Microwave-assisted solvent-free synthesis of 3-alkyl-6-aryl[1,2,4] triazolo[3,4-b][1,3,4]thiadiazines

Article abstract of DOI:10.3184/030823407X198203

An efficient microwave-assisted solvent-free synthesis of 3-alkyl-6-aryl[1,2,4]triazolo[3,4-b)][1,3,4]thiadiazine derivatives is reported. Twelve derivatives have been synthesised in excellent yields in short reaction times.

Full text of DOI:10.3184/030823407X198203

JOURNAL OF CHEMICAL RESEARCH 2007
FEBRUARY, 107–108
RESEARCH PAPER 107
Microwave-assisted solvent-free synthesis of 3-alkyl-6-aryl[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazines
Xin-Ping Hui*, Ren-Lin Wang and Zi-Yi Zhang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730 000, P.R. China
An efficient microwave-assisted solvent-free synthesis of 3-alkyl-6-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
derivatives is reported. Twelve derivatives have been synthesised in excellent yields in short reaction times.
Keywords: microwave heating, solvent-free synthesis, fused 1,2,4-triazoles, fused 1,3,4-thiadiazines
NH
N
[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine derivatives have
received extensive attention in recent years because of
their diverse biological activities, including analgesic,
anti-inflammatory, antibacterial and antiviral activities.1-8
Although the condensation of 4-amino-5-substituted-1,2,4-
triazol-3(2H)-thiones with 2-halogencarbonyl compounds has
been carried out in solution, this cyclisation affords different
products under various reaction conditions. There are also
some problems associated with above synthesis, such as
severe conditions, long time and low to moderate yields for
the reaction, difficulty in separating the products from the
system, and serious environmental pollution.
D
reflux
1
(H NNH) C=S
+
R CO H
2
1
2
2
S
R
N
NH
2
1
R
= (a) n-C H , (b) n-C H , (c) n-C H
3
7
4
9
5
11
2a-c
S
O
N
1
2a-c
N
BrCH
2
N
MWI
solid
state
N
R
2
R
2
R
In recent years, microwave-induced rate acceleration
technology has become a powerful tool in organic synthesis9-12
in view of the mild, clean, and convenient methodology and
the enhanced selectivity of the reaction processes in
comparison to conventional solution reactions, and the
associated ease of manipulation. Solvent-free synthesis has
many advantages including high efficiency and selectivity,
easy separation and purification and environmental
acceptability.13 One particularly attractive field is the coupling
of microwave irradiation with solvent-free synthesis, since
it reduces the risks of hazards by pressure build-up in the
reaction vessel, and scale-up is made easier. This method
has been widely used in organic synthesis.14 However, the
microwave-assisted synthesis of [1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine derivatives under solvent-free conditions has not
so far been reported. We now report the efficient condensation
reaction of 5-alkyl-4-amino-1,2,4-triazole-3(2H)-thiones with
2-bromo-4′-substituted acetophenones.
3a-d
4a-l
2
R
= (a) H, (b) CH , (c) Cl, (d) Br
3
Scheme 1
Experimental
The melting points were determined on an X-4 microscopic melting
point apparatus. Elemental analyses were carried out using an
Elementar Vario EL analyser. IR spectra were obtained in KBr discs
on a 5-DX spectrometer. 1H NMR spectra were recorded in DMSO-d6
on a Mercury-Plus 300 instrument with TMS as an internal standard.
MS were measured on a VG-7070E spectrometer (EI at 70 eV).
The microwave oven was a domestic model (LG WD700).
Thiocarbohydrazide16 (1) and 5-alkyl-4-amino-1,2,4-triazol-3(2H)-
thiones17 (2a–c) were prepared according to the literature methods.
Thiocarbohydrazide (1), m.p. 169–171°C (lit.16 m.p. 171°C).
4-Amino-5-propyl-1,2,4-triazol-3(2H)-thione (2a), yield 50%, m.p.
104–105°C (lit.17 m.p. 103–104°C). 4-Amino-5-butyl-1,2,4-triazol-
3(2H)-thione (2b), yield 62%, m.p. 96–97°C (lit.17 m.p. 95–97°C).
