Microwave-enhanced reactions of 4-amino-5-merecapto-1,2,4-triazoles with benzoyl chloride and aromatic aldehydes

Article abstract of DOI:10.1080/00397910802136649

The microwave-enhanced reactions of 4-amino-5-mercapto-3-substituent-1,2,4- triazoles with benzoyl chloride or arylaldehydes under solvent-free conditions without catalyst were studied. 3-Substituded-6-phenyl-1,2,4-triazolo[3,4-b]-1,3, 4-thiadiazoles were

Full text of DOI:10.1080/00397910802136649

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Microwave-Enhanced Reactions
of 4-Amino-5-merecapto-1,2,4-
triazoles with Benzoyl Chloride
and Aromatic Aldehydes
Yinjuan Bai a b , Guifang Zhao a , Chunyuan Li b
Shuixia Zhao b & Zhen Shi b
,
a College of Life Science, Northwest University,
Xi'an, China
b Department of Chemistry, Northwest University,
Xi'an, China
Published online: 12 Sep 2008.
To cite this article: Yinjuan Bai , Guifang Zhao , Chunyuan Li , Shuixia Zhao & Zhen
Shi (2008) Microwave-Enhanced Reactions of 4-Amino-5-merecapto-1,2,4-triazoles
with Benzoyl Chloride and Aromatic Aldehydes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:19,
3311-3319, DOI: 10.1080/00397910802136649
To link to this article: http://dx.doi.org/10.1080/00397910802136649
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Synthetic Communications1, 38: 3311–3319, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802136649
Microwave-Enhanced Reactions of
4-Amino-5-merecapto-1,2,4-triazoles with
Benzoyl Chloride and Aromatic Aldehydes
Yinjuan Bai,1,2 Guifang Zhao,1 Chunyuan Li,2
Shuixia Zhao,2 and Zhen Shi2
1College of Life Science, Northwest University, Xi’an, China
2Department of Chemistry, Northwest University, Xi’an, China
Abstract: The microwave-enhanced reactions of 4-amino-5-mercapto-3-
substituent-1,2,4-triazoles with benzoyl chloride or arylaldehydes under
solvent-free conditions without catalyst were studied. 3-Substituded-6-phenyl-
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles were easily prepared by the reactions of
4-amino-5-merecapto-3-substituded-1,2,4-triazoles with benzoyl chloride.
4-Arylideneamino-5-mercapto-3-substituted-1,2,4-triazoles were obtained by
the condensation of 4-amino-5-mercapto-3-substituent-1,2,4-triazoles with aryl-
aldehydes. This method possessed such advantages as short reaction time,
environmentally benign procedures, easy purification, and high yield.
Keywords: 4-Arylideneamino-5-mercapto-3-substituted-4H-1,2,4-triazoles, micro-
wave irradiation, solvent free, 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles, uncatalyzed
INTRODUCTION
1,2,4-Triazole derivatives are among the most biologically active classes
of compounds, processing diverse types of biological properties such as
antimicrobial,[1] antibacterial,[2] anti-inflammatory,[3] antihypertensive,[4]
antitubercular,[5] and antiviral[6] activities. Since 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles were first made by Kanaoka[7] in 1956, a large number
of compounds with this kind of carbon skeleton have been prepared.
They combine the properties of triazoles and thiadiazoles and possess a
Received January 2, 2008.
Address correspondence to Yinjuan Bai, College of Life Science, Northwest
University, Xi’an 710069, China. E-mail: baiyinjuan@sina.com.cn
3311

