Development of a Scalable Synthesis of <i>trans</i>-4-Fluorocyclohexylamine via Directed Hydrogenation

Herein, a scalable and practical process to prepare trans-4-fluorocyclohexylamine hydrochloride (1a) is described. By exploitation of the embedded gem-difluoride motif in the commercially available 4,4-difluorocyclohexanecarboxylic acid, a derived orthoester-masked acid underwent dehydrofluorination to provide the requisite vinyl fluoride for a directed hydrogenation event, enabling selective access to the trans-configuration of 1a.本文报道了一种可规模化且实用的反式-4-氟环己胺盐酸盐（trans-4-fluorocyclohexylamine hydrochloride，1a）的制备工艺。通过利用市售4,4-二氟环己烷羧酸中内嵌的偕二氟（gem-difluoride）结构单元，经衍生得到的原酸酯保护羧酸发生脱氟化氢反应，生成定向氢化所需的氟代烯烃中间体，从而实现1a反式构型的选择性构建。