Derivatives of 2-pyridones are of interest due to their biological activity,1 in particular anticonvulsant (perampanel),2 antifungal, and antimicrobial (cyclopirox)3 properties, together with the ability to inhibit phosphodiesterase, 3 which is used in the treatment of heart failure (milrinone).4 In addition, the 2-pyridone ring is part of natural compounds (trichodin A, B and pyridoxatin, Fig. 1), including alkaloids.5 Derivatives of 2-pyridones are used as herbicides, insecticides,6 and luminophores.7 6-(Pyridin-2-yl)-2-pyridones are of interest as ligands and fluorescent sensors of zinc cations in the composition of living cells,8 and also have promising photophysical properties.9

Figure 1.
figure 1

Structures of biologically active 2-pyridones.

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To date, a variety of synthetic approaches to 2-pyridones are presented in the literature, summarized in several reviews.10 However, the method based on the use of 1,2,4-triazines as dienes, well-established in the synthesis of bi- and oligopyridines,11 is limited to only a few examples of intramolecular reactions of 1,2,4-triazines with terminal acetylene for the preparation of 2-pyridones.12 Moreover, the formation of a mixture of products is noted in a number of cases.13

Earlier, we reported the possibility of synthesizing 5-aryl-2,2'-bipyridines with a methoxy, pyrrolidine,14 or phenyl- (cyano)methyl15 substituent at position 6, as well as 8-(pyridin-2-yl)coumarins16via the aza-Diels–Alder reaction under conditions of elevated pressure and temperature in an autoclave. In the present work, 2-pyridones, including new derivatives with a pyridin-2-yl substituent at position 6 (2,2'-bipyridines), using easily accessible precursors, 1,2,4-triazin-5-ones, were obtained in a similar manner.

The precursors 1,2,4-triazin-5-ones 1a–d were obtained from readily available 5-cyano-1,2,4-triazines 2a–d.17 Of the described procedures for performing this transformation, 17b,18 we chose the most convenient18d (Scheme 1). The subsequent aza-Diels–Alder reaction of the synthesized 1,2,4-triazin-5-ones 1a–d with 2,5-norbornadiene as dienophile was carried out in an autoclave in 1,2-dichlorobenzene at 215°C for 20 h, as a result of which 2-pyridones 3a–d were obtained with high yields. Use of 6-(4-fluorophenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-one (1b) and another dienophile, 4-(cyclopent-1-en-1-yl)- morpholine, allowed to obtain 2-pyridone 4 with an annulated cyclopentene ring in one step. This reaction was carried out also according to the previously described method19 without solvent, but in this case it took more time to complete it. In all cases, the formation of a single product was recorded and flash chromatography was used for its final purification.

scheme 1

Scheme 1

The structures of products 3a–d and 4 were proved on the basis of 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis data. In particular, upon conversion of 1,2,4-triazin-5-ones 1a–d to 2-pyridones 3a–d, the 1H NMR spectra show an upfield shift of the signals of the protons of the pyridine ring and the proton of the NH group from 13.99–14.60 to 10.98–11.79 ppm. In addition, the 1H NMR spectroscopy data of product 3d correlate with previously published data when compound 3d was obtained by an alternative method.20 In case of product 4, the characteristic signals of the annulated cyclopentene ring appear in the resonance region of aliphatic protons.

To conclude, we have proposed an efficient synthetic approach to novel 2-pyridones containing a pyridin-2-yl substituent using readily available precursors 5-cyano-1,2,4-triazines and 1,2,4-triazin-5-ones. The products were obtained in high yields.

Experimental

1H and 13C NMR spectra were acquired on a Bruker Avance II 400 spectrometer (400 and 100 MHz, respectively) in DMSO-d6, with TMS as internal standard. Mass spectra were recorded on a Bruker Daltonics MicrOTOF-Q II instrument, electrospray ionization. Elemental analysis was performed on a Perkin Elmer 2400 CHN-analyzer. Melting points were determined on a Boetius heating bench. Monitoring of the reaction progress and assessment of the purity of synthesized compounds were done by TLC on Sigma-Aldrich SiO2 plates with a fluorescent indicator (254 nm). Products were purified by column chromatography on SiO2 (230–400 mesh).

