A General Three-Component Alkyl Petasis Boron-Mannich Reaction

Aryl amines are one of the most common moieties in biologically active molecules, and approximately 37% of drug candidates contain aromatic amines. Recent advancements in medicinal chemistry, coined as “escaping from flatland”, have led to a greater focus on accessing highly functionalized C(sp3)-rich amines to improve the physiochemical and pharmacokinetic properties of compounds. This communication presents a modular and operationally straightforward three-component alkyl Petasis boron-Mannich (APBM) reaction that utilizes ubiquitous starting materials, including amines, aldehydes and alkyl boronates. Overcoming the long-standing synthetic hurdle of accomplishing the Petasis boron-Mannich reaction with alkyl boronate coupling partners was achieved via the formation of an electron donor-acceptor (EDA) complex and sequential radical-radical coupling. By adapting this transformation to high-throughput experimentation (HTE), it offers rapid access to an array of diverse C(sp3)-rich complex amines, amenable for facile drug candidate development.