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M. Giorgis et al. / European Journal of Medicinal Chemistry 46 (2011) 383e392
5.1.1.8. N-(4-Nitrophenyl)furazancarboxamide (10a). White solid;
flash chromatography eluent: PE/EtOAc 8:2 v/v; yield 25%; m.p.
266.9e267.1 ꢀC dec. (from hexane/isopropyl ether 1:1 v/v); 1H-
5.1.2.3. 3-[3,5-Bis(trifluoromethyl)phenyl]amino-2-hydroxyimino-
3-oxopropionitrile (5b). White solid; yield 98%; m.p. 191 ꢀC dec.
(from toluene); 1H-NMR (DMSO-d6):
d
7.85 (s, 2H, C(2)H), 8.45
NMR (DMSO-d6): d 8.05e8.32 (m, 4H, aromatic protons), 9.47 (s,1H,
(s, 2H, C(2)H), 11.03 (s, 1H, NH), 14.89 (s, 1H, OH); 13C-NMR (DMSO-
NH), 11.62 (s, 1H, FzCH); 13C-NMR (DMSO-d6):
d
124.8, 142.6, 143.3,
d6): d 108.6, 117.2e117.3 (m, C(4)), 120.4e120.6 (m, C(2)), 123.8
143.8, 151.3, 155.4, 157.6; MS (CI) m/z 235 (M þ 1)þ. Anal.
(q, CF3, 1JCF 272.7 Hz),128.3, 130.8 (q, C(3), 2JCF 32.9 Hz), 139.7, 157.8;
MS (CI) m/z 326 (M þ 1)þ. Anal. (C11H5F6N3O2) C, H, N.
(C9H6N4O4) C, H, N.
5.1.1.9. N-Phenylfurazancarboxamide (11a). Pale yellow solid; flash
chromatography eluent: PE/EtOAc 6:4 v/v; yield 34%; m.p. 138 ꢀC
(from hexane/isopropyl ether 9:1 v/v); 1H-NMR (DMSO-d6):
5.1.2.4. 3-(4-Fluorophenyl)amino-2-hydroxyimino-3-oxopropioni-
trile (6b). Pale yellow; yield 78%; m.p. 184 ꢀC dec. (triturated with
toluene); 1H-NMR (DMSO-d6):
d
7.17e7.63 (m, 4H, aromatic
d
7.16e7.79 (m, 5H, aromatic protons), 9.43 (s, 1H, FzCH), 11.08 (br s,
protons), 14.65 (br s, 1H, OH), 10.49 (br s, 1H, NH); 13C-NMR (DMSO-
1H, NH);13C-NMR (DMSO-d6):
d
121.4,125.7,129.7,138.6,143.4,152.5,
d6): d 109.1, 116.4 (d, C(3), JCF 22.8 Hz), 124.1 (d, C(2), JCF 8.0 Hz),
2
3
155.6; MS (CI) m/z 190 (M þ 1)þ. Anal. (C9H7N3O2$0.1H2O) C, H, N.
129.8, 134.8 (d, C(1), 4JCF 2.9 Hz), 158.8, 161.2 (d, C(4), 1JCF 243.0 Hz);
MS (CI) m/z 208 (M þ 1)þ. Anal. (C9H6FN3O2) C, H, N.
5.1.1.10. N-(4-Methylphenyl)furazancarboxamide
(12a). White
solid; flash chromatography eluent: PE/EtOAc 7:3 v/v; yield 46%;
5.1.2.5. 3-(3-Fluorophenyl)amino-2-hydroxyimino-3-oxopropioni-
m.p. 138 ꢀC (from hexane/isopropyl ether 1:1 v/v); 1H-NMR
trile (7b). White solid; yield 86%; m.p. 190 ꢀC (from toluene);
(DMSO-d6):
d
3.33 (s, 3H, CH3), 7.19e7.66 (m, 4H, aromatic protons),
21.1,
1H-NMR (DMSO-d6):
d 6.94e7.65 (m, 4H, aromatic protons), 14.71
9.40 (s, 1H, NH), 10.99 (s, 1H, FzCH); 13C-NMR (DMSO-d6):
d
(s, 1H, OH), 10.61 (s, 1H, NH); 13C-NMR (DMSO-d6):
d 108.9, 108.9
122.2, 130.5, 136.2, 136.3, 142.8, 153.0, 156.6; MS (CI) m/z 204
(M þ 1)þ. Anal. (C10H9N3O2) C, H, N.
