Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides

03 June 2024, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags be-hind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards indus-trial applications. We report here the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples (67 ± 16% average yield) including a diverse array of heteroaryl bromides and precursors to difluoromethyl-containing preclinical pharmaceuti-cals. This reaction can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles in cross-electrophile coupling, the mechanism of this process was investigated. Studies confirmed the formation of •CF2H instead of difluorocarbene. A series of modified difluoromethyl sulfones revealed that sulfone reactivity does not correlate ex-clusively with reduction potential and that coordination of cations or nickel to the pyridyl group is essential to reactivity, setting out pa-rameters for matching the reactivity of sulfones in cross-electrophile coupling.

Keywords

difluoromethylation
nickel catalysis
cross-electrophile coupling

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.