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

Melissa LeeAshley AdamsPhilip B CoxMelanie S Sanford
Published in: Synlett : accounts and rapid communications in synthetic organic chemistry (2019)
In this Letter, we adapt a recently reported Pd-catalyzed transannular C(sp 3 )-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.
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