(d, C(4), 2JCF 26.6 Hz), 112.4 (d, C(2), 2JCF 21.5 Hz), 117.4 (d, C(6), 4JCF
3.0 Hz), 131.3 (d, C(5), 3JCF 9.3 Hz), 140.9 (d, C(1), 3JCF 10.9 Hz), 129.8,
1
158.7, 164.2 (d, C(3), JCF 243.1 Hz); MS (EI) m/z 207 (M)þ. Anal.
5.1.1.11. N-(4-Methoxyphenyl)furazancarboxamide (13a). Pale gray
solid; flash chromatography eluent: PE/EtOAc 7:3 v/v; yield 62%;
m.p. 131 ꢀC (from hexane/isopropyl ether 1:1 v/v); 1H-NMR
(C9H6FN3O2) C, H, N.
5.1.2.6. 3-(2-Fluorophenyl)amino-2-hydroxyimino-3-oxopropioni-
(DMSO-d6):
d
3.76 (s, 3H, OCH3), 6.96e7.71 (m, 4H, aromatic
trile (8b). White solid, yield 99%; m.p. 198 ꢀC dec. (from toluene);
protons), 9.40 (s, 1H, NH), 10.96 (s, 1H, FzCH); 13C-NMR (DMSO-d6):
1H-NMR (DMSO-d6):
d 7.20e7.64 (m, 4H, aromatic protons), 10.11
d
55.1, 113.9, 122.1, 130.6, 142.4, 151.6, 154.2, 156.2; MS (CI) m/z 220
(s, 1H, NH), 14.82 (s, 1H, OH); 13C-NMR (DMSO-d6):
d 108.6, 115.8
(M þ 1)þ. Anal. (C10H9N3O3) C, H, N.
(d, C(3), 2JCF 19.6 Hz), 124.1 (d, C(1), 2JCF 12.0 Hz), 124.4 (d, C(4), 3JCF
3.7 Hz), 126.5 (d, C(5), 4JCF 1.3 Hz), 127.5 (d, C(6), JCF 7.9 Hz), 127.8,
3
5.1.1.12. N-(Biphenyl-4-yl)furazancarboxamide (14a). Yellow solid;
flash chromatography eluent: PE/EtOAc 7:3 v/v; yield 39%; m.p.
199 ꢀC (from hexane/isopropyl ether 1:1 v/v); 1H-NMR (DMSO-d6):
155.4 (d, C(2), 1JCF 247.3 Hz), 156.9; MS (CI) m/z 208 (Mþ1)þ. Anal.
(C9H6FN3O2) C, H, N.
d
9.79 (s, 1H, FzCH), 7.33e7.90 (m, 9H, aromatic protons), 11.20 (br s,
5.1.2.7. 3-(3,5-Difluorophenyl)amino-2-hydroxyimino-3-oxopropio-
nitrile (9b). White solid; yield 89%; m.p. 202 ꢀC dec. (from toluene);
1H, NH); 13C-NMR (DMSO-d6):
d 122.0, 127.4, 128.0, 128.1, 129.7,
138.0, 138.4, 141.0, 142.8, 152.6, 155.9; MS (CI) m/z 266 (M þ 1)þ.
1H-NMR (DMSO-d6):
d 6.98e7.53 (m, 4H, aromatic protons), 10.76
Anal. (C15H11N3O2) C, H, N.
(s, 1H, NH), 14.78 (s, 1H, OH); 13C-NMR (DMSO-d6):
d 100.7 (t, C(4),
3
2JCF 26.1 Hz), 104.4e104.8 (m, C(2)), 108.8, 129.7, 141.4 (t, C(1), JCF
3
5.1.2. 2-Hydroxyiminopropionitrile derivatives: general synthetic
procedure
13.5 Hz), 158.9, 164.5 (dd, C(3), 1JCF 244.9 Hz, JCF 14.7 Hz); MS (CI)
m/z 226 (M þ 1)þ. Anal. (C9H5F2N3O2) C, H, N.
1 M NaOH (4.2 mmol, 4.2 mL) was added to an ice-cooled
solution of the amide 3ae13a (1 mmol) in MeOH (11 mL). The
mixture was stirred at room temperature for 2 h, then diluted with
water (5 mL). The pH of the mixture was adjusted to 1 by addition
of 6 M HCl. The resulting suspension was exhaustively extracted
with Et2O. The organic layers were collected, dried and concen-
trated under reduced pressure to afford the pure title compound.
