Solid-phase synthesis of 4,5-disubstituted-1,2,4-triazole-3-thione derivatives based on the resin-bound acylhydrazines

Article abstract of DOI:10.1080/00397911.2010.521609

Highly efficient solid-phase synthesis of 4,5-disubstituted-1,2,4-triazole- 3-thiones under mild conditions has been developed. 4,5-Disubstituted-1,2,4- triazole-3-thione derivatives were synthesized from resin-bound acylhydrazines in several steps, provi

Full text of DOI:10.1080/00397911.2010.521609

This article was downloaded by: [York University Libraries]
On: 20 November 2014, At: 11:34
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Solid-Phase Synthesis of 4,5-
Disubstituted-1,2,4-triazole-3-thione
Derivatives Based on the Resin-Bound
Acylhydrazines
Zhanxiang Liu a , Yunrui Yi a , Jinlong Zhao a & Mingxue Tang a
a Department of Chemistry , Zhejiang University (Campus Xixi) ,
Hangzhou , China
Accepted author version posted online: 27 Jun 2011.Published
online: 14 Sep 2011.
To cite this article: Zhanxiang Liu , Yunrui Yi , Jinlong Zhao & Mingxue Tang (2012) Solid-Phase
Synthesis of 4,5-Disubstituted-1,2,4-triazole-3-thione Derivatives Based on the Resin-Bound
Acylhydrazines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:1, 55-61, DOI: 10.1080/00397911.2010.521609
To link to this article: http://dx.doi.org/10.1080/00397911.2010.521609
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 42: 55–61, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.521609
SOLID-PHASE SYNTHESIS OF
4,5-DISUBSTITUTED-1,2,4-TRIAZOLE-3-THIONE
DERIVATIVES BASED ON THE RESIN-BOUND
ACYLHYDRAZINES
Zhanxiang Liu, Yunrui Yi, Jinlong Zhao, and Mingxue Tang
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou,
China
GRAPHICAL ABSTRACT
Abstract Highly efficient solid-phase synthesis of 4,5-disubstituted-1,2,4-triazole-3-thiones
under mild conditions has been developed. 4,5-Disubstituted-1,2,4-triazole-3-thione deriva-
tives were synthesized from resin-bound acylhydrazines in several steps, providing 76–89%
overall yields and excellent purity.
Keywords Resin-bound acylhydrazine; solid-phase synthesis; 1,2,4-triazole-3-thiones
INTRODUCTION
Many natural and synthetic compounds bearing five-membered heterocyclic
rings in their structure have an extensive spectra of pharmacological activities.
Among these heterocycles, new derivatives of 1,2,4-triazole-3-thiones have potential
anticonvulsant,[1] antimicrobial,[2] and anti-inflammatory activities.[3] It is also well
established that various derivatives of 1,2,4-triazole can be used for treating
non-Hodgkin‘s lymphoma.[4]
As a result of these useful applications, chemists have been encouraged to
design new synthetic methodologies for the preparation of this medicinally impor-
tant heterocyclic building block. In the literature, several methods for the synthesis
of 1,2,4-triazole-3-thiones derivatives were described. 1,2,4-triazole-3-thiones have
been prepared from the reaction of thiosemicarbazide with acyl halides and a
Received December 18, 2009.
Address correspondence to Zhanxiang Liu, Department of Chemistry, Zhejiang University
(Campus Xixi), Hangzhou 310028, China. E-mail: liuzhanx@zju.edu.cn
55

56
Z. LIU ET AL.
subsequent cyclization of the intermediate acylthiosemicarbazides in basic media.[5,6]
They also have been prepared from the reaction of acid hydrazides and isothiocya-
nates.[3b,7–9] Formation of these compounds from the reaction of acid hydrazides
with carbon disulfide and hydrazine hydrate was also reported in the literature.[10]
The reaction of aroyl isothiocyanates with hydrazine derivatives has also led to
the formation of these types of compounds.[11,12] Thionation of 1,2,4-triazole-3-ones
is another synthetic route to these compounds.[13]
Many of the solution-phase methodologies described possess important draw-
backs such as long reaction times, poor yields, and exhaustive purification protocols.
