6732
X.-Y. He et al. / Bioorg. Med. Chem. 19 (2011) 6726–6734
5.1.25. 3-(3-Nitrophenyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-
2,5-dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-
one (13f)
5.1.31. 3-(Phenylethyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-2,5-
dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-one
(13l)
Starting with 6 (133 mg, 0.5 mmol) and 12f (127 mg, 0.5 mmol) to
afford150 mgof13f, yellowsolid, 60%yield. Mp140–142 °C;1H NMR
(DMSO-d6) d ppm 8.46 (1H, s, ArH-20), 8.39 (1H, d, J = 8.0 Hz, ArH-40),
8.23 (1H, d, J = 8.0 Hz, ArH-4), 7.98–7.95 (2H, m, ArH), 7.87 (1H, t,
J = 8.0 Hz, ArH-50), 7.84 (1H, t, J = 8.0 Hz, ArH-5), 7.76 (1H, s, @CH),
7.65 (1H, d, J = 8.0 Hz, ArH-6), 6.40 (1H, s, PyH-4), 2.45 and 2.09 (each
3H, s, CH3 ꢁ 2); MS m/z 502 (Mꢀ1, 100); HPLC purity 97.04%.
Starting with 6 (133 mg, 0.5 mmol) and 12l (112 mg, 0.5 mmol)
to afford 192 mg of 13n, yellow solid, 79% yield. Mp 148–150 °C;
1H NMR (DMSO-d6) d ppm 8.22 (1H, d, J = 8.0 Hz, ArH-4), 7.96
(1H, s, ArH-2), 7.85 (1H, t, J = 8.0 Hz, ArH-5), 7.70 (1H, s, @CH),
7.65 (1H, d, J = 8.0 Hz, ArH-6), 7.33–7.21 (5H, m, ArH ꢁ 5), 6.31
(1H, s, PyH-4), 4.23 (2H, t, J = 8.0 Hz, N-CH2), 2.95 (2H, t,
J = 8.0 Hz, CH2-Ar), 2.21 and 2.06 (each 3H, s, CH3 ꢁ 2); MS m/z
485 (Mꢀ1, 100); HPLC purity 99.72%.
5.1.26. 3-(4-Methoxyphenyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-
2,5-dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-
one (13g)
5.1.32. Ethyl 2-(3-(4-methoxyphenyl)ureido)acetate (14a)
Triethylamine (17 mL) in dichloromethane (30 mL) was slowly
Starting with 6 (133 mg, 0.5 mmol) and 12g (120 mg, 0.5 mmol)
to afford 180 mg of 13g, yellow solid, 73% yield. Mp 256–258 °C
(dec); 1H NMR (DMSO-d6) d ppm 8.22 (1H, d, J = 8.0 Hz, ArH-4),
7.97 (1H, s, ArH-2), 7.84 (1H, t, J = 8.0 Hz, ArH-5), 7.73 (1H, s,
@CH), 7.64 (1H, d, J = 8.0 Hz, ArH-6), 7.30 (2H, d, J = 8.8 Hz, ArH-
20, 60), 7.09 (2H, d, J = 8.8 Hz, ArH-30, 50), 6.37 (1H, s, PyH-4), 3.82
(3H, s, OCH3), 2.23 and 2.09 (each 3H, s, CH3 ꢁ 2); MS m/z 487
(Mꢀ1, 100); HPLC purity 99.15%.
added to a mixture of ethyl glycinate hydrochloride (4.2 g,
30 mmol) and triphosgene (3.0 g, 10 mmol) in dichloromethane
(20 mL) at ꢀ10 °C for 30 min. The mixture was warmed to 0 °C
with stirring for 1 h and then added dropwise to a solution of 4-
methoxyphenylamine (3.7 g, 30 mmol) in 15 mL dichoromethane
at 0 °C for 20 min with continued stirring at room temperature
for 6 h. The solid precipitate was filtered out, and the filtrate was
washed with water, 5% HCl aq, and brine, successively, and then
dried over Na2SO4. After removal of solvent under reduced pres-
sure, the crude product was purified by flash silica column [gradual
eluant: EtOAc/petroleum ether, 0–30%] to afford 4.54 g of 14a,
white solid, 60% yield. Mp 122–124 °C; 1H NMR d ppm 7.23 (2H,
d, J = 6.8 Hz, ArH-2, 6), 6.86 (2H, d, J = 6.8 Hz, ArH-3, 5), 6.72 (1H,
br s, NH), 5.42 (1H, br s, NH), 4.21 (2H, q, J = 7.6 Hz, CH2CH3),
4.03 (2H, d, J = 5.6 Hz, CH2N), 3.79 (3H, s, OCH3), 1.27 (3H, t,
J = 7.6 Hz, CH2CH3); MS m/z 253 (M+1, 100), 275 (M+23, 60).
5.1.27. 3-(4-(Trifluoromethyl)phenyl)-5-((1-(3-(1H-tetrazol-5-
yl)phenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-2-
thioxothiazolidin-4-one (13h)
Starting with 6 (133 mg, 0.5 mmol) and 12h (140 mg, 0.5 mmol)
to afford 145 mg of 13h, yellow solid, 55% yield. Mp 156–158 °C
(dec); 1H NMR (DMSO-d6) d ppm 8.22 (1H, d, J = 7.8 Hz, ArH-4),
7.97 (3H, m, ArH), 7.83 (1H, t, J = 7.8 Hz, ArH-5), 7.76 (1H, s,
@CH), 7.71 (2H, d, ArH-30, 50), 7.66 (1H, d, J = 7.8 Hz, ArH-6), 6.39
(1H, s, PyH-4), 2.24 and 2.09 (each 3H, s, CH3 ꢁ 2); MS m/z 525
(Mꢀ1, 100); HPLC purity 95.96%.
