5-Furan-2yl[1,3,4]oxadiazole-2-thiol, 5-furan-2yl-4h [1,2,4] triazole-3-thiol and their thiol-thione tautomerism

Article abstract of DOI:10.3390/10020475

5-Furan-2-yl[1,3,4]oxadiazole-2-thiol (Ia) and 5-furan-2-yl-4H-[1,2,4]- triazole-3-thiol (Ib) were synthesized from furan-2-carboxylic acid hydrazide. Mannich bases and methyl derivatives were then prepared. The structures of the synthesized compounds were confirmed by elemental analyses, IR and ¹H-NMR spectra. Their thiol-thione tautomeric equilibrium is described.

Full text of DOI:10.3390/10020475

Molecules 2005, 10, 475-480
molecules
ISSN 1420-3049
http://www.mdpi.org
5-Furan-2yl[1,3,4]oxadiazole-2-thiol, 5-Furan-2yl-4H [1,2,4]
triazole-3-thiol and Their Thiol-Thione Tautomerism
M. Koparır *, A. Çetin and A. Cansız
Department of Chemistry, Faculty of Science, Fırat University, 23119, Elazıg, Turkey.
*Author to whom correspondence should be addressed; e-mail: mkoparir@hotmail.com
Received: 30 June 2004; in revised form: 15 July 2004 / Accepted: 1 August 2004 / Published: 28
February 2005
Abstract: 5-Furan-2-yl[1,3,4]oxadiazole-2-thiol (Ia) and 5-furan-2-yl-4H-[1,2,4]-
triazole-3-thiol (Ib) were synthesized from furan-2-carboxylic acid hydrazide. Mannich bases
and methyl derivatives were then prepared. The structures of the synthesized compounds
were confirmed by elemental analyses, IR and 1H-NMR spectra. Their thiol-thione tautomeric
equilibrium is described.
Keywords: 1,3,4-Oxadiazoles; 1,2,4-triazoles; Mannich bases; thiol-thione tautomerism.
Introduction
Triazoles and their derivatives have been proven to be effective bactericides, pesticides and
fungicides [1-3] Further, some findings that the 1,2,3-triazole nucleus is associated with diverse
pharmacological activities such as analgesic, antiasthematic, diuretic, antihypertensive and
antiinflammatory properties have made them important chemotherapeutic agents [4-7]. Derivatives of
1,3,4-oxadiazole are also known to have a broad spectrum of biological activities [8-10]. Acyl
hydrazides have been in general use as the starting materials in some 1,2,4-triazole and 1,3,4-oxadiazole
syntheses [11, 12]. In addition there are some studies on electronic structures and thiol-thione tautomeric
equilibrium of heterocyclic thione derivatives [13-15].
In the present study 5-furan-2-yl[1,3,4]oxadiazole-2-thiol (Ia) and 5-furan-2-yl-4H[1,2,4]-triazole-
3-thiol (Ib) and some of their derivatives were synthesized. Compound Ia was synthesized by the ring
closure reaction of furan-2-carboxylic acid hydrazide with carbon disulfide. A series of Mannich bases
of 5-furan-2-yl[1,3,4]oxadiazole-2-thiol (IIIa-g) were then synthesized by the reaction of Ia with
suitably substituted amines and formaldehyde in ethanol. 5-Furan-2-yl-4H[1,2,4]triazole-3-thiol (Ib)
was prepared by the reaction of the appropriate 2-furoyl thiosemicarbazide and potassium hydroxide in

