Addition-cyclisation of 3-(2-thienyl)acryloyl isothiocyanate with hydrazine derivatives as a source of triazoles and thiadiazoles

Article abstract of DOI:10.3184/030823409X12474221035136

3-(2-Thienyl)acryloyl isothiocyanate reacts additively with hydrazine hydrate, phenylhydrazine, 2-pyridyl hydrazine, (thio) semicarbazides, as well as benzoyl- and ethoxycarbonyl hydrazine. Simultaneous or subsequent cyclisation of the resulting 1 : 1 add

Full text of DOI:10.3184/030823409X12474221035136

JOURNAL OF CHEMICAL RESEARCH 2009
AUGUST, 489–491
RESEARCH PAPER 489
Addition–cyclisation of 3-(2-thienyl)acryloyl isothiocyanate with
hydrazine derivatives as a source of triazoles and thiadiazoles
Magdy M. Hemdan*
Department of Chemistry, Faculty of Science, Ain Shams University, 11566 Abbasia, Cairo, Egypt
3-(2-Thienyl)acryloyl isothiocyanate reacts additively with hydrazine hydrate, phenylhydrazine, 2-pyridyl hydrazine,
(thio) semicarbazides, as well as benzoyl- and ethoxycarbonyl hydrazine. Simultaneous or subsequent cyclisation of
the resulting 1:1 adducts in acidic or alkaline media yields substituted 1,3,4-thiadiazoles or 1,2,4-triazoles respectively.
Keywords: 1,2,4-triazole derivatives, hydrazine derivatives, thiourea derivatives, aroyl isothiocyanate
1,2,4-Triazole derivatives exhibit anti-inflammatory,1
antiviral,2 analgesic,3 antimicrobial,4 anticonvulsant,5 and
antidepressant activities.6 A series of 1,2,4-triazoles7 have
been patented and extensively employed in agriculture.
Our previous investigations on the utilisation of aroyl
isothiocyanates8-10 afforded many different sizes heterocyclic
rings. In the present work, we use the prototype hydrazine itself
and some of its simple congeners and 3-(2-thienyl)acryloyl
isothiocyanate as a source of 1,2,4-triazoles bearing thiophene
nucleus aiming to enhance their biological activities.
Refluxing of isothiocyanate 1 with semicarbazide HCl or
thiosemicarbazide in acetonitrile was accompanied by release
of H2S gas. The product obtained was formulated as an
E-isomer of another differently substituted 1,2,4-triazole
derivatives 5a,b. Formation of compounds 5a,b was based
on addition of amino group of semi or thiosemicarbazide to
isothiocyanato carbon atom followed by cyclisation of the
intermediate thiourea 4a,b with liberation of H2S molecule.
The release of H2S gas was detected during the reaction
progress by turning wet lead acetate paper black. However,
when the reaction of 1 with thiosemicarbazide was carried out
at room temperature, the thiourea derivative 4b was separated.
The structures of compounds 3a–c, 4b and 5a,b were
confirmed by their microanalytical and spectral data. Their
IR spectra showed absorption bands correlated with υ(NH),
υ(C=N), υ(C=C) and υ(C=S), in addition to υ(C=O) for
compounds 4b and 5a,b. The 1H NMR spectra displayed
signals corresponded very well with their structures.
1H NMR spectrum of 3a found: four NH protons exchangeable
with D2O two of them have integration ratio 72% and the
other two a ratio 28%. Moreover, olefinic protons appear as
four doublets, two doublets have an integration ratio 72%
with coupling constant (J) in the range 14–15 Hz and the
other two have the ratio 28% with (J) in the range 11–12 Hz.