3312
Y. Bai et al.
Scheme 1. Reactions of 4-amino-5-merecapto-1,2,4- triazoles with benzoyl chlo-
ride and aromatic aldehydes: 2a–g: R ¼ CH3 (2a); CH3CH2 (2b); CH3CH2CH2
(2c); PhCH2 (2d); Ph (2e); 4-ClPh (2f); 3,4,5-triMeO (2g); 3a–i: R0 ¼ 4-N(CH3)2-
Ph: R: H (3a), CH3 (3b), CH3CH2 (3c), CH3CH2CH2 (3d), R ¼ CH3CH2: R0:
2-Cl-Ph (3e), Ph (3f), 4-NO2-Ph (3g), 2-OH-Ph (3h), 4-Cl-Ph (3i).
wide spectrum of biological properties.[8] Many Schiff bases carrying a
1,2,4-triazole group not only have kept the original biological activities
but also are good ligands[9,10] and organic synthetic intermediates.[11,12]
Both of these kinds of compounds can be synthesized from 4-amino-5-
mercapto-1,2,4-triazoles 1. Condensation of the triazoles 1 with aromatic
acids or aromatic acyl chloride produces a series of 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles 2,[13] whereas condensation with aromatic aldehydes
affords a series of Schiff bases, 3-subsituted-5-mercapto-4-arylmethy-
lene-1,2,4-triazoles 3, or 5,6-dihydro analogs of 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles.[14] By the conventional heating method, the conden-
sation reaction of 4-amino-5-mercapto-1,2,4-triazoles 1 with benzoyl
chloride and aromatic aldehydes needs a large volume of organic
solvents, acid catalysts, and a long reaction time.
Microwave-assisted reactions without solvents have attracted
much interest because of the simplicity in operation, greater selectivity,
and rapid synthesis of a variety of heterocyclic compounds.[15,16] This
gave a great impetus to the search for a new technique of preparing
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 3-subsituted-5-mercapto-
4-arylmethylene-1,2,4-triazoles. Here, we present the results of 4-amino-
5-mercapto-1,2,4-triazoles reacted with benzoyl chloride and aromatic
aldehydes, giving corresponding 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole
and
3-subsituted-5-mercapto-4-arylmethylene-1,2,4-triazoles
under
microwave-enhanced conditions without solvents and catalysts. The
synthetic route is shown in Scheme 1.
EXPERIMENTAL
Melting points were measured on an X-4 digital melting-point apparatus
and are uncorrected. A Midea Microwave oven PJ17F-F(Q) was used.
IR spectra were obtained in KBr discs on a Brucker Equinox-55

4-Amino-5-merecapto-1,2,4-triazoles
3313
spectrophotometer. 1H NMR spectra were recorded on a Varian spectro-
photometer (400 MHz) in CDCl3 using TMS as an internal standard.
Mass spectra (MS) were recorded on a HP5973 GC-MS mass spectro-
photometer. 4-Amino-5-merecapto-3-substituted-1,2,4-triazoles was pre-
pared according to the literature;[17] other chemicals were purchased
and used without any further purification.
Synthesis of 3-Substituded-6-phenyl-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles
Benzoyl chloride (2.5 mmol) and 4-amino-5-mercapto-3-substituent-
1,2,4-triazoles 1 (2 mmol) were mixed in a beaker covered with a watch
glass. The beaker was placed in a microwave oven and irradiated at
385 W for 7 min. When it was cold, 10% NaHCO3 was added until
pH was 8. The precipitate was filtered, washed with water, and dried.
The impure products were obtained and recrystallized from ethanol.
The results are shown in Table 1.
Synthesis of 4-Arylideneamino-5-mercapto-3-substituted-1,2,4-triazoles
Arylaldehyde (2 mmol) and 4-amino-5-mercapto-3-substituent-1,2,4-tri-
azoles 1 (2 mmol) were mixed in a beaker covered with a watch glass.
Table 1. Reaction time and yields of the products
Power Time
Compound (W) (min) Appearance
Yield (%)
Mp
2a
2b
2c
2d
2e
2f
385
385
385
385
385
385
385
231
385
385
385
385
385
385
385
385
7
7
7
7
7
7
7
6
3
5
8
8
9
White solid
White solid
White solid
White solid
White solid
White solid
White solid
Light yellow solid
Light yellow solid
Light yellow solid
Light yellow solid
White solid
67
75
82
89
85
86
84
92
83
86
83
84
81
90
86
84
178–179 (176–177)[18]
122–123 (121–122)[18]
135–136
159–160 (157–159)[19]
206–208 (204–205)[13]
205–206 (205)[20]
2g
3a
3b
3c
3d
3e
3f
224–226
220–222 (222–223)[21]
216–217 (214–215)[22]
218–219 (215–217)[22]
204–206 (202–203)[23]
228–230 (225–227)[22]
163–165 (160–163)[22]
223–224 (220–222)[22]
181–183 (179–180)[22]
175–176 (172–174)[22]
White solid
3g
3h
3i
10 Yellow solid
10 White solid
8
White solid

