Hexafluoroisopropanol (HFIP) as a Multifunctional Agent in Gold-Catalyzed Cycloisomerizations and Sequential Transformations

Despitethe unique position of gold catalysis in contemporaryorganicsynthesis, this area of research is notorious for requiring activatorsand/or additives that enable catalysis by generating cationic formsof gold catalysts. Cycloisomerization reactions occupy a significantportion of the gold-catalyzed reaction space, while they representa diverse family of reactions that are frequently utilized in synthesis.Herein, hexafluoroisopropanol (HFIP) is shown to be a uniquely simpletool for gold-catalyzed cycloisomerizations, rendering the use ofexternal activators obsolete and leading to highly active catalyticsystems with ppm levels of catalyst loading in certain cases. HFIPassumes a dual role as a solvent and an activator, operating via the dynamic activation of the Au-Cl bond throughhydrogen bonding, which initiates the catalytic cycle. This specialmode of catalysis can enable efficient and scalable cyclization reactionsof propargylamides and ynoic acids with simple [AuCl(L)] complexes.A thorough screening of ancillary ligands and counter anions has beenperformed, establishing this methodology as an alternative to elaborateligand/catalyst design and to the use of activators. Additionally,this concept is applied in C-C bond-forming cycloisomerizationreactions leading to 2H-chromenes and to the designof catalytic systems for sequential or one-pot transformations leadingto activated ketoesters, a functionalized N-heterocycliccarbene (NHC) precursor salt, and a compound bearing the bioactiveindole core, among others. Importantly, through mechanistic investigations,including a "snapshot" of the species of interest inthe solid state, we were able to unambiguously detect the key H-bondinginteraction between HFIP and the gold catalyst, shedding light onthe intermolecular mode of activation that enables catalysis. In thecases examined herein, HFIP is not only an excellent solvent but alsoa potent activator and a valuable synthetic handle when incorporatedinto functional groups of products.