Α-oxo Gold Carbene Research Articles

Intramolecular Insertions into Unactivated C(sp³)-H Bonds by Oxidatively Generated β-Diketone-α-Gold Carbenes: Synthesis of Cyclopentanones.

Generation of reactive α-oxo gold carbene intermediates via gold-catalyzed oxidation of alkynes has become an increasing versatile strategy of replacing hazardous diazo carbonyl compounds with benign and readily available alkynes in the development of efficient synthetic methods. However, one of the hallmarks of metal carbene/carbenoid chemistry, i.e., insertion into an unactivated C(sp(3))-H bond, has not be realized. This study reveals for the first time that this highly valuable transformation can be readily realized intramolecularly by oxidatively generated β-diketone-α-gold carbenes using ynones as substrates. Substrate conformation control via the Thorpe-Ingold effect is the key design feature that enables generally good to excellent efficiencies, and synthetically versatile cyclopentanones including spiro-, bridged, and fused bicyclic ones can be readily accessed.

ChemInform Abstract: Gold‐Catalyzed Oxidation of Propargylic Ethers with Internal C—C Triple Bonds: Impressive Regioselectivity Enabled by Inductive Effect.

Abstract Inductive perturbations of C–C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C–C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of β-alkoxy-α,β-unsaturated ketones (up to >50/1 selectivity) via α-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a α-phenyl-β-alkoxy-α,β-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.

A Novel Method to Prepare Multisubstituted Pyrazoles

This paper reports a new strategy to construct multisubstituted pyrazoles from hydrazine and 1,3-diketone which is generated through α-oxo gold carbene using readily available propargyl alcohol. The carbene formation and C—C bond migration could be applied in a tandem process, connected by a carbene cyclization, leading to complex diketone products.

Gold-catalyzed selective oxidation of 4-oxahepta-1,6-diynes to 2H-pyran-3(6H)-ones and chromen-3(4H)-ones via β-gold vinyl cation intermediates.

α-Oxo gold carbenes generated in situ via the gold-catalyzed selective oxidation of 4-oxahepta-1,6-diynes were effectively trapped by internal alkynes, resulting in the formation of 2H-pyran-3(6H)-ones, , and chromen-3(4H)-ones, , upon facile trapping the vinyl cation intermediates by an external N-oxide and internal aryl ring system.

C–H insertions in oxidative gold catalysis: synthesis of polycyclic 2H-pyran-3(6H)-ones via a relay strategy

A new application of oxidatively generated, highly electrophilic α-oxo gold carbenes in synthetically streamlining insertions into unactivated C–H bonds is realized by converting them to putative vinyl cation intermediates in a relay approach. This chemistry permits expedient access to cyclic dihydropyran-3-ones.

Enantioselective oxidative gold catalysis enabled by a designed chiral P,N-bidentate ligand.

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.

Gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water.

A gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water has been developed, which provides ready access to highly functionalized indole derivatives from o-alkynyl anilines and ynamides. Importantly, gold serves dual catalytic roles to mediate both the cycloisomerization of o-alkynyl anilines and the intermolecular oxidation of ynamides at the same time, thus providing a new type of concurrent tandem catalysis. The use of readily available starting materials, a simple procedure, and mild reaction conditions are other notable features of this method.

Gold-catalyzed oxidation of propargylic ethers with internal C–C triple bonds: Impressive regioselectivity enabled by inductive effect

Inductive perturbations of C–C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C–C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of β-alkoxy-α,β-unsaturated ketones (up to >50/1 selectivity) via α-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a α-phenyl-β-alkoxy-α,β-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.

Gold-catalyzed Synthesis of 4-(2-Oxoalkoxy)butyl Methanesulfonates via Ring-opening of Tetrahydrofuran

Abstract A variety of terminal alkynes were converted into the corresponding 4-(2-oxoalkoxy)butyl methanesulfonates via a gold-catalyzed intermolecular oxidation reaction using 8-ethylquinoline N-oxide as the oxidant and THF as the solvent. This reaction is proposed to proceed through the ring-opening of THF via an α-oxo gold carbene intermediate.

ChemInform Abstract: Catalytic Access to α‐Oxo Gold Carbenes by N—O Bond Oxidants

AbstractReview: 71 refs.

