Cationic Gold Catalyst Research Articles

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination.

Kinetic studies on the intramolecular hydroamination of protected variants of 2,2-diphenylpent-4-en-1-amine were carried out under a variety of conditions with cationic gold catalysts supported by phosphine ligands. The impact of ligand on gold, protecting group on nitrogen, and solvent and additive on reaction rates was determined. The most effective reactions utilized more Lewis basic ureas, and more electron-withdrawing phosphines. A DCM/alcohol cooperative effect was quantified, and a continuum of isotope effects was measured with low KIE's in the absence of deuterated alcoholic solvent, increasing to large solvent KIE's when comparing reactions in pure MeOH to those in pure MeOH-d4. The effects are interpreted both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls.

Synthesis of vinylidenecyclopropanes via gold(I)-catalyzed cyclopropanation of vinyl arenes with γ-stannylated propargyl esters.

The reaction of γ-stannylated propargyl esters in the presence of a cationic gold(I) catalyst affords vinylidenecyclopropane derivatives as a mixture of diastereomers. The cis-geometry of the alkenes is almost entirely retained in the product. DFT calculations suggest the involvement of the gold(I)-stabilized propargyl cation as a resonance form of gold(I)-coordinated allenylidene species.

Gold‐Catalyzed 1,2‐Aryl Shift and Double Alkyne Benzannulation

AbstractThe tandem intramolecular hydroarylation of alkynes accompanied by a 1,2‐aryl shift is described. Harnessing the unique electron‐rich character of 1,4‐dihydropyrrolo[3,2‐b]pyrrole scaffold, we demonstrate that the hydroarylation of alkynes proceeds at the already occupied positions 2 and 5 leading to a 1,2‐aryl shift. Remarkably, the reaction proceeds only in the presence of cationic gold catalyst, and it leads to heretofore unknown π‐expanded, centrosymmetric pyrrolo[3,2‐b]pyrroles. The utility is verified in the preparation of 13 products that bear six conjugated rings. The observed compatibility with various functional groups allows for increased tunability with regard to the photophysical properties as well as providing sites for further functionalization. Computational studies of the reaction mechanism revealed that the formation of the six‐membered rings accompanied with a 1,2‐aryl shift is both kinetically and thermodynamically favourable over plausible formation of products containing 7‐membered rings. Steady‐state UV/Visible spectroscopy reveals that upon photoexcitation, the prepared S‐shaped N‐doped nanographenes undergo mostly radiative relaxation leading to large fluorescence quantum yields. Their optical properties are rationalized through time‐dependent density functional theory calculations. We anticipate that this chemistry will empower the creation of new materials with various functionalities.

Gold-Catalyzed 1,2-Aryl Shift and Double Alkyne Benzannulation.

The tandem intramolecular hydroarylation of alkynes accompanied by a 1,2-aryl shift is described. Harnessing the unique electron-rich character of 1,4-dihydropyrrolo[3,2-b]pyrrole scaffold, we demonstrate that the hydroarylation of alkynes proceeds at the already occupied positions 2 and 5 leading to a 1,2-aryl shift. Remarkably, the reaction proceeds only in the presence of cationic gold catalyst, and it leads to heretofore unknown π-expanded, centrosymmetric pyrrolo[3,2-b]pyrroles. The utility is verified in the preparation of 13 products that bear six conjugated rings. The observed compatibility with various functional groups allows for increased tunability with regard to the photophysical properties as well as providing sites for further functionalization. Computational studies of the reaction mechanism revealed that the formation of the six-membered rings accompanied with a 1,2-aryl shift is both kinetically and thermodynamically favourable over plausible formation of products containing 7-membered rings. Steady-state UV/Visible spectroscopy reveals that upon photoexcitation, the prepared S-shaped N-doped nanographenes undergo mostly radiative relaxation leading to large fluorescence quantum yields. Their optical properties are rationalized through time-dependent density functional theory calculations. We anticipate that this chemistry will empower the creation of new materials with various functionalities.

