Synthesis of biologically important n-heteroaryl-2-(heteroarylthio) acetamides

Article abstract of DOI:10.1002/jhet.1804

The synthesis of compounds having triazole and selena/thiadiazole rings connected by a chain having sulfur and nitrogen in the link has been described. The resultant N-heteroaryl-2-(heteroarylthio)acetamide may be biologically important as related compounds found application in the inhibition of HIV 1 replications.

Full text of DOI:10.1002/jhet.1804

1012
Synthesis of Biologically Important N-Heteroaryl-2-
Vol 51
(heteroarylthio)acetamides
*
Thulasiraman Krishnaraj and Shanmugam Muthusubramanian
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
*
E-mail: muthumanian2001@yahoo.com
Received May 12, 2012
DOI 10.1002/jhet.1804
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
N
N
Y
S/Se
S
H
N
X
NH
NH
N
N
S
N
O
NH
X
O
NNHCONH2
Y
N
The synthesis of compounds having triazole and selena/thiadiazole rings connected by a chain having sulfur
and nitrogen in the link has been described. The resultant N-heteroaryl-2-(heteroarylthio)acetamide may be
biologically important as related compounds found application in the inhibition of HIV 1 replications.
J. Heterocyclic Chem., 51, 1012 (2014).
INTRODUCTION
The therapeutic importance of 1,2,4-triazoles are well
documented. Among these, there are simple molecules
having 1,2,4-triazole ring, besides biheterocyclic and
polyheterocyclic compounds that contain triazole ring or
triazole fused compounds [1–9]. For instance, some bihe-
terocyclic compounds, consisting of 1,2,4-triazole and
1,3,4-thiadiazole rings, have impressive antimicrobial
activity [10]. Compounds with a 1,2,3-thiadiazole moiety
have been found to exhibit various pharmacological
properties such as antifungal, pesticidal, and antibacterial
activities [11,12]. Dong et al. have synthesized a series of
new acrylamide derivatives containing 1,2,3-thiadiazole
and evaluated their anti-hepatitis B virus activities
in vitro [13]. Compounds containing 1,2,3-selenadiazole
moieties are well known for their antimicrobial activities
[14,15]. Realizing the biological importance of 1,2,4-
triazole and the thia/selenadiazole rings, it has been
planned to synthesize new compounds containing these
skeletons connected by a chain containing a hetero atom,
which are expected to have enhanced biological activity
as evidenced by related studies [16–18].
4a–4h. All these ketones are new and fully characterized.
These ketones were then converted to their semicarbazones
5a–5h by the conventional procedure. Although there is a
chance for the formation of a mixture of geometrical iso-
mers during this reaction, only one geometrical isomer
was isolated in all the cases with no trace of the other
isomer suggesting the reaction to be a stereoselective one.
1
There is only one set of hydrogens and carbons in the H
and 13C NMR spectra of 5f.
It has been well established that the semicarbazones with
active methylene at the a-carbon are capable undergoing
ring closure when treated with thionyl chloride [19]. Such
a ring closure has been effected on the semicabazones 5
and the reaction proceeded smoothly yielding the respec-
tive 1,2,3-thiadiazole 6a–6g in good yield. It must be
admitted the reaction has not gone at all even in poor
yield when the para-cyano substituted and meta-nitro
substituted aryl compounds were subjected to this reac-
tion (5c–6c and 5h–6h). This is surprising as the whole
of the starting material was recovered unreacted under
the reaction conditions employed in the former case, and
the mass obtained could not be purified in the latter case.
Thus, 6c and 6h were not formed.
RESULTS AND DISCUSSION
A related oxidative cyclization process leads to the
formation of 1,2,3-selenadiazole from semicarbazone by
selenium dioxide. This can be effected in different sol-
vents, and the solvent optimized in the present investiga-
tion is ethanol. A range of selenadiazoles 7a–7h has been
attempted by this protocol (Scheme 1). But 7e and 7h were
not obtained in pure form. It seems that the conversion of
the semicarbazone to selenadiazole is relatively difficult
compared with thiadiazole as revealed by the yields.
The following scheme has been proposed to generate the
targeted linked heterocycles (Scheme 1). The commer-
cially available 3-amino-1,2,4-triazole (1) was allowed to
react with thioglycolic acid (2) under neat condition at
room temperature. The amide (3) formation occurred quite
efficiently. The amide formed was then allowed to react
with substituted phenacyl bromides in presence of potas-
sium carbonate to provide a host of carbonyl compounds
© 2013 HeteroCorporation

July 2014
Synthesis of Biologically Important N-Heteroaryl-2-(heteroarylthio)acetamides
1013
Scheme 1 Reagents and conditions (i) Neat heating (175ꢀC), 15 min; (ii) ArCOCH2Br, EtOH, K2CO3, RT, stirring, 5 h; (iii) NH2NHCONH2.HCl, Anhyd.
CH3COOK, (Methanol : Water (v/v 1:1)), reflux, 8 h; (iv) SOCl2, À15ꢀC to RT, stirring, 12 h; and (v) SeO2, EtOH, reflux, 12 h.
H
H2N
O
(i)
NH
N
N
COOH
SH
(ii)
+
HS
N
N
H
N
N
3
2
1
O
O
NH
N
Y
X
S
N
N
H
4
(iii)
Y
N
N
Se
H
X
N
(v)
NH
S
N
S
N
NH
N
O
NNHCONH2
O
NH
X
5
Y
N
(iv)
7
N
N
S
a: X = Y = H
b: X = Cl; Y = H
c: X = CN; Y = H
d: X = CH3; Y = H
S
NH
NH
N
N
O
X
e
: X = OCF3; Y = H
Y
f
: X = H, Y = OCH3
6
g
: X = H; Y = Cl
h: X = H; Y = NO2
After synthesizing selenadiazoles and thiadiazoles
linked to triazole by –S-CH2-CONH- group, it has been
realized that the selena/thiadiazoles connected to –S-
CH2-CONHAr, where Ar is simple aryl, have not been
reported in literature. Hence, it has been planned to
synthesize such compounds starting from aniline. Ani-
line reacts with thioglycolic acid to give the amide 9.
The free thiol present in 9 was then functionalized with
substituted phenacyl bromides to give a collection of
10. The keto compounds 10 were then converted to
their semicarbazones 11 by the usual procedure. As
described earlier, these semicarbazones have been
subjected to (i) thinoyl chloride treatment to yield
thiadiazoles 12, and (ii) selenium dioxide treatment to
give selenadiazole derivatives 13 (Scheme 2). 11g
could not be obtained in pure form. It must be noted
that for the oxidative cyclization of 11 to yield 13 by
selenium dioxide, the preferred solvent is THF,
whereas for the selenadiazoles 7, ethanol was preferred.
12c and 12f were not formed. The reaction is not at all
taking place in À78ꢀC in these cases and at higher
temperature, around À10ꢀC, the semicarbazone got
hydrolyzed to give back the parent ketone.
At this juncture, it is appropriate to indicate the impor-
tance of N-heteroaryl-2-(heteroarylthio)acetamide syn-
thesized in the present work. Although this work was
being carried out in our laboratory, the same class of
compounds has been synthesized and reported, of course
by a different route, by Liu and co-workers [16–18]. It
has been realized that these compounds of the type
X-S-CH2-CONHAr (where X is a five-membered hetero-
cycle like triazole or tetrazole or thia/selenadiazole), thia
acetanilide derivatives, belong to non-nucleoside reverse
transcriptase inhibitors group. These are the key targets
for inhibition of HIV 1 replications.
EXPERIMENTAL
All chemicals used in this investigation were of reagent
grade quality and used without further purification. All melting
points were recorded in open capillaries and are uncorrected.
