Regioselective Dihalohydration Reactions of Propargylic Alcohols: Gold‐Catalyzed and Noncatalyzed Reactions

The regioselective conversion of propargylic alcohols into previously unreported α,α‐diiodo‐β‐hydroxyketones was achieved by treatment with N‐iodosuccinimide in the presence of a gold catalyst. The corresponding α,α‐dichloro‐β‐hydroxyketones were obtained by treatment with trichloroisocyanuric acid in the absence of a catalyst. The latter reaction can be extended to other alkynols. These transformations can be used to prepare potentially useful halogenated building blocks. Preliminary mechanistic studies suggest that the reaction involves participation of the acetonitrile solvent in the formation of a 5‐halo‐1,3‐oxazine intermediate.     

Atom‐Efficient Gold(I)‐Chloride‐Catalyzed Synthesis of α‐Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation

Gold(I)‐chloride‐catalyzed synthesis of α‐sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated α‐sulfenylated aldehydes and ketones in 60–97 % yield. Secondary aliphatic propargylic alcohols generated α‐sulfenylated ketones in yields of 47–71 %. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3‐position, and that the hydride from the alcohol was transferred to the 2‐position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2‐position of propargylic alcohol was determined by a low‐energy, five‐membered cyclic protodeauration transition state instead of the strained, four‐membered cyclic transition state found for attack at the 3‐position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2‐hydride shift, generating the final product of the reaction.     

Skeletal Rearrangement of O‐Propargylic Formaldoximes by a Gold‐Catalyzed Cyclization/Intermolecular Methylene Transfer Sequence

Skeletal rearrangement of O‐propargylic formaldoximes, in the presence of gold catalysts, afforded 4‐methylene‐2‐isoxazolines in good to excellent yields by an intermolecular methylene transfer. In addition, the cascade reaction with maleimide in the presence of a gold catalyst afforded isoxazole derivatives by cyclization/methylene transfer and a subsequent ene reaction, whereas that using a copper catalyst gave oxazepines through a 2,3‐rearrangement.     

Gold‐Catalyzed Annulations of 2‐Alkynyl Benzaldehydes with Vinyl Ethers: Synthesis of Dihydronaphthalene,Isochromene, and Bicyclo[2.2.2]octane Derivatives

With the suitable selection of a gold catalyst as well as the appropriate control of the reaction conditions, various new gold‐catalyzed cyclizations of 2‐alkynyl benzaldehyde with acyclic or cyclic vinyl ethers have been developed. Acetal‐tethered dihydronaphthalene and isochromenes were obtained from the reactions of 2‐alkynyl benzaldehydes with acyclic vinyl ethers under mild conditions. And, more interestingly, the gold‐catalyzed reactions of 2‐alkynyl benzaldehyde with a cyclic vinyl ether afforded the bicyclo[2.2.2]octane derivative involving two molecules of cyclic vinyl ethers. These products contain interesting substructures that have been found in many biologically active molecules and natural products. In addition, a gold‐catalyzed homo‐dimerization of 2‐phenylethynyl benzaldehyde 1 a was observed when the reaction was carried out in the absence of vinyl ether, affording a set of separable diastereomeric products. Plausible mechanisms for these transformations are discussed; a gold‐containing benzopyrylium was regarded as the crucial intermediate by which a number of these new transformations took place.     

Enantioselective Copper‐Catalyzed Decarboxylative Propargylic Alkylation of Propargyl β‐Ketoesters with a Chiral Ketimine P,N,N‐Ligand

The first enantioselective copper‐catalyzed decarboxylative propargylic alkylation has been developed. Treatment of propargyl β‐ketoesters with a catalyst, prepared in situ from [Cu(CH₃CN)₄BF₄] and a newly developed chiral tridentate ketimine P,N,N‐ligand under mild reaction conditions, generates β‐ethynyl ketones in good yields and with high enantioselectivities without requiring the pregeneration of ketone enolates. This new process provides facile access to a range of chiral β‐ethynyl ketones in a highly enantioenriched form.     

