Novel Approach to the Synthesis of 3-amino-4-arylpyridin-2(1H)-one Derivatives.

The reaction of 4-arylidene-2-phenyloxazol-5(4H)-ones with enamines of ethyl acetoacetate gave 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylic acid esters, which, when heated with phosphorus oxychloride, were converted into esters of 7-aryl-5-methyl-2-phenyloxazolo[5,4-b]pyridine-6-carboxylic acids. Alkaline hydrolysis of these compounds gave 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylic acid esters. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10593-021-02980-w. © Springer Science+Business Media, LLC, part of Springer Nature 2021.

Pyridin-2(1H)-ones are privileged structures that are part of many biologically active compounds of natural and synthetic origin.1 3-Aminopyridin-2(1H)-ones are of particular interest since they contain an amino acid amide fragment in their structure and can be used for the synthesis of peptidomimetics. Among these compounds, enzyme inhibitors2–6 such as Mpro protease which prevents the replication of the coronavirus SARS-CoV-2,7,8 agonists and modulators of cannabinoid receptors CB2,9,10 antagonists of prostaglandin receptor EP3,11 and an inhibitor of jasmonate signaling12 have been found. 5-Amino-3,4'-bipyridin-(1H)-one, known as the cardiotonic drug amrinone,13 is widely used in clinical practice. 3-Aminopyridin-2(1H)-ones are used in the synthesis of more complex compounds.14–16 Recently, it was shown that 3-amino-4-arylpyridin-2(1H)-ones are good antioxidants,17,18 possess luminescent properties,19 and can be used as luminescent dyes for enzyme-linked immunosorbent assay.20 Despite the wide range of biological activity, the methods for the preparation of 3-amino-4-arylpyridin-2(1H)-ones are few and, as a rule, involve multistep synthesis.19–22

It was previously reported that azlactones are capable of reacting with enamines of 1,3-diketones and 1,3-keto esters to form the corresponding amides of 3-amino-4-aryl-3,4-dihydropyridin-2(1H)-ones,23–25 which, in principle, can be oxidized to the corresponding amides of 3-aminopyridin-2(1H)-ones.26–28 Therefore, it seemed necessary to study the possibility of such an approach to the synthesis of 3-amino-4-arylpyridin-2(1H)-one derivatives.

For this purpose, azlactones 1a–e were synthesized by the known method29 by condensation of hippuric acid with aromatic aldehydes in the presence of polyphosphoric acid. Compounds 1a–e obtained in this way were subjected to a reaction with enamines 2, 3 by heating at 180°С for 1.5 h without a solvent. As a result, ethyl 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylates 4a–f were obtained. Compounds 4a–c were isolated as cis-isomers, while compounds 4d–f represented mixtures of cis-/trans-isomers with yields of 64/22% (compound 4d), 79/16% (compound 4e), 47/18% (compound 4f); the mixtures were then resolved by silica gel column chromatography. It should be noted that the yields of dihydropyridones 4с–е containing acceptor substituents in the aryl fragment were higher than those of unsubstituted and methoxy-substituted products 4a,b (Scheme 1, Table 1).

Scheme 1

Table 1.

Yields of isomers of compounds 4a–f

Compound	Yield, %
	cis-Isomer	trans-Isomer
4a	58	–
4b	53	–
4c	74	–
4d	64	22
4e	79	16
4f	47	18

The structure and composition of the obtained compounds were confirmed by the data of IR, 1H and 13C NMR spectroscopy, X-ray structural analysis, and elemental analysis. In the 1H NMR spectra of cis-isomers 4a–e, the protons at position С-4 of the pyridone ring are present in the form of doublets, whereas at position С-5 – as doublets of doublets with 3J5-СH,NH = 5.3–6.7 Hz and total coupling constant 3J4-СH,5-СH = 7.4–8.0 Hz. Due to the low solubility of trans-isomers 4d,е in CDCl3, their 1H NMR spectra were recorded in DMSO-d6.

According to X-ray diffraction data, the crystal of compound 4а consists of molecules of only one pair of enantiomers with the cis arrangement of substituents and the 3R*,4R* configuration of the atoms of the methine groups (the numbering of atoms is shown in Figure 1). The conformation of the pyridone ring can be described as a highly distorted boat. Atoms N(1), C(1), C(2), and C(3) lie in the same plane, atoms C(5) and C(4) deviate from this plane to one side by 0.15 and 0.67 Å, respectively. In the solid state, molecules are linked into infinite chains via N(1)–H(1)···O(2) hydrogen bonds. To oxidate obtained 3,4-dihydropyridin-2(1H)-ones, MnO2,27,28 FeCl3,30 and DDQ31,32 were employed. However, in our case, oxidation with these reagents, chloranil, NaNO2 in AcOH, K2S2O8 in MeCN, by heating compounds 4а,f with KMnO4 in Me2CO or heating with 10% Pd/C in xylene did not lead to the formation of pyridones 5a,f (Scheme 2).

Figure 1.

The molecular structure of compound 4а with atoms represented as thermal vibration ellipsoids with 30% probability.

