Stereochemical Studies of the Isomerization of Novel 2-Alkyl-9-phenyl-2,3,4,4a- and 2,3,4,9-tetrahy dro-1H-indeno [2,1 -c]pyridines

Abstract

Abstract The published synthetic route to the antihistaminic tetrahydroindeno[2,1-c]pyridines (phenindamines) relies on catalytic reduction of the precursor dihydroindenopyridines. This reduction gives mixtures of 9,9a- and 4a,9a-enes and the clinically active 4a,9a isomer has to be isolated by recrystallization 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 tetrahydroindeno[2,1-c]pyridines and their diene precursors has been synthesized from accessible piperidines. The structures and geometry of the piperidines and the dihydro- and tetrahydroindenopyridines have been determined by 1H and 13C NMR. An unusual feature of the proton spectra of the piperidines is the resonance of the axial protons at lower field than their equatorial counterparts. By controlling the reaction conditions for the reduction of the dihydroindenopyridines to their tetrahydro derivatives the kinetic or thermodynamic product can be selected as required. A predictable outcome for the reductions investigated was achieved and is generally applicable.