Chemistry
All reagents and solvents were commercially available and were used without further treatment unless otherwise noted. 1H NMR and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, using a Varian Unity Inova 400 MHz instrument. Chemical shifts are stated in ppm (δ) with reference to tetramethylsilane as an internal standard. HRMS spectra were recorded with a Bruker Daltonics ESI-BioTOF Q spectrometer. Column chromatography was performed on silica gel (200–300 mesh). Thin-layer chromatography on glass slides precoated with GF-254 silica gel was used to monitor the progress of reactions.
The following equipment and reagents were used for the biological activity tests: biochemical incubators made by Changzhou Wanhe instrument manufacturing company: 150A and 250B; microplate reader: SpectraMax M5, Molecular Devices; 3T3L1 mouse embryonic fibroblasts: Cyagen Biosciences Inc.
pyridin-2(1H)-one ( 3 ).To a 25 mL flask were added 3.40 mL 50% sulfuric acid (v/v) and 1.00 g (10 mmol) 2-aminopyridine (1). The mixture turned milky white after being stirred for a few minutes below 10°C on an ice-salt bath. Then, 1.72 g (25 mmol) NaNO2 in 3 mL H2O was added dropwise, which produced an irritant gas. The pH of the resulting pale yellow solution was adjusted to 7–8 using 10% dilute sulfuric acid and the mixture was refluxed with stirring for 20 min. Water was mostly removed in vacuo, and the residue was mixed with a moderate amount of silica gel, concentrated to dryness, and then washed with ethyl acetate in a sand core funnel. The filtrate was concentrated to afford the crude product 3, which was used in the following reaction without further purification.
4-(2-oxopyridin-1(2H)-yl)benzaldehyde ( 4 ).In a 25 mL round-bottom flask, a mixture of 0.10 g (1 mmol, 1 equiv.) 3, 0.17 g (1 mmol, 1 equiv.) 4-bromobenzaldehyde, 1.4 g (10 mmol, 10 equiv.) K2CO3, and 0.05 g (0.26 mmol, 0.25 equiv.) CuI in dimethylformamide (5 mL) was stirred under reflux for 1 h. After cooling, 30 mL water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:3 (v/v)) to give 4 as a pale yellow solid.
1-(4-(3a,4,5,6,7,7a-Hexahydro-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2(1H)-one ( 5a ).A mixture of 10 mL tert-butanol, 0.22 g (1 mmol, 1 equiv.) 4, 0.086 g (1.2 mmol, 1.2 equiv.) 1,2-diaminopropane, 0.32 g (2.5 mmol, 2.5 equiv.) iodine, and 0.43 g (3 mmol, 3.0 equiv.) K2CO3 in a 25 mL round-bottom flask was stirred for 3 h at 70°C. The pH of the mixture was adjusted to 7–8, and the mixture was then concentrated in vacuo to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:2 (v/v) → ethanol (3–5 drops triethylamine)) to give 5b as a yellow solid. 5b and 5c were obtained using procedures similar to that used for 5a.
1-(4-(Hydrazonomethyl)phenyl)pyridin-2(1H)-one( 5d ).In a 25 mL flask, to a solution of 0.21 g (1 mmol, 1 equiv.) 4 in 15 mL absolute ethanol 0.13 g (1.2 mmol, 1.2 equiv.) 30% hydrazine hydrate was added dropwise with 3 drops glacial acetic acid as a catalyst. The mixture was stirred for 3 h at room temperature. Removal of the solvent and recrystallization from ethanol provided 5d as a white solid. 5e and 5h were obtained using procedures similar to that used for 5d.
5-methyl-1-phenyl-2(1H)-pyridone (pirfenidone).Yellow solid, yield: 76%, m.p. 121–123°C. 1H NMR (400 MHz, DMSO) δ 7.49 (t, J = 7.4 Hz, 2H), 7.44–7.32 (m, 5H), 6.43 (d, J = 9.3 Hz, 1H), 2.03 (s, 3H). 13C NMR (101 MHz, DMSO) δ 160.41, 142.98, 141.01, 136.04, 128.96, 127.92, 126.71, 120.21, 114.01, 16.30.
1-(4-(3a,4,5,6,7,7a-Hexahydro-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2(1H)-one ( 5a ).Yellow solid, yield: 64%, m.p. 254–256°C. 1H NMR (400 MHz, DMSO) δ 8.07 (d, J = 8.6 Hz, 2H), 7.83–7.69 (m, 3H), 7.59–7.52 (m, 1H), 6.51 (d, J = 9.3 Hz, 1H), 6.38 (td, J = 6.7, 1.1 Hz, 1H), 3.50–3.37 (m, 1H), 3.08 (dd, J = 14.5, 7.2 Hz, 1H), 2.57 (dd, J = 11.1, 6.1 Hz, 4H), 1.75 (s, 1H), 1.44 (dd, J = 16.8, 11.7 Hz, 4H). 13C NMR (101 MHz, DMSO) δ 163.61, 160.91, 145.35, 141.14, 138.39, 129.26, 127.76, 122.32, 120.64, 106.21, 56.01, 53.84, 31.94, 25.33, 23.97, 18.45. HRMS (ESI) calcd for C18H19N3O [M + H]+ 294.1607, found 294.1604.
