Synthesis of Bicyclo[2.1.0]pentanes and Vinylcyclopropanes Using Palladium Carbenes: Ligand-Controlled Carbene Reactivity
Isaiah K. Eckart-Frank, Emily S. Arnold, Larry Murphy, Sidney M. Wilkerson‐Hill
Abstract
Once physical organic curiosities, bicyclo[2.1.0]pentanes (colloquially termed housanes) are useful strain-release reagents and are unique structural motifs for medicinal chemistry campaigns because of their high Fsp 3 content. Despite this, methods to synthesize housanes are lacking due to their highly strained nature. Herein, we report an intramolecular cyclopropanation strategy to obtain functionalized housanes using palladium carbenes (20 substrates, up to 89% yield). Key to the success of this reaction was the insight that the reactivity of Pd(0) carbenes is controlled by the supporting ligand. Strongly donating N -heterocyclic carbene ligands promote cyclopropanation reactivity, while some π-accepting phosphoramidite ligands (e.g., rac -MonoPhos) afford C–H insertion products (8 examples, up to 20:1 selectivity). Deuterium-labeling studies revealed a KIE of 2.1 at 80 °C, suggesting a palladium carbene is involved in the C–H insertion step, and the independent synthesis of alkyldiazenes confirms that they are not relevant intermediates in this reaction. The housane products were amenable to late-stage cross-coupling reactions and ring-opening reactions to provide cyclopentanes.