Synthesis and reactions of 1,2,3,4,5,6-hexahydro-3,6-dimethyl-2,6-methano-3-benzazocin-11-one (2,5-dimethyl-9-oxo-6,7-benzomorphan); a new route to 3-benzazocines

Abstract

In second-order Beckmann reactions oximes of the title compound (1) and 1-[2-(N,N-dimethylamino)ethyl]-3,4-dihydro-1-methylnaphthalen-2(1H)-one (14) gave 1,2,3,4-tetrahydro-3,6-dimethyl-3-benzazocine-2-carbonitrile (8) and (E)-2-[o-(2-cyanoethyl)phenyl]-4-dimethylaminobut-2-ene (15), respectively. The benzazocine-2-carbonitrile (8) was hydrolysed to the corresponding carboxylic acid (10), which was converted into its ethyl (11) and methyl esters (12) and reduced to the 2-aminomethyl-3-benzazocine (13). An attempt to prepare the ethyl ester (11) in hot 10% aqueous ethanol saturated with hydrogen chloride resulted in ring contraction, to give 1-methyl-2-(N-methylaminomethyl)naphthalene (17). In a Pinner reaction in ethanol the benzazocine-2-carbonitrile (8) gave the corresponding amide (9) instead of the ethyl imidate.

An evaluation of the May and Murphy synthesis of the title compound (1) is given. 1-[2-(N-Benzyl-N-methylamino)ethyl]-3,4-dihydro-1-methylnaphthalen-2(1H)-one (20), prepared from 1-[2-(N,N-dimethylamino)ethyl]-3,4-dihydro-1-methylnaphthalen-2(1H)-one and benzyl chloride, was converted into its ethylene acetal (31; R = CH₂Ph) and removal of the benzyl group followed by hydrolysis of the deprotected acetal gave the 2,3,5,9b-tetrahydrobenz[e]indole (23; R = H), a key intermediate in the Takeda-style synthesis of the title compound. 1-[2-(N-Chloro-N-methylamino)ethyl]-3,4-dihydro-1-methylnaphthalen-2(1H)-one ethylene acetal (31; R = Cl) was prepared but failed to cyclise under various conditions.

Under the same conditions 1-[2-(N-benzyl-N-methylamino)ethyl]-3,4-dihydro-1-methylnaphthalen-2(1H)-one (20; R = CH₂Ph) failed to brominate whilst the corresponding 1-[2-(N-ethoxycarbonyl-N-methylamino)ethyl] compound (22; R¹= Et, R²= H) gave its 3,3-dibromo derivative (28).