Palladium and copper co-catalyzed chloro-arylation of gem-difluorostyrenes - use of a nitrite additive to suppress β-F elimination

Abstract

The installation of fluorine and fluorinated functional groups in organic molecules perturbs the physicochemical properties of those molecules and enables the development of new therapeutics, agrichemicals, biological probes and materials. However, current synthetic methodologies cannot access some fluorinated functional groups and fluorinated scaffolds. One such group, the gem-difluorobenzyl motif, might be convergently synthesized by reacting a nucleophilic aryl precursor and an electrophilic gem-difluoroalkene. Previous attempts have relied on forming unstable anionic or organometallic intermediates that rapidly decompose through a β-F elimination process to deliver monofluorovinyl products. In contrast, we report a fluorine-retentive palladium and copper co-catalyzed chloro-arylation of gem-difluorostyrenes that takes advantage of a nitrite (NO₂ ^-) additive to avoid the favorable β-F elimination pathway that forms monofluorinated products, instead delivering difluorinated products.

Scheme 1. Metal catalyzed arylation reactions of gem-difluoroalkenes typically proceed through organometallic intermediates prone to undergo β-fluoride elimination, which can be overcome using a nitrite additive.

Fig. 1. Scope of gem-difluorostyrenes and aryl sulfonyl chlorides. ^aUnless otherwise stated, all reactions were carried out with gem-difluorostyrene (1.0 mmol), aryl sulfonyl chloride (2.0 mmol), 2.5% Pd(OAc)₂, 10% Cu powder, 25% NaNO₂, 1,4-dioxane (5.0 mL) and heated at 130 °C for 3 h under an atmosphere of nitrogen. ^b5% mmol Pd(OAc)₂. All reported yields and selectivities represent an average of two independent runs.

Fig. 2. Proposed mechanisms by which ⁻NO₂ prevents β-F elimination.