Condensation of 3-methoxyphenethylamine (I) with methyl chloroformate in the presence of Et3N gave carbamate (II). This was cyclized to the isoquinolinone (III) by treatment with polyphosphoric acid at 140 C. Reduction of lactam (III) with LiAlH4 provided the tetrahydroisoquinoline (IV). Reductive condensation of (IV) with 4-(5-cyano-3-indolyl)cyclohexanone (V) employing sodium triacetoxyborohydride furnished the corresponding 1,4-disubstituted cyclohexane as a cis/trans mixture from which the desired cis-isomer was isolated by column chromatography.
Acylation of 3-methoxyphenethyl amine (VI) with methyl chloroformate gave the corresponding carbamate (VII). Intramolecular cyclization of (VII) with hot polyphosphoric acid produced a mixture of isomeric isoquinolinones (VIII) and (IX) from which the desired 6-methoxy isomer (IX) was isolated by column chromatography. Reduction of (IX) with LiAlH4 furnished the tetrahydro isoquinoline (X). Then reductive alkylation of amine (X) with ketone (V) in the presence of NaBH(OAc)3 produced the corresponding cyclohexyl amine as a mixture of cis/trans isomers. The title trans compound was obtained from the reaction mixture by chromatographic separation.
The intermediate 4-(5-cyano-1H-indol-3-yl)cyclohexanone (V) has been obtained as follows: The condensation of 1H-indole-5-carbonitrile (VI) with cyclohexanone monoethyleneketal (VII) by means of KOH in refluxing methanol gives the cyclohexenone ethyleneketal (VIII), which is reduced with H2 over Pd/C in ethanol to yield 4-(5-cyano-1H-indol-3-yl)cyclohexanone ethyleneketal (IX). Finally, this compound is hydrolyzed to the target intermediate (V) with HCl in THF.
Base-catalyzed condensation of 5-cyanoindole (I) with 1,4-cyclohexanedione mono-ethylene ketal (II) furnished the cyclohexenyl indole (III), which was further hydrogenated in the presence of Pd/C to the cyclohexyl analogue (IV). Subsequent hydrolysis of the ethylene ketal function of (IV) gave ketone (V).