Synthesis of Strained Rings Using Palladium-Catalyzed Cyclopropanation and C–H Insertion Reactions

Bicyclo[2.1.0]pentanes, colloquially known as housanes, are potentially useful motifs in medicinal chemistry due to their high Fsp3 content and well-defined exit vectors. However, due to their highly strained nature (57 kcal/mol), there are few effective synthetic methods to make housanes. In this work, we report an intramolecular cyclopropanation reaction to make housanes from a palladium carbene intermediate, using hydrazones as bench-stable nonstabilized carbene precursors (up to 89% yield). While a Pd–NHC complex is effective for the intramolecular cyclopropanation, using a phosphoramidite ligand with palladium enables a switch in reactivity to produce vinylcyclopropanes through a C–H insertion reaction (up to >20:1 selectivity vinylcyclopropane:housane). Deuterium-labeling studies were performed and a kinetic isotope effect (KIE) of 2.1 at 80 °C suggests that a palladium carbene is an operative intermediate in the C–H insertion reaction. Alkyldiazenes were independently synthesized to confirm that diazenes do not undergo ring contraction to cyclopropanes under the reaction conditions and therefore are not intermediates in the reaction. Functionalization of the housane products was possible to produce arylated housanes through cross-coupling reactions and cyclopentanes through ring-opening reactions.