The 1H and 13C NMR spectra were recorded on a Bruker
400 MHz (Bruker, Fallanden, Switzerland) spectrometer at
400 MHz and 100 MHz, respectively in CDCl3/DMSO-d6
using TMS as internal standard. The chemical shifts are
presented in d-scale. Microanalyses were carried out on a
PerkinElmer instrument (PerkinElmer, Lu Vento, The Netherlands).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1014
T. Krishnaraj and S. Muthusubramanian
Vol 51
Scheme 2 Reagents and conditions (i) Neat heating (130ꢀC), 3 h; (ii) ArCOCH2Br, EtOH, K2CO3, RT, stirring, 6 h; (iii) NH2NHCONH2.HCl, Anhyd.
CH3COOK, (Methanol : Water (v/v 1:1)), reflux, 8 h; (iv) SOCl2, À78ꢀC stirring, 4 h ; and (v) SeO2, THF, reflux, 2 h.
(i)
O
NH2
+
SH
(ii)
HS
COOH
N
H
8
9
2
O
O
S
Y
X
N
H
10
(iii)
Y
N
N
Se
X
(v)
NH
S
S
NH
O
NNHCONH2
O
X
Y
11
(iv)
13
N
N
S
a: X = Y = H
b: X = Cl; Y = H
c: X = CN; Y = H
d: X = CH3; Y = H
S
NH
O
X
e
: X = F; Y = H
Y
f
: X = H, Y = NO2
12
g:
X = H, Y = OCH3
All chromatographic separations were performed on 60–120
mesh silica gel using petroleum ether-ethyl acetate as eluent,
unless mentioned otherwise.
3.42 (s, 2H), 4.22 (s, 2H), 7.60 (d, J = 8.4Hz, 2H), 7.70 (s, 1H)
7.98 (d, J = 8.4 Hz, 2H), 11.64 (bs, 1H), 13.40 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 34.6, 38.4, 129.3, 130.8, 134.4,
138.8, 148.5, 149.2, 168.3, 194.0; ESI-mass (m/z) calcd
[C12H11ClN4O2S]+ 310.03, found 310.9.
2-Mercapto-N-(4H-1,2,4-triazol-3-yl)acetamide (3). 4H-3-
Amino-1,2,4-triazole (1) was treated with thioglycolic acid (2) in
equimolar amount, and the reaction mass was heated at 175ꢀC for
15 min. The resultant mass was worked out to give 3, which was
2-((2-(4-Cyanophenyl)-2-oxoethyl)thio)-N-(4H-1,2,4-triazol-3-
yl)acetamide (4c).
(KBr) 3229, 2233, 1675, 1596cmÀ1 1H NMR (400MHz,
;
Yellow solid; yield: 80%; mp = 231ꢀC; IR
1
purified by crystallization. 85% yield as a white solid; H NMR
(400 MHz, DMSO-d6) 3.04 (s, 2H), 7.71 (s, 1H), 10.42 (bs,
1H), 11.64 (bs, 1H), 13.44 (bs, 1H).
DMSO-d6) 3.41 (s, 2H), 4.24 (s, 2H), 7.82 (s, 1H), 8.00
(d, J = 8.2Hz, 2H), 8.10 (d, J = 8.2 Hz, 2H), 11.65 (bs, 1H), 13.41
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) 34.6, 38.6, 115.7,
118.5, 129.5, 133.1, 139.0, 148.7, 149.2, 168.0, 194.2; ESI-mass
(m/z) calcd [C13H11N5O2S + H]+ 302.06, found 302.0.
2-((2-Oxo-2-arylethyl)thio)-N-(4H-1,2,4-triazol-3-yl) acetamide,
(4). The thiol 3 was treated with substituted phenacyl bromides
and potassium carbonate in equimolar amount taken in ethanol.
The mixture was left at room temperature for 5 h, and the resultant
mass was worked out to give 4, which was purified by
crystallization. Compounds 4a–h were prepared by this method.
2-((2-Oxo-2-phenylethyl)thio)-N-(4H-1,2,4-triazol-3-yl)acetamide
(4a). White solid; yield: 87%; mp = 220ꢀC; IR (KBr) 3254, 1695,
2-((2-Oxo-2-(p-tolyl)ethyl)thio)-N-(4H-1,2,4-triazol-3-yl)acetamide
(4d). White solid; yield: 90%; mp = 223–224ꢀC; IR (KBr) 3227,
1672, 1662, 1596 cmÀ1 1H NMR (400MHz, DMSO-d6) 2.37
;
(s, 3H), 3.41 (s, 2H), 4.19 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.70
(s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 11.72 (bs, 1H), 13.48 (bs, 1H);
13C NMR (100 MHz, DMSO-d6) 21.6, 34.6, 38.4, 129.0, 129.7,
133.2, 144.4, 148.8, 149.0, 168.2, 194.6; ESI-mass (m/z) calcd
[C13H14N4O2S + H]+ 291.08, found 291.0.
1681, 1609 cmÀ1 1H NMR (400 MHz, DMSO-d6) 3.44 (s, 2H),
;
4.25 (s, 2H), 7.54 (t, J=7.2Hz, 2H), 7.66 (t, J=7.2Hz, 1H), 7.71
(s, 1H), 7.98 (d, J= 7.2 Hz, 2H), 11.67 (bs, 1H), 13.40 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 34.5, 38.5, 128.5, 129.4, 133.9, 135.7,
148.5, 149.1, 168.4, 195.0; ESI-mass (m/z) calcd [C12H12N4O2S]+
276.0, found 276.6.
2-((2-Oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)thio)-N-(4H-1,2,4-
triazol-3-yl)acetamide (4e). White solid; yield: 54%; mp = 216ꢀC;
IR (KBr) 3230, 1673, 1600, 1257, 1204, 1160 cmÀ1 1H NMR
;
2-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-N-(4H-1,2,4-triazol-3-
(400 MHz, DMSO-d6) 3.43 (s, 2H), 4.24 (s, 2H), 7.51 (d, J=8.0Hz,
2H), 7.70 (s, 1H), 8.10 (d, J= 8.8 Hz, 2H), 11.65 (bs, 1H), 13.40 (bs,
1H); 13C NMR (100MHz, DMSO-d6) 34.6, 38.5, 119.8, 121.4,
yl)acetamide (4b).
White solid; yield: 79%; mp= 219ꢀC; IR
1
(KBr) 3233, 1672, 1602cmÀ1; H NMR (400MHz, DMSO-d6)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of Biologically Important N-Heteroaryl-2-(heteroarylthio)acetamides
1015
131.4, 134.6, 148.5, 149.1, 152.1, 168.3, 193.8; ESI-mass (m/z) calcd
[C13H11F3N4O3S]+ 360.05, found 360.6.
2H), 8.08 (d, J = 8.4 Hz, 2H), 9.88 (bs, 1H), 11.69 (bs, 1H),
13.52 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) 25.3, 34.7,
110.6, 118.8, 126.8, 132.0, 139.6, 140.9, 148.4, 149.7, 156.5,
167.9; ESI-mass (m/z) calcd [C14H14N8O2S]+ 358.10, found 358.8.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl) thio)-1-
2-((2-(3-Methoxyphenyl)-2-oxoethyl)thio)-N-(4H-1,2,4-triazol-
3-yl)acetamide (4f). White solid; yield: 84%; mp= 205ꢀC; IR
(KBr) 3252, 1682, 1615, 1593 cmÀ1 1H NMR (400 MHz,
;
DMSO-d6) 3.43 (s, 2H), 3.82 (s, 3H), 4.23 (s, 2H), 7.21–7.24
(m, 1H), 7.43–7.47 (m, 2H), 7.57 (d, J = 6.8 Hz, 1H), 7.71 (s, 1H),
11.66 (bs, 1H), 13.42 (bs, 1H); 13C NMR (100 MHz, DMSO-d6)
34.6, 38.6, 55.8, 113.4, 119.8, 121.4, 130.3, 137.2, 148.7, 149.2,
159.9, 167.3, 194.8; ESI-mass (m/z) calcd [C13H14N4O3S]+
306.08, found 306.6.
(p-tolyl)ethylidene)hydrazinecarboxamide (5d).