In the process of drug development and=or lead structure optimization, it is most
welcome to use a method that allows easy access to diverse compounds. Synthetic
routes on solid support offer the opportunity for development of novel methodolo-
gies for construction of libraries of small heterocyclic compounds.[14] A few examples
of solid-phase synthesis of 3-thio-1,2,4-triazoles have been reported,[15] including
polymer-bound base 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-
diazaphosphorine on polystyrene (P-BEMP)–mediated synthesis and a Rink amide
resin–supported route. In this context, we have foreseen that the use of new solid-
phase strategies to obtain 1,2,4-triazole-3-thiones could overcome some of the defi-
ciencies observed in previous synthetic protocols. We present a novel solid-phase
procedure that can be conducted in parallel form.
Substituted 1,2,4-triazole-3-thiones have been successfully prepared by tra-
ditional synthesis via acylhydrazine. To the best of our knowledge, solid-phase syn-
thesis of 1,2,4-triazole-3-thione derivatives has not been reported until now. In
continuation of our particular interest in solid-phase synthesis of heterocycles from
resin-bound acylhydride,[16] herein we describe a new method for solid-phase
synthesis of 1,2,4-triazole-3-thione derivatives from resin-bound acylhydrazines.
Scheme 1 shows the synthetic route of 1,2,4-triazole-3-thione derivatives. We
have prepared resin-bound acylhydrazine 1 from the Merrifield resin according to
our previously reported method.[15] The acylhydrazine resin 1 was reacted
with excess aryl=alkyl isothiocyanates in EtOH to give the corresponding
resin-bound thiosemicarbazides 2. After alkaline ring closures of the corresponding
Scheme 1. Reagents and conditions: (a) R1NCS, EtOH, reflux, 6 h; (b) 5% NaOH, reflux, 8 h; (c) (i) NaOH
in EtOH, reflux, 2 h; (ii) R2X, reflux, 4 h; (d) TFA=CH2Cl2(1=6), rt.

4,5-DISUBSTITUTED-1,2,4-TRIAZOLE-3-THIONES DERIVATIVES
57
Table 1. Solid-phase synthesis of 1,2,4-triazole-3-thione derivatives
Entry
Product
R1
R2
Yielda (%)
Purityb (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
Ph
C6H5CH2
H
89
76
88
86
81
84
86
82
84
92
88
90
95
86
90
92
89
90
H
4-CH3-C6H4
4-CH3O-C6H4
H
H
Ph
Ph
Ph
Ph
Ph
n-C4H9
CH3
5g
5h
5i
4-NO2-C6H4CH2
Allyl
C6H5CH2
aYield of crude product based on the loading of acylhydrazine resin 1.
bDetermined by HPLC analysis (area %).
aroylthiosemicarbazides resin 2, the resin 3 was obtained. Further reaction with
NaOH and electrophilic reagents (R2X) gave the corresponding resin 4. The desired
1,2,4-triazole-3-thiones derivatives 5 were released at trifluoroacetic acid=dichloro-
methane (TFA=DCM) cleavage for 4 h in good yield and purity and were
characterized by spectroscopic methods. The results are summarized in Table 1.
The successful formation of resin 2 was supported by a comparative FT-IR
(Fourier transform–infrared) study and a sample of resin 2 (KBr pellets). The
N-H stretch at 3429, 3318 cmꢀ1 shifted to 3298 and 3247 cmꢀ1, and a strong C O
=
stretch appeared at 1676 cmꢀ1 for aroylsemicarbazide resin 2, which is different from
the C O signal of acylhydrazine resin at 1630 cmꢀ1. When resin 2 was converted into
=
resin 3, a strong carbonyl peak at 1676 cmꢀ1 disappeared, and the signal of N-H
shifted to 3470 cmꢀ1. The resin 3 was treated with the base (NaOH) and then reacted
with a variety of electrophilic reagents, such as alkyl halides, allyl bromide, and ben-
zyl halides. When the resin 4 was cleaved by TFA=DCM, product 5 was obtained in
good yields and high purity.
