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

Abstract

Despite the unique position of gold catalysis in contemporary organic synthesis, this area of research is notorious for requiring activators and/or additives that enable catalysis by generating cationic forms of gold catalysts. Cycloisomerization reactions occupy a significant portion of the gold-catalyzed reaction space, while they represent a diverse family of reactions that are frequently utilized in synthesis. Herein, hexafluoroisopropanol (HFIP) is shown to be a uniquely simple tool for gold-catalyzed cycloisomerizations, rendering the use of external activators obsolete and leading to highly active catalytic systems with ppm levels of catalyst loading in certain cases. HFIP assumes a dual role as a solvent and an activator, operating via the dynamic activation of the Au−Cl bond through hydrogen bonding, which initiates the catalytic cycle. This special mode of catalysis can enable efficient and scalable cyclization reactions of propargylamides and ynoic acids with simple [AuCl(L)] complexes. A thorough screening of ancillary ligands and counter anions has been performed, establishing this methodology as an alternative to elaborate ligand/catalyst design and to the use of activators. Additionally, this concept is applied in C−C bond-forming cycloisomerization reactions leading to 2H-chromenes and to the design of catalytic systems for sequential or one-pot transformations leading to activated ketoesters, a functionalized N-heterocyclic carbene (NHC) precursor salt, and a compound bearing the bioactive indole core, among others. Importantly, through mechanistic investigations, including a "snapshot" of the species of interest in the solid state, we were able to unambiguously detect the key H-bonding interaction between HFIP and the gold catalyst, shedding light on the intermolecular mode of activation that enables catalysis. In the cases examined herein, HFIP is not only an excellent solvent but also a potent activator and a valuable synthetic handle when incorporated into functional groups of products.

Synthesis of N-heterocyclic carbene (NHC)-Au/Ag/Cu benzotriazolyl complexes and their catalytic activity in propargylamide cycloisomerization and carbonyl hydrosilylation reactions

“…34 The molecular structures of complexes 4a, 5a, and 6a-b were unambiguously established by X-ray diffraction analysis of With the new family of 1H-benzotriazole-derived CMAs in hand, we explored their application in two useful organic transformations: the intramolecular cyclization of propargyl amide, leading selectively to the corresponding 5-exo-dig pro-ducts, and the hydrosilylation of a range of carbonyl compounds (both aldehydes and ketones). Considering the numerous studies based on the catalytic activity of Au-based 35 CMAs, 36,37 we focused mostly on the study of the catalytic activity of Ag-and Cu-based complexes 5a-b and 6a-b. [38][39][40] As the initial benchmark reaction, we studied the cyclization of the electron rich N-(2-methylbut-3-yn-2-yl)benzamide 7a to alkylidene oxazoline 8a (5-exo-dig product), monitoring the reaction via 1 H NMR spectroscopy, using an internal standard (1,3,5 trimethoxybenzene) as reference.…”

“…HFIP has been shown to exert unique properties as solvent, due to the strong electron-withdrawing character of its fluoroalkyl groups. 35 Its mildly acidic character in combination with its strong hydrogen-bond donating ability make it ideal for several transformations. 41 For example, we have recently explored the dual role of HFIP as a solvent and an activator, achieving the activation of Au–Cl bonds through hydrogen bonding alone, in gold-catalysed cycloisomerizations.…”

Chiral Auxiliary Approach for Gold(I)‐Catalyzed Cyclizations

“…Product 5 p could finally also be isolated in 70 % yield using JohnphosAuCl as a catalyst, [24] confirming that HFIP can additionally activate gold(I)-chloride precursors, as recently reported by Nolan and Vougioukalakis. [32] Different tethers were then tested, and while the malonate substrate 9 afforded 10 only in moderate yield and 92 : 8 dr using 10 mol % of gold(I) catalyst at 23 °C (very slow conversion was observed at À 20 °C), the N-tosyl tethered enynamide 11 afforded 12 under the optimized conditions in good NMR yield and 98 : 2 dr.…”

An In‐Situ‐Formed Copper‐Based Perfluorinated Catalytic System for the Aerobic Oxidation of Alcohols

“…In the framework of our interest in sustainable catalysis, [20][21][22][23][24][25] and considering the lack of a thorough study on the catalytic activity of a simple, in situ prepared NHC/Cu-based biphasic catalytic system in alcohols oxidation, we herein report the development of such a straightforward, user-friendly protocol for the oxidation of primary and secondary alcohols. Our catalytic protocol is based on an in situ generated catalytic system consisting of copper (I) oxide, easily accessible NHCs bearing perfluorinated ponytails, as ligands, TEMPO as additive, and oxygen as the oxidant of the reaction.…”