700
Y. Wang et al. / Bioorg. Med. Chem. 22 (2014) 692–702
(7.7 mL, 43.9 mmol) at room temperature. The reaction mixture
was heated at reflux under nitrogen overnight. The reaction mix-
ture was partitioned between DCM (150 mL) and water
(80 mL).The organic phase was washed with water (50 mL ꢀ 2),
brine (50 mL), dried over anhydrous sodium sulfate, and concen-
trated. The residue was purified by column chromatography (silica
gel, EtOAc:PE = 25–50%) to give N-(4-(3-chlorophenyl)thiophen-2-
yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (19c) (7.0 g, 68% yield)
as a pale brown solid: MS(ES+) m/z 419.9 (M+H+).
phen-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (19g) (260 mg,
0.633 mmol) in the same manner as described for 9g as a white so-
lid: 1H NMR (400 MHz, DMSO-d6) d ppm 12.13 (s, 1H), 7.87 (d,
J = 8.4 Hz, 2H), 7.55–7.86 (m, 5H), 7.36–7.46 (m, 4H), 7.24 (t,
J = 7.6 Hz, 2H), 6.88 (s, 1H), 3.96 (s, 2H), 3.29 (q, J = 7.2 Hz, 2H),
1.10 (t, J = 7.2 Hz, 3H). HRMS
C
28H23N2O4S2 (M+H)+ calcd
515.1099, found 515.1107. LCMS: tR = 3.18 min, >95%, MS(ES+) m/
z 514.9 (M+H)+.
To a solution of 19c (200 mg, 0.476 mmol) and 3-fluorobenzoyl
chloride (151 mg, 0.953 mmol) in 1,2-dichloroethane (DCE)
(16 mL) was added dropwise tin(IV) chloride (1 M in DCM,
0.953 mL, 0.953 mmol). The reaction mixture was heated to reflux
overnight. The reaction mixture was diluted with DCM (50 mL),
and then washed with water (20 mL). The aqueous phase was ex-
tracted with DCM (20 mL). The combined organic phase was dried
over anhydrous sodium sulfate. After filtration and concentration,
the residue was purified by column chromatography (silica gel,
EtOAc:PE = 1:1 to EtOAc:PE:THF = 5:5:2) to give the crude product,
which was further purified by MDAP to afford 9g (15 mg, 6% yield)
as a white solid: 1H NMR (400 MHz, DMSO-d6) d ppm 12.20
(s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.18–7.25
(m, 8H), 6.86 (s, 1H), 3.97 (s, 2H), 3.32 (q, J = 7.6 Hz, 2H), 1.11
(t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) d ppm 187.9
(d, J = 2.2 Hz), 168.5, 161.8 (d, J = 245.8 Hz), 146.6, 145.1, 141.4, 141.1
(d, J = 6.6 Hz), 138.0, 137.6, 133.1, 130.9 (2C), 130.5 (d, J = 8.1 Hz),
130.2, 129.4, 128.4 (2C), 128.2, 128.1, 127.3, 125.2 (d, J = 2.2 Hz),
118.8 (d, J = 21.3 Hz), 115.7 (d, J = 22.7 Hz), 115.6, 49.7, 42.0, 7.7.
HRMS C27H22NO4S2ClF (M+H)+ calcd 542.0663, found 542.0665.
LCMS: tR = 3.51 min, >95%. MS(ES+) m/z 541.8, 543.7 (M+H)+.
5.1.17. N-(5-(2-Chlorobenzoyl)-4-(3-chlorophenyl)thiophen-2-
yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (9d)
Compound 9d (1.9 g, 29% yield) was prepared 2-chlorobenzoyl
chloride (4.2 g, 23.8 mmol) and 19c (5.0 g, 11.9 mmol) in the same
manner as described for 9g as a white solid: 1H NMR (400 MHz,
DMSO-d6) d ppm 12.16 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.61 (d,
J = 8.0 Hz, 2H), 7.16–7.31 (m, 8H), 6.76 (s, 1H), 3.95 (s, 2H), 3.30
(q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
DMSO-d6) d ppm 186.4, 168.2, 147.4, 145.6, 140.9, 138.8, 137.1,
136.9, 132.2, 131.2, 130.4 (2C), 129.7, 129.5, 129.2, 129.2, 128.7,
127.9 (2C), 127.7, 127.5, 127.3, 126.7, 115.9, 49.2, 41.5, 7.2. HRMS
C
27H22NO4S2Cl2 (M+H)+ calcd 558.0367, found 558.0378. LCMS:
tR = 3.54 min, >95%, MS(ES+) m/z 557.8, 559.8 (M+H)+.
5.1.18. N-(5-(3-Chlorobenzoyl)-4-(3-chlorophenyl)thiophen-2-
yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (9e)
Compound 9e (30 mg, 11% yield) was prepared 3-chlorobenzoyl
chloride (167 mg, 0.953 mmol) and 19c (200 mg, 0.476 mmol) in
the same manner as described for 9g as a white solid: 1H NMR
(400 MHz, DMSO-d6) d ppm 12.16 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H),
7.62 (d, J = 8.0 Hz, 2H), 7.17–7.38 (m, 8H), 6.85 (s, 1H), 3.96 (s,
2H), 3.30 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) d ppm 187.8, 168.5, 146.7, 145.2, 141.4,
140.6, 137.9, 137.6, 133.2, 133.1, 131.6, 130.9 (2C), 130.3, 130.2,
129.4, 128.9, 128.4 (2C), 128.2, 128.1, 127.5, 127.4, 115.6, 49.7,
42.0, 7.7. HRMS C27H22NO4S2Cl2 (M+H)+ calcd 558.0367, found
558.0372. LCMS: tR = 3.66 min, >95%, MS(ES+) m/z 557.8, 559.8
(M+H)+.