4-Amino-5-pentyl-1,2,4-triazol-3(2H)-thione (2c), yield 64%, m.p.
108–109°C (lit.17 m.p. 106–108°C).
The target compounds 4a–l were prepared by irradiating
a mixture of 5-alkyl-4-amino-1,2,4-triazole-3(2H)-thiones
(2a–c) and 2-bromo-4′-substituted acetophenones (3a–d) in a
microwave oven under solvent-free conditions. The results are
presented in the Experimental section. From this it is evident
that the reactions proceed well; reaction times are short and
yields are high.
3-Alkyl-6-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (4a–l): general
procedure
Therequisite5-alkyl-4-amino-1,2,4-triazol-3(2H)-thione(2)(5mmol)
and 2-bromo-4′-substituted acetophenone (3) (5 mmol) were mixed
and heated under microwave irradiation at 750W for 1 minute.
The reaction mixture was cooled and ground with water (50 ml).
The solid product was filtered off, washed with water, and
recrystallised from ethanol.
6-Phenyl-3-propyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4a),
Yellow powder (yield 87%), m.p. 152–153°C (lit.18 m.p. 155°C).
6-(4-Methylphenyl)-3-propyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4b): Yellow powder (yield 84%), m.p. 174–176°C (lit.15
m.p. 170°C). IR: 3036 (w, ArH), 2960, 2931 (w, CH3, CH2), 1610
(m, C=N), 1533 cm-1 (m, C–N). 1H NMR: δ 1.06 (t, J = 7.2 Hz, 3H,
CH3CH2CH2), 1.61–2.08 (m, 2H, CH3CH2CH2), 2.46 (s, 3H, CH3),
2.93 (t, J = 7.2 Hz, 2H, CH3CH2CH2), 3.96 (s, 2H, SCH2), 7.46 (d,
J = 8.8 Hz, 2H, ArH), 7.78 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 272
(M+, 20), 244 (100), 204 (11), 155 (12), 140 (17), 127 (87), 117 (17),
91 (33).
The products were characterised by their elemental analysis
and spectral data. The IR spectra showed three characteristic
absorption bands at 1583–1609 cm-1 (C=N), 1224–1266
cm-1 (N–N=C) and 658–691 cm-1 (C–S–C), respectively.
1
In the H NMR spectra, SCH2 protons exhibited signals at
around δ 4 ppm. The signal of SCH2 accorded with those of
the compounds synthesised by Eweiss.15 Their mass spectra
exhibited the expected molecular peaks.
In conclusion, we have developed an efficient microwave-
assisted solvent-free synthesis of 3-alkyl-6-aryl[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazine derivatives. The advantages of the
reaction are high yields (82–91%), short working time (1 min)
and easy purification. This procedure also avoids the usage of
organic solvent.
6-(4-Chlorophenyl)-3-propyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4c): Yellow needles (yield 91%), m.p. 186–187°C (lit.18
m.p. 183°C). IR: 3063 (w, ArH), 2958, 2922 (w, CH3, CH2), 1588
(m, C=N), 1526 cm-1 (m, C–N). 1H NMR: δ 1.06 (t, J = 7.2 Hz, 3H,
CH3CH2CH2), 1.66–2.12 (m, 2H, CH3CH2CH2), 2.97 (t, J = 7.2 Hz,
* Correspondent. E-mail address: huixp@lzu.edu.cn
PAPER: 06/4162

108 JOURNAL OF CHEMICAL RESEARCH 2007
2H, CH3CH2CH2), 3.99 (s, 2H, SCH2), 7.52 (d, J = 8.8 Hz, 2H, ArH),
7.87 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 294 (2), 292 (5.4) (M+),
264 (54), 137 (23), 127 (100), 111 (25), 101 (45), 84 (46).
