Gold Carbenoid Research Articles

Formation and Intramolecular Capture of α-Imino Gold Carbenoids in the Au(I)-Catalyzed [3 + 2] Reaction of Anthranils, 1,2,4-Oxadiazoles, and 4,5-Dihydro-1,2,4-Oxadiazoles with Ynamides

α-Imino gold carbenoid species have been recognized as key intermediates in a plethora of processes involving gold-activated alkynes. Here, we explored the pathways of the Au(I)-catalyzed [3 + 2] reaction between the mild nucleophiles: anthranil, 1,2,4-oxadiazole, or 4,5-dihydro-1,2,4-oxadiazole, and an ynamide, PhC≡C-N(Ts)Me, proceeding via the formation of the aforementioned α-imino gold carbene intermediate which, after intramolecular capture, regioselectively produces 2-amino-3-phenyl-7-acyl indoles, N-acyl-5-aminoimidazoles, or N-alkyl-4-aminoimidazoles, respectively. In all cases, the regioselectivity of the substituents at 2, 3 in the 7-acyl-indole ring and 4, 5 in the substituted imidazole ring is decided at the first transition state, involving the attack of nitrogen on the C1 or C2 carbon of the activated ynamide. A subsequent and steep energy drop furnishes the key α-imino gold carbene. These features are more pronounced for anthranil and 4,5-dihydro-1,2,4-oxadiazole reactions. Strikingly, in the 4,5-dihydro-1,2,4-oxadiazole reaction the significant drop of energy is due to the formation of an unstable α-imino gold carbene, which after a spontaneous benzaldehyde elimination is converted to a stabilized one. Compared to anthranil, the reaction pathways for 1,2,4-oxadiazoles or 4,5-dihydro-1,2,4-oxadiazoles are found to be significantly more complex than anticipated in the original research. For instance, compared to the formation of a five-member ring from the α-imino gold carbene, one competitive route involves the formation of intermediates consisting of a four-member ring condensed with a three-member ring, which after a metathesis and ring expansion led to the imidazole ring.

Gold catalyzed efficient preparation of dihydrobenzofuran from 1,3-enyne and phenol.

A gold catalyzed formal intermolecular [2+3] cyclo-coupling of 1,3-enynes with phenols was developed to prepare dihydrobenzofuran derivatives with the addition of 2,6-dichloropyridine N-oxide, in which, a highly ortho-selective phenol SEAr functionalization was achieved by using 1,3-enynes as α-oxo vinyl gold carbenoid surrogates.

Mechanism and Origins of Product Selectivity of Au‐Catalyzed Coupling Benzisoxazoles with Ynamides: A Computational Study

AbstractAu(I)‐catalyzed coupling of benzisoxazoles and ynamides was recently reported to synthesize challenging indoloquinoline core structures. In this report, we employed DFT methods to elucidate the mechanistic details of this reaction. The results reveal that the catalytic cycle involves initial coupling of ynamide with benzisoxazole, simultaneous ring opening of the isoxazole unit and attack of the dimethoxybenzene (DMOB) unit to gold carbenoid, proton transfer from the DMOB group to hydroxyl group, thioether migration, ring closure, and proton transfer. The experimentally observed ligand‐controlled product selectivity is reproduced well by the calculations. The product selectivity‐determining step is the ring opening of the isoxazole unit. The flexible P(t‐Bu)2(o‐biphenyl) ligand facilitates the approach of the DMOB group to gold carbenoid, which brings about significant C−H/π interactions in the transition state for ring opening, and thus leads to the indoloquinoline product. The rigid 1,3‐bis(diisopropylphenyl)imidazol‐2‐ylidene ligand prefers keeping the DMOB group away from the gold carbenoid, which can cause strong orbital interaction in the transition state for ring opening, and thus results in indole product.

Synthesis of Pyrrolo[1,2-b]isoquinolines via Gold(I)-Catalyzed Cyclization/Enyne Cycloisomerization/1,2-Migration Cascade.

A gold(I)-catalyzed cascade transformation of N-alkynic 2-ynamides for the rapid and efficient synthesis of the indolizidine scaffold is developed. Through a sequential nucleophilic cyclization/enyne cycloisomerization/1,2-migration process, diverse pyrrolo[1,2-b]isoquinolines are obtained under mild conditions in a regiospecific and convergent manner. Various alkyl and aryl migrating groups are tolerated in this process. The electronic effect of the migrating group is comprehensively investigated. The study of the mechanism indicates that the pathway involving a gold carbenoid species is the main pathway and that the 1,2-migration of alkyl and aryl groups to the gold carbenoid occurs in an intramolecular fashion. This cascade reaction is also employed as the key step for the synthesis of a decumbenine B analogue.