Using this methodology, we have synthesized a representative set of
1,2,4-triazole-3-thione derivatives 5 (Table 1) in 76–89% overall yield, indicating a
good yield for each step of the reaction.
In summary, we have studied and developed a new strategy for the preparation
of 4,5-disubstituted-1,2,4-triazole-3-thiones on solid support. The use of resin-bound
acylhydrazines in the reaction benefits the solid-phase synthetic route because it not
only provides a short synthetic route to the desired products but also its chemical
versatility adds to the diversity of the library. The 1,2,4-triazole-3-thione derivatives
were synthesized in several steps, providing 76–89% overall yields and excellent
purity. This synthetic methodology is ideally suitable for the high-throughput syn-
thesis of drug libraries for potential drug discovery because all the reactions were
carried out under mild conditions. Further work is in progress on the solid-phase
synthesis of heterocyclic compounds via the resin-bound acylhydrazines.
EXPERIMENTAL
Starting materials were obtained from commercial suppliers and used without
further purification. Solvents were distilled before use: CH2Cl2 was distilled from

58
Z. LIU ET AL.
CaH2. Merrifield resin (100–200 mesh, cross-linked with 1% divinylbenzene,
loadingꢁC1.95 mmol=g Cl) was purchased from a commercial source (Nankai
University).
Acylhydrazine resin 1 was prepared from the Merrifield resin according to our
previously reported method.[15] 1H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were recorded on a Bruker Avance (400-MHz) spectrometer, using CDCl3 as the
solvent and tetramethylsilane (TMS) as internal standard. MS spectra (EI, 70 eV)
were recorded on a HP5989B mass spectrometer. IR spectra were recorded on a
Bruck Vector 22 spectrophotometer. Elemental analyses were performed on a Flash
EA1112 instrument. High-performance liquid chromatography (HPLC) was per-
formed on an Agilent 1100 (column, Eclipse XDB-C18 5 mm, 4.6 ꢂ 150 mm; mobile
phase, MeOH=H2O, 80=20 (v=v); flow rate, 1.0 mL=min; detector, UV 254 nm). The
samples were further purified by thin-layer chromatography (TLC) for 13C NMR
and microanalyses.
General Procedure for Synthesis of 1,2,4-Triazole-3-thiones
Phenyl isothiocyanate (0.324 g, 2.4 mmol) was added to the mixture of the acyl-
hydrazine resin 1 (0.5 g, loadingꢁC1.59 mmol=g, based on N microanalysis) in absol-
ute EtOH (5 mL). Then the mixture was stirred and refluxed for 6 h. The resin was
filtered and washed with EtOH (5 mL ꢂ 3) and CH2Cl2 (5 mL ꢂ 3) to remove
contaminated species and then dried to afford resin 2.
Resin 2 was added to 2 mL of 5% NaOH solution. The mixture was heated to
reflux for 8 h. Then it was filtered, and the resin was washed with 10% HCl
(5 mL ꢂ 3), H2O (10 mL ꢂ 3), EtOH (5 mL ꢂ 3), and CH2Cl2 (5 mL ꢂ 3) and dried
to affored resin 3.
To the solution of NaOH (2 mmol, 80 mg) in 5 mL EtOH, resin 3a was added.
The mixture was heated under reflux for 2 h, n-BuBr (2 mmol, 0.272 g) and was
added, and the reaction mixture was filtered after reflux for another 4 h. The resin
was washed with H2O (10 mL ꢂ 3), EtOH (5 mL ꢂ 3), and CH2Cl2 (5 mL ꢂ 3) and
dried to afford the resin 4.
The resin 4e was well swollen in 3 mL CH2Cl2, and then 0.5 mL TFA was
added. The mixture was stirred at room temperature for 4 h and then filtered. The
resin was washed completely with EtOH (5 mL ꢂ 3) and acetone (5 mL ꢂ 3). The fil-
trate was combined to afford the crude product 5 by evaporation.
Compounds 5a–5d were obtained directly from resin 3, which was cleaved by
TFA=CH2Cl2 using a similar procedure.
