Pd-catalyzed C(sp3)–H functionalization of alkylamines has stimulated significant interest as the products of such a transformation display structural features that are highly represented in pharmaceutical agents. While a vast array of directing group auxiliaries have been designed to promote C(sp3)–H functionalization of amine derivatives, an alternative approach has been to exploit the innate coordinating ability of unprotected alkylamines for site-selective cyclopalladation. In this regard, the use of oxidative conditions to access a reactive PdIV intermediate has enabled a diverse range of reductive elimination pathways. However, previous methods have been limited to hindered cyclic alkylamines, and therefore the design of suitably mild oxidants compatible with a diverse range of alkylamines presents a significant challenge. Herein, the discovery of an approach to functionalize secondary alkylamines using 2-halobenzoic acids is reported. These reagents promote a facile carboxylate-assisted oxidative addition to alkylamine-derived palladacycles. In the presence of AgI salts, a decarboxylative C(sp3)−C(sp2) bond reductive elimination leads to γ-aryl secondary alkylamines and renders the carboxylate motif a traceless directing group. Stoichiometric mechanistic studies were effectively translated to a Pd-catalyzed γ-C–H arylation process for secondary alkylamines. Conversely, in the absence of AgI additives, selectivity of the reductive elimination switches to C(sp3)–O bond formation. Recent work focusing on extending this reactivity mode towards a general strategy for remote heteroatom incorporation within alkylamines will be discussed.

Carboxylate-assisted oxidative addition to aminoalkyl-PdII complexes: C(sp3)–H functionalization of alkylamines by distinct PdII/PdIV pathway

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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