Studies on the synthesis of the benzo[a]quinolizidin-2-one ring system. Preparation of a 1,1-dimethyl derivative

Abstract

The first Synthesis of a 1,l-dialkyl-substituted bem[a]quinolizidin-2-0ne is reported. Condensation of mescaline and ethyl 2-(chloroformyl)-2-methylpropionate followed by Bischler-Napieralski cyclodehydration and sodium cyanoborohydride reduction gave tetrahydroiioquinoline 20, which was converted into amido ester 21 by reaction with ethyl acrylate. Dieckmann cyclization of 21 gave the desired tricyclic system 22. Alternative synthetic routes based on the BischlepNapieralski cyclization of N-phenethyl-&hydroxy amide 5 or N-phenethylpiperidine-2,4dione ethylene ketal 15 failed. The reluctance of the tertiary phenethyl amides 11 and 15 to give cyclized products under Bischler-Napieralski conditions contrary to the behavior of the secondary phenethyl amides 5 and 18 is discussed.Although attention to the benzo[a]quinolizidin-2-one ring system2 was initially focused on ita application as an intermediate in the synthesis of emetine and other related ipecac alkaloid^,^ the Brossi findings& about the reserpine-like activity of some $alkyl derivatives suggested that members with other substitution in ring C might be worthy of study. In this context, a number of 1-, 3-, and 4-alkyl-substituted, as well as 4,4-dialkyl-substituted, benzo-[a]quinolizidin-2-ones have been prepared2" for synthetic or/and pharmacological purposes, but to our knowledge only one unsuccessful attempt to synthesize a 1,l-dimethyl derivative by an intramolecular Mannich-type cyclization of an appropriate 3,4-dihydroisoquinolinium salt has been made.s Hence, the synthesis of this system by other methods seemed of interest.In this paper we report the first synthesis of a 1,l-dimethylbenzo[a]quinolizidin-2-one system and the full details of our different synthetic approaches. As a synthetic goal we chose a derivative possessing three methoxy groups on the aromatic ring! because of its similarity to several 2-(3,4,5-trimethoxyphenyl)-4-piperidinones prepared by us in previous work.' Initially, we planned the synthesis by Bischler-Napieralskie cyclization of hydroxy amide 5, which was expected to be readily accessible through condensation of mescaline and lactone 4, as shown in Scheme I. This methodology [two ring closures in N-(arylethyl)-6-hydroxy amides] has been successfully applied to the synthesis of the benzo[a]quinolizidine ring system: but no reports have been made of its extension to the 2-oxo series.Lactone 4, the key compound in this route, was prepared as follows. Ethyl 2,2-dimethylacetoacetate was allowed to react with sodium and ethyl formate according to the procedure developed for the diethyl analoguelo to give the hydroxymethylene derivative 1 which, without further purification, was converted (44% overall yield) into the hydroxy ester 2 by hydrogenation over Raney nickel catalyst. Cyclization to lactone 3 was initially effected by heating it in the presence of p-toluenesulfonic acid in benzene solution. Under these conditions, the desired compound 3 was isolated in low yield (29%), the enone 6 being the main product (40%). However, whe...