Molecules 2005, 10
476
ethanol for 3 h under reflux, followed by acidification with acetic acid. The 2-furoyl thiosemicarbazide
employed in these reactions was obtained by refluxing the corresponding furan-2-carboxylic acid
hydrazide with ammonium thiocynate in presence of aq. hydrochloric acid for 3 h. IIa and IIb were
obtained from reaction of Ia and Ib with CH3I in an alkaline medium. These synthetic reactions are
summarized in Scheme 1.
Scheme 1
N
N
N
N
S
CH3
S
CH3
O
O
O
N
IIa
H
IIb
CH3-I , H2
O
CH3-I , H2
O
NaOH
NaOH
NaOH
ethanol
NH4SCN, HCI aq
N
N
O
KOH , ethanol
O
S
N
N
SH
N
NH2
N
N
NH2
SH
CS2
O
O
H
H
H
O
O
O
N
H
Ia
I
Ib
H2
C
H
N
N
H
R
N
N
N
N
H2CO, amines
S
S
O
N
H
O
O
S
O
O
IIIa-g
Results and Discussion
The characterization data of compounds Ia and Ib are given in the Experimental section and that of
the other compounds synthesized is summarized in Table 1. All the newly synthesized compounds gave
satisfactory analyses for the proposed structures, which were confirmed on the basis of their IR and
1H-NMR spectral data. The IR spectra of these compounds showed moderately strong bands around
3100-3360 cm-1, 1600-1650 cm-1 and 1250-1270 cm-1, characteristic of the NH, C=N and C=S groups,
respectively. In the 1H-NMR spectra, a characteristic signal due to the –N-CH2-N- protons appeared at
5.00-6.05. The signal due to the NH protons appeared at 5.50-5.52. The signals due to the aromatic
protons appeared as multiplets at 6.50-8.40.
We have observed that extensive thiol-thione tautomerism exists in compounds Ia and Ib. In the
1H-NMR the signal of the SH protons were recorded, although they were very weak and also the ready
synthesis of the Mannich bases IIa, IIIa-g, IIb and Ib [16] from Ia and Ib confirmed the tautomerism. It
has been reported that the crystal structures of Ia- and Ib-like compounds correspond to the thione form
[17-19], but the reaction conditions for the synthesis of IIa prove that Ia can be in the thiol form too.
Finally, the crystal structures of Ia and Ib [17, 18] corresponded to the thione form, but they showed
thiol-thione tautomerism in solution.
476

Molecules 2005, 10
477
Experimental
General
Melting points were determined in open capillary tubes on a digital Gallenkamp melting point
apparatus and are uncorrected. The IR spectra were recorded in KBr with a Mattson 1000 FT-IR
1
spectrometer. H-NMR spectra were recorded on a FX 90 JEOL 90MHz NMR and Varian Gemini
200MHz, spectrometers in CDCl3 + DMSO- d6 with TMS as an internal standard. Elemental analyses
were done on a LECO-CHNS-938. Starting chemicals were obtained from Merck or Aldrich.
5-Furan-2-yl[1,3,4]oxadiazole-2-thiol (Ia). A mixture of furan-2-carboxylic acid hydrazide (0.01 mole,
1.26 g), sodium hydroxide (0.01 mole, 0.4 g), carbon disulfide (0.02 mole, 1.2 mL) and absolute ethanol
(100 mL) was heated under reflux for 12 h. The excess solvent was removed by vacuum evaporation,
and the residue was dissolved in water and acidified with acetic acid. The product was recrystallised
from water-ethanol (60-40). Yield 55 %; mp: 135-137 oC; IR, cm-1: 3356 (NH), 1642 (C=N), 1255(C=S);
1H-NMR, ppm: 6.56-7.65 (m, 3H, furyl), 13.70 (s, 1H, SH).
5-Furan-2-yl-4H[1,2,4]triazole-3-thiol (Ib). An equimolar quantity of furan-2-carboxylic acid
hydrazide (0.01 mole, 1.26 g), ammonium thiocyanate (0.01 mole, 1.52 g) and hydrocholoric acid (5 mL)
in absolute ethanol (50 mL) was refluxed for 4 h. The white solid that appeared on cooling was filtered
and the excess solvent was removed by vacuum evaporation. The residue was recrystallised from
DMF-ethanol (30-70 v/v) to give 1-(2-furoyl)-3-thiosemicarbazide (Yield 90 %; mp: 233-235 oC). This
intermediate (0.01 mole 1.85 g) was refluxed in 10 % sodium hydroxide solution (5 mL) for 3 h. The
resulting solution was cooled and filtered. The filtrate was acidified with hydrocholoric acid to pH 5-6.
The solid which appeared was filtered, dried and recrystallised from dilute ethanol. Yield 75 %; mp: 295
oC; IR, cm-1: 3356-3155 (NH), 1642 (C=N), 1255(C=S); 1H-NMR, ppm: 13.80 (s, 1H, SH), 6.56-7.65
(m, 3H, furyl), 5.10 (s, 1H, NH).
General Procedure for the Preparation of IIa,b.
A mixture of thione Ia-b (0.005 mole), sodium hydroxide (0.005 mole, 0.2 g), and methyl iodide
(0.006 mole, 0.840 g) was stirred in water for 14 h. The resulting thioether solution was removed by
vacuum evaporation, and the products collected by filtration, washed with water, dried and recrystallised
from a suitable solvent. Spectroscopic and physical data are summarized in Table 1.
General Procedure for the Preparation of IIIa-g.
A mixture of Ia (0.01 mole, 1.56 g) and an alkyl or aryl amine (0.01 mole) was refluxed in ethanol
(50 mL) with 36 % formaldehyde (0.02 mole, 1.7 mL) for 3 h. The resulting solid was crystallised from
a suitable solvent. Spectroscopic and physical data are summarized in Table 1.
477

