Kinetic Modeling Enables Understanding of Off-Cycle Processes in Pd-Catalyzed Amination of Five-Membered Heteroaryl Halides

The mechanism of Pd-catalyzed amination of five-membered heteroaryl halides was investigated by integrating experimental kinetic analysis with kinetic modeling through predictive testing and likelihood ratio analysis, revealing an atypical productive coupling pathway and multiple off-cycle events. The GPhos-supported Pd catalyst, along with the moderate-strength base NaOTMS, was previously found to promote efficient coupling between five-membered heteroaryl halides and secondary amines. However, slight deviations from the optimal concentration, temperature, and/or solvent resulted in significantly lower yields, contrary to typical reaction optimization trends. We found that the coupling of 4-bromothiazole with piperidine proceeds through an uncommon mechanism in which the NaOTMS base, rather than the amine, binds first to the oxidative addition complex; the resulting OTMS-bound Pd species is the resting state. Formation of the Pd-amido complex via base/amine exchange was identified as the turnover-limiting step, unlike other reported catalyst systems for which reductive elimination is turnover-limiting. We determined that the amine-bound Pd complex, usually an on-cycle intermediate, is instead a reversibly generated off-cycle species, and that base-mediated decomposition of 4-bromothiazole is the primary irreversible catalyst deactivation pathway. Predictive testing and kinetic modeling were key to the identification of these off-cycle processes, providing insight into minor mechanistic pathways that are difficult to observe experimentally. Collectively, this report reveals the unique enabling features of the Pd-GPhos/NaOTMS system, implementing mechanistic insights to improve the yields of particularly challenging coupling reactions. Moreover, these findings highlight the utility of applying predictive tests to kinetic models for the rapid evaluation of mechanistic possibilities in small-molecule catalytic systems.