Controlling Selectivity in Cross-Coupling Reactions with Ester Electrophiles

Abstract

First popularized in the 1970s, transition metal-catalyzed cross-couplings now constitute staple reactions for the formation of carbon-carbon and carbon-heteroatom bonds. Recent endeavours in the field have been invested towards expanding the range of compatible coupling partners, with the aim of accessing complex molecules from simple, widely available starting materials. Notably, esters represent an attractive class of alternative coupling partners compared to traditional aryl halides, due to their ubiquity and robustness. Moreover, different cleavage modes can be accessed with esters. Which bond cleavage occurs is highly dependent on which catalyst is used, providing an opportunity to quickly access diverse products from a common precursor. Chapter 1 of this thesis provides a literature overview of cross-couplings with carboxylic acid derivatives to contextualize our contributions described in Chapter 2 and 3. Chapter 2 describes the Pd-catalyzed cross-coupling of phenyl esters with alkyl boranes. Two reaction modes are enabled, namely C(acyl)–O bond activation with carbonyl-retention and C(acyl)–O bond activation with decarbonylation. As such, both alkyl ketones and alkylated arenes are accessed selectively by simple changes in the catalytic system. The disclosed reaction is applied to the diversification of bioactive molecules and discussed in light of recent mechanistic studies of related transformations. In Chapter 3, the first additive-free Ni-catalyzed amidation and transesterification of methyl esters are disclosed. In both transformations, a simple Ni catalyst enables widely available methyl or ethyl esters to be converted into value-added products, producing methanol as the only stoichiometric waste by-product. The Ni-catalyzed amidation protocol strongly contrasts wasteful yet common methods used to convert methyl esters into amides, involving wasteful hydrolysis and coupling with stoichiometric activating agents.