Scheme 2

It is known that 1,4-dihydropyridines can be easily oxidized to pyridines. In some cases, oxidation with atmospheric oxygen occurs already upon the preparation of 1,4-dihydropyridines (Scheme 3).33 We studied the possibility of obtaining 4,7-dihydrooxazolo[5,4-b]pyridine 6a by the action of the following dehydrating reagents on compound 4a (Scheme 3, Table 2): POCl3, SOCl2, polyphosphoric acid (PPA), Ac2O in the presence of H2SO4. Heating compound 4а with POCl3, SOCl2, or Ac2O in H2SO4 as a result of oxidation of intermediate 6a with atmospheric oxygen gave oxazolo[5,4-b]pyridine 7a, isolated in 40, 34, and 10% yields (Scheme 3, Table 2). The yields of oxazolo[5,4-b]pyridines 7a–e obtained by heating compounds 4a–e with POCl3 were 23–47%.

Scheme 3

Table 2.

Yields of oxazolo[5,4-b]pyridine 7a by the action of dehydrating reagents on compound 4a

Reagent	Temperature, °С	Time, h	Yield, %
POCl3	25	24	0
POCl3	110	1.5	40
SOCl2	25	24	0
SOCl2	75	3	34
Ac2O, H2SO4	140	17	10
PPA	150	10	0

Comparison of the electronic spectrum of compound 7a with the previously reported34 spectrum of oxazolo[5,4-b]-pyridine 8а, which does not contain an ethoxycarbonyl group at the C-5 position of the heterocycle, showed that they differ little from each other (Table 3, Fig. 2). The introduction of an acceptor substituent into the pyridine ring results in a hypsochromic shift of both absorption and luminescence bands by 15–35 nm and a decrease in the luminescence quantum yield from 0.82 to 0.16. The absorption spectra of oxazolo[5,4-b]pyridines 7a–е have two maxima centered at 256–279 and 313–323 nm. Compound 7е, containing a nitro group, does not luminesce, whereas compounds 7a,c,d contain an intense band at 366–371 nm in the luminescence spectrum. The introduction of electron-donating methoxy group into the aryl substituent (compound 7b) results in a significant bathochromic shift. The center of the emission band in the spectrum of compound 7b is shifted by 46 nm compared with the spectrum of 5-methyl-2,7-diphenyloxazolo[5,4-b]-pyridine-6-carboxylic acid ethyl ester (7a), while the Stokes shift increases from 0.57 (compound 7a) to 0.94 eV (compound 7b). The luminescence quantum yields of compounds 7a–d are 0.14–0.19.

Table 3.

The data of absorption and fluorescence spectra of compounds 7a–e and 8a

Figure 2.

The normalized absorption and fluorescence spectra of compounds 7a–e and 8a in EtOH.

Upon heating with an aqueous ethanol solution of NaOH for 1.5 h, opening of the oxazole ring of oxazolo[5,4-b]- pyridines 7a–e takes place leading to amides 9a–e in 74– 94% yields (Scheme 4).

Scheme 4

To conclude, we developed a simple method for the preparation of 7-aryloxazolo[5,4-b]pyridines based on the accessible azlactones and enamines of ethyl acetoacetate. The photophysical properties of these compounds were studied and it has been shown that their hydrolysis leads to 3-aminopyridin-2(1H)-one derivatives in good yields.

Experimental

IR spectra were registered on a Simex FT-801 Fourier transform spectrometer in KBr pellets. Absorption spectra were recorded on a PerkinElmer Lambda 750 diode array spectrophotometer, photoluminescence spectra were recorded on a Cary Eclipse fluorescence spectrophotometer. In both cases, the test compounds were dissolved in EtOH so that the concentration of the resulting solutions was lower than 10–5 mol/dm3. The molar light absorption coefficient was determined according to the described method.35 The quantum yield was determined relative to quinine sulfate in 0.5 M H2SO4 (Фf 0.546) using the comparison method.36 1H and 13C NMR spectra were acquired on a Bruker DRX-400 spectrometer (400 and 100 MHz, respectively) in CDCl3 or DMSO-d6, with the residual solvent signals (CDCl3: 7.26 ppm for 1H nuclei and 77.0 ppm for 13C nuclei; DMSO-d6: 2.50 ppm for 1H nuclei and 39.5 ppm for 13C nuclei) serving as internal standards. Elemental analysis was performed on a Carlo Erba EA 1106 CHN-analyzer. Melting points were determined on a Reach Devices RD-MP apparatus and are uncorrected. Monitoring of the reaction progress and assessment of the purity of synthesized compounds were done by TLC on Silufol UV-254 plates, eluents CHCl3 and CHCl3–EtOAc, 10:1. Visualization of plates was done under UV light. Silica gel 60 (0.063–0.200 mm, Macherey-Nagel) was used for column chromatography.

