TRANSITION METAL CATALYZED CROSS-COUPLINGS OF ALKYL SULFONE ELECTROPHILES
Cross-coupling , Sulfone , Nickel
Sulfones are an important class of organic molecules that can participate in a wide variety of synthetic transformations. For this reason, they have been described as chemical chameleons. While their use as Csp2 electrophiles in cross-coupling dates to the early 1970’s, their potential as competent Csp3 electrophiles has not been recognized until recently. Our group has made significant contributions to the development of new cross-coupling methodologies utilizing alkyl sulfones as electrophiles. This thesis describes the use of alkyl sulfones as electrophiles in both nickel and palladium catalyzed cross-coupling reactions. First, we developed a nickel-catalyzed Suzuki–Miyaura cross-coupling of π-extended tertiary benzylic and allylic sulfones with arylboroxines. A variety of tertiary sulfones were reacted to afford quaternary products in good yields and we identified a unique phosphine ligand capable of promoting the challenging cross-coupling reaction. The method enabled the concise synthesis of a biologically active molecule. We then adapted and extended the nickel-catalyzed system to the cross-coupling of simple tertiary benzylic sulfones using olefins as removable directing groups. Several dialkydiarylmethanes were prepared in good yields and we revealed that the mechanism likely involves an η2-nickel coordination complex with the olefin, which facilitates oxidative addition. Following cross-coupling, the olefin could be cleaved to introduce new functionalities. Next, we developed a nickel-catalyzed Kumada cross-coupling of cyclic alkyl sulfones with aryl Grignard nucleophiles. Uniquely, the sulfinate leaving group was retained following ring-opening cross-coupling and it served as a handle for further functionalization. Overall, the methodology provided access to doubly functionalized products in a one-pot procedure. Finally, we developed a palladium-catalyzed Suzuki-Miyaura cross-coupling of α-fluorinated benzylic triflones with arylboronic acids. The method afforded a variety of mono- and difluorinated diarylmethanes and we demonstrated that both mono- and difluorinated benzylic triflones could be desulfonylated to afford the corresponding α-fluoromethylarenes. Because α-fluoromethylarenes are important substructures in pharmaceuticals and agrochemicals, we utilized our methodology to prepare several fluorinated analogues and derivatives of biologically active compounds.