An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

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Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya Naberezhnaya, St. Petersburg 199034, Russia
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Associate Editor: T. J. J. Müller
Beilstein J. Org. Chem. 2022, 18, 738–745.
Received 06 Mar 2022, Accepted 17 Jun 2022, Published 23 Jun 2022
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A method has been developed for the preparation of 2-alkyl-6-aryl-, 2-aryl-6-aryl and 2,6-diaryl-5-aryl/hetaryl-substituted methyl 4-oxo-1,4-dihydropyridine-3-carboxylates by Mo(CO)6-mediated ring expansion of methyl 2-(isoxazol-5-yl)-3-oxopropanoates. The high reactivity of 4-oxo-1,4-dihydropyridine-3-carboxylates synthesized provide easy access to 2,4,6-triaryl-substituted and 1,2,5,6-tetrasubstituted nicotinates.


Pyridine moieties are present in many natural products, drugs, pesticides and industrial materials. Pyridine fragments are used in drugs due to their specific characteristics such as basicity, hydrogen bond forming ability, water solubility, and especially because of pyridine rings are bioisosteres of amines, amides, N-heterocyclic rings and benzene rings [1-5]. A special type of pyridine, the 4-pyridones, is also fairly well represented among drugs [5-12]. Some of bioactive compounds, such as ciprofloxacin, levofloxacin, delafloxacin, and elvitegravir, contain the fragment of 4-oxo-1,4-dihydropyridine-3-carboxylic acid [6,8] and some others, ivacaftor, dolutegravir, bictegravir, aspernigrin B, and 4PYR, contain the fragment of 4-oxo-1,4-dihydropyridine-3-carboxamide [5-7]. Finding new synthetic methods for the preparation of derivatives of 4-oxo-1,4-dihydropyridine-3-carboxylic acid are therefore relevant. Some alkyl 6-aryl-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylates were prepared by refluxing a xylene solution of methyl/ethyl 3-aminobut-2-enoates and methyl/ethyl 3-aryl-3-oxopropanoates in the presence of molecular sieves, with methyl 3-aryl-3-oxopropanoates giving higher product yields (37–46%) than ethyl derivatives (13–25%) (Scheme 1) [13]. General methods for the preparation of 2,6-diaryl- and 2,5,6-triaryl-substituted derivatives of 4-oxo-1,4-dihydropyridine-3-carboxylic acid, to the best of our knowledge, have not been published to date. We would like to present here a method for the preparation of 2-alkyl-6-aryl-, 2-aryl-6-aryl/hetaryl and 2,6-diaryl-5-aryl-substituted derivatives of 4-oxo-1,4-dihydropyridine-3-carboxylic acid 2 via Mo(CO)6-mediated rearrangement of methyl 2-(isoxazol-5-yl)-3-oxopropanoates 1 (Scheme 1).


Scheme 1: Approaches to the synthesis of alkyl 4-oxo-1,4-dihydropyridine-3-carboxylates.

Results and Discussion

Based on our experience of using isoxazoles in the synthesis of heterocyclic compounds [14-18], we hypothesized that isoxazoles 1 can undergo reductive ring opening under the action of Mo(CO)6/H2O/MeCN [14,19-23] to enamines 3, which can be cyclized on acyl R3C(O) group to form pyridones 2 (Scheme 2, route a). The alternative cyclization scenario, which may involve the ester group of enamine 3 and lead to the formation of pyridone 5 (route b), is less likely due to the lower electrophilicity of the ester carbon compared to the acyl carbon. To check this, isoxazole 1g was synthesized and reacted with Mo(CO)6 in wet acetonitrile at 60 °C for 2 d to give pyridone 2g in 45% yield. The reaction at 70 °C was completed in a day to give pyridone 2g in 74% yield. A further increase in temperature, although it led to a reduction in the reaction time, was accompanied by resinification of the reaction mixture and, as a result, led to a decrease in the yields of pyridone 2g (80 °C, 3 h, 63%; 85 °C, 3 h, 42%). Enamine 6, resulted from the deacylation of intermediate 3g, was isolated in the reaction carried out at 70 °C. This side process is probably the reason for the decrease in the yield of the target pyridone 2g. Considering that isoxazoles were previously reduced to enaminones by other reducing systems [24-28], we checked the possibility of using NaBH4/NiSO4·7H2O [25], H2/PtO2/NiRaney [26,27] and H2/NiRaney [28] to obtain pyridone 2g from isoxazole 1g. However, analysis of reaction mixtures, obtained by using the above reductants, showed the formation of a large amount of products, but pyridone 2g was not detected. It is most probable that, in addition to the reductive opening of isoxazole, Mo(CO)6 catalyzes the cyclization of enaminone 3g to pyridine 2g [14]. In the absence of such catalysis, the unstable enaminone intermediate undergoes deacylation and decomposes through other destructive processes.


