Compounds with bridgehead nitrogen. Part 70. The synthesis and stereochemistry of the 12-methyl- and 9-ethyl-12-methylperhydropyrido-[1,2-c][1,3]benzoxazepines

Abstract

The diastereoisomeric 2-[1-(2-piperidyl)ethyl]cyclohexanols and the corresponding 2-[1-(5-ethylpiperidin-2-yl)ethyl]cyclohexanols were synthesised by reaction between the lithio derivatives of 2-ethylpyridine and 2,5-diethylpyridine and cyclohexene oxide followed by catalytic hydrogenation of the product. The individual amino alcohols were isolated and treated with formaldehyde to give the 12-methyl- and 9-ethyl-12-methylperhydropyrido[1,2-c][1,3]benzoxazepines. The configurations of these compounds were assigned by comparison of the NMR spectra with those of perhydropyrido-[1,2-c][1,3]benzoxazepines of known configuration. The rel-(4aR,12aS,12R,11aR) and rel-(4aS,12aR,12R,11aR)-12-methylperhydropyrido[1,2-c][1,3]benzoxazepines were shown to exist exclusively in the trans-fused conformation in CDCl₃ solution at room temperature. The rel-(4aR,12aS,12S,11aR) and rel-(4aS,12aR,12S,11aR)-12-methylperhydropyrido[1,2-c][1,3]benzoxazepines exist predominantly in the trans-fused conformations (ca. 75% and 72%, respectively) in equilibrium with O-inside cis-fused and O-outside cis-fused conformations, respectively. Equilibria positions for the corresponding 9-ethyl-12-methyl substituted compounds were also determined.