Efficient One-Pot Synthesis of 7-Azacoumarins by Knoevenagel Reaction Using Water as Reaction Medium

Abstract

3-Substituted 5-hydroxymethyl-8-methyl-7-azacoumarins were prepared by a Knoevenagel reaction of pyridoxal hydrochloride with acetonitriles in a one-pot procedure in a water-only medium.The reactions occurred in heterogeneous phase with much better yields than those obtained in a homogeneous alcoholic medium.Coumarins, particularly 3-substituted coumarins, are widely used molecules of great biological interest.'Various protocols and experimental conditions have been developed to synthesize them easily.2On the contrary 2H-pyranopyridin-2-ones, called "azacoumarins", are difficult to synthesize and their biological and pharmacological activities have been little investigatedla Very few papers3 concerning azacoumarins are reported in the literature and the thirty or so known compounds have been prepared by condensation reactions such as the Knoevenagel,3*d the Knoevenagel-D ~b n e r , ~e the Perkin,3a the Pechman, 3a.c and the Wittig reactions3f under severe conditions.The processes have been carried out by multi-step procedures in solvents such as ethanol, acetic anhydride, pyridine and dry benzene with generally unsatisfactory reaction yields.Continuing to use water as the reaction medium in organic synthesis,2g.4we recently reported that active methylene compounds gave aldol-type condensation with arylaldehydes in a water-only medium which allowed chalcones, flavonols, acrylonitriles and coumarins to be obtained in high yields using a one-pot p r o c e d ~r e .~g , ~~ While the reactions occurred in heterogeneous medium, the unique chemical and physical properties of water5 and the possibility of accurately controlling the pH of the reaction medium, guaranteed the success of the rea~tions.2g.~At the end of the process, the products were collected in pure form by simple filtration.