The synthesis of highly strained molecules (i.e. > 27 kcal/mol strain energy) is becoming an important component of medicinal chemistry programs, because these compounds increase the fraction of sp³ hybridized carbon atoms (Fsp³) of molecules and have well-defined exit vectors. Consequently, complex hydrocarbons such as cubanes, propellanes, housanes and their aza analogues are becoming more frequently encountered in drug design. New cyclopropanation methods are desperately needed for the synthesis of highly strained ring to help streamline the synthesis of these more structurally complex active pharmaceutical ingredients.

Previously, the Wilkerson-Hill group has disclosed a method to obtain spirocyclic cyclobutanes and alkylidene cyclobutanes using a palladium-catalyzed cross-coupling reaction between aryl bromides and α-crotyl- and α-allyl hydrazones, respectively. During these studies, we observed the formation of [2.1.0]-bicycles (housanes), which presumably were formed from an intramolecular cyclopropanation reaction of palladium carbene intermediates with the pendant allyl group. We showed that the reactivity of these carbene intermediates could be controlled by the choice of the oxidation state of the metal and ligand identity.

Herein we describe mechanistic studies aimed at understanding the nature of the Pd-catalyzed cyclopropanation reactions to obtain [2.1.0]-bicycles. Both reaction kinetic and deuterium labeling studies are used to elucidate the mechanism of the transformation. We have benchmarked the reactivity of palladium carbene intermediates generated in our reaction against other transition metals known to produce cyclopropane products by metal-carbene intermediates. Additionally, we have studied how the oxidation level and choice of ligand impact the product distribution of these reactions. These studies have resulted in the production of 20 unique housanes in 11–93% yield and have provided new insights into the reactivity of palladium carbenes intermediates.

Liam Murphy

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