3314
Y. Bai et al.
The beaker was placed in the microwave oven and irradiated for an
appropriate time at an appropriate power (Table 1) until the reaction
were complete as determined by thin-layer chromatography (TLC)
examination. When it was cold, water was added, and the precipitates
were separated by suction. The solid was washed with water, dried,
and recrystallized from ethanol. The results are shown in Table 1.
3-Methyl-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2a: 1H NMR
d: 7.89 (d, J ¼ 8.0 Hz, 2H), 7.61–7.53 (m, 3H), 2.80 (s, 3H); IR n: 3058,
2952, 1596, 1536, 1478, 1315, 1267, 1229, 763, 688 cmꢀ1
.
1
3-Ethyl-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2b: H NMR
d: 8.03 (d, J ¼ 8.0 Hz, 2H), 7.69–7.63 (m, 3H), 3.11 (q, J ¼ 8.4 Hz, 2H),
1.45 (t, J ¼ 8.4 Hz, 3H); IR n: 3066, 2979, 2937, 1599, 1520, 1479, 1313,
1251, 1212, 764, 685 cmꢀ1
.
3-Propyl-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2c: 1H NMR
d: 7.90 (d, J ¼ 7.6 Hz, 2H), 7.61–7.53 (m, 3H), 3.14 (t, J ¼ 7.2 Hz, 2H),
2.01–1.95 (m, 2H), 1.09 (t, J ¼ 7.2 Hz, 3H); IR n: 3065, 2964, 2935,
1599, 1515, 1470, 1316, 1246, 1199, 766, 687 cmꢀ1; MS (70 eV) m=z
(%): 244 (Mþ, 5), 229 (15), 216 (100), 121 (16), 103 (4), 84 (3.8).
3-Benzyl-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2d: 1H NMR
d: 7.87 (d, J ¼ 7.6 Hz, 2H), 7.64 (t, J ¼ 7.2 Hz, 1H), 7.57 (t, J ¼ 8.0 Hz,
2H), 7.51 (d, J ¼ 7.6 Hz, 2H,), 7.36 (t, J ¼ 8.0 Hz, 2H), 7.29 (t, J ¼ 7.6 Hz,
1H), 4.60 (s, 2H); IR n: 3037, 2915, 2848, 1598, 1517, 1492, 1469, 1267,
1163, 760, 681 cmꢀ1
.
1
3,6-Diphenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2e: H NMR d:
8.42 (d, J ¼ 8.0 Hz, 2H), 7.97 (d, J ¼ 7.6 Hz, 2H), 7.63–7.53 (m, 6H); IR
n: 3060, 1600, 1514, 1467, 1312, 1288, 768, 686 cmꢀ1
.
3-(4-Chlorophenyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole 2f:
1H NMR d: 8.39 (d, J¼ 8.0 Hz, 2H), 7.96 (d, J ¼ 7.8 Hz, 2H), 7.67–7.55
(m, 5H); IR n: 3054, 1599, 1525, 1467, 1316, 1280, 1238, 828, 766, 686 cmꢀ1
3-(3,4,5-Trimethoxylphenyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-
.
1
thiadiazole 2g: H NMR d: 7.92 (d, J ¼ 7.2 Hz, 2H), 7.72 (s, 2H), 7.64–
7.57 (m, 3H), 4.01 (s, 6H), 3.95 (s, 3H); IR n: 3067, 2937, 2835, 1591,
1528, 1477, 1306, 1127, 764, 685 cmꢀ1. MS (70 eV) m=z (%): 368 (Mþ,
100), 353 (64), 325 (12), 193 (18), 178 (32), 150 (30), 135 (24), 121 (46),
103 (18), 77 (23).
4-(N,N-Dimethylbenzylideneamino)-5-mercapto-4H-1,2,4-triazole 3a:
1H NMR d: 10.85 (s, 1H), 9.77 (s, 1H), 8.02 (s, 1H), 7.73 (d, J ¼ 8.4 Hz,
2H), 6.74 (d, J ¼ 8.4 Hz, 2H), 3.08 (s, 6H); IR n: 3454, 3100, 3047,
2823, 2766, 1613, 1591, 1534, 1300, 1184, 811 cmꢀ1
.
4-(N,N-Dimethylbenzylideneamino)-5-mercapto-3-methyl-4H-1,2,4-
1
triazole 3b: H NMR d: 10.75 (s, 1H), 9.80 (s, 1H), 7.75 (d, J ¼ 8.0 Hz,
2H), 6.75 (d, J ¼ 8.0 Hz, 2H), 3.08 (s, 6H), 2.43 (s, 3H); IR n: 3450,
3100, 3057, 2924, 2751, 1591, 1531, 1498, 1311, 1162, 815 cmꢀ1
.

