A.S. Bhambra et al. / European Journal of Medicinal Chemistry 108 (2016) 347e353
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4.3.2. Methyl-6-(1H-benzo[d]imidazol-1-yl)-4,5,7-trifluorobenzo
[b]thiophene-2-carboxylate (5ab)
and was extracted with ethyl acetate (15 ml ꢁ 3). The combined
extracts were washed with 0.2 M HCl solution and deionized water
successively and dried with sodium sulfate. The product was pu-
rified by silica column chromatography (elution with light petro-
leum/ethyl acetate). Yield 62%, white solid, m.p. 118e120 ꢂC. NMR
dH (CDCl3), 8.09 (1H, d, J ¼ 3.2 Hz), 3.98 (3H, s), 3.69 (3H, s), 3.65
(2H, s); NMR dF (CDCl3), 52.4 (1F, dd, J ¼ 18, 3 Hz), 28.5 (1F, d,
J ¼ 21 Hz), 18.3 (1F, dd, J ¼ 21, 18 Hz); NMR dc (CDCl3), 169.2, 161.9,
153.1 (d, J ¼ 246 Hz), 147.3 (ddd, J ¼ 242, 15, 4 Hz), 142.4 (ddd,
J ¼ 253, 14, 4 Hz), 137.6, 130.4 (ddd, J ¼ 15, 7, 4 Hz), 125.6e125.2 (m),
125.5 (d, J ¼ 7 Hz), 110.1 (t, J ¼ 22 Hz), 53.1, 52.8, 36.1; IR, nmax/cmꢀ1
1728 (C]O), 1273 (CeO); MS, m/z found 350.9969, C13H10F3O4S2,
(MþHþ) requires 350.9967; elemental analysis, C13H9F3O4S2 re-
quires: C, 44.57; H, 2.59; found: C, 44.40; H, 2.53.
Yield 57%, white solid, m.p. 178e179 ꢂC. NMR dH (CDCl3), 8.26
(1H, d, J ¼ 3.2 Hz), 8.10 (1H, s), 7.92 (1H, dd, J ¼ 7.6, 2.4 Hz),
7.42e7.37 (2H, m), 7.30 (1H, d, J ¼ 8.0 Hz), 4.02 (3H, s); NMR dF
(CDCl3), 38.9 (1F, d, J ¼ 19 Hz), 20.2 (1F, t, J ¼ 19 Hz), 16.8 (1F, d,
J ¼ 19 Hz); NMR dc (CDCl3),171.1,161.5,147.6 (dt, J ¼ 251, 4 Hz),143.1,
142.8, 142.7 (dt, J ¼ 249, 5 Hz), 142.5 (dt, J ¼ 251, 5 Hz), 138.2, 133.8,
129.5 (ddd, J ¼ 19, 7, 2 Hz), 125.8 (ddd, J ¼ 17, 5, 2 Hz), 125.3 (d,
J ¼ 5 Hz), 124.4, 123.5, 120.8, 112.9 (t, J ¼ 6 Hz), 110.4, 53.2; IR, nmax
/
cmꢀ1 1720 (C]O), 1249 (CeO); MS, m/z found 363.0402,
C
C
17H9F3N2O2S, (MþHþ) requires 363.0410; elemental analysis,
17H9F3N2O2S requires: C, 56.51; H, 2.21; N, 7.75; found: C, 56.36; H,
2.56; N, 7.62.
4.3.3. Methyl-6-(2-bromophenoxy)-4,5,7-trifluorobenzo[b]
thiophene-2-carboxylate (5ac)
4.4. Syntheses of compounds 5bae5be
Yield 78%, white solid, m.p. 126e128 ꢂC. NMR dH (CDCl3), 8.19
(1H, d, J ¼ 3.2 Hz), 7.67 (1H, dd, J ¼ 8, 1.6 Hz, H-300), 7.24 (1H, td,
J ¼ 7.6 Hz, 1.6 Hz, H-500), 7.03 (1H, td, J ¼ 7.6, 1.6 Hz, H-400), 6.78 (1H,
dd, J ¼ 7.6, 0.8 Hz), 4.01 (3H, s); NMR dF (CDCl3), 29.9 (1F, dd, J ¼ 17,
3 Hz), 19.4 (1F, dd, J ¼ 19, 17 Hz), 10.3 (1F, d, J ¼ 19 Hz); NMR dC
(CDCl3), 161.9, 154.1, 146.0 (dt, J ¼ 248, 4 Hz), 142.8 (ddd, J ¼ 254, 12,
4 Hz), 141.8 (ddd, J ¼ 248, 13, 3 Hz), 136.3, 134.1, 131.5 (t, J ¼ 14 Hz),
128.7, 125.9 (dd, J ¼ 18, 4 Hz), 125.6 (dd, J ¼ 19, 4 Hz), 125.3 (d,
J ¼ 6 Hz), 125.0, 115.5, 111.9, 53.1; IR, nmax/cmꢀ1 1720 (C]O), 1257
(CeO); MS, m/z found 416.9400, C16H9BrF3O3S, (MþHþ) requires
416.9402; elemental analysis, C16H8BrF3O3S requires: C, 46.06; H,
1.93; found: C, 46.07; H, 1.93.
