On the discovery and applications of a palladium-catalysed organoboron homologation

Abstract

Organoboron compounds have become a cornerstone of contemporary synthetic chemistry. Classical methods towards their preparation typically require the use of stoichiometric quantities of organometallic reagents; namely, by metalation-borylation or Matteson homologations. The latter transformation exploits a facile 1,2-metalate rearrangement of a boronate complex, where a leaving group is appended to the alpha-boryl carbon atom. As a conceptually distinct approach to the Matteson homologation, this thesis will discuss how a carbanion surrogate can be applied under palladium catalysis to homologate arylboronic acids. Rather than relying upon a 1,2-metalate rearrangement used in classical boron homologation, this reaction involves a rare oxidative addition of an alpha-halogenated boronic ester to palladium.

Following a review of the literature surrounding boron homologation and related reactions of alpha-halogenated boronic esters, the first results section shall describe the development of the palladium-catalysed homologation of boronic acids. This reaction is remarkably chemoselective at the transmetalation step, with one organoboron reagent being selected out of a possible four, including a byproduct formed due to boron speciation. The generality of the process is discussed, including the disclosure of current limitations in the methodology.

The second results section will consider the mechanism of the developed palladium-catalysed homologation in relation to the Suzuki–Miyaura cross-coupling. In an analogous manner to Matteson’s original empirical observations made during nucleophilic substitution reactions, alpha-halogenated organoboron reagents exhibit a remarkable level of electrophilicity: the oxidative addition of an α-boryl C(sp³)–Br bond is more facile than the C(sp²)–Br bond of bromobenzene. This ‘alpha-boryl electrophile effect’ is explored further in a series of empirical control studies.

The third results section will demonstrate the synthetic potential of the developed homologation process by using the benzyl boronic esters as a general synthetic platform for the formation of benzylic C–X bonds, including several active pharmaceutical ingredients, with limitations of each operation disclosed