Synthesis of lactam and ketone precursors of 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazines and octahydro-2H-pyrido[1,2-a]pyrazines

Abstract
This report describes the synthesis of the hexahydropyrrolo[1,2-a]pyrazin-6(2H)-ones 6, the hexahydro-pyrrolo[1,2-a]pyrazin-7(6H)-ones 7, and the hexahydro-2H-pyrido[1,2-a]pyrazin-7-(6H)-ones 8, precursors of 2,7-substituted octahydropyrrolo- and octahydro-2H-pyrido[1,2-a]pyrazines. The synthetic sequence leading to the ketones 7 and 8 starts with the construction of the piperazine ring through intramolecular 1,4-addition of the unsaturated amino ester 18 or reductive cyclization of the amino keto ester 11. The resulting piperazin-2-yl-acetates 19 and -propanoates 12 are then subjected to alkylation with methyl bromoacetate, Dieckmann cyclization and acidic demethoxycar-bonylation. Depending on the reaction conditions, ring closure of the piperazin-2-ylpropanoates 12 afforded the lactams 6 or the 8a-methoxy lactam 14.

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