Gold‐Catalyzed Carbenoid Transfer Reactions of Diynes – Pinacol Rearrangement versus Retro‐Buchner Reaction

Aromatic diyne systems bearing one terminal propargylic acetate moiety and one tertiary propargylic alcohol subunit were converted in the presence of a gold catalyst. After an initial 1,2‐migration of the acetoxy group at the terminal alkyne, a gold carbenoid is formed which is then transferred onto the internal alkyne of the propargylic alcohol. This combination enables the use of propargylic acetates as precursors for a gold‐catalyzed pinacol‐type rearrangement. In the final pinacol‐like step the shift of an alkyl or aryl moiety onto an electrophilic gold carbenoid/cation terminates the reaction and 1‐naphthyl ketones are obtained as products. If electron‐rich aromatic backbones are used, a mechanistically interesting alternative pathway including a retro‐Buchner reaction is opened.

     

Gold‐Catalyzed Synthesis of 1‐Naphthylcarbenoids and Their Synthetic Utilization in Cyclopropanation Reactions

1‐Naphthylcarbenoids are generated via 1,2‐acyl migration and subsequent carbene shift from simple, easily available diyne starting materials. These highly reactive species were allowed to react with differently substituted alkenes in both intermolecular and intramolecular fashions. In the intermolecular cases even a simple 1:1 ratio of the starting materials delivered the corresponding cyclopropylnaphthalenes in high yields by the use of a gold(III) catalyst. The methodology offers a completely new approach to these valuable targets, the new route represents an efficient alternative to common methods that are based on cross‐coupling strategies.

     

Gold‐Catalyzed Highly Diastereoselective Synthesis of Functionalized 3,4‐Disubstituted Butyrolactams via Phosphatyloxy or Carbonate Double Migrations

A gold‐catalyzed highly diastereoselective synthesis of functionalised 3,4‐disubstituted butyrolactams via phosphatyloxy or carbonate double migrations is reported, which is proposed to proceed by a tandem 1,3‐phosphatyloxy or carbonate migration and a “long‐range” 1,5‐phosphatyloxy or carbonate migration, which overall corresponds to a formal 1,6‐migration.     

Gold‐Catalyzed Synthesis of Dibenzopentalenes – Evidence for Gold Vinylidenes

A series of easily accessible arene‐1,2‐diynes, bearing one aryl substituent on one of the alkynyl groups, is readily converted to dibenzopentalenes in good yields by gold(I) catalysts. The participation of gold acetylides could be proven by the direct conversion to the corresponding gem‐diaurated dibenzopentalenes with a gold catalyst. From an experiment with a gold acetylide complex and stoichiometric amounts of the gold “catalyst” the corresponding gem‐diaurated complex of a dibenzopentalene could be obtained and characterized by X‐ray crystal structure analysis. Labelling studies with deuterated alkynes show the expected deuteration of the two remaining positions of the pentalene core. All this provides evidence for a dual activation mode of the reaction and gold(I) vinylidene complexes as intermediates of the catalytic cycle.     

Gold‐ and Silver‐Catalyzed Intramolecular Hydroamination of Terminal Alkynes: Water‐Triggered Chemo‐ and Regioselective Synthesis of Fused Tricyclic Xanthines

A simple, convenient and green synthetic approach to diverse fused tricyclic xanthines has been developed via gold(I) complex‐catalyzed intramolecular hydroamination or silver(I)‐catalyzed isomerization‐hydroamination of terminal alkynes under microwave irradiation in water. The first synthesis of N9‐annelated xanthines has also been reported.     

Synthesis of Substituted Quinolizidines via a Gold‐Catalyzed Double Cyclization Cascade

A novel synthesis of quinolizidines by a cationic gold‐catalyzed double cyclization cascade has been developed. The reaction was initiated by the gold‐catalyzed 6‐exo‐dig cyclization of ynamides, which was followed by a second cyclization of an enamide intermediate to provide the corresponding quinolizidine derivatives. The utility of this reaction was demonstrated by application to the synthesis of multi‐substituted quinolizidines and by the total synthesis of a quinolizidine alkaloid, (±)‐lupinine.

