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K. Kumpan et al. / Bioorg. Med. Chem. 23 (2015) 3013–3032
(Ph 4-C), 144.01 (7-C), 154.27 (8a-C), 154.93 (2-C), 162.94 (5-C);
dd, J = 8.0, 4.5 Hz, 3-H), 7.60 (2H, d, J = 8.6 Hz, Ph 3,5-H2), 7.71
(2H, d, J = 8.7 Hz, Ph 2,6-H2), 8.49 (1H, dd, J = 8.0, 1.8 Hz, 4-H),
8.90 (1H, dd, J = 4.8, 1.8 Hz, 2-H), 11.50 (1H, br, NH); 13C NMR d
99.08 (8-C), 113.59 (Ph 3,5-C2), 117.55 (3-C), 122.16 (4a-C),
124.87 (Ph 1-C), 127.78 (4-C), 130.51 (Ph 2,6-C2), 136.95 (7-C),
150.62 (2-C), 153.57 (Ph 4-C), 156.59 (8a-C), 161.65 (5-C).
MS m/z 259.0826 (M+Na)+ (C15H12N2NaO requires 259.0847).
4.1.3. 7-(4-Methoxyphenyl)-1,6-naphthyridin-5-one (9c)
Compound 25c was treated with H2SO4, then NH3, as for the
synthesis of 9a, to give 9c (70%) as an off-white solid: mp 276–
280 °C; 1H NMR d 3.89 (3H, s, Me), 6.92 (1H, s, 8-H), 7.12 (2H, d,
J = 8.9 Hz, Ph 3,5-H2), 7.50 (1H, dd, J = 8.0, 4.6 Hz, 3-H), 7.86 (2H,
d, J = 8.9 Hz, Ph 2,6-H2), 8.54 (1H, dd, J = 8.0, 1.8 Hz, 4-H), 8.95
(1H, dd, J = 4.5, 1.8 Hz, 2-H), 11.65 (1H, br, NH); 13C NMR d 55.36
(Me), 114.24 (Ph 3,5-C2), 120.01 (8-C), 122.42 (4a-C), 123.65 (Ph
1-C), 125.60 (3-C), 128.39 (Ph 2,6-C2), 134.94 (7-C), 136.92 (4-C),
143.77 (2-C), 154.90 (8a-C), 156.99 (5-C), 158.82 (Ph 4-C); MS
m/z 275.0767 (M+Na)+ (C15H12N2NaO2 requires 275.0796),
253.0978 (M+H)+ (C15H13N2O2 requires 253.0977).
4.1.8. 7-(4-Hydroxyphenyl)-1,6-naphthyridin-5-one (9i)
Compound 25h was treated with H2SO4, then NH3, as for the
synthesis of 9a, to give 9i (10%) as a pale buff solid: mp 258–
260 °C; IR mmax 3423, 1660, 1617, 1589 cmꢁ1 1H NMR d 6.87 (1H,
;
s, 8-H), 6.93 (2H, d, J = 8.6 Hz, Ph 2,6-H2), 7.37 (1H, d, J = 7.4 Hz,
3-H), 7.73 (2H, d, J = 8.6 Hz, Ph 3,5-H2), 8.52 (1H, d, J = 2.5 Hz, 4-
H), 8.94 (1H, d, J = 2.5 Hz, 2-H), 9.99 (1H, br, OH), 11.67 (1H, br,
NH); 13C NMR d 115.57 (8-C), 119.0 (3-C), 121.0 (Ph 1-C), 126.0
(4a-C), 128.11 (Ph 2,6-C2), 128.42 (Ph 3,5-C2), 135.0 (4-C), 147.0
(2-C), 153.0 (Ph 4-C), 154.89 (8a-C), 163.0 (5-C); MS m/z
239.0816 (M+H)+ (C14H11N2O2 requires 239.0816); MS m/z
237.0632 (M - H)- (C14H9N2O2 requires 237.0659).
