1302
A. P. Skoumbourdis et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1297–1303
(1.5 equiv) was added and stirred to dissolve. To this
7.08 (dd, 1.6, 7.6 Hz, 1H), 6.89 (d, 8.4 Hz, 1H), 3.97 (s,
2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H);
LC–MS: rt (min) = 6.35; [M+H]+ 413.1; HRMS calcd for
C20H21N4O4S (M+H) 413.1205, found: 413.1281.
3-(2,4-dimethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,
4]-triazolo-[3,4-b]-[1,3,4]-thiadiazine (5E):1H NMR
(CDCl3, 400 MHz) d 7.59 (d, 8.8 Hz, 1H), 7.43–7.41 (m,
2H), 6.93 (d, 8.8 Hz, 1H), 6.60 (dd, 2.4, 8.8 Hz, 1H), 6.54
(d, 2.4 Hz), 4.06 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.86 (s,
3H), 3.75 (s, 3H); LC–MS: rt (min) = 6.18; [M+H]+ 413.1;
HRMS calcd for C20H21N4O4S (M+H) 413.1205, found:
413.1288.
3-(2,5-dimethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,
4]-triazolo-[3,4-b]-[1,3,4]-thiadiazine (5F):1H NMR
(CDCl3, 400 MHz) d 7.43 (d, 2.0, 1H), 7.40 (dd, 2.0,
8.4 Hz, 1H), 7.23 (d, 3.2 Hz, 1H), 7.06 (dd, 3.2, 9.2 Hz,
1H), 6.93 (dd, 3.2, 12 Hz, 2H), 4.04 (s, 3H), 3.93 (s, 3H),
3.84 (s, 3H), 3.79 (s, 3H), 3.69 (s, 3H); LC–MS: rt
(min) = 6.29; [M+H]+ 413.1; HRMS calcd for
C20H21N4O4S (M+H) 413.1205, found: 413.1278.
3-(3,4-dimethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,
4]-triazolo-[3,4-b]-[1,3,4]-thiadiazine (5G): 1H NMR
(CDCl3, 400 MHz) d 7.76–7.73 (m, 2H), 7.56 (d, 2.4 Hz,
1H), 7.44 (dd, 2.0, 8.4 Hz, 1H), 6.98–6.94 (m, 2H), 3.98
(s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.93 (s,
3H); LC–MS: rt (min) = 6.22;[M+H]+ 413.1; HRMS
calcd for C20H21N4O4S (M+H) 413.1205, found:
413.1279.
solution, carbon disulfide (1.5 equiv) was added in a
dropwise fashion. Within a period of 1–10 min, the
potassium salt precipitated from solution and was allowed
to stir as a suspension for 12 h. The suspension was filtered
and dried to give the potassium aryldithiocarbazates as
pale yellow powders in >85%.
Formation of substituted triazoles: To a mixture of
aryldithiocarbazate (1 equiv) in water (10.0 M) was added
hydrazine monohydrate (2 equiv). The mixture was heated
to 113 ꢀC to induce cyclization to the triazole with
formation of hydrogen sulfide gas (reaction mixture
turned greenish brown). After 0.75 h, the reaction mixture
was cooled and ice chips were added. Acidification with
conc. hydrochloric acid precipitated a white solid. The
product was filtered and washed with 2 · 20 mL portions
of cold water to give the triazoles. If necessary, recrystal-
lization from 95% ethanol garnered analytically pure
products. Final yields ranged from 75% to 90%.
Formation of substituted 2-bromoacetophenones: To a
solution of substituted acetophenone in chloroform
(0.35 M) was added bromine (1.2 equiv). The solution
was stirred at room temperature for 0.5 h, then heated to
reflux for another 0.5–2 h until TLC showed full con-
sumption of starting materials. The reaction mixture was
concentrated by rotary evaporation and the crude product
was purified by column chromatography. Final yields
ranged from 50% to 95%.
Formation of substituted 3,6-diphenyl-7H-[1,2,4]-triazol-
o[3,4-b] [1,3,4] thiadiazines: To a mixture of triazole
(1.0 equiv) and substituted 2-bromoacetophenone
(1.0 equiv) was added ethanol (0.1 M). The reaction
mixture was sealed in a crimp-top high pressure vessel
and stirred at 105 ꢀC for 4 h. The crude reaction mixture
was partitioned between methylene chloride and water.
The aqueous layer was removed and the organic layer was
washed with a mixture of water and brine, then concen-
trated by rotary evaporation. The crude product was
purified by preparative HPLC (see General Experimental
for details).
3-(2-methoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (5A):1H NMR (d6-
DMSO, 400 MHz) d 7.61–7.55 (m, 2H), 7.50 (dd, 2.0,
8.4 Hz, 1H), 7.41 (d, 2.0 Hz, 1H), 7.24 (d, 8.0 Hz, 1H),
7.15–7.07 (m, 2H), 4.22 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H),
3.73 (s, 3H); 13C NMR (d6-DMSO, 100 MHz) d 158.3,
156.3, 152.9, 150.5, 149.5, 142.9, 6, 132.2, 125.9, 122.4,
121.0, 114.3, 112.6, 112.2, 110.6, 56.5, 56.4, 56.2, 23.5;
LC–MS: rt (min) = 6.19; [M+H]+ 383.1; HRMS calcd for
C19H19N4O3S (M+H) 383.1100, found: 383.1181.
