Fundamental Principles in Catalysis from Mechanistic Studies of Oxidative Decarboxylative Coupling Reactions.

ConspectusOxidative decarboxylative coupling (ODC) reactions have been recognized as powerful alternatives to traditional cross-coupling reactions due to the ability to generate (hetero)biaryl structures from simple and readily available carboxylic acid precursors. These reactions, however, are underdeveloped due to the requirement for ortho-nitrobenzoate coupling partners and silver salts as oxidants. Our research program has focused on the development of new catalytic ODC reactions, as well as mechanistic studies of these reactions to uncover the origin of these synthetic limitations. As the framework for these studies, we explored two key ODC reactions developed in our group: (1) a Ni-catalyzed decarboxylative arylation reaction that relies on silver as the oxidant and (2) a Cu-catalyzed decarboxylative thiolation reaction capable of operating under aerobic conditions. Our findings, disclosed in this Account, have uncovered the importance of the ortho-substituent and revealed that Ag-based oxidants are also responsible for mediating the decarboxylation and transmetalation steps.Systematic exploration of the decarboxylation of a series of well-defined Ag-benzoate complexes allowed us to probe the importance of the ortho-nitro group in the decarboxylation step. Kinetic measurements of a large series of differently substituted benzoates were found to correlate with the field effect (F) of the ortho-substituent, revealing this feature to be responsible for the enhanced reactivity of these favored benzoates.Our studies of the Ni-catalyzed decarboxylative arylation reaction uncovered an unexpected redox transmetalation step in this system. Synthesis and isolation of the proposed nickelacycle and Ag-aryl intermediates enabled direct study of the fundamental coupling steps. Catalytic and stoichiometric reactions of these complexes, paired with DFT calculations, supported a redox transmetalation step in which the Ag-aryl intermediate transfers the aryl ligand from Ag^I to Ni^II with concomitant oxidation to generate a Ni^III-bis(aryl) intermediate.Finally, detailed mechanistic studies of our Cu-catalyzed decarboxylative thiolation reaction demonstrated how this catalyst system is able to use O₂ as the terminal oxidant. Kinetic studies paired with the synthesis and reactivity of well-defined copper intermediates revealed decarboxylation from a Cu^I-benzoate resting state, despite the oxidizing reaction conditions which could support higher oxidation state intermediates. We also identified the intermediacy of diphenyl disulfide (PhSSPh) formed from the thiophenol (PhSH) coupling partner under the aerobic Cu-catalyzed conditions. The reaction of PhSSPh with the catalyst proceeds via oxidative transfer of the PhS fragment to Cu^I that is analogous to that of the redox transmetalation observed in Ni-catalyzed decarboxylative arylation.These studies combined suggest significant implications for ODC reactions more broadly. For example, it appears that silver is important for mediating the decarboxylation step when the catalyst is unable (as is the case with nickel) but is not needed when the catalyst is an efficient decarboxylation mediator on its own (as with copper). Furthermore, silver plays an additional role in mediating an oxidative transfer of the coupling partner in arylation reactions but is not required when the coupling partner is itself oxidizing (such as PhSSPh). We anticipate that these mechanistic insights will facilitate the development of new ODC reactions that operate under milder conditions and with broader substrate scopes.