Results and discussion
The new derivatives of 1,2,4-triazole were prepared following
the reaction sequences depicted in scheme 1 and 2. Addition
of equimolar amounts of hydrazine derivatives like hydrazine
hydrate, phenylhydrazine, or 2-pyridylhydrazine to
a
solution of 3-(2-thienyl)acryloyl isothiocyanate (1) in boiling
acetonitrile produced 1,2,4-triazole derivatives 3a–c in one pot
reaction. The triazoles 3a–c were obtained as E/Z mixture in
the case of 3a and exclusively as E-isomers for 3b and 3c.The
formation of 1,2,4-triazoles 3a–c can be visualised on the
basis of cyclocondensation of hydrazines with isothiocyanate
1 via the non isolable thiourea derivatives 2a–c.
O
CH=CH
S
N=C=S
1
R'NHNH2
S
NH2NHC(X)NH2
NH2NHC(O)R"
O
X
S
O
NHNHCOR"
S
R
NH
R-C-NH-C-NHNHR'
R-C-NH-C-NHNH-C-NH2
O
2a-c
4a,b
6a) R'' = Ph
b) R'' = OEt
N
R
H
S
NH
N
X
N
N
NH
R'
R =
RCOHN
CH=CH-
S
3 a) R' = H
b) R' = Ph
5 a) X = O
b) X = S
c) R' = 2-pyridyl
Scheme 1
* Correspondent. E-mail: mhemdan39@hotmail.com

490 JOURNAL OF CHEMICAL RESEARCH 2009
R
O
S
EtOH/HCl
Ph
NH
Ph
O
N
N
7
COR
N
S
EtOH/NaOH
EtOH/NaOH
NHNHCOR"
R
NH
HN
N
O
S
8
6a,b
COR
N
S
HN NH
9
Scheme 2
Faculty of Science, Cairo University by using Perkin-Elemer 2400
CHN elemental analyser. The IR spectra were recorded on Perkin–
Elmer Spectrum RXIFT-IR systems as KBr discs. The 1H NMR
spectra were measured on Varian Gemini 200 MHz instrument with
chemical shift (d) expressed in ppm downfield from TMS as internal
standard, in DMSO-d6. Mass spectra were recorded on Shimadzu
GC-MS, QP 1000 EX instrument operating at 70 eV. TLC was carried
out to monitor the progress of all reactions and homogeneity of the
synthesised compounds. TLC was determined using TLC aluminum
sheets silica gel F254 (Merck).
3-(2-thienyl)acryloyl isothiocyanate (1): To a solution of 3-(2-
thienyl)acryloyl chloride (3 mmole), in dry acetonitrile (30 mL), solid
ammonium thiocyanate (4.5 mmole) was added. The reaction mixture
was stirred for half an hour at room temperature.12,13 The precipitated
ammonium chloride was filtered off to give a clear yellow solution of
isothiocyanate 1.
The former two doublets correspond very well with the
E-isomer and the latter doublets are in agreement with the
Z-isomer. This observation is a good evidence for the existence
of the compound 3a as E/Z mixture of a ratio 72:28. The MS
spectra of representative compounds revealed their molecular
ions which in accordance with their proposed assignments
(see Experimental).
The reaction of equimolar quantities of isothiocyanate 1
with benzoylhydrazine or ethoxycarbonylhydrazine gave good
yields of the linear 1:1 adducts 6a,b as shown in Scheme 1.
Refluxing of the adduct 6a in ethanolic hydrochloric acid
effected ring closure with elimination of water, to give
thiadiazole derivative 7 (compound 7 gave negative spot test
characteristics for the C=S group11). On the other hand, when
a solution of 6a in ethanol was boiled with a catalytic amount
of sodium hydroxide, 1,2,4-triazole derivative 8 was obtained
as shown in Scheme 2. Similarly, compound 6b was cyclised
by ethanolic sodium hydroxide to 1,2,4-triazoline derivatives
9 via elimination of ethanol molecule (see Experimental).
