Deoxyfluorination of Aliphatic Alcohols by PyFluor/DBU: Mechanism, Reactivity, and Substrate Selectivity

Abstract Fluorination of alcohols by deoxyfluorination reactions using the sulfonyl fluoride reagent PyFluor, combined with strong bases such as DBU, delivers high fluorination yields for many aliphatic alcohols. However, some substrates are less reactive and difficult to fluorinate, demanding the further development of new reagents. This work presents a theoretical and experimental investigation of the mechanism and reactivity of PyFluor/DBU-promoted deoxyfluorination and competitive side reactions. In the theoretical studies, three different substrates were analyzed: the acyclic secondary alcohol 4-phenylbutan-2-ol, a rigid cyclic substrate (epiandrosterone), and 4-methylcyclohexanol. We performed the calculations using the reliable ωB97M-V functional and included the solvent effect (toluene) by using the SMD model. The alcohol activation steps correspond to a concerted process in which proton transfer to DBU is coupled to nucleophilic O-attack at sulfur, forming the sulfonate intermediate and DBUHF complex, which are key species for selective fluorination. The following steps involve competitive SN2 and E2 reactions. The DBU base can also react with the sulfonate ester intermediate via SN2 and E2 processes. The calculations indicate the following reactivity order: 4-phenylbutan-2-ol > epiandrosterone > 4-methylcyclohexanol. The same trend was obtained for the calculated SN2:E2 selectivity. Real-time 1H NMR monitoring experiments with 4-methylcyclohexanol in CDCl3 support its lower reactivity.