Novel and efficient solid-state synthesis of 3-alkyl-6-aryl-s-triazolo[3,4- b]-1,3,4-thiadiazine derivatives

Article abstract of DOI:10.1080/00397910600616461

A novel and efficient solid-state synthesis of s-triazolo[3,4-b]-1,3,4- thiadiazine derivatives has been reported. Twelve 3-alkyl-6-aryl-s-triazolo[3,4- b]-1,3,4-thiadiazine derivatives have been synthesized in excellent yields with short reaction time. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600616461

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Novel and Efficient Solid‐State Synthesis of
3‐Alkyl‐6‐Aryl‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazine
Derivatives
Xin‐Ping Hui a , Ren‐Zhong Qiao a , Peng‐Fei Xu a & Zi‐Yi Zhang a
a State Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering , Lanzhou University , Lanzhou , China
Published online: 22 Aug 2006.
To cite this article: Xin‐Ping Hui , Ren‐Zhong Qiao , Peng‐Fei Xu & Zi‐Yi Zhang (2006) Novel and
Efficient Solid‐State Synthesis of 3‐Alkyl‐6‐Aryl‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:12,
1655-1660, DOI: 10.1080/00397910600616461
To link to this article: http://dx.doi.org/10.1080/00397910600616461
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Synthetic Communicationsw, 36: 1655–1660, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600616461
Novel and Efficient Solid-State Synthesis
of 3-Alkyl-6-Aryl-s-triazolo[3,4-b]-1,3,4-
thiadiazine Derivatives
Xin-Ping Hui, Ren-Zhong Qiao, Peng-Fei Xu,
and Zi-Yi Zhang
State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, China
Abstract: A novel and efficient solid-state synthesis of s-triazolo[3,4-b]-1,3,4-thia-
diazine derivatives has been reported. Twelve 3-alkyl-6-aryl-s-triazolo[3,4-b]-1,3,4-
thiadiazine derivatives have been synthesized in excellent yields with short
reaction time.
s-Triazolo[3,4-b]-1,3,4-thiadiazine derivatives have been reported to show
diverse biological activities, including analgesic, anti-inflammatory, anti-
bacterial, and antiviral activities.[1–4] Recently, much interest has been paid
to s-triazolo[3,4-b]-1,3,4-thiadiazine derivatives.[5–8] The condensation of
4-amino-5-mercapto-3-substituted-1,2,4-triazoles with 2-halocarbonyl com-
pounds has been carried out in solution. However, this cyclization afforded
different products under various reaction conditions. There are also some
problems associated with this synthesis, such as severe conditions, long
reaction times, low to moderate yields, difficulty in separating the products,
and serious environmental pollution.
Quite a few organic reactions proceed well in solid state. Moreover, solid-
state organic synthesis has many advantages, including high efficiency and
selectivity,[9] easy separation and purification,[10] and environmental
Received in R.O.C. December 8, 2005
Address correspondence to Xin-Ping Hui, State Key Laboratory of Applied Organic
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
1655

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X.-P. Hui et al.
acceptability.[11,12] All these merits are in accord with the “green” require-
ments of energy saving and high efficiency. In recent years, this method
hasa been widely used in a variety of organic syntheses, such as substi-
tution,[13] condensation,[14] oxidation–reduction,[15,16] rearrangements,[17]
and elimination reactions.[18] However, solid-state synthesis of s-
triazolo[3,4-b]-1,3,4-thiadiazine derivatives has not been reported. This
article reports a novel and efficient solid-state condensation reaction of
3-alkyl-4-amino-5-mercapto-1,2,4-triazole with 2-bromo-40- substituted acet-
ophenone to afford new 3-alkyl-6-aryl-s-triazolo[3,4-b]-1,3,4-thiadiazine
derivatives (Scheme 1).
