ABSTRACT
Palladium-catalyzed enantioselective C(sp3)-H functionalization reactions has attracted considerable attention due to its ability for the synthesis of enantiomerically enriched molecules and stimulation of novel retrosynthetic disconnections. Understanding the reaction mechanism, especially the stereochemical process of the reaction, is crucial for the rational design of more efficient catalytic systems. Previously, we developed a Pd(II)/sulfoxide-2-hydroxypridine (SOHP) catalytic system for asymmetric C(sp3)-H functionalization reactions. In this study, we focused on unraveling the chemistry of chiral palladacycles involved in the Pd(II)-catalyzed enantioselective C(sp3)-H functionalization. We have isolated key palladacycle intermediates involved in the enantioselective ß-C(sp3)-H arylation of carboxylic acids catalyzed by the Pd(II)/SOHP system. These palladacycles, exhibiting ligand-induced chirality, provided a significant opportunity to investigate the stereochemical process and the ligand effect in this asymmetric C-H functionalization. Our investigation provided direct evidence for the C-H palladation step as the enantioselectivity-determining step, which forms diastereomeric palladacycles that exhibited preservation of chirality in the functionalization step. DFT calculations provided insights into the chiral induction in palladacycle formation. This work highlights the value of chiral palladacycle chemistry in offering mechanistic insights into the Pd(II)-catalyzed asymmetric C(sp3)-H functionalization reactions.
ABSTRACT
The Pd(II)/sulfoxide-2-hydroxypyridine catalytic system shows promising activity in C-H activation chemistry. In this study, we showcase how this catalytic system solves the problem of native primary amine-directed γ-C(sp3)-H arylation. Primary amines with different complexities are compatible with the established methodology, and the range of applicable substrates can be expanded to include pyridine, oxime ether, and pyridine N-oxide.
ABSTRACT
Amide is one of the most widespread functional groups in organic and bioorganic chemistry, and it would be valuable to achieve stereoselective C(sp3 )-H functionalization in amide molecules. Palladium(II) catalysis has been prevalently used in the C-H activation chemistry in the past decades, however, due to the weakly-coordinating feature of simple amides, it is challenging to achieve their direct C(sp3 )-H functionalization with enantiocontrol by PdII catalysis. Our group has developed sulfoxide-2-hydroxypridine (SOHP) ligands, which exhibited remarkable activity in Pd-catalyzed C(sp2 )-H activation. In this work, we demonstrate that chiral SOHP ligands served as an ideal solution to enantioselective C(sp3 )-H activation in simple amides. Herein, we report an efficient asymmetric PdII /SOHP-catalyzed ß-C(sp3 )-H arylation of aliphatic tertiary amides, in which the SOHP ligand plays a key role in the stereoselective C-H deprotonation-metalation step.
ABSTRACT
Efficient control of regioselectivity is a key concern in transition-metal-catalyzed direct C-H functionalization reactions. Various strategies for regiocontrol have been established by tuning the selectivity of the C-H activation step as a common mode. Herein, we present our study on an alternative mode of regiocontrol, in which the selectivity of the C-H activation step is no longer a key concern. We found that, in a reaction where the C-H activation step exhibits a different regio-preference from the subsequent functionalization step, a ligand-enabled switch of the regioselectivity-determining step could provide efficient regiocontrol. This mode has been exemplified by the Pd(ii)-catalyzed aerobic oxidative Heck reaction of indoles, in which a ligand-controlled C3-/C2-selectivity was achieved for the first time by the development of sulfoxide-2-hydroxypyridine (SOHP) ligands.