Catalytic Access to α-Oxo Gold Carbenes by N–O Bond Oxidants

Metal carbenes are highly versatile species that mediate various transformations. Recent advances in gold catalysis have allowed catalytic access to α-oxo metal carbenes from the alkyne functionality. Compared with traditional methods that rely upon metal-catalyzed decomposition of diazo precursors, the generation of this synthon occurs in an environmentally more appealing fashion by gold-catalyzed alkyne oxygenation. Hydroxylamine derivatives are typically prepared from hydroxylamine salts that are cheap and can be handled without special precaution. In reactions with an alkyne activated by gold, relatively stable nitrones and related reagents undergo efficient O-atom transfer to form putative α-oxo gold carbenes. The highly reactive nature of these species could be utilized in a variety of cascade transformations. Herein, recent synthetic methods based on this reactivity as well as the currently available mechanistic and structural studies through computational and experimental methods have been discussed. A variety of tandem reactions performed by our laboratory and others have demonstrated the synthetic utility of catalytically generated α-oxo gold carbenes and enabled access to various heterocycles. For example, a reaction between nitrones and alkynes led to azomethine ylides for the [3 + 2] dipolar cycloaddition. Alternatively, α-oxo gold carbenes can be transformed into enolate equivalents through a 1,2-pinacol shift. The addition of hydroxylamine derivatives across triple bonds led to oxoamination, providing α-aminocarbonyl compounds or regioselective Fisher indole-type synthesis. N-O bond cleaving redox chemistry paved the way for intermolecular redox processes, most notably by use of pyridine-N-oxide derivatives with expanding synthetic applications. In closing, other metal-based oxygenations using N-O bond oxidants will be highlighted. One particularly interesting aspect is the process leading to metal vinylidene complexes. Trapping of this intermediate resulted in opposite regioselectivity from gold catalysis in alkyne oxygenation and led to ketene intermediates for use in subsequent cascade transformations.

A Non-Diazo Approach to α-Oxo Gold Carbenes via Gold-Catalyzed Alkyne Oxidation

For the past dozen years, homogeneous gold catalysis has evolved from a little known topic in organic synthesis to a fully blown research field of significant importance to synthetic practitioners, due to its novel reactivities and reaction modes. Cationic gold(I) complexes are powerful soft Lewis acids that can activate alkynes and allenes toward efficient attack by nucleophiles, leading to the generation of alkenyl gold intermediates. Some of the most versatile aspects of gold catalysis involve the generation of gold carbene intermediates, which occurs through the approach of an electrophile to the distal end of the alkenyl gold moiety, and their diverse transformations thereafter. On the other hand, α-oxo metal carbene/carbenoids are highly versatile intermediates in organic synthesis and can undergo various synthetically challenging yet highly valuable transformations such as C–H insertion, ylide formation, and cyclopropanation reactions. Metal-catalyzed dediazotizations of diazo carbonyl compounds are the principle and most reliable strategy to access them. Unfortunately, the substrates contain a highly energetic diazo moiety and are potentially explosive. Moreover, chemists need to use energetic reagents to prepare them, putting further constrains on operational safety.In this Account, we show that the unique access to the gold carbene species in homogeneous gold catalysis offers an opportunity to generate α-oxo gold carbenes if both nucleophile and electrophile are oxygen. Hence, this approach would enable readily available and safer alkynes to replace hazardous α-diazo carbonyl compounds as precursors in the realm of gold carbene chemistry.For the past several years, we have demonstrated that alkynes can indeed effectively serve as precursors to versatile α-oxo gold carbenes. In our initial study, we showed that a tethered sulfoxide can be a suitable oxidant, which in some cases leads to the formation of α-oxo gold carbene intermediates. The intermolecular approach offers excellent synthetic flexibility because no tethering of the oxidant is required, and its reduced form is not tangled with the product. We were the first research group to develop this strategy, through the use of pyridine/quinolone N-oxides as the external oxidants. In this manner, we can effectively make a C–C triple bond a surrogate of an α-diazo carbonyl moiety in various gold catalyses. With terminal alkynes, we demonstrated that we can efficiently trap exclusively formed terminal carbene centers by internal nucleophiles en route to the formation of cyclic products, including strained oxetan-3-ones and azetidin-3-ones, and by external nucleophiles when a P,N-bidentate ligand is coordinated to gold. With internal alkynes, we generated synthetically useful regioselectivities in the generation of the α-oxo gold carbene moiety, which enables expedient formation of versatile enone products. Other research groups have also applied this strategy en route to versatile synthetic methods. The α-oxo gold carbenes appear to be more electrophilic than their Rh counterpart, which many chemists have focused on in a large array of excellent work on metal carbene chemistry. The ease of accessing the reactive gold carbenes opens up a vast area for developing new synthetic methods that would be distinctively different from the known Rh chemistry and promises to generate a new round of “gold rush”.

Expanding the horizon of intermolecular trapping of in situ generated α-oxo gold carbenes: efficient oxidative union of allylic sulfides and terminal alkynes via C–C bond formation

With a new P,S-bidentate phosphine as the ligand to gold(I), the α-oxo gold carbenes generated in situ via gold-catalyzed intermolecular oxidation of terminal alkynes were effectively trapped by various allylic sulfides, resulting in the formation of α-aryl(alkyl)thio-γ,δ-unsaturated ketones upon facile [2,3]sigmatropic rearrangements.