Gold(I)‐Catalyzed Selective Heterocyclization of Propargylic Thioureas: Mechanistic Study of Competitive Gold‐Activation Mode

A new selective gold(I)‐catalyzed intramolecular heterocyclization of propargylic thioureas has been developed, efficiently affording two kinds of cycloadducts in moderate to excellent yields with a broad substrate scope. Further mechanistic investigations indicate that competitive different gold activation modes feature in these cyclization processes. Kinetic experiments reveal that the gold activation mode is influenced by the ligand of the gold catalyst and the reaction conditions.     

Gold‐Catalyzed Intermolecular Anti‐Markovnikov Hydroamination of Alkylidenecyclopropanes

The cationic gold phosphine complex [{PCy₂(o‐biphenyl)}Au(NCMe)]⁺SbF₆^? (Cy=cyclohexyl) catalyzes the intermolecular, anti‐Markovnikov hydroamination reaction of monosubstituted and cis‐ and trans‐disubstituted alkylidenecyclopropanes (ACPs) with imidazolidin‐2‐ones and other nucleophiles. This reaction forms 1‐cyclopropyl alkylamine derivatives in high yield and with high regio‐ and diastereoselectivity. NMR spectroscopic analysis of gold π‐ACP complexes and control experiments point to the sp hybridization of the ACP internal alkene carbon atom as controlling the regiochemistry of the ACP hydroamination reaction.     

Gold‐Catalyzed 1,2‐Oxoarylations of Nitriles with Pyridine‐Derived Oxides

We report the first success in the gold‐catalyzed oxoarylations of nitriles with pyridine‐derived N‐oxides using gold carbenes as initiators. These oxoarylations were also achieved satisfactorily in intermolecular three‐component oxidations, including diverse alkenyldiazo esters, nitriles, and pyridine‐based oxides.     

Chirality Transfer and Memory of Chirality in Gold‐Catalyzed Reactions

Over the last few years, gold‐catalyzed reactions that involved chirality transfer and memory of chirality (MOC) have emerged as a powerful tool in enantioselective synthesis. This technique has allowed for the single‐step synthesis of enantioenriched compounds from readily available starting materials. This Focus Review discusses this emerging field with an emphasis on mechanistic aspects and their applications in synthetic organic chemistry.     

Gold‐Catalyzed Diastereoselective Cycloisomerization of Alkylidene‐Cyclopropane‐Bearing 1,6‐Diynes

An unprecedented gold‐catalyzed diastereoselective cycloisomerization of 1,6‐diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2‐trimethylenenorbornanes, which are important building blocks in the preparations of abiotic and sesquiterpene core structures.     

Mechanistic Intricacies of Gold‐Catalyzed Intermolecular Cycloadditions between Allenamides and Dienes

The mechanism of the gold‐catalyzed intermolecular cycloaddition between allenamides and 1,3‐dienes has been explored by means of a combined experimental and computational approach. The formation of the major [4+2] cycloaddition products can be explained by invoking different pathways, the preferred ones being determined by the nature of the diene (electron neutral vs. electron rich) and the type of the gold catalyst (AuCl vs. [IPrAu]⁺, IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazole‐2‐ylidene). Therefore, in reactions catalyzed by AuCl, electron‐neutral dienes favor a concerted [4+3] cycloaddition followed by a ring contraction event, whereas electron‐rich dienes prefer a stepwise cationic pathway to give the same type of formal [4+2] products. On the other hand, the theoretical data suggest that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF₆, the mechanism involves a direct [4+2] cycloaddition between the diene and the gold‐activated allenamide. The theoretical data are also consistent with the observed regioselectivity as well as with the high selectivity towards the formation of the enamide products with a Z configuration. Finally, our data also explain the formation of the minor [2+2] products that are obtained in certain cases.     

