Nucleophilic cobalt photocatalysis: Vitamin B₁₂-photocatalyzed cyclopropanation reactions

Recently, the cyclopropane moiety has become crucial in drug design. This ubiquitous moiety in natural products and other biologically active compounds has been shown to enhance drug properties and is extensively studied for various pharmaceutical and therapeutic applications. Over the years, the need for synthetic methods to make this strained three-carbon ring structure remains, due to challenges such as limited substrate scope and selectivity issues that affect common approaches, including the Simmons-Smith and Corey-Chaykovsky reactions. Additionally, the demand for more effective, efficient, and environmentally friendly approaches to organic synthesis emphasizes the need for alternative methods. Photocatalyzed radical-polar crossover approaches to making cyclopropanes have been developed; however, they rely on expensive and/or reactive methylene sources, such as methyl diazo salts and diiodomethane. This work leverages nucleophilic cobalt photocatalysis, employing dichloromethane as a cheap, readily available methylene source to install the cyclopropyl ring onto alkenes. Biocompatible, environmentally friendly cyanocobalamin (vitamin B₁₂) has shown highly nucleophilic properties in its reduced form (the Coᴵ oxidation state) and can perform Sₙ2-type substitution reactions with carbon electrophiles. The resulting Coᴵᴵᴵ–C bond is relatively weak (BDE ≈ 14-42 kcal/mol) and can be homolyzed under photochemical or thermal conditions to generate useful reactive intermediates. In this work, we present a photo-mediated approach to the synthesis of cyclopropanes, enabling the generation of chloromethyl radicals from dichloromethane using vitamin B₁₂ photocatalysis to install the cyclopropyl group onto a variety of electron-deficient alkenes. We have advanced this approach further by using haloforms as a source of halomethyl radical intermediates under vitamin B₁₂ photocatalysis to prepare monohalogenated cyclopropanes from electron-rich alkenes, which can serve as excellent building blocks for diverse molecular scaffolds. This mild approach to preparing monohalogenated cyclopropanes also provides access to the synthetically less accessible cis-1,2-disubstituted cyclopropane. Finally, we have successfully demonstrated the synthetic utility of our approach with various pharmaceutically relevant transformations. Currently, efforts to synthesize monofluorocyclopropanes using our vitamin B₁₂-photocatalyzed approach are underway. Consequently, this vitamin B₁₂-photocatalytic approach to cyclopropane synthesis could be useful for the preparation of a variety of cyclopropanes, offering a direct and efficient route to these valuable moieties.