1) The cyclization of 4-hydrazinobenzonitrile (I) with 4-(benzoyloxy)cyclohexanone (II) in refluxing acetic acid gives 3-(benzoyloxy)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (III), which is hydrolyzed with aqueous KOH to the corresponding alcohol (IV). The tosylation of (IV) with tosyl chloride in pyridine yields the tosylate (V), which by treatment with methylamine in hot ethanol is converted into 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (VI). The partial hydrolysis of the nitrile group with NaOH/H2O2, with previous protection of the amino group with di-tert-butyl dicarbonate, affords 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (VII) as a racemic mixture. The reaction of (VII) with di-tert-butyl dicarbonate gives the carbamate (VIII), which is submitted to chiral HPLC in hexane/ethanol giving the (R)-isomer (IX). Finally, this carbamate is hydrolyzed with aqueous HCl/methanol. 2) The optical resolution can also be performed with the benzoyloxycarbonyl derivative of (VII) in a similar way. 3) The optical resolution of (VII) can also be performed directly with (1S)-(+)-camphorsulfonic acid in methanol. 4) The reaction of cyclohexane-1,4-dione mono 2,2-dimethyltrimethylene ketal (X) with methylamine in toluene gives the corresponding methylimine (XI), which is reduced with H2 over Pd/C in ethanol to the expected methylamine (XII). Finally, this compound is cyclized with 4-aminobenzamide (XIII) by treatment first with NaNO2/HCl and then with sodium dithionite affording the racemic mixture (VII) already described.
5) The cyclization of 4-phthalimidocyclohexanone (XIV) with 4-hydrazinobenzamide (XV) in relfuxing acetic acid gives 3-phthalimido-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (XVI), which is treated with hydrazine in methanol yielding 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (XVII) as a racemic mixture. Reaction of (XVII) with di-tert-butyl dicarbonate gives the corresponding carbamate that is resolved by chiral HPLC in hexane/ethanol to give (XVIII). The hydrolysis of (XVIII) with HCl in dioxane affords the enantiomerically pure (R)-amine (XIX) (1-3). The reductoalkylation of (XIX) with benzaldehyde and NaBH3CN yields the corresponding benzylamine (XX), which is methylated with formaldehyde and NaBH3CN to the N-benzyl-N-methylamine (XXI). Finally, this compound is debenzylated by hydrogenation as usual. 6) The monomethylation of (XIX) can also be performed by its reaction with carbon disulfide and dicyclohexylcarbodiimide (DCC) in pyridine to give the expected isothiocyanato (XXII), which is finally reduced with NaBH4 in ethanol.