S.N. Manjula et al. / European Journal of Medicinal Chemistry 44 (2009) 2923–2929
2927
40 ꢂC. The resulting compounds were purified over silica gel
using CHCl3:EtOAc (7:3) to yield pure optically active thiourea
derivatives.
4.1.3.6. 1-(3-Chloro-4-fluorophenyl)-3-((S)-1-cyclohexylethyl)thiourea
(IVf). The compound was prepared as per the general procedure
mentioned above purified and isolated as colourless solid; yield
20
75%; mp 74–75 ꢂC; [
a]
¼ ꢀ45.7 (c1.05 CHCl3); IR (KBr) vmax 3237,
D
4.1.3. General procedure for the synthesis of optically active
substituted 2-aminobenzothiazoles (Va–h, Scheme 1)
3052, 2933, 2850,1608,1544 cmꢀ1; 1H NMR (CDCl3)
s, 1H, NH), 7.33–7.14 (m, 3H, Ar-H), 5.78 (br s, 1H, NH), 4.37 (br s,
1H), 1.77–1.05 (m, 14H); 13C NMR (CDCl3)
ppm; 180.0, 158.4, 155.0,
d ppm; 8.25 (br
Optically active substituted thioureas (0.01 mol) were dissolved
in chloroform (15 ml), the reaction mixture was cooled in an ice
bath and then bromine:chloroform (1:9) mixture was added drop
wise. The reaction was monitored by TLC and after an hour, was
poured on to crushed ice. The solid that separated was filtered,
dried in each case and then purified by column chromatography
using silica gel. It was eluted with CHCl3:EtOAc (7:3) and the
eluents on evaporation and crystallization yielded pure optically
active substituted 2-aminobenzothiazoles.
d
133.0, 127.8, 125.3, 117.6, 55.7, 42.9, 29.2, 29.0, 26.3, 26.1, 26.0, 17.2;
DIPMS 315.1 (Mþ).
4.1.3.7. 1-(3-Chloro-4-fluorophenyl)-3-((R)-octan-2-yl)thiourea
(IVg). The compound was prepared as per the general procedure
mentioned above purified and isolated as colourless solid; yield
20
74%; mp 60–61 ꢂC; [
a
]
¼ ꢀ41.1 (c1.24 CHCl3); IR (KBr) vmax 3224,
D
3045, 2927, 2856,1600,1544 cmꢀ1; 1H NMR (CDCl3)
d ppm; 8.45 (br
s, 1H, NH), 7.35–7.18 (m, 3H, Ar-H), 5.75 (br s, 1H, NH), 4.47 (br s,
4.1.3.1. 1-(3-Chloro-4-fluorophenyl)-3-((R)-1-phenylethyl)thiourea
(IVa). This compound was prepared as per the above-mentioned
1H), 1.31–1.24 (m, 10H), 1.21 (d, 3H, J ¼ 6.4 Hz), 0.91 (m, 3H); 13C
NMR (CDCl3)
d 179.7, 158.4, 133.0, 127.8, 125.3, 122.2, 117.5, 51.5,
procedure purified and isolated as pale yellow liquid: yield 64%;
36.4, 31.6, 29.0, 25.8, 22.5, 20.3, 14.0 ppm; DIPMS 317.1 (Mþ).
20
mp 110 ꢂC [
a
]
D
¼ þ4.2(c1.20 CHCl3); IR (KBr) vmax 3130, 2928,
2831, 2120, 1610 cmꢀ1
;
1H NMR (CDCl3)
d
ppm; 7.70 (br s, 1H,
4.1.3.8. 1-(2-(Benzyloxy)cyclohexyl)-3-(3-chloro-4-fluorophenyl)thiourea
NH), 7.62–7.29 (m, 5H, Ar-H), 6.25 (br s, 1H, NH), 4.65 (m, 1H), 3.62
(IVh). The compound was prepared as per the general procedure
(m, 1H), 3.44 (m, 2H), 1.76–1.25 (m, 8H); 13C NMR (CDCl3)
mentioned above purified and isolated as colourless solid: yield
20
d
ppm; 138.5, 132.0, 129.0, 128.0, 128.2, 80.9, 60.5, 32.0, 31.3, 30.0,
61%; mp 112–113 ꢂC; [
a]
¼ þ75.4 (c1.18 CHCl3); IR (KBr) vmax
D
23.7, 23.4.
