C. Nava-Zuazo et al. / Bioorg. Med. Chem. 22 (2014) 1626–1633
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4.1.1.5. N-(4-Methoxyphenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
(5). Yield: 46%, after recrystallization from ethanol. Mp:
4. Experimental
4.1. Chemistry
212–214 °C. 1H NMR (400 MHz, DMSO-d6) d: 8.52 (1H, s, H-4),
7.31 (2H, d, Jo = 9.2 Hz, H-20-60), 6.86 (2H, d, Jo = 10 Hz, H-30-50),
3.70 (3H, s, O-CH3) ppm; 13C NMR (100 MHz, DMSO-d6) d: 162.1
(C-2), 155.1 (C-40), 150.8 (CO), 142.4 (C-4), 132.4 (C-5), 129.9
(C-10), 120.5 (C-20-60), 113.5 (C-30-50), 54.6 (O-CH3) ppm. MS (CI+)
m/z 295 (M+1). Anal. Calcd for C11H10N4O4S: C, 44.89; H, 3.43; N,
19.04. Found: C, 44.77; H, 3.56; N, 19.85.
Melting points were determined on an EZ-Melt MPA120 auto-
mated melting point apparatus from Stanford Research Systems
and are uncorrected. Reactions were monitored by TLC on
0.2 mm precoated silica gel 60 F254 plates (E. Merck). 1H NMR
spectra were recorded on Varian Oxford (400 MHz) and 13C NMR
(100 MHz), as well as Varian Mercury (200 MHz) and 13C NMR
(50 MHz) instruments. Chemical shifts are given in ppm relative
to tetramethylsilane (Me4Si, d = 0) in DMSO-d6; J values are given
in Hz. The following abbreviations are used: s, singlet; d, doublet;
q, quartet; dd, doublet of doublet; t, triplet; m, multiplet; br s,
broad signal. MS were recorded on a JEOL JMS-700 spectrometer
by Fast Atom Bombarded [FAB (+)]. Starting materials were com-
mercially available from Aldrich and used without purification.
4.1.1.6.
(6).
N-(4-Ethoxyphenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield: 72%, after recrystallization from ethanol. Mp:
204–208 °C. 1H NMR (400 MHz, DMSO-d6) d: 8. 33 (1H, s, H-4),
7.39 (2H, d, Jo = 8 Hz, H-20-60), 6.88 (2H, d, Jo = 8 Hz, H-30-50), 3.95
(2H, q, J = 7 Hz, O-CH2), 1.29 (3H, t, J = 6.8 Hz, CH3) ppm; 13C
NMR (100 MHz, DMSO-d6) d: 165.3 (C-2), 155.20 (C-40), 154.1
(CO), 142.8 (C-4), 133. 3 (C-5), 131.3 (C-10), 121.4 (C-20-60), 115.1
(C-30-50), 63.6 (O–CH2), 15.1 (CH3) ppm; MS (FAB+) m/z 309
(M+H+). Anal. Calcd for C12H12N4O4S: C, 46.75; H, 3.92; N, 18.17.
Found: C, 46.60; H, 3.96; N, 18.23.
4.1.1. General method of synthesis of ureas (1–8)
To
a
solution of 2-amino-5-nitro-1,3-thiazole (0.3 g,
0.0020 mol) in toluene (5 mL), was added dropwise the appropri-
ate isocyanate (0.0031 mol, 1.5 equiv) at 25 °C. The mixture was
stirred at reflux under nitrogen atmosphere for 12 h. Solvent was
removed in vacuo, and the residue was suspended in water. The
precipitates were filtered and dried. Crude compounds were
4.1.1.7.
(7).
