An Efficient Oxidation of 1,4-Dihydropyridines to Pyridines Using Silver Carbonate on Silica Gel and Celite

Abstract

The oxidation of Hantzsch 1,4-dihydropyridines to the corresponding pyridines has been extensively studied in view of the pertinence of the reaction to the metabolism of Hantzsch esters and the calcium channel blocking drugs used in the treatment of various cardiovascular disorders. The reaction has also been used to study the biologically significant NADH redox processes. Consequently, this aromatization reaction continues to attract the attention of researchers for the discovery of milder and general protocols applicable to a wide range of 1,4-dihydropyridines. Several oxidizing agents and methods such as KMnO4, 3 solid supported pyridinium chlorochromate (PCC), silica gel supported ferric nitrate, nitric oxide, MnO2, 7 ceric ammonium nitrate (CAN), tert-butylhydroproxide, clay supported cupric nitrate, Bi(NO3)3, 11 I2/MeOH, 12 Zr(NO3)4, 13 tetrakispyridine cobalt(II) dichromate (TPCD), iodobenzene diacetate, NaNO2/NaHSO4/SiO2, 16 3-Carboxypyridinium chlorochromate (CPCC), BaMnO4, 18 Tl(NO3)3·3H2O, 19 or photochemical reactions have been introduced in the literature for this purpose. The introduction of supported reagents for bringing about various chemical transformations has provided an attractive option for organic synthesis. These reagents not only modify the activity but also may impart product selectivity. Because of our interest in oxidation processes, we decided to develop a practical and general approach for oxidative conversion of 1,4-dihydropyridines using a mild oxidant, silver carbonate. This reagent is a mild oxidizing agent. This operates under neutral and heterogeneous conditions. Silver carbonate on celite was employed for organic reactions such as oxidation of alcohols, 1,2-diols, phenols, amines and hydrazines. Silver carbonate on silica gel and celite can be readily available. We wish to indicate that it can also serves as an excellent oxidant for a variety of Hantzsch 1,4dihydropyridines. A series of 1,4-DHP derivatives (1-12, Scheme 1) were synthesized to investigate their conversion to the corresponding pyridines. Initially 4-phenyl-dihydropyridine (entry 3) has been used as a substrate to test the feasibility of silver carbonate used as an oxidant for DHP’s. Investigation on the oxidation efficiency of silver carbonate alone at ambient temperature as well as higher temperature indicated that, oxidation of (3) into aromatized product did not proceed effectively. A better activity of silver carbonate was obtained when combined with silica gel or celite. Silver carbonate on celite as mentioned above is known, but silver carbonate on silica gel was used for the first time in this study. Subsequent experiments revealed that at reflux conditions in acetonitrile a ratio of DHP : Ag2CO3 = 1 : 6 on silica gel and DHP : Ag2CO3 = 1 : 12 on celite was most effective. Under similar conditions various substituted 1,4-dihydropyridines were efficiently converted to the pyridine derivatives and the results are given in Table 1. According to the experiment we observed that oxidation of 1,4-dihydropyridines with secondary alkyl group (entry 5) and benzyl groups (entry 6) at the 4-position were performed efficiently and only dealkylated pyridine derivative (13) was obtained. This is a general trend in the oxidation of 1,4dihydropyridines. 1,4-Dihydropyridine (entry 4) with propyl group at the 4-position yielded two products, dealkylated