Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profile.<sup>1-4</sup> Drug candidates increasingly contain CF<sub>3</sub> and CF<sub>2</sub>H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life.<sup>5,6</sup> New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF<sub>2</sub>X (X = F or H) groups in complex drug-like molecules are rare.<sup>7-13</sup> For pyridine, the most common aromatic heterocycle in pharmaceuticals,<sup>14</sup> only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development.<sup>15-17</sup> Here, we have developed a new 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 pre-installed 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 via initial phosphonium salt formation followed by <i>sp</i><sup>2</sup>-<i>sp</i><sup>3</sup> phosphorus ligand-coupling, an underdeveloped manifold for C–C bond formation.
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