Reactions of arynes promoted by silver ions.

Arynes are unique aromatic species that display versatile reactivity in a variety of transformations. It has been demonstrated that the reaction profiles of arynes can be altered by transition metal additives, and one of the earliest examples of the metal additive effect was observed with silver ions (Ag(+)). Especially, in the presence of Ag(+), benzyne showed distinctive reactivity and selectivity toward π-nucleophiles compared to the corresponding reaction in its absence. Although more experimental data need to be accumulated to accurately define the Ag(+) additive effect, based on its role displayed in various transformations, we can infer that Ag(+) interacts with arynes to form a reactive intermediate, which behaves like a silver-bound aryl cation or 1,2-carbene-silver carbenoid. In this tutorial review, various aryne-mediated reactions involving Ag(+) or other organosilver species are discussed, which show a bird's-eye view on the Ag(+) effect in aryne chemistry such that further explorations of the unique reactivity of arynes under the influence Ag(+) will be inspired.

Hydrohalogenative aromatization of multiynes promoted by ruthenium alkylidene complexes.

A new functionalization method of arynes promoted by a novel catalytic role of the Grubbs-type ruthenium alkylidene complex is described. Through a sequence of aryne formation followed by their halo-functionalization, various bis-1,3-diynes were directly converted to functionalized aryl chlorides, bromides and iodides in good yields in the presence of a catalytic amount of a ruthenium alkylidene complex and halogenated hydrocarbons such as CH2Cl2, CHCl3, CH2Br2, and CH2I2. The utility of this novel transformation is demonstrated by a formal synthesis of herbindole B.

Synthesis of Phenolic Compounds by Trapping Arynes with a Hydroxy Surrogate.

Trapping of arynes with various nucleophiles provides a range of heteroatom-functionalized arene derivatives, but the corresponding reaction with water does not provide phenol derivatives. Silver trifluroacetate (AgO2CCF3) can nicely solve this problem. It was found that in typical organic solvent, AgO2CCF3 readily reacts with arynes to generate trifluoroacetoxy organosilver arene intermediate, which, upon treating with silica gel, provides phenolic products. This protocol can be extended to the synthesis of α-halofunctionalized phenol derivatives by simply adding NBS (N-bromosuccinimides) or NIS (N-iodosuccinimides) to the reaction along with silver trifluroacetate, which provided α-bromo or α-iodophenol derivatives in good yield. However, the similar reactions with NCS (N-chlorosuccinimides) afforded only the protonated product instead of the expected α-chlorophenols derivatives. Interestingly, substrates containing silyl substituents on 1,3-diynes resulted in α-halotrifluoroacetates rather than their hydrolyzed product. Additionally, trapping the same arynes with other oxygen-based nucleophiles containing silver counter cation, along with NXS (N-halosuccinimides), generated α-halooxyfunctionalized products.

Benzannulation of triynes to generate functionalized arenes by spontaneous incorporation of nucleophiles.

The thermal reaction of ester-tethered 1,3,8-triynes provides novel benzannulation products with concomitant incorporation of a nucleophile. Evidence suggests that this reaction proceeds via an allene-enyne intermediate generated by an Alder-ene reaction in the first step. Depending on the substituent of the alkyne moiety on the allene-enyne intermediate, the subsequent transformation can take one of two different paths, each leading to discrete aromatization products. The benzannulation of a silane-substituted 1,3,8-triynes provides arene products with a nucleophile incorporated onto the newly formed benzene core, whereas an aryl substituent leads to nucleophile trapping at the benzylic carbon atom connected to the aryl substituent. The formation of these two different products results from the involvement of two regioisomeric allene-enyne intermediates.

Reactivity of Enyne-Allenes Generated via an Alder-Ene Reaction.

