Synthesis of Distally Halogenated Ketones: Proton-Coupled Electron Transfer Enabled Ring-Opening of Cyclic Alcohols

Abstract

The functionalization of simple C–H bonds has long been a goal of synthetic organic chemistry. The inertness of these bonds and their prevalence in common organic molecules dictate the great importance of the field. A number of powerful tools for C–H bond functionalization have been developed, but these protocols are limited in their ability to transform unactivated sp3 C–H bonds remote from other functional groups. These limitations advocate the development of unorthodox ways for achieving similar transformations. In particular, ring-opening of cyclic alcohols for the synthesis of distally halogenated ketones has become a particularly popular method of affording functionalized products. These procedures rely on transition metal catalysts and highly strained cyclic starting materials to overcome the poor thermodynamics associated with cleaving C–C bonds. Herein, I investigate photoredox protocols for the ring-opening of cyclic alcohols to generate d-brominated, fluorinated, trifluoromethylated, and chlorinated ketone products. These protocols rely on an iridium based photocatalyst and an organic base to abstract a hydrogen atom from the alcohol and promote beta scission and as a result, these protocols are able to activate compounds that are not encumbered by excessive ring strain. I was able to develop effective protocols for the d-bromination, chlorination and fluorination of these compounds and the development of the trifluoromethylation procedure is ongoing. Preliminary studies indicate that this system can also achieve functionalization at even more remote positions through the cleavage of larger rings. These distally functionalized products are difficult to otherwise synthesize and the corresponding ring-opening procedures for these large rings have met with limited success.