Cu(C22H22N2O2), a New Reagent for Aromatization of Hantzsch

A variety of Hantzsch 1,4-dihydropyridines were oxidized to their corresponding pyridines in high yields in the presence of Cu(C22H22N2O2) in refluxing acetic acid.

In recent years considerable emphasis has been placed on diminishing the environmental impact of industrial processes [16] and it is well recognized that solid acid catalysts and reagents can play a significant role in the development of cleaner technologies [17].
Copper(II) complexes of N 2 O 2 ligands have generated considerable interest because of their interesting physio-chemical properties, potentially useful in catalytical reaction and biological activities [18].Recently we have reported the synthesis and structure of N,N'-ethylene-bis(benzoylacetoniminato) copper (II), Cu(C 22 H 22 N 2 O 2 ) [19].

Results and Discussion
In order to determine the best reaction conditions, the efficiency of a variety of solvents in the oxidation of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate as a model reaction was studied.First we carried out the model reaction under solvent-free conditions at room temperature.The temperature of the reaction mixture started to rise but the reaction was not complete after 24 h.Then we decided to examine the effect of the solvent on the reaction.As shown in Table 1, the best results in terms of yield and time were obtained in refluxing acetic acid.In order to establish the scope of this novel oxidation protocol, we tested a variety of 1,4-DHPs under the optimized reaction conditions.As shown in Table 2 the presence of both electron donating and electron withdrawing substituents on the precursors afforded the corresponding pyridines in good to excellent yields.In the presence of excess reagent the corresponding products were obtained in shorter times.(cf.entries 8 and 9, Table 2).As expected, in the case of a 1,4-DHP bearing an isopropyl group in the 4-position, a pyridine derivative resulting from the elimination of isopropyl group was formed.This may be attributed to the stability of the isopropyl cation (Table 2, entry 10).
The oxidizing species in the reaction is the copper(II) complex and it can be reduced to Cu(I) during the reaction.As Cu(I) prefers the tetrahedral structure and we believe it is unstable in it's complex form, so, after reduction, the complex will be decomposed.The produced species are soluble in acetic acid and ethanol and could be separated by recrystallization from ethanol or chromatography.a) Yields were analyzed by GC.
b) Products exhibited physical properties in accordance with the assigned structures.
c) The reaction was carried out in the presence of 1.2 equivalents of the reagent.
d) The product resulting from the elimination of isopropyl group was formed.

Conclusions
In summary, we have developed the use of Cu(C 22 H 22 N 2 O 2 ) as an easy to handle, non-corrosive and environmentally benign reagent for the aromatization of Hantzsch 1,4-dihydropyridines.The advantages of the present procedure are simplicity of operation and the good yields of the products.

General
Melting points were measured by using the capillary tube method with an Electrothermal 9200 apparatus. 1H-NMR spectra were recorded on a Bruker AC-80 MHZ spectrometer using TMS as an internal standard (CDCl 3 solution).IR spectra were recorded using KBr disks on a Bruker Tensor 27FT-IR instrument.GC spectra were recorded on an Agilent 5973 GC instrument.All products were characterized by spectra and physical data.Silica gel 60 for column chromatography was purchased from Merck.The Cu(II) reagent [19] was prepared as follows: the Schiff base N,N'-ethylenebis(benzoyl-acetoniminate) (2 mmol) was dissolved in boiling methanol (20 mL) and mixed with a solution of copper(II) acetate (2 mmol) in the same volume of solvent.The mixture was heated on a water bath for about 3 min and then left to stand overnight.The crystals which had formed were filtered off, washed with methanol and dried.All the dihydropyridines were prepared according to the literature procedure [32], using the appropriate aldehydes, ammonia, and ethyl acetoacetate.

Aromatization of Hantzsch 1,4-dihydropyridines: General procedure
The Hantzsch 1,4-dihydropyridine (1 mmol) was reacted with Cu(C 22 H 22 N 2 O 2 ) (1 mmol) in refluxing acetic acid (3 mL).The progress of the reaction was monitored by TLC using 80:20 petroleum ether-ethyl acetate as eluent.After completion of the reaction, diethyl ether (5 mL) was added to the mixture.The solution obtained was washed successively with 5% NaHCO 3 (10 mL) and brine (10 mL) and dried over MgSO 4 .The solvent was evaporated under reduced pressure to yield the crude products.Further purification was achieved by recrystallization from ethanol (in the case of solid products) and flash chromatography.Yields were obtained using GC analysis.All products were known compounds and their physical and spectroscopic data were compared with those of authentic samples [4,11,12,30,31] and found to be identical.
a) Yields were analyzed by GC.