5.1.33. Ethyl 2-(3-(3-(trifluoromethyl) phenyl)ureido) acetate
(14b)
The preparation was the same as 14a. Starting with 3-trifluo-
romethylphenylamine (4.8 g, 30 mmol) to afford 5.3 g of 14b with
a 61% yield, white solid. Mp 100–102 °C; 1H NMR d ppm: 7.60 (1H,
s, ArH-2), 7.41 (1H, d, J = 8.4 Hz, ArH-6), 7.30 (2H, m, ArH-5, NH),
7.23 (1H, d, J = 8.0 Hz, ArH-4), 5.73 (1H, br s, NH), 4.25 (2H, q,
J = 7.2 Hz, CH2CH3), 4.03 (2H, d, J = 5.6 Hz, CH2N), 1.30 (3H, t,
J = 7.2 Hz, CH2CH3); MS m/z 291 (M+1, 100).
5.1.28. 3-(4-Hydroxyphenyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-
2,5-dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-
one (13i)
Starting with 6 (133 mg, 0.5 mmol) and 12i (113 mg, 0.5 mmol)
to afford 161 mg of 13i, yellow solid, 68% yield. Mp 156–158 °C
(dec); 1H NMR (DMSO-d6) d ppm 9.87 (1H, s, OH), 8.22 (1H, d,
J = 8.0 Hz, ArH-4), 7.96 (1H, s, ArH-2), 7.85 (1H, t, J = 8.0 Hz, ArH-
5), 7.72 (1H, s, @CH), 7.65 (1H, d, J = 8.0 Hz, ArH-6), 7.15 (2H, d,
J = 8.8 Hz, ArH-20,60), 6.89 (2H, d, J = 8.8 Hz, ArH-30, 50), 6.36 (1H,
s, PyH-4), 2.22 and 2.08 (each 3H, s, CH3 ꢁ 2); MS m/z 473 (Mꢀ1,
100); HPLC purity 95.59%.
5.1.34. 3-(4-Methoxyphenyl)imidazolidine-2,4-dione (15a)
To a suspension of 14a (1.08 g, 4 mmol) in 10 mL water was
added 4 mL of 10% NaOH aq and heated to reflux for 1 h. After cool-
ing to room temperature, the solution was acidified by 36% HCl to
pH 1–2 and heated again to reflux overnight. When staying at
room temperature, the solid precipitate was collected and dried
to afford 530 mg of 15a, white needle solid, 64% yield. Mp 208–
210 °C; 1H NMR d ppm 7.31 (2H, d, J = 8.8 Hz, ArH-2, 6), 7.01 (2H,
d, J = 8.8 Hz, ArH-3, 5), 6.16 (1H, br s, CONH), 4.13 (2H, s, NCH2),
3.84 (3H, s, OCH3); MS m/z 207 (M+1, 100), 224 (M+18, 70), 229
(M+23, 80).
5.1.29. 3-(4-Bromophenyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-
2,5-dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-
one (13j)
Startingwith 6 (133 mg, 0.5 mmol)and12j(144 mg, 0.5 mmol) to
afford 183 mg of 13j, yellow solid, 68% yield. Mp 274–276 °C (dec);
1H NMR (DMSO-d6) d ppm 8.22 (1H, d, J = 8.0 Hz, ArH-4), 7.97 (1H,
s, ArH-2), 7.78–7.74 (3H, m, @CH, ArH), 7.66 (1H, d, J = 8.0 Hz, ArH-
6), 7.40 (2H, d, ArH-30, 50), 6.38 (1H, s, PyH-4), 2.23 and 2.09 (each
3H, s, CH3 ꢁ 2); MS m/z 537 (Mꢀ1, 100); HPLC purity 97.36%.
5.1.35. 2,3-(3-(Trifluoromethyl)phenyl)imidazolidine-2,4-dione
(15b)
The preparation was the same as 15a. Starting with 14b (1.16 g,
4 mmol) to afford 15b with 40% yield, white needle solid, mp 112–
114 °C; 1H NMR d ppm 7.75 (1H, s, ArH-2), 7.67–7.59 (3H, m, ArH),
6.06 (1H, br s, CONH), 4.18 (2H, s, NCH2); MS m/z 243 (Mꢀ1, 100).
5.1.30. 3-Benzyl-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-2,5-
dimethyl-1H-pyrrol-3-yl)methylene)-2-thioxothiazolidin-4-one
(13k)
Starting with 6 (133 mg, 0.5 mmol) and 12k (112 mg, 0.5 mmol)
to afford 210 mg of 13k, yellow solid, 90% yield. Mp 180–182 °C;
1H NMR (DMSO-d6) d ppm 8.21 (1H, d, J = 8.0 Hz, ArH-4), 7.95
(1H, s, ArH-2), 7.82 (1H, t, J = 8.0 Hz, ArH-5), 7.78 (1H, s, @CH),
7.63 (1H, d, J = 8.0 Hz, ArH), 7.51–7.32 (5H, m, ArH ꢁ 5), 6.29 (1H,
s, PyH-4), 4.70 (2H, s, ArCH2), 2.20 and 2.05 (each 3H, s,
CH3 ꢁ 2); MS m/z 471 (Mꢀ1, 100); HPLC purity 97.25%.
5.1.36. 3-(4-Methoxyphenyl)-5-((1-(3-(1H-tetrazol-5-yl)phenyl)-
2,5-dimethyl-1H-pyrrol-3-yl)methylene) imidazolidine-2,4-
dione (16a)
A mixture of 6 (133 mg, 0.5 mmol) and 15a (105 mg, 0.5 mmol)
in ethanol (10 mL) in the presence of piperidine (0.2 mL) was
heated to reflux for 8 h and then poured into ice water, and pH