92
D. Cappoen et al. / European Journal of Medicinal Chemistry 74 (2014) 85e94
microanalysis. The figures, obtained for C, H, N analysis, were al-
ways within ꢃ0.35% of the calculated values.
128.5, 139.6, 152.8, 156.1; Anal. Calcd for: C14H12F3N3O: C, 56.95; H,
4.10; N, 14.23. Found: C, 57.02; H, 4.03; N, 14.23.
The diazene derivatives 4 [17] 6 [24], 9 [25], 10 [25], 11 [26] used
in this study were prepared as described previously.
4.2.1.5. 4-Phenyl-1-(pyridin-2-yl)semicarbazide (70). Yield 90%; mp
185e187 ꢁC (acetonitrile); IR (KBr) 3320, 3250, 3220, 2980, 1650,
1600, 1550, 1500, 1460, 1440, 1315, 1300, 1240, 1150, 1000,
4.2.1. General procedure for the preparation of semicarbazides
An appropriate (hetero)aryl hydrazine (50 mmol) was dissolved
in dichloromethane (50 mL). In those instances where (hetero)aryl
hydrazine hydrochloride was used, triethylamine (8.54 mL,
106 mmol) was added to the reaction mixture. A solution of phenyl
isocyanate (5.2 mL, 55 mmol) in dichloromethane (50 mL) was
added dropwise under stirring. The reaction mixture was stirred at
room temperature for 1 h. After cooling overnight at z4 ꢁC the
precipitate was collected by filtration and washed with dichloro-
methane to obtain pure semicarbazide 20, 30, 50, 70 and 80 (Scheme
1a). For analyses the crude product was recrystallized from the
solvent indicated below.
740 cmꢄ1; 1H NMR (300 MHz, DMSO-d6)
d 6.63e6.75 (m, 2H), 6.93
(m,1H), 7.23 (m, 2H), 7.47e7.60 (m, 3H), 8.08 (m, 1H), 8.11 (br s, 1H),
8.21 (br s, 1H), 8.72 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d
106.6, 114.7, 118.5, 121.6, 128.4, 137.4, 139. 7, 147.4, 156.3, 160.1;
Anal. Calcd for C12H12N4O: C, 63.15; H, 5.30; N, 24.55. Found: C,
63.00; H, 5.36; N, 24.75.
4.2.1.6. 4-Phenyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)semi-
carbazide (80). Yield 96%; mp 219e220 ꢁC (methanol); IR (KBr)
3300 (NH), 1655 (CO), 1595, 1570, 1470, 1460, 1405, 1330, 1255,
1200, 1150, 1130, 1050, 995, 920, 870, 845, 790, 750 cmꢄ1; 1H NMR
In the case of 4-phenyl-1-(4-fluorophenyl)semicarbazide (10)
the solvents of the reaction mixture were evaporated and the res-
idue was triturated with a mixture of EtOH (20 mL) and water
(10 mL). After cooling overnight at z4 ꢁC the precipitate was
collected by filtration and washed with water to give pure product.
For analyses the crude product 10 was recrystallized from MeOH.
(300 MHz, DMSO-d6): d 6.94 (m,1H), 7.22 (m, 3H), 7.45 (m, 2H), 8.22
(s, 1H), 8.74 (d, J ¼ 4. 9 Hz, 1H), 8.81 (s, 1H), 9.46 (s, 1H); 13C NMR
(125 MHz, DMSO-d6)
d
107.4,118.5 (br s),120.5 (q, J ¼ 275 Hz),121.8,
128.6, 139.8, 154.7 (q, J ¼ 35.1 Hz), 155.6 (br s), 161.7, 163.9; 19F NMR
(471 MHz, DMSO-d6)
d
ꢄ69.2 (br s); EI-MS m/z (%): 297 (9, [M]þ);
178 (100); 149 (40); 93 (35); 77 (21); FAB-MS m/z (%): 298 (60,
[M þ H]þ); 179 (100); Anal. Calcd for C12H10F3N5O: C, 48.47; H, 3.37;
N, 23.56. Found: C, 48.42; H, 3.37; N, 23.65.