5-Cyano-1,2,4-triazines 2a–d were synthesized according to a literature method.17a 1,2,4-Triazin-5-ones 1a–d were obtained from the respective 5-cyano-1,2,4-triazines 2a–d according to the previously described procedure for similar compounds.18d

6-Phenyl-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-one (1а). Yield 193 mg (77%), yellow crystals, mp 177–179°C (mp 174–176°C21). 1H NMR spectrum, δ, ppm (J, Hz): 7.49–7.52 (3H, m, H Ph); 7.73–7.76 (1Н, m, H-5 Py); 8.11–8.17 (3Н, m, Н-4 Py, H Ph); 8.35 (1Н, d, J = 8.0, Н-3 Py); 8.84 (1Н, d, J = 4.8, Н-6 Py); 14.60 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 251 [M+H]+ (100). Found, %: C 67.09; H 3.99; N 22.31. С14Н10N4O. Calculated, %: C 67.19; H 4.03; N 22.39.

6-(4-Fluorophenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)- one (1b). Yield 196 mg (73%), yellow crystals, mp 171–173°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.17–7.21 (2H, m, H Ar); 7.60–7.68 (1Н, m, H-5 Py); 8.08 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4 Py); 8.31–8.42 (3Н, m, H Ar, Н-3 Py); 8.79 (1Н, d, J = 4.8, Н-6 Py); 14.44 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 269 [M+H]+ (100). Found, %: C 62.60; H 3.29; N 20.80. С14Н9FN4O. Calculated, %: C 62.69; H 3.38; N 20.89.

6-(4-Methoxyphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)- one (1c). Yield 210 mg (75%), yellow crystals, mp 183–185°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.84 (3Н, s, OСН3); 7.05–7.08 (2H, m, H Ar); 7.71–7.75 (1Н, m, H-5 Py); 8.13 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4 Py); 8.21–8.24 (2Н, m, H Ar); 8.34 (1Н, d, J = 8.0, Н-3 Py); 8.83 (1Н, d, J = 4.8, Н-6 Py); 14.50 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 281 [M+H]+ (100). Found, %: C 64.19; H 4.28; N 19.90. С15Н12N4O2. Calculated, %: C 64.28; H 4.32; N 19.99.

6-(4-Chlorophenyl)-1,2,4-triazin-5(4H)-one (1d). Yield 160 mg (78%), light-yellow crystals, mp 190–192°C. 1H NMR spectrum, δ, ppm: 7.48–7.50 (2H, m, H Ar); 8.16–8.25 (2H, m, H Ar); 8.65 (1Н, br. s, Н-3); 13.99 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 208 [M+H]+ (100). Found, %: C 52.00; H 2.85; N 20.16. С9Н6ClN3O. Calculated, %: C 52.07; H 2.91; N 20.24.

Synthesis of pyridones 3а–d (General method). 2,5-Norbornadiene (0.41 ml, 4 mmol) was added to a suspension of 1,2,4-triazin-5-one 1a–d (0.5 mmol) in 1,2-dichlorobenzene (15 ml). The resulting mixture was stirred under an argon atmosphere in an autoclave at 215°С for 20 h. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (SiO2, eluent CH2Cl2–EtOAc, 10:1). An analytical sample was obtained by recrystallization from MeCN.

5-Phenyl-2,2′-bipyridin-6(1H)-one (3a). Yield 87 mg (70%), light-yellow crystals, mp 166–168°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.23 (1Н, d, J = 8.0, H-3); 7.31–7.35 (1Н, m, H Ph); 7.37–7.43 (2Н, m, H Ph); 7.46–7.48 (1H, m, Н-5'); 7.73–7.81 (3Н, m, H Ph, H-4); 7.95 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4'); 8.17 (1Н, d, J = 8.0, Н-3'); 8.70 (1Н, d, J = 4.8, Н-6'); 11.00 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 103.2; 119.6; 124.4; 128.0; 128.3; 128.5; 132.9; 136.3; 137.3; 138.4; 140.7; 147.9; 149.3; 161.5. Mass spectrum, m/z (Irel, %): 249 [M+H]+ (100). Found, %: C 77.18; H 4.73; N 11.01. С16Н12N2O. Calculated, %: C 77.40; H 4.87; N 11.28.