Asymmetric Construction of α,γ-Disubstituted α,β-Butenolides Directly from Allylic Ynoates Using a Chiral Bifunctional Phosphine Ligand Enables Cooperative Au Catalysis

A highly efficient construction of chiral γ-substituted α-allyl-α,β-butenolides with up to >99% enantiomeric excess from readily available allylic ynoates is realized. In this asymmetric gold catalysis, the cationic gold(I) catalyst featuring a bifunctional phosphine ligand enables a four-step cascade which permits the conversion of a diverse array of allylic ynoates into valuable chiral α,γ-disubstituted α,β-butenolides.

Cooperative photoredox/gold catalysed cyclization of 2-alkynylbenzoates with arenediazonium salts: synthesis of 3,4-disubstituted isocoumarins.

Several isocoumarins have been synthesised in good to excellent yields starting from 2-alkynylbenzoates and arenediazonium salts. The strategy involves a domino arylation/oxo-cyclization catalysed by a dual photoredox/gold catalytic system. The reactions run under mild conditions at room temperature in wet acetonitrile under irradiation with a blue-LED lamp, in the presence of a cationic gold catalyst and a cheap organic photocatalyst. The scope is quite broad and allows the preparation of isocoumarins differently disubstituted in positions 3 and 4. A plausible reaction mechanism is proposed.

Synthesis of 4-amino-5-allenylisoxazoles via gold(I)-catalysed propargyl aza-Claisen rearrangement.

Propargyl aza-Claisen rearrangement of 4-propargylaminoisoxazoles 1 proceeded in the presence of cationic gold(i) catalysts to give 4-amino-5-allenylisoxazoles 2 in good to high yields. The silyl group at the terminal alkyne and a cationic gold(i) catalyst bearing a sterically bulky ligand are essential for the generation of isolable allene intermediates. The N-protection of the generated 4-amino-5-allenylisoxazoles 2 allowed the isolation of 5-allenylisoxazoles 4 that have never been synthesized. N-Propargyl aniline 5 was successfully converted to the corresponding ortho-allenyl aniline 6 under the current reaction conditions.

Synthesis of substituted anilines via a gold-catalyzed three-component reaction.

A three-component reaction for the synthesis of substituted anilines by a gold(i)-catalyzed domino reaction was developed. Cationic gold catalysts selectively and sequentially activated two different alkynes, which were involved in pyrrole synthesis and subsequent Diels-Alder reaction. The sequential formal (3 + 2) annulation/Diels-Alder reaction of three components provided a variety of substituted anilines in a modular fashion. Moreover, utility of the aniline products was demonstrated by derivatization to substituted benzoxazines, which are pharmaceutically important heterocycles.

Intramolecular activation of imidate with cationic gold(I) catalyst: A new benzylation reaction of alcohols

Benzylation of alcohols with benzyl (Z)-2,2,2-trifluoro-N-(2-alkynylphenyl)acetimidates 5a-f in the presence of a cationic gold(I) catalyst was investigated. Reagent 5f was the most effective, affording benzyl ethers in good yields. Our results indicate that these gold(I)-activated imidates are effective leaving groups.

Gold-Catalyzed Oxidations of 1,3-Diynamides with C(1) versus C(3) Regioselectivity: Catalyst-Dependent Oxidative Cyclizations in the C(3) Oxidation.

This work reports two distinct paths in catalytic oxidations of 1,3-diynamides with 8-methylquinoline oxide. A typical C(1) regioselectivity was observed for aryl-substituted 1,3-diyn-1-amides, whereas an unexpected C(3) regioselectivty occurred for 5-hydroxy1,3-diyn-1-amides. We focused on the C(3) oxidations of 5-hydroxy1,3-diyn-1-amides because we observed two oxidative cyclizations of the same substrates to yield 2-aminomethylenefuran-3(2H)-ones and 2-amino-4H-pyran-4-ones using AuCl3 and a cationic gold catalyst, respectively. Density functional theory calculations were performed to rationalize the C(3) regioselectivity on 5-hydroxy1,3-diyn-1-amides.

Gold-catalyzed dual C-C bond cleavage of biphenylenes bearing a pendant alkyne at ambient temperature.

