Borane-Mediated Highly Secondary Selective Deoxyfluorination of Alcohols

Abstract

Organofluorine compounds are vital across multiple sectors, hence highly selective methods to install fluorine are of considerable importance. The deoxyfluorination of alcohols is a key approach to prepare organofluorine compounds, however, a highly secondary (2°)-selective deoxyfluorination of alcohols has not been realized to date. Herein, we report that borane-mediated deoxyfluorination results in high 2°-selectivity in inter- and intra-molecular competition reactions versus primary (1°), tertiary (3°) and even benzylic (Bn) alcohols. This is an operationally simple method using only commercial reagents (e.g., Et3N ⋅ 3HF) that starts from the alcohol which is converted to the O-alkyl-N-H-isourea in situ. The origin of the high 2°-selectivity was elucidated to be due to the relative barriers to carbodiimide elimination from the O-alkyl-N-(BR2)-isoureas. As the selectivity controlling step does not involve fluoride, this borane-mediated approach can be applied to other nucleophiles, as demonstrated by 2°-selective deoxychlorination using HCl occurring in preference to substitution of 1° and Bn analogues. This borane-mediated nucleophilic substitution therefore provides a new approach to circumvent the selectivity limitations inherent in classical SN2 and SN1 type reactions.