Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles

J Org Chem. 2018 Apr 6;83(7):3417-3425. doi: 10.1021/acs.joc.7b03100. Epub 2018 Mar 13.

Abstract

Small molecules containing cyclopropane-heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan-Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about N-cyclopropylation. The transformation is catalyzed by Cu(OAc)2 and 1,10-phenanthroline and employs 1 atm of O2 as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aza Compounds / chemistry*
  • Catalysis
  • Copper / chemistry*
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Heterocyclic Compounds / chemistry*
  • Molecular Structure
  • Phenols / chemistry*

Substances

  • Aza Compounds
  • Cyclopropanes
  • Heterocyclic Compounds
  • Phenols
  • Copper