Stereodivergent Alkyne Hydrofluorination Using Protic Tetrafluoroborates as Tunable Reagents

Abstract

The discovery of safe, general, and practical procedures to prepare vinyl fluorides from readily available precursors remains a synthetic challenge. The metal‐free hydrofluorination of alkynes constitutes an attractive though elusive strategy for their preparation. Introduced here is an inexpensive and easily handled reagent that enables the development of simple and scalable protocols for the regioselective hydrofluorination of alkynes to access both the E and Z isomers of vinyl fluorides. These reaction conditions were suitable for a diverse collection of alkynes, including several highly functionalized pharmaceutical derivatives. Computational and experimental mechanistic studies support C−F bond formation through vinyl cation intermediates, with the E‐ and Z‐hydrofluorination products forming under kinetic and thermodynamic control, respectively.

Gold N‐Heterocyclic Carbene Catalysts for the Hydrofluorination of Alkynes Using Hydrofluoric Acid: Reaction Scope, Mechanistic Studies and the Tracking of Elusive Intermediates

“…[3] While the uncatalyzed hydrofluorination is not particularly effective, [4] gold catalysis has emerged as a convenient method. [5] Sadighi and co-workers published the first example of gold-catalysed hydrofluorination of alkynes using Et 3 N • 3HF as the HF source and a gold-N-heterocyclic carbene (NHC) catalyst. [6] This initial study has paved the way for further development by Miller, [7] Hammond, [8] Nolan [9] and Toste, [10] using various HF sources (DMPU • HF, Et 3 N • 3HF, pyridine • HF) in combination with gold-NHC/phosphine catalysts (Scheme 1A).…”

Au(I) Fluorido Phosphine Complexes: Tools for the Hydrofluorination of Alkynes

“…The best results were achieved on using 2,6‐dichloropyridinium salts to mediate the conversions. The regioselectivity, however, was reverse to the one found for gold(I) catalyzed hydrofluorinations [15] . Note that for silver(I) promoted hydrofluorination reactions both regioselectivities were reported [16]…”

“…The regioselectivity, however, was reverse to the one found for gold(I) catalyzed hydrofluorinations. [15] Note that for silver(I) promoted hydrofluorination reactions both regioselectivities were reported. [16] The fluorido complex 1 was also treated with other alkynes.…”

Recent Advances in the Functionalization of Terminal and Internal Alkynes

“…In 2020, Wang group has developed a greener protocol for the synthesis of vinyl fluoride by metal‐free stereo‐divergent hydro‐fluorination of alkynes with tetrafluoroborate (BF 4 − ) salts (Scheme 40). [39] A wide range of substrate scope with high regio‐ and stereo‐selectivity, mild reaction conditions, ease of reaction handling and synthesis of several significant molecular framework's atom economically are the highlights of this protocol. For the screening of proper amine salt of HBF 4 as hydro‐fluorinating reagent, they have carried out an experiment using (cyclohexylethynyl)benzene as the model substrate in chloroform or 1,2‐dichloroethane (DCE) at 70 °C and concluded that 1 equiv.…”