Tandem transformations of 1,3-diynyl propiolate derivatives are described. The Alder-ene reaction generates an enyne-allene, which undergoes a formal 1,7-H shift or a Diels-Alder reaction, depending on the substituent on the alkyne. A terminal or aryl-substituted alkyne promotes a 1,7-H shift to generate a new enyne-allene, which undergoes a Myers-Saito cycloaromatization followed by a 1,5-H transfer-mediated cyclization to form highly functionalized benzo-fused 6-membered cycles. The reactivity of the preformed enyne-allene shows comparable reactivity profiles.

Studies Targeting Ryanodol Result in an Annulation Reaction for the Synthesis of a Variety of Fused Carbocycles.

An annulation reaction is described to access a range of polycyclic and highly oxygenated carbocycles. First developed in an approach to the synthesis of ryanodol, metallacycle-mediated annulative diketone-alkyne coupling defines a framework for realization of new retrosynthetic relationships for complex molecule synthesis. In addition to demonstrating this reaction in the context of forging distinct carbocyclic systems, including those featuring a seven-membered ring, the choice of quenching reagent leads to unique reaction outcomes.

A Complementary Process to Pauson-Khand-Type Annulation Reactions for the Construction of Fully Substituted Cyclopentenones.

A complementary process to the Pauson-Khand annulation is described that is well suited to forging densely substituted/oxygenated cyclopentenone products (including fully substituted variants). The reaction is thought to proceed through a sequence of metallacycle-mediated bond-forming events that engages an internal alkyne and a ß-keto ester in an annulation process that forges two C-C bonds. A variant of this annulation process has also been established that delivers deoxygenated cyclopentenones that lack the allylic tertiary alcohol.

Reactivity of Arynes for Arene Dearomatization.

An unprecedented aryne-mediated dearomatization reaction is described. An aryne intermediate generated from arenesulfonyl ynamide-tethered triynes and tetraynes reacts with both the π-systems of a tethered alkene and the arenesulfonyl group to generate cyclohexa-1,3-diene-containing pentacyclic and hexacyclic frameworks. Density functional theory (DFT) calculations show a nucleophilic dearomatization mechanism involving a zwitterionic intermediate derived from an aryne. A novel halogen effect on the efficiency of the dearomatization and deterrence of aromatization of the cyclohexa-1,3-diene moiety was also observed.

Total Synthesis of Selaginpulvilin C and D Relying on in Situ Formation of Arynes and Their Hydrogenation.

The total syntheses of selaginpulvilins C and D is described. The key strategy for the construction of the core fluorene moiety involves in situ formation of an aryne intermediate followed by its formal hydrogenation. The precursor tetraynes that undergo aromatization via hexadehydro Diels-Alder reaction were prepared from readily available building blocks through typical alkyne-coupling reactions.

Benzannulation of Triynes Initiated by an Alder-Ene Reaction and Subsequent Trifluoromethylthiolate Addition.

A new benzannulation reaction with accompanied trifluoromethylthiolation is described. This benzannulation can generate a range of trifluoromethylthiolated benzolactams and benzolactones from 1,3,8-triynes and a stoichiometric amount of AgSCF3 at 90 °C through an initial Alder-ene reaction, 1,4-addition of AgSCF3, and a series of bond-reorganization processes that include double bond migration, 6π-electrocyclization, and a [1,3]-H shift. For certain substrates containing a triisopropylsilyl (TIPS) group, the final [1,3]-H shift-interrupted products, were obtained.

Regioselectivity in the nucleophile trapping of arynes: the electronic and steric effects of nucleophiles and substituents.

The regioselectivity in nucleophile trapping is investigated with arynes generated directly from bis-1,3-diynes. The regioselectivity is profoundly influenced by not only the nature of nucleophiles but also the substituents on the arynes, which is the consequence of both the unfavorable steric interaction between the incoming nucleophile and the nearby substituent and the inherent electronic bias induced by different substituents on the arynes.

Alder-ene reactions of arynes.

Efficient Alder-ene reactions of various arynes generated directly from bis-1,3-diynes are described. The reactivity of ene donors with different tethers was examined under thermal and metal-catalyzed conditions, which indicates that both the formation of aryne intermediates and their ene reactions are less sensitive to the catalyst than to the structural features of the substrates.