4.2.1.1. 1-(4-Fluorophenyl)-4-phenylsemicarbazide (10). Yield 83%;
mp 191e193 ꢁC (methanol); IR (KBr) 3340, 3320, 3290, 1630, 1610,
1590,1550,1500,1445,1310,1295,1255,1230,1215,1100,1045, 870,
4.2.2. General procedure for the preparation of diazenecarboxamides
To a stirred suspension of semicarbazide 10, 20, 30 or 50 (2 mmol)
in MeOH (5 mL), a solution of cerium(IV) ammonium nitrate (CAN,
2.30 g, 4.2 mmol) in MeOH (10 mL) was added dropwise at room
temperature. After additional stirring for 5e10 min at room tem-
perature, water (30 mL) was added and the precipitated dia-
zenecarboxamide 1, 2, 3 or 5 (Scheme 1a) was collected by filtration
and crystallized from the appropriate solvent.
830, 740, 700, 675, 635 cmꢄ1; 1H NMR (300 MHz, DMSO-d6)
d 6.79
(m, 2H), 6.93 (m, 1H), 7.02 (m, 2H), 7.22 (m, 2H), 7.53 (d, J ¼ 7.7 Hz,
2H), 7.69 (br s, 1H), 8.18 (br s, 1H), 8.67 (br s, 1H); 13C NMR
(75.5 MHz, DMSO-d6)
d 113.6, 113.7, 115.0, 115.3, 118.7, 121.7, 128.4,
139.6, 145.8, 154.5, 156.4, 157.6; 19F NMR (282 MHz, DMSO-d6)
d
ꢄ125.7 (br s); Anal. Calcd for C13H12FN3O: C, 63.67; H, 4.93; N,
17.13. Found: C, 63.60; H, 4.84; N, 17.27.
4.2.2.1. 2-(4-Fluorophenyl)-N-phenyldiazenecarboxamide
Yield 91%; mp 127e129 ꢁC (methanol/water). IR 1710, 1690, 1595,
1535, 1500, 1445, 1320, 1235, 1140, 885, 855, 760, 695 cmꢄ1 1H
NMR (300 MHz, DMSO-d6) 7.17 (m, 1H), 7.41 (m, 2H), 7.51 (m, 2H),
7.75 (m, 2H), 8.04 (m, 2H), 10.91 (br s, 1H); 13C NMR (75.5 MHz,
DMSO-d6) 116.6,116. 9,119.4,124.3,125.7,125.8,129.0,137.9,147.8,
147.9, 159.7, 163.3, 166.7; 19F NMR (282 MHz, DMSO-d6)
(1).
4.2.1.2. 1-(4-Chlorophenyl)-4-phenylsemicarbazide (20). Yield 80%;
mp 196e197 ꢁC (methanol) (lit. [39] mp 194 ꢁC). IR (KBr) 3340,
3300, 1625, 1590, 1550, 1490, 1445, 1310, 1290, 1240, 1170, 1090,
;
d
1045, 825, 740, 695 cmꢄ1; 1H NMR (300 MHz, DMSO-d6)
d 6.78 (m,
2H), 6.93 (m, 1H), 7.18e7.27 (m, 4H), 7.51 (m, 2H), 7.88 (br s, 1H),
d
8.21 (br s, 1H), 8.72 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d
ꢄ106.3
d
113.9, 118.7, 121.7, 122.1, 128.4, 128.4, 139.6, 148.4, 156.3; Anal.
(m); Anal. Calcd for C13H10FN3O: C, 64.19; H, 4.14; N,17.28. Found: C,
64.39; H, 3.90; N, 17.16.
Calcd for: C13H12ClN3O: C, 59.66; H, 4.62; N, 16.06. Found: C, 59.53;
H, 4.79; N, 16.07.
4.2.2.2. 2-(4-Chlorophenyl)-N-phenyldiazenecarboxamide
(2).