White solid;
yield: 96%; mp = 248ꢀC; IR (KBr) 3471, 3214, 1678, 1678,
1
1604, 1552 cmÀ1; H NMR (400 MHz, DMSO-d6) 2.29 (s, 3H),
3.49 (s, 2H), 4.00 (s, 2H), 6.56 (bs, 2H), 7.14 (d, J = 7.8 Hz,
2H), 7.71 (s, 1H), 7.75 (d, J = 7.8 Hz, 2H), 9.52 (bs, 1H), 11.67
(bs, 1H), 13.47 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) 21.2,
26.1, 35.1, 126.4, 129.3, 134.2, 138.5, 141.8, 148.4, 149.2,
157.2, 168.8; ESI-mass (m/z) calcd [C14H17N7O2S]+ 347.12,
found 347.8.
2-((2-(3-Chlorophenyl)-2-oxoethyl)thio)-N-(4H-1,2,4-triazol-3-
yl)acetamide (4g).
White solid; yield: 61%; mp= 204ꢀC; IR
1
(KBr) 3238, 1672, 1600cmÀ1; H NMR (400 MHz, DMSO-d6)
3.42 (s, 2H), 4.23 (s, 2H), 7.54–7.56 (m, 1H), 7.70–7.73 (m, 2H),
7.95–7.97 (m, 1H), 7.98 (s, 1H), 11.63 (bs, 1H), 13.39 (bs, 1H);
13C NMR (100 MHz, DMSO-d6) 34.7, 38.5, 127.5, 128.5, 131.1,
133.5, 134.1, 137.6, 148.8, 149.1, 168.4, 193.9; ESI-mass (m/z)
calcd [C12H11ClN4O2S]+ 310.03, found 310.9.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl) thio)-1-
(4-(trifluoromethoxy)phenyl)ethylidene) hydrazinecarboxamide
(5e).
3479, 3233, 1680, 1557, 1256, 1210 cmÀ1
White solid; yield: 70%; mp = 218–219ꢀC; IR (KBr)
;
1H NMR (400 MHz,
DMSO-d6) 3.50 (s, 2H), 4.04 (s, 2H), 6.63 (bs, 2H), 7.30
(d, J= 8.5 Hz, 2H), 7.71 (s, 1H), 8.00 (d, J= 8.5 Hz, 2H), 9.70
(bs, 1H), 11.69 (bs, 1H), 13.45 (bs, 1H); 13C NMR (100 MHz,
DMSO-d6) 26.1, 35.1, 121.0, 121.4, 121.8, 124.1, 131.2,
131.4. 148.8, 149.1, 152.2, 168.4; ESI-mass (m/z) calcd
[C14H14F3N7O3SÀ H]+ 417.08, found 416.0.
2-((2-(3-Nitrophenyl)-2-oxoethyl)thio)-N-(4H-1,2,4-triazol-3-
yl)acetamide (4h). \Pale yellow solid; yield: 67%; mp= 201ꢀC;
IR (KBr) 3083, 1685, 1678, 1605, 1528cmÀ1
;
1H NMR
(400 MHz, DMSO-d6) 3.44 (s, 2H), 4.32 (s, 2H), 7.69 (s, 1H),
7.82 (t, J = 7.6 Hz, 1H), 8.39 (d, J = 7.6Hz, 1H), 8.45–8.48
(m, 1H), 8.66 (s, 1H), 11.64 (bs, 1H), 13.38 (bs, 1H); not
sufficiently soluble to record 13C NMR spectrum; ESI-mass (m/z)
calcd [C12H11N5O4S]+ 321.05, found 321.9.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)thio)-1-(3-
methoxyphenyl)ethylidene) hydrazinecarboxamide (5f). White
solid; yield: 94%; mp = 224ꢀC; IR (KBr) 3474, 3225, 1677, 1614,
1
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)
thio)-1-
1586, 1556 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.50 (s, 2H),
aryl ethylidene)hydrazinecarboxamide (5). The semicarbazide
was prepared by dissolving 0.78g of semicarbazide hydrochloride
in 5 mL of water and adding to this a solution of 1.15 g of
potassium acetate in 5 mL of methanol. The potassium chloride
thus formed was filtered out after 30min, leaving the
semicarbazide solution as the filtrate. A solution of 0.5g of ketone
3.76 (s, 3H), 4.01 (s, 2H), 6.58 (bs, 2H), 6.89–6.94 (m, 1H), 7.25
(t, J = 7.9 Hz, 1H), 7.38–7.53 (m, 2H), 7.71 (s, 1H), 9.61 (bs,
1H), 11.68 (bs, 1H), 13.45 (bs, 1H); 13C NMR (100 MHz,
DMSO-d6) 26.0, 34.7, 55.1, 111.5, 114.4, 118.6, 129.3, 138.1,
141.4, 148.1, 148.8, 156.7, 159.3, 168.8; ESI-mass (m/z) calcd
[C14H17N7O3S À H]+ 363.11, found 361.8.
4
in 3 mL of methanol was treated with the prepared
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)thio)-1-(3-
semicarbazide reagent. The mixture was refluxed for 8 h. The
solvent was removed, and the crude mass was poured onto
crushed ice, filtered to give the respective semicarbazones 5.
Compounds 5a–5h were prepared by this method.
chlorophenyl)ethylidene) hydrazinecarboxamide (5g).
White
solid; yield: 84%; mp = 262ꢀC; IR (KBr) 3478, 3215, 1679,
1
1606, 1551 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.50 (s, 2H),
4.02 (s, 2H), 6.69 (bs, 2H), 7.33–7.37 (m, 2H), 7.71 (s, 1H),
7.79–7.81 (m, 1H), 7.97 (s, 1H), 9.69 (bs, 1H), 11.69 (bs, 1H),
13.46 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) 26.0, 35.1,
125.2, 126.1, 128.7, 130.4, 133.8, 139.1, 140.4, 148.6, 149.2,
157.1, 168.5; ESI-mass (m/z) calcd [C13H14ClN7O2S]+ 367.06,
found 367.9.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl) thio)-1-
phenylethylidene)hydrazinecarboxamide (5a).
White solid;
yield: 96%; mp = 241ꢀC; IR (KBr) 3477, 3218, 1676, 1601,
1
1548 cmÀ1; H NMR (300 MHz, DMSO-d6) 3.50 (s, 2H), 4.02
(s, 2H), 6.59 (bs, 2H), 7.33 (m, 3H), 7.71 (s, 1H), 7.86 (m, 2H),
9.61 (bs, 1H), 11.70 (bs, 1H), 13.48 (bs, 1H); 13C NMR
(100 MHz, DMSO-d6) 26.1, 35.1, 126.5, 128.7, 129.0, 137.0,
141.7, 148.8, 149.2, 157.2, 168.8; ESI-mass (m/z) calcd
[C13H15N7O2S À H]+ 333.10, found 332.0.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)thio)-1-(3-
nitrophenyl)ethylidene) hydrazinecarboxamide (5h).
Yellow
solid; yield: 89%; mp = 264ꢀC; IR (KBr) 3482, 3216, 1686, 1610,
1
1558, 1529cmÀ1; H NMR (400 MHz, DMSO-d6) 3.50 (s, 2H),
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)thio)-1-(4-
chlorophenyl)ethylidene) hydrazine carboxamide (5b). White
solid; yield: 88%; mp = 250ꢀC; IR (KBr) 3479, 3228, 1680,
4.32 (s, 2H), 6.71 (bs, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H),
8.15 (d, J = 7.3 Hz, 1H), 8.35–8.40 (m, 1H), 8.57 (s, 1H), 9.85 (bs,
1H), 11.66 (bs, 1H), 13.42 (bs, 1H); not quite soluble to record
13C NMR spectrum; ESI-mass (m/z) calcd [C13H14N8O4S À H]+
378.09, found 377.0.
