MECHANISTIC STUDY AND THE DESIGN OF IRON-CATALYZED MULTI-COMPONENT CROSS-COUPLING REACTION

Abstract

Cross-coupling reactions (CCRs) are one of the most versatile methods for the formation of C-C bonds. Traditionally, palladium and nickel are broadly used as the catalyst in this type of transformation. However, due to the low cost, low toxicity, and high natural abundance, iron has become an alternative metal catalyst for CCRs. The first iron-catalyzed asymmetric cross-coupling reaction was reported by Nakamura in 2015 but the mechanism remained unknown. Since then, our lab has been working on 1) the elucidation of the mechanism using quantum mechanical calculations and experimental probes; and 2) the rational design and development of new types of iron-catalyzed cross-coupling reactions. Quantum mechanical calculations were applied to study the mechanism (Chapter 1). With multiple possible pathways computed and extensive conformational search, we determined that the lowest energy pathway proceeds via radical formation by Fe(I), radical addition to Fe(II), and reductive elimination from Fe(III) to form the desired cross-coupled product. With the mechanism in hand, we then designed and developed many new types of iron-catalyzed CCRs (Chapter 2-5), that included an intra- and inter-molecular dicarbofunctionalization of vinyl cyclopropanes, a three-component difunctionalization of unactivated alkenes, and a multicomponent radical cascade/annulation reaction. Finally, in Chapter 6, we introduced the [1.1.1]propellane as the σ-type radical acceptor in the three-component difunctionalization of iron-catalyzed cross-coupling reaction. These reactions showcases the potential of iron-catalyzed CCRs and expanded the toolbox for organic synthesis.