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

Hexafluorisopropanol (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 hexafluorisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Automated summary

Hexafluorisopropanol (HFIP) is used as an additive for the generation of 3-(chloromethylene)oxindoles and 2-quinolinones without the need for a metal catalyst, leading to high yields and stereoselectivities. This reaction is scalable and allows for a variety of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with HFIP is utilized for the synthesis of 2-quinolinones.