High-efficiency carbon-carbon cross-coupling reactions
Over the last half century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesised. Cross-coupling reactions are widely used by chemists as they offer a way of creating carbon-carbon bonds that are the staple of modern drug development. Construction of sp3-sp3 bonds provides a powerful way for creating carbon-carbon bonds; however, this bond construction through cross-coupling methodologies has hitherto proved challenging. Within the EU-funded project PHOCATSORS (Photoredox catalysis for sustainable organic synthesis), researchers developed a new sp3-sp3 coupling methodology using the combined effect of photoredox and nickel-bearing catalysts with carboxylic acids as a starting material. Initial findings demonstrated that a range of electrophiles were suitable reaction partners, including allylic carbonates, benzylic chlorides and unactivated alkyl bromides. A wide range of cyclic and acyclic amino acids proved suitable coupling partners for the allylation protocol chosen, generating a range of functionalised homoallylic amines. Based on photoredox-mediated decarboxylative allylation reactions, the project team focused on a general platform for the cross-coupling of carboxylic acids to introduce a wide array of different substituents. This greatly broadened the scope of products that can be formed using this dual catalytic photoredox-nickel sp3-sp3 coupling procedure. Following optimisation, the reaction was found to be amenable to a wide array of primary and secondary carboxylic acids and did not require the presence of radical stabilising groups. By selecting the appropriate electrophile, the carboxylic acid moiety could be converted into a benzyl, cyclopropyl or methyl group in a single step. Furthermore, the synthetic utility of this decarboxylative coupling protocol was illustrated by the synthesis of a known pharmaceutical from commercially available starting materials. Researchers expect that the newly developed general methods and the readily available starting materials should aid the uptake of sp3-sp3 cross-coupling across several fields of synthetic organic chemistry.
Keywords
Carbon-carbon, cross-coupling reactions, drug development, PHOCATSORS, synthetic organic chemistry