IR: 3050 (w, ArH), 2961, 2924 (w, CH3, CH2), 1588 (m, C=N), 1523
cm-1 (m, C–N). 1H NMR: δ 0.92 (t, J = 6.3 Hz, 3H, CH3), 1.19–1.56
(m, 4H, CH3(CH2)2CH2CH2), 1.70–1.96(m, 2H, CH3(CH2)2CH2CH2),
2.47 (s, 3H, ArCH3), 2.99 (t, J = 7.5 Hz, 2H, CH3(CH2)3CH2), 3.97
(s, 2H, SCH2), 7.34 (d, J = 8.8 Hz, 2H, ArH), 7.81 (d, J = 8.8 Hz,
2H, ArH). EI-MS: m/z 300 (M+, 21), 272 (28), 257 (70), 244 (100),
140 (58), 127 (67), 117 (16), 91 (41). Anal. calcd. for C16H20N4S: C,
63.97; H, 6.71; N, 18.65. Found C, 64.06; H, 6.60; N, 18.52%.
6-(4-Chlorophenyl)-3-pentyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4k): Yellow powder (yield 90%). m.p. 171–172°C (lit.19
m.p. 175°C). IR: 3098 (w, ArH), 2957, 2925 (w, CH3, CH2), 1589
(m, C=N), 1532 cm-1 (m, C–N). 1H NMR: δ 0.92 (t, J = 6.3 Hz, 3H,
CH3), 1.18–1.54 (m, 4H, CH3(CH2)2CH2CH2), 1.74–1.97 (m, 2H,
CH3(CH2)2CH2CH2), 3.03 (t, J = 7.5 Hz, 2H, CH3(CH2)3CH2), 4.02
(s, 2H, SCH2), 7.42 (d, J = 8.8 Hz, 2H, ArH), 7.84 (d, J = 8.8 Hz, 2H,
ArH). EI-MS: m/z 322 (2), 320 (5.3) (M+), 264 (61), 154 (24), 140
(100), 127 (74), 101 (50), 84 (75).
6-(4-Bromophenyl)-3-propyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4d): Yellow powder (yield 88%), m.p. 191–192°C (lit.18
m.p. 185°C). IR: 3059 (w, ArH), 2957, 2922 (w, CH3, CH2), 1583
(m, C=N), 1526 cm-1 (m, C–N); 1H NMR: δ 1.06 (t, J = 7.2 Hz, 3H,
CH3CH2CH2), 1.68–2.10 (m, 2H, CH3CH2CH2), 2.95 (t, J = 7.2 Hz,
2H, CH3CH2CH2), 4.00 (s, 2H, SCH2), 7.48 (d, J = 8.8 Hz, 2H, ArH),
7.86 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 338 (11), 336 (11) (M+),
308 (96), 257 (10), 155 (23), 127 (94), 102 (51), 84 (29).
3-Butyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
(4e):
Yellow powder (Yield 85%), m.p. 112–113°C. IR: 3045 (w, ArH),
2965, 2933 (w, CH3, CH2), 1599 (m, C=N), 1527 cm-1 (m, C–N).
1H NMR: δ 1.00 (t, J = 7.2 Hz, 3H, CH3(CH2)2CH2), 1.12–2.10 (m,
4H, CH3(CH2)2CH2), 2.98 (t, J = 7.2 Hz, 2H, CH3(CH2)2CH2), 4.06
(s, 2H, SCH2), 7.67 (s, 5H, ArH). EI-MS: m/z 272 (M+, 7), 243 (21),
230 (100), 169 (8), 140 (13), 127 (28), 103 (6), 77 (8). Anal. calcd.
for C14H16N4S: C, 61.74; H, 5.92; N, 20.57. Found C, 61.77; H, 5.88;
N, 20.51%.
