Access to 3D Alicyclic Amine-Containing Fragments through Transannular C-H Arylation

In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp³)-H arylation of alicyclic amines for applications in fragment-based drug discovery (FBDD). We apply this method to the synthesis of a series of 6-arylated 3-azabicyclo[3.1.0]hexanes that are rule-of-three compliant fragments. Several modifications were made to the Pd-catalyzed C-H arylation method to enhance its utility in fragment synthesis. These include the use of microwave heating to shorten reaction times to under 1 h and the development of new approaches for directing group cleavage. Finally, we demonstrate that this fragment library falls within desirable physicochemical space for FBDD applications.