The starting azlactones 1a–e were obtained according to a known procedure29 by condensation of hippuric acid with aromatic aldehydes in the presence of polyphosphoric acid. The starting enamines of acetoacetic ester 2, 3 were obtained by the previously described methods.37

Synthesis of 1,4,5,6-tetrahydropyridin-6-ones 4a–f (General method). A mixture of azlactone 1a–e (10 mmol) and enamine 2 or 3 (10 mmol) was heated at 180°С for 1.5 h. The mixture was then cooled and purified by column chromatography on silica gel, eluent CHCl3–EtOAc, 10:1.

Ethyl -2-methyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)-amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4a). Yield 2190 mg (58%), colorless crystals, mp 205–206°C (EtOH) (mp 200–201°C (PhН)24). IR spectrum, ν, cm–1: 3397, 3337, 3165, 3031, 2992, 2979, 2953, 2904, 1701, 1645, 1634, 1602, 1580, 1528, 1490, 1454, 1401, 1295, 1255, 1226, 1193, 1171, 1082, 941, 734, 716, 697, 647. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.12 (3H, t, J = 7.0, CH2CH3); 2.46 (3H, s, 2-CH3); 3.99–4.12 (2H, m, CH2CH3); 4.71 (1H, d, J = 7.8, 4-СН); 5.21 (1H, dd, J = 7.8, J = 6.7, 5-СН); 6.46 (1H, d, J = 6.7, 5-NHCOPh); 7.08–7.11 (2H, m, H Ph); 7.23–7.25 (3H, m, H Ph); 7.36–7.40 (2H, m, H Ph); 7.46–7.50 (1H, m, H Ph); 7.62–7.64 (2H, m, H Ph); 7.99 (1H, s, 1-NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.0; 18.8; 42.3; 53.4; 60.4; 108.9; 127.0; 127.7; 128.3; 128.6; 128.7; 131.8; 133.9; 136.8; 145.2; 166.2; 167.4; 169.2. Found, %: C 69.96; H 6.03; N 7.46. C22H22N2O4. Calculated, %: C 69.83; H 5.86; N 7.40.

Ethyl -4-(4-methoxyphenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4b). Yield 2160 mg (53%), beige crystals, mp 161–162°C (i-PrOH) (mp 212–214°C (PhН)24). IR spectrum, ν, cm–1: 3397, 3232, 3156, 3067, 2982, 2955, 2938, 2906, 2838, 1701, 1637, 1612, 1581, 1529, 1512, 1489, 1465, 1445, 1399, 1385, 1374, 1288, 1249, 1206, 1177, 1091, 1030, 831, 765, 712, 693, 647. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.14 (3H, t, J = 7.1, CH2CH3); 2.45 (3H, s, 2-CH3); 3.74 (3H, s, OCH3); 3.99–4.13 (2H, m, CH2CH3); 4.65 (1H, d, J = 7.8, 4-СН); 5.17 (1H, dd, J = 7.8, J = 6.7, 5-СН); 6.46 (1H, d, J = 6.7, 5-NHCOPh); 6.75–6.79 (2H, m, H-3,5 Ar); 7.00–7.03 (2H, m, H-2,6 Ar); 7.37–7.41 (2H, m, H Ph); 7.46–7.50 (1H, m, H Ph); 7.64–7.67 (2H, m, H Ph); 7.98 (1H, br. s, 1-NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.0; 18.8; 41.5; 53.6; 55.2; 60.3; 109.2; 114.0; 127.0; 128.6 (2C); 129.3; 131.8; 133.9; 144.9; 159.1; 166.3; 167.4; 169.3. Found, %: C 67.50; H 5.98; N 6.92. C23H24N2O5. Calculated, %: C 67.63; H 5.92; N 6.86.

Ethyl -4-(4-chlorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4c). Yield 3060 mg (74%), colorless crystals, mp 197–198°C (i-PrOH). IR spectrum, ν, cm–1: 3416, 3235, 3133, 2985, 2962, 2902, 1702, 1660, 1635, 1580, 1517, 1487, 1394, 1298, 1270, 1228, 1184, 1103, 1085, 1014, 832, 790, 717, 668. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.13 (3H, t, J = 7.0, CH2CH3); 2.47 (3H, s, 2-CH3); 4.01–4.12 (2H, m, CH2CH3); 4.73 (1H, d, J = 7.8, 4-СН); 5.15 (1H, dd, J = 7.8, J = 6.0, 5-СН); 6.56 (1H, d, J = 6.0, 5-NHCOPh); 7.00–7.03 (2H, m, H-2,6 Ar); 7.18–7.22 (2H, m, H-3,5 Ar); 7.38–7.43 (2H, m, H Ph); 7.48–7.52 (1H, m, H Ph); 7.64–7.67 (2H, m, H Ph); 8.04 (1H, br. s, 1-NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.0; 18.8; 41.5; 53.4; 60.5; 108.6; 127.0; 128.7; 128.8; 129.6; 132.0; 133.5; 133.6; 135.3; 145.4; 166.0; 167.5; 169.0. Found, %: C 63.81; H 5.18; N 6.74. C22H21ClN2O4. Calculated, %: C 64.00; H 5.13; N 6.79.