The structures of compounds 6–9 were elucidated from
their microanalytical and spectral data. Thus, their IR spectral
data showed absorption correlated with υ(NH), υ(C=C), and
υ(C=O), in addition to υ(C=N) for compounds 7,8. Their
1H NMR spectra displayed signals correspond very well with
their structures. Configurational assignments to compounds
6–9 as E-isomers was based on the appearance of two
doublets of the two olefinic protons with coupling constant (J)
in the range 15–16 Hz. The MS spectra of compounds 6–9
revealed their molecular ions peaks, as well as some important
peaks which are in accord with their proposed structures (see
Experimental).
Reaction of isothiocyanate 1 with the hydrazine derivatives:
General procedure
To a solution of isothiocyanate 1 (3 mmole), hydrazine hydrate,
phenylhydrazine, 2-pyridyl hydrazine, semicarbazide HCl,
thiosemicarbazide, benzoyl hydrazine, or ethyl hydrazine carboxylate,
in acetonitrile (50 mL) was added. A few drops of triethylamine were
added in the case of the reaction with semicarbazide HCl. The mixture
was refluxed for 2–3 hours (TLC), and cooled to room temperature.
The precipitated solid was filtered off, washed with ethanol and
recrystallised from the suitable solvent.
5-[(E,Z)-2-(Thiophen-2-yl)vinyl]-1H-1,2,4-triazole-3(2H)-thione
(3a): (87% yield); yellow crystals; m.p. > 300°C (DMF); IR: 3238,
3160 (NH), 1674 (C=N), 1604 (C=C), 1148 (C=S); 1H NMR (DMSO-
d6)d:7.21–7.78(m,3H,ArH),forZ-isomerd:6.22(d,1H,J=11.12Hz,
CH=), 7.91 (d, 1H, J = 12.0 Hz, CH=), 12.35, 13.52 (br. s, 2NH
exchangeable); for E-isomer d: 6.76 (d, 1H, J = 15.4 Hz, CH=), 8.00
(d, 1H, J = 14.6 Hz, CH=), 11.95, 14.10 (br. s, 2NH exchangeable),
MS m/z (%): 209 (M+., 6.8), 153(8.5), 139 (15.4), 137 (100), 122(5),
109 (72); Anal. Calcd for C8H7N3S2 (209.29); C, 45.91; H, 3.37; N,
20.08. Found: C, 45.67; H, 3.51; N, 20.14%.
[(E)-1-Phenyl-5-(2-(thiophen-2-yl)vinyl)]-1H-1,2,4-triazole-3(2H)-
thione (3b): (92% yield); yellow crystals; m.p. 228–231°C (ethanol);
Conclusion
Synthetic utilisation of a,b-unsaturated acy isothiocyanate
is based on the different reactivity of both centres against
nucleophiles. It is observed from all reactions mentioned that
the nucleophilic attach proceeds at the isothiocyanao group
rather than the a,b-unsaturated system which reflects the
higher reactivity of isothiocyanate group.
IR: 3120 (NH), 1644 (C=N), 1598 (C=C), 1242 (C=S), 766, 688
1
d
5H; H NMR (DMSO-d6) d: 6.72 (d, 1H, CH=, J = 16.8 Hz), 7.75
(d, 1H, CH=, J = 17.6 Hz), 7.15–7.99 (m, 8H, ArH), 13.99 (br. s, NH
exchangeable); MS m/z (%): 285 (M+., 36), 286 (M+. + 1, 10), 287 (M+.
+ 2, 5), 284 (20), 252 (18), 143 (45), 109 (12), 91 (100); Anal. Calcd
for C14H11N3S2 (285.39); C, 58.92; H, 3.89; N, 14.72. Found: C, 58.78;
H, 3.70; N, 14.59%.