1
1603, 1552 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.50 (s, 2H),
4.02 (s, 2H), 6.63 (bs, 2H), 7.38 (d, J = 8.4 Hz, 2H) 7.71 (s, 1H),
7.91 (d, J = 8.4 Hz, 2H), 9.67 (bs, 1H), 11.68 (bs, 1H), 13.46 (bs,
1H); 13C NMR (100 MHz, DMSO-d6) 25.5, 34.7, 127.9, 128.2,
133.2, 135.4, 140.2, 148.0, 148.7, 156.7, 168.2; ESI-mass (m/z)
calcd [C13H14ClN7O2S À H]+ 367.06, found 366.0.
2-((4-Aryl-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4- triazol-3-
yl)acetamide (6).
The semicarbazone 5 (0.001 mol) was
added to 10 mL of thionyl chloride and cooled to À15ꢀC. The
mixture was then slowly stirred at RT for 12 h. The excess
thionyl chloride was decomposed by pouring an aqueous
solution of sodium carbonate. The product was filtered and
dried. Compounds 6 were prepared by this method.
2-(2-((2-((4H-1,2,4-Triazol-3-yl)amino)-2-oxoethyl)thio)-1-(4-
cyanophenyl)ethylidene) hydrazinecarboxamide (5c).
Pale
yellow solid; yield: 86%; mp = 226ꢀC; IR (KBr) 3467, 3238,
2223, 1688, 1588 cmÀ1; 1H NMR (400 MHz, DMSO-d6) 3.46 (s,
2H), 4.05 (s, 2H), 6.72 (bs, 2H), 7.73 (s, 1H), 7.78 (d, J = 8.4 Hz,
2-((4-Phenyl-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4-triazol-3-
yl)acetamide (6a).
White solid; yield: 73%; mp = 199ꢀC; IR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1016
T. Krishnaraj and S. Muthusubramanian
Vol 51
1
(KBr) 3234, 2898, 1681, 1603, 1549 cmÀ1; H NMR (400 MHz,
DMSO-d6) 4.25 (s, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.59
(t, J = 7.9 Hz, 2H), 7.73 (bs, 1H), 7.87 (d, J = 7.9 Hz, 2H), 12.01
(bs, 1H), 13.53 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) 40.7,
127.1, 128.4, 129.2, 130.3, 147.2, 148.2, 149.4, 156.9, 166.7;
ESI-mass (m/z) calcd [C12H10N6OS2 À H]+ 318.04, found 317.0.
semicarbazone dissolved in absolute alcohol, 0.01 mol of
powdered selenium dioxide was added portion wise with stirring.
The reaction mixture was heated to reflux at 95ꢀC for 12 h. The
deposited selenium was removed by filtration, and the filtrate was
poured into crushed ice and the solid filtered. Compounds 7 were
prepared by this method.
2-((4-Phenyl-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-triazol-
Anal. Calcd for C12H10N6OS: C, 45.27; H, 3.17; N, 26.40.
Found: C, 45.32; H, 2.99; N, 26.58%.
2-((4-(4-Chlorophenyl)-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4-
3-yl)acetamide (7a). Brown solid; yield: 42%; mp = 156ꢀC; IR
1
(KBr) 3231, 2894, 1681, 1601, 1548 cmÀ1; H NMR (400 MHz,
DMSO-d6) 4.23 (s, 2H), 7.48–7.51 (m, 1H), 7.56 (t, J = 7.4 Hz,
2H), 7.79 (bs, 1H), 7.80 (d, J = 7.4 Hz, 2H), 11.94 (bs, 1H), 13.51
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) 44.0, 129.1, 129.2,
129.3, 129.4, 131.6, 149.3, 156.6, 157.0, 168.2; ESI-mass (m/z)
calcd [C12H10N6OSSeÀ H]+ 365.98, found 364.9.
triazol-3-yl)acetamide (6b).
Pale yellow solid; yield: 63%;
mp = 202ꢀC; IR (KBr) 3113, 2904, 1690, 1627, 1594 cmÀ1; 1H NMR
(400 MHz, DMSO-d6) 4.24 (s, 2H), 7.65 (d, J=8.4Hz, 2H), 7.90 (d,
J= 8.4 Hz, 2H), 8.00 (bs, 1H), 11.63 (bs, 1H), 13.51 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 41.2, 129.4,* 129.6, 130.5, 134.3, 147.0,
149.0, 156.3, 166.0; ESI-mass (m/z) calcd [C12H9ClN6OS2 À H]+
352.0, found 351.0. *Two carbon signals merged here.
Anal. Calcd for C12H10N6OSSe: C, 39.46; H, 2.76; N, 23.01.
Found: C, 39.32; H, 2.71; N, 23.17%.
2-((4-(4-Chlorophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-
triazol-3-yl)acetamide (7b). White solid; yield: 33%; mp = 198–
Anal. Calcd for C12H9ClN6OS2: C, 40.85; H, 2.57; N, 23.82.
Found: C, 40.78; H, 2.62; N, 23.79%.
1
200ꢀC; IR (KBr) 3096, 2852, 1677, 1583, 1531 cmÀ1; H NMR
2-((4-(p-Tolyl)-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4-triazol-
3-yl)acetamide (6d). White solid; yield: 78%; mp= 217–218ꢀC;
IR (KBr) 3232, 2951, 1681, 1601, 1552 cmÀ1; 1H NMR (400MHz,
DMSO-d6) 2.38 (s, 3H), 4.22 (s, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.75
(d, J = 7.9 Hz, 2H), 7.75 (s, 1H), 11.94 (bs, 1H), 13.51 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 20.9, 40.6, 127.4, 128.2, 128.8, 129.0,
138.8, 147.5, 148.9, 157.4, 166.1; ESI-mass (m/z) calcd
[C13H12N6OS2 À H]+ 332.05, found 330.8.
(400MHz, DMSO-d6) 4.22 (s, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.84
(d, J = 8.4 Hz, 2H), 8.02 (bs, 1H), 11.58 (bs,1H); dC (100MHz,
DMSO-d6) 43.6, 128.9, 130.3, 130.5, 133.3, 148.2, 149.4, 154.9,
157.1, 165.5; ESI-mass (m/z) calcd [C12H9ClN6OSSe À H]+
399.94, found 398.8.
Anal. Calcd for C12H9ClN6OSSe: C, 36.06; H, 2.27; N, 21.02.
Found: C, 35.98; H, 2.19; N, 21.41%.
2-((4-(4-Cyanophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-
Anal. Calcd for C13H12N6OS2: C, 46.97; H, 3.64; N, 25.28.
Found: C, 46.83; H, 3.58; N, 25.32%.
N-(4H-1,2,4-Triazol-3-yl)-2-((4-(4-(trifluoromethoxy) phenyl)-
triazol-3-yl)acetamide (7c). Yellow solid; yield: 28%; mp = 168ꢀC;
IR (KBr) 3230, 2916, 1680, 1599 cmÀ1 1H NMR (400 MHz,
;
DMSO-d6) 4.26 (s, 2H), 7.98 (s, 1H), 8.03 (s, 4H), 11.60 (bs,1H),
1H signal not visible; 13C NMR (100 MHz, DMSO-d6) 44.4, 112.4,
119.0, 128.2, 128.5, 133.2, 133.6, 136.4, 154.8, 159.6, 165.9; ESI-
mass (m/z) calcd for [C13H9N7OSSe À H]+ 390.98, found 389.8.
1,2,3-thiadiazol-5-yl)thio)acetamide (6e).
White solid; yield:
52%; mp= 197ꢀC; IR (KBr) 3233, 2906, 1682, 1609, 1259 cmÀ1
;
1H NMR (400MHz, DMSO-d6) 4.25 (s, 2H), 7.59 (d, J = 8.4Hz,
2H), 7.72 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 11.96 (bs, 1H), 13.51
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) 41.2, 116.6, 119.2,
121.8, 122.2, 129.5, 130.0, 130.9, 149.1, 156.2, 166.2; ESI-mass
(m/z) calcd [C13H9F3N6O2S2 À H]+ 402.02, found 401.0.
Anal. Calcd for C13H9N7OSSe: C, 40.01; H, 2.32; N, 25.12.