Following the method for compounds 5aaeae, reaction of
compounds 2aee (2 mmol) and 3b (0.304 g, 2 mmol) provided
compounds 5baebe, purified by flash column chromatography
eluting with light petroleum/ethyl acetate.
4.4.1. Phenyl-(4,5,7-trifluoro-6-(1H-imidazol-1-yl)benzo[b]
thiophen-2-yl)methanone (5ba)
Yield 49%, cream solid, m.p. 132e134 ꢂC. NMR dH (CDCl3), 7.98
(1H, d, J ¼ 3.2 Hz), 7.92 (2H, d, J ¼ 7.2 Hz), 7.87 (1H, s), 7.67 (1H, tt,
J ¼ 7.6, 1.6 Hz), 7.57 (2H, t, J ¼ 7.6 Hz), 7.31 (1H, s), 7.28 (1H, s); NMR
dF (CDCl3), 36.6 (1F, d, J ¼ 19 Hz), 20.2 (1F, t, J ¼ 17 Hz), 14.7 (1F, d,
J ¼ 17 Hz); NMR dC (CDCl3), 188.1, 147.6, 146.5 (d, J ¼ 255 Hz), 143.1
(ddd, J ¼ 255, 16, 5 Hz), 141.8 (dd, J ¼ 250, 14 Hz), 138.0, 136.6, 133.6,
129.9, 129.4, 129.2 (dd, J ¼ 19, 7 Hz), 129.0, 126.2 (dd, J ¼ 19, 7 Hz),
125.6 (d, J ¼ 5 Hz),120.5,114.8 (t, J ¼ 15 Hz); IR, nmax/cmꢀ11643 (C]
O); MS, m/z found 359.0454, C18H10F3ON2S, (MþHþ) requires
359.0460; elemental analysis, C18H9F3N2OS requires: C, 60.33; H,
2.53; N, 7.82; found: C, 60.08; H, 2.60; N, 7.68.
4.3.4. Methyl-6-[(2-bromophenyl)thio]-4,5,7-trifluorobenzo[b]
thiophene-2-carboxylate (5ad)
Yield 66%, white solid, m.p. 143e145 ꢂC. NMR dH (CDCl3), 8.20
(1H, d, J ¼ 3.2 Hz), 7.60 (1H, dd, J ¼ 8.0 Hz, 1.2 Hz), 7.20 (1H, td,
J ¼ 7.2 Hz,1.2 Hz), 7.10 (1H, td, J ¼ 7.2,1.2 Hz), 6.94 (1H, d, J ¼ 7.6 Hz),
4.02 (3H, s); NMR dF (CDCl3), 53.7 (1F, dd, J ¼ 17, 3 Hz), 29.7 (1F, d,
J ¼ 21 Hz), 18.9 (1F, t, J ¼ 20 Hz); NMR dC (CDCl3), 161.9, 153.2 (d,
J ¼ 248 Hz), 143.7 (ddd, J ¼ 250, 16, 5 Hz), 141.3 (d, J ¼ 245, 21,
10 Hz), 138.0, 135.4, 133.4, 130.5 (dd, J ¼ 17, 7 Hz), 128.9, 128.0, 128.0
(d, J ¼ 7 Hz), 125.9e125.4 (m), 125.4 (d, J ¼ 5 Hz), 122.7, 109.2 (t,
J ¼ 21 Hz), 53.2; IR, nmax/cmꢀ1 1720 (C]O), 1265 (CeO); MS, m/z
4.4.2. 6-(1H-Benzo[d]imidazol-1-yl)-4,5,7-trifluorobenzo[b]
thiophen-2-yl(phenyl)methanone (5bb)
Yield 51%, orange solid, m.p. 140e142 ꢂC. NMR dH (CDCl3), 8.09
(1H, s), 8.04 (1H, d, J ¼ 3.2 Hz), 7.94 (2H, d, J ¼ 7.8 Hz), 7.93e7.89
(1H, m) 7.70 (1H, t, J ¼ 7.2 Hz), 7.59 (2H, t, J ¼ 7.6 Hz), 7.42e7.34 (2H,
m), 7.31e7.27 (1H, m); NMR dF (CDCl3), 39.34 (1F, d, J ¼ 17 Hz), 20.6
(1F, t, J ¼ 20 Hz), 16.9 (1F, d, J ¼ 20 Hz); NMR dc (CDCl3), 188.2, 147.8
(d, J ¼ 251 Hz),147.7,143.1 (ddd, J ¼ 254,13, 4 Hz),143.2,142.8,142.7
(dd, J ¼ 249, 14 Hz), 136.6, 133.8, 133.6,129.9 (dd, J ¼ 17, 4 Hz), 129.5,
129.0, 126.2 (ddd, J ¼ 18, 4, 3 Hz), 125.7 (d, J ¼ 6 Hz), 124.6, 123.6,
120.9, 113.3 (t, J ¼ 16 Hz), 110.5; IR, nmax/cmꢀ1 1643 (C]O); MS, m/z
found 432.9129,
elemental analysis, C16H8BrF3O2S2 requires: C, 44.35; H, 1.86;
found: C, 44.18; H, 1.74.