[(E)-1-(Pyridin-2-yl)-5-(2-(thiophen-2-yl)vinyl)]-1H-1,2,4-triazole-
3(2H)-thione (3c): (88% yield); yellow crystals; m.p. 239–241°C
(ethanol); IR: 3215 (NH), 1637 (C=N), 1594 (C=C), 1213 (C=S);
1H NMR (DMSO-d6) d: 6.69 (d, 1H, CH=, J = 15.6 Hz), 6.73–7.79 (m,
6H, ArH), 7.88 (d, 1H, CH=, J = 15.6 Hz), 8.10 (d, 1H, H, J = 6.8 Hz),
11.16(br.s,NHexchangeable);MSm/z(%):286(M+.,34),287(M+.+1,7),
Experimental
General
Melting points were determined in open capillary tubes on
a
Gallenkemp melting point apparatus and are uncorrected.
The elemental analyses were carried out at the Micro Analytical Unit,

JOURNAL OF CHEMICAL RESEARCH 2009 491
288 (M+. + 2, 2), 285 (35), 253 (21), 150 (47), 109 (9), 92 (100); Anal.
Calcd for C13H10N4S2 (286.38); C, 54.52; H, 3.52; N, 19.56. Found: C,
54.39; H, 3.46; N, 19.41%.
to give (83% yield); pale yellow crystals; m.p. 244–246°C (toluene);
IR: 3120 (NH), 1684, (C=O), 1610 (C=N), 1564 (C=C), 784, 694
1
d
5H; H NMR (DMSO) d: 6.20 (d, 1H, CH=, J = 15.0 Hz), 7.76 (d,
(E)-N-[2-(carbamothioyl)hydrazinylcarbonothioyl]-3-(thiophen-
2-yl)acrylamide (4b): (91% yield); pale yellow crystals; m.p. 203–
205°C with decomposition (ethanol); IR: 3406, 3250, 3178, 3076
(NH), 1680 (C=O), 1604 (C=C), 1216, 1134 (C=S); 1H NMR
(DMSO-d6) d: 6.76 (d, 1H, CH=, J = 15.4 Hz), 7.20–7.80 (m, 3H,
ArH), 7.94 (d, 1H, CH=, J = 16.0 Hz), 8.19, 9.74, 10.72, 11.58, 13.60
1H, CH=, J = 13.8 Hz), 7.16–7.94 (m, 8H, ArH), 13.66 (br. s, NH
exchangeable); MS m/z (%): 313 (M+., 28), 314 (M+. + 1, 5), 315
(M+. + 2, 1), 161 (2), 152 (33), 137 (100), 109 (44), 103 (7), 89 (13),
77 (76), 76 (52); Anal. Calcd for C15H11N3OS2 (313.40); C, 57.49; H,
3.54; N, 13.41. Found: C, 57.32; H, 3.37; N, 13.23%.
Reaction of 6a and 6b with ethanolic sodium hydroxide: general
procedure A solution of 6a or 6b in ethanol (30 mL), 3M sodium
hydroxide (10 mL) was refluxed for 1 h, vacuum-distilled to ca half-
volume and acidified with 3M hydrochloric acid. The precipitate was
collected and crystallised from ethanol to give compounds 8 or 9.
[(E)-1-(3-phenyl-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)-3-(thiophen-
2-yl)]prop-2-en-1-one (8): A pale yellow crystals; (79% yield); m.p.
295–297°C; IR: 3180 (NH), 1682, (C=O), 1618 (C=N), 1556 (C=C),
(br. s, 5NH exchangeables); MS m/z (%): 286 (M+., 19), 287 (M+.
+
1, 3), 288 (M+. + 2, 2), 253 (14), 252 (29), 152 (43), 137 (100), 109
(23), 100 (3); Anal. Calcd for C9H10N4OS3 (286.40); C, 37.74, H,
3.52; N, 19.56. Found: C, 37.38; H, 3.39; N, 19.48%.
