Nucleoside analogues are widely employed as bioactive compounds against cancer and viral infections. Consequently, it is important to develop efficient synthetic methods to access them with high efficiency and structural diversity. Herein, we present a full account of our work on the synthesis of nucleoside analogues via annulations of donor acceptor aminocyclopropanes and aminocyclobutanes. Thymine- and uracil-derived diester cyclopropanes were accessed from the corresponding nucleobases via vinylation and rhodium-catalyzed cyclopropanation, and were then used in (3+2) annulations with aldehydes, ketones and enol ethers. The obtained analogues could be transformed into important hydroxymethyl derivatives. Thymine and fluoro-uracil-derived diester cyclobutanes obtained from the nucleobases via vinylation and (2+2) cycloaddition could also be used in a (4+2) annulation with aldehydes. Finally, purine-derived diester cyclopropanes could be accessed using the condensation of nucleobases with chloromethyl ethylidene malonates, but annulation reactions with this class of substrates were not successful.

Hypervalent iodine compounds are privileged reagents in organic synthesis because of their exceptional reactivity. Among these compounds, cyclic derivatives stand apart because of their enhanced stability. They have been widely used as oxidants, but their potential for functional-group transfer has only begun to be investigated recently. The use of benziodoxol(on)es for trifluoromethylation (Togni's reagents) is already widely recognized, but other transformations have also attracted strong interest recently. In this Review, the development in the area since 2011 will be presented. After a short summary of synthetic methods to prepare benziodoxol(on)e reagents, their use to construct carbon–heteroatom and carbon–carbon bonds will be presented. In particular, the introduction of alkynes by using ethynylbenziodoxol(on)e (EBX) reagents has been highly successful. Breakthroughs in the introduction of alkoxy, azido, difluoromethyl, and cyano groups will also be described.

Hypervalente Iodverbindungen nehmen als Reagentien in der organischen Synthese aufgrund ihrer außergewöhnlichen Reaktivität eine Sonderstellung ein. Unter ihnen ragen cyclische Derivate wegen ihrer erhöhten Stabilität heraus. Sie finden zwar weitreichende Anwendung als Oxidationsmittel, die Erforschung ihrer Möglichkeiten zum Transfer funktioneller Gruppen begann jedoch erst kürzlich. Während die Verwendung von Benziodoxol(on)en zur Trifluormethylierung (Togni-Reagens) schon weitgehend anerkannt ist, erfuhren vor kurzem auch andere Transformationen große Aufmerksamkeit. Der vorliegende Aufsatz bespricht die Entwicklungen auf diesem Gebiet seit 2011. Nach einer kurzen Zusammenfassung der Methoden zur Synthese von Benziodoxol(on)reagentien wird ihre Verwendung zum Aufbau von Kohlenstoff-Heteroatom- und Kohlenstoff-Kohlenstoff-Bindungen diskutiert. Äußerst erfolgreich war die Einführung von Alkinen mithilfe von Ethinylbenziodoxol(on)(EBX)-Reagentien. Durchbrüche bei der Einführung von Alkoxy-, Azido-, Difluormethyl- und Cyangruppen werden ebenfalls vorgestellt.

Alkynes are used as building blocks in synthetic and medicinal chemistry, chemical biology, and materials science. Therefore, efficient methods for their synthesis are the subject of intensive research. Herein, we report the direct synthesis of alkynes from readily available carboxylic acids at room temperature under visible-light irradiation. The combination of an iridium photocatalyst with ethynylbenziodoxolone (EBX) reagents allowed the decarboxylative alkynylation of carboxylic acids in good yields under mild conditions. The method could be applied to silyl-, aryl-, and alkyl- substituted alkynes. It was particularly successful in the case of α-amino and α-oxo acids derived from biomass.

Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium-catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes.

