S. Krawczyk et al. / Bioorg. Med. Chem. 19 (2011) 6309–6315
6313
by column chromatography over silica gel using an eluent mixture
of chloroform/ethyl acetate (70/30).
3.03–3.11 (m, 1H, 4-H), 3.66 (d, J = 5.3 Hz, 1H, 3-H), 4.63 (d,
J = 15.0 Hz, 1H, N–CHB), 4.70 (d, J = 15.0 Hz, 1H, N–CHA), 5.12 (dd,
J = 7.8, 3.8 Hz, 1H, 5-H), 6.05 (dd, J = 7.8, 1.5 Hz, 1H, 6H),
7.18–7.36 (m, 10H, aromatic H). Anal. Calcd for C20H18N2O: C,
79.44; H, 6.30; N, 9.26. Found: C, 79.04; H, 6.47; N, 9.36.
4.1.3.1. Methyl 1-benzyl-2-oxo-4-phenyl-1,2,3,4-tetrahydronic-
otinate (4a). Yellow oil; yield 16%; MS (EI) m/z 321 (M+, 5%), 91
(Bn, 100%). 1H NMR (CDCl3) d 3.69 (s, 3H, COOCH3), 3.71 (d,
J = 9.1 Hz, 1H, 3-H), 4.19 (ddd, J = 9.1 Hz, 4.2 Hz, 1.2 Hz, 1H, 4-H),
4.71 (d, J = 14.9 Hz, 1H, N–CHB), 4.77 (d, J = 14.9 Hz, 1H, N–CHA),
5.22 (dd, J = 7.9 Hz, 4.2 Hz, 1H, 5-H), 6.17 (dd, J = 7.9 Hz, 1.2 Hz,
1H, 6-H), 7.20–7.35 (m, 10H, aromatic H). Anal. Calcd for
4.1.3.8. 1-Benzyl-3-cyano-4-(2-methylphenyl)-2-oxo-1,2,3,4-
tetrahydropyridine (4h). Brownish semisolid compound; yield
50%; MS (EI) m/z 302 (M+, 42%), 91 (Bn, 100%). 1H NMR (CDCl3) d
1.41 (m, 3H, CH3), 3.77 (d, J = 7.1 Hz, 1H, 3-H), 4.10 (dd, J = 7.1,
3.6 Hz, 1H, 4-H), 4.26 (d, J = 15.0 Hz, 1H, N–CHB), 4.33 (d,
J = 15.0 Hz, 1H, N–CHA), 5.20 (dd, J = 7.9 Hz, 3.6 Hz, 1H, 5-H), 6.28
(dd, J = 7.9 Hz, 1H, 6H), 6.72–7.41 (m, 9H, aromatic H). Anal. Calcd
for C20H18N2O: C, 79.44; H, 6.0; N, 9.26. Found: C, 79.25; H, 5.98;
N, 8.94.
C20H19NO3: C, 74.75; H, 5.96; N, 4.35. Found: C, 74.44; H, 5.68;
N, 3.95.
4.1.3.2. Methyl 1,4-dibenzyl-2-oxo-1,2,3,4-tetrahydronicotinate
(4b). Brownish oil; yield 38%; MS (EI) m/z 335 (M+, 6%), 91 (Bn,
100%). 1H NMR (CDCl3) d 2.63 (dd, J = 13.3 Hz, 8.3 Hz, 1H, C4-
CHB), 2.68 (dd, J = 13.3 Hz, 7.1 Hz, 1H, C4-CHA), 3.19 (m, 1H, 4-H),
3.45 (d, J = 6.2 Hz, 1H, 3-H), 3.71 (s, 3H, COOCH3), 4.65 (d,
J = 14.9 Hz, 1H, N–CHA), 4.75 (d, J = 14.9 Hz, 1H, N–CHB), 5.06 (dd,
J = 7.9 Hz, 4.6 Hz, 1H, 5-H), 5.99 (d, J = 7.9 Hz, 1H, 6-H), 7.21–7.34
(m, 10H, aromatic H). Anal. Calcd for C21H21NO3: C, 75.14; H,
6.31; N, 4.18. Found: C, 74.85; H, 5.96; N, 3.79.