1
All compounds gave satisfactory H NMR, IR, and MS spectra.
Selected Data
2,4-Dihydro-5-(4-hydroxyphenyl)-4-phenyl-3H-1,2,4-triazole-3-thione (5a).
1
Mp 252–256 ꢁC; H NMR 6.65 (m, 2H), 7.07–7.45 (m, 7H), 9.95 (s, 1H) 13.95 (s,
1H); 13C NMR 115.60, 116.59, 126.95, 129.02, 129.56, 130.06, 135.06, 151.02,
159.45, 168.55; MS (EI, 70 eV): m=z (%) 269 (100), 216 (16), 149 (9.8); IR 3421,
3243, 3145, 2940, 1610, 1594, 1513, 1498, 1399, 1330, 1315, 1281, 1246, 1176, 843,

4,5-DISUBSTITUTED-1,2,4-TRIAZOLE-3-THIONES DERIVATIVES
59
757, 694 cmꢀ1. Calcd. for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60; O, 5.94; S, 11.91.
Found: C, 62.67; H, 4.38; N, 15.88.
2,4-Dihydro-5-(4-hydroxyphenyl)-4-benzyl-3H-1,2,4-Triazole-3 (2H)-thione
1
(5b). Mp 303 ꢁC; H NMR 5.32 (s, 2H), 6.82 (d, 2H, J ¼ 8.2 Hz), 7.04 (d, 2H,
J ¼ 7.0 Hz), 7.25 (m, 3H), 7.34 (d, 2H, J ¼ 8.2 Hz), 10.11 (s, 1H), 13.98 (s, 1H);
13C NMR 47.07, 116.02, 116.88, 126.95, 127.86, 128.93, 130.36, 136.31, 152.06,
159.88, 168.19; MS (EI, 70 eV): m=z (%) 283 (6.2), 254 (13), 121 (100); IR 3366,
3133, 2958, 1611, 1515, 1439, 1401, 1275, 1208, 1176, 1140, 843, 728 cmꢀ1. Calcd.
for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83; O, 5.65; S, 11.32. Found: C, 63.89;
H, 4.68; N, 14.97.
2,4-Dihydro-5-(4-hydroxyphenyl)-4-(4-methylphenyl)-3H-1,2,4-triazole-3
1
(2H)-thione (5c). Mp 234–236 ꢁC. H NMR 2.34 (s, 3H), 6.66 (m, 2H), 7.10–7.26
(m, 4H), 7.71 (m, 2H), 9.94 (s, 1H), 13.92 (s, 1H); 13C NMR 21.11, 115.79,
116.72, 126.74, 130.26, 132.00, 132.39, 139.49, 151.40, 159.44, 168.56; MS (EI,
70 eV): m=z (%) 283 (Mþ, 100), 282 (74), 269 (23); IR 3269, 3113, 1611, 1561,
1511, 1478, 1403, 1326, 1274, 1238, 1174, 1069, 972, 846, 818 cmꢀ1. Calcd. for
C15H13N3OS: C, 63.58; H, 4.62; N, 14.83; O, 5.65; S, 11.32. Found: C, 63.71; H,
4.44; N, 14.69.
2,4-Dihydro-5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-3H-1,2,4-triazole-3
1
(2H)-thione (5d). Mp 256–258 ꢁC; H NMR 3.79 (s, 3H), 6.68 (d, 2H, J ¼ 8.4 Hz),
7.01 (d, 2H, J ¼ 8.4 Hz), 7.11 (d, 2H, J ¼ 8.0 Hz), 7.23 (d, 2H, J ¼ 8.0 Hz), 9.97 (s,
1H), 13.93 (s, 1H); 13C NMR 59.90, 118.93, 119.83, 120.95, 131.80, 134.29,
134.42, 155.41, 163.65, 166.82, 172.98; IR 3321, 3147, 2943, 1612, 1593, 1514,
1496, 1398, 1329, 1315, 1281, 1246, 1176, 843, 757, 694 cmꢀ1. MS (EI, 70 eV): m=z
(%) ꢁ 299 (Mþ, 13), 180 (100), 121 (40). Calcd for C15H13N3O2S: C, 60.18; H, 4.38;
N, 14.04; O, 10.69; S, 10.71. Found: C, 60.47; H, 4.49; N, 13.88.
