K. Takrouri et al. / European Journal of Medicinal Chemistry 77 (2014) 361e377
373
yield, mp 182 ꢀC; RP-HPLC (C18): 50e100% (ACN/Water/0.1%TFA) in
25 min, tR ¼ 13.16 min, purity of 98%; 1H NMR (DMSO-d6,
calcd; 516.97470, found 516.97550. Z-Isomer: Yellow solid, 58%
(397 mg) yield, mp 192 ꢀC; RP-HPLC (C18): 30e100% (ACN/Water/
0.1%TFA) in 25 min, tR ¼ 12.48 min, purity of 98%; 1H NMR
500 MHz):
d
8.06 (d, J ¼ 2.0 Hz, 1H), 7.84 (dd, J ¼ 8.5, 2.1 Hz, 1H),
7.63 (d, J ¼ 8.6 Hz, 1H), 7.46 (s, 1H), 7.29 (dd, J ¼ 8.4, 5.6 Hz, 2H), 7.06
(399 MHz, DMSO-d6)
d
8.49 (s, 1H), 8.19 (d, J ¼ 9.0 Hz, 1H), 7.98 (s,
(t, J ¼ 8.8 Hz, 2H), 3.68 (s, 2H); 13C NMR (DMSO,125 MHz):
d
169.29,
1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 7.65 (d, J ¼ 8.0 Hz, 1H), 7.58 (d,
166.61, 146.52, 136.05, 132.07, 131.30, 130.20, 127.79, 126.31, 115.34,
115.10, 110.93, 110.91, 106.07, 39.34; HRMS (ESI) for
J ¼ 8.4 Hz, 1H), 7.50 (s, 1H), 4.24 (s, 2H); 13C NMR (100 MHz, DMSO)
d
168.02, 166.22, 164.73, 149.68, 148.36, 137.53, 135.23, 134.34,
C
18H12Cl2FN3O2S [MþH]þ: m/z calcd; 422.01270, found; 422.01380.
134.26, 132.15, 131.47, 130.64, 127.81, 126.25, 125.82, 108.45, 37.07;
HRMS (ESI) for C19H12Cl2N4O6S [MþNa]þ: m/z calcd; 516.97470,
found; 516.97550.
4.9.9. 2-(2-(4-(3,4-Dichlorophenyl)thiazol-2-yl)hydrazono)-3-(4-
(trifluoromethyl)phenyl)propanoic acid, 10i
Using general procedure-5, employing 4g to afford 10i. E-Iso-
mer: White solid, 45% (213 mg) yield, mp 166 ꢀC; RP-HPLC (C18):
50e100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 10.60 min, purity of
4.9.12. 2-(2-(5-(3,4-Dichlorophenyl)thiazol-2-yl)hydrazono)-3-(4-
hydroxy-3-nitrophenyl)propanoic acid, 11c
Using general procedure-5, employing 4j to afford 11c. E-Isomer:
Yellow solid, 37% (172 mg) yield, mp 141 ꢀC; RP-HPLC (C18): 50e
100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 7.82 min, purity of 97%;
97%; 1H NMR (Acetone-d6, 500 MHz):
d
8.04 (d, J ¼ 2.0 Hz, 1H), 7.83
(dd, J ¼ 8.4, 2.1 Hz, 1H), 7.69 (d, J ¼ 8.0 Hz, 2H), 7.60 (s, 1H), 7.59 (d,
J ¼ 8.0 Hz, 2H), 7.52 (d, J ¼ 8.0 Hz, 1H), 4.36 (s, 2H); 13C NMR
(Acetone-d6, 125 MHz): 168.20, 164.91, 148.99, 143.06, 138.94,
135.37, 132.34, 130.95, 130.91, 130.03, 129.36, 127.78, 125.77, 125.67,
1H NMR (DMSO-d6, 500 MHz):
d 10.84 (s, 1H), 8.11 (s, 1H), 7.85 (dd,
J ¼ 8.6, 2.3 Hz, 1H), 7.82 (d, J ¼ 2.2 Hz, 1H), 7.66 (d, J ¼ 7.9 Hz, 1H),
7.57 (s, 1H), 7.42 (dd, J ¼ 8.7, 2.2 Hz, 1H), 7.10 (d, J ¼ 8.5 Hz, 1H), 4.01
125.33, 107.29, 30.93; 19F NMR (Acetone-d6, 470 MHz)
d
ꢄ76.47;
(s, 2H); 13C NMR (DMSO, 100 MHz):
d 168.69, 166.16, 151.33, 136.91,
HRMS (ESI) for C19H12Cl2F3N3O2S [MþH]þ: m/z calcd; 474.00521,
found; 474.00560. Z-Isomer: White solid, 53% (251 mg) yield, mp
185 ꢀC; RP-HPLC (C18): 50e100% (ACN/Water/0.1% TFA) in 25 min,
tR ¼ 15.12 min, purity of 98%; 1H NMR (Acetone-d6, 500 MHz):
136.84, 136.28, 132.12, 131.49, 130.44, 127.84, 126.34, 125.70, 125.30,