4.1.3.9. 1-Benzyl-3-cyano-4-(4-methylphenyl)-2-oxo-1,2,3,4-
tetrahydropyridine (4i). Brownish semisolid compound; yield
62%; MS (EI) m/z 302 (M+, 34%), 91 (Bn, 100%). 1H NMR (CDCl3) d
1.41 (m, 3H, CH3), 2.97 (d, J = 7.9 Hz, 1H, 3-H), 3.74 (ddd, J = 7.9,
3.5, 2.1 Hz, 1H, 4-H), 4.56 (d, J = 14.9 Hz, 1H, N–CHB), 4.93 (d,
J = 14.9 Hz, 1H, N–CHA), 5.25 (dd, J = 7.9, 3.5 Hz, 1H, 5-H), 6.23
(dd, J = 7.9, 2.1 Hz, 1H, 6H), 6.70–7.31 (m, 9H, aromatic H). Anal.
Calcd for C20H18N2O: C, 79.44; H, 6.0; N, 9.26. Found: C, 79.15; H,
6.04; N, 8.91.
4.1.3.3. Methyl 1-benzyl-2-oxo-4-(2-methylphenyl)-1,2,3,4-tet-
rahydronicotinate (4c). Brownish oil; yield 23%; MS (EI) m/z 335
(M+, 7%), 276 (M+-COOCH3, 100%). 1H NMR (CDCl3) d 2.40 (s, 3H,
Ph–CH3), 3.72 (d, J = 5.7 Hz, 1H, 3-H), 3.73 (s, 3H, COOCH3), 4.19
(‘dt’, J = 5.7 Hz, 1.1 Hz, 1H, 4-H), 4.73 (d, J = 14.7 Hz, 1H, N–CHB),
4.82 (d, J = 14.7 Hz, 1H, N–CHA), 5.17 (dd, J = 7.7 Hz, 5.7 Hz, 1H,
5-H), 6.23 (dd, J = 7.7 Hz, 1.1 Hz, 1H, 6-H), 7.12–7.37 (m, 9H, aro-
matic H). Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18.
Found: C, 74.95; H, 5.93; N, 3.78.
4.1.3.10. 1-Benzyl-3-cyano-4-(2-methoxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyridine (4j). Yellow semisolid compound; yield 38%;
MS (EI) m/z 318 (M+, 66%), 91 (Bn, 100%). 1H NMR (CDCl3) d
3.73–3.85 (m, 2H, 3-H, 4-H), 3.75 (s, OCH3), 4.70 (d, J = 14.9 Hz,
1H, N–CHB), 4.75 (d, J = 14.9 Hz, 1H, N–CHA), 5.20 (dd, J = 7.9,
5.3 Hz, 1H, 5-H), 6.31 (dd, J = 7.9, 2.1 Hz, 1H, 6H), 6.71–7.31 (m,
9H, aromatic H). Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.75; N,
8.80. Found: C, 75.78; H, 6.12; N, 8.70.
4.1.3.4. Methyl 1-benzyl-2-oxo-4-(4-methylphenyl)-1,2,3,4-tet-
rahydronicotinate (4d). Brownish oil; yield 42%; MS (EI) m/z 335
(M+, 5%), 276 (M+-COOCH3, 100%). 1H NMR (CDCl3) d 2.30 (s, 3H,
Ph–CH3), 3.69 (s, 3H, COOCH3), 3.70 (d, J = 8.7 Hz, 1H, 3-H), 4.19
(ddd, J = 8.7, 4.2, 1.7 Hz, 1H, 4-H), 4.72 (d, J = 14.9 Hz, 1H,
N–CHB), 4.77 (d, J = 14.9 Hz, 1H, N–CHA), 5.21 (dd, J = 7.9, 4.2 Hz,
1H, 5-H), 6.16 (dd, J = 7.9, 1.7 Hz, 1H, 6-H), 7.19–7.36 (m, 9H,
aromatic H). Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18.
Found: C, 74.83; H, 6.00; N, 3.82.
4.1.3.11. 1-Benzyl-3-cyano-4-(4-methoxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyridine (4k). Yellow semisolid compound; yield 12%;
MS (EI) m/z 318 (M+, 14%), 91 (Bn, 100%). 1H NMR (CDCl3) d 2.95
(dd, J = 7.8, 3.8 Hz, 1H, 4-H), 3.75 (s, OCH3), 4.00 (d, J = 7.8 Hz, 1H,
3-H), 4.73 (d, J = 14.9 Hz, 1H, N–CHB), 4.76 (d, J = 14.9 Hz, 1H,
N–CHA), 5.25 (dd, J = 7.9, 3.8 Hz, 1H, 5-H), 6.23 (dd, J = 7.9 Hz, 1H,
6H), 6.75–7.42 (m, 9H, aromatic H). Anal. Calcd for C20H18N2O2: C,
75.45; H, 5.75; N, 8.80. Found: C, 75.34; H, 5.83; N, 8.34.
