Synthesis of novel thiadiazoles and bis-thiadiazoles from carbonothioic dihydrazide

Article abstract of DOI:10.1016/j.tetlet.2010.06.060

Efficient syntheses of 1,3,4-thiadiazoles and bis-thiadiazoles by the reaction of hydrazonoyl halides with carbonothioic dihydrazide are reported. In addition, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole is obtained via oxidative cyclization of bis-(substitut

Full text of DOI:10.1016/j.tetlet.2010.06.060

Tetrahedron Letters 51 (2010) 4490–4493
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel thiadiazoles and bis-thiadiazoles from
carbonothioic dihydrazide
Abdelwahed R. Sayed
Department of Chemistry, Faculty of Science, University of Beni Suef, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient syntheses of 1,3,4-thiadiazoles and bis-thiadiazoles by the reaction of hydrazonoyl halides with
carbonothioic dihydrazide are reported. In addition, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole is obtained via
oxidative cyclization of bis-(substituted methylene)carbonothioic dihydrazone.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 March 2010
Revised 30 May 2010
Accepted 11 June 2010
Available online 17 June 2010
Keywords:
Hydrazonoyl halides
Carbonothioic dihydrazide
Bis-hydrazone
Thiadiazole
Oxidative cyclization
1,3,4-Thiadiazoles have been screened for their antibacterial and
antifungal,1–4 anti-inflammatory,5 and anti-tuberculosis activities,6
as well as for their activity against cancer.7 They have also been ap-
plied in the areas of pharmaceutical, agricultural, industrial, and
polymer chemistry.8–17 The 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole
ring system was first reported by Kanaoka,18 and much attention
has been devoted to the chemistry of 3,6-disubstituted derivatives
of this class of heterocycles as many of them possess biological activ-
ity. For example, some of these derivatives were reported to possess
antibacterial,19–21 analgesic,22 and fungicidal activities23 as well as
interesting CNS depressant action,24 whereas others exhibited mod-
erate antimalarial and antitumor activity.25 Herein the synthesis of
1,3,4-thiadiazole, bis(1,3,4-thiadiazole), and triazole[3,4-b][1,3,4]
thiadiazole derivatives is reported.
reacted with 2a or 2b to afford 1,3,4-thiadiazoles 3b–g as shown
in Scheme 1.
Compound 3a reacted with benzaldehyde to give the corre-
sponding hydrazone 4a. The 1H NMR spectrum of 4a exhibited res-
onances at d 2.52 (s, 3H, CH3), and d 7.49–8.51 (m, 14H, ArH, vinyl
CH@) and its 13C NMR spectrum showed signals at appropriate
chemical shifts. Compound 4a was also obtained via the reaction
of 1a with 2-(phenylmethylene)carbonothioic dihydrazide28 (5)
in ethanolic triethylamine and was identical in all respects (mp,
mixed mp, and spectra) with that obtained from 3a. Similarly, reac-
tions of 1b–g with 5 afforded hydrazones 4b–g as shown in
Scheme 1.
Also, the reaction of 2a with N,N0-diphenylethane(bis-hydrazo-
noyl dichloride)29 (6) in ethanol gave bis-thiadiazole 7 as the only
product. The molecular formula of 7, C16H14N8S2, was consistent
with the elimination of 2HCl and 2NH2NH2. The structure of 7
was elucidated by elemental analysis and spectroscopy. The IR
spectrum of 7 revealed absorption bands at 3290 and 3274 cmꢀ1
due to the NH2 group. The 1H NMR spectrum showed signals at d
5.73 (s, 2H, NH2, exchangeable with D2O) and d 7.23–7.91 (m,
10H, ArH). Compound 7 was also obtained via the reaction of 6
with hydrazine carbodithioate 2b in ethanolic triethylamine and
was identical in all respects (mp, mixed mp, and spectra) with that
obtained from 2a (Scheme 2). Bis-thiadiazole 7 reacted with benz-
aldehyde to give the corresponding bis-hydrazone 8, the structure
of which was confirmed by elemental analysis and spectral data.
The 1H NMR spectrum of 8 exhibited a multiplet resonance at
d 7.32–8.52 (m, 22H, ArH, and vinyl CH@). Compound 8 was also
obtained via the reaction of 6 with 2-(phenylmethylene)carbon-
Treatment of carbonothioic dihydrazide26a (2a) with the appro-
priate hydrazonoyl halide27 1 in ethanol under heating gave a sin-
gle isolated product in each case. For example, the reaction of 1a
with 2a in boiling ethanol afforded product 3a via the elimination
of HBr and hydrazine. The IR spectrum of 3a revealed absorption
bands at 3300 and 3200 cmꢀ1 due to the NH2 group. The 1H NMR
spectrum showed signals at d 2.51 (s, 3H, CH3), d 5.70 (s, 2H,
NH2, exchangeable with D2O), and at d 7.35–8.46 (m, 8H, ArH).
Compound 3a was also obtained via the reaction of 1a with methyl
hydrazine carbodithioate26b (2b) in ethanolic triethylamine and
was an identical product in all respects (mp, mixed mp, and
spectra) with that obtained from 2a. Similarly, compounds 1b–g
E-mail address: arashad_2003@yahoo.com
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.060

