Rhodium-catalyzed C–H functionalization approaches for the carboamidation of alkenes will be presented for the rapid, modular synthesis of complex, pharmaceutically relevant α-branched amine products. A three-component method for the <i>syn</i> 1,2-carboamidation of bridged bicyclic alkenes with C–H bond substrates and dioxazolones provides access to medicinally relevant [2.2.1]- and [3.2.1]-bicyclic scaffolds. This reaction was demonstrated for readily available aromatic and heteroaromatic C–H bond substrates with tertiary and secondary amide, lactam, pyrazole, and triazole directing groups, and a variety of bridged bicyclic alkenes, including norbornene, benzonorbornadiene, oxygen- and nitrogen-bridged analogs, and an unsaturated tropinone. A broad dioxazolone scope was also observed. The use of a chiral Cp-derived Rh(III) catalyst enabled asymmetric synthesis of the carboamidated products. A readily diversifiable aldehyde-derived hydrazone directing group will also be described for the regiodivergent three- and four-component 1,1-carboamidation of terminal alkenes. The hydrazone coupling partner could either be pre-formed for use in the three-component reaction or formed <i>in situ</i> in the four-component method. The hydrazone in these α-branched amine products was readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study, which exhibited very broad scope with respect to terminal alkene and dioxazolone coupling partners, represents the first example of a four-component sequential C–H functionalization reaction.

Regiodivergent three- and four-component carboamidation of alkenes via Rh(III)-catalyzed addition of C–H bonds and amidating reagents

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ACS Fall 2022

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