4.2.1.3. 1-(4-Methoxyphenyl)-4-phenylsemicarbazide
(30). Yield
Yield 94%; mp 152e153 ꢁC (methanol/water) (lit. [39] mp 151e
152 ꢁC); IR (KBr) 3320, 1700, 1600, 1520, 1490, 1440, 1405, 1315,
1300,1245,1190, 1155,1090,1010, 980, 850, 760, 695 cmꢄ1; 1H NMR
54%; mp 187e189 ꢁC (ethyl acetate) (lit. [39] mp 182 ꢁC); IR (KBr)
3360, 3275, 2950, 2820, 1670, 1635, 1590, 1525, 1500, 1440, 1410,
1320, 1305, 1290, 1245, 1225, 1180, 1170, 1155, 1110, 1080, 1030, 920,
875, 825, 800, 765, 735, 700, 650 cmꢄ1; 1H NMR (300 MHz, DMSO-
(300 MHz, DMSO-d6)
(m, 2H), 10.96 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
124.4, 124.8, 129.0, 129.8, 137.9, 138.2, 149.7, 159.6; Anal. Calcd for
13H10ClN3O: C, 60.13; H, 3.88; N, 16.18. Found: C, 60.09; H, 3.72; N,
d
7.18 (m, 1H), 7.42 (m, 2H), 7.75 (m, 4H), 7.98
d
119.4,
d6)
1H), 7.55 (m, 2H), 8.12 (br s, 1H), 8.64 (br s, 1H); 13C NMR (75.5 MHz,
DMSO-d6) 55.2, 113.9, 114.2, 118.6, 121.6, 128.4, 139.7, 143.0, 153.0,
d 3.67 (s, 3H), 6.79 (m, 4H), 6.93 (m, 1H), 7.22 (m, 2H), 7.44 (br s,
C
d
16.10.
156.6; Anal. Calcd for C14H15N3O2: C, 65.36; H, 5.88; N, 16.33.
Found: C, 65.26; H, 5.82; N, 16.30.
4.2.2.3. 2-(4-Methoxyphenyl)-N-phenyldiazenecarboxamide
(3).
Yield 98%; mp 126e127 ꢁC (petrolether/ethyl acetate) (lit. [39] mp
104 ꢁC); IR (KBr) 3300, 3250, 3190, 3130, 3070, 1710, 1690, 1600,
1580, 1540, 1500, 1470, 1440, 1420, 1315, 1300, 1260, 1200, 1180,
1150, 1140, 1110, 1080, 1030, 980, 905, 850, 765, 690 cmꢄ1; 1H NMR
4.2.1.4. 4-Phenyl-1-(4-(trifluoromethyl)phenyl)semicarbazide
(50).
Yield 91%; mp 214e215 ꢁC (methanol/water); IR (KBr) 3330, 3310,
1630, 1620, 1600, 1560, 1520, 1500, 1450, 1135, 1310, 1300, 1250,
1190, 1150, 1110, 1070, 1050, 1015, 950, 875, 840, 740, 700, 660,
(300 MHz, DMSO-d6)
7.77 (m, 2H), 7.97 (m, 2H), 10.82 (br s, 1H); 13C NMR (75.5 MHz,
DMSO-d6) 55.8, 114.8, 119.4, 124.1, 125.6, 128.9, 138.2, 145.3, 159.9,
d 3.91 (s, 3H), 7.12e7.23 (m, 3H), 7.40 (m, 2H),
620 cmꢄ1; 1H NMR (300 MHz, DMSO-d6)
d
6.86e7.98 (m, 3H), 7.24
(dd, J ¼ 7.5 Hz, 2H), 7.51 (m, 4H), 8.29 (br s, 1H), 8.30 (br s, 1H), 8.76
(br s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
111.8, 118.5 (q,
J ¼ 31.8 Hz), 118.8, 121.9, 125.0 (q, J ¼ 270 Hz), 126.1 (q, J ¼ 3.9 Hz),
d
d
163.7. Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46. Found:
C, 65.85; H, 5.25; N, 16.68.