We report a catalytic skeletal rearrangement of biphenylenes with a pendant alkyne moiety at room temperature by a cationic gold catalyst, which involves the cleavage of two bonds: the C-C bond of biphenylene and the C(sp)-C(sp2 or sp3) bond. Experimental and theoretical studies revealed that the reaction mechanism included π-activation of the alkyne, ring expansion and 1,2-carbon shift.

Synthesis of Propargylic Ethers by Gold-Mediated Reaction of Terminal Alkynes with Acetals

A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimization of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent effects were observed. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME), and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that various alkynes and acetals were feasible to provide a wide range of propargylic ethers.

Gold-Catalyzed Rearrangement of Propargyl Alcohols Using Coupling Constants To Determine Isomeric Ratios

Gold is an increasingly prominent transition metal in organic synthesis. The air-stable, water-insensitive cationic gold(I) catalysts enable varieties of synthetic transformations with a simple reaction setup. However, this increased importance has not coincided with an increase in the application of gold in second-year organic chemistry courses. An experiment is described that includes a gold-catalyzed rearrangement of propargyl alcohols targeted at second-year organic chemistry students. The reaction produces a mixture of E and Z isomers of an enone product that students analyze by 1H NMR spectroscopy to determine the major product.

Phosphinine-Based Ligands in Gold-Catalyzed Reactions.

A series of substituted phosphinines, 1-phosphabarrelenes and 5-phosphasemibullvalenes were synthesized and evaluated for their potential application as ligands in homogeneous catalytic reactions. While their buried volume (%Vbur ) was calculated to get insight into the steric properties, [LNi(CO)3 ] complexes were prepared in order to determine the corresponding Tolman electronic parameter. ETS-NOCV (extended-transition-state natural orbital for chemical valence) calculations on [LAuCl] complexes further allowed an estimation of the σ- and π-contributions to the L-M interaction. AuI coordination compounds of selected examples were prepared and characterized by single crystal X-ray diffraction. Finally, the three classes of PIII compounds were successfully used in the AuI -catalyzed cycloisomerization of N-2-propyn-1-ylbenzamide, showing very good activities and selectivities, which are comparable with the reported data of cationic phosphorus-based gold catalysts.

Improving Homogeneous Cationic Gold Catalysis through a Mechanism-Based Approach.

Homogeneous gold catalysis is regarded as a landmark addition to the field of organic synthesis. It is the most effective way to activate alkynes for the addition of a diverse host of nucleophiles. However, the literature reveals that a relatively high catalyst loading is needed in many gold-catalyzed applications (1-10 mol %), which is impractical in large-scale synthesis or multistep synthesis because of the high price and recyclization difficulty of the gold. A more thorough understanding of the factors that operate on homogeneous gold catalysis can provide better guidelines for the future design of more efficient gold-catalyzed reactions. In this Account, we will summarize our group's extensive investigation of factors impacting cationic gold catalysis, namely, the effects of ligands, counterions, additives, and catalyst decay and deactivation, using a mechanism-based approach with the aim of improving the efficiency of homogeneous gold catalysis. Through NMR-assisted kinetic studies, we investigated the above factors. Our systematic ligand effect investigation provided a clearer understanding of how ligands influence each of the three stages in the gold catalytic cycle. On the basis of this study, we synthesized a novel phosphine ligand and achieved parts per million-level gold catalysis by manipulating the electron density of the substituents and the steric strain around phosphorus. Our investigation of counterion effects led to the design of a gold affinity index and hydrogen-bonding basicity index for counterions, which can forecast the reactivity of counterions in cationic gold catalysis. We studied the adverse silver effects in cationic gold catalyst activation and proposed a more efficient practical guide. Our additive effect investigation revealed that additives that are good hydrogen-bond acceptors increase the efficiency of gold-catalyzed reactions in those occurrences where protodeauration is the rate-determining step. The first detailed experimental analysis of gold catalyst decay and the influence of each component in the reaction system (substrate, counterion, solvent) on the decay process was also conducted. We found that high-gold-affinity impurities (halides, bases) in solvents, starting materials, filtration, or drying agents decrease the reactivity of a gold catalyst but that a suitable acid activator can reactivate the gold catalyst and enable the reaction to proceed smoothly at competitively low gold catalyst loadings. The effects of acid additives were also systematically investigated using typical reactions. We are convinced that better mechanistic understandings will offer clearer guidelines for the search for more efficient gold-catalyzed reactions.