Found: C, 39.92; H, 2.30; N, 25.43%.
2-((4-(p-Tolyl)-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-triazol-
3-yl)acetamide (7d). Brown solid; yield: 38%; mp = 154ꢀC; IR
Anal. Calcd for C13H9F3N6O2S2: C, 38.80; H, 2.25; N, 20.89.
Found: C, 38.72; H, 2.18; N, 20.93%.
1
(KBr) 3237, 2920, 1681, 1593, 1536 cmÀ1; H NMR (400MHz,
DMSO-d6) 2.39 (s, 3H), 4.20 (s, 2H), 7.20 (s, 1H), 7.28
(d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz, 2H), 11.90 (bs,1H), 13.53
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) 20.9, 43.6, 128.8,
129.2, 129.3, 131.2, 138.3, 155.9, 156.1, 160.1, 166.2; ESI-mass
(m/z) calcd [C13H12N6OSSe À H]+ 380.0, found 379.0.
2-((4-(3-Methoxyphenyl)-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4-
triazol-3-yl)acetamide (6f). White solid; yield: 78%; mp = 200ꢀC;
IR (KBr) 3248, 2953, 1681, 1597, 1268 cmÀ1; 1H NMR (400 MHz,
DMSO-d6) 3.82 (s, 3H), 4.25 (s, 2H), 7.09 (d, J= 7.9 Hz, 1H),
7.40–7.51 (m, 3H), 7.78 (s, 1H), 11.96 (bs, 1H), 13.51 (bs, 1H); 13
C
NMR (100 MHz, DMSO-d6) 40.9, 55.7, 114.1, 115.3, 121.0, 130.5,
* 131.9, 148.1, 148.9, 157.0, 159.8, 166.1; ESI-mass (m/z) calcd
[C13H12N6O2S2]+ 348.05, found 348.7. *Two carbon signals
merged here.
Anal. Calcd for C13H12N6O2S2: C, 44.82; H, 3.47; N, 24.12.
Found: C, 44.76; H, 3.38; N, 24.23%.
Anal. Calcd for C13H12N6OSSe: C, 41.17; H, 3.19; N, 22.16.
Found: C, 41.10; H, 3.12; N, 22.20%.
]2-((4-(3-Methoxyphenyl)-1,2,3-selenadiazol-5-yl)thio)-N-(4H-
1,2,4-triazol-3-yl)acetamide (7f).
Brown solid; yield: 42%;
mp= 160ꢀC; IR (KBr) 3244, 2903, 1678, 1592, 1553 cmÀ1; H
NMR (400MHz, DMSO-d6) 3.81 (s, 3H), 4.21 (s, 2H), 7.05–7.07
(m, 1H), 7.34–7.38 (m, 2H), 7.48 (t, J = 7.9 Hz, 1H), 7.78 (s, 1H),
11.93 (bs,1H), 13.48 (bs, 1H); 13C NMR (100MHz, DMSO-d6)
44.0, 55.7, 114.7, 114.9, 121.5, 130.4, 133.1, 148.1, 148.9, 156.2,
157.4, 159.8, 166.1; ESI-mass (m/z) calcd [C13H12N6O2SSe À H]+
395.99, found 397.0.
1
2-((4-(3-Chlorophenyl)-1,2,3-thiadiazol-5-yl)thio)-N-(4H-1,2,4-
triazol-3-yl)acetamide (6g).
White solid; yield: 57%;
mp = 218ꢀC; IR (KBr) 3231, 2955, 1682, 1602, 1292 cmÀ1
;
1H
NMR (400 MHz, DMSO-d6) 4.25 (s, 2H), 7.58–7.64 (m, 3H),
7.84 (d, J= 6.9 Hz, 1H), 7.91(s, 1H), 12.01 (bs, 1H), 13.62 (bs,
1H); 13C NMR (100 MHz, DMSO-d6) 41.1, 127.4, 128.3, 129.5,
130.1, 131.3, 131.4, 132.7, 134.0, 149.7, 155.9, 166.1; ESI-mass
(m/z) calcd [C12H9ClN6OS2 À H]+ 352.0, found 351.0.
Anal. Calcd for C13H12N6O2SSe: C, 39.50; H, 3.06; N, 21.26.
Found: C, 39.38; H, 2.28; N, 21.41%.
2-((4-(3-Chlorophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-
Anal. Calcd for C12H9ClN6OS2: C, 40.85; H, 2.57; N, 23.82.
Found: C, 40.77; H, 2.48; N, 23.86%.
triazol-3-yl)acetamide (7g).
Brown solid; yield 28%; mp
192ꢀC; IR (KBr) 3231, 2910, 1681, 1604, 1559 cmÀ1
;
1H
NMR (400 MHz, DMSO-d6) 4.23 (s, 2H), 7.55–7.62
(m, 3H), 7.79 (d, J = 7.2 Hz, 1H), 7.86 (s, 1H), 11.92
2-((4-Aryl-1,2,3-selenadiazol-5-yl)thio)-N-(4H-1,2,4-triazol-3-
yl)acetamide (7). To a solution of 0.001 mol of the appropriate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis of Biologically Important N-Heteroaryl-2-(heteroarylthio)acetamides
1017
(bs,1H), 13.52 (bs, 1H); 13C NMR (100 MHz, DMSO-d6)
44.0, 127.9, 128.8, 129.1, 129.3, 131.2, 133.8, 133.9, 155.0,
158.3, 166.0; ESI-mass (m/z) calcd [C12H9ClN6OSSe À H]+
399.94, found 398.7.
(t, J = 7.8Hz, 1H), 8.40–8.42 (m, 2H), 8.45–8.48 (m, 1H), 10.07
(bs, 1H); 13C NMR (100 MHz, DMSO-d6) 36.0, 38.5, 119.5,
123.3, 123.8, 128.0, 129.1, 131.0, 135.2, 137.0, 139.3, 148.4,
167.5, 193.6; ESI-mass (m/z) calcd [C16H14N2O4S À H]+ 330.07,
found 328.8.
2-(2-(3-Methoxyphenyl)-2-oxoethyl)thio)-N-phenylacetamide
(10g). Colorless viscous liquid; yield: 84%; 1H NMR (400MHz,
DMSO-d6) 3.36 (s, 2H), 3.80 (s, 3H), 4.20 (s, 2H), 7.04
(t, J = 7.6 Hz, 1H), 7.20–7.23 (m, 1H), 7.29 (t, J = 7.6Hz, 2H),
7.44 (m, 2H), 7.53–7.58 (m, 3H), 10.07 (bs, 1H); 13C NMR
(100MHz, DMSO-d6) 35.5, 37.9, 55.3, 113.0, 119.1, 119.4,
120.9, 123.3, 128.7, 129.8, 136.7, 138.8, 159.3, 167.2, 194.5;
ESI-mass (m/z) calcd [C17H17NO3S +H]+ 315.09, found 316.0.
2-(2-(2-Oxo-2-(phenylamino)ethyl)thio)-1-arylethylidene)
Anal. Calcd for C12H9ClN6OSSe: C, 36.06; H, 2.27; N, 21.02.
Found: C, 35.98; H, 2.21; N, 20.97%.
2-Mercapto-N-phenylacetamide (9). Aniline (8) was treated
with thioglycolic acid (2) in equimolar amount, and the reaction
mixture was heated at 130ꢀC for 3 h, and the resultant mass was
worked out to give 9, which was purified by crystallization.
2-((2-Oxo-2-arylethyl)thio)-N-phenylacetamide (10).
The
thiol 9 was treated with substituted phenacyl bromides and
potassium carbonate in equimolar amount taken in ethanol. The
mixture was left at room temperature for 6 h, and the resultant
mass was worked out to give 10, which was purified by
crystallization. Compounds 10a–g were prepared by this method.
2-(2-Oxo-2-phenylethyl)thio)-N-phenylacetamide (10a). White
solid; yield: 92%; mp = 72ꢀC; IR (KBr) 3300, 3048, 1692,
hydrazinecarboxamide (11).
