A Desulfonylative Approach in Oxidative Gold Catalysis: Regiospecific Access to Donor‐Substituted Acyl Gold Carbenes

Donor‐substituted acyl gold carbenes are challenging to access selectively by gold‐promoted intermolecular oxidation of internal alkynes as the opposite regioisomers frequently predominate. By using alkynyl sulfones or sulfonates as substrates, the oxidative gold catalysis in the presence of substituted pyridine N‐oxides offers regiospecific access to acyl/aryl, acyl/alkenyl, and acyl/alkoxy gold carbenes by in situ expulsion of sulfur dioxide. The intermediacies of these reactive species are established by their reactivities, including undergoing further oxidation by the same oxidant, cyclopropanation of styrenes, engaging in a [3+2] cycloaddition with α‐methylstyrene, and conversion into dienones.     

Direct Observation of Aryl Gold(I) Carbenes that Undergo Cyclopropanation,C−H Insertion,and Dimerization Reactions

Mesityl gold(I) carbenes lacking heteroatom stabilization or shielding ancillary ligands have been generated and spectroscopically characterized from chloro(mesityl)methylgold(I) carbenoids bearing JohnPhos‐type ligands by chloride abstraction with GaCl₃. The aryl carbenes react with PPh₃ and alkenes to give stable phosphonium ylides and cyclopropanes, respectively. Oxidation with pyridine N‐oxide and intermolecular C?H insertion to cyclohexane have also been observed. In the absence of nucleophiles, a bimolecular reaction, similar to that observed for other metal carbenes, leads to a symmetrical alkene.     

Expedient Synthesis of Fused Azepine Derivatives Using a Sequential Rhodium(II)‐Catalyzed Cyclopropanation/1‐Aza‐Cope Rearrangement of Dienyltriazoles

A general method for the formation of fused dihydroazepine derivatives from 1‐sulfonyl‐1,2,3‐triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α‐imino rhodium(II) carbenoid, leading to a transient 1‐imino‐2‐vinylcyclopropane intermediate which rapidly undergoes a 1‐aza‐Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst‐free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.     

Acyl Migration versus Epoxidation in Gold Catalysis: Facile,Switchable, and Atom‐Economic Synthesis of Acylindoles and Quinoline Derivatives

We report a switchable synthesis of acylindoles and quinoline derivatives via gold‐catalyzed annulations of anthranils and ynamides. α‐Imino gold carbenes, generated in situ from anthranils and an N,O‐coordinated gold(III) catalyst, undergo electrophilic attack to the aryl π‐bond, followed by unexpected and highly selective 1,4‐ or 1,3‐acyl migrations to form 6‐acylindoles or 5‐acylindoles. With the (2‐biphenyl)di‐tert‐butylphosphine (JohnPhos) ligand, gold(I) carbenes experienced carbene/carbonyl additions to deliver quinoline oxides. Some of these epoxides are valuable substrates for the preparation of 3‐hydroxylquinolines, quinolin‐3(4H)‐ones, and polycyclic compounds via facile in situ rearrangements. The reaction can be efficiently conducted on a gram scale and the obtained products are valuable substrates for preparing other potentially useful compounds. A computational study explained the unexpected selectivities and the dependency of the reaction pathway on the oxidation state and ligands of gold. With gold(III) the barrier for the formation of the strained oxirane ring is too high; whereas with gold(I) this transition state becomes accessible. Furthermore, energetic barriers to migration of the substituents on the intermediate sigma‐complexes support the observed substitution pattern in the final product.     

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.     

Isolation of a Reactive Tricoordinate α‐Oxo Gold Carbene Complex

The [(P,P)Au=C(Ph)CO₂Et]⁺ complex 3 [where (P,P) is an o‐carboranyl diphosphine ligand] was prepared by diazo decomposition at ?40 °C. It is the first α‐oxo gold carbene complex to be characterized. Its crystallographic structure was determined and DFT calculations have been performed, unraveling the key influence of the chelating (P,P) ligand. The gold center is tricoordinate and the electrophilicity of the carbene center is decreased. Complex 3 mimics transient α‐oxo gold carbenes in a series of catalytic transformations, and provides support for the critical role of electrophilicity in the chemoselectivity of phenol functionalization (O?H vs. C?H insertion).     

