Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

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This proposal aims to study new chemical processes for the streamlined syntheses of three common structural motifs in bioactive small molecules: phenols/aryl ethers (e.g., DetrolTM, Nexium®), tertiary amides (e.g., Januvia®, Diovan®) and tertiary carbons bearing two aryl groups (e.g., Zoloft®, Condylox®). Contingent upon the successful design of these new methodologies, kinetic and spectroscopic studies will aid in the elucidation of their catalytic mechanisms. Toward the production of phenolic and aryl ether building blocks, a palladium-catalyzed aerobic oxidation strategy that converts arene C(sp2)−H bonds into arene C(sp2)−O bonds is being pursued. Most palladium-catalyzed arene C−H oxygenation reactions use expensive and waste-generating oxidants such as PhI(OAc)2 and persulfates, and precedents for desirable aerobic alternatives suffer from low turnover numbers (<15) and or hazardously high O2 pressures (e.g. 60 atm). The proposed research entails using a redox mediator strategy in order to kinetically facilitate aerobic palladium-catalyzed arene C−H oxygenation. In particular, NOx- based co-oxidants (e.g., HNO3, tert-butyl nitrite), which can readily be reoxidized by O2, are being employed in order to achieve high turnover numbers for palladium. Toward the synthesis of tertiary amides, a new copper/nitroxyl-catalyzed aerobic reaction is being explored that enables oxidation of primary alcohols to tertiary amides in the presence of secondary amines. Oxidation of primary alcohols to tertiary amides has been achieved via ruthenium- or gold nanoparticle-catalyzed processes, yet limitations include narrow substrate scope, and the catalysts are expensive and/or challenging to synthesize. The proposed aerobic copper-catalyzed strategy utilizes inexpensive, commercially available catalysts and builds upon previous methodology for copper/nitroxyl-catalyzed alcohol oxidation of alcohols to aldehydes. Toward the synthesis of tertiary carbons bearing two aryl groups, such motifs are often accessed via cross-coupling reactions with prefunctionalized benzylic substrates and prefunctionalized aryl substrates. To our knowledge, non-directed benzylic C−H arylation has never been achieved. A copper-catalyzed strategy for benzylic C−H arylation (using arylboronic esters) is currently being explored. This method was inspired by Kharasch-Sosnovsky C(sp3)−H to C(sp3)−O or C(sp3)−N oxidative transformations; however, the Kharasch-Sosnovsky reaction has thus far not been achieved for the construction of C(sp3)−C bonds.