Gold Catalyzed Cyclopropanation/[5+3] Cycloaddition of 1,4,9‐ and 1,4,10‐Allenenynes to Bicyclo[3.3.1]nonane Derivatives

AbstractA synthetic method to prepare cycloalkyl‐ and (hetero)aryl‐fused bicyclo[3.3.1]nonane derivatives from gold(I)‐catalyzed cyclopropanation/[5+3] cycloaddition of 1,4,9‐ and 1,4,10‐allenenynes is described. The suggested double cycloisomerization mechanism delineates the first example of a stepwise [5+3] cycloaddition pathway in gold catalysis, a mode of reactivity that is also sparse in organic chemistry. Experimental and Density Functional Theory (DFT) computational studies based on a proposed gold carbenoid species provides insight into this unique selectivity that leads to the assembly of the architecturally challenging bridged carbocyclic motif.magnified image

Transition states of the gold-catalyzed transannular [4+3] cycloaddition reactions: A computational study

The transition state structures for the gold-catalyzed transannular [4 + 3] cycloaddition reaction are located for two distinct mechanisms at the B3LYP/6-31G(d) level of theory. A direct [4 + 3] cycloaddition pathway is found to be favored over the step-wise cyclopropanation-Cope rearrangement pathway. In the former, partial bonding are apparent between the furan ring and the gold-stabilized allylic carbocation. The gold atom bearing the N-heterocyclic carbene ligand is bonded to the allylic system located near the center carbon. The acetate group, which is attached to C1 of the allylic carbocation, is anti to the gold atom. The C–Au distance in this transition state is 2.06 Å. The forming bonds between the furan ring and the allylic carbocation are 1.66 and 2.0 Å, respectively, indicating an asynchronous process. The calculated second pathway starts with a gold carbenoid intermediate, which must overcome two higher energy transition states in order to reach the same reaction product.

Gold(I)-Catalyzed Intramolecular C(sp3 )-H Insertion by Decarbenation of Cycloheptatrienes.

A novel synthesis of indanes and dihydronaphtalenes based on the intramolecular insertion into C(sp3 )-H bonds of gold(I) carbenes generated by retro-Buchner reaction (decarbenation) has been developed. Deuterium-labeling and kinetic isotope effect experiments, DFT calculations, and generation of the proposed carbene intermediate from a well-characterized gold(I) carbenoid support the involvement of a three-center concerted mechanism for the C(sp3 )-H functionalization process.

Gold‐Catalyzed Synthesis of 2,5‐Disubstituted Oxazoles from Carboxamides and Propynals

Abstract2,5‐Disubstituted oxazoles are synthesized by oxidative gold catalysis. In contrast to a reported procedure that delivers 2,4‐disubstituted oxazoles starting from terminal alkynes, a switch in selectivity towards a 2,5‐disubstitution is achieved by the use of propynals as starting materials. In the new reaction, the key intermediate is formed by the nucleophilic attack of the carboxamide onto a gold carbenoid, and then condensates with the more electrophilic aldehyde moiety already present in the substrate and not with the ketone that is derived from the oxygen donor. This new cyclization mode introduces a new carbonyl moiety as substituent at the 2,5‐disubstituted oxazole, an attractive motive that can be found in bioactive compounds or be used for further derivatizations.magnified image

Gold-Catalyzed 1,2-Acyloxy Migration/Coupling Cascade of Propargyl Diazoacetates: Synthesis of Isomycin Derivatives.

An efficient gold(I)-catalyzed carbocyclization reaction for the synthesis of isomycin derivatives from propargyl diazoacetates has been developed. The suggested cyclization pathway delineated the first example of a vinyl gold carbenoid species generated in situ from gold(I)-catalyzed 1,2-acyloxy migration and intercepted by a cross-coupling reaction with the remaining tethered diazo functionality. The use of protic additives was essential to regulating the reaction outcome by fine-tuning the catalytic preference of the gold(I) complex.

Gold-Catalysed Oxidative Cycloisomerisation of 1,6-Diyne Acetates to 1-Naphthyl Ketones

A synthetic method to prepare 1-naphthyl ketones from gold(i)-catalysed oxidative cycloisomerisation of 1,6-diyne acetates is described. The proposed mechanism involves cyclopropenation–cycloreversion of the 1,6-diyne motif initiated by a 1,2-acyloxy migration. This is followed by nucleophilic attack of the ensuing gold carbenoid species by a molecule of water and autoxidation to give the aromatic product.

