Functionalization of strained rings via nucleophilic catalysis

Nucleophilic addition to strained rings offers a straightforward and effective strategy for synthesizing small aliphatic rings which serve a pivotal role as bioisosteres in medicinal research and drug development. However, incorporating sp³ C–H bonds into strained rings remains challenging due to their lack of electron lone pairs and weak acidity. Additionally, the frequent need for external stoichiometric bases or strong nucleophiles, such as organometallic reagents, presents issues related to practicality, compatibility, limited scope, and waste production. Here, we present a nucleophilic catalysis strategy that unlocks the nucleophilic addition of sp³ C–H bonds to strained rings and eliminates the need for an external stoichiometric base. This approach is also applicable to a wide range of heteroatom-based nucleophiles including carboxylic acids, amides, phosphine oxides, and thiols which typically require an external base for achieving reactivity in previously reported methods. Mechanistic studies suggest that this approach involves a covalent intermediate generated via the nucleophilic addition of the catalyst to the strained ring substrate, which serves as a key step in facilitating the reaction.