Investigations into the Synthesis of Multiply Arylated Alkanes through Iterative Cross-Coupling

Abstract

The palladium-catalyzed Suzuki-Miyaura cross-coupling, in which a carbon-carbon bond is formed between an organohalide or pseudo-halide electrophile and an organoboron nucleophile, has developed into one of the most widely used bond-forming reactions in academic and industrial research alike. The development of automated syntheses in the past decade using this powerful methodology shows significant promise towards accessing a general approach to small-molecule synthesis. One of the largest drawbacks in this Nobel-Prize winning methodology is the sparsity of robust methods for incorporating sp3-hybridized coupling partners. The development of methods which allow sp3-hybridized reagents to participate in cross-couplings is of vital importance to the long-term goal of using Suzuki-Miyaura cross-coupling as a widely applicably technique in small molecule synthesis.

This thesis describes the development of two methodologies which aim to incorporate sp3-hybridized coupling partners in iterative cross-coupling reactions. We report the use of benzyl trifluoromethyl sulfones as unique electrophiles in desulfonative cross-coupling reactions to synthesize diarylmethanes. This manifold was found to be tolerant to a range of structurally and electronically diverse organoboron coupling partners, although heteroaromatic species proved problematic. A sulfone bearing a pendant aryl bromide was found to undergo highly selective iterative cross-coupling reactions in which chemoselectivity is controlled through the oxidative addition step. Additionally, the application of sulfones towards a desulfonative borylation strategy for the synthesis of benzylic boronic esters was examined.

The selective cross-coupling of vicinal 1,2-diboronates was also examined. These substrates were found to undergo highly chemoselective coupling at the terminal position based solely on the intrinsic reactivity difference due to the substitution at carbon, without the use of boron masking agents. Importantly, it proved feasible to functionalize both boron substituents through cross-coupling in an iterative fashion, affording multiply arylated structures with complete regioselectivity and excellent stereocontrol. Preliminary investigations into the origin of this chemoselectivity were performed.

The research described herein will detail our efforts towards the development of these two novel methods in iterative cross-coupling.