[(E)-N-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3-(thiophen-2-
yl)]acrylamide (5a): (77% yield); yellow crystals; m.p. 219–221°C
(ethanol); IR: 3314, 3234, 3160 (NH), 1682 (C=O), 1588 (C=N),
1544 (C=C), 1254 (C=S); 1H NMR (DMSO-d6) d: 6.76 (d, 1H, CH=,
J = 15.8 Hz), 7.18–7.76 (m, 3H, ArH), 7.88 (d, 1H, CH=, J = 15.8 Hz),
9.47, 9.82 11.12 (br. s, 3NH exchangeables); MS m/z (%): 236 (M+.,
5), 237 (M+. + 1, 1), 152 (61), 137 (100), 109 (52); Anal. Calcd for
C9H8N4O2S (236.25); C, 45.75; H, 3.41; N, 23.72. Found: C, 45.58;
H, 3.23; N, 23.49%.
1
1172 (C=S), 744, 688 d5H; H NMR (DMSO) d: 6.72 (d, 1H, CH=,
J = 15.4 Hz), 7.16–8.04 (m, 9H, 8ArH + 1CH=), 12.84 (br. s, NH
exchangeable); MS m/z (%): 313 (M+., 8.0), 314 (M+. + 1, 0.6), 182
(6.5), 176 (3.5), 151 (2), 137 (100), 109 (39), 103 (11), 89 (7), 77
(25), 76 (10); Anal. Calcd for C15H11N3OS2 (313.40); C, 57.49; H,
3.54; N, 13.41. Found: C, 57.28; H, 3.43; N, 13.54%.
[E-N-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3-(thiophen-2-
yl)]acrylamide (5b): (86% yield); yellow crystals; m.p. 246–248°C
(toluene); IR: 3356, 3182, 3102 (NH), 1666 (C=O), 1610 (C=N),
1510 (C=C), 1192 (C=S); 1H NMR (DMSO-d6) d: 6.63 (d, 1H, CH=,
J = 15.4 Hz), 6.82 (br. s, 2NH exchangeable), 7.17–7.74 (m, 3H,
ArH), 7.85 (d, 1H, CH=, J = 15.8 Hz), 12.04 (br. s, NH exchangeable);
MS m/z (%): 252 (M+., 65), 253 (M+. + 1, 11), 254 (M+. + 2, 5),
219 (23), 152 (33), 137 (100), 109 (19), 100 (11); Anal. Calcd for
C9H8N4OS2 (252.32); C, 42.84, H, 3.20; N, 22.21. Found: C, 42.68;
H, 3.03; N, 21.96%.
(E)-4-(3-(thiophen-2-yl)acryloyl)-5-thioxo-1,2,4-triazolidin-3-
one (9): (68% yield); pale yellow crystals; m.p. 260–262°C; IR:
3315, 3220 (NH), 1681, 1665 (C=O), 1574 (C=C), 1196 (C=S);
1H NMR (DMSO) d: 6.22 (d, 1H, CH=, J = 16.6 Hz), 7.12–7.61 (m,
3H, ArH), 7.60 (d, 1H, CH=, J = 14 Hz), 9.42, 13.53 (br. s, 2NH
exchangeable); MS m/z (%): 253 (M+., 12), 254 (M+. + 1, 3), 255
(M+. + 2, 1.7), 116 (2), 151 (21), 137 (100), 109 (36); Anal. Calcd for
C9H7N3O2S2 (253.30); C, 42.68; H, 2.79; N, 16.59. Found: C, 42.37;
H, 2.56; N, 16.22%.