120.11, 107.39, 34.38; HRMS (ESI) for C18H12Cl2N4O5S [MꢄH]ꢄ: m/z
calcd; 464.98330, found; 464.98260. Z-Isomer: Yellow solid, 60%
(280 mg) yield, mp 190 ꢀC; RP-HPLC (C18): 50e100% (ACN/Water/
0.1%TFA) in 25 min, tR ¼ 11.29 min, purity of 99%; 1H NMR (DMSO-
d
8.09 (d, J ¼ 2.0 Hz, 1H), 7.88 (dd, J 8.4, 2.1 Hz, 1H), 7.70 (d,
¼
J ¼ 8.0 Hz, 2H), 7.60 (d, J ¼ 8.4 Hz, 2H), 7.60 (s, 1H), 7.53 (s, 1H), 4.01
d6, 500 MHz): d 12.95 (s, 1H), 10.84 (s, 1H), 8.06 (s, 1H), 7.82 (dd,
(s, 2H); 13C NMR (DMSO,125 MHz):
d
168.03,164.99,143.28, 135.28,
J ¼ 8.6, 2.3 Hz, 1H), 7.77 (d, J ¼ 2.2 Hz, 1H), 7.64 (s, 1H), 7.63 (d,
132.20, 131.52, 130.71, 130.34, 129.72, 127.90, 127.66, 126.34, 125.84,
J ¼ 7.9, 1H), 7.43 (dd, J ¼ 8.7, 2.2 Hz, 1H) 7.10 (d, J ¼ 8.5 Hz, 1H), 3.76
125.80, 125.76, 108.60, 39.30; 19F NMR (Acetone-d6, 470 MHz)
(s, 2H); 13C NMR (DMSO, 125 MHz):
d 168.19, 165.10, 151.53, 148.56,
d
ꢄ63.21; HRMS (ESI) for C19H12Cl2F3N3O2S [MþH]þ: m/z calcd;
136.94, 136.87, 135.35, 132.20, 131.51, 130.68, 129.44, 127.90, 126.34,
125.83, 119.76, 108.43, 38.09; HRMS (ESI) for C18H12Cl2N4O5S
[MꢄH]ꢄ: m/z calcd; 464.98330, found; 464.98310.
474.00521, found; 474.00577.
4.9.10. 3-(4-Amino-3-nitrophenyl)-2-(2-(5-(3,4-dichlorophenyl)
thiazol-2-yl)hydrazono)propanoic acid, 11a
4.9.13. 2-(2-(5-(3,4-Dichlorophenyl)thiazol-2-yl)hydrazono)-3-(4-
methoxy-2-nitrophenyl)propanoic acid, 11d
Using general procedure-5, employing 4h to afford 11a. E-Iso-
mer: Yellow solid, 20% (93 mg) yield, mp 170 ꢀC; RP-HPLC (C18):
30e100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 12.30 min, purity of
Using general procedure-5, employing 4m to afford 11d. E-Iso-
mer: Yellow solid, 25% (120 mg) yield, mp 92 ꢀC; RP-HPLC (C18):
50e100% (ACN/Water/0.1% TFA) in 25 min, tR ¼ 8.01 min, purity of
98%; 1H NMR (DMSO-d6, 500 MHz):
d 12.11 (bs, 1H), 8.09 (s, 1H),
7.84 (d, J ¼ 10.0 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J ¼ 10.0 Hz, 1H), 7.63 (s,
95%; 1H NMR (DMSO-d6, 500 MHz):
d
8.05 (s,1H), 7.80 (d, J ¼ 6.5 Hz,
1H), 7.36 (bs, 2H), 7.28 (d, J ¼ 10.0 Hz, 1H), 6.96 (d, J ¼ 10.0 Hz, 1H),
1H), 7.73 (s, 1H), 7.62 (d, J ¼ 8.3 Hz, 1H), 7.55 (s, 1H), 7.28 (d,
3.90 (s, 2H); 13C NMR (126 MHz, DMSO)
d
169.50, 166.25, 148.71,
J ¼ 8.4 Hz, 1H), 7.28 (d, J ¼ 8.4 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 2H); 13
C
145.76, 137.27, 135.54, 132.21, 131.61, 130.61, 130.54, 127.94, 126.27,
124.98, 123.77, 120.26, 108.77, 30.27; HRMS (ESI) for
NMR (DMSO, 100 MHz): d 170.78, 168.65, 165.53, 150.88, 148.43,
139.49, 136.05, 135.74, 132.04, 131.48, 127.81, 126.16, 125.84, 114.77,
106.15, 57.30, 25.53; HRMS (ESI) for C19H14Cl2N4O5S [MꢄH]ꢄ: m/z
calcd; 478.99890, found; 479.00060. Z-Isomer: Yellow solid, 60%
(288 mg) yield, mp 105 ꢀC; RP-HPLC (C18): 50e100% (ACN/Water/
0.1%TFA) in 25 min, tR ¼ 10.68 min, purity of 98%; 1H NMR (DMSO-
C
18H13Cl2N5O4S [MþH]þ: m/z calcd; 466.01381, found; 466.01470.