4-Amino-5-merecapto-1,2,4-triazoles
3315
4-(N,N-Dimethylbenzylideneamino)-5-mercapto-3-ethyl-4H-1,2,4-
1
triazole 3c: H NMR d: 10.84 (s, 1H), 9.79 (s, 1H), 7.75 (d, J ¼ 8.8 Hz,
2H), 6.75 (d, J ¼ 8.8 Hz, 2H), 3.08 (s, 6H), 2.83 (q, J ¼ 7.2 Hz, 2H),
1.32 (t, J ¼ 7.2 Hz, 3H); IR n: 3449, 3103, 3064, 2937, 2750, 1589, 1529,
1498, 1316, 1159, 813 cmꢀ1
4-(N,N-Dimethylbenzylideneamino)-5-mercapto-3-propyl-4H-1,2,4-
.
1
triazole 3d: H NMR d: 10.48 (s, 1H), 9.83 (s, 1H), 7.76 (d, J ¼ 8.2 Hz,
2H), 6.80 (d, J ¼ 8.2 Hz, 2H), 3.08 (s, 6H), 2.76 (t, J ¼ 7.6 Hz, 2H), 1.79
(m, 2H), 1.01 (t, J ¼ 7.4 Hz, 3H); IR n: 3446, 3100, 3062, 2956, 2765,
1592, 1530, 1500, 1319, 1163, 815 cmꢀ1
.
4-(2-Chlorobenzylideneamino)-5-mercapto-3-ethyl-4H-1,2,4-triazole
3e: 1H NMR d: 11.01 (s, 1H), 10.23 (s, 1H), 8.13 (d, J ¼ 8.0 Hz, 1H), 7.48–
7.35 (m, 3H), 2.87 (q, J ¼ 6.8 Hz, 2H), 1.36 (t, J ¼ 6.8 Hz, 3H); IR n: 3453,
3101, 3065, 2936, 2774, 1585, 1502, 1463, 1282, 1102, 768 cmꢀ1
.
4-Benzylideneamino-5-mercapto-3-ethyl-4H-1,2,4-triazole 3f: 1H NMR
d: 10.42 (s, 1H), 10.33 (s, 1H), 7.87 (d, J ¼ 8.0Hz, 2H), 7.56–7.46 (m, 3H),
2.86 (q, J ¼ 7.2 Hz, 2H), 1.34 (t, J ¼ 7.2 Hz, 3H); IR n: 3483, 3097, 3058,
2938, 2783, 1604, 1575, 1498, 1290, 1102, 762 cmꢀ1
.
4-(4-Nitrobenzylideneamino)-5-mercapto-3-ethyl-4H-1,2,4-triazole 3g:
1H NMR d: 10.93 (s, 1H), 10.47 (s, 1H), 8.34 (d, J ¼ 8.8 Hz, 2H), 8.03
(d, J ¼ 8.8 Hz, 2H), 2.88 (q, J ¼ 7.6 Hz, 2H), 1.38 (t, J ¼ 7.6 Hz, 3H); IR
n: 3500, 3325, 2975, 2938, 1583, 1524, 1460 , 1345, 1278, 1103 , 849cmꢀ1
.
4-(2-Hydroxybenzylideneamino)-5-mercapto-3-ethyl-4H-1,2,4-triazole
3h: 1H NMR d: 10.49 (s, 1H), 10.30 (s, 1H), 10.23 (s, 1H), 7.49–7.43 (m, 2H),
7.10–7.00 (m, 2H), 2.82 (q, J ¼ 7.2 Hz, 2H), 1.36 (t, J ¼ 7.2 Hz, 3H); IR n:
3448, 3106, 3067, 2942, 2789, 1619, 1587, 1462, 1297, 1109, 757 cmꢀ1
.
4-(4-Chlorobenzylideneamino)-5-mercapto-3-ethyl-4H-1,2,4-triazole
1
3i: H NMR d: 10.66 (s, 1H), 10.51 (s, 1H), 7.81 (d, J ¼ 8.2 Hz, 2H),
7.47 (d, J ¼ 8.2 Hz, 2H), 2.86 (q, J ¼ 7.4 Hz, 2H), 1.36 (t, J ¼ 7.4 Hz,
3H); IR n: 3482, 3104, 3067, 2939, 2762, 1589, 1496, 1414, 1284, 1091,
819 cmꢀ1
.
RESULTS AND DISCUSSION
The reported synthetic methods for 3,6-disubstituted-1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazoles required 5–8 h of reaction time under refluxing in
phosphoryl chloride conditions. The reaction mixture needed to use
crushed ice and solid potassium carbonate or potassium hydroxide to
neutralize the excess of phosphoryl chloride, or the excess of phosphoryl
chloride was remove under reduced pressure.[23,24] The reaction time for
preparing 4-benzylideneamino-5-mercapto-3-alkyl-4H-1,2,4-triazoles
under refluxing condition was 1–4 h in ethanol, and acidic catalyst also