Gold‐Catalyzed CH Annulation of Anthranils with Alkynes: A Facile,Flexible, and Atom‐Economical Synthesis of Unprotected 7‐Acylindoles

The gold‐catalyzed C? H annulation of anthranil derivatives with alkynes offers a facile, flexible, and atom‐economical one‐step route to unprotected 7‐acylindoles. An intermediate α‐imino gold carbene, generated by an intermolecular reaction, promotes ortho‐aryl C? H functionalization to afford the target products. The transformation proceeds with a broad range of substrates under mild conditions. Moreover, the obtained functionalized indole products represent a versatile platform for the construction of diverse indolyl frameworks.     

Enantioselective Aza‐Ene‐type Reactions of Enamides with Gold Carbenes Generated from α‐Diazoesters

Carbophilic gold carbenes generated from the decomposition of α‐diazoesters show high reactivity towards enamides, leading to an unprecedented aza‐ene‐type reaction. The presence of 0.1 mol % of a chiral Brønsted acid co‐catalyst is sufficient to give synthetically relevant γ‐keto esters in excellent yields and selectivities (up to 99 % yield, 97 % ee ).     

Gold-catalyzed nitrene transfer to activated alkynes: formation of α,β-unsaturated amidines

A gold-catalyzed intermolecular nitrene transfer to alkynes was developed for the first time, revealing a new mode of nitrene transfer and providing a novel access to versatile α-imino metal carbenes. Various mild nitrene-transfer reagents were examined, and iminopyridium ylides especially those based on 3,5-dichloropyridine proved be highly effective. With activated alkynes such as N-alkynyloxazolidinones as substrates, α,β-unsaturated amidines were formed in mostly good yields.     

Ring Expansion and 1,2‐Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies

Demonstrated herein is an Au^I‐catalyzed annulation of sulfonyl‐protected ynamides with substituted 1,2‐benzisoxazoles for the synthesis of E‐benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold‐activated ynamide, ring expansion of the benzisoxazole fragment to provide an α‐imino vinylic gold intermediate, and 1,2‐migration of the sulfonamide motif to the masked carbene center to deliver the respective ring‐expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α‐imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.     

Sulfur and selenium ylide bond enthalpies

The bond dissociation enthalpies (BDEs) of sulfur and selenium ylides have been estimated by applying MP2/6-311++G(3df,2p)//MP2/6-31G(d,p), G3, and other computational methods. Computed sulfoxide bond enthalpies were compared to experimental results to ensure the reliability of the computational methods before extending to related compounds. The examined ylides include the following: sulfoxides, sulfilimines, S,C-sulfonium ylides, and selenoxides. Selenoxides have BDEs about 10 kcal/mol smaller than the corresponding sulfoxides. N-H sulfilimines and CH2-S,C-sulfonium ylides have low BDEs, unless the sulfilimine or S,C-sulfonium ylide is stabilized by an electronegative substituent on N or C, respectively. Incorporation of the S or Se into a thiophene or selenophene-type ring lowers the BDE for the ylide.     

Chemoselective Carbophilic Addition of α‐Diazoesters through Ligand‐Controlled Gold Catalysis

The chemoselective addition of arenes and 1,3‐diketones to α‐aryldiazoesters was achieved through ligand‐controlled gold catalysis. Unlike a dirhodium catalyst (which promotes C? H insertion and cyclopropanation) and a copper catalyst (which catalyzes O? H and N? H insertions), the gold catalyst with an electron‐deficient phosphite as the ancillary ligand exclusively gave the carbophilic addition product, thus representing a new and efficient approach to form “carbophilic carbocations”, which selectively react with carbon nucleophiles.     

α-Imino Gold Carbene Intermediates from Readily Accessible Sulfilimines: Intermolecular Access to Structural Diversity

Catalytic approaches to pharmaceutically important bioactive skeletons through gold carbene intermediates have experienced a dramatic development in the last decade. Although various carbene precursors continue to play an important role in heterocyclic syntheses, these reagents are associated with some drawbacks in terms of functional group tolerance, synthetic methods and safety limitations. A new generation of nitrene transfer reagents was established in 2019: the sulfilimines. These are safe, inexpensive and readily available. They can conveniently be stored and handled, and thus represent ideal reagents for the fast and modular modification of scaffolds and the preparation of libraries by intermolecular reactions of two components. Both the practical methods for synthesizing sulfilimines and the versatility of these ylidic species in gold-catalyzed preparation of structural diversity, for both heterocycles and carbocycles, will be outlined in this Concept article.     