The semicarbazide was prepared
by dissolving 0.78 g of semicarbazide hydrochloride in 5 mL of water;
and adding to this, a solution of 1.15 g of potassium acetate in 5 mL of
methanol. The potassium chloride thus formed was filtered out after
30 min, leaving the semicarbazide solution as the filtrate. A solution
of 0.5 g of ketone 10 in 3 mL of methanol was treated with the
prepared semicarbazide reagent. The mixture was refluxed for 8 h.
The solvent was removed and the crude mass was poured onto
crushed ice, filtered to give the respective semicarbazones 5.
Compounds 11a–11f were prepared by this method.
1
1597 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.37 (s, 2H), 4.21 (s,
2H), 7.04 (t, J= 7.1 Hz, 1H), 7.29 (t, J=7.1Hz, 2H), 7.54 (m, 4H),
7.66 (t, J= 7.3 Hz, 1H), 7.98 (d, J= 7.1 Hz, 2H), 10.09 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 36.0, 38.3, 119.6, 123.8, 128.9, 129.2,
133.9, 134.1, 135.7, 139.3, 167.7, 195.1; ESI-mass (m/z) calcd
[C16H15NO2S]+ 285.08, found 285.7.
2-(2-((2-Oxo-2-(phenylamino)ethyl)thio)-1-phenylethylidene)
2-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-N-phenylacetamide
hydrazine carboxamide (11a).
White solid; yield:À192%;
(10b).
3325, 1661, 1588, 1512 cmÀ1
White solid; yield: 86%; mp= 121–122ꢀC; IR (KBr)
mp = 145–146ꢀC; IR (KBr) 3475, 3303, 1685, 1657 cm
;
1H
;
1H NMR (400MHz, DMSO-d6)
NMR (400 MHz, DMSO-d6) 3.41 (s, 2H), 4.05 (s, 2H), 6.58
(bs, 2 H), 7.07 (t, J = 7.3 Hz, 1H), 7.27–7.41 (m, 5H), 7.59
(d, J = 7.9 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 9.69 (bs, 1H),
10.18 (bs, 1H); 13C NMR (100 MHz, DMSO-d6) 26.1, 35.8,
119.7, 119.8, 124.0, 126.5, 128.1, 129.0, 129.1, 129.2, 137.0,
139.2, 157.2, 168.3; ESI-mass (m/z) calcd [C17H18N4O2S + H]+
342.12, found 343.0.
3.36 (s, 2H), 4.20 (s, 2H), 7.04 (t, J = 7.2Hz, 1H), 7.29
(t, J = 7.2Hz, 2H), 7.53–7.60 (m, 4H), 7.99 (d, J = 8.4 Hz, 2H),
10.09 (bs, 1H); 13C NMR (100MHz, DMSO-d6) 35.5, 37.9,
119.2, 123.4, 128.7, 128.8, 130.4, 134.0, 138.3, 138.9, 167.2, 193.7;
ESI-mass (m/z) calcd [C16H14ClNO2S]+ 320.04, found 320.0.
2-((2-(4-Cyanophenyl)-2-oxoethyl)thio)-N-phenylacetamide
(10c). White solid; yield 88%; mp 94–95ꢀC; IR (KBr) 3292,
2-(1-(4-Chlorophenyl)-2-(2-oxo-2-(phenylamino) ethyl)thio)
1
2231, 1681, 1596 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.37
ethylidene)hydrazinecarboxamide (11b).
White solid; yield:
(s, 2H), 4.25 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.30
(t, J = 7.3 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.99 (d, J=8.2Hz),
8.01 (d, J= 8.2 Hz, 2H), 10.09 (bs, 1H); 13C NMR (100 MHz,
DMSO-d6) 35.5, 38.0, 115.2, 118.0, 119.2, 123.3, 128.6, 129.0,
132.7, 138.6, 138.8, 167.0, 193.9; ESI-mass (m/z) calcd
[C17H14N2O2SÀ H]+ 310.08, found 309.0.
88%; mp = 208–209ꢀC; IR (KBr) 3473, 3303, 1682, 1657,
1
1560 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.38 (s, 2H), 4.03
(s, 2H), 6.62 (bs, 2H), 7.06 (t, J = 7.8 Hz, 1H), 7.31
(t, J = 7.8 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.8 Hz,
2H), 7.92 (d, J = 8.6 Hz, 2H), 9.75 (bs, 1H), 10.14 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 25.8, 35.8, 119.8, 124.0, 128.4,
128.6, 129.2, 133.6, 135.8, 139.2, 140.9, 157.1, 168.2; ESI-
mass (m/z) calcd [C17H17ClN4O2S À H]+ 376.08, found 375.0.
2-(1-(4-Cyanophenyl)-2-((2-oxo-2-(phenylamino)ethyl) thio)
2-(2-Oxo-2-(p-tolyl)ethyl)thio)-N-phenylacetamide (10d). White
solid; yield: 90%; mp = 129–130ꢀC; IR (KBr) 3300, 1656, 1599,
1518 cmÀ1 1H NMR (400MHz, DMSO-d6) 2.37 (s, 3H), 3.36
;
(s, 2H), 4.17 (s, 2H), 7.04 (t, J= 7.4 Hz, 1H), 7.27–7.33 (m, 4H),
7.55 (d, J= 7.4 Hz, 2H), 7.87 (d, J= 8.2 Hz, 2H), 10.08 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 21.6, 36.0, 38.3, 119.6, 123.8, 129.0,
129.1, 129.7, 133.3, 139.3, 144.3, 167.7, 194.7; ESI-mass (m/z) calcd
[C17H17NO2S]+ 299.10, found 299.7.
ethylidene)hydrazinecarboxamide (11c).
White solid; yield:
84%; mp = 189–190ꢀC; IR (KBr) 3476, 3306, 2233, 1690,
1
1657 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.39 (s, 2H), 4.07
(s, 2H), 6.73 (bs, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.31
(t, J = 7.4 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 8.4 Hz,
2H), 8.10 (d, J = 8.4 Hz, 2H), 9.94 (bs, 1H), 10.14 (bs, 1H); 13C
NMR (100 MHz, DMSO-d6) 25.7, 35.8, 111.0, 119.3, 119.8,
124.0, 127.3, 129.2, 132.5, 133.2, 139.1, 141.4, 157.0, 168.2;
ESI-mass (m/z) calcd [C18H17N5O2S À H]+ 367.11, found 366.0.
2-(2-(2-Oxo-2-(phenylamino)ethyl)thio)-1-(p-tolyl)ethylidene)
2-(2-(4-Fluorophenyl)-2-oxoethyl)thio)-N-phenylacetamide
(10e).
3326, 1665, 1593, 1517 cmÀ1
White solid; yield: 90%; mp= 117–118ꢀC; IR (KBr)
;
1H NMR (400MHz, DMSO-d6)
3.38 (s, 2H), 4.21 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.28–7.39 (m,
4H), 7.55 (d, J = 7.3 Hz, 2H), 8.06–8.09 (m, 2H), 10.10 (bs, 1H);
13C NMR (100 MHz, DMSO-d6) 35.6, 37.9, 115.8, 119.2, 123.4,
128.7, 131.6, 132.0, 138.9, 163.9, 164.4, 193.4; ESI-mass (m/z)
calcd [C16H14FNO2S + H]+ 303.07, found 304.2.
hydrazine carboxamide (11d).
White solid; yield:À190%;
mp = 213–214ꢀC; IR (KBr) 3476, 3304, 1661, 1562 cm
;
1H
NMR (400 MHz, DMSO-d6) 2.30 (s, 3H), 3.40 (s, 2H), 4.02
(s, 2H), 6.58 (bs, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.16 (d,
J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H),
7.79 (d, J = 8.2 Hz, 2H), 9.64 (bs, 1H), 10.17 (bs, 1H); 13C NMR
(100 MHz, DMSO-d6) 21.2, 26.0, 35.8, 119.7, 124.0, 126.5,
2-(2-(3-Nitrophenyl)-2-oxoethyl)thio)-N-phenyl acetamide
(10f).
