[1.1.1]Propellane is a “propeller”-shaped hydrocarbon in which three three-membered rings share one central C–C bond. Bicyclo[1.1.1]pentane has a similar structure, but without the central bond, so it consists of three four-membered rings. Bicyclo[1.1.1]pentanes can be used, e.g., to replace other groups such as aromatic rings or tert-butyl groups in medicinal chemistry and tune the properties of a drug candidate. Functionalized bicyclo[1.1.1]pentanes can be synthesized from [1.1.1]propellane, e.g., by radical additions.
Fei Pan, Sichuan Normal University, Chengdu, China, and colleagues have developed a three-component reaction that gives alkyl-alkynyl-substituted bicyclo[1.1.1]pentane derivatives. The reaction involves a radical cross-coupling of carboxylic acids, alkynes, and [1.1.1]propellane, using both photoredox and copper catalysis (example product pictured). The carboxylic acids were converted to hypervalent iodine(III) carboxylates and served as alkyl radical precursors. The team used Ir(ppy)3 as a photocatalyst, Cu(acac)2 as a copper catalyst, 4,4-dimethoxy-2,2-bipyridine as a ligand, tetramethylguanidine (TMG) as a base, and MeCN as the solvent. The reactions were performed at room temperature under blue LED light.
The desired alkyl-alkynyl-substituted bicyclo[1.1.1]pentane derivatives were obtained in moderate to good yields. The carboxylic acids and alkynes used as starting materials are readily available. The reaction shows good functional group tolerance and proceeds under mild conditions.
The researchers propose a reaction mechanism that involves the formation of an alkyl radical intermediate under photocatalysis, which is added to the propellane. The resulting bicyclo[1.1.1]pentane-based radical is then trapped by an acetylide-ligated copper complex, and the product is formed by reductive elimination.
- Radical Multicomponent Alkyl Alkynylation of Propellane via Synergistic Photoredox and Copper Catalysis,
Jie Shi, Qiao-Lin Xu, Yu-Qing Ni, Lin Li, Fei Pan,
Org. Lett. 2022.