N-(4-Butoxyphenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield 87%, mp: 148–153 °C. 1H NMR (200 MHz, DMSO-
d6) d: 8.54 (1H, s, H-4), 7.37 (2H, d, Jo = 9 Hz, H-20-60), 6.89 (2H, d,
Jo = 9 Hz, H-30-50), 3.92 (2H, t, J = 6.4 Hz, H-100), 1.65 (2H, q,
J = 6.7 Hz, J = 7.9 Hz, H-20’), 1.41 (2H, q, J = 7.4 Hz, J = 7.6 Hz, H-
300), 0.92 (3H, t, J = 7.3 Hz, H-400) ppm; 13C NMR (50 MHz, DMSO-
d6) d: 163.9 (C-2), 155.1 (C-40), 151.6 (CO), 143.0 (C-4), 130.5 (C-
10), 121.0 (C-20-60), 114.7 (C-30-50), 67.3 (C-100), 30.8 (C-200), 18.7
(C-300), 13.6 (C-400) ppm; MS (FAB+) m/z 337 (M+H+). Anal. Calcd
for C14H16N4O4S: C, 49.99; H, 4.79; N, 16.66. Found: C, 49.87; H,
4.79; N, 16.62.
recrystallized from
chromatography.
a
ethanol or purified by column
4.1.1.1.
(1).
N-Cyclohexyl-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield 86%, after recrystallization from ethanol. Mp: 200–
203 °C. 1H NMR (400 MHz, DMSO-d6) d: 8.47 (1H, s, H-4), 3.45
(1H, d, J = 7.9 Hz, H-10), 1.15–1.80 (10H, m, H-20-60) ppm; 13C
NMR (100 MHz, DMSO-d6) d: 164.5 (C-2), 152.8 (CO), 143.8 (C-4),
141.2 (C-5), 48.8 (C-10), 32.7 (C-20-60), 25.5 (C-40), 24.5 (C-30-50)
ppm; MS (FAB+) m/z 271 (M+H+). Anal. Calcd for C10H14N4O3S: C,
44.43; H, 5.22; N, 20.73. Found: C, 44.47; H, 5.30; N, 20.79.
4.1.1.8.
(8).
N-(4-Nitrophenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield: 80%, after recrystallization from ethanol. Mp:
259-desc °C. 1H NMR (400 MHz, DMSO-d6) d: 8.58 (1H, s, H-4),
8.19 (2H, d, Jo=8.8 Hz, H-30-50), 7.73 (2H, d, Jo = 8.8 Hz, H-20-60)
ppm; 13C NMR (100 MHz, DMSO-d6) d: 164.2 (C-2), 152.8 (CO),
151.5 (C-4), 144.6 (C-10), 142.1 (C-40), 125.0 (C-30-50), 117.9 (C-20-
6-0) ppm; MS (FAB+) m/z 310 (M+H+). Anal. Calcd for C10H7N5O5S:
C, 38.84; H, 2.28; N, 22.65. Found: C, 38.80; H, 2.35; N, 22.79.
4.1.1.2. N-(5-Nitro-1,3-thiazol-2-yl)-N-phenylurea (2).
Yield
72%, after recrystallization from ethanol. Mp: 207–212 °C. 1H NMR
(400 MHz, DMSO-d6) d: 8.52 (1H, s, H-4), 7.65 (2H, dd, Jo = 8.8,
Jo = 2.0 Hz, H-20-60), 7.32 (2H, t, Jo = 8 Hz, H-30-50), 7.07 (1H, t,
Jo = 7.6 Hz, Jo = 7.2 Hz, H-40) ppm; 13C NMR (100 MHz, DMSO-d6)
d:163.9 (C-2), 152.9 (CO), 140.1 (C-4), 138.1 (C-5), 129.4 (C-30-50),
129.2 (C-10), 124.0 (C-40), 119.5 (C-20-60) ppm; MS (FAB+) m/z 265
(M+H+). Anal. Calcd for C10H8N4O3S: C, 45.45; H, 3.05; N, 21.20.
Found: C, 45.50; H, 3.10; N, 21.32.
