J. M. Figueiredo et al. / Bioorg. Med. Chem. 8 (2000) 2243±2248
2247
ethanol, 5 mL of acetone, one drop of hydrochloridric
acid and the mixture was re¯uxed for 2 h. The evapora-
tion under reduced pressure and the ®ltration of the
resulting solid in Buchner furnished 0.91 g (71%) of the
acetone±ꢀhydrazone derivative (9) as a yellow solid, mp
245±250 C (dec.); MS (70 eV) 180 (M+, 5%); 165 (5%),
109 (100%); IR (KBr) cm 1: 3385, 3252 and 3151 (n N±
trans-hydrazonation of 9 with benzaldehyde as a yellow
solid, mp>250 ꢀC; MS (70 eV) relative abundance: 228
1
(M+, 7%), 125 (30%), 109 (100%); IR (KBr) cm
:
3314, 3207 and 3174 (n N±H), 1668 (n CO), 1593 (n
CC); 1H NMR (200 MHz, DMSO-d6) d 12.50 (br, 1H,
Im-NH), 11.42 (s, 1H, CONH), 8.48 (s, 1H, NCH),
7.70 (s, 1H, Im H-2), 7.60 (m, 5H, Ph), 2.55 (s, 3H, Im-
CH3); 13C NMR (50 MHz, DMSO-d6) d 159.8 (CO),
145.0 (CHN), 134.1 (C-10), 133.7 (Im C-2), 132.8 (Im
C-5), 131.7 (C-30 and C-50), 128.7 (C-20 and C-60), 128.0
(Im C-4), 122.7 (C-40), 10.6 (Im-CH3). Anal. calcd for
C12H12N4O: C, 63.13; H, 5.30; N, 24.56. Found: C,
63.18; H, 5.39; N, 24.48.
1
H), 1668 (n CO); H NMR (200 MHz, DMSO-d6) d
9.85 (br, 1H, CONH), 7.60 (s, 1H, Im H-2), 3.50 (br, 2H,
NH2), 2.45 (s, 3H, Im-CH3), 2.00 (s, 3H, NCCH3), 1.90
(s, 3H, NCCH3); 13C NMR (50 MHz, DMSO-d6) d
160.0 (CO), 154.5 (Me2CN), 134.0 (C-2), 133.0 (C-
5), 128.5 (C-4), 25.5 (CH3), 17.0 (CH3), 14.0 (Im-CH3).
General procedure for the preparation of N-acylhydra-
zone derivatives (4a±e). Equimolar amounts of the
appropriate aromatic aldehydes and two drops of
hydrochloridric acid, acting as a catalyst, were added to a
solution of acetone±hydrazone derivative (9) in 20 mL of
ethanol. At the end of the reaction, which was monitored
by TLC analysis, compounds 4a±e were isolated by
concentrating the reaction mixture under reduced pres-
sure, followed by the addition of dichloromethane (ca.
25 mL), cooling and ®ltration under vacuum.
(20-Furylidene)-5-methyl-imidazole-4-carbohydrazide (4d).
Derivative 4d was obtained with a yield of 93% by
trans-hydrazonation of 9 with furfuraldehyde as a yellow
solid, mp 158±160 ꢀC; MS (70 eV) relative abundance:
1
218 (M+, 18%), 125 (16%), 109 (100%); IR (KBr) cm
:
3468, 3332 and 3214 (n N±H), 1662 (n CO) and 1592 (n
1
CC); H NMR (200 MHz, DMSO-d6) d 11.75 (br, 1H,
Im-NH), 8.47 (s, 1H, NCH), 8.04 (br, 1H, CONH), 7.82
(s, 1H, C-50), 6.89 (s, 1H, C-30), 6.78 (s, 1H, Im H-2), 6.6
(s, 1H, C-40), 2.6 (s, 3H, Im-CH3); 13C NMR (50 MHz,
DMSO-d6) d 158.7 (CO), 149.6 (C5), 144.8 (CHN),
136.8 (C-20), 133.6 (Im C-2), 133.3 (Im C-5), 126.6 (Im C-
4), 112.9 (C-40), 112.1 (C-30) and 10.6 (Im-CH3). Anal.
calcd for C10H10N4O2: C, 55.03; H, 4.62; N, 25.68.
Found: C, 55.11; H, 4.69; N, 55.08.
