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A. Castro et al. / Bioorg. Med. Chem. 16 (2008) 495–510
was heated to 140–160 ꢁC where 3-(4-methylphenyl)-5-
oxo-4,1,2-oxathiazole36 (0.4 g, 2.1 mmol) was added
slowly. The reaction mixture was stirred for 2.5 h. The
reaction mixture was allowed to cool to room tempera-
ture and a cream solid was collected, washed with
hexane, and recrystallized from hexane/AcOEt (8:2).
Yield: 0.51 g (73%). Mp 125–126 ꢁC. 1H NMR (CDCl3)
d 2.41 (s, 3H, CH3), 2.48 (s, 3H, CH3), 7.28 (d, 2H,
J = 8.1 Hz), 7.44 (d, 2H, J = 8.2 Hz); 8.08 (d, 2H,
J = 8.4 Hz), 8.14 (d, 2H, J = 8.2 Hz). 13C NMR
(DMSO-d6) d 180.3 (C5), 173.8 (C3), 136.7 (Ci), 134.8
(Cp), 131.4 (Cm), 129.9 (Ci), 129.5 (Co), 128.0 (Cm),
130.1 (Co), 126.1 (Cp), 23.8 (CH3), 24.6 (CH3). MS
(EI): m/z 330 (M+, 73%), 239 (15%), 176 (39%), 155
(100%). Anal. Calcd for C16H14N2O2S2: C, 58.16; H,
4.27; N, 8.48; S, 19.41. Found: C, 58.50; H, 4.08; N,
8.78; S, 19.16.
cipitate was filtered off and purified as indicated in each
case.
5.1.22.1. 3,5-Diethylamino-1,2,4-thiadiazole (56). Re-
agents: ethylthiourea (104 mg, 1 mmol), DIB (322 mg,
1 mmol). Conditions: room temperature, 3 h. Purifica-
tion: silica gel column chromatography using hexane/
1
AcOEt (10:1). Yield: 95 mg (55%). Mp 198–200 ꢁC. H
NMR (DMSO-d6) d 12.23 (br s, 1H, NH); 8.61 (br s,
1H, NH); 3.15 (c, 2H, CH2); 1.07 (t, 3H, CH3); 3.22
(c, 2H, CH2); 1.13 (t, 3H, CH3). 13C NMR (DMSO-
d6) d 182.7 (C5); 168.4 (C3); 38.4 (NCH2); 14.6 (CH3);
41.1 (NCH2); 15.2 (CH3). MS (ESI, positive): 173.0
(M+). Anal. Calcd for C6H12N4S: C, 41.84; H, 7.02;
N, 32.53; S, 18.62. Found: C, 42.17; H, 7.09; N, 32.60;
S, 18.64.
27
5.1.22.2. 3,5-Diacetylamino-1,2,4-thiadiazole (57).
5.1.20.
3-(4-Methylphenyl)-5-oxo-4,5-dihydro-1,2,4-
Reagents: acetylthiourea (118 mg, 1 mmol), DIB
(322 mg, 1 mmol). Conditions: room temperature, 3 h.
Purification: Recrystallization from ethanol. Yield:
90 mg (45%). Mp 340–342 ꢁC. (lit.27 336–338 ꢁC). 1H
NMR (DMSO-d6) d 12.41 (br s, 1H, NH); 10.75 (br s,
1H, NH); 2.08 (s, 3H, CH3); 2.21 (s, 3H, CH3). 13C
NMR (DMSO-d6) d 174.4 (C5); 168.0 (C3); 170.8
(CO); 23.8 (CH3); 170.8 (CO); 22.10 (CH3). MS (ESI,
positive): 201.0 (M+). Anal. Calcd for C6H8N4O2S: C,
35.99; H, 4.03; N, 27.98; S, 16.02. Found: C, 36.04; H,
4.27; N, 28.25; S, 16.13.
thiadiazole (52). To a mixture of potassium tert-butoxide
in 25 ml of tert-butyl alcohol was added thiadiazole 51
(268 mg, 0.6 mmol) and refluxed for 15 min. The reac-
tion mixture was diluted with 30 ml of AcOEt, washed
with brine (2· 50 ml), dried over anhydrous sodium sul-
fate and the solvent was removed by evaporation under
reduced pressure. The solid was triturated with Et2O/
hexane to yield 132 mg (71%). Mp 216–217 ꢁC; 1H
NMR (CDCl3) d 2.39 (s, 3H, CH3), 7.31 (d, 2H, ArH,
J = 8.3 Hz), 7.92 (d, 2H, ArH, J = 8.4 Hz), 11.10 (s,
1H, NH). 13C NMR (DMSO-d6) d 178.8 (C3), 153.9
(C5), 132.4 (Cp), 129.4 (2Cm), 128.4 (2Co), 126.1 (Ci),
24.2 (CH3). MS (ESI, positive): 193.0 (MH+). Anal.