Ruthenium‐Catalyzed trans‐Selective Hydrostannation of Alkynes

In contrast to all other transition‐metal‐catalyzed hydrostannation reactions documented in the literature, the addition of Bu₃SnH across various types of alkynes proceeds with excellent trans selectivity, provided the reaction is catalyzed by [Cp*Ru]‐based complexes. This method is distinguished by a broad substrate scope and a remarkable compatibility with functional groups, including various substituents that would neither survive under the conditions of established Lewis acid mediated trans hydrostannations nor withstand free‐radical reactions. In case of unsymmetrical alkynes, a cooperative effect between the proper catalyst and protic functionality in the substrate allows outstanding levels of regioselectivity to be secured as well.     

Highly Efficient Gold‐Catalyzed Synthesis of Dibenzocycloheptatrienes

Dibenzocycloheptatrienes are obtained by a gold‐catalyzed 7‐exo‐dig hydroarylation protocol in a highly efficient manner. The gold‐catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and efficient access to dibenzocycloheptanoids, which are an interesting and unique class of natural products. This was underlined by the first total synthesis of reticuol.     

Oxidative Interception of the Hydroamination Pathway: A Gold‐Catalyzed Diamination of Alkenes

A complimentary diamination of alkenes by using homogeneous gold catalysts is described. The reaction is one of very few examples of homogeneous gold oxidation catalysis and proceeds with high selectivity under mild conditions. Individual steps of the suggested catalytic cycle were investigated on isolated model gold complexes, and new pathways for gold‐catalyzed amination reactions were established. The key step is an intramolecular alkyl–nitrogen bond formation from a gold(III) intermediate. This process validates the concept of reductive elimination from high oxidation catalyst states for this type of C? N bond forming reactions.     

Gold‐Catalyzed Formal Dehydro‐Diels–Alder Reactions of Ene‐Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and Mechanistic Studies

A new protocol for the synthesis of a variety of N‐containing aromatic heterocycles by a formal gold‐catalyzed dehydro‐Diels–Alder reaction of ynamide derivatives has been developed. Deuterium‐labeling experiments and kinetic studies support the involvement of a dual gold catalysis mechanism in which a gold acetylide moiety adds onto an aurated keteneiminium.     

Gold‐Catalyzed Oxa‐Povarov Reactions for the Synthesis of Highly Substituted Dihydrobenzopyrans from Diaryloxymethylarenes and Olefins

Oxa‐Povarov reactions involving readily available diaryloxymethylarenes and aryl‐substituted alkenes are reported. Their [4+2] cycloadditions were efficiently catalyzed by IPrAuSbF₆ (IPr=1,3‐bis(diisopropylphenyl)imidazol‐2‐ylidene) with high diastereoselectivity. Product analysis revealed that the reactions likely proceed by a stepwise ionic mechanism, because both E‐ and Z‐configured β‐methylstyrene gave the same cycloadducts in the same proportions.     

Rhodium‐Catalyzed Alkene Difunctionalization with Nitrenes

The Rh^II‐catalyzed oxyamination and diamination of alkenes generate 1,2‐amino alcohols and 1,2‐diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides an efficient method for the preparation of pyrrolidines, and the intermolecular reaction produces vicinal amines with orthogonal protecting groups. These alkene difunctionalizations proceed by aziridination followed by nucleophilic ring opening induced by an Rh‐bound nitrene generated in situ, details of which were uncovered by both experimental and theoretical studies. In particular, DFT calculations show that the nitrogen atom of the putative [Rh]₂=NR metallanitrene intermediate is electrophilic and support an aziridine activation pathway by N ??? N=[Rh]₂ bond formation, in addition to the N ??? [Rh]₂=NR coordination mode.     

Enantioselective Copper‐Catalyzed Quinoline Alkynylation

A highly enantioselective copper‐catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole‐based chiral biaryl P,N ligand, and copper bromide to effect a three‐component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)‐galipinine, (+)‐angustureine, and (?)‐cuspareine are reported.