Synthesis of Bicyclo1.1.1pentane Bioisosteres of Internal Alkynes and para‐Disubstituted Benzenes from 1.1.1Propellane

Key Points

• To establish a general synthetic route for accessing bis-arylated bicyclo[1.1.1]pentanes from [1.1.1]propellane as bioisosteres of internal alkynes and para-disubstituted benzenes.
• Opened [1.1.1]propellane using diverse arylmagnesium halides.
• Performed transmetalation with zinc chloride followed by Negishi cross-coupling with aryl and heteroaryl halides.
• Synthesized bioisosteres of the drug tazarotene and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine to evaluate their physicochemical properties.
• Successfully produced a broad library of bis-arylated bicyclo[1.1.1]pentane scaffolds via sequential Grignard addition and cross-coupling.
• Prepared target bioisosteric analogs of clinically relevant molecules, validating the synthetic method's utility for optimizing drug-like properties.