5.1.2.8. 2-Hydroxyimino-3-(4-nitrophenyl)amino-3-oxopropionitrile
(10b). Pale yellow solid; yield 83%; m.p. 273.6e274.5 ꢀC dec. (from
toluene); 1H-NMR (DMSO-d6):
d
7.96e8.29 (m 4H, aromatic
protons), 10.99 (br s, 1H, NH), 14.84 (br s, 1H, OH); 13C-NMR (DMSO-
d6):
d 108.6, 120.4, 124.7, 128.4, 143.0, 143.8, 157.6; MS (CI) m/z 235
(M þ 1)þ. Anal. (C9H6N4O4$0.1 H2O) C, H, N.
5.1.2.1. 2-Hydroxyimino-3-oxo-3-[4-(trifluoromethyl)phenyl]amino-
propionitrile (3b). White solid; yield 89%; m.p. 210e211 ꢀC (from
5.1.2.9. 2-Hydroxyimino-3-oxo-3-phenylaminopropionitrile (11b). Pale
yellow solid; yield 91%; m.p. 202.2e202.7 ꢀC dec. (triturated with
toluene); 1H-NMR (DMSO-d6):
d
7.72e7.96 (m, 4H, aromatic
toluene; lit 229e230 ꢀC [24]); 1H-NMR (DMSO-d6):
d
7.12e7.71 (m,
protons), 10.78 (s, 1H, NH), 14.76 (br s, 1H, OH); 13C-NMR (CD3OD):
d
5H, aromatic protons), 10.43 (s, 1H, NH), 14.66 (br s, 1H, OH); 13C-NMR
1
2
108.7, 120.6, 124.1 (q, CF3, JCF 271.7 Hz), 124.3 (q, C(4), JCF
(DMSO-d6): d 108.8, 120.7, 124.5, 128.5, 128.6, 137.5, 156.7; MS (CI) m/z
32.0 Hz), 125.9 (q, C(3), 3JCF 3.8 Hz), 141.2 (q, C(2), 4JCF 1.4 Hz), 157.3;
190 (M þ 1)þ. Anal. (C9H7N3O2) C, H, N.
MS (CI) m/z 258 (M þ 1)þ. Anal. (C10H6F3N3O2) C, H, N.
5.1.2.10. 2-Hydroxyimino-3-(4-methylphenyl)amino-3-oxopropioni-
5.1.2.2. 2-Hydroxyimino-3-oxo-3-[3-(trifluoromethyl)phenyl]amino-
propionitrile (4b). White solid; yield 74%; m.p. 181 ꢀC (from
trile (12b). Yellow solid; yield 94%; m.p. 238 ꢀC (from toluene; lit
242e244 ꢀC [24]); 1H-NMR (DMSO-d6)
d
2.27 (s, 3H, CH3), 7.14e7.58
toluene); 1H-NMR (DMSO-d6):
d
7.49e8.16 (m, 4H, aromatic
(m, 4H, aromatic protons), 10.35 (s, 1H, NH), 14.61 (br s, 1H, OH);
protons), 10.75 (br s, 1H, NH), 14.78 (br s, 1H, OH); 13C-NMR (DMSO-
13C-NMR (DMSO-d6):
d 20.4, 108.8, 120.6, 128.5, 129.0, 133.3, 134.9,
3
3
d6):
d
109.6, 117.8 (q, C(4), JCF 4.2 Hz), 121.7 (q, C(2), JCF 3.8 Hz),
156.5; MS (CI) m/z 204 (M þ 1)þ. Anal. (C10H9N3O2) C, H, N.
124.9 (q, CF3, 1JCF 272.3 Hz), 125.2e125.3 (m), 129.3, 130.3 (q, C(3),
2JCF 31.8 Hz), 130.8, 139.3, 158.3; MS (CI) m/z 258 (M þ 1)þ. Anal.
(C10H6F3N3O2) C, H, N.
5.1.2.11. 2-Hydroxyimino-3-(4-methoxyphenyl)amino-3-oxopropio-
nitrile (13b). Yellow solid; yield 81%; m.p. 221 ꢀC (from toluene; lit