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.

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 inhibitors^2–6 such as M_pro 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

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 ³J_5-СH,NH = 5.3–6.7 Hz and total coupling constant ³J_4-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 DDQ_31,32 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

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 (Ф_f 0.546) using the comparison method.^{36 1}H 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 cis-2-methyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)-amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 cis-4-(4-methoxyphenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 cis-4-(4-chlorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 cis-4-(4-fluorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 trans-4-(4-fluorophenyl)-2-methyl-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (trans-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 cis-2-methyl-4-(4-nitrophenyl)-6-oxo-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 trans-2-methyl-4-(4-nitrophenyl)-6-oxo-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (trans-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 cis-1,2-dimethyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-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 trans-1,2-dimethyl-6-oxo-4-phenyl-5-[(phenylcarbonyl) amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (trans-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- b ]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- b ]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- b ]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-b]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- b ]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- b ]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) ų; Z 4; d_calc 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, R_int 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.