An Efficient Oxidation of 1,4-Dihydropyridines by Hydrogen Peroxide in the Presence of Copper(II) Chlorideat at Room Temperature

Introduction

For the first time 1,4-dihydropyridine synthesized by Hantzsch about one century ago. 1,4-Dihydropyridine ring is the common feature for various pharmacological activities such as antitumours [1], antivirals  [2], calcium  antagonists [3], antidiabetics [4], and antagonists [5]. Aromatization of 1,4-dihydropyridines (1,4-DHPs)  to pyridine derivatives the principal metabolic in biologically activity NADH redox processes  [6],  an efficient route for synthesis of pyridine derivatives are oxidation of 1,4-DHPs [7]. Consequently, this aromatization   reaction continues to attract the attention of many organic and  medicinal  chemists for  the  discovery of  many of  protocols  applicable  to  a wide  range  of  1,4-DHPs  [8].  Many of the reported oxidation procedures either suffer from KMnO₄ [9], CrO₃ [10], Bi(NO₃)₃ [11], PCC [12], an so on.

Previously, we have synthesized a number of heterocyclic compounds [13-17]. Although many methods are capable of effecting these oxidations but most of the reported are difficult such as separate from the products, long reaction times and low yields. Therefore, we reported the development of an efficient, a facile method for the aromatization of 1,4-DHPs by hydrogen peroxide in the presence of Copper (II) chloride as catalyst at room temperature (Scheme 1). The hydrogen peroxide [18] was selected as the oxidant and Copper (II) chloride as the catalyst was cheap, environmentally friendly, and easy separation.

Scheme 1: General procedure for oxidation of Diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate. Click here to View Scheme

 

Diethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (1 mmol) was dissolved in 20 ml ethanol and Copper (II) chloride (1 mmol) was added to this solution and then 0.2 ml hydrogen peroxide 30% was added in portions over 30 min at room temperature along with stirring of the reaction mixture. The progress of the reaction was monitored by TLC. After recrystallization of the product in ethanol, 96% yield of diethyl 2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate was obtained.

Spectral data for diethyl 2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate

 Pale yellow solid; m.p.: 60-62 ºC (Ref. [19], 60–61 ºC); FT-IR (KBr): 2976, 1723, 1561, 1230, 1100 cm1; ¹H NMR (CDCl₃): δ (ppm) = 1.03 (t, 6H, J = 7.5 Hz), 2.66 (s, 6H), 4.03 (q, 4H, J = 7.5 Hz), 7.4-7.8 (m, 5H).

Results and Discussion

Herein, we report oxidation of 1,4-DHPs  by hydrogen peroxide and Copper(II) chloride as catalyst was used to pyridine derivatives (Scheme 1), which could provide an efficient, cheap, environmentally friendly, easy separation, high yield and simple route at room temperature for the oxidation of 1,4-DHPs  to pyridine derivatives.

Acknowledgements

We gratefully acknowledge the financial support from the Research Council of Tonekabon Branch Islamic Azad University.

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