Advancing Iron Catalyzed Three-Component Cross-Coupling Reactions

Abstract

Transition metal���catalyzed cross-coupling reactions are some of the most widely used methods in chemical synthesis. Notable advantages of iron as a potentially cheaper, more abundant, and a less toxic transition metal catalyst have drawn the interest of our lab, in particular to explore the mechanism of action in three-component radical cross-couplings. In the first project, we explored the difunctionalization of unactivated olefins with alkyl halides and Grignard reagents. The reaction tolerates a wide range of sp^2 hybridized nucleophiles, alkyl halides, and unactivated olefins bearing a diverse range of functional groups. Our second work highlights iron���s practical application in more elaborate multicomponent cross-couplings including formation and trapping of ��-boryl radicals and allyl alkyl halides for practical synthesis of cyclic fluorous compounds. Incorporating fluorine into drug scaffolds remains of utmost importance in medicinal chemistry since it generally increases lipophilicity, stability, and overall lifetime, and ~20% of drugs on the market contain at least one C-F bond. In that vein, pinacol boronate esters and boronic acids are excellent building blocks due to their reaction efficiency, low cost, and ability to be transformed into many other desired functional groups. The final research focus is on using a mechanistic-driven approach towards designing new chiral organoiron catalytic species capable of controlling the C-C bond formation with diverse C-centered radicals. To date, there are only three examples of enantioselective iron-catalyzed cross-coupling reactions, and all are limited to the union of only two components. We reported a practical and simple protocol that uses commercially available and inexpensive iron salts in combination with chiral bisphosphine ligands to enable the regio- and enantioselective (up to 91:9) multicomponent cross-coupling of vinyl boronates, (fluoro)alkyl halides, and Grignard reagents. Preliminary mechanistic studies are consistent with rapid formation of ��-boryl radical followed by reversible radical addition to mono-aryl bisphosphine-Fe(II) and subsequent enantioselective inner-sphere reductive elimination. Overall, my research is expected to expand the field of asymmetric iron cross-couplings and have broad implications towards the synthesis of bioactive compounds via the use of alkenes to translocate alkyl radicals, modify their steric and electronic properties, and induce stereocontrol