Synthesis of Carbazoles and Related Heterocycles from Sulfilimines by Intramolecular C−H Aminations

While direct nitrene insertions into C?H bonds have become an important tool for building C?N bonds in modern organic chemistry, the generation of nitrene intermediates always requires transition metals, high temperatures, ultraviolet or laser light. We report a mild synthesis of carbazoles and related building blocks through a visible light‐induced intramolecular C?H amination reaction. A striking advantage of this new method is the use of more reactive aryl sulfilimines instead of the corresponding hazardous azides. Different catalysts and divergent light sources were tested. The reaction scope is broad and the product yield is generally high. An efficient gram‐scale synthesis of Clausine C demonstrates the applicability and scalability of this new method.     

Direct Observation of Aryl Gold(I) Carbenes that Undergo Cyclopropanation,C−H Insertion,and Dimerization Reactions

Mesityl gold(I) carbenes lacking heteroatom stabilization or shielding ancillary ligands have been generated and spectroscopically characterized from chloro(mesityl)methylgold(I) carbenoids bearing JohnPhos‐type ligands by chloride abstraction with GaCl₃. The aryl carbenes react with PPh₃ and alkenes to give stable phosphonium ylides and cyclopropanes, respectively. Oxidation with pyridine N‐oxide and intermolecular C?H insertion to cyclohexane have also been observed. In the absence of nucleophiles, a bimolecular reaction, similar to that observed for other metal carbenes, leads to a symmetrical alkene.     

Copper‐Catalyzed Azide–Ynamide Cyclization to Generate α‐Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N‐Heterocycles

Here an efficient copper‐catalyzed cascade cyclization of azide‐ynamides via α‐imino copper carbene intermediates is reported, representing the first generation of α‐imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N‐heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX‐Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.     

Gold‐Catalyzed Oxidation/C−H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones

An efficient strategy to construct salicyl ketones through gold‐catalyzed oxidation/C?H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non‐diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α‐oxo gold carbenes generated in situ through gold‐catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC‐3 prostate cancer cell line and SKOV‐3 human ovarian carcinoma cell line yield IC₅₀ were 0.81±0.05 and 0.87±0.15 μm , respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.     

Visible‐Light‐Driven Photocatalytic Activation of Inert Sulfur Ylides for 3‐Acyl Oxindole Synthesis

Bicarbonyl‐substituted sulfur ylide is a useful, but inert reagent in organic synthesis. Usually, harsh reaction conditions are required for its transformation. For the first time, it was demonstrated that a new, visible‐light photoredox catalytic annulation of sulfur ylides under extremely mild conditions, permits the synthesis of oxindole derivatives in high selectivities and efficiencies. The key to its success is the photocatalytic single‐electron‐transfer (SET) oxidation of the inert amide and acyl‐stabilized sulfur ylides to reactive radical cations, which easily proceeds with intramolecular C?H functionalization to give the final products.     

Gold(I)‐Catalysed Cycloisomerisation of 1,6‐Cyclopropene‐enes

The gold(I)‐catalysed cycloisomerisation of appropriately substituted 1,6‐cyclopropene‐enes proceeds through regioselective electrophilic ring opening of the three‐membered ring to generate an alkenyl gold carbenoid that achieves the intramolecular cyclopropanation of the remote olefin. This strategy allows straightforward, highly efficient and diastereoselective access to a variety of substituted 3‐oxa‐ and 3‐azabicyclo[4.1.0]heptanes, as well as to bicyclo[4.1.0]heptan‐3‐ol derivatives. Since the isopropylidene group in the resulting cycloisomerisation products can be subjected to ozonolysis, 3,3‐dimethylcyclopropenes behave as interesting surrogates for α‐diazoketones.     

Formal Asymmetric (4+1) Annulation Reaction between Sulfur Ylides and 1,3‐Dienes

A highly enantioselective synthesis of functionalized cyclopentanoids by a formal asymmetric (4+1) annulation strategy was developed. The methodology consists of a stereoselective cyclopropanation reaction between chiral sulfur ylides and 1,3‐dienes followed by a, in situ, stereospecific MgI₂‐catalyzed rearrangement of vinylcyclopropanes. This method is distinguished by a remarkable compatibility with functional groups and a high stereocontrol.