3232, 3035, 2944,1594,1556 cmꢀ1; 1H NMR (CDCl3)
d ppm; 9.39 (br
s, 1H, NH), 7.37–7.21 (m, 3H, Ar-H), 7.79–7.95 (m, 5H, Ar-H), 6.25 (br
s, 1H, NH), 4.76 (d, 3H, J ¼ 6.0 Hz, 1H), 4.44 (d, 3H, J ¼ 6.2 Hz, 1H),
3.43 (m, 2H), 2.36–1.27 (m, 8H); HRMS (EI) m/z calculated for
C20H22ClFN2OS: 393.1198; found: 393.1198.
4.1.3.2. 1-(3-Chloro-4-fluorophenyl)-3-((R)-1-phenylpropyl)thiourea
(IVb). The compound was prepared as per the general procedure
mentioned above purified and isolated as colourless solid; yield
20
60%; mp 210–211 ꢂC; [
a
]
D
¼ ꢀ50.4 (c1.30 CHCl3); IR (KBr) vmax
3224, 3041, 2967, 1600, 1542 cmꢀ1; 1H NMR (CDCl3)
d
ppm; 7.77 (br
4.1.3.9. 5-Chloro-6-fluoro-N-((R)-1-phenylethyl)benzo[d]thiazol-2-
amine (Va). The compound was prepared as per the general
s, 1H, NH) 7.38–7.28, (m, 3H, Ar-H), 7.15–7.07, (m, 5H, Ar-H), 6.30 (br
s, 1H, NH), 5.26 (1H), 1.09 (m, 2H), 0.92 (t,3H, J ¼ 7.25 Hz,
procedure mentioned above purified and isolated as colourless
20
J ¼ 7.23 Hz); 13C NMR (CDCl3)
d
ppm; 185.5, 155.2, 140.6, 133.1,
solid; yield 55%; mp 109–110 ꢂC; [
a
]
D
¼ þ11.2 (c1.06 CHCl3); IR
129.0, 128.0, 127.7, 126.5, 125.3, 125.2, 117.7, 60.6, 29.8, 10.5.
(KBr) vmax 3303, 2975, 1629, 1563 cmꢀ1; 1H NMR (DMSO-d6)
d ppm;
7.62–7.04 (m, 7H, Ar-H) 6.88, (br s, 1H, NH), 4.89, (m, 1H), 1.41 (d,
4.1.3.3. 1-(3-Chloro-4-fluorophenyl)-3-((R)-1-(4-methoxyphenyl)ethyl)
thiourea (IVc). The compound was prepared as per the general
procedure mentioned above purified and isolated as colourless solid;
yield 68%; mp 29–30 ꢂC; IR (KBr) vmax 3326, 2969, 1637, 1598, 1563,
3H, J ¼ 6.9 Hz); 13C NMR (DMSO-d6)
d ppm; 156.2, 155.3, 154.8,
145.0, 137.7, 129.0, 127.4, 126.4, 120.5, 117.9, 116.7, 49.5, 23.2; HRMS
(EI) m/z calcd for C15H12ClFN2S: 307.0467; found: 307.0462.
1496 cmꢀ1; 1H NMR (CDCl3)
d
ppm; 7.30–7.27 (m, 3H, Ar-H), 7.14–6.82
(m, 4H, Ar-H), 6.31 (br s, 1H, NH), 5.50 (b, 1H), 3.84 (s, 3H), 1.54 (d, 3H),
3.43; 13C NMR (CDCl3)
ppm; 180.1, 160.0, 158.3, 155.0, 143.5, 133.2,
4.1.3.10. 5-Chloro-6-fluoro-N-((R)-1-phenylpropyl)benzo[d]thiazol-2-
amine (Vb). The compound was prepared as per the general
d
procedure mentioned above purified and isolated as colourless
20
130.0, 127.7, 125.2, 118.2, 113.0, 55.3, 21.7; HRMS (EI) m/z calcd for
C16H16ClFN2OS: 339.0729; found: 339.0730.
