Organic chemistry

Combinatorial chemistry

Catalysis

Chemistry

Domino

Oxindole

Intramolecular force

Accounts of Chemical Research

ConspectusThe oxindole scaffold is a privileged structural motif that is found in a variety of bioactive targets and natural products. Moreover, derivatives of the oxindole structure are widely present in a number of biologically relevant compounds and are key intermediates in the synthesis of diverse natural products and pharmaceuticals. Therefore, novel methods to obtain oxindoles remain of high priority in synthetic organic chemistry.Over the past several decades, novel transition-metal-catalyzed methodologies have been applied toward the synthesis of a variety of heterocycles. A detailed mechanistic understanding facilitates the disruption of traditional catalytic pathways to access useful synthetic intermediates. The strategies employed have generally revolved around the generation of high-energy organometallic intermediates, which undergo cyclization reactions through domino processes. Domino cyclization methodologies are therefore attractive, as they allow facile access to functionalized oxindoles containing all-carbon quaternary centers or tetrasubstituted olefins with high chemo- and stereoselectivities. Furthermore, these developed synthetic strategies can often be easily applied in the syntheses of other related scaffolds.In this Account, we discuss the three unique strategies that our group has leveraged for the synthesis of valuable oxindole scaffolds. The first section in this Account outlines the use of an initial oxidative addition to a C(sp2)–X bond, followed by a migratory insertion, yielding a neopentyl species amenable to a variety of subsequent functionalizations. From this reactive neopentyl metal species, we have reported C–X reductive eliminations, anionic capture cascade reactions, and intramolecular C–H functionalization processes. The second section of this Account summarizes our group's findings on 1,2-insertions of a metal–nucleophile species across an unsaturation, generating a reactive organometallic intermediate; subsequent reactions with tethered electrophiles form the desired heterocyclic core. We have explored a wide array of transition metal-catalyzed strategies using this approach, including rhodium-catalyzed conjugate additions, an asymmetric copper-catalyzed borylcupration, and a palladium(II)-catalyzed chloropalladation protocol. The final section of this Account details the use of dual-metal catalysis to perform a cyclization through a C–H functionalization–allylation domino reaction. Throughout this Account, we provide details of mechanistic studies that better enabled our understanding of the domino processes.Overall, our group has developed methods exploiting the unique reactivity of palladium, nickel, copper, rhodium, and ruthenium catalysts to develop methods toward a wide array of oxindole scaffolds. On the basis of the utility, diversity, and applicability of the strategies developed, we believe that they will prove to be highly useful in the syntheses of other important targets and inspire further development and mechanistic understanding of various metal-catalyzed processes.

Metal-Catalyzed Approaches toward the Oxindole Core