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.