5.1.14. N-(5-Benzoyl-4-phenylthiophen-2-yl)-2-(4-
(ethylsulfonyl)phenyl)acetamide (9a)
Compound 9a (68 mg, 50% yield) was prepared from benzoyl
chloride (0.061 mL, 0.529 mmol) and 2-(4-(ethylsulfonyl)phenyl)-
N-(4-phenyl-2-thienyl)acetamide (19a) (102 mg, 0.265 mmol) in
the same manner as described for 9g as a white solid: 1H NMR
(400 MHz, DMSO-d6) d ppm 7.81 (d, J = 8.3 Hz, 2H), 7.55 (d,
J = 8.3 Hz, 2H), 7.35–7.40 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.05–
7.16 (m, 7H), 6.77 (s, 1H), 3.88 (s, 2H), 3.22 (q, J = 7.3 Hz, 2H),
1.04 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) d ppm
189.5, 168.3, 146.1, 145.7, 141.5, 138.8, 137.6, 136.1, 132.1, 130.8
(2C), 129.6 (2C), 129.3 (2C), 128.4 (4C), 128.2 (2C), 128.1, 127.0,
115.5, 49.7, 42.1, 7.6. HRMS C27H24NO4S2 (M+H)+ calcd 490.1147,
found 490.1149. LCMS: tR = 3.32 min, >95%, MS(ES+) m/z 490.0
(M+H)+.
5.1.19. N-(4-(3-Chlorophenyl)-5-(2-fluorobenzoyl)thiophen-2-
yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (9f)
Compound 9f (73 mg, 12% yield) was prepared 2-fluorobenzoyl
chloride (574 mg, 3.62 mmol) and 19c (760 mg, 1.81 mmol) in the
same manner as described for 9g as a white solid: 1H NMR
(400 MHz, DMSO-d6) d ppm 12.15 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H),
7.61 (d, J = 8.0 Hz, 2H), 7.31–7.36 (m, 2H), 7.17–7.24 (m, 4H),
7.06 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 9.6 Hz, 1H), 6.78 (s, 1H), 3.96 (s,
2H), 3.29 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) d ppm 185.1, 168.6, 158.9 (d, J = 248.6 Hz),
147.4, 145.8, 141.4, 137.6, 137.4, 133.1 (d, J = 8.1 Hz), 132.8,
130.9 (2C), 130.3 (d, J = 2.9 Hz), 130.0, 129.4, 128.4 (2C), 128.4,
128.3 (d, J = 15.4 Hz), 128.1, 128.0, 124.6 (d, J = 2.9 Hz), 116.1,
5.1.15. N-(5-Benzoyl-4-(3-chlorophenyl)thiophen-2-yl)-2-(4-
(ethylsulfonyl)phenyl)acetamide (9b)
Compound 9b (24 mg, 9% yield) was prepared from benzoyl
chloride (134 mg, 0.953 mmol) and 19c (200 mg, 0.476 mmol) in
the same manner as described for 9g as a white solid: 1H NMR
(400 MHz, DMSO-d6) d ppm 1.11 (t, J = 7.2 Hz, 3H), 3.30 (q,
J = 7.2 Hz, 2H), 3.96 (s, 2H), 6.85 (s, 1H), 7.19–7.26 (m, 6H), 7.38–
7.47 (m, 3H), 7.62 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H),
12.11 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 189.3, 168.4,
145.9, 144.5, 141.5, 138.9, 138.1, 137.6, 133.0, 132.2, 130.8 (2C),
130.2, 129.4, 129.2 (2C), 128.4 (2C), 128.3 (2C), 128.2, 127.9,
127.5, 115.4, 49.7, 42.0, 7.7. HRMS C27H23NO4S2Cl (M+H)+ calcd
524.0757, found 524.0764. LCMS: tR = 3.48 min, >95%, MS(ES+)
m/z 523.9, 525.9 (M+H)+.
115.8 (d, J = 21.3 Hz), 49.7, 42.0, 7.6. HRMS
C27H22NO4FS2Cl
(M+H)+ calcd 542.0663, found 542.0666. LCMS: tR = 3.45 min,
>95%, MS(ES+) m/z 541.8, 543.8 (M+H)+.
5.1.20. 2-(4-(Ethylsulfonyl)phenyl)-N-(5-(3-fluorobenzoyl)-4-(3-
(trifluoromethyl)phenyl)thiophen-2-yl)acetamide (9h)
Compound 9h (61 mg, 34% yield) was prepared 3-fluorobenzoyl
chloride (129 mg, 0.811 mmol) and 2-(4-(ethylsulfonyl)phenyl)-
N-(4-(3-(trifluoromethyl)phenyl)thiophen-2-yl)acetamide (19h)
(184 mg, 0.406 mmol) in the same manner as described for 9g as
a white solid: 1H NMR (400 MHz, DMSO-d6) d ppm 12.15 (s, 1H),
7.88 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.53–7.58 (m, 2H),
7.42–7.48 (m, 2H), 7.14–7.22 (m, 4H), 6.89 (s, 1H), 3.97 (s, 2H),
3.28 (q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz,
5.1.16. N-(5-Benzoyl-4-(3-cyanophenyl)thiophen-2-yl)-2-(4-
(ethylsulfonyl)phenyl)acetamide (9c)
Compound 9c (57 mg, 33% yield) was prepared from benzoyl
chloride (89 mg, 0.633 mmol) and N-(4-(3-cyanophenyl)thio-
DMSO-d6)
d
ppm 187.9 (d, J = 2.2 Hz), 168.5, 161.8 (d,