The target compounds 3a–l were prepared by heating a mixture of
3-alkyl-4-amino-5-mercapto-1,2,4-triazole (1a–c) and 2-bromo-40-substi-
tuted acetophenone (2a–d) carefully until melting occurred and were kept
20 min at this temperature. The results are listed in Table 1. From Table 1,
we can see that 3-alkyl-4-amino-5-mercapto-1,2,4-triazole and 2-bromo-40-
substituted acetophenone readily participated in this reaction. The yields are
high, and the reaction time is short, regardless of the variations in the
substituent of the substrate.
The compounds synthesized were characterized by their elemental
analyses and spectral data. Their IR spectra showed three characteristic
absorption bands at 1583–1609 cm21 (C55N), 1224–1266 cm21 (N-N55C),
1
and 658–691 cm21 (C-S-C), respectively. In the H NMR spectra, SCH2
protons exhibited signals at around d 4.0 ppm. Their mass spectra exhibited
the expected molecular peaks.
In conclusion, we have developed a novel and efficient solid-state
synthesis of 3-alkyl-6-aryl-s-triazolo[3,4-b]-1,3,4-thiadiazine derivatives in
high yields (85–92%) with a short working time (20 min) and easy purifi-
cation. This procedure also avoids the use of organic solvent.
Scheme 1. R1 ¼ n-Pr,R2¼H(3a);R1 ¼ n-Pr,R2 ¼ CH3 (3b);R1 ¼ n-Pr,R2 ¼ Cl(3c);
R1 ¼ n-Pr, R2 ¼ Br (3d); R1 ¼ n-Bu, R2 ¼ H (3e); R1 ¼ n-Bu, R2 ¼ CH3 (3f); R1 ¼ n-
Bu, R2 ¼ Cl (3g); R1 ¼ n-Bu, R2 ¼ Br (3h); R1 ¼ n-Pentyl, R2 ¼ H (3i); R1 ¼ n-Pentyl,
R2 ¼ CH3 (3j); R1 ¼ n-Pentyl, R2 ¼ Cl (3k); R1 ¼ n-Pentyl, R2 ¼ Br (3l).

3-Alkyl-6-aryl-s-triazolo[3,4-b]-1,3,4-thiadiazine Derivatives
1657
Table 1. Melting points, yields, and elemental analyses of compounds 3a–l
Found (Calcd.) (%)
m.p.
(8C)
Yield
(%)
Compd.
C
H
N
3a
3b
3c
3d
3e
3f
153–154
175–176
186–187
191–192
114–115
140–141
147–148
163–164
115–116
107–108
171–172
177–178
85
90
92
87
86
91
89
88
88
90
92
91
60.41 (60.44)
61.56 (61.74)
53.45 (53.33)
46.14 (46.30)
61.87 (61.74)
62.73 (62.91)
54.53 (54.81)
47.94 (47.87)
62.80 (62.91)
64.14 (63.97)
56.41 (56.15)
49.13 (49.32)
5.32 (5.46) 21.48 (21.69)
5.73 (5.92) 20.41 (20.57)
4.40 (4.48) 19.08 (19.14)
3.94 (3.89) 16.38 (16.61)
5.98 (5.92) 20.46 (20.57)
6.14 (6.33) 19.41 (19.56)
4.80 (4.93) 18.05 (18.26)
4.55 (4.30) 15.80 (15.95)
6.58 (6.33) 19.29 (19.56)
6.52 (6.71) 18.43 (18.65)
5.11 (5.34) 17.18 (17.46)
4.87 (4.69) 15.08 (15.34)
3g
3h
3i
3j
3k
3l
EXPERIMENTAL
The melting points were determined on an X-4 microscopic melting-point
apparatus and are uncorrected. Elementary analyses were carried out on
Elementar Vario EL analyzer. IR spectra were obtained in KBr disc on a
1
5-DX spectrometer. H NMR spectra were recorded in DMSO-d6 solution
on a Mercury-Plus 300 instrument with TMS as an internal standard. MS
were performed on a VG-7070E spectrometer (EI at 70 eV).
