Experimental and theoretical investigation of the cycloisomerization of N-propargylcarboxamide catalyzed by NHC-Au-X in green solvents

Segato, Jacopo; Baratta, Walter; Belanzoni, Paola; Belpassi, Leonardo; Zotto, Alessandro Del; Zuccaccia, Daniele

doi:10.1016/j.ica.2021.120372

Cited by 6 publications

(7 citation statements)

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“…Comparing the catalytic activity of 7 to that of 1 and in turn to those of the already activated complexes 8 and 9 , which bear weakly coordinating anions, provides information relating to counterion effects in HFIP-assisted systems. In the case of N -propargyl benzamide cyclization, ,, counterion effects were determined to be minimal, more so than in systems examined in other protic solvents; therefore, it was deemed necessary to also conduct these experiments in other gold-catalyzed reactions in HFIP.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…Of note, catalysts 21–23 were as active as 9 , however they led to by-products after 1 hour and the reactions should be closely monitored for preparative purposes when using these. 18 Finally, additives to assist in proton-transfer and weakly-coordinating anions had little to no effect, suggesting that either the H-bond network neutralizes their function, or the mechanism is different than in other solvents. Of note, this effect was not observed to be as prominent in other protic solvents.…”

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confidence: 99%

“…2c,17 Detailed solvent screening has also been performed for this reaction, although the vast majority of systems use dichloromethane (DCM) or chloroform. 18 A proof-of-concept was rapidly obtained using [AuCl(IPr)] (IPr = N,N 0 -bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (4) as the catalyst, (Table 1, entry 1). Entries 2-5 in Table 1 demonstrate that increased steric bulk on the NHC ligand proves disadvantageous.…”

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confidence: 99%

“…Of note, this effect was not observed to be as prominent in other protic solvents. 18 Considering the acidity and unusual properties of HFIP, we reasoned that Brønsted-basic Au complexes might also be catalytically competent under these conditions. The Carbene-Metal-Amide (CMA) complex [Au(Cbz)(IPr)] (26, Cbz = carbazolyl) led to a 69% yield after 3 hours (Table 2, entry 1), a result which is strikingly similar to the one obtained when complex 4 was used.…”

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confidence: 99%

“…2 c ,17 Detailed solvent screening has also been performed for this reaction, although the vast majority of systems use dichloromethane (DCM) or chloroform. 18…”

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confidence: 99%

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