C
16H9O2 BrF3S2, (MþHþ) requires 432.9174;
4.3.5. Methyl-6-((4-(tert-butyl)phenyl)thio)-4,5,7-trifluorobenzo
[b]thiophene-2-carboxylate (5ae)
Yield 76%, white solid, m.p. 127e129 ꢂC. NMR dH (CDCl3), 8.15
(1H, d, J ¼ 3.2 Hz), 7.37e7.31 (4H, m), 4.00 (3H, s), 1.31 (9H, s); NMR
dF (CDCl3), 52.6 (1F, d, J ¼ 17 Hz), 29.3 (1F, d, J ¼ 23 Hz), 18.2 (1F, t,
J ¼ 20 Hz); NMR dc (CDCl3), 161.9, 152.9 (dt, J ¼ 248, 5 Hz), 151.1,
147.0 (ddd, J ¼ 245, 13, 4 Hz), 142.5 (ddd, J ¼ 253, 18, 4 Hz), 137.4,
130.5, 130.2 (ddd, J ¼ 22, 9, 4 Hz), 130.0, 126.4 (C-300, C-500),
125.6e125.2 (m), 125.3 (d, J ¼ 5 Hz), 111.8 (t, J ¼ 22 Hz), 53.0, 34.6,
31.2; IR, nmax/cmꢀ1 1712 (C]O), 1249 (CeO); MS, m/z found
411.0696, C20H18F3O2S2, (MþHþ) requires 411.0695; elemental
analysis, C20H17F3O2S2 requires: C, 58.52; H, 4.17; found: C, 58.40;
H, 4.12.
found 409.0608,
elemental analysis, C22H11F3ON2S requires: C, 64.70; H, 2.69; N,
6.86; found: C, 64.47; H, 2.70; N, 6.96.
C
22H12F3ON2S, (MþHþ) requires 409.0617;
4.4.3. 6-(2-Bromophenoxy)-4,5,7-trifluorobenzo[b]thiophen-2-
yl(phenyl)methanone (5bc)
Yield 48%, yellow solid, m.p. 110e112 ꢂC. NMR dH (CDCl3), 7.95
(1H, d, J ¼ 2.8 Hz), 7.92 (2H, d, J ¼ 7.6 Hz), 7.71e7.61 (2H, m), 7.56
(2H, t, J ¼ 7.6 Hz), 7.21 (1H, t, J ¼ 7.6 Hz), 7.01 (1H, t, J ¼ 7.2 Hz), 6.76
(1H, d, J ¼ 8.4 Hz); NMR dF (CDCl3), 30.3 (1F, d, J ¼ 15 Hz), 19.6 (1F, t,
J ¼ 20 Hz), 10.5 (1F, d, J ¼ 20 Hz); NMR dC (CDCl3), 188.4, 154.1, 146.1
(dd, J ¼ 249, 4 Hz), 146.0, 143.2 (ddd, J ¼ 251, 14, 3 Hz), 142.1 (ddd,
J ¼ 251, 14, 4 Hz), 136.9, 134.1, 133.3, 131.9 (t, J ¼ 14 Hz), 129.4, 128.9,
128.7, 126.4 (dd, J ¼ 17, 4 Hz), 126.3e125.8 (m), 126.1 (d, J ¼ 4 Hz),
125.1, 115.6, 112.0; IR, nmax/cmꢀ1 1643 (C]O); MS, m/z found
462.9601, C21H11BrF3O2S, (MþHþ) requires 462.9610; elemental
analysis, C21H10BrF3O2S requires: C, 54.44; H, 2.18; found: C, 54.37;
H, 2.04.
4.3.6. Methyl-4,5,7-trifluoro-6-((2-methoxy-2-oxoethyl)thio)benzo
[b]thiophene-2-carboxylate (5af)
Methyl mercaptoacetate (4 mmol) was added dropwise to a
solution of pentafluorobenzaldehyde (2 mmol) and Et3N (5 mmol)
in THF (5 ml) with ice cooling. The mixture was stirred at room
temperature for 16 h. The reaction was poured into deionized water