Establishing base-catalyzed halogen transfer as a general platform for C–H functionalization

Abstract

In contrast to traditional multi-step routes, C–H functionalization offers a resource and time efficient route to desired products. Current methods for oxidative C–H functionalization are developed on three predominate reactivity platforms (1) hydrogen atom transfer, (2) single- electron transfer, and (3) C–H insertion. Despite their synthetic power, methods built on these platforms are restricted to similar bond conversions, substrates, and selectivities. Thus, there remains a strong demand for new mechanistic approaches to oxidative C–H functionalization that offer a departure from traditional reactivity. In efforts to address this need, new methods for oxidative coupling based on a base-catalyzed halogen transfer (X-transfer) reactivity platform are described herein. Chapter one provides an overview on the development of a X-transfer enabled direct C–H hydroxylation of mildly acidic N-heteroarenes and benzenes. Hydroxylated (hetero)arenes are valued in many industries as both key constituents of end products and diversifiable synthetic building blocks. Accordingly, the development of reactions that complement and address the limitations of existing methods for the introduction of aromatic hydroxyl groups is an important goal. To this end, this chapter discusses the development of a protocol that employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming SNAr-active intermediates that undergo nucleophilic hydroxylation. Key to this process is the use of 2-phenylethanol as an inexpensive hydroxide surrogate that, after aromatic substitution and ii rapid elimination, provides the hydroxylated arene and styrene byproduct. Use of simple 2-halothiophenes allows for C–H hydroxylation of 6-membered N-heteroarenes and 1,3-azole derivatives, while a rationally designed 2-halobenzothiophene oxidant extends the scope to electron-deficient benzene substrates. Mechanistic studies indicate that aromatic X-transfer is reversible, suggesting that the deprotonation, halogenation, and substitution steps operate in synergy, manifesting in unique selectivity trends that are not necessarily dependent on the most acidic aryl position. The utility of this method is further demonstrated through streamlined target molecule syntheses, examples of regioselectivity that contrast alternative C–H hydroxylation methods, and the scalable recycling of the thiophene oxidants. Chapter two describes the elaboration the X-transfer enabled C–H functionalization platform to encompass benzylic C(sp3)–H bonds. Thus, a benzylic C–H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence is discussed. In contrast to existing radical-based pathways for C–H functionalization, this process is guided by C–H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision regioselectivity for polyalkylarenes and use of a double C–H etherification process to controllably oxidize methylarenes to benzaldehydes.