Ethyl 4-(4-fluorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4d). Yield 2530 mg (64%), colorless crystals, mp 180–181°C (i-PrOH). IR spectrum, ν, cm–1: 3408, 3246, 3135, 2979, 2874, 1707, 1634, 1604, 1581, 1510, 1486, 1387, 1299, 1230, 1160, 1097, 1083, 941, 837, 786, 718, 694. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.12 (3H, t, J = 7.1, CH2CH3); 2.47 (3H, s, 2-CH3); 4.02–4.10 (2H, m, CH2CH3); 4.74 (1H, d, J = 7.8, 4-СН); 5.15 (1H, dd, J = 7.8, J = 6.0, 5-СН); 6.53 (1H, d, J = 6.0, 5-NHCOPh); 6.89–6.95 (2H, m, H-3,5 Ar); 7.03–7.08 (2H, m, H-2,6 Ar); 7.38–7.42 (2H, m, H Ph); 7.48–7.52 (1H, m, H Ph); 7.63–7.66 (2H, m, H Ph); 8.16 (1H, br. s, 1-NH). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 14.0; 18.8; 41.4; 53.5; 60.4; 108.9; 115.5 (d, J = 21.7); 127.0; 128.6; 129.8 (d, J = 7.8); 131.9; 132.5 (d, J = 3.5); 133.7; 145.2; 162.3 (d, J = 246.2); 166.1; 167.5; 169.1. Found, %: C 66.86; H 5.47; N 7.15. C22H21FN2O4. Calculated, %: C 66.66; H 5.34; N 7.07.

Ethyl 4-(4-fluorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4d). Yield 870 mg (22%), colorless crystals, mp 183–184°C (i-PrOH). IR spectrum, ν, cm–1: 3240, 3160, 3069, 2979, 2962, 2931, 1709, 1644, 1604, 1580, 1537, 1511, 1492, 1366, 1275, 1226, 1192, 1124, 1097, 1016, 833, 693. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.88 (3H, t, J = 7.0, CH2CH3); 2.30 (3H, s, 2-CH3); 3.80–3.91 (2H, m, CH2CH3); 4.19 (1H, d, J = 6.7, 4-СН); 4.59 (1H, dd, J = 8.0, J = 6.7, 5-СН); 7.10–7.14 (2H, m, H-3,5 Ar); 7.21–7.25 (2H, m, H-2,6 Ar); 7.43–7.54 (3H, m, H Ph); 7.79 (2H, d, J = 7.4, H Ph); 8.91 (1H, d, J = 8.0, 5-NHCOPh); 10.15 (1H, s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 13.7; 17.9; 44.8; 55.1; 59.3; 104.3; 115.2 (d, J = 21.7); 127.5; 128.2; 129.0 (d, J = 7.8); 131.4; 133.9; 137.1 (d, J = 2.6); 146.2; 161.0 (d, J = 242.7); 166.5 (2C); 167.1. Found, %: C 66.87; H 5.46; N 7.15. C22H21FN2O4. Calculated, %: C 66.66; H 5.34; N 7.07.

Ethyl 2-methyl-4-(4-nitrophenyl)-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4e). Yield 3340 mg (79%), light-yellow crystals, mp 201–202°C (i-PrOH) (mp 201–202°C (PhН)24). IR spectrum, ν, cm–1: 3399, 3238, 3126, 2977, 2869, 1707, 1634, 1603, 1581, 1521, 1486, 1446, 1388, 1349, 1298, 1233, 1212, 1169, 1084, 939, 855, 789, 719, 694. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.12 (3H, t, J = 7.1, CH2CH3); 2.51 (3H, s, 2-CH3); 4.00–4.13 (2H, m, CH2CH3); 4.95 (1H, d, J = 8.0, 4-СН); 5.16 (1H, dd, J = 8.0, J = 5.3, 5-СН); 6.64 (1H, d, J = 5.3, 5-NHCOPh); 7.24–7.27 (2H, m, H-2,6 Ar); 7.39–7.42 (2H, m, H Ph); 7.49–7.53 (1H, m, H Ph); 7.63–7.65 (2H, m, H Ph); 8.02 (1H, s, 1-NH); 8.06–8.10 (2H, m, H-3,5 Ar). 13C NMR spectrum (CDCl3), δ, ppm: 14.0; 18.9; 41.9; 53.4; 60.7; 108.0; 123.8; 127.0; 128.8; 129.2; 132.2; 133.2; 144.8; 145.8; 147.5; 165.8; 167.6; 168.4. Found, %: C 62.80; H 5.12; N 9.97. C22H21N3O6. Calculated, %: C 62.41; H 5.00; N 9.92.