A new method for the cyanation of thiols and disulfides using cyanobenziodoxol(on)e hypervalent iodine reagents is described. Both aliphatic and aromatic thiocyanates can be accessed in good yields in a few minutes at room temperature starting from a broad range of thiols with high chemioselectivity. The complete conversion of disulfides to thiocyanates was also possible. Preliminary computational studies indicated a low energy concerted transition state for the cyanation of the thiolate anion or radical. The developed thiocyanate synthesis has broad potential for various applications in synthetic chemistry, chemical biology and materials science.

Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium-catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes.

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum-catalyzed cyclization/alkynylation domino process to selectively obtain C5- or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.

Alkynes are used as building blocks in synthetic and medicinal chemistry, chemical biology, and materials science. Therefore, efficient methods for their synthesis are the subject of intensive research. Herein, we report the direct synthesis of alkynes from readily available carboxylic acids at room temperature under visible-light irradiation. The combination of an iridium photocatalyst with ethynylbenziodoxolone (EBX) reagents allowed the decarboxylative alkynylation of carboxylic acids in good yields under mild conditions. The method could be applied to silyl-, aryl-, and alkyl- substituted alkynes. It was particularly successful in the case of α-amino and α-oxo acids derived from biomass.

Indoles are omnipresent in natural products, bioactive molecules, and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene-ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Reported herein is a platinum-catalyzed cyclization/alkynylation domino process to selectively obtain C5- or C6-functionalized indoles starting from easily available pyrroles. The work combines, for the first time, a platinum catalyst with ethynylbenziodoxole hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine-, uracil-, and 5-fluorouracil-substituted diester donor–acceptor cyclopropanes and their use in the indium- and tin-catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine-, uracil-, and 5-fluorouracil-substituted diester donor–acceptor cyclopropanes and their use in the indium- and tin-catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.

Herein, we report a detailed study on the electrophilic alkynylation of cyclic keto esters and amides with ethynylbenziodoxolone (EBX) reagents. The structure and stability of this class of reagents is first described more in details. Differential scanning calorimetry (DSC) experiments showed a strong exothermic decomposition with EBX reagents, leading to guidelines for the safe use of these compounds. The extension of the method to aromatic alkynes and a broad range of benziodoxol(on)e reagents is then reported. Based on our preliminary results using Cinchona-based phase-transfer catalysts, the enantioselective alkynylation of cyclic keto esters could be achieved. Binaphthyl-derived ammonium catalysts developed by Maruoka and co-workers gave the highest asymmetric induction with up to 79% ee for an indanone-derived keto ester. Throughout this work, asymmetric induction was observed only in the case of benziodoxolone reagents, demonstrating their superiority over conventional alkynyliodonium salts. The deeper understanding gained about the factors leading to higher asymmetric induction will be very useful in the future to develop a truly general and highly enantioselective alkynylation method.

Over the last fifteen years, gold has been raised from the status of an inert noble metal to one of the most-often-used catalysts in synthetic chemistry. The functionalization of the triple bond of alkynes has been especially successful in this respect. In contrast, gold-catalyzed alkynylation reactions only began to emerge in 2007. Since then, three different approaches have been successfully used for this transformation. 1) Gold nanoparticles have been shown to promote catalytic cycles based on the oxidative arylation of aryl halides to give a “palladium-free Sonogashira reaction”. 2) The use of benziodoxol(on)e hypervalent iodine compounds as oxidative alkynylation reagents has allowed the CH functionalization of electron-rich heterocycles under mild conditions with a very broad functional-group tolerance. 3) The use of iodobenzene acetate or Selectfluor as an external oxidant has led to the first alkynylation methods based on direct CH/CH coupling reactions. In only six years, gold-catalyzed alkynylation methods have grown from non-existent to useful synthetic procedures for the synthesis of structurally diverse alkynes. Considering that acetylenes are among the most-important building blocks for applications in synthetic chemistry, chemical biology, and materials science, there is tremendous potential for the further development of gold-catalyzed alkynylation reactions in the future.

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.

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.