4.1.2. General method of synthesis of amides (9–12)
To a solution of 2-amino-5-nitrothiazole (0.3 g, 0.0020 mol) in
dichloromethane was added 1.2 molar equiv of triethylamine
(TEA). After the reaction mixture was stirred at 5 °C for 15 min,
acetic anhydride (0.0100 mol, 5 equiv), or respectively acyl chlo-
rides (0.0022 mol, 1.1 equiv) were added drop-wise. The reaction
mixture was stirred at room temperature for 4–24 h. After com-
plete conversion, the solvent was removed in vacuo and the resi-
due was neutralized with saturated NaHCO3 solution. The
precipitated solids were recrystallized from a mixture of solvents.
4.1.1.3.
(3).
N-(4-Chlorophenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield 55%, after recrystallization from ethanol. Mp: 243
(dec) °C. 1H NMR (400 MHz, DMSO-d6) d: 8.55 (1H, s, H-4), 7.51
(2H, d, Jo = 8.8 Hz, H-20-60), 7.37 (2H, d, Jo = 8.8 Hz, H-30-50) ppm;
13C NMR (100 MHz, DMSO-d6) d: 163.9 (C-2), 152.7 (CO), 138.9
(C-4), 137.2 (C-5), 129.2 (C-30-50), 127.6 (C-10), 125.9 (C-40), 120.2
(C-20-60) ppm; MS (FAB+) m/z 298 (M+H+). Anal. Calcd for C10H7-
ClN4O3S: C, 40.21; H, 2.36; N, 18.76. Found: C, 40.01; H, 2.30; N,
18.60.
4.1.2.1. N-(5-Nitro-1,3-thiazol-2-yl)acetamide (9).
Yield:
91%, after recrystallization from acetonitrile/methanol 75:25. Mp:
267–270 °C. 1H NMR (400 MHz, DMSO-d6) d: 8.55 (1H, s, H-4),
2.21 (3H, s, CH3) ppm; 13C NMR (100 MHz, DMSO-d6) d: 170.65
(CO), 162.15 (C-2), 142.93 (C-5), 142.11 (C-4), 22.87 (CH3) ppm;
MS (FAB+) m/z 188 (M+H). Anal. Calcd for C5H5N3O3S: C, 32.08;
H, 2.69; N, 22.45. Found: C, 32.13; H, 2.73; N, 22.53.
4.1.1.4.
(4).
N-(4-Fluorophenyl)-N-(5-nitro-1,3-thiazol-2-yl)urea
Yield: 94%, after recrystallization from ethanol. Mp:
211–214 °C. 1H NMR (400 MHz, DMSO-d6) d: 9.30 (1H, s, H-4),
7.48 (2H, m, Jo = 8.4 Hz, H-20-60), 7.17 (2H, m, Jo = 8.4 Hz, H-30-50)
4.1.2.2. N-(5-Nitro-1,3-thiazol-2-yl)benzamide (10).
Yield
13
ppm; C NMR (100 MHz, DMSO-d6) d: 159.8 (J = 130.5 Hz, C-40),
87%, after recrystallization from ethanol. Mp 258–261 °C 1H NMR
(200 MHz, DMSO-d6) 7.34–7.60 (3H, m, H-30, H-400, H-50), 8.09
(2H, dd, H-20, H-60, Jo = 8.4, Jm = 1.6 Hz), 8.33 (1H s, H-4) ppm; 13C
NMR (50 MHz, DMSO-d6) 128.5 (2C, C-30-50), 128.7 (2C, C-20-60),
156.8 (CO), 151.4 (C-2), 134.5 (J = 21.1 Hz, C-30-50), 115.6 (J = 9.1,
C-20-60) ppm; MS (FAB+) m/z 283 (M+H+). Anal Calcd for C10H7FN4-
O3S: C, 42.55; H, 2.50; N, 19.85. Found: C, 42.65; H, 2.46; N, 19.72.