Introduction of pharmacophoric groups into polycyclic systems. Part 3. Amine derivatives of adamantane and diaza-adamantane

Abstract

Methods for introducing various pharmacophoric amine-containing substituents into the adamantane system have been investigated. These include β-and α-aminoalkyloxyimino, β-aminoalkylidene, β-hydroxyethylamino, and β-phenylethylamino. Aminoalkyloxyimines were prepared by alkylation of the anion of adamantanone oxime with the corresponding aminoalkyl chloride, and a 2-aminoethylidene derivative was prepared by Wittig reaction of 2-dimethylaminoethyltriphenylphosphonium bromide with adamantanone. The reaction of 6-hydroxy-7-methyl-6-phenyladamantane-2,4-dione with aqueous sodium cyanide has been shown to be both regio- and stereo-selective, only the C-2 carbonyl group reacting from the most hindered direction. This is possibly due to stabilisation of the cyanohydrin by hydrogen bonding between the hydroxy and C-4 carbonyl groups. When trimethylsilyl cyanide was used in place of sodium cyanide, the reaction remained regioselective but, in the absence of hydrogen bond stabilisation, the stereoselectivity was lost and two trimethylsilyloxy cyanides were isolated, epimeric at C-2. The stereochemistry of one epimer has been determined by X-ray crystallography, details of which are reported here. Hydrogenation of the trimethylsilyloxy cyanides then gave the corresponding β-hydroxyamine, isolated as the hydrochloride. Finally 5,7-diphenyl-1,3-diaza-adamantan-6-one was prepared by a literature method and converted, with difficulty, into the oxime which was reduced by RedAl to the corresponding amine.