Ethyl 2-methyl-4-(4-nitrophenyl)-6-oxo-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4e). Yield 677 mg (16%), light-yellow crystals, mp 157–158°C (i-PrOH). IR spectrum, ν, cm–1: 3243, 3163, 3075, 2979, 1711, 1645, 1603, 1581, 1519, 1490, 1349, 1267, 1195, 1103, 1080, 1014, 841, 701. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.82 (3H, t, J = 7.0, CH2CH3); 2.31 (3H, s, 2-CH3); 3.79–3.85 (2H, m, CH2CH3); 4.35 (1H, d, J = 6.7, 4-СН); 4.65 (1H, dd, J = 7.1, J = 6.7, 5-СН); 7.43–7.57 (5H, m, H Ph); 7.72–7.83 (2H, m, H-2,6 Ar); 8.11–8.22 (2H, m, H-3,5 Ar); 8.93 (1H, d, J = 7.1, 5-NHCOPh); 10.24 (1H, s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.6; 17.9; 45.6; 54.6; 59.4; 103.5; 123.7; 127.4; 128.3; 128.6; 131.5; 133.7; 146.4; 146.9; 149.7; 166.2; 166.5; 166.8. Found, %: C 62.82; H 5.10; N 9.98. C22H21N3O6. Calculated, %: C 62.41; H 5.00; N 9.92.

Ethyl 1,2-dimethyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4f). Yield 1840 mg (47%), beige crystals, mp 127–128°C (i-PrOH). IR spectrum, ν, cm–1: 3389, 3070, 3034, 2979, 2931, 2849, 1687, 1651, 1627, 1601, 1579, 1521, 1486, 1383, 1318, 1291, 1259, 1240, 1193, 1177, 1115, 1089, 1037, 919, 843, 803, 788, 765, 714, 589. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.13 (3H, t, J = 7.1, CH2CH3); 2.62 (3H, s, 2-CH3); 3.31 (3H, s, 1-NCH3); 4.01 –4.15 (2H, m, CH2CH3); 4.73 (1H, d, J = 7.4, 4-СН); 5.07 (1H, dd, J = 7.4, J = 5.7, 5-СН); 6.67 (1H, d, J = 5.7, 5-NHCOPh); 6.94–6.99 (2H, m, H Ph); 7.20–7.24 (3H, m, H Ph); 7.36–7.41 (2H, m, H Ph); 7.46–7.51 (1H, m, H Ph); 7.65–7.68 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 14.0; 16.9; 30.0; 41.2; 53.6; 60.5; 112.2; 127.0; 127.6; 128.2; 128.5; 128.6; 131.7; 134.1; 136.0; 148.4; 166.5; 167.2; 168.4. Found, %: C 70.76; H 5.97; N 6.69. C23H24N2O4. Calculated, %: C 70.39; H 6.16; N 7.14.

Ethyl 1,2-dimethyl-6-oxo-4-phenyl-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (4f). Yield 706 mg (18%), beige crystals, mp 187–188°C (i-PrOH). IR spectrum, ν, cm–1: 3311, 3061, 3035, 2962, 2920, 2850, 1695, 1637, 1602, 1578, 1547, 1491, 1455, 1365, 1332, 1288, 1273, 1203, 1177, 1123, 1105, 1093, 1075, 1053, 1006, 904, 860, 799, 754, 719, 701, 693, 692, 586. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.87 (3H, t, J = 7.0, CH2CH3); 2.43 (3H, d, J = 1.6, 2-CH3); 3.18 (3H, s, 1-NCH3); 3.79–3.89 (2H, m, CH2CH3); 4.19 (1H, dd, J = 7.6, J = 1.6, 4-СН); 4.96 (1H, dd, J = 8.4, J = 7.6, 5-СН); 6.38 (1H, d, J = 8.4, 5-NHCOPh); 7.10–7.22 (5H, m, H Ph); 7.28–7.32 (2H, m, H Ph); 7.37–7.42 (1H, m, H Ph); 7.55–7.59 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 13.7; 16.7; 29.9; 45.6; 54.8; 60.5; 110.6; 127.1; 127.4; 127.5; 128.5; 128.7; 131.7; 134.0; 138.5; 145.9; 167.3 (3C). Found, %: C 70.75; H 5.99; N 6.73. C23H24N2O4. Calculated, %: C 70.39; H 6.16; N 7.14.

Synthesis of oxazolo[5,4- ]pyridines 7a–e (General method). A mixture of 1,4,5,6-tetrahydropyridin-6-one 4a–e (1 mmol) and POCl3 (3 ml) was heated under reflux for 1.5 h. The reaction mixture was evaporated to dryness, diluted with cold H2O (10 ml) and triturated to a homogeneous powder, which was filtered and washed with H2O (3×5 ml). The product was purified by column chromatography on silica gel (eluent СНCl3) and recrystallized from i-PrOH.

Ethyl 5-methyl-2,7-diphenyloxazolo[5,4- ]pyridine-6-carboxylate (7a). Yield 143 mg (40%), colorless crystals, mp 145–146°C (i-PrOH). IR spectrum, ν, cm–1: 3062, 3056, 3034, 2980, 2941, 2929, 2904, 1720, 1623, 1602, 1595, 1573, 1549, 1495, 1480, 1451, 1419, 1380, 1371, 1361, 1352, 1316, 1270, 1253, 1199, 1184, 1176, 1158, 1079, 1048, 1021, 950, 911, 825, 787, 780, 763, 723, 708, 690, 669, 651. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.01 (3H, t, J = 7.2, CH2CH3); 2.73 (3H, s, 5-CH3); 4.14 (2H, q, J = 7.2, CH2CH3); 7.45–7.55 (6H, m, H Ph); 7.62–7.65 (2H, m, H Ph); 8.23–8.26 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 13.6; 23.0; 61.6; 126.4 (2C); 127.9; 128.4; 128.9; 129.1; 129.3; 130.1; 132.1; 133.8; 140.6; 152.1; 159.4; 163.2; 168.5. Found, %: C 73.95; H 4.87; N 7.38. C22H18N2O3. Calculated, %: C 73.73; H 5.06; N 7.82.