A. R. Sayed / Tetrahedron Letters 51 (2010) 4490–4493
4491
R
S
NHNH2
N
NH
Ar
N
R
Br
NH2
S
N
+
- HBr
NH
Ar
H2NHN
NHNH2
R
2a
S
1a-g
NHNH2
NH
N
N
NH2
Ar
S
NHNH2
2b
H3CS
S
R
N
Ph
R
S
S
H2NHN
N
H
PhCHO
1a-g
NH2
N
H
N
N
N
N
5
Ph
N
N
Ar
H
Ar
3a-g
4a-g
H
R:a, 4-CH3C6H4; b, 4-FC6H4;c,4-ClC6H4; d, 3-BrC6 4; e, 2-furanyl;
f, 2-thienyl; g, 2-pyridyl
Ar = 4-NO2C6H4
Scheme 1. Synthesis of 1,3,4-thiadiazole derivatives 3a–g and 4a–g.
H2NHN
S
H2NN
S
N
NHNH2
NNH2
HN
Ph
N
Cl
NH
Ph
S
Cl
+
PhHNN
NHNH2
H2NHN
NNHPh
2a
6
H2NHN
H2NHN
NHNH2
NHNH2
Ph
S
S
N
N
N
N
Ph
H
H
H2NN
Ph
S
NNH2
Ph
N
S
N
2 PhCHO
Ph
S
N
N
N
S
N
N
N
N
N
H
Ph
N
N
Ph
Ph
7
8
6
S
S
Cl
N
Ph
H3CS
NHNH2
2b
Cl
H2NHN
N
+
PhHNN
H
NNHPh
6
5
Scheme 2. Synthesis of bis(1,3,4-thiadiazole) derivatives 7 and 8.
othioic dihydrazide (5) in ethanolic triethylamine and was identi-
cal (mp, mixed mp, and spectra) with that obtained from 7.
We previously reported the synthesis of 1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole30 via oxidative cyclization of an asymmetric
bis-hydrazone. These principles were extended to the synthesis
of the new amine 16 as shown in Scheme 3. Compound 10 is also
novel and was prepared by the condensation of 5 with 4-nitro-
benzaldehyde as shown in Scheme 3. Treatment of the bis-hydra-
zone 10 with ferric chloride in ethanol yielded
a single
crystalline product that was identified as 12 and not the antici-
pated thiadiazole 11. The structure of 12 was confirmed by an
alternative synthesis involving the reaction of 15 with 4-nitrobenz-

4492
A. R. Sayed / Tetrahedron Letters 51 (2010) 4490–4493
S
CHO
O2N
H
N
H
NH2
+
N
H
5
N
H
Ph
NO2
S
N
N
N
N
NH2
Ph
N
H
N
H
N
H
S
Ph
H
15
10
CHO
NO2
FeCl3/EtOH
N
N
N
N
NH
N
S
O2N
Ph
NH
N
Ph
S
11
FeCl3
EtOH
Ph
N
S
O2N
N
NO2
12
N
N
Fe Cl3
EtOH
13
NO2
N
N
Ph
N
S
N
14
H2/ Pd
NH2
N
N
Ph
N
S
N
16
Scheme 3. Synthesis of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives 10, 14 and 16.
aldehyde.31,32 Elemental analysis and the mass spectrum revealed
that the product 12 had two hydrogen atoms less than the precur-
sor bis-hydrazone 10. Its 1H NMR spectra showed the presence of
one methine proton –N@CH– and one hydrazone (–NHN@C). Fur-
ther oxidation of 12 with ferric chloride led to 6-phenyl-3-(4-nitro-
phenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (14).
Acknowledgments
Professor J. S. Wiggins, University of Southern Mississippi, USA
is thanked for providing laboratory facilities and Professor A. O.
Abdelhamid for the valuable discussions.
The structure of 14 was confirmed by elemental analysis and
from spectral data (MS, IR and 1H NMR). The 1H NMR spectrum
of 14 was devoid of the signal characteristic of the –NH–N@CH–
proton that appeared in the spectra of precursors 10 and 12. Iso-
meric compound 13 was prepared according to the literature.33
Compounds 13 and 14 have similar structures which are almost
identical according to spectral analysis. Thus the structure of com-
pound 14 was confirmed by an unambiguous alternative synthesis
starting from 15. Reduction of compound 14 with H2/Pd gave the
aniline derivative 16 (molecular formula C15H11N5S). The IR spec-
trum revealed absorption bands at 3359 and 3205 cmꢀ1 due to
the NH2 group. Its 1H NMR spectrum showed signals at d 4.65 (s,
2H, NH2) and d 7.25–8.40 (m, 9H, ArH).
Supplementary data
Supplementary data (experimental details for the synthesis and
characterization for all the new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.060.
References and notes
1. Trost, B. M. Chem. Rev. 1978, 78, 363.
2. Ganellin, R. J. Med. Chem. 1981, 24, 913.
3. Dogan, H. N.; Rollas, S.; Erdeniz, H. Farmaco 1998, 53, 462.
4. Dogan, H. N.; Duran, A.; Rollas, S.; Sener, G.; Uysal, M. K.; Gulen, D. Bioorg. Med.
Chem. 2002, 10, 2893.
5. Palaska, E.; Sahin, G.; Kelicen, P.; Turlu, N. T.; Altinok, G. Farmaco 2002, 57, 101.
6. Karakus, S.; Rollas, S. Farmaco 2002, 57, 577.
In summary, new and efficient syntheses of 1,3,4-thiadiazoles,
bis-thiadiazoles, and an aniline derivative have been reported.

