390 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Chua et al.
night. After cooling, the precipitated product was collected and
washed with benzene and diethyl ether to furnish 18 as a
white powder (0.7 g, 88%): mp 147-149 °C; IR 1710, 1479,
1366, 1253, 1018, 757, 626, 600 cm-1; δH (CDCl3) 8.13-8.10
(m, 2H, H-2′, H-4), 8.01 (dd, 1H, J ) 2.0, 8.1 Hz, H-6′), 7.94
(d, 1H, J ) 7.8 Hz, H-7), 7.54 (dt, 1H, J ) 1.3, 7.7 Hz, H-5),
7.43 (dt, 1H, J ) 1.2, 7.6 Hz, H-6), 7.24 (d, 1H, J ) 8.1 Hz,
H-5′), 2.33 (s, 6H, 2 × COCH3); δC (CDCl3) 172.9 (2 × C), 167.1
(C), 154.5 (CH), 125.9 (CH), 123.8 (CH), 122.2 (CH), 27.1 (2 ×
COCH3), 18.0 (CH3). Anal. (C18H16N2O2S) C, H, N.
8.08 (m, 3H, H-4, H-2′, H-6′), 8.03 (d, 1H, J ) 7.5 Hz, H-7),
7.89 (d, 2H, J ) 8.8 Hz, H-3′, H-5′), 7.52 (dt, 1H, J ) 1.3, 7.6
Hz, H-5), 7.42 (dt, 1H, J ) 1.2, 7.5 Hz, H-6), 6.98 (s, 1H,
CHCl2); δC (DMSO-d6) 167.6 (C), 163.0 (C), 154.3 (C), 141.4
(C), 135.2 (C), 129.6 (C), 129.0 (2 × CH), 127.5 (CH), 126.2
(CH), 123.5 (CH), 123.2 (CH), 120.9 (2 × CH), 67.9 (CHCl2).
Anal. (C15H10Cl2N2OS‚HCl) C, H, N.
The free base of 22 was liberated as a white powder (0.2 g,
89%): mp 223-225 °C; IR 3254, 3054, 1679, 1605, 1543, 1481,
1409, 1250, 968, 841, 806, 758, 729 cm-1; δH (DMSO-d6) 11.01
(br s, 1H, NH), 8.13 (d, 3H, J ) 8.7 Hz, H-4, H-2′, H-6′), 8.05
(d, 1H, J ) 7.9 Hz, H-7), 7.83 (d, 2H, J ) 8.6 Hz, H-3′, H-5′),
7.55 (t, 1H, J ) 7.4 Hz, H-5), 7.45 (t, 1H, J ) 7.4 Hz, H-6),
6.66 (s, 1H, CHCl2); δC (DMSO-d6) 167.5 (C), 162.9 (C), 154.5
(C), 141.2 (C), 135.2 (C), 129.8 (C), 129.1 (2 × CH), 127.5 (CH),
126.3 (CH), 123.6 (CH), 123.2 (CH), 121.0 (2 × CH), 68.2
(CHCl2).
2-(4-Dia ceta m id o-3-ch lor op h en yl)ben zoth ia zole (19).
Prepared from 5 (0.50 g, 1.92 mmol) and acetic anhydride (0.4
mL, 4.24 mmol) in refluxing pyridine (4.5 mL) overnight, the
product 19 was isolated as a pale-yellow powder (0.11 g,
16%): mp 155-157 °C; IR 1728, 1478, 1370, 1242, 1017, 762,
598 cm-1; δH (CDCl3) 8.30 (d, 1H, J ) 2 Hz, H-2′), 8.12-8.05
(m, 2H, H-4, H-7), 7.92 (dd, 1H, J ) 2, 8.25 Hz, H-6′), 7.54 (dt,
1H, J ) 2 Hz, H-6), 7.44 (dt, 1H, J ) 2, 8.25 Hz, H-5), 7.37 (d,
2-(4-Ch lor oacetam ido-3-iodoph en yl)ben zoth iazole (23).
To a solution of compound 7 (0.15 g, 0.426 mmol) in benzene
(15 mL) was added dropwise chloroacetyl chloride (0.18 g) at
room temperature. A yellow precipitate was formed, and the
resulting mixture was stirred at 50 °C for 30 min and cooled
in an ice bath. The solid was collected, washed with petroleum
ether, and dried to give a yellow powder of a hydrate of 23
(0.13 g, 71%): mp 192-194 °C; IR 3441, 3312, 1695, 1569,
1534, 1511, 1484, 1384, 1308, 750 cm-1; δH (DMSO-d6) 9.88
(br s, 1H, NH), 8.58 (d, 1H, J ) 1.9 Hz, H-2′), 8.18 (d, 1H, J )
7.9 Hz, H-4), 8.13-8.08 (m, 2H, H-7, H-6′), 7.77 (d, 1H, J )
8.4 Hz, H-5′), 7.58 (t, 1H, J ) 7.7 Hz, H-5), 7.49 (t, 1H, J )
7.5 Hz, H-6), 4.47 (s, 2H, CH2Cl); δC (DMSO-d6) 166.1 (C), 165.8
(C), 154.3 (C), 142.1 (C), 137.9 (CH), 135.5 (C), 132.5 (C), 128.6
(CH), 127.7 (CH), 127.1 (CH), 126.6 (CH), 123.9 (CH), 123.3
(CH), 97.1 (C), 44.0 (CH2). Anal. (C15H10ClIN2OS‚H2O) C, H,
N.
