Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes† †Electronic supplementary information (ESI) available. CCDC 1825056–1825060. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8sc01355a

• Published in: Chemical science (Cambridge) Vol. 9; no. 23; pp. 5295 - 5300
• Main Authors: Caputo, Dimitri F. J., Arroniz, Carlos, Dürr, Alexander B., Mousseau, James J., Stepan, Antonia F., Mansfield, Steven J., Anderson, Edward A.
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 21.05.2018
• Subjects: Chemistry
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c8sc01355a

A wide range of halogenated bicyclo[1.1.1]pentanes are accessed by functional group tolerant radical ring-opening of tricyclo[1.1.1.0 1,3 ]pentane, using triethylborane as initiator. Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert -butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.0 1,3 ]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/ tert -butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.