Bridge Heteroarylation of Bicyclo[1.1.1]pentanes

Bridge Heteroarylation of Bicyclo[1.1.1]pentanes

Author: ChemistryViews

Bicyclo[1.1.1]pentane (BCP) groups can be useful, e.g., in drug discovery, where they can serve as alternatives to tert-butyl groups, alkynes, or arenes. Some polysubstituted BCP derivatives can, however, be challenging to synthesize. BCPs with heterocyclic substituents bound to the bridgehead, for example, atoms are well-known, while BCP derivatives with heterocyclic substituents at the bridge position are rare.

Darren L. Poole, GSK Medicines Research Centre, Stevenage, UK, and colleagues have developed a method for the heteroarylation at the bridge position of bicyclo[1.1.1]pentane derivatives (general reaction pictured). The team used a direct decarboxylative Minisci-type reaction of free bridge carboxylic acids under hypervalent iodine activation. They reacted different BCP and 2-oxabicyclo[2.1.1]hexane (oBCH) derivatives with a range of heterocyclic compounds, such as quinolines or isoquinolines, using the iodine(III) oxidant phenyliodine bis(trifluoroacetate) (PIFA) with dimethyl carbonate (DMC) as the solvent. The reactions were performed at 25–35 °C using LED irradiation.

The desired—usually difficult to access—products were obtained in low to moderate, but often synthetically useful yields. For example, moderately electron-rich or electron-poor quinolines and isoquinolines were tolerated, while monocyclic heterocycles such as pyridines were not well-suited as substrates. The approach could provide a modular pathway to unsymmetrical 1,2,3-trisubstituted BCP derivatives that are of interest, e.g., in pharmaceutical chemistry.


 

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