J ) 8.25 Hz, H-5), 2.34 (s, 6H, 2 × COCH3). Anal. (C17H13
-
ClN2O2S) C, H, N.
2-(4-Ch lor oa ceta m id op h en yl)ben zoth ia zole (20). To a
solution of 3 (0.8 g, 3.45 mmol) in refluxing benzene (40 mL)
was added dropwise chloroacetyl chloride (0.8 mL), and the
mixture was boiled for a further 30 min. The precipitate was
collected and washed with diethyl ether to give 2-(4-chloroac-
etamidophenyl)benzothiazole hydrochloride as a yellow powder
(1.08 g, 90%): mp 232-234 °C; IR 3160, 3082, 3025, 2435,
1703, 1598, 1535, 1446, 1384, 1342, 1191, 838, 754 cm-1; δH
(DMSO-d6) 11.03 (s, 1H, NH), 9.45 (br s, 1H, N+H), 8.13-8.01
(m, 4H, H-2′, H-6′, H-4, H-7), 7.85 (d, 2H, J ) 8.6 Hz, H-3′,
H-5′), 7.53 (t, 1H, J ) 7.6 Hz, H-5), 7.43 (t, 1H, J ) 7.5 Hz,
H-6), 4.38 (s, 2H, CH2Cl); δC (DMSO-d6) 167.8 (C), 166.0 (C),
154.4 (C), 142.3 (C), 135.2 (C), 128.9 (2 × CH), 127.5 (CH),
126.2 (CH), 123.5 (CH), 123.1 (CH), 120.5 (2 × CH), 44.4 (CH2).
Basification of the salt (0.8 g) with 10% aqueous Na2CO3
(40 mL) at 50 °C for 1 h gave the pale-yellow free base 20 (0.63
g, 88%): mp 214-215 °C; IR 3453, 3321, 1674, 1528, 1410,
1384, 828, 754 cm-1; δH (DMSO-d6) 10.66 (s, 1H, NH), 8.15-
8.02 (m, 4H, H-2′, H-6′, H-4, H-7), 7.81 (d, 2H, J ) 8.6 Hz,
H-3′, H-5′), 7.54 (t, 1H, J ) 7.5 Hz, H-5), 7.44 (t, 1H, J ) 7.4
Hz, H-6), 4.33 (s, 2H, CH2Cl); δC (DMSO-d6) 167.7 (C), 165.9
(C), 154.5 (C), 142.1 (C), 135.2 (C), 129.0 (2 × CH), 127.5 (CH),
126.2 (CH), 123.5 (CH), 123.1 (CH), 120.5 (2 × CH), 44.5 (CH2).
Anal. (C15H11ClN2OS) C, H, N.
2-(4-Ch lor oa ceta m id op h en yl)ben zoxa zole (21). Simi-
larly prepared, from 2-(4-aminophenyl)benzoxazole (8) (0.28
g, 1.33 mmol) and chloroacetyl chloride (0.5 mL) in benzene
(15 mL), 2-(4-chloroacetamidophenyl)benzoxazole hydrochlo-
ride was formed (0.31 g, 72%): mp 211-215 °C; IR 3253, 3100,
3042, 2415, 1716, 1674, 1606, 1537, 1460, 1340, 1182, 933, 749
cm-1; δH (DMSO-d6) 10.93 (s, 1H, NH), 8.18 (d, 2H, J ) 8.7
Hz, H-2′, H-6′), 7.87 (d, 2H, J ) 8.7 Hz, H-3′, H-5′), 7.78 (m, 2
H, H-4, H-7), 7.40 (m, 2 H, H-5, H-6), 7.00 (br s, 1H, N+H),
4.37 (s, 2H, CH2Cl); δC (DMSO-d6) 166.1 (C), 162.9 (C), 151.0
(C), 142.7 (C), 142.5 (C), 129.2 (2 × CH), 126.1 (CH), 125.7
(CH), 122.3 (C), 120.5 (CH), 120.3 (2 × CH), 111.7 (CH), 44.5
(CH2).
The hydrochloride salt was basified with 10% aqueous Na2-
CO3 to form the free base of 21 as white crystals (0.18 g,
89%): mp 200-202 °C; IR 3262, 3122, 1670, 1618, 1542, 1501,
1405, 1343, 1249, 1061, 840, 744 cm-1; δH (DMSO-d6) 10.68
(s, 1H, NH), 8.19 (d, 2H, J ) 8.7 Hz, H-2′, H-6′), 7.85 (d, 2H,
J ) 8.7 Hz, H-3′, H-5′), 7.81-7.76 (m, 2H, H-4, H-7), 7.45-
7.37 (m, 2H, H-5, H-6), 4.33 (s, 2H, CHCl2); δC (DMSO-d6) 166.0
(C), 163.0 (C), 152.0 (C), 142.6 (C), 142.5 (C), 129.2 (2 × CH),
126.1 (CH), 125.7 (CH), 122.3 (C), 120.5 (CH), 120.4 (2 × CH),
111.7 (CH), 44.5 (CHCl2). Anal. (C15H11ClN2O2) C, H, N.
