NHC-Cu(I)-Catalyzed Friedländer-Type Annulation of Fluorinated o-Aminophenones with Alkynes on Water: Competitive Base-Catalyzed Dibenzo[b,f][1,5]diazocine Formation

An efficient, easily scalable synthesis of 4-trifluoromethylquinolines and naphthydrines (as well as their difluoro- and perfluoro-analogues) as a result of tandem direct catalytic alkynylation/dehydrative condensation of o-aminofluoromethylketones (o-FMKs), for the first time catalyzed by NHC-copper(I) complexes on water, is reported. A wide range of terminal alkynes is tolerated under the reaction conditions, including β-lactam-, steroid-, and sugar-derived ones, leading to desired quinolines and naphthydrines with good yields. Further investigations proved that o-FMKs could be efficiently transformed into a rare class of heterocyclic compounds-dibenzo[b,f][1,5]diazocines-by a base-catalyzed condensation, also on water. The developed method was applied for gram-scale synthesis of a fluorinated analogue of G protein-coupled receptor antagonist (GPR91).