Molecules 2005, 10
Table 1. Analytical and spectroscopic data for compounds IIa,b and IIIa-g.
478
Comp.
No.
Yield,
%
mp,
ºC
R
X
O
IR spectrum, υ, cm-1
1H NMR spectrum, δ, ppm (J, Hz)
IIa
IIb
45
50
82
161
132
133
2982 (CH),1636(C=N),
1260(C=S).
6.60-7.60 (m, 3H, furyl), 2.10 (s, 3H, SCH3)
NH
O
3130(NH), 2982(CH),
1636(C=N),1260(C=S).
6.60-7.50 (m, 3H, furyl), 5.70 (1H, NH), 2.10
(s, 3H, SCH3
N
O
IIIa
2990(CH),1632(C=N)
1270(C=S).
6.56-7.60 (m, 3H, furyl), 5.0 (s, 2H, N-CH2-N)
3.70-3.50 (m, 4H, CH2-O-CH2), 2.70-2.60 (m,
CH2-N-CH2).
CH3
NH
NH
IIIb
O
O
60
62
145
148
3320(NH),2970(CH),1630 8.24-7.60 (m, 4H, Ar.CH), 6.50-7.60 (m, 3H,
(C=N),1268(C=S).
furyl), 5.50 (br, 1H, N-CH2-NH), 5.90 (d, J=7
2H, N-CH2-NH), 2.15 (s, 3H, CH3 ).
3315(NH),2970(CH),1630 8.40-7.80 (m, 4H, Ar.CH), 6.50-7.60 (m, 3H,
CH3O
IIIc
IIId
(C=N),1268(C=S).
furyl), 5.50 (br, 1H, N-CH2-NH), 5.90 (d, J=7
2H, N-CH2-NH), 3.70 (s, 3H, OCH3 ).
NH
O
O
50
40
193
128
3330(NH), 2982(CH),
1636(C=N),1280(C=S).
8.20-7.80 (m, 7H, Ar.CH), 6.50-7.60 (m, 3H,
furyl), 5.52 (br, 1H, N-CH2-NH), 5.85 (d, J=7
2H, N-CH2-NH).
IIIe
3323(NH), 2982(CH),
1636(C=N),1260(C=S).
8.25-7.90 (m, 5H, Ar.CH), 6.50-7.60 (m, 3H,
furyl), 5.52 (br, 2H, -NH), 5.92 (d, J=7 2H,
N-CH2-NH), 3.80 (d, J=9 Ar-CH2-NH).
CH2NH
N
IIIf
O
O
70
35
133
174
2982(CH),1636(C=N),126 6.50-7.60 (m, 3H, furyl), 5.80 (s, 2H, N-CH2),
5(C=S).
2.10-2.80 (m, 10H, CH2).
IIIg
3315(NH), 2982(CH),
1636(C=N),1270(C=S).
8.40-7.80 (m, 4H, Ar.CH), 6.50-7.60 (m, 3H,
furyl), 5.50 (br, 1H, N-CH2-NH), 6.05 (d, J=7
2H, N-CH2-NH).
O2N
NH
Found, %
Calculated,%
Comp
No.
Formula
C
H
N
S
C
H
N
S
IIa
IIb
46.15
46.38
49.41
58.49
55.45
63.13
58.48
54.28
48.98
3.29
3.87
4.89
4.54
4.32
3.99
4.55
5.68
3.15
15.33
23.11
15.72
14.60
13.83
13.00
14.60
15.78
17.59
17.58
17.65
11.98
11.13
10.55
10.00
11.13
12.01
10.10
C7H6N2O2S
C7H7N3OS
46.15
46.40
49.43
58.52
55.43
63.14
58.52
54.32
49.05
3.32
3.89
4.90
4.56
4.32
4.05
4.56
5.70
3.17
15.37
23.19
15.72
14.62
13.85
12.99
14.62
15.84
17.60
17.60
17.69
12.00
11.16
10.57
9.92
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
C11H13N3O3S
C14H13N3O2S
C14H13N3O3S
C17H13N3O2S
C14H13N3O2S
C12H15N3O2S
C13H10N4O4S
11.16
12.08
10.07
478

