Access to 3D Alicyclic Amine-Containing Fragments through Transannular C–H ArylationThis work was supported by Abbvie as well as by the NIH NIGMS (GM073836). ML thanks the National Science Foundation and Rackham Graduate School for graduate fellowships. The authors declare the following competing financial interest(s): Ashley Adams and Phil Cox are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Received: 26 November 2018
Accepted after revision: 16 January 2019
05 February 2019 (online)
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.
Key wordsdirected C–H functionalization - fragment based drug discovery - amines - palladium - arylation - microwave - directing group
References and Notes
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For papers and reviews on FBDD, see: