A. Md. Ahad et al. / Bioorg. Med. Chem. 19 (2011) 2046–2054
2049
29.6, 29.7, 30.9, 31.9, 36.0, 126.9, 129.5, 141.7, 151.6. Reaction of 2-
amino-1,3,4-thiadiazole (179 mg, 1.77 mmol) with p-tetra-
decylbenzenesulfonyl chloride (440 mg, 1.18 mmol) afforded the
product 30 (240 mg, 0.55 mmol, 47% yield), Rf 0.46 (5% MeOH/
CH2Cl2), as a solid, mp 116–117 °C, after chromatography on silica
gel (70–230 mesh) eluted with CH2Cl2/MeOH 19:1; 1H NMR
(300 MHz, CDCl3) d 0.88 (3, t, J = 6.9 Hz), 1.25 (22, m), 1.60 (2,
m), 2.64 (2, t, J = 7.2 Hz), 7.29 (2, d, J = 8.4 Hz), 7.84 (2, d,
J = 8.4 Hz), 8.23 (1, s); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2,
29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6,
148.6, 167.4; HRMS (ESI+, m/z) calcd for C22H36N3O2S2 438.2243,
observed 438.2243 (M+H)+.
and the resulting mixture extracted with EtOAc (3 Â 10 mL). The
organic extracts were washed with water, brine, dried over
anhydrous Na2SO4, filtered, and volatiles evaporated in vacuo
to yield a solid mass. Chromatography on silica gel (70–230
mesh) eluted with CH2Cl2/MeOH 49:1 gave the product 33
(310 mg, 0.73 mmol, 84%), Rf 0.23 (50% EtOAc/hexanes). Recrys-
tallization from EtOAc/hexanes 7:3 gave an analytical sample,
mp 149–150 °C; 1H NMR (500 MHz, CDCl3)
d 0.88 (3, t,
J = 7.0 Hz), 1.20–1.36 (18, m), 1.54–1.63 (2, m), 2.51 (3, s), 2.63
(2, t, J = 7.5 Hz), 7.25 (2, d, J = 7.5 Hz), 7.82 (2, d, J = 7.5 Hz),
12.36 (1, br s); 13C NMR (125 MHz, CDCl3) d 14.1, 16.5, 22.7,
29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.4, 128.8, 138.3,
148.3, 154.1, 168.6; HRMS (ESI+, m/z) calcd for C21H34N3O2S2
424.2092, observed 424.2085 (M + H)+.
2.1.7. 4-Hexadecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfon-
amide (31)
In a similar manner, 1-phenylhexadecane (0.76 g, 2.5 mmol)
and chlorosulfonic acid (0.50 mL, 7.5 mmol) gave p-hexadec-
ylbenzenesulfonyl chloride as a white solid (0.71 g, 1.8 mmol,
72%), mp 35–36 °C, after chromatography on silica gel eluted
with hexanes/EtOAc (49:1); 1H NMR (300 MHz, CDCl3) d 0.88
(3, t, J = 7.2 Hz), 1.25 (26, m), 1.62 (2, m), 2.72 (2, t, J = 7.8 Hz),
7.42 (2, d, J = 8.4 Hz), 7.95 (2, d, J = 8.4 Hz); 13C NMR (75 MHz,
CDCl3) 14.4, 22.9, 29.4, 29.64, 29.8, 29.9, 31.2, 32.2, 36.3,
127.3, 129.8, 142.0, 151.9. Reaction of 2-amino-1,3,4-thiadiazole
(228 mg, 2.25 mmol) with p-hexadecylbenzenesulfonyl chloride
(600 mg, 1.50 mmol) afforded the product 31 (320 mg,
0.69 mmol, 46% yield), Rf 0.46 (5% MeOH/CH2Cl2), as a solid,
mp 118–119 °C, after chromatography on silica gel (70–230
mesh) eluted with CH2Cl2:MeOH 19:1; 1H NMR (300 MHz,
CDCl3) d 0.88 (3, t, J = 6.9 Hz), 1.25 (26, m), 1.59 (2, m), 2.64
(2, t, J = 8.1 Hz), 7.29 (2, d, J = 7.8 Hz), 7.84 (2, d, J = 7.8 Hz),
8.23 (1, s); 13C NMR (75 MHz, CDCl3) 14.1, 22.7, 29.2, 29.3,
29.4, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.5,
148.7, 167.5; HRMS (ESI+, m/z) calcd for C24H40N3O2S2
466.2556, observed 466.2558 (M+H)+.
2.1.10. 4-Dodecyl-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesul-
fonamide (34)
In a similar manner, reaction of 2-amino-5-ethyl-1,3,4-thiadi-
azole (169 mg, 1.3 mmol) and p-dodecylbenzenesulfonyl chlo-
ride (300 mg, 0.87 mmol) gave the product 34 (225 mg,
0.51 mmol, 59%), Rf 0.27 (50% EtOAc/hexanes), after chromatog-
raphy on silica gel (70–230 mesh) eluted with CH2Cl2/MeOH
49:1. Recrystallization from EtOAc/hexanes 7:3 gave an analyti-
cal sample, mp 93–94 °C; 1H NMR (500 MHz, CDCl3) d 0.88 (3, t,
J = 6.5 Hz), 1.20–1.36 (18, m), 1.33 (3, t, J = 7.5 Hz), 1.54–1.63 (2,
m), 2.63 (2, t, J = 7.5 Hz), 2.84 (2, q, J = 7.5 Hz), 7.25 (2, d,
J = 8.5 Hz), 7.83 (2, d, J = 8.5 Hz), 12.30 (1, br s); 13C NMR
(125 MHz, CDCl3)
d 12.6, 14.1, 22.7, 24.4, 29.2, 29.3, 29.4,
29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.8, 138.4, 148.2, 160.1
168.2; HRMS (ESI+, m/z) calcd for C22H36N3O2S2 438.2249, ob-
served 438.2247 (M+H)+.