Molecules 2005, 10
479
References
1. Sengupta, A.K.; Bajaj, O.P.; Chandura, U.J. Synthesis and antibacterial activity of some
phenoxyacetyl thiosemicarbazides, substituted 1,3,4-oxadiazoles, 1,2,4-triazoles and alkyl-phenyl
carbamates of substituted 1,3,4-oxadiazole-2-thiones. J. Ind. Chem. Soc. 1978, 55, 962.
2. Singh, H.; Yadav, L.D.S.; Battacharya, B.K.J. Synthesis of some new bis(1,2,4-triazol-3-yl)
disulfides, sulfides and sulfones as potential pesticides. J. Ind. Chem. Soc. 1979, 56, 1013.
3. Giri, S.; Singh, H.; Yadav, L.D.S.; Kahre, R.K. Synthesis of some new 1, 3, 4-oxa(thia)diazoles and
1,2,4-triazoles as potential fungicides. J. Ind. Chem. Soc. 1978, 55, 168.
4. Yale, H.L.; Piale, J.J. Substituted S-Triazoles and Related Compounds. J. Med. Chem. 1696, 9, 42.
5. Hirota, T.; Sasaki, K.; Yamamoto, H.; Nakayama, T. Polycyclic n-hetero compounds 36 Syntheses
and antidepressive evaluation of 11,13,15,17-tetraazasteroids and their 17-oxides. J. Heterocycl.
Chem. 1991, 28, 257.
6. Goswami, B.N.; Kataky, J.C.S.; Baruah, J.N. Synthesis and antibacterial activity of
1-(2,4-dichlorobenzoyl)-4-substituted
thiosemicarbazides,
1,2,4-triazoles
and
their
methyl-derivatives. J. Heterocycl. Chem. 1984, 21, 1225.
7. Sengupta, A.K.; Misra, H.K. Studies on potential pesticides 13 Synthesis and evaluation of
s-(3-substituted phenoxymethyl-4-aryl/cyclohexyl-4h-1,2,4-triazol-5-yl)-2-mercaptomethyl benz-
imidazoles for anti-bacterial and insecticidal activities. J. Ind. Chem. Soc. 1981, 58, 508.
8. Ram,V.J.; Vlietinck, A.J. Chemotherapeutical agents .7. Synthesis and pesticidal activities of
sulfides and sulfones derived from bis[4-aryl-1,2,4-triazoline-5-thione-3-yl]alkane and
5-phenyl-1,3,4-oxadiazole-2-thione. J. Heterocycl. Chem. 1988, 25, 253.
9. Boschelli D.H.; Connor, D.T.; Bornemeier, D.A.; Dyer, R.D.;. Kennedy, J.A.; Kuipers, P.J.;
Okonkwo, G.C.; Svhrier, D.J.; Wright, C.D. 1,3,4-oxadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole
analogs of the fenamates - in-vitro inhibition of cyclooxygenase and 5-lipoxygenase activities. J.
Med. Chem. 1993, 36, 1802.