A. R. Sayed / Tetrahedron Letters 51 (2010) 4490–4493
4493
7. Terzioglu, N.; Gursoy, A. Eur. J. Med. Chem. 2003, 38, 781.
8. Molina, P.; Alajarin, M.; Lapez, L. C. J. Chem. Res. 1989, 5, 140.
9. Eisa, H. M. Mansoura J. Pharm. Sci. 1990, 6, 1.
10. Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki, T.; Furukawa, M.
Synthesis 1990, 1020.
22. Ahluwalia, V. K.; Arora, K. K.; Kaur, G. Indian J. Chem. 1986, 25B, 556.
23. Li, D.; Fu, H. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2229.
24. Deshmukh, A. A.; Mody, M. K.; Ramalingamat, T.; Sattur, P. B. Indian J. Chem.
1984, 23B, 793.
25. Invidtiata, F. P.; Grimoudo, S.; Giammanco, P.; Giammanco, L. Farmaco 1991,
46, 1489.
26. (a) Autenrieth, W.; Henfner, H. Ber. Dtsch. Chem. Ges. 1925, 58B, 2151; (b) Beger,
J.; Thielemann, C.; Thong, P. D. J. Prakt. Chem. 1979, 321, 959.
27. Scott, F. L.; Aylward, J. B. Tetrahedron Lett. 1965, 13, 841.
28. Kabashima, S.; Okawara, T.; Yamasaki, T.; Furukawa, M. Heterocycles 1990, 31,
1129.
29. Grundmann, C.; Datta, S. K.; Sprecher, R. F. Justus Liebigs Ann. Chem. 1971, 744,
88.
30. Shawali, A. S.; Sayed, A. R. J. Sulfur Chem. 2006, 27, 233.
31. Carvalho, S. A.; Da Silva, E. F.; Santa-Rita, R. M.; De Castro, S. L.; Fraga, C. A. M.
Bioorg. Med. Chem. Lett. 2004, 14, 5967.
11. Bayoumy, B. E.; El-Bahie, S.; Youssif, S. Pol. J. Chem. 1991, 65, 1279.
12. Mohan, J.; Anjaneyulu, G. S. R.; Yamini, K. V. S. J. Indian Chem. Soc. 1991, 68, 474.
13. Bano, Q.; Tiwari, N.; Giri, S. Indian J. Chem. 1992, 31B, 467.
14. Mohan, J.; Singh, V.; Kataria, S. Indian J. Heterocycl. Chem. 1993, 3, 43.
15. Dubey, A. K.; Sangwan, N. K. Indian J. Heterocycl. Chem. 1994, 3, 277.
16. Talawar, M. B.; Laddi, U. V.; Somannavar, Y. S.; Bennur, R. S.; Bennur, S. C. Indian
J. Heterocycl. Chem. 1995, 4, 297.
17. Pramanik, S. S.; Mukherjee, A. J. Indian Chem. Soc. 1998, 75, 53.
18. Kanaoka, M. Yakugaku Zasshi 1956, 76, 1133.
19. Mohan, J.; Anjaneyulu, G. S. R.; Verma, P. Curr. Sci. 1989, 58, 1028.
20. Omar, A. M.; Aboul-Wafa, O. M. J. Heterocycl. Chem. 1986, 23, 1339.
21. Ghannoum, M. A.; Eweiss, N. F.; Bahajaj, A. A.; Quereshi, M. A. Microbios 1983,
37, 151.
32. Kurzer, F.; Secker, J. L. Tetrahedron 1981, 37, 1429.
33. Chadha, V. K.; Sharma, G. R. J. Indian Chem. 1980, 57, 1112.