solid; yield 40%; mp 159–160 ꢂC; [
a
]
¼ þ10.5 (c1.04 CHCl3); IR
D
(KBr) vmax 3153, 3070, 2929, 1619, 1519 cmꢀ1
ppm; 9.20 (br s, 1H, NH), 7.90–7.32, (2H, Ar-H), 7.29–7.01, (5H, Ar-
H), 4.90, (1H), 1.98, (m, 2H), 0.99, (3H); 13C NMR (DMSO-d6)
ppm;
167.0, 153.7, 142.5, 130.6, 128.5, 127.3, 126.6, 117.7, 116.7, 114.4, 110.0,
60.3, 29.7, 10.9; 19F NMR
;
1H NMR (DMSO-d6)
d
4.1.3.4. 1-(3-Chloro-4-fluorophenyl)-3-((R)-1-(4-fluorophenyl)ethyl)
thiourea (IVd). The compound was prepared as per the general
d
procedure mentioned above purified and isolated as colourless
d
ꢀ124.3, 126.6 ppm; HRMS (EI) m/z calcd
20
solid; yield 70%; mp 55–56 ꢂC; [
a
]
D
¼ ꢀ52.2 (c1.18 CHCl3); IR (KBr)
for C16H14ClFN2S: 321.0623; found: 321.0618.
vmax 3224, 3033, 2969, 1602, 1535 cmꢀ1 1H NMR (CDCl3)
; d ppm;
8.31 (br s, 1H, NH), 7.31–7.00 (m, 7H, Ar-H), 6.23 (br s,1H, NH), 5.56
4.1.3.11. 5-Chloro-6-fluoro-N-((R)-1-(4-methoxyphenyl)ethyl)benzo[d]
thiazol-2-amine (Vc). The compound was prepared as per the
(br s, 1H), 1.55 (d, 3H, J ¼ 6.7 Hz); 13C NMR (CDCl3)
d ppm; 179.9,
163.8, 160.5, 158.4, 137.7, 127.7, 125.1, 117.8, 117.5, 115.5, 53.7, 21.6;
general procedure mentioned above purified and isolated as col-
20
DIPMS 327.0 (Mþ).
ourless solid; yield 38%; mp 119–120 ꢂC; [
a
]
¼ þ11.9 (c1.00
D
CHCl3); IR (KBr) vmax 3421, 3153, 3077, 2850, 1627, 1525 cmꢀ1
;
1H
4.1.3.5. 1-(3-Chloro-4-fluorophenyl)-3-((R)-1-(4-chlorophenyl)ethyl)
thiourea (IVe). The compound was prepared as per the general
NMR (DMSO-d6) ppm; 7.82–7.22 (6H, Ar-H), 5.70 (br s, 1H, NH),
4.63 (br s, 1H), 3.98 (s, 3H, OCH3), 1.62 (d, 3H, J ¼ 6.8 Hz, 3H); HRMS
(EI) m/z calcd for C16H14ClFN2OS: 336.0499; found: 336.0478.
d
procedure mentioned above purified and isolated as colourless
20
solid; yield 55%; mp 58–60 ꢂC; [
a
]
¼ ꢀ77.2 (c1.23 CHCl3); IR (KBr)
D
vmax 3218, 3035, 1598, 1542, 1496 cmꢀ1
;
1H NMR (CDCl3)
d
ppm;
4.1.3.12. 5-Chloro-6-fluoro-N-((R)-1-(4-fluorophenyl)ethyl)benzo[d]
thiazol-2-amine (Vd). The compound was prepared as per the
8.20 (br s, 1H, NH), 7.33–7.28 (m, 3H, Ar-H), 7.23–7.09 (m, 4H, Ar-H),
6.18 (br s, 1H, NH), 5.57 (1H), 1.51 (d, 3H, J ¼ 6.7 Hz); 13C NMR
general procedure mentioned above and isolated as colourless solid;
20
(CDCl3)
d
ppm; 180.1, 158.5, 155.2, 140.5, 133.5, 129.0, 127.5, 125.3,
yield 45%; mp 124–125 ꢂC; [
a]
¼ þ20.8 (c1.25 CHCl3); IR (KBr) vmax
D
125.2, 117.8, 117.5, 53.7, 21.5; DIPMS 343.0 (Mþ).
3405, 2915, 1627, 1511 cmꢀ1; 1H NMR (DMSO-d6)
d ppm; 7.88–6.96