10. Bahadur, S.; Pandey, K.K. Synthesis of para-alkyl-(2-benzimidazolyl)-methyl-minobenzoates and
corresponding hydrazides as possible anti-malarial agents. J. Ind. Chem. Soc. 1980, 57, 447.
11. Cansız,
A.;
Koparır,
M.;
Demirdag.
A.
Synthesis
of
some
new
4,5-substituted-4H-1,2,4-triazole-3-thiol derivatives. Molecules 2004, 9, 204.
12. Rostom, S.A.F.; Shalaby, M.A.; EL-Demellawy, M.A. Polysubstituted pyrazoles, part 5. Synthesis
of new 1-(4-chlorophenyl)-4-hydroxy-1h-pyrazole-3-carboxylic acid hydrazide analogs and some
derived ring systems. A novel class of potential antitumor and anti-HCV agents Eur. J. Med. Chem.
2003, 38, 959.
13. Aydogan, F.; Turgut, Z.; Olcay, N.; Erdem, S.S. Synthesis and electronic structure of new aryl- and
alkyl-substituted 1,3,4-oxadiazole-2-thione derivatives. Turk. J. Chem. 2002, 26, 159.
14. Charistos, D.A.; Vagenes, G.V.; Tzavellas, L.C.; Tsoleridis, C.A.; Rodios, N.A. Synthesis and a
UV and IR spectral study of some 2-aryl-delta(2)-1,3,4-oxadiazoline-5-thiones. J. Heterocycl.
Chem. 1994, 31, 1593.
15. Tsoleridi, C.A.; Charistos, D.A.; Vagenes, G.V. UV and MO study on the deprotonation of some
2-aryl-delta(2)-1,3,4-oxadiazoline-5-thiones. J. Heterocycl. Chem. 1997, 34, 1715.
16. Cansiz, A.; Servi, S.; Koparir, M.; Altintas, M.; Digrak, M. Synthesis and biological activities of
some Mannich bases of 5-(2-furyl)-1,2,4-triazole-3-thiones. J. Chem. Soc. Pakistan 2001, 23, 237.
479

Molecules 2005, 10
480
17. Ozturk, S.; Akkurt, M.; Cansiz, A.; Cetin, A.; Sekerci, M.; Heinemann, F.W.
5-(furan-2-yl)-1,3,4-oxadiazole-2(3H)-thione. Acta Cryst. E. 2004, E60, O322.
18. Ozturk, S.; Akkurt, M.; Cansiz, A.; Koparir, M.; Sekerci, M.; Heinemann, F.W.
4-(4-Chlorophenyl)-3-(furan-2-yl)-1H-1,2,4-triazole-5(4H)-thione. Acta Cryst 2004, E60, O425.
19. Ozturk, S., Akkurt, M.; Cansiz, A.; Koparir, M.; Sekerci, M.; Heinemann, F.W.
3-Benzyl-4-(4-chlorophenyl)-1H-1,2,4-triazole-5(4H)-thione. Acta Cryst 2004, E60, O642.
Sample availability: Available from the authors.
© 2005 by MDPI (http:www.mdpi.org). Reproduction is permitted for noncommercial purposes.
480