key: cord-0900093-qrtn3s4r
authors: Shuvalov, Vladislav Yu.; Chernenko, Sergei А.; Shatsauskas, Anton L.; Samsonenko, Anna L.; Dmitriev, Maksim V.; Fisyuk, Alexander S.
title: Novel Approach to the Synthesis of 3-amino-4-arylpyridin-2(1H)-one Derivatives
date: 2021-09-07
journal: Chem Heterocycl Compd (N Y)
DOI: 10.1007/s10593-021-02980-w
sha: eeb4e14c775274f09bb74f9af6ddf181ddaf6d98
doc_id: 900093
cord_uid: qrtn3s4r

[Image: see text] 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.

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 signaling 12 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] [15] [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] [20] [21] [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] [24] [25] which, in principle, can be oxidized to the corresponding amides of 3-aminopyridin-2(1H)-ones. [26] [27] [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 method 29 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 Chemistry of Heterocyclic Compounds 2021, 57 (7/8), 764-771 Novel approach to the synthesis of 3-amino-4-arylpyridin-2(1H)-one derivatives substituents in the aryl fragment were higher than those of unsubstituted and methoxy-substituted products 4a,b (Scheme 1, Table 1 ). xylene did not lead to the formation of pyridones 5a,f (Scheme 2). The structure and composition of the obtained compounds were confirmed by the data of IR, 1 H and 13 C NMR spectroscopy, X-ray structural analysis, and elemental analysis. In the 1 H 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-5as doublets of doublets with 3 J 5-СH,NH = 5.3-6.7 Hz and total coupling constant 3 J 4-СH,5-СH = 7.4-8.0 Hz. Due to the low solubility of trans-isomers 4d,е in CDCl 3 , their 1 H NMR spectra were recorded in DMSO-d 6 .

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, MnO 2 , 27,28 FeCl 3 , 30 and DDQ 31,32 were employed. However, in our case, oxidation with these reagents, chloranil, NaNO 2 in AcOH, K 2 S 2 O 8 in MeCN, by heating compounds 4а,f with KMnO 4 in Me 2 CO or heating with 10% Pd/C in 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 

in H 2 SO 4 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 POCl 3 were 23-47%.

Comparison of the electronic spectrum of compound 7a with the previously reported 34 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 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.

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/dm 3 . 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 H 2 SO 4 (Ф f 0.546) using the comparison method. 36 Table 3 . The data of absorption and fluorescence spectra of compounds 7a-e and 8a The starting azlactones 1a-e were obtained according to a known procedure 29 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 CHCl 3 -EtOAc, 10:1.

Yield 2190 mg (58%), colorless crystals, mp 205-206°C (EtOH) (mp 200-201°C (PhН) 24 

Yield 2160 mg (53%), beige crystals, mp 161-162°C (i-PrOH) (mp 212-214°C (PhН) 24 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 SHELXS 39 program and refined using the SHELXL 40 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. Supplementary information file containing 1 H and 13 C 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. 

Ethyl cis-1,2-dimethyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)amino]-1,4,5,6-tetrahydropyridine-3-carboxylate (cis-4f)

(2H, m, H Ph). 13 C NMR spectrum

ml) was heated under reflux for 1.5 h. The reaction mixture was evaporated to dryness, diluted with cold H 2 O (10 ml) and triturated to a homogeneous powder, which was filtered and washed with H 2 O (3×5 ml). The product was purified by column chromatography on silica gel (eluent СНCl 3 ) and recrystallized from i-PrOH. Ethyl 5-methyl-2,7-diphenyloxazolo[5,4-b]pyridine-6-carboxylate (7a)

Yield 89 mg (23%), beige crystals, mp 155-156°C (i-PrOH). IR spectrum, ν, cm -1 : 3068

Yield 185 mg (47%), light-beige crystals, mp 148-149°C (i-PrOH). IR spectrum, ν, cm -1 : 3070

1 H NMR spectrum (CDCl 3 ), δ, ppm

Yield 161 mg (40%), colorless crystals, mp 192-193°C (i-PrOH). IR spectrum, ν, cm -1 : 3110

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) its original volume. The residue was poured into Н 2 О (15 ml) and acidified with 10% aqueous HCl to pH ~3. The precipitate that formed was filtered, washed with H 2 O, and recrystallized. Ethyl 2-methyl-6-oxo-4-phenyl-5-[(phenylcarbonyl)-amino]-1,6-dihydropyridine-3-carboxylate (9a)

1 H NMR spectrum (DMSO-d 6 ), δ, ppm

08 (1H, br. s, 5-NHCOPh); 11.95 (1H, br. s, 1-NH). 13 C NMR spectrum (DMSO-d 6 ), δ, ppm: 12.9

Yield 300 mg (74%), beige crystals, mp >250°C (PhMe)

CH 3 ); 2.30 (3H, s, 2-CH 3 ); 3.68 (3H, s, OCH 3 ); 3.82 (2H, q, J = 7.2, CH 2 CH 3 ); 6.87 (2H, d, J = 8.8, H-3,5 Ar)

Yield 366 mg (89%), light-beige crystals, mp >250°C (i-PrOH). IR spectrum, ν, cm -1 : 3288

H-3,5 Ar); 7.50 (1H, t, J = 7.3, H Ph)

Yield 315 mg (80%), beige crystals, mp >250°C (i-PrOH)

CH 3 ); 2.33 (3H, s, 2-CH 3 ); 3.81 (2H, q, J = 7.0, CH 2 CH 3 )

5); 166.0 (2C). Found, %: C 67

Measurement of Fluorescence Quantum Yields; Thermo Fisher Scientific: Madison. Technical note: 52019. (b) Brouwer, A. M

Agilent Technologies