Borane-Mediated Highly Secondary Selective Deoxyfluorination of Alcohols

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 S_N2 and S_N1 type reactions.