3-Butyl-6-(4-methylphenyl)[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4f): Yellowish pellets (yield 84%), m.p. 143–145°C. IR:
3038 (w, ArH), 2955, 2930 (w, CH3, CH2), 1594 (m, C=N), 1530
cm-1 (m, C–N). 1H NMR: δ 1.00 (t, J = 7.2 Hz, 3H, CH3(CH2)2CH2),
1.12–2.12 (m, 4H, CH3(CH2)2CH2), 2.37 (s, 3H, CH3), 2.97
(t, J = 7.2 Hz, 2H, CH3(CH2)2CH2), 4.03 (s, 2H, SCH2), 7.67 (d,
J = 8.8 Hz, 2H, ArH), 7.82 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 286
(M+, 14), 257 (21), 244 (100), 204 (9), 140 (30), 127 (81), 117 (14),
91 (33). Anal. calcd. for C15H18N4S: C, 62.91; H, 6.33; N, 19.56.
Found C, 62.81; H, 6.23; N, 19.50%.
6-(4-Bromophenyl)-3-pentyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4l): Yellow powder (yield 86%), m.p. 177–178°C (lit.19
m.p. 182°C).
We are grateful for financial support from the National
Natural Science Foundation of China (No. 20 021 001) and
the Natural Science Foundation of Gansu Province (3ZS051-
A25-005).
Received 30 August 2006; accepted 20 December 2006
Paper 06/4162
doi:10.3184/030823407X198203
3-Butyl-6-(4-chlorophenyl)[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4g): Yellow powder (yield 90%), m.p. 147–148°C. IR:
3041 (w, ArH), 2956, 2929 (w, CH3, CH2), 1590 (m, C=N), 1525
cm-1 (m, C–N). 1H NMR: δ 1.00 (t, J = 7.2 Hz, 3H, CH3(CH2)2CH2),
1.10–2.12 (m, 4H, CH3(CH2)2CH2), 3.00 (t, J = 7.2 Hz, 2H,
CH3(CH2)2CH2), 4.00 (s, 2H, SCH2), 7.45 (d, J = 8.8 Hz, 2H, ArH),
7.72 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 308 (2), 306 (5.4) (M+),
278 (25), 264 (57), 127 (100), 111 (25), 101 (52), 75 (50). Anal.
calcd. for C14H15ClN4S: C, 54.81; H, 4.93; N, 18.26. Found C, 54.62;
H, 4.81; N, 18.12%.
6-(4-Bromophenyl)-3-butyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4h): Yellow powder (yield 87%), m.p. 165–166°C. IR:
3060 (w, ArH), 2959, 2932 (w, CH3, CH2), 1584 (m, C=N), 1522
cm-1 (m, C–N). 1H NMR: δ 1.00 (t, J = 7.2 Hz, 3H, CH3(CH2)2CH2),
1.12–2.14 (m, 4H, CH3(CH2)2CH2), 3.01 (t, J = 7.2 Hz, 2H,
CH3(CH2)2CH2), 4.02 (s, 2H, SCH2), 7.60 (d, J = 8.8 Hz, 2H, ArH),
7.76 (d, J = 8.8 Hz, 2H, ArH). EI-MS: m/z 352 (2), 350 (1.4) (M+),
308 (15), 183 (11), 155 (13), 140 (30), 127 (91), 102 (65). Anal.
calcd. for C14H15BrN4S: C, 47.87; H, 4.30; N, 15.95. Found C, 47.80;
H, 4.41; N, 15.79%.
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3-Pentyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
(4i):
Yellow powder (yield 86%), m.p. 115–116°C (lit.19 m.p. 115°C). IR:
3065 (w, ArH), 2954, 2930 (w, CH3, CH2), 1593 (m, C=N), 1533 cm-1
(m, C–N). 1H NMR: δ 0.92 (t, J = 6.3 Hz, 3H, CH3), 1.19–1.56 (m,
4H, CH3(CH2)2CH2CH2), 1.70–1.96 (m, 2H, CH3(CH2)2CH2CH2),
3.04 (t, J = 7.5 Hz, 2H, CH3(CH2)3CH2), 4.00 (s, 2H, SCH2), 7.58 (s,
5H, ArH). EI-MS: m/z 286 (M+, 6), 257 (27), 230 (86), 169 (8), 140
(16), 127 (100), 103 (16), 77 (87).
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6-(4-Methylphenyl)-3-pentyl[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4j): Yellow powder (yield 82%), m.p. 106–107°C.
PAPER: 06/4162