Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

Beilstein J Org Chem. 2018 Apr 6:14:786-795. doi: 10.3762/bjoc.14.66. eCollection 2018.

Abstract

A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.

Keywords: Heck reaction; axitinib; ball-milling; dehalogenation; indazoles.