A scalable, enantioselective synthesis of the r2-adrenergic agonist, lofexidine

A scalable and high-yielding synthetic route toward pure enantiomers of the α₂-adrenergic agonist, lofexidine hydrochloride, is presented. Salient features include a rapid one-pot amide alkylation-imidazoline formation sequence on the carboxamide function of α-(2,6-dichlorophenoxy) propionamide, while preserving the sensitive configuration about the α-carbon of the resulting product. A means to accelerate the sluggish O-alkylation of the carboxamide function of α-(2,6-dichlorophenoxy) propionamide by Me₃O⁺BF₄^- is also described, which may be of general applicability.