(E)-N-[2-(benzoyl)hydrazinylcarbonothioyl]-3-(thiophen-2-yl)
acrylamide (6a): (88% yield); pale yellow crystals; m.p. 203–204°C
(ethanol); IR: 3320, 3182, 3160 (NH), 1680, (C=O), 1628 (C=C),
Received 2 May 2009; accepted 19 June 2009
Paper 09/0562 doi: 10.3184/030823409X12474221035136
Published online: 10 August 2009
1
1228 (C=S); H NMR (DMSO) d: 6.23 (d, 1H, CH=, J = 14.6 Hz),
7.31 (d, 1H, CH=, J = 18.6 Hz), 7.11–8.03 (m, 8H, ArH), 8.54, 9.92,
13.50 (br. s, 3NH exchangeable); MS m/z (%): 331 (M+., 5.4), 332
(M+. + 1, 1.4), 333 (M+. + 2, 1.1), 194 (2.5), 137 (77), 109 (47.4), 105
(98), 77 (100), 76 (12); Anal. Calcd for C15H13N3O2S2 (331.41); C,
54.36; H, 3.95; N, 12.68. Found: C, 53.98; H, 3.76; N, 12.55%.
(E)-Ethyl 2-(3-(thiophen-2-yl)acryloylcarbamothioyl) hydrazine
carboxylate (6b): (96% yield); yellow crystals; m.p. 150–152°C
(ethanol); IR: 3320, 3200 (NH), 1738, 1684 (C=O), 1614 (C=C),
References
1
P.C. Unangst, G.P. Shurum, D.T. Connor, R.D. Dye and D. J. Schrier,
J. Med. Chem., 1992, 35, 3691.
2
D.H. Jones, R. Slack, S. Squires and K.R.H. Wooldridge, J. Med. Chem.,
1965, 8, 676.
3
4
J.K. Sughen and T. Yoloye, Pharm. Acta Helv., 1978, 58, 64.
A. Cansiz, S. Servi, M. Koparir, M. Altintas and M. Digrak, J. Chem. Soc.
Pak., 2001, 23, 237.
1
1140 (C=S); H NMR (DMSO-d6) d: 1.22 (m, 3H, CH3CH2–), 4.11
5
6
M.R. Stilling, A.P. Welbourn and D.S. Walter, J. Med. Chem., 1986, 29,
2280.
J.M. Kane, M.W. Dudley, S.M. Sorensen and F.P. Miller, J. Med. Chem.,
1988, 31, 327.
(d, 2H, J = 6.8 Hz, CH3CH2–), 6.78 (d, 1H, CH=, J = 15.4 Hz),
7.20–7.78 (m, 3H, ArH), 7.92 (d, 1H, CH=, J = 15 Hz), 9.78, 11.61,
11.79 (br. s, 3NH exchangeables); MS m/z (%): 299 (M+., 3), 254
(12), 226 (4), 195 (27), 152 (42), 137 (100), 109 (18); Anal. Calcd
for C11H13N3O3S2 (299.37); C, 44.13; H, 4.38; N, 14.04. Found: C,
43.87; H, 4.17; N, 14.22%.
7
8
9
A. Vamvakides, Pharm. Fr., 1990, 48, 154.
M.M. Hemdan and M.M. El-shahawi J. Chem. Res., 2009, 75.
M.M. Hemdan, A.F. Fahmy, N.F. Ali, E. Hegazi and A. Abd-Elhaleem,
Chinese J. Chem., 2007, 25, 388.
(E)-N-[(5-phenyl-1,3,4-thiadiazol-2-yl)-3-(thiophen-2-yl)]acryl-
amide (7): A suspension of 6a (0.5 g) in ethanol (30 mL), 3M
hydrochloric acid (5 mL) was refluxed for 2 h. The solution was
vacuum-evaporated to a small volume. A solution of sodium
carbonate (0.1 N) was added until effervescence ceased. The yellow
precipitate obtained was filtered off and recrystallised from ethanol
10 M.M. Hemdan J. Phosphorus, Sulfur, Silicon Relat. Elem., (in press).
11 F. Feigl, Spot tests in organic analysis, Princeton, NJ, New York, 1960,
p.243.
12 M. Baeger and J. Drabac, Ger Offen DE 3,504,016, 1985; [Chem.Abstr.,
1985, 103, 215196,].
13 R. Hull and J.P. Seden, Synth. Commun, 1981, 10, 489.