Synthesis of Bridge-Substituted Bicyclo[1.1.1]Pentanes by Catalytic Metal Carbene Insertion into Bicyclo[1.1.0]Butanes

Abstract

1,2,3-Trisubstituted bicyclo[1.1.1]pentanes (BCPs) are emerging saturated hydrocarbon bioisosteres for polysubstituted benzenes; however, their synthesis from bicyclo[1.1.0]butanes (BCBs) via direct metal carbene insertion remains unrealized. Herein, we report the first catalytic metal carbene insertion into BCBs using triftosylhydrazones as safe and stable carbene precursors, which circumvents the use of [1.1.1]propellane in the synthesis of the BCPs scaffold. This operationally straightforward method accommodates a wide range of substituted BCB esters and triftosylhydrazones, enabling the synthesis of valuable 1,2,3-trisubstituted BCPs, including those bearing a trifluoromethylated quaternary all-carbon center, in good-to-excellent yields. Selective post-synthetic transformations of the product BCP esters into other useful small-ring building blocks, as well as the preparation of the BCP analogue of a drug molecule fragment, demonstrate the versatility and utility of this chemistry. Mechanistic investigations, including density functional theory calculations, support a direct, stepwise metal carbene addition into the C─C bond of the BCB.