An Efficient One-Pot Three-Component Synthesis of Fused 1,4-Dihydropyridines Using HY-Zeolite

A facile and convenient protocol was developed for the fast (2.5-3.5 h) and high yielding (70-90 %) synthesis of fused 1,4-dihydropyridines from dimedone in the presence of HY-zeolite as an efficient recyclable heterogeneous catalyst.


Introduction
1,4-Dihydropyridines represent an important class of compounds which are found in many biologically active products, such as vasodilator, bronchodilator, anti-atherosclerotic, antitumor, geroprotective, hepatoprotective and antidiabetic agents [1]. Numerous synthetic methods have been reported for the preparation of 1,4-dihydropyridine derivatives under classical or modified conditions [2][3][4][5][6][7][8][9][10]. However, some of these methods suffer from long reaction times, low yields, use of large quantities of volatile organic solvents, harsh reaction conditions and tedious workups, therefore, development of an efficient and versatile method is still required.
HY-zeolite is unique acid heterogeneous catalyst that has become popular over the last two decades. It is used in various chemical transformations, such as liquid phase acylation of amines [11], direct conversion of aldehydes into amines [12], selective removal of N-Boc protecting groups from aromatic amines [13], one-pot synthesis of 2,3-dihydro-2,2-dimethylbenzofurans [14], and one-pot syntheses of polyhydroquinolines [15].

OPEN ACCESS
This remarkable catalytic activity together with easy availability, operational simplicity and recoverability of HY-zeolite encouraged us to utilize this catalyst for the synthesis of fused 1,4dihydropyridine derivatives.

Results and Discussion
Recent developments in 1,4-dihydropyridine chemistry and our continued interest in the development of efficient and environmentally friendly procedures for the synthesis of heterocyclic compounds [16][17][18][19][20][21][22][23], prompted us to study the conversion of dimedone into fused 1,4-dihydropyridines in the presence of HY zeolite (Si/Al: 2.54). The reaction of dimedone (1, 2 eq.) with 1 equiv. of each of various arylaldehydes 2a-i and NH 4 OAc in EtOH in the presence of HY-zeolite furnished the desired fused 1,4-dihydropyridine derivatives 3a-i (Scheme 1) in reasonable reaction times (2.5-3.5 h) and high yields (70-90%) ( Table 1). Moreover, the catalyst was easily recovered and the high catalytic activity was maintained even after third reuse of the catalyst.  The reaction, using substrate 2a, was also performed in the presence of CH 3 CO 2 H (1 mL/mmol substrate, 5 h, 67%), ZnCl 2 (0.01 g/mmol substrate, 6 h, 65%) and RuCl 3 (0.01 g/mmol substrate, 5.5 h, 70%) under optimized condition, which furnished the desired product after longer reaction times and in lower yields. The control reaction was carried out on the substrates 2a and 2d in refluxing ethanol without the zeolite catalyst. Under this classical condition the reaction proceeded smoothly resulting in the expected 1,4-dihydropyridine products after longer reaction times and in lower yields (2a: 6.5 h, 65%; 2d: 8.0 h, 63%). These results revealed that using HY-zeolite as catalyst appreciably shortens the reaction times and increases the product yields. All of the products were fully characterized by spectroscopic methods (IR, 1 H-NMR, 13 C-NMR) and elemental analysis.  13 C-NMR) and elemental analyses. 3 A mixture of dimedone (20 mmol), aryl aldehydes (2a, 2d) (10 mmol) and NH 4 OAc (10 mmol) in EtOH (10 mL) was refluxed for the required reaction time, after which removal of the solvent produced the desired products 3a and 3d in 65% and 63% yields, respectively.

Conclusions
In summary, we report a simple protocol for the synthesis of fused 1,4-dihydropyridines using HY zeolite as an efficient catalyst. The simplicity, easy workup, together with the use of inexpensive, environmentally friendly and reusabile catalyst, are the notable features of this catalytic procedure.

General
Melting points were measured on an Electrothermal 9100 apparatus. IR spectra were determined on a Shimadzo IR-470 spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded on a 500 MHz Bruker DRX-500 in CDCl 3 as solvent and with TMS as internal standard. Chemicals were purchased from Merck and Fluka. Elemental analyses were done on a Carlo-Erba EA1110CNNO-S analyzer and agreed with the calculated values. All solvents used were dried and distilled according to standard procedures.

General procedure for the synthesis of 3a-i in the presence of HY-zeolite
A mixture of dimedone (20 mmol), aryl aldehydes (10 mmol), NH 4 OAc (10 mmol), HY-zeolite (0.1 g) in EtOH (10 mL) was refluxed for the required reaction time ( Table 1). The progress of the reaction was monitored by TLC (EtOAc: petroleum ether 3:1). After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethanol to produce 1,4-dihydropyridine derivatives 3a-i as pure crystalline products in 70-90% yields.