Copper-Catalyzed Chan–Lam Cyclopropylation of Phenols and Azaheterocycles

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.