New efficient synthesis of ethyl 2,3-cycloalkenopyridine-4-carboxylate

Abstract

Ethyl 2,3-cycloalkenopyridine-4-carboxylates (6a-c) from 2-chlorocycloalkanone and ethyl cyanoacetate have been synthesized in 4 steps with overall 68, 68, 25% isolation yield for cyclopenteno (68), cyclohexeno (6b) and cyclohepteno (6c) derivatives, respectively. Pyridine ring is constructed from 1,5-dicarbonyl precursor and nitrogen source. In order to prepare 1,5-dicarbonyl precursor, malonic ester synthesis is used. Alkylation of 2-chlorocycloalkanone (1a-c) with ethyl cyanoacetate affords ethyl cyano-(2-oxocycloalkanoyl)acetate (3a-c). Second alkylation of 3a-c with allyl bromide gives ethyl 2-cyano-2-(2-oxocycloalkanoyl)-4-pentenoate (4a-c). Ozonolysis of olefins (4a-c), and continuously pyridine ring formation with hydroxylamine provides ethyl 2,3-cycloalkenopyridine-4-carboxylate N-oxide (7a-c). This N-oxide is easily reduced with phosphorous trichloride in chloroform. Replacement of hydroxylamine hydrochloride by ammonium formate as a nitrogen source reduced one step in this process, directly forming 2,3-cycloalkenopyridine-4-carboxylate.