C-H Amidation Reactions via Metal Nitrenoid Transfer: Reaction Scope and Validation of Nitrene Intermediates
Presented by Prof. Sukbok Chang
Hosted by Prof. Tom Rovis
Abstract:
Direct amidation of C–H bonds is a highly desirable reaction considering high utility of amidated products in total synthesis, medicinal chemistry and materials science. Although tremendous research efforts have been made especially in recent years, the current status enabling such C–H reactions in excellent stereoselectivity and high efficiency is still rather limited. In this context, we have developed a novel methodology that employs tailor-made Ir-based catalysts in combination with dioxazolone substrates to access a short-lived metal-nitrenoid intermediate, thereby eventually leading to a construction of γ-lactams via an outer-sphere C–H insertion pathway. The scope was found to be broad and a range of carboxylic acids could be readily utilized for the lactam formation. More recently, we have successfully introduced an iridium-based catalyst system for asymmetric C−H amidation that enables facile construction of chiral γ-lactams starting from commodity chemicals. Various types of secondary C−H bonds, such as being positioned at the benzylic, unactivated aliphatic, propargylic, and allylic sites, were all smoothly reacted in a regio- and stereoselective manner. More recently, this strategy of C-N bond formation has been also successfully demonstrated to work with basic transition metal catalysts. The nitrenoid intermediacy was extensively investigated using mechanistic experiments, photocrystallography, and computational studies. In Particular, we designed a chromophoric octahedral rhodium complex with a bidentate dioxazolone ligand, in which photoinduced metal-to-ligand charge transfer initiates catalytic C–H amidation. X-ray photocrystallographic analysis of the Rh-dioxazolone complex allowed structural elucidation of the targeted Rh-acylnitrenoid and provided firm evidence that the singlet nitrenoid species is primarily responsible for acylamino transfer reactions. We also monitored in crystallo reaction of a nucleophile with the in situ generated Rh-acylnitrenoid, providing a crystallographically traceable reaction system to capture mechanistic snapshots of nitrenoid transfer. The present approach will find broad applications in medicinal chemistry, and the mechanistic insights may provoke further developments in related asymmetric catalysis
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