Synthesis of isothiocyanato-1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidines, potential irreversible ligands at the dopamine re-uptake site

Abstract

Isomeric isothiocyanate derivatives 2–7 of the potent dopamine re-uptake (DA) inhibitor 1-[1-(2-benzo-[b]thienyl)cyclohexyl]piperidine (BTCP 1) have been synthesized as potential irreversible ligands for this site. NaNO₂–CF₃CO₂H provided a mild procedure for mononitration of the benzo[b]thienyl ring of 1 as a route to aryl isothiocyanates 5–7. Novel methodology, utilizing 3,3-ethylenedioxypentane-1,5-diol dimethanesulfonate ester is described for the synthesis of piperidone 13, a precursor for 4-isothiocyanatopiperidine 2. NaBH₄ or LiAlH₄ reduction of 4-(2-benzo[b]thienyl)-4-hydroxycyclohexanone 18 and 4-(2-benzo[b]thienyl)-4-(piperidino)cyclohexanone oxime 35 gives the corresponding cis-diol 21 and cis-cyclohexane-1,4-diamine 36 as the major isomers which have been investigated as precursors to the cyclohexane ring isothiocyanates 3 and 4. Alternative routes to 3 and 4 are compared and their stereochemical outcome investigated.