3-Alkyl-4-amino-5-mercapto-1,2,4-triazoles (1a–c) were prepared accord-
ing to the methods in the literature.[19]
General Procedure for Preparation of 3-Alkyl-6-aryl-s-
triazolo[3,4-b]-1,3,4-thiadiazines (3a–l)
A mixture of 3-alkyl-4-amino-5-mercapto-1,2,4-triazoles 1 (0.01 mol) and
2-bromo-40-substituted acetophenones 2 (0.01 mol) was heated carefully
until melting occurred and then was kept at that temperature for 20 min.
The reaction mixture was then cooled and mixed with water (50 mL), and
the solid product was collected, washed with water, and finally recrystallized
from ethanol to give (3a–l).
Data
1
3-Pr-6-phenyl-s-triazolo[3,4-b]-1,3,4-thiadiazines (3a). H NMR (DMSO-
d6) d: 1.06 (t, 3H, J ¼ 7.2 Hz, CH3CH2CH2), 1.64–2.09 (m, 2H,

1658
X.-P. Hui et al.
CH3CH2CH2), 2.94 (t, 2H, J ¼ 7.2 Hz, CH3CH2 CH2), 3.97 (s, 2H, SCH2),
7.62 (s, 5H, ArH); IR (cm21) (KBr disc): 3051 (w, ArH), 2959, 2900
(w, CH3, CH2), 1578 (m, C55N), 1529 (m, C–N); EI-MS (m/z): 258 (Mþ,
9), 230 (87), 127 (100), 103 (43), 84 (40), 77 (96).
1
3-Pr-6-(4-methylphenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3b). H NMR
(DMSO-d6) d: 1.06 (t, 3H, J ¼ 7.2 Hz, CH3CH2CH2), 1.61–2.08 (m, 2H,
CH3CH2CH2), 2.46 (s, 3H, CH3), 2.93 (t, 2H, J ¼ 7.2 Hz, CH3CH2CH2),
3.96 (s, 2H, SCH2), 7.46 (d, 2H, J ¼ 8.8 Hz, ArH), 7.78 (d, 2H, J ¼ 8.8 Hz,
ArH); IR (cm21) (KBr disc): 3036 (w, ArH), 2960, 2931 (w, CH3, CH2),
1610 (m, C55N), 1533 (m, C–N); EI-MS (m/z): 272 (Mþ, 20), 244 (100),
204 (11), 153 (10), 127 (87), 117 (17), 91 (33).
3-Pr-6-(4-chlorophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3c). 1H NMR
(DMSO-d6) d: 1.06 (t, 3H, J ¼ 7.2 Hz, CH3CH2CH2), 1.66–2.12 (m, 2H,
CH3CH2CH2), 2.97 (t, 2H, J ¼ 7.2 Hz, CH3CH2 CH2), 3.99 (s, 2H, SCH2),
7.52 (d, 2H, J ¼ 8.8 Hz, ArH), 7.87 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21
)
(KBr disc): 3063 (w, ArH), 2958, 2922 (w, CH3, CH2), 1588 (m, C55N),
1526 (m, C–N); EI-MS (m/z): 292 (Mþ, 5.4), 294 (2), 264 (54), 127 (100),
111 (25), 101 (45), 75 (44).
3-Pr-6-(4-bromophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3d). 1H
NMR (DMSO-d6) d: 1.06 (t, 3H, J ¼ 7.2 Hz, CH3CH2CH2), 1.68–2.10
(m, 2H, CH3CH2CH2), 2.95 (t, 2H, J ¼ 7.2 Hz, CH3CH2 CH2), 4.00 (s, 2H,
SCH2), 7.48 (d, 2H, J ¼ 8.8 Hz, ArH), 7.86 (d, 2H, J ¼ 8.8 Hz, ArH); IR
(cm21) (KBr disc): 3059 (w, ArH), 2957, 2922 (w, CH3, CH2), 1583
(m, C55N), 1526 (m, C-N); EI-MS (m/z): 336 (Mþ, 11), 338 (11), 321 (2),
308 (96), 257 (10), 229 (3), 181 (9), 155 (23), 127 (94), 102 (51), 84 (29),
76 (22), 195 (6).
