Quaternary Carbons from Amines and Acids

Carbon-carbon bonds are the most frequently encountered bonds in drugs, natural products, agrichemicals, and perfumes. This makes reactions that can access C-C bonds, particularly those that access sterically complex architectures, of high impact to multiple industries and applications. Common C-C bond-forming reactions such as the Suzuki coupling or Diels-Alder cycloaddition have revolutionized synthesis, yet the building blocks required to perform these reactions, such as boronic acids or dienes, are only available in modest diversity from commercial suppliers compared to other common building blocks. A reaction that makes densely functionalized C-C bonds from broadly available starting materials would facilitate deeper access into chemical space. Here, we demonstrate an sp³-sp³ C-C coupling method that uses amines and carboxylic acids, which are among the most broadly available building blocks in vendor catalogs. Our method achieves the coupling of tertiary carbon centers to access dense carbon architectures including from complex pharmaceutical and natural product substrates. Preactivation of both the amine and acid functional groups enables an iron catalyst to unite the carbon-based building blocks under reducing conditions, which were identified using high-throughput experimentation. Extensive electron paramagnetic resonance measurements highlight the intermediacy of radicals and the spin state transformation of iron during the reaction. Our amine-acid coupling establishes a method for navigating chemical space that complements the current toolbox of carbon-carbon bond-forming reactions.