Phosphorus-mediated sp²-sp³ couplings for C-H fluoroalkylation of azines

Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile^1-4. Drug candidates increasingly contain trifluoromethyl (CF₃) and difluoromethyl (CF₂H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life^5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF₂X groups (where X is F or H) in complex drug-like molecules are rare^7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals¹⁴, but only one approach-via fluoroalkyl radicals-is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development^15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp²-sp³ coupling of phosphorus ligands-an underdeveloped manifold for forming C-C bonds.