1
3-Bu-6-phenyl-s-triazolo[3,4-b]-1,3,4-thiadiazines (3e). H NMR (DMSO-
d6) d: 1.00 (t, 3H, J ¼ 7.2 Hz, CH3(CH2)2CH2), 1.12–2.10 (m, 4H,
CH3(CH2)2CH2), 2.98 (t, 3H, J ¼ 7.2 Hz, CH3(CH2)2CH2), 4.06 (s, 2H,
SCH2), 7.67 (s, 5H, ArH); IR (cm21) (KBr disc): 3045 (w, ArH), 2965,
2933 (w, CH3, CH2), 1599 (m, C55N), 1527 (m, C–N); EI-MS (m/z): 272
(Mþ, 7), 243 (21), 230 (100), 169 (8), 140 (13), 127 (28), 103 (6).
3-Bu-6-(4-methylphenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3f). 1H NMR
(DMSO-d6) d: 1.00 (t, 3H, J ¼ 7.2 Hz, CH3(CH2)2CH2), 1.12–2.12 (m, 4H,
CH3(CH2)2CH2), 2.37 (s, 3H, ArCH3), 2.97 (t, 3H, CH3(CH2)2CH2), 4.03
(s, 2H, SCH2), 7.67 (d, 2H, J ¼ 8.8 Hz, ArH), 7.82 (d, 2H, J ¼ 8.8 Hz,
ArH); IR (cm21) (KBr disc): 3038 (w, ArH), 2955, 2930 (w, CH3, CH2),
1594 (m, C55N), 1530 (m, C–N); EI-MS (m/z): 286 (Mþ, 14), 257 (21),
244 (100), 229 (4), 204 (9), 169 (8), 140 (30), 127 (81), 117 (14), 91 (33).
1
3-Bu-6-(4-chlorophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3g). H NMR
(DMSO-d6) d: 1.00 (t, 3H, J ¼ 7.2 Hz, CH3(CH2)2CH2), 1.10–2.12 (m, 4H,
CH3(CH2)2CH2), 3.00 (t, 3H, CH3(CH2)2CH2), 4.00 (s, 2H, SCH2), 7.45

3-Alkyl-6-aryl-s-triazolo[3,4-b]-1,3,4-thiadiazine Derivatives
1659
(d, 2H, J ¼ 8.8 Hz, ArH), 7.72 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21) (KBr disc):
3041 (w, ArH), 2956, 2929 (w, CH3, CH2), 1590 (m, C55N), 1525 (m, C–N);
EI-MS (m/z): 306 (Mþ, 5.4), 308 (2), 264 (57), 127 (100), 111 (25), 101 (52),
75 (50).
1
3-Bu-6-(4-bromophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3h). H NMR
(DMSO-d6) d: 1.00 (t, 3H, J ¼ 7.2 Hz, CH3(CH2)2CH2), 1.12–2.14 (m, 4H,
CH3(CH2)2CH2), 3.01 (t, 3H, CH3(CH2)2CH2), 4.02 (s, 2H, SCH2), 7.60
(d, 2H, J ¼ 8.8 Hz, ArH), 7.76 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21) (KBr
disc): 3060 (w, ArH), 2959, 2932 (w, CH3, CH2), 1584 (m, C55N), 1522
(m, C–N); EI-MS (m/z): 350 (Mþ, 1.4), 352 (2), 308 (15), 183 (11), 155 (13),
140 (30), 127 (91), 102 (65), 80 (100).
