiazole C-2) appeared in the
13C NMR of 4a at δ = 154.0 (see Section 4). Whilst, the distinctive thioamide (C=S)
C
and the nitrile carbons appeared at δ = 180.2 and 115.0, respectively. The same trend
C
was obtained during the reaction of 1d with ethyl 2-cyano-3,3-bis(methylthio)acrylate
(2b). Compound 4b was obtained during reaction of 1d with 2b (Scheme 1). The struc-
ture of 4b was proved by IR, NMR and elemental analysis and was supported by mass
spectroscopy and elemental analysis that gave its molecular formula as C14H20N4O2S3.
IR showed the NH stretching at ν
= 3330–3240, whereas the aliphatic and carbonyl
max
groups appeared at ν
= 2960–2870 and 1700 cm−1, respectively. Strong vibrational
max
coupling was also noted due to the nitrogen containing thiocarbonyl derivative appeared
1
at ν
= 1390 cm−1. H NMR spectrum of 4b revealed the ester group as a triplet at
max
δ
= 1.22 (J = 7.2 Hz) and quartet at δ = 4.00. The SMe protons resonated as a singlet
H
H
1
in the H NMR spectrum centered at δ = 2.65, whereas the two allyl-NCH2 protons
H
appeared as two broad singlets in different regions at δ = 4.20 and 3.90 (see Section
H
4). Two multiplets were recognized in the 1H NMR spectrum of 4b indicated the allylic
asymmetric structure (allyl-CH= and allyl-CH2 =) of 4b, appeared at δ = 5.86−5.80
H
(2H) and 5.19–5.15 (4H). The 13C NMR spectrum of 4b indicated the allylic carbons at
δ = 116.5, 118.0 (allyl NCH2 =), 133.2, 130.6 (allyl-CH=) and 44.8, 42.4 (allyl-CH2-
C
N). The exo-azomethine carbon of thiazole C-2 appeared at δ = 152.0 (see Section 4).
C
Mechanistically, the reaction between 1a–c and 2a or 2b can be described as due to nucle-
ophilic attack of the sulfur lone pair of 1 at the C-2 carbon of 2 to form salt 5 (Scheme 2).

4
A. A. ALY ET AL.
Scheme 2. Plausible mechanism of internal cyclization 1a–c during its reaction with 2a,b.
Scheme 3. Plausible mechanism describing reaction between 1d and 2a,b.
Thereafter, further nucleophilic attack of the other sulfur lone pair at the positively charged
thiocarbonyl would cause cyclization to give intermediate 6. The cyclization is followed by
hydrogen transfer followed by neutralization to form 3a–c and 7. Ultimately, elimination of
H2S from 7 would reproduce 2 (Scheme 2). It might therefore be concluded that compound
2 initiates internal cyclization process of 1a–c. The same trend occurs between 1d and 2a,b
to form salt 5 (Scheme 3). Instead of the aforementioned second step in Scheme 2, neutral-
ization occurred via proton transfer to form intermediate 8 (Scheme 3). Finally, cyclization
occurs with the nitrogen lone pair accompanied by elimination of the HCN molecule to
form 4a or 4b (Scheme 3)
3. Conclusion
Although there are many reports of the synthesis of thiadiazoles, few reports are available
for the synthesis of symmetrical 2,5-disubstituted amino-1,3,4-thiadiazoles in the litera-
ture. Therefore our method is a valuable addition to the literature for the synthesis of
this class of compound in good yields without requiring the aforesaid hazardous acidic
conditions.

JOURNAL OF SULFUR CHEMISTRY
5
4. Experimental
Melting points are uncorrected. The IR spectra were recorded as KBr disks on a Shimadzu-
408 infrared spectrophotometer, Faculty of Science, Minia University. TLC analysis was
performed on analytical Merck 9385 silica aluminum sheets (Kieselgel 60) with PF254 indi-
cator. The NMR spectra were measured using a Bruker AV-400 spectrometer at Institute
of Organic Chemistry, Karlsruhe, Germany. Chemical shifts were expressed as δ (ppm)
with tetramethylsilane as internal reference. The samples were dissolved in DMSO-d6,
s = singlet, d = doublet, dd = doublet of doublet and t = triplet. Mass spectra were
recorded on a Varian MAT 312 instrument in EI mode (70 eV), Center of National
Research, Dokki, Cairo, Egypt. Elemental analyses were carried out using Varian Elemen-
tary device in the National Research Center, Giza, Egypt, or by the Microanalytical Unit at
Cairo University, Cairo, Egypt.
4.1. Crystal structure determination of 3b
The single-crystal X-ray diffraction study was carried out on a Bruker D8 Ven-
ture diffractometer with Photon100 detector at 123(2) K using Cu–Kα) radiation
(l = 1.54178 Å. Direct Methods (SHELXS-97) [16] were used for structure solu-
tion and refinement was carried out using SHELXL-2014 (full-matrix least-squares
on F2) [17]. Hydrogen atoms were localized by difference electron density deter-
mination and refined using a riding model (H(N) free). A semi-empirical absorp-
tion corrections was applied. 3b: colorless crystals, C16H16N4S, Mr = 296.39, crystal
size 0.36 × 0.18 × 0.09 mm, monoclinic, space group Pbca (No. 60), a = 6.6154(3) Å,
b = 8.5679(3) Å, c = 25.561(10) Å, V = 1448.80(10) Å3, Z = 4, ρ = 1.359 Mg/m−3
,
µ(Cu–Kα) = 1.963 mm−1, F(000) = 624, 2θ
= 144.4°, 7112 reflections, of which 1435
max
were independent (Rint = 0.026), 100 parameters, 1 restraint, R1 = 0.031 (for 1316
I > 2σ(I)), wR2 = 0.086 (all data), S = 1.03, largest diff. peak/hole = 0.227/−0.273
e Å−3. CCDC 1494906 (3b) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4.1.1. Starting materials
1,6-Disubstituted 2,5-dithioureas were parepared according to published procedures as
were N,N’-diphenylhydrazine-1,2-dicarbothioamide (1a) and N,N’-bis(benzyl)hydrazine-
1,2-dicarbothioamide (1c) [14] and N,N’-bis(4ꢀ-methylphenyl)hydrazine-1,2-dicarbothio-
amide (1b) [15] and N,N’-diallylhydrazine-1,2-dicarbothioamide (1d) [4,14]. 2-(bis
(methylthio)-methylene)-malononitrile (2a) and ethyl 2-cyano-3,3-bis(methylthio)acry-
late (2b) were bought from Fluka.
5. General procedure
5.1. Reaction of bisthioureas 1a-d with compounds 2a or 2b
A mixture of a dithiouears (1a–c, 1 mmol), an activated nitrile 2a or 2b (1 mmol) and a
few drops of triethylamine in THF (30 mL) was gently refluxed for 1 h; the reaction was
followed by TLC analysis. After cooling at room temperature, the preceiptates of 3a–c