4-[5-(Butylthio)-4-phenyl-4H-1,2,4-triazol-3-yl] phenol (5e). Mp 254–256 ꢁC.
1H NMR 0.80 (t, 3H, J ¼ 7.2 Hz), 1.27 (m, 2H), 1.58 (m, 2H), 3.05 (t, 2H,
J ¼ 6.8 Hz), 6.63 (d, 2H, J ¼ 8.0 Hz), 7.12 (d, 2H, J ¼ 8.0 Hz), 7.31 (m, 2H), 7.49
(m, 3H), 9.88 (s, 1H); 13C NMR 17.90, 26.62, 35.63, 36.37, 119.85, 122.19, 123.94,
132.30, 134.01, 134.41, 138.73, 151.05, 159.06, 163.71; MS (EI, 70 eV): m=z (%)
325 (Mþ, 17.43), 278 (100), 268 (97), 121 (37), 77 (48), 91 (27); IR 3427, 2925,
2683, 1609, 1477, 1438, 1385, 1319, 1286, 1256 cmꢀ1. Calcd. for C18H19N3OS: C,
66.43; H, 5.88; N, 12.91; O, 4.92; S, 9.85. Found: C, 66.72; H, 5.67; N, 13.17.
4-[5-(Methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl] phenol (5f). Mp 242–
1
244 ꢁC; H NMR 2.58 (s, 3H), 6.68 (d, 2H, J ¼ 7.8 Hz), 7.16 (d, 2H, J ¼ 7.8 Hz),
7.37 (m, 2H), 7.54 (m, 3H), 9.91 (s, 1H); 13C NMR 18.95, 119.82, 121.64, 132.16,
133.99, 134.46, 138.52, 156.60, 159.04, 163.20; MS (EI, 70 eV): m=z (%) 283 (Mþ,
100), 267 (9.5), 250 (28), 174 (27), 121 (24), 91 (82), 77 (44); IR 3423, 2923, 2684,
1609, 1477, 1438, 1384, 1319, 1283, 1256, 1208, 1138, 836, 804, 771, 698 cmꢀ1. Calcd.
for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83; O, 5.65; S, 11.32. Found: C, 63.42; H,
4.81; N, 15.04.
4-[5-(4-Nitrobenzylthio)-4-phenyl-4H-1,2,4-triazol-3-yl] phenol (5g). Mp
272–274 ꢁC. 1H NMR 4.52 (s, 2H), 6.69 (d, 2H, J ¼ 8.4 Hz), 7.15 (d, 2H, J ¼ 8.8 Hz),

60
Z. LIU ET AL.
7.30 (d, 2H, J ¼ 8.0 Hz), 7.537 (m, 3H), 7.66 (d, 2H, J ¼ 8.8 Hz), 8.18 (d, 2H,
J ¼ 8.4 Hz), 9.94 (s, 1H); 13C NMR 67.14, 119.68, 121.48, 127.82, 132.02, 133.78,
134.22, 134.27, 134.58, 138.29, 150.04, 151.06, 154.45, 159.09, 163.16; MS (EI,
70 eV): m=z (%) 404 (Mþ, 57), 295 (43), 268 (29), 252 (37), 212 (48), 196 (36), 121
(50), 91 (49), 77 (100); IR 3426, 2924, 2683, 1609, 1536, 1477, 1438, 1352, 1319,
1256, 1208, 1138, 836, 804, 771, 698 cmꢀ1. Calcd. for C21H16N4O3S: C, 62.36; H,
3.99; N, 13.85; O, 11.87; S, 7.93. Found: C, 62.45; H, 4.13; N, 13.76.