3-Penty-6-phenyl-s-triazolo[3,4-b]-1,3,4-thiadiazines (3i). 1H NMR
(DMSO-d6) d: 0.92 (t, 3H, J ¼ 7.2 Hz, CH3), 1.19–1.56 (m, 4H,
CH3(CH2)2(CH2)2, 1.70–1.96 (m, 2H, CH3(CH2)2CH2 CH2, 3.04
(t, J ¼ 7.2 Hz, CH3(CH2)3CH2), 4.00 (s, 2H, SCH2), 7.58 (s, 5H, ArH); IR
(cm21) (KBr disc): 3065 (w, ArH), 2954, 2930 (w, CH3, CH2), 1593
(m, C55N), 1533 (m, C–N); EI-MS (m/z): 286 (Mþ, 6), 257 (27), 230 (86),
127 (100), 103 (16), 77 (87).
3-Penty-6-(4-methylphenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3j). 1H
NMR (DMSO-d6) d: 0.92 (t, 3H, J ¼ 7.2 Hz, CH3), 1.19–1.56 (m, 4H,
CH3(CH2)2(CH2)2, 1.70–1.96 (m, 2H, CH3(CH2)2CH2 CH2, 2.47 (s, 3H,
ArCH3), 2.99 (t, J ¼ 7.2 Hz, CH3 (CH2)3CH2), 3.97 (s, 2H, SCH2), 7.34
(d, 2H, J ¼ 8.8 Hz, ArH), 7.81 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21) (KBr
disc): 3050 (w, ArH), 2961, 2924 (w, CH3, CH2), 1588 (m, C55N), 1523
(m, C–N); EI-MS (m/z): 300 (Mþ, 21), 272 (28), 257 (70), 244 (100), 204
(11), 186 (8), 140 (58), 127 (67), 117 (16), 91 (41).
3-Penty-6-(4-chlorophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3k). 1H
NMR (DMSO-d6) d: 0.92 (t, 3H, J ¼ 7.2 Hz, CH3), 1.18–1.54 (m, 4H,
CH3(CH2)2(CH2)2, 1.74–1.97 (m, 2H, CH3(CH2)2CH2CH2, 3.03
(t, J ¼ 7.2 Hz, CH3(CH2)3CH2), 4.02 (s, 2H, SCH2), 7.42 (d, 2H,
J ¼ 8.8 Hz, ArH), 7.84 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21) (KBr disc):
3098 (w, ArH), 2957, 2925 (w, CH3, CH2), 1589 (m, C55N), 1532 (m, C–
N); EI-MS (m/z): 320 (Mþ, 5.3), 322 (2), 264 (61), 154 (24), 140 (100),
127 (74), 111 (24), 101 (50), 84 (75), 75 (58).
3-Penty-6-(4-bromophenyl)-s-triazolo[3,4-b]-1,3,4-thiadiazines (3l). 1H
NMR (DMSO-d6) d: 0.92 (t, 3H, J ¼ 7.2 Hz, CH3), 1.18–1.56 (m, 4H,
CH3(CH2)2(CH2)2, 1.72–1.96 (m, 2H, CH3(CH2)2CH2CH2, 3.02
(t, J ¼ 7.2 Hz, CH3(CH2)3CH2), 4.06 (s, 2H, SCH2), 7.67 (d, 2H, J ¼ 8.8Hz,
ArH), 7.82 (d, 2H, J ¼ 8.8 Hz, ArH); IR (cm21) (KBr disc): 3040 (w, ArH),
2959, 2928 (w, CH3, CH2), 1590 (m, C55N), 1528 (m, C–N); EI-MS (m/z):
364 (Mþ, 7), 366 (8), 335 (8), 321 (44), 308 (63), 285 (6), 250 (7), 195 (8),
181 (20, 168 (18), 155 (20), 140 (89), 127 (100), 102 (64), 76 (22).

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X.-P. Hui et al.
ACKNOWLEDGMENT
We are grateful for financial support from the National Natural Science Foun-
dation of China (No. 20021001) and Natural Science Foundation of Gansu
Province (3ZS051-A25-005).
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