5-(4-Fluorophenyl)-2,2′-bipyridin-6(1H)-one (3b). Yield 98 mg (74%), light-yellow crystals, mp 181–183°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.09–7.13 (2Н, m, H Ar); 7.18 (1Н, d, J = 8.0, H-3); 7.41–7.44 (1H, m, Н-5'); 7.72 (1Н, d, J = 8.0, H-4); 7.80–7.84 (2H, m, H Ar); 7.91 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4'); 8.12 (1Н, d, J-= 8.0, Н-3'); 8.67 (1Н, d, J = 4.8, Н-6'); 10.98 (1H, br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 103.3; 115.2 (d, J = 21.6); 119.6; 124.5; 130.2; 130.3; 131.9; 132.2 (d, J = 3.4); 137.4; 138.2; 140.6; 147.8; 149.4; 161.5; 162.6 (d, J = 247.8). Mass spectrum, m/z (Irel, %): 267 [M+H]+ (100). Found, %: C 72.08; H 4.01; N 10.45. С16Н11FN2O. Calculated, %: C 72.17; H 4.16; N 10.52.

5-(4-Methoxyphenyl)-2,2′-bipyridin-6(1H)-one (3c). Yield 100 mg (72%), light-yellow crystals, mp 199–201°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.86 (3Н, s, OCH3); 7.03–7.06 (2Н, m, H Ar); 7.24–7.26 (1Н, m, Н-3); 7.54–7.58 (1H, m, H-5'); 7.84–7.87 (3Н, m, H-4, H Ar); 8.04 (1H, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4'); 8.23 (1Н, d, J = 8.0, Н-3'); 8.77 (1Н, d, J = 4.8, Н-6'); 11.18 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 55.4; 117.5; 125.6; 126.9; 127.4; 127.8; 129.0; 129.3; 129.4; 130.0; 130.3; 131.5; 133.7; 135.8; 139.0; 141.0; 154.5. Mass spectrum, m/z (Irel, %): 279 [M+H]+ (100). Found, %: C 73.30; H 4.99; N 10.01. С17Н14N2O2. Calculated, %: C 73.37; H 5.07; N 10.07.

3-(4-Chlorophenyl)pyridin-2(1H)-one (3d). Yield 76 mg (74%), light-yellow crystals, mp 177–179 °C (mp 182–184°C20). 1H NMR spectrum, δ, ppm (J, Hz): 6.22 (1Н, dd, J = 6.6, J = 6.6, Н-5); 7.28–7.34 (3H, m, H Ar, H-4); 7.56 (1H, dd, J = 6.6, J = 2.0, H-6); 7.71–7.73 (2H, m, H Ar); 11.79 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 107.2; 128.5; 129.9; 130.4; 133.8; 134.3; 134.9; 139.8; 164.0. Mass spectrum, m/z (Irel, %): 206 [M+H]+ (100). Found, %: C 64.16; H 3.85; N 6.72. С11Н8ClNO. Calculated, %: C 64.25; H 3.92; N 6.81.

4-(4-Fluorophenyl)-1-(pyridin-2-yl)-2,5,6,7-tetrahydro-3H-cyclopenta[c]pyridin-3-one (4). A mixture of 1,2,4-triazin-5-one 1b (200 mg, 0.75 mmol) and 4-(cyclopent-1-en-1-yl)morpholine (0.6 ml, 3.75 mmol) was stirred under an argon atmosphere at 200°С for 10 h. The product was isolated from the reaction mixture by column chromatography (SiO2, eluent CH2Cl2–EtOAc, 10:1). The solvent was evaporated under reduced pressure from the combined fractions containing product 4, and the residue was treated with EtOH (20 ml). The formed precipitate was filtered off, washed with EtOH (20 ml), and dried. Yield 172 mg (75%), light-yellow crystals, mp 124–126°C (MeCN), Rf 0.40 (CH2Cl2–EtOAc, 10:1). 1H NMR spectrum, δ, ppm (J, Hz): 2.02–2.05 (2H, m, 6-CH2); 2.80 (2H, t, J = 7.6, 7-CH2); 3.11 (2H, t, J = 7.6, 5-CH2); 7.08–7.12 (2Н, m, H Ar); 7.43–7.47 (3Н, m, H-5 Py, H Ar); 7.86 (1Н, d, J = 7.6, Н-3 Py); 7.93 (1Н, ddd, J = 7.9, J = 7.9, J = 1.0, Н-4 Py); 8.71 (1Н, d, J = 4.8, Н-6 Py); 10.60 (1H, br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 26.3; 31.8; 33.0; 115.0 (d, J = 21.8); 121.9; 122.3; 123.8; 127.1; 131.3 (d, J = 3.2); 131.5; 134.0; 137.1; 148.8; 149.5; 158.2; 161.8; 162.1 (d, J = 246.4). Mass spectrum, m/z (Irel, %): 307 [M+H]+ (100). Found, %: C 74.42; H 4.89; N 9.05. С19Н15FN2O. Calculated, %: C 74.50; H 4.94; N 9.14.