Ethyl 5-methyl-7-(4-methoxyphenyl)-2-phenyloxazolo-[5,4- ]pyridine-6-carboxylate (7b). Yield 89 mg (23%), beige crystals, mp 155–156°C (i-PrOH). IR spectrum, ν, cm–1: 3068, 3050, 3013, 2985, 2956, 2933, 2903, 2837, 1720, 1622, 1612, 1603, 1546, 1518, 1484, 1464, 1451, 1443, 1381, 1371, 1362, 1353, 1320, 1294, 1274, 1260, 1252, 1203, 1184, 1161, 1082, 1051, 1031, 1021, 914, 835, 782, 714, 708, 692. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.10 (3H, t, J = 7.1, CH2CH3); 2.71 (3H, s, 5-CH3); 3.87 (3H, s, OCH3); 4.20 (2H, q, J = 7.1, CH2CH3); 7.01–7.05 (2H, m, H-3,5 Ar); 7.47–7.56 (3H, m, H Ph); 7.61–7.64 (2H, m, H-2,6 Ar); 8.23–8.26 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 13.8; 22.9; 55.3; 61.7; 114.0; 126.0; 126.2; 126.5; 127.9; 128.9; 130.0; 130.9; 132.1; 140.2; 152.0; 159.3; 160.5; 162.9; 168.8. Found, %: C 70.98; H 5.23; N 7.25. C23H20N2O4. Calculated, %: C 71.12; H 5.19; N 7.21.

Ethyl 7-(4-chlorophenyl)-5-methyl-2-phenyloxazolo-[5,4-]pyridine-6-carboxylate (7c). Yield 185 mg (47%), light-beige crystals, mp 148–149°C (i-PrOH). IR spectrum, ν, cm–1: 3070, 3034, 2986, 2937, 2901, 2871, 1721, 1621, 1603, 1543, 1498, 1484, 1474, 1452, 1423, 1382, 1372, 1362, 1353, 1320, 1276, 1257, 1202, 1183, 1157, 1091, 1081, 1073, 1053, 1021, 1010, 956, 939, 328, 915, 872, 831, 783, 734, 712, 692. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.09 (3H, t, J = 7.1, CH2CH3); 2.72 (3H, s, 5-CH3); 4.18 (2H, q, J = 7.1, CH2CH3); 7.47–7.60 (7H, m, H Ph, H Ar); 8.22–8.24 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm: 13.7; 23.0; 61.8; 126.2; 126.3; 127.9; 128.8; 129.0; 130.0; 130.7; 132.2; 132.3; 135.5; 139.1; 152.3; 159.4; 163.4; 168.3. Found, %: C 67.06; H 4.18; N 7.15. C22H17ClN2O3. Calculated, %: C 67.26; H 4.36; N 7.13.

Ethyl 7-(4-fluorophenyl)-5-methyl-2-phenyloxazolo-[5,4- ]pyridine-6-carboxylate (7d). Yield 173 mg (46%), beige crystals, mp 143–144°C (i-PrOH). IR spectrum, ν, cm–1: 3074, 2984, 2939, 2903, 1720, 1620, 1608, 1544, 1517, 1483, 1452, 1361, 1317, 1273, 1256, 1239, 1198, 1179, 1163, 1079, 1069, 1053, 1023, 950, 916, 877, 836, 803, 781, 735, 709, 691, 574. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.08 (3H, t, J = 7.1, CH2CH3); 2.72 (3H, s, 5-CH3); 4.17 (2H, q, J = 7.2, CH2CH3); 7.17–7.23 (2H, m, H-3,5 Ar); 7.47–7.56 (3H, m, H Ph); 7.62–7.65 (2H, m, H-2,6 Ar); 8.22–8.24 (2H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm (J, Hz): 13.7; 23.0; 61.7; 115.6 (d, J = 22.5); 126.3 (2C); 127.9; 128.9; 129.8 (d, J = 8.7); 130.0; 131.4 (d, J = 8.7); 132.2; 139.3; 152.2; 159.4; 163.3 (d, J = 249.7); 163.3; 168.4. Found, %: C 70.56; H 4.39; N 7.38. C22H17FN2O3. Calculated, %: C 70.20; H 4.55; N 7.44.