Scheme 2: Synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates.

To evaluate the scope of the disclosed reaction a set of isoxazoles 1 was prepared using approaches shown in the Scheme 3 and Scheme 4. Isoxazoles 11af were prepared by cycloaddition of nitrile oxides, generated from N-hydroxyimidoyl chlorides 7af, to propargyl halides [29], followed by the cyanation of the resulted isoxazoles 8af to cyanides 9af using Me2C(OH)CN/(Me2N)2C=NH [29], their acid hydrolysis, followed by esterification of the resulting acids 9af with diazomethane. 4-Iodoisoxazoles 12af, necessary for the preparation of 3,4-disubstituted isoxazoles, were obtained by iodination of 11a,c,eg with NIS/TFA [30]. The reaction of 11d gave the product of double iodination 12c. 4-Iodoisoxazoles 12a,b,df were transformed into 3,4-substituted isoxazoles 13ag by Suzuki reaction using a published procedure with some modifications [31].


Scheme 3: Synthesis of Isoxazoles 1113.

Isoxazoles 1, except for isoxazole 1a, were synthesized in 44–98% yield by acylation of isoxazoles 11, 12 and 13 with acyl chlorides in the presence of NaH (Scheme 4). For the preparation of isoxazole 1a propionic anhydride was used.


Scheme 4: Synthesis of isoxazoles 1.

Further, isoxazoles 1 were reacted with Mo(CO)6/H2O/MeCN under the optimal conditions to give pyridones 2 (Scheme 5). Isoxazole 1j with Mo(CO)6/H2O/MeCN gives the corresponding pyridone 2j in trace amounts, while the reaction of isoxazoles 1l,m,r leads to complete resinification. It is likely that one of the reasons for the decrease in the yields of pyridones 2 is the occurrence of a side reaction of deacylation of enamine intermediate 3, as shown for the reaction of isoxazole 1g (Scheme 2).


Scheme 5: Synthesis of pyridones 2.

Taking into account that compounds 2 can potentially exist in pyridone and pyridole tautomeric forms, we performed calculations at the DFT B3LYP-D3/6-311+G(d,p) level of theory with SMD solvent model to evaluate this tautomeric equilibrium. According to the calculation results compounds 2 exist in the pyridone form in acetonitrile or chloroform solution (Table 1).

Table 1: Gibbs free energies of the pyridole tautomer relatively to the pyridone tautomer of compounds 2 (in kcal/mol, 298 K).

[Graphic 1]
Solvent R1 = Ph, R2 = H, R 3 = Me R1 = R3 = Ph, R2 = H R1 = R2 = R3 = Ph
MeCN 6.1 4.4 4.7
CHCl3 3.5 3.1 2.6

All new compounds were characterized by 1H, 13C NMR and HRMS methods. Moreover, the structure of 2k was also confirmed by single-crystal X-ray diffraction analysis (Figure S1, Supporting Information File 1).

Compounds 2 have several reactive centers that make them attractive starting materials for the synthesis of new libraries of 4-pyridone and pyridine derivatives (Scheme 6). The methoxycarbonyl group of compound 2c was selectively reduced to give 3-(hydroxymethyl)pyridin-4(1H)-one 14 in 89% yield. The reaction of pyridone 2e with PBr3 afforded methyl 4-bromo-6-(4-fluorophenyl)-2-phenylnicotinate (15) in 80% yield. The latter was employed in the Suzuki reaction in the high-yield synthesis of 2,4,6-triaryl-substituted nicotinate 16. The nitrogen of 2,3,4,6-tetrasubstituted pyridone 2n can be quantitatively benzylated by benzyl chloride to give derivative 17.


Scheme 6: Transformations of pyridones 2.


A method has been developed for the preparation of 2-alkyl-6-aryl-, 2-aryl-6-aryl and 2,6-diaryl-5-aryl/hetaryl-substituted derivatives of 4-oxo-1,4-dihydropyridine-3-carboxylic acid 2 via Mo(CO)6-mediated rearrangement of methyl 2-(isoxazol-5-yl)-3-oxopropanoates 1. High yield transformations of compound 2 provide easy access to 2,4,6-triaryl-substituted and 1,2,5,6-tetrasubstituted nicotinates.

Supporting Information

Supporting Information File 1: Experimental procedures, compound characterization data, X-ray diffraction experiment, and copies of NMR spectra of new compounds.
Format: PDF Size: 25.7 MB Download
Supporting Information File 2: Crystallographic information file for compound 2k.
Format: CIF Size: 275.9 KB Download


We gratefully acknowledge the financial support of the Russian Science Foundation project 21-73-00019. This research was carried out using resources of the Centre for Magnetic Resonance, the Research Centre for X-ray Diffraction Studies, the Centre for Chemical Analysis and Materials, and the Computer Centre of the Science Park of Saint Petersburg State University.


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