Aligning Catalyst Structure With Reactivity: Cross‐Coupling of Neopentyl Centers

The cross‐coupling of deactivated (sterically and/or electronically) amines, sulfides, and aryls has invariably followed the trend within a catalyst family that bulkier catalysts show greatly increased proficiency. In this report, we have systematically “paired” substrate bulk of neopentylalkylzinc building blocks with a series of Pd‐NHC (N‐heterocyclic carbene) complexes and found two key observations. With these hindered alkylzincs, the N‐aryl ortho substituents can be no larger than isopropyl, which is normally far less reactive than its isopentyl‐ and isoheptyl‐congeners, but the NHC‐core backbone must be chlorinated (i.e., Pd‐PEPPSI‐IPr Cl ). Through this investigation, a general, scalable approach to sterically hindered, biomedically important, α‐heteroarylmethyl nonnatural amino acids has been developed employing late‐stage functionalization. The method is also broadly applicable to other challenging neopentylzincs, including those containing poisoning/coordinating groups (e.g., esters), including intensively hindered secondary substrates.