Viscous liquid; yield: 84%; 1H NMR (400 MHz,
DMSO-d6) 3.38 (s, 2H), 4.31 (s, 2H), 7.03 (t, J = 7.4 Hz, 1H),
7.28 (t, J = 7.4 Hz, 2H), 7.52 (d, J = 7.4Hz, 2H), 7.83
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DOI 10.1002/jhet

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T. Krishnaraj and S. Muthusubramanian
Vol 51
129.2, 129.3, 134.2, 138.5, 139.2, 142.1, 157.3, 168.3; ESI-mass
(m/z) calcd [C18H20N4O2S + H]+ 356.13, found 357.1.
2-(1-(4-Fluorophenyl)-2-((2-oxo-2-(phenylamino)ethyl) thio)
2H), 7.16 (t, J= 7.2 Hz, 1H), 7.21–7.26 (m, 2H), 7.33 (t, J=7.2Hz,
2H), 7.38 (d, J=7.2Hz, 2H), 7.86 (bs, 1H), 7.93–7.96 (m, 2H); 13C
NMR (100 MHz, CDCl3) 41.9, 116.0, 120.1, 125.3, 126.3, 129.1,
130.7, 130.8, 136.6, 145.0, 160.0, 164.5; ESI-mass (m/z) calcd
[C16H12FN3OS2 +H]+ 345.04, found 346.1.
ethylidene)hydrazinecarboxamide (11e).
White solid; yield:
86%; mp = 179–180ꢀC; IR (KBr) 3475, 3306, 1685, 1657,
1
1563 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.39 (s, 2H), 4.03
Anal. Calcd for C16H12FN3OS2: C, 55.63; H, 3.50; N, 12.17.
Found: C, 55.57; H, 3.48; N, 12.22%.
(s, 2H), 6.61 (bs, 2H), 7.06 (t, J = 7.8 Hz, 1H), 7.16
(t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.58 (d, J = 8.0 Hz,
2H), 7.93–7.96 (m, 2H), 9.69 (bs, 1H), 10.15 (bs, 1H); 13C NMR
(100 MHz, DMSO-d6) 26.0, 35.7, 115.4, 119.7, 124.0, 128.8, 129.1,
133.4, 139.2, 141.1, 157.2, 163.0, 168.3; ESI-mass (m/z) calcd
[C17H17FN4O2S+H]+ 360.11, found 361.2.
N-Phenyl-2-((4-aryl-1,2,3-selenadiazol-5-yl)thio)acetamide
(13). To a solution of 0.001 mol of the appropriate semicarbazone
dissolved in tetrahydrofuran, 0.01 mol of powdered selenium
dioxide was added portion wise with stirring. The reaction mixture
was heated to reflux at 95ꢀC for 2 h. The deposited selenium was
removed by filtration, and the filtrate was poured into crushed ice
and the solid filtered. Compounds 13 were prepared by this method.
N-Phenyl-2-((4-phenyl-1,2,3-selenadiazol-5-yl)thio)acetamide
(13a). Viscous liquid; yield: 68%; 1H NMR (400 MHz, DMSO-d6)
3.87 (s, 2H), 7.16 (t, J=7.2Hz, 1H), 7.33 (t, J=7.2Hz, 2H), 7.40 (d,
J= 8.5 Hz, 2H), 7.50–7.65 (m, 3H), 7.89 (d, J= 8.5 Hz, 2H), 8.00 (bs,
1H); 13C NMR (100 MHz, DMSO-d6) 44.5, 119.3, 120.1, 123.7,
128.6, 128.7, 130.3, 131.5, 138.3, 155.9, 156.6, 165.2; ESI-mass
(m/z) calcd [C16H13N3OSSe + H]+ 374.99, found 375.0.
2-(1-(3-Nitrophenyl)-2-(2-oxo-2-(phenylamino)ethyl) thio)
ethylidene)hydrazinecarboxamide (11f). Yellow solid; yield:
82%; mp = 160–161ꢀC; IR (KBr) 3489, 3187, 1672, 1602,
1
1521 cmÀ1; H NMR (400 MHz, DMSO-d6) 3.39 (s, 2H), 4.12
(s, 2H), 6.71 (bs, 2H), 7.05 (t, J = 7.4 Hz, 1H), 7.28–7.32 (m,
2H), 7.55–7.64 (m, 3H), 8.13–8.16 (m, 1H), 8.38 (d, J = 7.2 Hz,
1H), 8.60 (s, 1H), 9.93 (bs, 1H), 10.12 (bs, 1H); 13C NMR
(100 MHz, DMSO-d6) 25.5, 35.2, 119.2, 120.6, 122.9, 123.5,
128.7, 129.6, 132.5, 138.3, 138.7, 139.6, 148.1, 156.6, 167.6;
ESI-mass (m/z) calcd [C17H17N5O4S + H]+ 387.10, found 388.1.
N-Phenyl-2-((4-aryl-1,2,3-thiadiazol-5-yl)thio) acetamide (12).
The semicarbazone 11 (0.001mol) was added to 10 mL of thionyl
chloride and cooled to À78ꢀC and stirred at that temperature for
4 h. Then the excess thionyl chloride was decomposed by pouring
an aqueous solution of sodium carbonate. The product was filtered
and dried. Compounds 12 were prepared by this method.
Anal. Calcd for C16H13N3OSSe: C, 51.34; H, 3.50; N, 11.23.
Found: C, 51.26; H, 3.43; N, 11.20%.
2-((4-(4-Chlorophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-phenylacetamide
(13b). Viscous liquid; yield: 63%; 1H NMR (400MHz, DMSO-
d6) 4.19 (s, 2H), 7.08 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2Hz, 2H),
7.55 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.86 (d,
J = 7.2 Hz, 2H), 10.42 (bs, 1H); 13C NMR (100MHz, DMSO-d6)
45.1, 119.7, 124.3, 129.3,* 130.9, 131.0, 133.7, 138.8, 155.2,
157.8, 165.7; ESI-mass (m/z) calcd [C16H12ClN3OSSe+ H]+
408.96, found 410.0. *Two carbon signals merged here.
N-Phenyl-2-(4-phenyl-1,2,3-thiadiazol-5-yl)thio)acetamide
(12a).
3265, 3051, 1662, 1597, 1539 cmÀ1
White solid; yield: 62%; mp = 52–53ꢀC; IR (KBr)
;
1H NMR (400 MHz,
CDCl3) 3.85 (s, 2H), 7.15 (t, J = 7.1 Hz, 1H), 7.30–7.37 (m,
4H), 7.49–7.58 (m, 4H), 7.95 (d, J = 7.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) 41.9, 120.1, 125.2, 128.7, 128.8, 129.0,
129.4, 130.1, 136.6, 145.2, 158.7, 163.8; ESI-mass (m/z)
calcd [C16H13N3OS2 À H]+ 327.05, found 326.0.
Anal. Calcd for C16H12ClN3OSSe: C, 47.01; H, 2.96; N, 10.28.
Found: C, 46.97; H, 3.01; N, 10.32%.
2-((4-(4-Cyanophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-phenylacetamide
(13c). White solid; yield: 62%; mp = 161–162ꢀC; IR (KBr) 3254, 2226,
1652, 1599 cmÀ1; 1H NMR (400 MHz, Acetone-d6) 4.23 (s, 2H), 7.12 (t,
J= 7.2 Hz, 1H), 7.34 (t, J= 7.2 Hz, 2H), 7.65 (d, J= 7.2 Hz, 2H), 8.00
(d, J= 8.2 Hz, 2H), 8.16 (d, J=8.2Hz, 2H), 9.65 (bs, 1H); 13C NMR
(100 MHz, Acetone-d6) 44.9, 111.8, 118.2. 119.4, 124.1, 128.8, 129.7,
132.5, 136.4, 138.5, 154.7, 158.5, 165.0; ESI-mass (m/z) calcd
[C17H12N4OSSe + H]+ 399.99, found 401.0.