3316
Y. Bai et al.
was needed.[25,26] Under refluxing conditions in acetic acid, the reaction
time can be reduced.[22] The products can be precipitated from acetic
acid. However, the wasted acid needs to be treated. While under micro-
wave irradiation, the reaction required shorter times, no solvents, and
no catalysts. Purification was simple, and higher product yields make it
an environmentally friendly method.
4-Amino-5-mercapto-1,2,4-triazoles
1 are important kinds of
heterocyclic compounds. Triazole cycle has been incorporated into a wide
variety of molecules by 4-amino-5-mercapto-1,2,4-triazoles. 1,2,4-Tri-
azolo[3,4-b]-1,3,4-thiadiazoles generally be prepared from condensation
with carboxylic acid or acyl chloride, using phosphoryl chloride as
catalyst and dehydrating agent (Scheme 2). Under microwave irra-
diation, the condensation with benzoic acid was more difficult than
with benzoyl chloride, even when phosphoryl chloride was added. Subli-
mation of benzoic acid and volatilization of phosphoryl chloride
occurred badly.
The condensation of compound 1 with aromatic aldehydes afforded
a series of Schiff bases or 5,6-dihydro triazolothiadiazoles according to
different reaction conditions (Scheme 2). It was reported that compound
1 reacted with aromatic aldehydes, catalyzed by acid such as acetic acid
and H2SO4 in ethanol or refluxed in acetic acid, to give Schiff bases.
However, when it was refluxed in an aprotic solvent such as benzene,
5,6-dihydrotriazolothiadiazoles (4) were obtained.[14] These Schiff bases
Scheme 2. Conventional reactions of 4-amino-5-merecapto-1,2,4-triazoles with
aromatic carboxylic acids or acyl chloride and aromatic aldehydes.

4-Amino-5-merecapto-1,2,4-triazoles
3317
also could be converted to 2 if stirred with bromine in acetic acid.[27] It
was found that by refluxing 1 and aldehyde in ethanol, catalyzed by
hydrogen chloride, the amino group of 1 combined with the carbonyl
group of aldehydes first. The products precipitated from the solution,
and the precipitates were confirmed to be Schiff bases. With the reaction
development, the precipitates were dissolved in the solvent gradually
again. Finally, precipitates of 4 were generated, and the total reaction
time was about 8–10 h.[28] Under microwave irradiation without catalyst
and solvent, the reaction is very simple. The mercapto group does not
react with the imine group, so the products with two heterocycles are
not be obtained. There is only one kind of compound produced, the
Schiff base, 4-arylmethylene-5-mercapto-1,2,4-triazoles.
ACKNOWLEDGMENTS
We gratefully acknowledge the Special Foundation of the Education
Committee of Shaanxi Province (No. 07JK378) for support of this work.
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