     

Gold(I)‐Catalyzed Synthesis of Tetrahydrocarbazoles via Cascade [3,3]‐Propargylic Rearrangement/[4+2] Cycloaddition of Vinylindoles and Propargylic Esters

A gold(I)‐catalyzed cascade [3,3]‐propargylic rearrangement and [4+2] cycloaddition reaction of 2‐vinylindoles with propargylic esters is reported. The reaction leads to the synthesis of highly substituted tetrahydrocarbazole derivatives in high yields and diasteroselectivities. Furthermore, a preliminary screening for an asymmetric version of this reaction is described.

     

Gold‐Catalyzed Tandem Cycloisomerization of Alkynyloxiranes with Nucleophiles: An Efficient Approach to 2,5‐Disubstituted Furans

An efficient approach to 2,5‐disubstituted furans has been developed by utilizing gold‐catalyzed sequential nucleophilic attack onto metal‐complexed alkynes with complete regioselectivity. The reaction proceeds efficiently under mild conditions with commercially available catalysts to afford furans in moderate to excellent yields (up to 96 %) with high diversity.     

Synthesis of Difurylmethane Derivatives via the Gold‐Catalyzed Tandem Cycloisomerization/Dimerization of Epoxide Alkynes

A simple and convenient synthetic approach to difurylmethane derivatives has been developed via gold‐catalyzed cycloisomerization of 1‐oxiranyl‐2‐alkynyl esters and dimerization of the 2‐(α‐hydroxyalkyl)furans. The reaction takes place in the presence of 2 mol% of tetrachloroauric acid tetrahydrate (HAuCl₄⋅4 H₂O) under very mild conditions.     

Gold‐Catalyzed Redox Synthesis of Imidazo[1,2‐a]pyridines using Pyridine N‐Oxide and Alkynes

A mild, catalytic, atom economical synthesis of imidazo[1,2‐a]pyridines has been developed: catalytic dichloro(2‐pyridinecarboxylato)gold [PicAuCl₂] in the presence of an acid produces a range of imidazo[1,2‐a]pyridines in good yields starting from alkynes and 2‐aminopyridine N‐oxides. This strategy is mild and foreseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2‐a]pyridine ring without loss of enantiomeric excess.

     

Gold‐ vs. Platinum‐Catalyzed Polycyclizations by O‐Acyl Migration. Solvent‐Free Reactions

Polycyclic derivatives incorporating a cyclopropyl group have been efficiently synthesized from propargyl acetates using platinum(II), gold(I) and gold(III) catalysis. These reactions which are also viable for the preparation of medium‐sized rings, proceed with a complete diastereocontrol and can also be run in neat conditions.     

An Alternative Approach to Direct Aldol Reaction Based on Gold‐Catalyzed Methoxyl Transfer

A mild and catalyzed alternative to the direct aldol reaction has been developed based on the gold‐catalyzed methoxy group transfer from dimethyl acetals to terminal alkynes. Due to the simultaneous activation of the acetals, this aldol approach is only functional for acetals but not aldehydes. A ligand effect from the gold complex has also been observed.     

Intermolecular Gold(I)‐Catalyzed Alkyne Carboalkoxylation Reactions for the Multicomponent Assembly of β‐Alkoxy Ketones

A new gold(I)‐catalyzed multicomponent synthesis of β‐alkoxy ketones from aldehydes, alcohols, and alkynes is described. This atom economical synthesis was achieved through the use of the gold complex (SPhos)AuNTf₂ as a catalyst, and allows for the preparation of a diverse array of β‐alkoxy ketone products. Mechanistic studies illustrate that these reactions proceed via gold(I)‐catalyzed hydrolysis of the alkyne to an aryl ketone, which then undergoes an aldol reaction with an oxocarbenium ion generated in situ from the aldehyde and alcohol components.     

A Gold‐Catalyzed A3 Coupling/Cyclization/Elimination Sequence as Versatile Tool for the Synthesis of Furfuryl Alcohol Derivatives from Glyceraldehyde and Alkynes

The reaction of glyceraldehyde with alkynes delivers furfuryl alcohol derivatives within only one reaction step in the presence of a gold(III) catalyst. The reaction cascade is initiated by an intermolecular gold‐catalyzed A3 coupling sequence in which morpholine is used as additive. Intramolecular cyclization and subsequent aromatization under elimination of the amine then deliver the target molecules. The protocol offers a valuable alternative to the common routes that are based on functionalization of already existing furan cores.