4.1.3.5. Methyl 1-benzyl-2-oxo-4-(4-methoxyphenyl)-1,2,3,4-
tetrahydronicotinate (4e). Brownish oil; yield 13%; MS (ESI)
m/z 374 (M+Na+, 100%). 1H NMR (CDCl3) d 3.66 (d, J = 8.7 Hz, 1H,
3-H), 3.68 (s, 3H, COOCH3), 3.76 (s, 3H, Ph–OCH3), 4.14 (ddd,
J = 8.7, 4.2, 1.7 Hz, 1H, 4-H), 4.70 (d, J = 14.9 Hz, 1H, N–CHB), 4.76
(d, J = 14.9 Hz, 1H, N–CHA), 5.20 (dd, J = 7.9, 4.2 Hz, 1H, 5-H), 6.15
(dd, J = 7.9, 1.7 Hz, 1H, 6-H), 6.78–7.35 (m, 9H, aromatic H). Anal.
Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.66;
H, 5.75; N, 3.68.
4.1.3.12. Benzyl 1-Benzyl-2-oxo-4-phenyl-1,2,3,4-tetrahydronic-
otinate (4l). Brownish oil; yield 12%; MS (EI) m/z 397 (M+, 6%), 91
(Bn, 100%). 1H NMR (CDCl3) d 3.71 (d, J = 9.1 Hz, 1H, 3-H), 4.19
(ddd, J = 9.1, 4.2, 1.2 Hz, 1H, 4-H), 4.71 (d, J = 14.9 Hz, 1H,
N–CHB), 4.77 (d, J = 14.9 Hz, 1H, N–CHA), 5.13 (d, J = 12.5 Hz,
O–CHB), 5.17 (d, J = 12.5 Hz, O–CHA), 5.22 (dd, J = 7.9, 4.2 Hz, 1H,
5-H), 6.17 (dd, J = 7.9, 1.2 Hz, 1H, 6-H), 7.20–7.35 (m, 10H, aromatic
H). Anal. Calcd for C26H23NO3: C, 78.57; H, 5.83; N, 3.52. Found: C,
78.25; H, 5.53; N, 3.12.
4.1.3.6.
1-Benzyl-3-cyano-4-phenyl-2-oxo-1,2,3,4-tetrahydro-
pyridine (4f). Yellow semisolid compound; yield 14%; MS (EI) m/
z 288 (M+, 31%), 91 (Bn, 100%). 1H NMR (CDCl3) d 3.77 (d,
J = 6.1 Hz, 1H, 3-H), 4.00 (ddd, J = 6.1, 3.4, 2,1 Hz, 1H, 4-H), 4.70
(d, J = 15.0 Hz, 1H, N–CHB), 4.76 (d, J = 15.0 Hz, 1H, N–CHA), 5.27
(dd, J = 8.0, 3.4 Hz, 1H, 5-H), 6.25 (dd, J = 8.0, 2.1 Hz, 1H, 6H),
7.02–7.47 (m, 10H, aromatic H). Anal. Calcd for C19H16N2O: C,
79.14; H, 5.59; N, 9.71. Found: C, 78.84; H, 5.79; N, 9.51.
4.1.4. General procedure for the synthesis of the aromatized
pyridine-2-ones (5a–l)
One equivalent of the corresponding 1,2,3,4-tetrahydropyri-
dine-2-one 4 is dissolved in toluene (50 mL). Two equivalents of
heat-activated (120 °C, 12 h) manganese(IV) oxide were added.
The suspension was heated under reflux for 6–8 h at 130 °C. Then
the solution was filtered and the residue was washed for three
times with ethyl acetate (50 mL each). The organic layers were uni-
fied and the solvent was evaporated to dryness in vacuum. The
remaining oily residue was purified by column chromatography
over silica gel using an eluent mixture of chloroform/ethyl acetate
(40/60).
4.1.3.7. 1,4-Dibenzyl-3-cyano-2-oxo-1,2,3,4-tetrahydropyridine
(4g). Yellow semisolid compound; yield 56%; MS (EI) m/z 302
(M+, 11%), 91 (Bn, 100%). 1H NMR (CDCl3) d 2.75 (dd, J = 13.6,
8.7 Hz, 1H, C4-CHB), 2.79 (dd, J = 13.6, 7.8 Hz, 1H, C4-CHA),