Z-Isomer: Yellow solid, 60% (280 mg) yield, mp 199 ꢀC; RP-HPLC
(C18): 30e100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 15.09 min,
purity of 99%; 1H NMR (500 MHz, DMSO-d6)
d 13.33 (s, 2H), 8.08 (s,
1H), 7.83 (s, 1H), 7.68e7.61 (m, 2H), 7.44 (s, 1H), 7.36 (s, 2H), 7.31 (d,
d6, 400 MHz):
d
8.07 (s, 1H), 7.82 (d, J ¼ 6.5 Hz, 1H), 7.76 (s, 1H), 7.65
J ¼ 8.7 Hz, 1H), 6.98 (d, J ¼ 8.6 Hz, 1H), 3.66 (s, 2H); 13C NMR
(d, J ¼ 8.3 Hz, 1H), 7.63 (d, J ¼ 8.4 Hz, 1H), 7.43 (s, 1H), 7.31 (d,
(126 MHz, DMSO)
d 168.39, 165.31, 148.57, 145.68, 137.80, 135.48,
J ¼ 8.4 Hz,1H), 3.91 (s, 3H), 3.80 (s, 2H); 13C NMR (DMSO,100 MHz):
132.18, 131.53, 130.57, 127.89, 126.36, 125.66, 125.43, 119.88, 108.06,
d 170.74, 168.65, 166.13, 151.21, 148.43, 139.49, 136.14, 135.08,
38.24; HRMS (ESI) for
466.01381, found; 466.01253.
C
18H13Cl2N5O4S [MþH]þ: m/z calcd;
132.04, 130.46, 130.14, 126.33, 125.84, 125.43, 115.27, 107.44, 57.30,
38.35; HRMS (ESI) for
481.01350, found; 481.01440.
C
19H14Cl2N4O5S [MþH]þ: m/z calcd;
4.9.11. 4-(2-Carboxy-2-(2-(5-(3,4-dichlorophenyl)thiazol-2-yl)
hydrazono)ethyl)-3-nitrobenzoic acid, 11b
4.9.14. 3-(4-Bromo-2-nitrophenyl)-2-(2-(4-(3,4-dichlorophenyl)
thiazol-2-yl)hydrazono)propanoic acid, 11e
Using general procedure-5, employing 4i to afford 11b. E-Iso-
mer: Yellow solid, 22% (109 mg) yield, mp 164 ꢀC; RP-HPLC (C18):
30e100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 11.81 min, purity of
Using general procedure-5, employing 3-(4-bromo-2-
nitrophenyl)-2-oxopropanoic acid [16] to afford 11e. E-Isomer:
Yellow solid, 10% (53 mg) yield, mp 166 ꢀC; RP-HPLC (C18): 30e
100% (ACN/Water/0.1%TFA) in 25 min, tR ¼ 15.54 min, purity of 95%;
HRMS (ESI) for C18H11BrCl2N4O4S [MþH]þ: m/z calcd; 530.91110,
found; 530.91230. Z-Isomer: Yellow solid, 80% (425 mg) yield, mp
168 ꢀC; RP-HPLC (C18): 30e100% (ACN/Water/0.1%TFA) in 25 min,
96%; 1H NMR (399 MHz, DMSO-d6)
d
8.49 (s, 1H), 8.15 (d, J ¼ 8.0 Hz,
1H), 8.02 (s, 1H), 7.77 (d, J ¼ 8.3 Hz, 1H), 7.65 (s, 1H), 7.61 (d,
J ¼ 8.4 Hz, 1H), 7.21 (d, J ¼ 8.1 Hz, 1H), 4.34 (s, 2H); 13C NMR
(100 MHz, DMSO)
d 169.20, 166.09, 166.03, 149.61, 137.66, 136.63,
135.44, 134.74, 132.17, 131.59, 131.22, 130.60, 130.31, 127.88, 126.27,
126.19,108.88, 30.32; HRMS (ESI) for C19H12Cl2N4O6S [MþNa]þ: m/z
tR ¼ 18.04 min, purity of 95%; 1H NMR (399 MHz, DMSO-d6)
d 8.22