(4-Dimethylaminebenzylidene)-5-methyl-imidazole-4-car-
bohydrazide (4a). Derivative 4a was obtained with a
yield of 69% by trans-hydrazonation of 9 with 4-dime-
thylaminobenzaldehyde as a yellow solid, mp 247±250 ꢀC
(dec.); MS (70 eV) relative abundance: 271 (M+, 74%),
163 (52%), 146 (100%), 125 (7%), 109 (43%); IR (KBr)
cm1: 3468, 3432, 3386 and 3236 (n N±H), 1664 (n CO),
(3,5-Di-tert-butyl-4-hydroxybenzylidene)-5-methyl-imida-
zole-4-carbohydrazide (4e). Derivative 4e was obtained
with a yield of 60% by trans-hydrazonation of 9 with
3,5-di-tert-butyl-4-hydroxybenzaldehyde as a yellow
solid, mp 176±179 ꢀC; MS (70 eV) relative abundance:
356 (M+, 25%), 341 (3%), 248 (3%), 233 (17%), 125
(27%), 109 (100%); IR (KBr) cm 1: 3438 (n O±H),
3318, 3376 and 3167 (n N±H), 1651 (n CO), 1605 (n
1
1599 (n CC); H NMR (200 MHz, DMSO-d6) d 12.70
(br, 1H, Im-NH), 11.00 (br, 1H, CONH), 8.35 (s, 1H,
CHN), 7.63 (s, 1H, Im H-2), 7.50 (d, 2H, C-40, J=
15 Hz), 6.75 (d, 2H, C-30, J=15 Hz), 2.96 (N(CH3)2),
2.45 (s, 3H, Im-CH3); 13C NMR (50 MHz, DMSO-d6) d
159.8 (CO), 151.6 (C-40), 147.7 (CHN), 133.7 (Im C-
2), 132.5 (Im C-5), 128.6 (C-30 and C-50), 128.0 (Im C-4),
122.0 (C-10), 112.0 (C-20 and C-60), 40.0 (N(CH3)2) and
11.0 (Im-CH3). Anal. calcd for C14H17N5O: C, 61.96; H,
6.32; N, 25.82. Found: C, 62.07; H, 6.34; N, 25.90.
1
CC); H NMR (200 MHz, DMSO-d6) d 12.34 (br, 1H,
Im-NH), 10.92 (s, 1H, CONH), 8.37 (s, 1H, NCH),
7.60 (s, 1H, Im H-2), 7.45 (s, 2H, H6-H2), 7.24 (s, 1H,
OH), 2.48 (s, 3H, Im-CH3), 1.41 (s, 18H, C(CH3)3); 13C
NMR (50 MHz, DMSO-d6) d 159.5 (CO), 155.7 (C-40),
147.7 (NCH), 139.1 (C-30 and C-50), 133.3 (Im C-4),
132.1 (Im C-2), 129.0 (C-1), 126.0 (Im C-5), 123.6 (C-20
and C-60), 34.4 (C(CH3)3), 30.1 (C(CH3)3), 10.4 (Im-
CH3). Anal. calcd for C20H28N4O2: C, 67.37; H, 7.92;
N, 15.72. Found: C, 67.42; H, 7.89; N, 15.78.
(4-Bromobenzylidene)-5-methyl-imidazole-4-carbohydra-
zide (4b). Derivative 4b was obtained with a yield of
76% by trans-hydrazonation of 9 with 4-bromo-
benzaldehyde, as a yellow solid, mp>250 ꢀC (dec.); MS
(70 eV) relative abundance: 306 (M+, 5%), 308 (5%),
198 (5%), 200 (5%), 125 (33%), 109 (100%); IR (KBr)
cm 1: 3471, 3322, 3386 and 3186 (n N±H), 1668 (n CO),
Molecular modeling
1
1591 (n CC); H NMR (200 MHz, DMSO-d6) d 12.60
(br, 1H, Im-NH), 11.40 (br, 1H, CONH), 8.50 (s, 1H,
CHN), 7.68 (s, 1H, Im H-2), 7.65 (m, 2H, C-20 and C-
60), 7.45 (m, 2H, C-30 and C-50), 2.50 (s, 3H, Im-CH3);
13C NMR (50 MHz, DMSO-d6) d 159.8 (CO), 146.4
(CHN), 134.8 (Im C-2), 133.7 (C-10), 129.6 (C-40), 129.2
(Im C-5), 128.8 (C-30 and C-50), 127.9 (Im C-4), 126.9 (C-
20 and C-60), 10.7 (Im-CH3). Anal. calcd for C12H11
BrN4O: C, 47.06; H, 3.62; N, 18.30. Found: C, 46.98; H,
3.69; N, 18.38.
All modeling procedures were performed on a Silicon
Graphics workstation IRIX 6.3 (CPU R5000). The
molecular models were built and pre-optimized on the
Builder module of InsightII (Molecular Simulations
Inc., San Diego, CA) and conformational analysis was
done using the CVFF force®eld within Search-Compare
module in InsightII environment (Molecular Simula-
tions Inc., San Diego, CA).
Conformational analysis by molecular mechanics was
done by ®ltering the conformations in a range of 5 kcal/
mol. The starting conformation was, in each case, the
(Benzylidene)-5-methyl-imidazole-5-carbohydrazide (4c).
Derivative 4c was obtained with a yield of 73% by