In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand 5 tremendously the scope of acetylene transfer reactions. The use of metal catalysis has recently led to a rebirth of this research area. Halogenoalkynes, hypervalent alkynyliodoniums, acetylene sulfones and in situ oxidation of terminal acetylenes are the most often used for electrophilic alkynylation. Heteroatoms such as N, O, S and P can be now efficiently alkynylated. For C-C bond formation, electrophilic acetylenes can be coupled with different organometallics reagents. Recently, the first breakthrough in 10 direct C-H and C=C bond alkynylation have also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals.

This report describes a full study of the gold‐catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3‐ and 6‐position of triisopropylsilylethynyl‐1,2‐benziodoxol‐3(1H)‐one (TIPS‐EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2‐pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.

In the last decades, hypervalent iodine reagents have raised from chemical curiosities to mainstream reagents in organic synthesis. The use of benziodoxole-derived reagents has been especially successful in oxidation methods, whereas non-cyclic iodinanes have been used both for oxidation and atom-transfer reactions. On the other hand, the exceptional properties of 10 benziodoxole reagents for atom-transfer reactions have only started to attract the attention of the synthetic community more recently. In this review, progress in the use of these compounds for C-X and C-C bond formations will be presented. In particular, recent breakthroughs in trifluoromethylation and alkynylation reactions have been realized since 2006 bas ed on benziodoxole-derived reagents and these results are the main focus of this article.

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Hot alkyne! The in situ generation of ethynyl‐1,2‐benziodoxol‐3(1H)‐one (EBX) from a silyl‐protected reagent by using TBAF is reported. EBX displayed exceptional acetylene transfer ability onto stabilized enolates (see scheme), even at −78 °C. The mild reaction conditions allowed the first ethynylation reactions of linear keto, cyano, and nitro esters in high yields to give all‐carbon quaternary centers or non‐natural amino acids after selective reduction of the nitro group.

The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.Since the first synthesis of indole by Baeyer almost 150 years ago, 1 interest in the preparation and functionalization of this privileged heterocycle has constantly grown.2 Indoles can indeed be found in numerous important molecules such as pharmaceuticals, dyes and natural products. Consequently, methods to synthesize and modify this heterocycle are of utmost importance in organic chemistry. † New Address: Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Freiburg, Germany.(1 This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/full/10.1021/ol3031389 groups among others. 8 In several cases, the C2/C3 regioselectivity of these functionalizations could be controlled by the reaction conditions or using directing groups. 4,9 Despite the important applications of acetylenes in synthetic chemistry, biochemistry, and material sciences, 10 there are only a few methods for the direct alkynylation of the indole core.11 In 2009, Gu and Wang first introduced the C3-selective alkynylation of indoles using bromoacetylenes and a Pd catalyst.11a C2-selective alkynylation is especially challenging and only two examples have been reported so far. Li and co-workers described an oxidative Heck-Cassar-Sonogashira type method for the alkynylation of 1,3-dimethylindole.11f This reaction could be applied to a broad scope of acetylenes, but only 3-methylindoles were reported. More recently, a method for the alkynylation of lithiated indoles using ethynylsulfonates as reagents was reported by Garcia Ruano and co-workers.11g,h Depending of the sterical hinderance of the substituent on the indole nitrogen, C2 or C3 alkynylation could be obtained. Nevertheless, the requirement for a strong base such as butyl lithium limited the scope of this transformation. Consequently, the most frequently used methods to access 2-alkynylated indoles are often based on the formation of the heterocycles via cyclisation reactions. 3(1H)-one (TIPS-EBX, 2)13 as an efficient reagent for the gold-catalyzed C3 alkynylation of indoles (Scheme 1). During our first investigation, palladium catalysts gave only traces of product, albeit with very high C2 selectivity. 11b We later demonstrated that efficient acetylene transfer with Pd catalysts was possible for the amino-and oxy-alkynylation o...

A method for the para selective alkynylation of anilines is reported using AuCl as catalyst and triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) as an electrophilic acetylene equivalent. Para-alkynyl anilines substituted at positions 2 or 3 were obtained in one step from simple anilines under mild conditions (room temperature to 60 °C) under air. The methodology could also be extended to the alkynylation of trimethoxybenzenes.Heteroarylacetylenes are important structures in both organic synthesis and material sciences.1 They are versatile building blocks thanks to the large number of transformations available based on the functionalization of the triple bond. In addition, both aromatics and acetylenes have been successfully used in extended π systems for organic electronic materials.2 In order to access heteroarylacetylenes, the Sonogashira reaction is one of the most popular methods for sp 2 -sp bond formation.3 However, the main drawback of this method is the required prefunctionnalization of the sp 2 carbon. Numerous methods have been developed in the field of C-H arylation in order to avoid this prefunctionalization of aromatics.

SummaryThe Au(III)-catalyzed cyclization of 2-alkynylanilines was combined in a one-pot procedure with the Au(I)-catalyzed C3-selective direct alkynylation of indoles using the benziodoxolone reagent TIPS-EBX to give a mild, easy and straightforward entry to 2-substituted-3-alkynylindoles. The reaction can be applied to unprotected anilines, was tolerant to functional groups and easy to carry out (RT, and requires neither an inert atmosphere nor special solvents).