C-H functionalisation, the ability to install new functional groups directly in place of existing C-H bonds, has recently emerged as a powerful strategy to streamline organic synthesis. The functionalisation of C–H bonds on sp3 centres provides a particular challenge, due to the increased degrees of freedom as well as poor orbital overlap with the metal catalyst. Despite this, huge efforts have been made to directly functionalise C(sp3)–H bonds, as doing so allows access to diverse and novel 3-dimensional frameworks with potential uses in drug discovery. To date this has been achieved through the use of amide linked directing groups (DGs), such as 8-aminoquinoline, to coordinate transition metal catalysts such as palladium and nickel. However, these DGs require additional steps to install and remove, reducing efficiency. In 2016, the concept of ‘transient’ directing groups (TDGs) emerged, whereby the DG is installed, C-H functionalisation occurs, and then the DG is removed, all in one reaction pot. This reversible binding of the DG to the substrate represents a significant advantage over amide attachments, but the field is very much in its infancy. This poster will describe our work on C(sp3)-H arylation of tertiary aldehydes in a single synthetic step. A new class of catalytic, reversibly imine-bound TDG has been developed, to mediate beta-C(sp3)–H arylation with aryl iodide coupling partners using palladium catalysis. Over 20 primary amine containing DGs with various secondary functionalities were examined. Bidentate TDGs were optimal and could be used in sub stoichiometric quantities; however, monodentate DGs could also promote arylation. Using the optimised TDG the palladium-catalysed arylation was successful using electron rich and electron poor aryl iodides, and on a selection of tertiary aldehydes bearing varied functionality. The reaction has been shown to be feasible on larger scales with low loadings of the amine demonstrating the catalytic efficiency of the imine directing group. Investigations into the imine formation and the role of the second coordinating group are described, including NMR studies and a crystal structure of an unusual palladacyclic intermediate.

Single-operation, palladium-catalysed C(sp3)–H functionalisation of tertiary aldehydes: Investigations into transient imine directing groups

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.