CC BY ND NC 4.0 · Synlett 2019; 30(04): 417-422
DOI: 10.1055/s-0037-1610861
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Copyright with the author

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

Melissa Lee
a  Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, USA   Email: mssanfor@umich.edu
,
Ashley Adams
b  Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA
,
Philip B. Cox
b  Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA
,
a  Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, USA   Email: mssanfor@umich.edu
› Author Affiliations
This 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.
Further Information

Publication History

Received: 26 November 2018

Accepted after revision: 16 January 2019

Publication Date:
05 February 2019 (eFirst)

 

Abstract

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.

Supporting Information

 
  • References and Notes

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