4.1.4. 7-(4-Trifluoromethylphenyl)-1,6-naphthyridin-5-one (9d)
Compound 25d was treated with H2SO4, then NH3, as for the syn-
thesis of 9a, to give 9d (55%) as a white solid: mp >325 °C; 1H NMR d
7.03 (1H, s, 8-H), 7.53 (1H, dd, J = 8.0, 4.6 Hz, 3-H), 7.92 (2H, d,
J = 8.4 Hz, Ph 3,5-H2), 8.10 (2H, d, J = 8.2 Hz, Ph 2,6-H2), 8.53 (1H,
dd, J = 8.0, 1.7 Hz, 4-H), 9.00 (1H, dd, J = 4.5, 1.8 Hz, 2-H), 11.25
(1H, br, NH); 13C NMR 105.92 (8-C), 120.90 (4a-C), 122.13 (3-C),
124.1 (q, J = 264 Hz, CF3), 125.62 (q, J = 3.6 Hz, Ph 3,5-C2), 128.03
(Ph 2,6-C2), 129.78 (q, J = 32 Hz, Ph 4-C), 135.05 (4-C), 137.31 (Ph
1-C), 142.51 (7-C), 153.90 (2-C), 155.09 (8a-C), 162.86 (5-C); 15N
NMR d 123.4 (6-N), 279.7 (1-N); 19F NMR d ꢁ61.20 (s, CF3); MS m/z
291.0727 (M+H)+ (C15H10N2O requires 291.0745).
4.1.9. 3-Phenyl-2,6-naphthyridin-1-one (10a)
Compound 35a (100 mg, 0.49 mmol) was stirred at 120 °C in
polyphosphoric acid (10 mL) for 1 h. After cooling, aq NaOH
(5 M) was added to pH 8. The mixture was extracted (EtOAc, 3ꢃ).
The combined extracts were dried. The evaporation residue was
transferred into a pressure tube and dissolved in MeO(CH2)2OH
(5 mL). NH3 was bubbled through the solution, the vessel was
closed and the mixture was heated at 130 °C for 30 min. The reac-
tion mixture was cooled in ice and NH3 was bubbled again, fol-
lowed by closure and heating (30 min). The cycle was repeated
thrice. Evaporation and trituration (EtOH) gave an inseparable
mixture of 10a and 32 (85 mg) as a gum. 1H NMR showed that
the mixture comprised 10a (56% yield) and 32 (22% yield). 10a:
1H NMR d 7.11 (1H, s, 4-H), 7.39 (1H, m, Ph 4-H), 7.42 (2H, m, Ph
3,5-H2), 7.67 (2H, d, J = 7.0 Hz, Ph 2,6-H2), 8.64 (1H, s, 8-H), 8.70
(1H, s, 7-H), 8.99 (1H, s, 5-H), 11.68 (1H, br, NH); 13C NMR d
101.50 (4-C), 121.20 (8-C), 125.50 (m, Ph 3,4,5-C3), 128.50 (Ph
2,6-C2), 131.00 (Ph 1-C), 132.90 (8a-C), 146.50 (7-C), 151.50 (5-
C); MS m/z 223.0875 (M+H)+ (C14H11N2O requires 223.0866). 32:
1H NMR d 7.10 (1H, s, 4-H), 7.86 (2H, d, J = 8.2 Hz, Ph 2,6-H2),
7.98–8.00 (3H, m, Ph 3,4,5-H3), 8.08 (1H, d, J = 5.2 Hz, 8-H), 8.67
(1H, d, J = 5.3 Hz, 7-H), 9.17 (1H, s, 5-H); 13C NMR d 98.52 (4-C),
118.0 (8-C), 125.42 (Ph 2,6-C2), 127.00 (8a-C), 129.01 (Ph 3,5-C2),
130.64 (Ph 4-C), 131.20 (Ph 1-C), 132.00 (3-C), 148.44 (7-C),
149.00 (5-C), 151.00 (1-C); MS m/z 245 (M+Na), 223.0875 (M+H)+
(C14H11N2O requires 223.0866).
4.1.5. 7-(4-Chlorophenyl)-1,6-naphthyridin-5-one (9e)
Compound 25e was treated with H2SO4, then NH3, as for the
synthesis of 9a, to give 9d (33%) as an off-white solid: mp 296–
298 °C; IR mmax 3163, 1669, 1627, 1588, 720 cmꢁ1 1H NMR d
;
6.95 (1H, s, 8-H), 7.50 (1H, dd, J = 8.0, 4.5 Hz, 3-H), 7.58 (2H, d,
J = 9.0 Hz, Ph 3,5-H2), 7.91 (2H, d, J = 8.5 Hz, Ph 2,6-H2), 8.51 (1H,
d, J = 8.0 Hz, 4-H), 8.98 (1H, d, J = 4.5 Hz, 2-H), 11.74 (1H, br, NH);
13C d 104.95 (8-C), 120.58 (4a-C), 121.83 (3-C), 128.82 (Ph 3,5-
C2), 128.93 (Ph 2,6-C2), 134.60 (4-C), 135.03 (Ph 1-C), 155.05
(C=O), 162.90 (8a-C); 15N NMR (HMBC) d 124.20 (s, 6-N); MS m/z
279.0278 (M+Na)+ (C14H935ClN2NaO requires 279.0296),
259.0420 (M+H)+ (C14H1037ClN2O requires 259.0450), 257.0482
(M+H)+ (C14H1035ClN2O requires 257.0476).
4.1.6. 7-(4-Bromophenyl)-1,6-naphthyridin-5-one (9f)
NH3 was bubbled through 26f (140 mg, 0.47 mmol) in
MeO(CH2)2OH (10 mL) for 10 min in a pressure vessel. The vessel
was closed and the mixture was heated at 120 °C for 30 min. The
reaction mixture was cooled in ice and NH3 was bubbled again, fol-
lowed by closure and heating (30 min). The cycle was repeated
twice. Evaporation and recrystallisation (EtOH) gave 9f (100 mg,
75%) as a buff powder: mp 304–305 °C; 1H NMR d 7.05 (1H, s, 8-
H), 7.50 (1H, dd, J = 7,7, 4.0 Hz, 3-H), 7.39 (2H, d, J = 8 Hz, Ph 3,5-
H2), 7.84 (2H, d, J = 8 Hz, Ph 2,6-H2), 8.30 (1H, d, J = 7.7 Hz, 4-H),
8.69 (1H, d, J = 4.8 Hz, 2-H), 9.15 (1H, br, NH); 13C NMR d 105.80
(8-C), 122.51 (4a-C), 122.97 (Ph 4-C), 123.61 (3-C), 127.41 (Ph 1-
C), 130.22 (Ph 2,6-C2), 130.75 (Ph 3,5-C2), 131.91 (7-C), 134.61 (4-
C), 156.71 (8a-C), 168.09 (5-C); MS m/z 627/625/623 (2M+Na)+,
324.9771 (M+Na)+ (C14H981BrN2NaO requires 324.9774), 322.9790
(M+Na)+ (C14H979BrN2NaO requires 322.9805), 302.9964 (M+H)+
(C14H1081BrN2O requires 302.9951), 301.0024 (M+H)+ (C14H10
79BrN2O requires 300.9971).
4.1.10. 3-(4-Methylphenyl)-2,6-naphthyridin-1-one (10b)
Compound 35b was treated with polyphosphoric acid, then
with NH3, as for the synthesis of 10a, except that the product
was recrystallised (EtOH) to give 10b (6%) as an off-white solid:
mp 188–189 °C; 1H NMR d 7.07 (1H, s, 4-H), 7.38 (2H, d,
J = 7.9 Hz, Ph 3,5-H2), 7.76 (2H, d, J = 8.2 Hz, Ph 2,6-H2), 8.04 (1H,
d, J = 5.3 Hz, 8-H), 8.66 (1H, d, J = 5.3 Hz, 7-H), 9.15 (1H, d,
J = 0.8 Hz, 5-H), 11.90 (1H, br, NH); 13C NMR d 20.70 (Me), 100.10
(4-C), 119.80 (8-C), 127.10 (Ph 2,6-C2), 129.53 (Ph 3,5-C2), 146.20
(7-C), 148.90 (5-C); MS m/z 495.1796 (2M+Na)+ (C30H24N4NaO2
requires 495.1797), 259.0834 (M+Na)+ (C15H12N2NaO requires
259.0847), 237.1022 (M+H)+ (C15H13N2O requires 237.1028).
4.1.11. 3-(4-Methoxyphenyl)-2,6-naphthyridin-1-one (10c)
Compound 35c was treated with polyphosphoric acid, then NH3,
as for the synthesis of 10b, to give 10c (37%) as an off-white solid:
mp 244–245 °C; 1H NMR d 3.90 (3H, s, Me), 7.11 (1H, s, 4-H), 7.12
(2H, d, J = 8.4 Hz, Ph 3,5-H2), 7.63 (2H, d, J = 8.9 Hz, Ph 2,6-H2),
7.80 (1H, d, J = 5.1Hz, 8-H), 8.83 (1H, d, J = 5.1Hz, 7-H), 9.04 (1H, s,
4.1.7. 7-(4-Aminophenyl)-1,6-naphthyridin-5-one (9g)
Compound 26g was treated with H2SO4, then NH3, as for the
synthesis of 9a, to give 9g (66%) as a yellow powder: mp
>300 °C; 1H NMR d 5.65 (2H, br, NH2), 6.80 (1H, s, 8-H), 7.43 (1H,