4-[5-(Allylthio)-4-phenyl-4H-1,2,4-triazol-3-yl] phenol (5h). Mp 206–208 ꢁC;
1H NMR 3.75 (d, 2H, J ¼ 6.9 Hz), 5.08 (d, 1H, J ¼ 10 Hz), 5.20 (d, 1H, J ¼ 16.8 Hz),
5.86 (m, 1H), 6.69 (d, 2H, J ¼ 8.4 Hz), 7.15 (d, 2H, J ¼ 8.4 Hz), 7.35 (m, 2H), 7.57 (m,
3H); 13C NMR 36.87, 118.23, 119.83, 121.68, 132.14, 133.13, 133.88, 134.43, 138.52,
156.58, 159.04, 163.32; MS (EI, 70 eV): m=z (%) 309 (77), 294 (100), 196 (44), 157
(35), 121 (39), 77 (86); IR 3426, 2984, 2808, 1608, 1543, 1479, 1439, 1382, 1281,
1256, 1185, 1128, 819, 835, 770, 732, 696 cmꢀ1. Calcd. for C17H15N3OS: C, 66.00;
H, 4.89; N, 13.58; O, 5.17; S, 10.36. Found: C, 65.86; H, 4.68; N, 13.42.
4-[5-(Benzylthio)-4-phenyl-4H-1,2,4-triazol-3-yl] phenol (5i). Mp 258–260 ꢁC;
1H NMR 4.52 (s, 2H), 6.63 (d, 2H, J ¼ 8.0 Hz), 6.78 (m, 3H), 6.90 (d, 2H,
J ¼ 8.0 Hz), 7.14–7.24 (m, 2H), 7.35 (m, 3H), 7.40 (m, 2H), 9.98 (s, 1H); MS (EI,
70 eV): m=z (%) 359 (45), 343 (11), 250 (48), 207 (48), 196 (20), 167 (29), 91 (100),
77 (49); IR 3423, 2924, 2683, 1609, 1477, 1438, 1319, 1268, 1208, 1136, 836, 804,
769, 692 cmꢀ1. Calcd. for C21H17N3OS: C, 70.17; H, 4.77; N, 11.69; O, 4.45; S,
8.92. Found: C, 70.25; H, 4.53; N, 11.83.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (Project
No. 20802068, J0830413), Zhejiang Provincial Natural Science Foundation of China
(Grant No. Y 4110100), and Science and Technology Department of Zhejiang Prov-
ince (2007C2116) for financial support.
REFERENCES
1. (a) Kane, J. M.; Staeger, M. A.; Dalton, C. R.; Miller, F. P.; Dudley, M. W.; Ogden, A.
M. L.; Kehne, J. H.; Ketteler, H. J.; McCloskey, T. C.; Senyah, Y.; Chmielewski, P. A.;
Miller, J. A. 5-Aryl-3-(alkylthio)-4H-1,2,4-triazoles as selective antagonists of strychnine-
induced convulsions and potential antispastic agents. J. Med. Chem. 1994, 37, 125–132;
(b) Hosam, S. Synthesis of some pyridyloxymethyloxadiazoles, thiadiazoles and triazoles
of expected pharmacological activity. Indian J. Chem. 1996, 35B, 980–984.
2. Hui, X. P.; Chu, C. H.; Zhang, Z. Y.; Wang, Q.; Zhang, Q. Synthesis and antibacterial
activities of 1,3,4-oxadiazole derivatives containing 5-methylisoxazole moiety. Indian J.
Chem. 2002, 41B, 2176–2179.
ꢀ
3. (a) Labanauskas, L.; Udrenaite, E.; Gaidelis, P.; Brukstus, A. Synthesis of 5-(2-,3- and
4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory
activity. Farmaco. 2004, 59, 255–259; (b) Maxwell, J. R.; Wasdahl, D. A.; Wolfson, A.
C.; Stenberg, V. I. Synthesis of 5-aryl-2H-tetrazoles, 5-aryl-2H-tetrazole-2-acetic acids,
and [(4-phenyl-5-aryl-4H-1,2,4-triazol-3-yl)thio]acetic acids as possible superoxide
scavengers and antiinflammatory agents. J. Med. Chem. 1984, 27, 1565–1570.

