3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO₃H]⁺Cl⁻): an efficient catalyst for one-pot synthesis of hexahydroquinoline-3-carboxamides

Introduction

Quinolines containing a 1,4-dihydropyridine (1,4-DHP) moiety show a variety of pharmacological properties [1], [2], [3], [4], [5], [6], [7], [8]. Acetoacetanilide is an important building block in the synthesis of heterocyclic compounds with antimicrobial [9], [10] and analgesic activities [11]. The synthesis of hexahydroquinoline-3-carboxamides via a four-component reaction of acetoacetanilide, aromatic aldehyde, dimedone and ammonium acetate in the presence of p-toluenesulfonic acid [12] and without catalyst under harsh conditions has been reported [13]. Herein, we report that this reaction can be conducted under much milder conditions in the presence of another catalyst.

Results and discussion

In this study, 3-carboxy-1-sulfopyridin-1-ium chloride ([CPySO₃H]⁺Cl⁻) was successfully used as a catalyst in the reaction of arylaldehydes, dimedone, acetoacetanilide and ammonium acetate in ethanol at 70°C to furnish a series of hexahydroquinoline-3-carboxamides 5a–l in excellent yields (Scheme 1). The catalyst was obtained by treatment of nicotinic acid with chlorosulfonic acid (Scheme 2). The structure of [CPySO₃H]⁺Cl⁻ was supported by infrared (IR), ¹H nuclear magnetic resonance (NMR), ¹³C NMR, thermal gravimetric analysis (TGA) and elemental analysis. In the IR spectrum, the stretching vibrations for O-H near 3151 cm⁻¹, for C=O at 1728 cm⁻¹, for C=N at 1633 cm⁻¹, for C=C at 1600 cm⁻¹ and 1537 cm⁻¹ and the SO₂ asymmetric and symmetric stretching at 1272 cm⁻¹ and 1172 cm⁻¹, respectively, were observed. These results provide evidence that sulfonic acid moiety is part of the molecular structure of the catalyst.

Scheme 1

Synthesis of hexahydroquinoline-3-carboxamides 5a–l.

Scheme 2

Preparation of [CPySO₃H]⁺Cl⁻.

The thermal behavior of [CPySO₃H]⁺Cl⁻ was studied by TGA. The thermal analysis indicated that the catalyst was stable up to 250°C. A slow decomposition could be observed starting around 300°C.

To optimize the reaction conditions, the four-component reaction of benzaldehyde, dimedone, acetoacetanilide and ammonium acetate was examined as a model reaction. The highest yield of 5a was obtained for the reaction conducted in ethanol at 70°C in the presence of 20 mol% of [CPySO₃H]⁺Cl⁻. Under these optimized conditions, the reaction furnished products 5b–l in the range of yields from 88% to 96%. The optimum reaction time was analyzed using thin-layer chromatography (TLC) and was found to vary from 25 min to 45 min. The structure of all products was fully supported by IR, ¹H NMR, ¹³C NMR and elemental analysis.

To study the recyclability of the catalyst, the synthesis of compound 5a was conducted 5 times. Upon completion of the reaction, the catalyst was filtered, washed with dichloromethane (2×10 mL) and then reused in the subsequent preparation of 5a. It was found that the initial yield of 5a of 95% decreased only to 90% in the fifth preparation. Also, the catalyst retained its activity after several months of storage.

Conclusions

A simple and efficient one-pot procedure for the synthesis of hexahydroquinolines using [CPySO₃H]⁺Cl⁻ as an ionic organocatalyst in ethanol at 70°C was decribed. Simplicity of the preparation, easy work-up, high yields and recyclability of the catalyst are the advantages of this method.

Experimental

Melting points were measured on an Electro-thermal 9100 apparatus and are uncorrected. Unless stated otherwise, ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded in CDCl₃ on a Bruker Avance DRX-400 spectrometer. Fourier-transform infrared (FT-IR) spectra were obtained for potassium bromide pellets on a Shimadzu SP-1100 instrument. The TGA was conducted using a Mettler TGA instrument. The thermograms were recorded at a heating rate of 10°C/min in the range of temperature from 25°C to 600°C in an inert atmosphere. Elemental analyses were done on a Carlo-Erba EA1110 analyzer.