2.1.11. N-(5-tert-Butyl-1,3,4-thiadiazol-2-yl)-4-dodecylbenzene-
sulfonamide (35)
In a similar manner, reaction of 2-amino-5-tert-butyl-1,3,4-
thiadiazole (204 mg, 1.3 mmol) and p-dodecylbenzenesulfonyl
chloride (300 mg, 0.87 mmol) gave the product 35 (350 mg,
0.75 mmol, 86%), Rf 0.45 (50% EtOAc/hexanes), after chromatogra-
phy on silica gel (70–230 mesh) eluted with CH2Cl2/MeOH 49:1.
Recrystallization from EtOAc/hexanes 7:3 gave an analytical sam-
ple, mp 117–118 °C; 1H NMR (500 MHz, CDCl3) d 0.88 (3, t,
J = 6.5 Hz), 1.20–1.36 (18, m), 1.38 (9, s), 1.56–1.64 (2, m), 2.63
(2, t, J = 7.5 Hz), 7.25 (2, d, J = 8.0 Hz), 7.86 (2, d, J = 8.0 Hz), 12.24
(1, br s); 13C NMR (125 MHz, CDCl3) d 14.1, 22.7, 29.2, 29.3, 29.4,
29.5, 29.6, 29.7, 31.1, 31.8, 35.8, 36.5, 126.5, 128.7, 138.5, 148.1,
167.8, 168.0; HRMS (ESI+, m/z) calcd for C24H40N3O2S2 466.2562,
observed 466.2562 (M+H)+.
2.1.8. 4-Octadecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide
(32)
In a similar manner, 1-phenyloctadecane (0.84 g, 2.5 mmol) and
chlorosulfonic acid (0.50 mL, 7.5 mmol) gave p-octadecylbenzen-
esulfonyl chloride as a white solid (0.60 g, 1.4 mmol, 56%), mp
43–44 °C, after chromatography on silica gel eluted with hex-
anes/EtOAc (49:1); 1H NMR (300 MHz, CDCl3)
d 0.86 (3, t,
J = 6.9 Hz), 1.25 (30, m), 1.65 (2, m), 2.72 (2, t, J = 7.8 Hz), 7.42 (2,
d, J = 8.4 Hz), 7.93 (2, d, J = 8.4 Hz); 13C NMR (75 MHz, CDCl3)
14.1, 22.7, 29.2, 29.4, 29.5, 29.7, 30.9, 31.9, 36.0, 127.1, 129.6,
141.8, 151.7. Reaction of 2-amino-1,3,4-thiadiazole (177 mg,
1.75 mmol) with p-octadecylbenzenesulfonyl chloride (500 mg,
1.17 mmol) afforded the product 32 (296 mg, 0.60 mmol, 51%
yield), Rf 0.46 (5% MeOH/CH2Cl2), as a solid, mp 116–117 °C, after
chromatography on silica gel (70–230 mesh) eluted with CH2Cl2/
MeOH 19:1; 1H NMR (300 MHz, CDCl3) d 0.86 (3, t, J = 6.9 Hz),
1.25 (30, m), 1.60 (2, m), 2.64 (2, t, J = 7.8 Hz), 7.29 (2, d,
J = 7.8 Hz), 7.82 (2, d, J = 7.8 Hz), 8.21 (1, s); 13C NMR (75 MHz,
CDCl3) 14.0, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.9,
35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; HRMS (ESI+, m/z)
calcd for C26H44N3O2S2 494.2869, observed 494.2869 (M+H)+.
2.1.12. 2-(5-(4-Dodecylphenylsulfonamido)-1,3,4-thiadiazol-2-
yl)acetic Acid (36)
Distilled water (3.0 mL) and 10% aqueous NaOH (0.65 mL)
were added to compound 37 (200 mg, 0.40 mmol) and the mix-
ture was heated under reflux for 2 h. The pH of the solution
was then adjusted to 4.0 by addition of 1.0 M HCl, the resulting
precipitate was isolated by filtration, washed with cold water,
and dried to give the product 36 (161 mg, 0.34 mmol, 85%),
Rf 0.34 (20% MeOH/CH2Cl2), as a light yellow solid, mp 194–
195 °C; 1H NMR (300 MHz, DMSO-d6) d 0.85 (3, t, J = 6.6 Hz),
1.23 (18, m), 1.53 (2, m), 2.57 (2, t, J = 7.5 Hz), 3.74 (2, s),
7.24 (2, d, J = 8.1 Hz), 7.61 (2, d, J = 7.8 Hz); 13C NMR
(75 MHz, DMSO-d6) d 14.0, 22.1, 28.8, 28.9, 29.1, 30.7, 31.3,
34.9, 37.4, 125.8,128.4, 141.2, 146.0, 153.3, 168.9, 170.8; HRMS
(ESI+, m/z) calcd for C22H34N3O4S2 468.1991, observed 468.1977
(M+H)+.
2.1.9. 4-Dodecyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesul-
fonamide (33)
A suspension of 2-amino-5-methyl-1,3,4-thiadiazole (150 mg,
1.3 mmol) in pyridine (0.5 mL) was stirred and cooled in an ice
bath
while
p-dodecylbenzenesulfonyl
chloride
(300 mg,
0.87 mmol) was added slowly. The reaction mixture was allowed
to attain rt, then heated in an oil bath at 95 °C for 1 h. The reac-
tion mixture was then cooled, added to aqueous 10% HCl (5 mL),