3-(3,5-dimethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,
4]-triazolo-[3,4-b]-[1,3,4]-thiadiazine (5H):1H NMR
(CDCl3, 400 MHz) d 7.65 (d, 1.6 Hz, 1H), 7.41 (d, 2.0 Hz,
1H), 7.39 (d, 2.4 Hz, 2H), 6.95 (d, 8.8 Hz, 1H), 6.58 (t,
2.4 Hz, 1H), 3.98 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.83 (s,
6H); LC–MS: rt (min) = 6.95 [M+H]+ 413.1; HRMS calcd
for C20H21N4O4S (M+H) 413.1205, found: 413.1278.
3-(2-methylpheny)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (5I):1H NMR (CDCl3,
400 MHz) d 7.99 (s, 1H), 7.92 (d, 7.6 Hz, 1H), 7.60 (d,
2.0 Hz, 1H), 7.42–7.35 (m, 2H), 7.30 (d, 7.6 Hz, 1H), 6.96 (d,
8.8 Hz, 1H), 3.98 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 2.42 (s,
3H); LC–MS: rt (min) = 7.04; [M+H]+ 367.1; HRMS calcd
for C19H19N4O2S (M+H) 367.1150, found: 367.1224.
3-(2-ethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (5J):1H NMR (CDCl3,
400 MHz) d 7.65 (d, 6.8 Hz, 1H), 7.52 (t, 8.4 Hz, 1H), 7.41 (d,
8.8 Hz, 1H), 7.07 (t, 7.2 Hz, 1H), 6.99 (d, 8.4 Hz, 1H), 6.92 (d,
8.0 Hz, 1H), 4.04 (s, 2H), 3.97 (q, 6.8 Hz, 2H), 3.92 (s, 3H),
3.81 (s, 3H), 1.18 (t, 6.8 Hz, 3H); LC–MS: rt (min) = 6.55;
[M+H]+ 397.1; HRMS calcd for C20H21N4O3S (M+H)
397.1256, found: 397.1337.
3-(3-methoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (5B):1H NMR
(CDCl3, 400 MHz) d 7.74–7.70 (m, 2H), 7.59 (d,2.0 Hz,
1H), 7.43–7.35 (m, 2H), 7.02 (dd, 2.8, 8.4 Hz, 1H), 6.94 (d,
8.4 Hz, 1H), 4.00 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.84 (s,
3H); LC–MS: rt (min) = 6.77; [M+H]+ 383.0; HRMS calcd
for C19H19N4O3S (M+H) 383.1100, found: 383.1184.
3-(4-methoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
3-(2-hydroxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (5K):1H NMR (CDCl3,
400 MHz) d 8.34 (dd, 1.6 Hz, 1H), 7.63 (d, 1.6 Hz, 1H), 7.44
(dd, 2.4, 8.4 Hz, 1H), 7.36 (ddd, 1.6, 7.2, 12 Hz, 1H), 7.13 (dd,
1.2, 8.4 Hz, 1H), 6.92 (ddd, 1.2, 8.4, 15.2 Hz, 1H), 4.00 (s,
2H), 3.98 (s, 3H), 3.97 (s, 3H); LC–MS: rt (min) = 7.63;
[M+H]+ 369.0; HRMS calcd for C18H17N4O3S (M+H)
369.0943, found: 369.1018.
3-(2-methoxyphenyl)-6-(2,5-dimethoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (10A):1H NMR (CDCl3,
400 MHz) d 7.60 (d, 7.6 Hz, 1H), 7.49 (app. t, 8.8 Hz, 1H),
7.07-6.98 (m, 4H), 6.91 (app. d, 10.4 Hz, 1H), 4.00 (s, 2H),
3.85 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H); LC–MS: rt
(min) = 6.79; [M+H]+ 383.1; HRMS calcd for
C19H19N4O3S (M+H) 383.1100, found: 383.1176.
triazolo-[3,4-b]-[1,3,4]-thiadiazine
(5C):1H
NMR
(CDCl3, 400 MHz) d 8.09 (dd, 2.4, 6.8 Hz, 2H), 7.57 (d,
2.4 Hz, 1H), 7.42 (dd, 2.0, 8.4 Hz, 1 H), 6.99 (dd, 2.0,
6.8 Hz, 2H), 6.96 (d, 8.4 Hz), 3.97 (s, 2H), 3.96 (s, 3H),
3.93 (s, 3H), 3.87 (s, 3H); LC–MS: rt (min) = 6.60;
[M+H]+ 383.1; HRMS calcd for C19H19N4O3S (M+H)
383.1100, found: 383.1176.
3-(2,3-dimethoxyphenyl)-6-(3,4-dimethoxyphenyl)-7H-[1,2,
4]-triazolo-[3,4-b]-[1,3,4]-thiadiazine (5D):1H NMR
(CDCl3, 400 MHz) d 7.42 (d, 2.0 Hz, 1H), 7.33 (dd, 2.0,
8.4 Hz, 1H), 7.21 (dd, 1.6, 7.6 Hz, 1H), 7.16 (t, 7.6 Hz),
3-(3-methoxyphenyl)-6-(3-methoxyphenyl)-7H-[1,2,4]-
triazolo-[3,4-b]-[1,3,4]-thiadiazine (7B):1H NMR (CDCl3,
400 MHz) d 7.85 (d, 8.8 Hz, 2H), 7.67 (d, 7.2 Hz, 2H), 7.36
(t, 8.0 Hz, 1H), 7.01–6.96 (m, 3H), 3.94 (s, 2H), 3.85 (s, 3H),