Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.