4,5-DISUBSTITUTED-1,2,4-TRIAZOLE-3-THIONES DERIVATIVES
61
4. Foley, K. Triazole derivatives and their preparation and method for treating
non-Hodgkin‘s lymphoma. US Patent 2006-808341, 2007.
5. Mullican, M. D.; Wilson, M. W.; Conner, D. T.; Kostlan, C. R.; Schrier, D. J.; Dyer, R.
D. Design of 5-(3,5-di-tert-butyl-4- hydroxyphenyl)-l,3,4-thiadiazoles-1,3,4-oxadiazoles,
and-1,2,4-triazoles as orally active, nonulcerogenic anti-inflammatory agents. J. Med.
Chem. 1993, 36, 1090–1099.
6. Kane, J. M.; Dudley, M. W.; Sorensen, S. M.; Miller, F. P. 2,4-Dihydro-3H-
1,2,4-triazole-3-thiones as potential antidepressant agents. J. Med. Chem. 1988, 31,
1253–1256.
7. Gulerman, N. N.; Dogan, H. N.; Rollas, S.; Johansson, C.; Celik, C. Synthesis and struc-
ture elucidation of some new thioether derivatives of 1,2,4-triazoline-3-thiones and their
antimicrobial activities. Farmaco. 2001, 56, 953–958.
8. Foks, H. Synthesis and tuberculostatic activity of some 2-piperazinmethylene derivatives
1,2,4-triazole-3-thiones. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 537–543.
9. Rigo, B.; Couturier, D. Studies on pyrrolidinones: Synthesis of 5-(5-oxo-
2-pyrrolidinyl)-1,2,4-triazole-3-thione derivatives. J. Heterocycl. Chem. 1989, 26,
1723–1727.
10. Talawar, M. B.; Bennur, S. C.; Kankanwadi, S. K.; Patil, P. A. Anti-inflammatory activity
of some new 3-substituted-4-amino-5-mercapto-4(H)-1,2,4-triazoles. Indian J. Pharm. Sci.
1995, 57, 194–197.
11. Hoggarth, E. Compounds related to thiosemicarbazide, I: 3-Phenyl-1,2,4-triazole deriva-
tives. J. Chem. Soc. 1949, 1160–1163.
12. Durant, G. J. The reaction of benzoyl isothiocyanate with hydrazine derivatives, I:
Reaction with some alkyl hydrazines. J. Chem. Soc. C 1967, 92–94.
13. Kane, J. M. The bis(tricyclohexylstannyl) sulfide thionation of 3H-1,2,4-triazol-3-ones.
Synthesis 1987, 912–913.
14. (a) Seneci, P. Solid-Phase Synthesis and Combinatorial Chemistry; Wiley Interscience: New
York, 2000; (b) Dorwald, F. Z. Organic Synthesis on Solid Phase; Wiley-VCH: Weinheim,
2000.
15. (a) Wilson, M. W.; Hernandez, A. S.; Calvet, A. P.; Hodges, J. C. Solid-supported synth-
eses of 3-thio-1,2,4-triazoles. Mol. Divers. 1998, 3, 95–112; (b) Graybill, T. L.; Thomas, S.;
Wang, M. A. A convenient ‘catch, cyclize, and release’ preparation of 3-thio-1,2,4--
triazoles mediated by polymer-bound BEMP. Tetrahedron Lett. 2002, 43, 5305–5309.
16. (a) Liu, Z. X.; Zhao, J. L.; Huang, X. Solid-phase synthesis of 1,3,4-oxadiazoline-5-thione
derivatives from resin-bound acylhydrazines. Bioorg. Med. Chem. Lett. 2006, 16,
1828–1830; (b) Liu, Z. X.; Mu, Y. Y.; Lin, J.; Chen, Y. Y. Traceless solid-phase synthesis
of 1,2,3-thiadiazole derivatives from resin-bound acylhydrazine. Synth. Commun. 2008,
38, 4407–4414; (c) Liu, Z. X.; Mu, Y. Y.; Song, Z. S. Solid-phase synthesis of 4,5-disub-
stituted 1,2,4-triazol-3-one derivatives from resin-bound acylhydrazines. J. Chem. Res.,
2008, 216–217.