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

Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles

Joseph Derosa  1 , Miriam L O'Duill  1 , Matthew Holcomb  1 , Mark N Boulous  1 , Ryan L Patman  2 , Fen Wang  2 , Michelle Tran-Dubé  2 , Indrawan McAlpine  2 , Keary M Engle  1
Affiliations

Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles

Joseph Derosa et al. J Org Chem. .

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.

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Figures

Figure 1
Figure 1
Transformations examined to probe trends in microsomal stability.
Figure 2
Figure 2
Representative bioactive compounds bearing cyclopropylaryl ethers.[9]
Scheme 1
Scheme 1
Comparisons of different methods for O-cyclopropylation of phenols.[–13]
See this image and copyright information in PMC

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