Calcd for C9H8N2OS: C, 56.23; H, 4.19; N, 14.57; S,
16.68. Found: C, 56.09; H, 3.97; N, 14.33; S, 16.29.
5.1.22.3. 3,5-Dianilin-1,2,4-thiadiazole (58).27 Re-
agents: phenylthiourea (152 mg, 1 mmol), DIB (322 mg,
1 mmol). Conditions: room temperature, 4 h. Purifica-
tion: silica gel column chromatography using hexane/
AcOEt (2:1) as eluent. Yield: 121 mg (45%). Mp 203–
205 ꢁC. (lit.27 200–202 ꢁC).1H NMR (DMSO-d6) d 9.34
(br s, 1H, NHR1); 5.62 (br s, 1H, NHR2); 7.16 (t, 2H,
J = 7.5 Hz, arom); 6.80 (t, 1H, J = 7.5 Hz, arom); 7.70
(d, 2H, J = 7.5 Hz, arom); 7.55 (dd, 2H, J = 7.5 Hz,
arom); 7.35 (t, 1H, J = 7.5 Hz, arom); 7.00–7.10 (m, 2H,
J = 7.5 Hz, arom). 13C NMR (DMSO-d6) d 175.1 (C5);
159.6 (C3); 141.5 (Ci); 128.3 (Cm); 119.8 (Cp); 116.5
(Co); 146.4 (Ci); 129.4 (Cm); 129.3 (Cp); 122.8 (Co). MS
(ESI, positive): 269.0 (M+). Anal. Calcd for C14H12N4S:
C, 62.66; H, 4.51; N, 20.88; S, 11. 95. Found: C, 62.97;
H, 4.46; N, 21.09; S, 12.18.
5.1.21.
4-Ethoxycarbonylmethyl-3-(4-methylphenyl)-
1,2,4-thiadiazole (53). A solution of 52 (0.1 g, 0.52 mmol)
in 5 ml of DMF was treated with NaH (21 mg,
0.52 mmol) at room temperature for 30 min. Then, ethyl
2-bromoacetate (0.6 ml, 0.52 mmol) was added and the
resulting solution was heated for 1 h at 80 ꢁC. The reac-
tion was cooled to room temperature, mixed with brine
solution, and extracted with AcOEt (3· 20 ml), the
resulting organic phases were dried over anhydrous so-
dium sulfate and the solvent was removed by evapora-
tion under reduced pressure. The crude was purified by
silica gel column chromatography using hexane/AcOEt
1
(9:1) as eluent. Yield (65 mg, 45%). Mp 68–69 ꢁC; H
5.1.22.4. 3,5-Bis(4-pyridylamino)-1,2,4-thiadiazole (59).
Reagents: pyridinylthiourea (153 mg, 1 mmol), DIB
(322 mg, 1 mmol). Conditions: room temperature, 2 h.
Purification: silica gel column chromatography using
hexane/AcOEt (2:1). Yield: 68 mg (25%). Mp 188–190
ꢁC. 1H NMR (DMSO-d6) d 12.20 (br s, 1H, NH);
10.60 (br s, 1H, NH); 8.20–7.00 (m, 4H, arom); 8.10–
6.50 (m, 4H, arom). 13C NMR (DMSO-d6) d 176.2
(C5); 167.8 (C3); 160.0 (Ci); 149.8 (Cm); 138.5 (Cm);
113.5 (Cp); 109.0 (Co); 164.0 (Ci); 150.6 (Cm); 140.3
(Cm); 115.7 (Cp); 112.0 (Co). MS (ESI, positive): 271.0
(M+). Anal. C12H10N6S: C, 53.32; H, 3.73; N, 31.09; S,
11.88. Found: C, 53.26; H, 3.50; N, 31.37; S, 11.48.
NMR (CDCl3) d 1.29 (t, 3H, CH3), 2.40 (s, 3H, CH3),
3.85 (s, 2H, CH2), 4.09 (q, 2H, CH2), 7.24 (d, 2H,
J = 8.3 Hz), 7.76 (d, 2H, J = 8.4 Hz). 13C NMR
(DMSO-d6) d 176.7 (C5), 168.2 (C3), 131.8 (Cp), 129.1
(2Cm), 128.6 (2Co), 126.3 (Ci), 62.4 (CH2CH3), 46.8
(CH2CO2Et), 14.2 (CH2CH3). MS (ESI, positive) 279
(M+). Anal. Calcd for C13H14N2O3S: C, 56.10; H, 5.07;
N, 10.06; S, 11.52. Found: C, 55.82; H, 4.73; N, 9.85;
S, 11.21.
5.1.22. General procedure for the synthesis of 3,5-
27
diamino-1,2,4-thiadiazoles (56–59). Over a suspension
of 1 mmol of monosubstituted thiourea in chloroform
1 mmol of DIB was added. The reaction mixture was
stirred at room temperature for 4 h. The resulting pre-
5.1.23. General procedure for the synthesis of 3,5-di-
substituted-1,2,4-thiadiazoles (73, 77, and 80). A solution