1-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)pyridin-2(1H)-one ( 5b ).Yellow solid, yield: 56%, m.p. 237–239°C. 1H NMR (400 MHz, DMSO) δ 8.00 (d, J = 8.6 Hz, 2H), 7.69 (dd, J = 12.3, 5.2 Hz, 3H), 7.57–7.51 (m, 1H), 6.50 (d, J = 9.2 Hz, 1H), 6.37 (td, J = 6.7, 1.1 Hz, 1H), 3.56–3.10 (m, 4H), 1.87 (s, 1H). 13C NMR (101 MHz, DMSO) δ 170.27, 163.97, 160.98, 144.55, 141.07, 138.51, 128.93, 127.49, 120.63, 106.14, 45.90, 45.74. HRMS (ESI) calcd for C14H13N3O [M + H]+ 240.1138, found 240.1138.
1-(4-(1,4,5,6-Tetrahydropyrimidin-2-yl)phenyl)pyridin-2(1H)-one ( 5c ).Yellow solid, yield: 56%, m.p. 146–148°C. 1H NMR (400 MHz, DMSO) δ 8.10 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.57–7.51 (m, 1H), 6.48 (d, J = 9.3 Hz, 1H), 6.37 (td, J = 6.7, 1.1 Hz, 1H), 3.53–3.41 (m, 6H), 2.94 (dd, J = 14.7, 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 170.34, 165.08, 162.01, 161.64, 159.06, 141.64, 138.91, 129.13, 128.63, 127.82, 120.99, 106.76, 46.31, 37.27, 35.33. HRMS (ESI) calcd for C15H15N3O [M + H]+ 254.1294, found 254.1292.
1-(4-(Hydrazonomethyl)phenyl)pyridin-2(1H)-one ( 5d ).Yellow solid, yield: 69%, m.p. 164–166°C. 1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.63 (ddd, J = 6.8, 2.0, 0.5 Hz, 1H), 7.61–7.55 (m, 2H), 7.53–7.46 (m, 1H), 7.39–7.30 (m, 2H), 6.95 (s, 2H), 6.48 (dd, J = 9.2, 0.5 Hz, 1H), 6.30 (td, J = 6.7, 1.3 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 161.21, 140.54, 139.59, 138.98, 136.86, 136.33, 126.84, 125.41, 120.51, 105.61. HRMS (ESI) calcd for C12H11N3O [M + H]+ 214.0981, found 214.0981; [M + Na]+ 236.0800, found 236.0809.
1-(4-((2-Phenylhydrazono)methyl)phenyl)pyridin-2(1H)-one ( 5e ).Yellow solid, yield: 62%, m.p. 208–210°C. 1H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 6.9, 1.7 Hz, 1H), 7.50 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.29–7.20 (m, 2H), 7.11 (d, J = 7.6 Hz, 2H), 7.02–6.88 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 9.0 Hz, 1H), 6.32 (td, J = 6.7, 1.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 161.21, 145.60, 145.15, 140.60, 140.01, 138.95, 135.73, 135.20, 129.06, 126.99, 125.93, 121.44, 120.53, 118.97, 114.45, 112.12, 105.69. HRMS (ESI) calcd for C18H15N3O [M + H]+ 290.1294, found 290.1292; [M + Na]+ 312.1111, found 312.1104.
2-(4-(2-Oxopyridin-1(2H)-yl)benzylidene)hydrazinecarboxamide ( 5f ).Pale-yellow solid, yield: 66%, m.p. 230–232°C. 1H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 7.89 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.66 (dd, J = 6.9, 1.6 Hz, 1H), 7.51 (ddd, J = 9.0, 6.6, 2.0 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 6.58 (s, 2H), 6.48 (d, J = 9.1 Hz, 1H), 6.32 (td, J = 6.7, 1.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 161.16, 157.83, 156.74, 141.00, 140.66, 138.92, 138.11, 134.66, 126.97, 120.55, 105.73. HRMS (ESI) calcd for C13H12N4O2 [M + H]+ 257.1039, found 257.1035.
2-(4-(2-Oxopyridin-1(2H)-yl)benzylidene)hydrazinecarbothioamide ( 5g ).Gray solid, yield: 68%, m.p. 222–224°C. 1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.66 (dd, J = 6.9, 1.6 Hz, 1H), 7.54–7.47 (m, 1H), 7.43 (d, J = 8.5 Hz, 2H), 6.49 (d, J = 8.9 Hz, 1H), 6.32 (td, J = 6.7, 1.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 178.11, 161.13, 141.65, 141.07, 140.69, 138.82, 134.02, 127.80, 127.00, 120.58, 105.78. HRMS (ESI) calcd for C13H12N4OS [M + H]+ 273.0811, found 273.0815.