     

Gold‐Catalyzed Regioselective Meyer–Schuster Rearrangement and Ring Expansion Cascade Leading to α‐Hydroxy‐α‐vinylcyclopentanones

Readily available cyclobutanols having a butyne‐1,4‐diol moiety underwent a sequential regioselective Meyer–Schuster rearrangement and 1,2‐shift, furnishing α‐hydroxy‐α‐vinylcyclopentanones. The reaction mechanism is consistent with the formation of an allenol intermediate that racemizes under the reaction conditions. Subsequent activation of the allenol leads to an enantio‐ and diastereoselective route to this scaffold.

     

Synthesis of Pyrazolo[1,2‐a]cinnolines via a Rhodium‐Catalyzed Oxidative Coupling Approach

An efficient synthetic strategy for the unique class of pyrazolo[1,2‐a]cinnolines was developed through a rhodium‐catalyzed oxidative coupling of N‐aryl‐1H‐pyrazol‐5(4H)‐ones with internal alkynes. This protocol features use of the pyrazolone function in the substrate as an intrinsic directing group, hexafluoroisopropyl alcohol (HFIP) as the solvent, and mild reaction conditions as well as a wide substrate scope.

     

Gold‐Catalyzed Synthesis of 3‐Acylimidazo[1,2‐a]pyridines via Carbene Oxidation

A convenient gold‐catalyzed strategy for the synthesis of imidazo[1,2‐a]pyridine derivatives has been developed via gold carbene complexes. This transformation opens a new synthetic route to a variety of 3‐carbonyl‐substituted imidazo[1,2‐a]pyridines using air as oxidant affording the products in good yields.

     

Gold‐Catalyzed Cyclizations: A Comparative Study of ortho,ortho′‐Substituted KITPHOS Monophosphines with their Biaryl Monophosphine Counterpart SPHOS

Electrophilic gold(I) triflimide (trifluoromethanesulfonimide) complexes of electron‐rich ortho,ortho′‐disubstituted KITPHOS (11‐dicyclohexylphosphino‐12‐phenyl‐9,10‐ethenoanthracene) monophosphines are efficient catalysts for intramolecular cycloisomerizations that afford phenols, 3‐acylindenes and methylene‐oxazolines; comparative catalyst testing showed that these catalysts either competed with or outperformed that based on SPHOS [2‐(2′,6′‐dimethoxybiphenyl)dicyclohexylphosphine]. An electron‐rich biarylmonophosphine containing a single ortho‐methoxy substituent, prepared by rhodium‐catalyzed [2+2+2] cycloaddition between a 1‐alkynyl(dicyclohexylphosphine) oxide and 1,7‐octadiyne, also formed a highly efficient catalyst for the same transformations. Monitoring of comparative catalyst testing between a KITPHOS‐based gold(I) triflimide complex containing a coordinated tetrahydrothiophene and its counterpart coordinated solely by the triflimide anion revealed that the former is an order of magnitude less efficient than the latter, confirming that tetrahydrothiophene can be an effective catalyst inhibitor.     

Gold-Catalyzed Cascade Reactions of Alkynes for Construction of Polycyclic Compounds

The development of cascade reactions is an area of considerable interest in modern organic chemistry. Efficient cascade reactions realize the economical synthesis of complex target molecules through multiple bond formations in a single operation. Elementary reactions that form fewer waste products are desirable in terms of atom economy and in order to suppress side product formation in sequential processes. Recent advances in homogeneous gold catalysis have opened up further possibilities for cascade reactions. In this review, recent advances in gold-catalyzed cascade cyclizations of alkynes are summarized. In particular, cascade reactions based on nucleophilic/electrophilic addition, carbene cyclopropanation/insertion, ring expansion, and cycloaddition are highlighted. Notably, many of the cascade reactions shown in this mini-review feature no theoretical waste products.