6
A. A. ALY ET AL.
were collected by suction filtration, washed with THF and dried at room temperature.
Compounds 3a–c were identified by comparing their mp,s, IR and NMR spectra and their
analytical data.
N,N’-Diphenyl-1,3,4-thiadiazole-2,5-diamine (3a), colorless crystals (DMF), 0.20 g,
(75%), m.p. 239–240°C (lit. [14] 239–240°C).
N,N’-Bis(4ꢀ-methylphenyl)-1,3,4-thiadiazole-2,5-diamine (3b), colorless crystals
(DMF), 0.25 g (85%), m.p. 137–138°C (lit. [15] 240–243°C).
N,N’-Bis(benzyl)-1,3,4-thiadiazole-2,5-diamine (3c). colorless crystals (MeOH), 0.24
(80%), m. p. 138–140°C (lit. [14] 137–139°C).
Z-N-Allyl-2-(3-allyl-4-cyano-5-(methylthio)thiazol-2(3H)ylidene)hydrazine-1-carbo-
thioamide (4a). Pale yellow crystals (CHCl3/MeOH), 0.28 g (90%), m.p. 166–168oC. IR
(νmax): = 2980–2860 (Aliph-CH), 3230 (NH), 2210 (CN), 1225 (C=S) cm−1. 1H NMR
(DMSO-d6): δ = 10.20 (s, 1H, NH), 9.40 (s,1H, NH), 5.80−5.72 (m, 2H, allyl=CH),
H
5.20–5.14 (m, 4H, allyl-CH2 =), 4.28 (bs, 2H, allyl-NCH2), 3.90 (bs, 2H, allyl-NCH2), 2.60
(s, 3H, SCH3). 13C NMR (DMSO-d6): δ = 180.2 (C=S), 154.0 (C=N), 133.0, (allyl-
C
CH=), 131.6 (C-4), 130.8 (allyl-CH=), 129.2 (C-5), 118.2, 116.1 (allyl-NCH2), 115.0
(CN), 44.0, 42.6 (CH2), 15.4 (SCH3). MS (70 eV, %): m/z = 325 (M+, 100), 310 (22), 278
(18), 252 (24), 137 (24). Calcd for C12H15N5S3 (325.47): C, 44.28; H, 4.65; N, 21.52. Found:
C, 44.10; H, 4.55; N, 21.65.
Ethyl (Z)-3-allyl-2-(3-allylcarbamothioyl)hydrazono-5-(methylthio)-2,3-dihydrothi-
azole-4-carboxylate (4b). Pale yellow crystals (MeOH), 0.34 g (92%), m.p. 198–200°C.
IR (νmax): = 2960–2870 (Aliph-CH), 3240 (NH), 1700 (CO-ester), 1390 (C=S) cm−1
.
1H NMR (DMSO-d6): δ = 10.20 (s, 1H, NH), 9.40 (s,1H, NH), 5.86−5.80 (m, 2H,
H
allyl=CH), 5.19–5.15 (m, 4H, allyl-CH2 =), 4.20 (bs, 2H, allyl-NCH2), 4.00 (q, 2H, CH2-
ester), 3.90 (bs, 2H, allyl-NCH2), 2.65 (s, 3H, SCH3), 1.22 (t, J = 7.2 Hz). 13C NMR
(DMSO-d6): δ = 180.4 (C=S), 165.4 (CO-ester), 152.0 (C=N), 133.2, 130.6 (NCH=),
C
130.2 (C-4), 129.2 (C-5), 118.0, 116.5 (allyl=CH2), 50.0 (CH2-ester), 44.8, 42.4 (allyl-
NCH2), 15.4 (SCH3), 12.4 (CH3-ester). MS (70 eV, %): m/z = 325 (M+, 100), 310 (22),
278 (18), 252 (24), 137 (24). Calcd for C14H20N4O2S3 (372.52): C, 45.14; H, 5.41; N, 15.04.
Found: C, 45.30; H, 5.55; N, 15.20.
Disclosure statement
No potential conflict of interest was reported by the authors.
Acknowledgements
We thank the DFG (BR 1750) for its financial support for the stay of Professor Aly at the Karlsruhe
Institute of Technology, Institute of Organic Chemistry, Germany
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