2-(4-Ben za m id op h en yl)ben zoth ia zole (24). A mixture of
compound 3 (0.3 g, 1.32 mmol) and benzoyl chloride (0.3 mL)
in pyridine (8 mL) was stirred at reflux for 2 h, then cooled,
and poured into water (100 mL). The precipitate was recrys-
tallized from dichloromethane-methanol to give a white
powder (0.36 g, 82%): mp 227-229 °C; IR 3456, 3364, 1657,
1530, 1480, 1404, 1385, 1316, 967, 829, 757, 712 cm-1; δH
(DMSO-d6) 10.60 (s, 1H, NH), 8.17-7.99 (m, 8H), 7.62 (m, 5H);
δC (DMSO-d6) 167.9 (C), 166.8 (C), 154.5 (C), 143.0 (C), 135.5
(C), 135.2 (C), 132.7 (CH), 129.3 (2 × CH), 128.82 (C), 128.76
(2 × CH), 128.7 (2 × CH), 127.5 (CH), 126.2 (CH), 123.5 (CH),
123.2 (CH), 121.3 (2 × CH); m/z 330 (M+), 105. Anal. (C20H14N2-
OS) C, H, N.
2-(4-Tr iflu or oacetam idoph en yl)ben zoth iazole (25). Com-
pound 3 (0.49 g, 2.17 mmol) was treated with trifluoroacetic
anhydride (1 g) in benzene under reflux for 5 h. The precipitate
was collected by filtration and washed with benzene to give
yellow microcrystals of 2-(4-trifluoroacetamidophenyl)ben-
zothiazole trifluoroacetate salt (0.935 g, 99%): mp 140-143
°C; IR 3305, 1745, 1601, 1543, 1297, 1184, 1150, 707 cm-1; δH
(DMSO-d6) 11.57 (s, 1H, NH), 9.73 (br s, 1H, N+H), 8.17-8.13
(m, 3H, H-4, H-2′, H-6′), 8.06 (d, 1H, J ) 8.0 Hz, H-7), 7.91 (d,
2H, J ) 8.8 Hz, H-3′, H-5′), 7.55 (t, 1H, J ) 7.6 Hz, H-5), 7.46
(t, 1H, J ) 7.5 Hz, H-6); δC (DMSO-d6) 167.3 (C), 159.2 (q, J
) 38.4 Hz, COCF3), 155.5 (q, J ) 37.2 Hz, NHCOCF3), 154.4
(C), 139.9 (C), 135.3 (C), 130.7 (C), 128.9 (2 × CH), 127.5 (CH),
126.4 (CH), 123.7 (CH), 123.2 (CH), 122.2 (2 × CH), 116.5 (q,
J ) 228.7 Hz, NHCOCF3), 115.9 (q, J ) 289.3 Hz, COCF3).
Basification of the salt gave the free base of 25 as a white
powder (0.23 g, 69%): mp 232-235 °C; IR 3345, 1705, 1596,
1537, 1482, 1415, 1287, 1249, 1156, 971, 908, 837, 760, 729
cm-1; δH (DMSO-d6) 11.57 (s, 1H, NH), 8.17-8.13 (m, 3H, H-4,
H-2′, H-6′), 8.06 (d, 1H, J ) 7.8 Hz, H-7), 7.91 (d, 2H, J ) 8.8
Hz, H-3′, H-5′), 7.56 (dt, 1H, J ) 1.2, 7.6 Hz, H-5), 7.47 (dt,
1H, J ) 1.2, 7.6 Hz, H-6); δC (DMSO-d6) 167.3 (C), 155.5 (q, J
) 37.3 Hz, NHCOCF3), 139.9 (C), 135.3 (C), 130.7 (C), 128.9
(2 × CH), 127.5 (CH), 126.4 (CH), 123.7 (CH), 123.2 (CH), 122.2
(2 × CH), 116.5 (q, J ) 228.7 Hz, NHCOCF3); m/z 322 (M+).
Anal. (C15H9F3N2OS) C, H, N.
2-(4-Dich lor oacetam idoph en yl)ben zoth iazole (22). Simi-
larly prepared, from compound 3 (0.4 g, 1.77 mmol) and
dichloroacetyl chloride (0.34 mL) in benzene according to the
above procedure, the yellow hydrochloride salt of 22 was
formed (0.56 g, 85%): mp 237-241 °C; IR 2998, 2426, 1708,
1594, 1534, 1500, 1444, 1344, 1248, 1187, 1165, 840, 753 cm-1
;
δH (DMSO-d6) 11.69 (s, 1H, NH), 10.06 (br s, 1H, N+H), 8.11-