Mechanism-Guided Development of Directed C-H Functionalization of Bicyclo[1.1.1]pentanes

This report describes a detailed study of the palladium-mediated directed C(2)-H functionalization of bicyclo[1.1.1]pentanes (BCPs). Previous attempts to achieve this transformation were reported as unsuccessful. To understand why, a combination of stoichiometric organometallic experiments (to isolate and study the coordination chemistry of these substrates), H/D exchange (to directly probe the C-H activation step), and DFT calculations (to predict optimal directing groups and supporting ligands) was conducted. Collectively, these revealed that cyclometalation at Pd(II) is kinetically facile but thermodynamically unfavorable with aminoquinoline as a directing group and acetonitrile as a supporting ligand. However, changing to a pyridine N-oxide directing group or dimethyl sulfoxide (DMSO) supporting ligand enabled the isolation of stable BCP palladacycles. The functionalization of these complexes was low-yielding with two-electron aryl iodide oxidants. However, moving to single-electron reactions (using in situ-generated aryl radicals) or to electrophilic functionalization (using I₂) resulted in synthetically useful yields of C(2)-functionalized products at room temperature. This C-H functionalization approach was leveraged to access derivatives of a key intermediate in the synthesis of bioisosteric analogues of the angiotensin II receptor blocker telmisartan. A four-step sequence from commercially available BCP carboxylic acids, involving directing group installation, cyclopalladation, C(2) arylation, and directing group cleavage, afforded a comparable or improved overall yield, step-count, and functional group compatibility relative to state-of-the-art synthetic approaches. Overall, these studies uncovered a mild Pd-mediated route for the C(2)-diversification of the BCP scaffold. In addition, the lessons learned herein provide a blueprint for achieving directed C-H functionalization of a broader array of strained ring benzene bioisosteres.