On the Mechanism and Selectivity of Palladium-Catalyzed C(sp3)-H Arylation of Pyrrolidines and Piperidines at Unactivated C4 Positions: Discovery of an Improved Dimethylaminoquinoline Amide Directing Group

Abstract

Directed C-H functionalization is a powerful means to functionalize otherwise unreactive C-H bonds, for which aminoquinoline amides provide a powerful and frequently used directing group. Saturated N-heterocycles are crucial motifs in medicinal chemistry. However, the C-H functionalization of N-heterocycles has posed considerable challenges, often giving incomplete conversions. On unsymmetrical substrates, poorly understood regio- and stereoselectivity considerations have prevented more forcing conditions and further limited yields. Here, we present a combined experimental and computational study on the regio- and stereoselective C4 arylation of pyrrolidines and piperidines with C3 aminoquinoline amide directing groups. Detailed mechanistic experiments are presented including deuteration, kinetics investigations, and isolation of palladacycles. Palladacycle formation is reversible and proceeds preferentially at C4, though activation of both C-H bonds at C4, cis and trans to the directing group, occurs equally. The cis-selectivity results from strain in the trans-palladacycle (ΔΔGtrans-cis ∼6 kcal mol-1), which is retained in subsequent transition states. Hence, the oxidative addition step is stereo-determining. However, the turnover-limiting step for the catalytic cycle is reductive elimination, and reduced rates and yields are observed with electron-poor aryl iodides. Importantly, kinetics experiments reveal a rapid loss of the active Pd catalyst, likely due to the buildup of iodide, and a role for K2CO3/PivOH in catalyst turnover. Finally, we present the discovery of an improved 4-dimethylamine-8-aminoquinoline directing group (DMAQ). This removable auxiliary achieves >2× rate acceleration, generally improved yields, as well as improved cis-selectivity, by promoting reductive elimination. A broad reaction scope of aryl iodides is demonstrated, including the late-stage functionalization of drug compounds which is enabled by the use of only one equivalent of functionalized iodides.