Gold-Catalyzed Cyclisation by 1,4-Dioxidation.

Amide-substituted diynes were cyclized in the presence of a cationic gold catalyst and an external nucleophile leading to 1-indenones and 1-iminoindenones. The electron-donating features of the nitrogen atom enable the formation of a reactive ketene iminium ion, which can be trapped by either diphenyl sulfoxide or anthranil as nucleophiles in a subsequent oxidation step, providing substituted inden-1-on-3-carboxamides.

Gold-Catalyzed Cascade Reactions of 4 H-Furo[3,2- b]indoles with Allenamides: Synthesis of Indolin-3-one Derivatives.

Merging the ability of cationic gold(I) catalysts to activate unsaturated π-systems with the electrophiles-driven ring-opening reactions of furans, we describe a new approach to synthesize 2-spiroindolin-3-ones from 4 H-furo[3,2- b]indoles. The reaction occurs through a cascade sequence involving addition of a gold-activated allene to the furan moiety of the starting furoindole followed by a ring-opening/ring-closing event affording 2-spirocyclopentane-1,2-dihydro-3 H-indolin-3-ones in moderate to good yields.

Chiral Bifunctional Phosphine Ligand Enabling Gold-Catalyzed Asymmetric Isomerization of Alkyne to Allene and Asymmetric Synthesis of 2,5-Dihydrofuran.

The asymmetric isomerization of alkyne to allene is the most efficient and the completely atom-economic approach to this class of versatile axial chiral structure. However, the state-of-the-art is limited to tert-butyl alk-3-ynoate substrates that possess requisite acidic propargylic C-H bonds. Reported here is a strategy based on gold catalysis that is enabled by a designed chiral bifunctional biphenyl-2-ylphosphine ligand. It permits isomerization of alkynes with nonacidic α-C-H bonds and hence offers a much-needed general solution. With chiral propargylic alcohols as substrates, 2,5-disubstituted 2,5-dihydrofurans are formed in one step in typically good yields and with good to excellent diastereoselectivities. With achiral substrates, 2,5-dihydrofurans are formed with good to excellent enantiomeric excesses. A novel center-chirality approach is developed to achieve a stereocontrol effect similar to an axial chirality in the designed chiral ligand. The mechanistic studies established that the precatalyst axial epimers are all converted into the catalytically active cationic gold catalyst owing to the fluxional axis of the latter.

Diastereospecific Gold(I)-Catalyzed Cyclization Cascade for the Controlled Preparation of N- and N,O-Heterocycles.

The reaction of oxime-tethered 1,6-enynes with a cationic gold(I) catalyst demonstrates a great potential for the synthesis of a range of heterocycles in a diastereospecific fashion. The control of the configuration of the oxime and the alkene of the enyne moiety is the key to selectively obtain dihydro-1,2-oxazines, isoxazolines or dihydropyrrole-N-oxides as single diastereoisomers. As supported by DFT calculations, these cascade reactions proceed stepwise, by the intramolecular addition of the O or N atom of the oxime onto cyclopropyl gold(I) carbene intermediates. In this study, a rare [3,3]-sigmatropic rearrangement of nitrones is also observed.

Gold-Catalyzed Dimerization of Diarylalkynes: Direct Access to Azulenes.

We have developed a simple gold-catalyzed procedure for the synthesis of substituted and modifiable azulenes. The azulenes are formed either by the dimerization of push-pull diarylalkynes bearing a fluorine atom in ortho or para position or by the dimerization of a symmetric electron-rich diarylalkyne. In the presence of a cationic gold catalyst, the two alkynes can form a highly reactive vinyl cation. Trapping of this high-energy intermediate by an appropriate aryl unit then delivers substituted azulenes in a single step and in a perfect atom economy.