Recent advances in catalytic asymmetric intermolecular oxidation of alkynes.

In recent years, gold-catalyzed intermolecular alkyne oxidation by an N-oxide oxidant, which presumably involves a gold carbenoid intermediate, has attracted increasing attention because it circumvents the employment of hazardous and potentially explosive diazocarbonyl compounds as starting materials for carbene generation. More importantly, the development of a catalytic enantioselective version of the reaction can help achieve an array of asymmetric synthesis processes modified from various racemic transformations of the gold carbenoid intermediate. In this review, we will present an overview of these recent advances in the asymmetric transformations by utilizing chiral ligands, chiral N,N'-dioxides and chiral substrates, aiming to facilitate progress in this fascinating field of research.

Gold‐Catalyzed Formal C−C Bond Insertion Reaction of 2‐Aryl‐2‐diazoesters with 1,3‐Diketones

The transition-metal-catalyzed formal C-C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3-diketones instead gives C-H bond insertion products. Herein, we report a protocol for a gold-catalyzed formal C-C bond insertion reaction of 2-aryl-2-diazoesters with 1,3-diketones, which provides efficient access to polycarbonyl compounds with an all-carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C-C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring-opening of the resulting donor-acceptor-type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis-acid-catalyzed C-C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step.

Recent Advances in Transition-Metal-Catalyzed/Mediated Transformations of Vinylidenecyclopropanes.

Vinylidenecyclopropanes (VDCPs), having an allene moiety connected to a highly strained cyclopropyl group, have attracted a substantial amount of attention since they are fascinating building blocks for organic synthesis. During recent years, the reactions of VDCPs in the presence of a Lewis acid or a Brønsted acid and those induced by heat or light have experienced significant advancements due to the unique structural and electronic properties of VDCPs. Transition-metal-catalyzed reactions of VDCPs were not intensely investigated until the last 5 years. Recently, significant progress has been made in transition-metal-catalyzed transformations of VDCPs, and they have emerged as a new direction for the chemistry of strained small rings, especially when new types of functionalized vinylidenecyclopropanes (FVDCPs) are used as substrates. To date, many interesting transformations have been explored using these novel VDCPs under the catalysis of transition metals, such as gold, palladium, or rhodium, and various novel and useful heterocyclic or polycyclic compounds have been generated. These new findings have enriched the chemistry of strained small carbocycles. This Account will describe the transition-metal-catalyzed transformations of VDCPs recently developed in our laboratory and by other groups. The chemistry of Au-catalyzed VDCPs has been enriched and extensively developed by our group. In this respect, a new process for generating gold carbenes from VDCPs has been disclosed. The reactivity of these new gold carbenoid species was fully investigated, and many novel reaction modes based on these new gold carbenoid species were explored, including oxidation reactions, intramolecular cyclopropanations, C(sp3)-H bond functionalizations, and C-O bond cleavage reactions. Rh-catalyzed reactions of VDCPs are another key field of transition-metal-catalyzed reactions of VDCPs. In particular, rhodium-catalyzed cycloadditions, Pauson-Khand reactions, and C-H bond activations of FVDCPs have been explored in detail by our group. A new trimethylenemethane rhodium (TMM-Rh) complex generated from VDCPs was discovered and utilized as an electrophilic Rh-π-allyl precursor. Moreover, some unprecedented highly regio- and enantioselective asymmetric allylic substitutions via this novel TMM-Rh complex were developed with different kinds of nucleophiles. This Account will also summarize the recent advances in palladium-, copper-, and iron-catalyzed cycloisomerization reactions of VDCPs reported by our group and others. These reactions always afford the desired products with excellent chemo-, regio-, diastereo-, and enantioselectivities, which will make them highly valuable for the synthesis of key scaffolds in natural products and pharmaceutical molecules in the future.

