Palladium‐Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes

• Published in: Angewandte Chemie 2022-10, Vol.134 (41), p.n/a
• Main Authors: Choi, Kyoungmin, Mormino, Michael G., Kalkman, Eric D., Park, John, Hartwig, John F.
• Format: Article
• Language: English
• Subjects: Alkylation; Aromatic compounds; Catalysts; Chemical synthesis; Chemistry; Cobalt; Computer applications; Cross-Coupling; Diaryl ethers; Ethers; Fluorine; Halides; Ketones; Palladium; Phosphine; Phosphines; Silanes; Synthetic Methods
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202208204

Diaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd‐catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α‐carbon, due to coordination of the difluorobenzyl π‐system to palladium. The co‐development of a cobalt‐catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes. Palladium‐catalyzed coupling of aryl halides with aryldifluoromethyl trimethylsilanes is shown to form diaryl difluoromethanes. A simple dialkyl(dimethoxyphenyl)phosphine ligand for palladium, stabilizing π‐interactions between palladium and the difluorobenzyl ligand during reductive elimination, and a cobalt‐catalyzed synthesis of the silanes enabled the reaction to form diverse products, including those possessing biological activities.