Ethyl 5-methyl-7-(4-nitrophenyl)-2-phenyloxazolo-[5,4- ]pyridine-6-carboxylate (7e). Yield 161 mg (40%), colorless crystals, mp 192–193°C (i-PrOH). IR spectrum, ν, cm–1: 3110, 3074, 3035, 2988, 2969, 2944, 2904, 2856, 1721, 1622, 1595, 1581, 1543, 1516, 1483, 1452, 1351, 1320, 1275, 1256, 1205, 1182, 1157, 1108, 1081, 1053, 1021, 1009, 945, 928, 916, 865, 859, 844, 782, 753, 723, 711, 692. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.08 (3H, t, J = 7.2, CH2CH3); 2.75 (3H, s, 5-CH3); 4.18 (2H, q, J = 7.2, CH2CH3); 7.49–7.53 (2H, m, H Ph); 7.55–7.59 (1H, m, H Ph); 7.79–7.82 (2H, m, H-2,6 Ar); 8.22–8.24 (2H, m, H Ph); 8.35–8.39 (2H, m, H-3,5 Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.8; 23.1; 62.0; 123.6; 125.9; 126.0; 128.0; 129.0; 130.0; 130.5; 132.6; 137.7; 140.4; 148.1; 152.7; 159.5; 164.0; 167.8. Found, %: C 65.30; H 4.16; N 10.53. C22H17N3O5. Calculated, %: C 65.50; H 4.25; N 10.42.

Synthesis of ethyl 4-aryl-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylates 9а–е (General method). A solution of NaOH (120 mg, 3 mmol) in Н2О (0.8 ml) was added to a suspension of oxazolo[5,4-b]-pyridine 7а–е (1 mmol) in EtOH (7 ml). The mixture was heated under reflux for 1.5 h, then concentrated in vacuo to 1/3 of its original volume. The residue was poured into Н2О (15 ml) and acidified with 10% aqueous HCl to pH ~3. The precipitate that formed was filtered, washed with H2O, and recrystallized.

Ethyl 2-methyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)-amino]-1,6-dihydropyridine-3-carboxylate (9a). Yield 316 mg (84%), colorless crystals, mp >250°C (i-PrOH). IR spectrum, ν, cm–1: 3287, 3121, 3051, 2984, 1721, 1674, 1642, 1615, 1517, 1488, 1398, 1287, 1201, 1157, 1089, 1027, 913, 898, 766, 705, 633. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.76 (3H, t, J = 7.1, CH2CH3); 2.33 (3H, s, 2-CH3); 3.79 (2H, q, J = 7.1, CH2CH3); 7.18–7.21 (2H, m, H Ph); 7.23–7.31 (3H, m, H Ph); 7.35–7.39 (2H, m, H Ph); 7.44–7.48 (1H, m, H Ph); 7.64–7.67 (2H, m, H Ph); 9.08 (1H, br. s, 5-NHCOPh); 11.95 (1H, br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 12.9; 16.9; 60.2; 111.4; 123.0; 127.1; 127.3 (2C); 127.4; 127.8; 130.9; 134.1; 136.2; 144.4; 148.7; 159.7; 165.9; 166.0. Found, %: C 70.60; H 5.34; N 7.26. C22H20N2O4. Calculated, %: C 70.20; H 5.36; N 7.44.

Ethyl 4-(4-methoxyphenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylate (9b). Yield 300 mg (74%), beige crystals, mp >250°C (PhMe). IR spectrum, ν, cm–1: 3249, 3132, 3054, 2981, 2932, 2907, 2837, 2781, 1720, 1671, 1644, 1611, 1580, 1553, 1514, 1486, 1466, 1444, 1396, 1366, 1291, 1249, 1199, 1178, 1157, 1110, 1088, 1028, 906, 872, 834, 781, 711, 692, 661, 634, 583. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.77 (3H, t, J = 7.2, CH2CH3); 2.30 (3H, s, 2-CH3); 3.68 (3H, s, OCH3); 3.82 (2H, q, J = 7.2, CH2CH3); 6.87 (2H, d, J = 8.8, H-3,5 Ar); 7.12 (2H, d, J = 8.8, H-2,6 Ar); 7.38–7.44 (2H, m, H Ph); 7.46–7.52 (1H, m, H Ph); 7.73 (2H, d, J = 7.4, H Ph); 9.32 (1H, br. s, 5-NHCOPh); 12.21 (1H, br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.3; 17.2; 55.1; 60.5; 111.7; 113.2; 123.2; 127.4; 128.2; 128.5; 128.7; 131.3; 134.1; 144.4; 148.6; 158.9; 160.1; 166.1; 166.3. Found, %: C 67.78; H 5.33; N 6.72. C23H22N2O5. Calculated, %: C 67.97; H 5.46; N 6.89.

Ethyl 4-(4-chlorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylate (9c). Yield 366 mg (89%), light-beige crystals, mp >250°C (i-PrOH). IR spectrum, ν, cm–1: 3288, 3127, 3056, 2981, 2928, 2869, 2788, 1722, 1674, 1642, 1606, 1582, 1571, 1556, 1517, 1487, 1445, 1393, 1366, 1286, 1247, 1200, 1188, 1157, 1087, 1027, 1015, 904, 871, 832, 822, 787, 707, 691, 662, 632. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.75 (3H, t, J = 7.1, CH2CH3); 2.34 (3H, s, 2-CH3); 3.81 (2H, q, J = 7.1, CH2CH3); 7.18 (2H, d, J = 8.4, H-2,6 Ar); 7.38–7.43 (4H, m, H Ph, H-3,5 Ar); 7.50 (1H, t, J = 7.3, H Ph); 7.70 (2H, d, J = 7.4, H Ph); 9.37 (1H, br. s, 5-NHCOPh); 12.34 (1H, br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.2; 17.4; 60.5; 110.7; 123.4; 127.4; 127.8; 128.2; 129.2; 131.4; 132.5; 133.9; 135.3; 145.5; 147.7; 159.9; 165.9; 166.0. Found, %: C 64.13; H 4.75; N 6.90. C22H19ClN2O4. Calculated, %: C 64.32; H 4.66; N 6.82.