ChemInform Abstract: Gold‐Catalyzed Oxidative Cyclization of 4‐Allenyl‐1‐ynes with 8‐Methylquinoline Oxide.

Gold-catalyzed oxidative cyclizations of 4-allenyl-1-ynes with 8-methylquinoline oxide are described; diverse products are produced depending on the allenyl substituents. This reaction comprises initial formation of α-oxo gold carbenes that are attacked by allene to form allyl cation intermediates.

Synthesis of 2,5-Disubstituted Dihydrofuran-3(2H)-ones via [2,3]-Sigmatropic Rearrangement of Oxonium Ylides Generated from α-Oxo Gold Carbenes

Novel [2,3]-sigmatropic rearrangements of oxonium ylides generated from α-oxo gold carbenes were discovered. An ­efficient synthetic method of 2,5-disubstituted dihydrofuran-3(2<i>H</i>)-ones via gold-catalyzed intermolecular oxidation of the allyl homopropargyl ethers with <i>N</i>-oxide was developed. And the synthetic utility of the current method has been proved by concise formal synthesis of (±)-kumausallene.

Gold-Catalyzed Oxidative Cyclization of 4-Allenyl-1-ynes with 8-Methylquinoline Oxide

Gold-catalyzed oxidative cyclizations of 4-allenyl-1-ynes with 8-methylquinoline oxide are described; diverse products are produced depending on the allenyl substituents. This reaction comprises initial formation of α-oxo gold carbenes that are attacked by allene to form allyl cation intermediates.

Gold-Catalyzed Intermolecular Oxidation of Terminal Alkynes: Simple and Efficient Synthesis of α-Mesyloxy Ketones

A variety of terminal alkynes were efficiently converted into the corresponding α-mesyloxy ketones through gold-catalyzed intermolecular oxidation in the presence of 3,5-dichloropyridine N-oxide as the oxidant. The reaction is proposed to proceed via α-oxo gold carbene intermolecular O–H insertion.

Straightforward and Highly Efficient Synthesis of α-Acetoxy Ketones through Gold-Catalyzed Intermolecular Oxidation of Terminal Alkynes

A variety of terminal alkynes were efficiently converted into the corresponding α-acetoxy ketones through gold-catalyzed intermolecular oxidation in the presence of 8-methylquinoline 1-oxide as the oxidant. The reaction probably proceeds through an α-oxo gold carbene intermolecular O–H insertion.

3,3]-Sigmatropic rearrangement versus carbene formation in gold-catalyzed transformations of alkynyl aryl sulfoxides: mechanistic studies and expanded reaction scope.

Gold-catalyzed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant is a reaction of high impact in gold chemistry, as it introduced to the field the highly valued concept of gold carbene generation via alkyne oxidation. The proposed intermediacy of α-oxo gold carbenes in these reactions, however, has never been substantiated. Detailed experimental studies suggest that the involvement of such reactive intermediates in the formation of dihydrobenzothiepinones is highly unlikely. Instead, a [3,3]-sigmatropic rearrangement of the initial cyclization intermediate offers a reaction path that can readily explain the high reaction efficiency and the lack of sulfonium formation. With internal alkyne substrates, however, the generation of a gold carbene species becomes competitive with the [3,3]-sigmatropic rearrangement. This reactive intermediate, nevertheless, does not proceed to afford the Friedel-Crafts-type cyclization product. Extensive density functional theory studies support the mechanistic conclusion that the cyclized product is formed via an intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel-Crafts-type cyclization. With the new mechanistic insight, the product scope of this versatile formation of mid-sized sulfur-containing cycloalkenones has been expanded readily to various dihydrobenzothiocinones, a tetrahydrobenzocyclononenone, and even those without the entanglement of a fused benzene ring. Besides gold, Hg(OTf)2 can be an effective catalyst, thereby offering a cheap alternative for this intramolecular redox reaction.

Optimizing P,N-bidentate ligands for oxidative gold catalysis: efficient intermolecular trapping of α-oxo gold carbenes by carboxylic acids.

Steric Bulk or Conformation Control? Optimization of P,N-bidentate ligands reveals the importance of conformation control in the development of highly efficient intermolecular trapping of reactive α-oxo gold carbene intermediates. While a pendant piperidine ring offers suitable steric bulk, fixing its conformation to provide better shielding to the highly electrophilic carbene center turned out to be crucial for the excellent reaction efficiency. A generally highly efficient and broadly applicable synthesis of carboxymethyl ketones from readily available carboxylic acids and terminal alkynes is developed under exceptionally mild reaction conditions.