Stereochemical studies of the isomerization of novel 2-alkyl-9-phenyl-2,3,4,4a- and 2,3,4,9-tetrahydro-1H-indeno[2,1-c]pyridines

The published synthetic route to the antihistaminic tetrahydroindeno[2,1-c] pyridines (phenindamines) relies on catalytic reduction of the precursor di hydroindenopyridines, This reduction gives mixtures of 9,9a- and 4a,9a-enes and the clinically active 4a,9a isomer has to be isolated by recrystalliza tion of an appropriate salt. The structure of the product recovered depends on the anion used to isolate the proton salt and appears to be arbitrary. To rationalize this outcome a series of novel N-2 alkylated tetrahydroinden o[2,1-c]pyridines and their diene precursors has been synthesized from acce ssible piperidines. The structures and geometry of the piperidines and the dihydro- and tetrahydroindenopyridines have been determined by H-1 and C-13 NMR, An unusual feature of the proton spectra of the piperidines is the re sonance of the axial protons at lower field than their equatorial counterpa rts. By controlling the reaction conditions for the reduction of the dihydr oindenopyridines to their tetrahydro derivatives the kinetic or thermodynam ic product can be selected as required. A predictable outcome for the reductions investigated was achieved and is g enerally applicable.