Ethyl 4-(4-fluorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylate (9d). Yield 315 mg (80%), beige crystals, mp >250°C (i-PrOH). IR spectrum, ν, cm–1: 3280, 3127, 3057, 2982, 2932, 2870, 2789, 1721, 1674, 1643, 1611, 1595, 1582, 1556, 1512, 1486, 1446, 1410, 1396, 1367, 1288, 1229, 1200, 1155, 1115, 1088, 1027, 1015, 903, 837, 800, 787, 710, 663, 635. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.76 (3H, t, J = 7.0, CH2CH3); 2.33 (3H, s, 2-CH3); 3.81 (2H, q, J = 7.0, CH2CH3); 7.14–7.22 (4H, m, H Ar); 7.35–7.45 (2H, m, H Ph); 7.46–7.54 (1H, m, H Ph); 7.69 (2H, d, J = 7.4, H Ph); 9.36 (1H, br. s, 5-NHCOPh); 12.31 (1H, br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 13.3; 17.3; 60.5; 111.1; 114.6 (d, J = 21.7); 123.4; 127.4; 128.2; 129.5 (d, J = 7.8); 131.4; 132.8 (d, J = 3.5); 134.0; 145.2; 148.0; 160.0; 161.7 (d, J = 244.5); 166.0 (2C). Found, %: C 67.10; H 4.76; N 7.04. C22H19FN2O4. Calculated, %: C 67.00; H 4.86; N 7.10.

Ethyl 2-methyl-4-(4-nitrophenyl)-6-oxo-5-[(phenylcarbonyl)amino]-1,6-dihydropyridine-3-carboxylate (9e). Yield 396 mg (94%), colorless crystals, mp 229–230°C (i-PrOH). IR spectrum, ν, cm–1: 3280, 3119, 2982, 2940, 2893, 2842, 2763, 2661, 1721, 1665, 1634, 1595, 1515, 1476, 1446, 1385, 1346, 1292, 1285, 1263, 1214, 1171, 1114, 1089, 1032, 965, 841, 782, 735, 689. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.68 (3H, t, J = 7.1, CH2CH3); 2.27 (3H, s, 2-CH3); 3.75 (2H, q, J = 7.1, CH2CH3); 7.20–7.29 (4H, m, H Ph, H-2,6 Ar); 7.33 (2H, t, J = 7.4, H Ph); 7.38–7.45 (1H, m, H Ph); 8.20 (2H, d, J = 8.6, H-3,5 Ar); 9.44 (1H, br. s, 5-NHCOPh); 12.00 (1H, br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 13.2; 13.8; 60.3; 109.7; 122.9; 126.9; 128.2; 129.5; 130.4; 132.2; 133.5; 134.0; 141.1; 144.8; 146.4; 157.0; 160.2; 165.8. Found, %: C 62.51; H 4.58; N 10.05. C22H19N3O6. Calculated, %: C 62.70; H 4.54; N 9.97.

X-ray structural analysis of compound 4a. Crystals suitable for X-ray structural analysis were obtained by slow evaporation of a solution of compound 4a in benzene at room temperature. The set of reflections was obtained on an Xcalibur Ruby (Agilent technologies, UK) diffractometer with a ССD detector according to the standard routine (MoKα radiation, 295(2)K, ω-scanning with a step of 1°). Absorption was corrected empirically using the SCALE3 ABSPACK algorithm.38 The structure was solved using the SHELXS39 program and refined using the SHELXL40 program with the OLEX2 graphical interface.41 The positions of the H atoms was refined using the rider model. The positions of the H atoms of the NH groups were refined independently in the isotropic approximation. The crystals of compound 4a (C22H22N2O4, M 378.41) are monoclinic, spatial symmetry group P21/c; a 10.433(3), b 9.748(2), c 20.107(6) Å; β 99.60(3)°; V 2016.1(10) Å3; Z 4; dcalc 1.247 g/cm3; μ 0.086 mm–1. The final refinement parameters: R1 0.0660 (for 2716 reflections with I > 2σ(I)), wR2 0.2089 (for all 4801 independent reflections, Rint 0.0417), S 1.021. The X-ray structural analysis data was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2096420).

Supplementary information file containing 1H and 13C NMR spectra of all new compounds is available at the journal website at http://link.springer.com/journal/10593.

The study was carried out with the financial support of the Russian Foundation for Basic Research within the framework of scientific project No. 19-33-90229.

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