Mechanistic study on gold(I)‐catalyzed crosscoupling of diazo compounds: A DFT study

AbstractThe reaction mechanisms of the gold(I)‐catalyzed cross‐coupling reaction of aryldiazoacetate R1 with vinyldiazoacetate R2 leading to N‐substituted pyrazoles have been theoretically investigated using density functional theory calculations. Two possible reaction mechanisms were examined and discussed. The preferred reaction mechanism (mechanism A) can be characterized by five steps: the formation of the gold carbenoid A2 via the attack of catalyst to R1 (step I), nucleophilic addition of another reactant R2 to generate intermediate A3 (step II), intramolecular cyclization of A3 to form intermediate A4 (step III), hydrogen migration to give intermediate A5 (step IV), and catalyst elimination affording the final product P1 (step V). Step IV is found to be the rate‐determining step with an overall free energy barrier of 28.3 kcal/mol. Our calculated results are in good agreement with the experimental observations. The present study may provide a useful guide for understanding these kinds of gold(I)‐catalyzed cross‐coupling reactions of diazo compounds.

Gold(I) Carbenoids: On-Demand Access to Gold(I) Carbenes in Solution.

Chloromethylgold(I) complexes of phosphine, phosphite, and N‐heterocyclic carbene ligands are easily synthesized by reaction of trimethylsilyldiazomethane with the corresponding gold chloride precursors. Activation of these gold(I) carbenoids with a variety of chloride scavengers promotes reactivity typical of metallocarbenes in solution, namely homocoupling to ethylene, olefin cyclopropanation, and Buchner ring expansion of benzene.

Gold(I) Carbenoids: On‐Demand Access to Gold(I) Carbenes in Solution

AbstractChloromethylgold(I) complexes of phosphine, phosphite, and N‐heterocyclic carbene ligands are easily synthesized by reaction of trimethylsilyldiazomethane with the corresponding gold chloride precursors. Activation of these gold(I) carbenoids with a variety of chloride scavengers promotes reactivity typical of metallocarbenes in solution, namely homocoupling to ethylene, olefin cyclopropanation, and Buchner ring expansion of benzene.

Gold-Catalyzed Rearrangement of (Silylcyclopropenyl)methyl Ethers into (Silylmethylene)cyclopropanes

Methoxymethyl ethers derived from 2-(dimethylphenylsilyl)cycloprop-1-enyl carbinols undergo gold-catalyzed rearrangement leading to [(Z)-(dimethylphenylsilyl)methylene]cyclopropanes in moderate to high yields with methyl formate as a byproduct. This transformation proceeds by initial regioselective ring opening of the three-membered ring leading to an α-silyl vinyl gold carbenoid. This latter organogold species evolves by 1,5-hydride transfer, which triggers subsequent rearrangement involving loss of methyl formate, 2π-electrocyclization of the resulting allylic cation, and elimination of the metal to regenerate the catalyst.

ChemInform Abstract: Gold(I)‐Catalyzed Addition of Silylacetylenes to Acylsilanes: Synthesis of Indanones by C—H Functionalization Through a Gold(I) Carbenoid.

A gold(I)-catalyzed synthesis of indanones from trimethylsilylacetylenes and acylsilanes is presented. The reaction is initiated through a synergistic acylsilane activation-gold acetylide formation and involves consecutive alkyne σ-gold(I) addition, π-activation, and 1,2-migration of a silyl group. Studies performed on the reaction mechanism allowed to establish the nature of the silyl migrating group and invoke the participation of a gold(I) carbenoid intermediate. The reaction is completed by a gold(I) C-H functionalization step.

Gold(I)‐Catalyzed Addition of Silylacetylenes to Acylsilanes: Synthesis of Indanones by CH Functionalization through a Gold(I) Carbenoid

AbstractA gold(I)‐catalyzed synthesis of indanones from trimethylsilylacetylenes and acylsilanes is presented. The reaction is initiated through a synergistic acylsilane activation–gold acetylide formation and involves consecutive alkyne σ‐gold(I) addition, π‐activation, and 1,2‐migration of a silyl group. Studies performed on the reaction mechanism allowed to establish the nature of the silyl migrating group and invoke the participation of a gold(I) carbenoid intermediate. The reaction is completed by a gold(I) CH functionalization step.

Gold(I)-Catalyzed Addition of Silylacetylenes to Acylsilanes: Synthesis of Indanones by C-H Functionalization through a Gold(I) Carbenoid.

A gold(I)-catalyzed synthesis of indanones from trimethylsilylacetylenes and acylsilanes is presented. The reaction is initiated through a synergistic acylsilane activation-gold acetylide formation and involves consecutive alkyne σ-gold(I) addition, π-activation, and 1,2-migration of a silyl group. Studies performed on the reaction mechanism allowed to establish the nature of the silyl migrating group and invoke the participation of a gold(I) carbenoid intermediate. The reaction is completed by a gold(I) C-H functionalization step.