Phosphorus(V) Fluoride Exchange (PFEx): Multidimensional Click Chemistry from Phosphorus(V) Connective Hubs

We report catalytic Phosphorus Fluoride Exchange (PFEx) as the latest advance in connective click-reaction technology. Emulating Nature, PFEx reaches into the biological world and creates stable tetrahedral P(V)- connections through efficient phosphorus-fluoride exchange chemistry. We showcase PFEx through the coupling of P(V)-F hubs with aryl alcohols, alkyl alcohols, and amines, delivering stable, multidimensional P(V)-O and P(V)- N connected products. The reactivity profile of P-F hubs surpasses that of their P-Cl counterparts, both in reaction performance, rate, and outcome, qualifying PFEx as a true click reaction. The rate of PFEx transformations is significantly enhanced by Lewis amine base catalysis [e.g., 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)]. When using substrates comprising multiple P-F bonds, selective, serial exchange reactions are realized through judicious catalyst selection. Synthesis of the final products (in up to 4 steps) allows controlled projections to be deliberately installed along 3 of the 4 tetrahedral axes departing the P(V) central hub. The unique reactivity window of PFEx allows for selective, modular click-reactions to be performed in series (e.g., SuFEx-PFEx-CuAAC) to rapidly generate complex multidimensional molecules, rendering PFEX a perfect addition to the click chemistry toolbox.