Jonathan P. Brand

Electrophilic alkynylation: the dark side of acetylene chemistry

In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand 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 oxidized terminal acetylenes are the most often used reagents 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 organometallic reagents. Recently, the first breakthrough in direct C-H and C[double bond, length as m-dash]C bond alkynylation has also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals.

Direct Alkynylation of Thiophenes: Cooperative Activation of TIPS–EBX with Gold and Brønsted Acids

United we stand! Cooperative activation of the hypervalent-iodine reagent TIPS-EBX with a gold catalyst and a Bronsted acid allowed the first direct ethynylation of thiophenes at room temperature (see scheme; TFA=trifluoroacetic acid). The obtained ethynylthiophenes are important building blocks for organic dyes and electronic materials.

Gold‐Catalyzed Regioselective Synthesis of 2‐ and 3‐Alkynyl Furans

Keywords: C-H functionalization ; domino reactions ; furans ; gold ; hypervalent iodine Reference EPFL-REVIEW-189600doi:10.1002/anie.201302210View record in Web of Science Record created on 2013-10-01, modified on 2017-08-01

Ethynyl-1,2-benziodoxol-3(1 H)-one (EBX): An Exceptional Reagent for the Ethynylation of Keto, Cyano, and Nitro Esters

Hot alkyne! The in situ generation of Ethynyl-1,2-BenziodoXol-3(1H)-one (EBX) from the corresponding silyl protected reagent using TBAF is reported. EBX displayed exceptional acetylene transfer ability to stabilized enolates, 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.

Ethynyl Benziodoxolones for the Direct Alkynylation of Heterocycles: Structural Requirement, Improved Procedure for Pyrroles, and Insights into the Mechanism

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.

C2-selective direct alkynylation of indoles.

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.

Para-Selective Gold-Catalyzed Direct Alkynylation of Anilines

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.

One-pot gold-catalyzed synthesis of 3-silylethynyl indoles from unprotected o-alkynylanilines.

Summary The 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).

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX.

Summary The selective functionalization of peptides containing only natural amino acids is important for the modification of biomolecules. In particular, the installation of an alkyne as a useful handle for bioconjugation is highly attractive, but the use of a carbon linker is usually required. Herein, we report the gold-catalyzed direct alkynylation of tryptophan in peptides using the hypervalent iodine reagent TIPS-EBX (1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one). The reaction proceeded in 50–78% yield under mild conditions and could be applied to peptides containing other nucleophilic and aromatic amino acids, such as serine, phenylalanine or tyrosine.