2,3,4,5,6,7,8,9-Octahydro-1H-pyrido[4,3-b]azepines. Synthesis and Properties

Abstract

SHORT COMMUNICATIONSThe synthesis and chemical properties of 1,7-disubstituted 2, 3,4,5,6,7,8,9-octahydro-1H-pyrido[4,3-b]azepines were studied. These compounds belong to a new heterocyclic system containing an endocyclic enamine fragment. Compounds XIII-XV were synthesized via a series of consecutive reactions including lithiation of 4-iminopiperidines I-III with lithium diethylamide, alkylation of lithium salts IV-VI with 1-bromo-4-chlorobutane, nucleophilic substitution of the chlorine atom in 3-(4-chlorobutyl)imines VII-IX by iodine, and intramolecular cyclization of 3-(4-iodobutyl)imines X-XII to target 1,7-disubstituted pyrido-[4,3-b]azepinium salts XIII-XV by heating in boiling acetonitrile. All these reactions were carried out without isolation of intermediate products VII-XV.We planned to obtain seven-membered enamines XVI-XVIII according to the procedure developed by us previously for the preparation of their six-membered analogs, 1,2,3,4,5,6,7,8-octahydro-1,6-naphthyridines [1].However, no cyclization of intermediate VII (R = Ph) to desired azepine XVI occurred under the conditions optimal for the synthesis of 1,6-naphthyridines. We succeeded in obtaining azepinium salt XIII only via cyclization of the corresponding iodide X which was prepared by nucleophilic substitution of the chlorine atom in 1-benzyl-3-(4-chlorobutyl)-4-phenyliminopiperidine (VII) by iodine on heating with NaI in boiling acetonitrile. 6-Benzyl-1-phenyl-2, 3,4,5,6,7,8,9octahydro-1H-pyrido[4,3-b]azepine (XVI) was isolated by treatment of salt XIII with alkali. The structure of enamine XVI was determined on the basis of the GC-MS data, MALDI spectra (using positive and negative ion registration), and 1 H and 13 C NMR