Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Angew Chem Int Ed Engl. 2022 Oct 10;61(41):e202208204. doi: 10.1002/anie.202208204. Epub 2022 Sep 7.
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 (TMSCF Ar). 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.
二芳基二氟甲烷是药物化学的重要研究目标，因为它们是二芳基醚的生物等排体，可以替代二芳基甲烷、酮和砜基。然而，制备二芳基二氟甲烷的方法很少，尤其是从丰富的芳基卤化物开始的方法。我们报告了钯催化的芳基卤化物与芳基二氟甲基三甲基硅烷（TMSCFAr）的芳基二氟甲基化反应。当催化剂含有一种简单但不寻常的二烷基芳基膦配体时，反应就会发生，该配体促进了硅烷的转金属化。计算研究表明，尽管α-碳上的氟原子存在，但由于二氟苄基π-体系与钯的配位，转金属化后发生的还原消除反应具有低的能垒。钴催化合成硅烷的共同发展拓宽了该过程的范围，包括在合成具有生物相关性的二芳基二氟甲烷方面的几个应用。