Anal. Calcd for C16H13N3OS2: C, 58.69; H, 4.00; N, 12.83.
Found: C, 58.62; H, 4.13; N, 12.88%.
2-(4-(4-Chlorophenyl)-1,2,3-thiadiazol-5-yl)thio)-N-phenylacetamide
(12b). Viscous liquid; yield: 65%; 1H NMR (400 MHz, CDCl3) 3.86
(s, 2H), 7.16 (t, J= 7.2 Hz, 1H), 7.31 (t, J= 7.2 Hz, 2H), 7.39 (d,
J= 7.2 Hz, 2H), 7.52 (d, J= 8.4 Hz, 2H), 7.90 (d, J=8.4Hz, 2H); NH
not seen; 13C NMR (100 MHz, CDCl3) 41.9, 120.0, 125.3, 128.6,
128.7, 129.1, 130.0, 135.6, 136.6, 145.2, 157.7, 163.5; ESI-mass (m/z)
calcd [C16H12ClN3OS2 +H]+ 361.01, found 362.0.
Anal. Calcd for C17H12N4OSSe: C, 51.13; H, 3.03; N, 14.03.
Found: C, 51.17; H, 3.05; N, 13.97%.
N-Phenyl-2-((4-(p-tolyl)-1,2,3-selenadiazol-5-yl)thio)acetamide
(13d). Viscous liquid; yield: 71%; 1H NMR (400 MHz, DMSO-
d6) 2.31 (s, 3H), 4.15 (s, 2H), 7.08 (t, J = 7.8Hz, 1H), 7.32
(t, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0Hz, 2H), 7.56 (d, J = 8.0Hz,
2H), 7.71 (d, J = 8.0Hz, 2H); 13C NMR (100MHz, DMSO-d6)
21.3, 45.0, 119.7, 124.3, 129.2, 129.3, 129.8,* 138.7, 138.9,
156.4, 156.5, 165.8; ESI-mass (m/z) calcd [C17H15N3OSSe+ H]+
389.01, found 390.0. *Two carbon signals merged here.
Anal. Calcd For C16H12ClN3OS2: C, 53.11; H, 3.34; N, 11.61.
Found: C, 53.17; H, 3.29; N, 11.65%.
N-Phenyl-2-((4-(p-tolyl)-1,2,3-thiadiazol-5-yl)thio)acetamide
(12d).
3257, 3035, 1662, 1597, 1527 cmÀ1
White solid; yield: 68%; mp = 136–137ꢀC; IR (KBr)
;
1H NMR (400 MHz,
CDCl3) 2.46 (s, 3H), 3.83 (s, 2H), 7.15 (t, J = 7.2 Hz, 1H),
7.29À7.37 (m, 6H), 7.84 (d, J = 8.1 Hz, 2H), 7.95 (bs, 1H); 13C
NMR (100 MHz, CDCl3) 21.3, 41.9, 120.0, 125.1, 127.2,
128.6, 129.0, 129.5, 136.6, 139.6, 144.2, 159.1, 163.8; ESI-
mass (m/z) calcd [C17H15N3OS2 + H]+ 341.07, found 342.1.
Anal. Calcd for C17H15N3OSSe: C, 52.58; H, 3.89; N, 10.82.
Found: C, 52.47; H, 3.92; N, 10.81%.
2-((4-(4-Fluorophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-phenylacetamide
(13e). Viscous liquid; yield: 66%; 1H NMR (400MHz, DMSO-
d6) 4.17 (s, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4Hz, 2H),
7.39–7.45 (m, 2H), 7.55 (d, J =8.7 Hz, 2H), 7.84–7.88 (m, 2H),
10.40 (bs, 1H); 13C NMR (100MHz, DMSO-d6) 44.9, 116.8,
119.6, 124.3, 128.5, 131.5, 134.1, 138.8, 155.5, 161.2, 163.6,
165.8; ESI-mass (m/z) calcd [C16H12FN3OSSeÀ H]+ 392.99,
found 391.2.
Anal. Calcd for C17H15N3OS2: C, 59.80; H, 4.43; N, 12.31.
Found: C, 59.79; H, 4.37; N, 12.38%; Calcd for C17H15N3OS2: C,
59.80; H, 4.43; N, 12.31. Found: C, 59.79; H, 4.37; N, 12.38%.
2-(4-(4-Fluorophenyl)-1,2,3-thiadiazol-5-yl)thio)-N-phenylacetamide
(12e). White solid; yield: 63%; mp = 140–141ꢀC; IR (KBr) 3251,
1
3058, 1658, 1597, 1535 cmÀ1; H NMR (400 MHz, CDCl3) 3.75 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis of Biologically Important N-Heteroaryl-2-(heteroarylthio)acetamides
1019
[5] Kucukguzel, S. G.; Rollas, S.; Erdeniz, H.; Kiraz, M. Eur J
Med Chem 1999, 34, 153.
[6] Yuksek, H.; Demirbas, A.; Ikizler, A.; Johansson, C. B.; Celik,
C.; Ikizler, A. A.; Forsh, A. Drug Res. 1997, 47, 405.
[7] Tozkoparan, B.; Gokhan, N.; Aktay, G.; Yesilada, E.; Ertan,
M. Eur J Med Chem 2000, 35, 743.
Anal. Calcd for C16H12FN3OSSe: C, 48.98; H, 3.08; N, 10.71.
Found: C, 48.92; H, 3.04; N, 10.78%.
2-((4-(3-Nitrophenyl)-1,2,3-selenadiazol-5-yl)thio)-N-phenylacetamide
(13f).
3282, 2956, 1653, 1520 cmÀ1
Yellow solid; yield: 32%; mp = 147–148ꢀC; IR (KBr)
;
1H NMR (400MHz, DMSO-d6)
4.25 (s, 2H), 7.10 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.57
(d, J = 7.6 Hz, 2H), 7.89 (t, J = 8.0Hz, 1H), 8.32–8.36 (m, 2H),
8.68 (s, 1H), 10.44 (bs, 1H); 13C NMR (100 MHz, DMSO-d6)
49.7, 124.4, 128.1, 128.4, 129.0, 134.0, 135.7, 138.2, 140.1,
143.5, 153.1, 158.9, 164.0, 170.3; ESI-mass (m/z) calcd
[C16H12N4O3SSe + H]+ 419.98, found 420.9.
[8] Ikizler, A. A.; Uzunali, E.; Demirbas, A. Indian J. Pharm. Sci.
2000, 5, 289.
[9] Chavan, A. A.; Pai, N. R. Arkivoc, 2007, xvi, 148.
[10] Demirbas, N.; Alpay-Karaoglu, S.; Demirbas, A.; Sancak, K.
Eur J Med Chem 2004, 39, 793.
[11] Kuroda, K.; Uchikurohane, T.; Tajima S.; Tsubata, K. U S
Pat., 6166054, 2000.
Anal. Calcd for C16H12N4O3SSe: C, 45.83; H, 2.88; N, 13.36.
Found: C, 45.86; H, 2.80; N, 13.29%.
[12] Fujii, K.; Hatano, K.; Yoshida, Y. Jpn. Kokai Tokai Tokkyo
Koho, 335570(2001); Chem Abstr., 136, 20074, 2001.
[13] Dong, W. L.; Liu, Z. X.; Liu, X. H.; Li, Z. M.; Zhao, W. G.;
Eur J Med Chem, 2010, 45, 6127.
Acknowledgment. The authors thank DST, New Delhi for
assistance under the IRHPA program for the NMR facility.
[14] Mandour, A. H.; EI-Shihi, T. H.; Abdel-Latif, N. A.;
EI-Bazza, Z. E. Phosphorus Sulfur Silicon Relat Elem. 1996,
113, 155.
[15] Karnik, A. V.; Kulkarni, A. M.; Malviya, N. J.; Mourya, B. R.;
Jadhav, B. L. Eur J Med Chem 2008, 43, 2615.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet