Benziodoxol(on)e Reagents as Tools in Organic Synthesis: The Background behind the Discovery at the Laboratory of Catalysis and Organic Synthesis

In this review, a personal account of our work in the field of hypervalent iodine reagents is presented. Pioneering experiments, which led to the discovery of the exceptional reactivity of EthynynnnlBenziodoXol( on)e (EBX) reagents as electrophilic alkyne synthons is first discussed, including the alkynylation of ketoesters, olefins and heterocycles. Our further work involving EBX reagents in domino reactions and the alkynylation of thiols, as well as the use of benziodoxole reagents for azidation reactions is then described. Finally, the most recent results involving radicals and carbenes as reaction partners for EBX reagents and their first use in chemical biology are presented. The purpose of this review is not to give an extensive overview of our results, but to show the 'true story' beyond the discovery by presenting the most important pioneering experiments. Failed attempts and near misses are also briefly discussed

Radical Alkynylations with EthynylBenziodoXolones: from Photocatalysis to Direct Excitation

Ethynylbenziodoxolones (EBXs) have recently emerged as potent reagents for the alkynylation of radicals. Their combination with photocatalysis allows the synthesis of valuable alkynes at room temperature. Herein, we discuss two photomediated strategies for the synthesis of internal alkynes. The first transformation is a 1,2-oxyalkynylation of N- and O-alkenes using 4ClCzIPN as a photocatalyst. The second strategy makes use of EBXs as strong photooxidants allowing the oxidation of a variety of substrates with no need for a photocatalyst

Pd(0)-Catalyzed Oxy- and Aminoalkynylation of Olefins for the Synthesis of Tetrahydrofurans and Pyrrolidines

The first Pd(0)-catalyzed intramolecular oxy- and aminoalkynylation of nonactivated olefins is reported. The reaction gives access to important tetrahydrofuran and pyrrolidine heterocycles with high diastereoselectivity. The unique synthetic potential of acetylenes is further exploited to access key building blocks for the synthesis of bioactive natural products

A Highly Chemoselective and Practical Alkynylation of Thiols

A thiol-alkynylation procedure utilizing the hypervalent iodine alkyne transfer reagent TIPS-ethynyl-benziodoxolone has been developed. This scalable reaction proceeds in five minutes at room temperature in an open flask using commercially available reagents. The scope of the reaction is broad, with a variety of phenolic, benzylic, heterocyclic, and aliphatic thiols undergoing alkynylation in excellent yield. The method is highly chemoselective as a vast array of functional groups are tolerated. The utility of the thiol-alkynylation in postsynthetic elaboration has been demonstrated through the facile installment of a fluorophore tag on a cysteine-containing peptide

One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ Aminal Formation and Carboamination

A synthesis of vicinal diamines via in situ aminal formation and carboamination of allyl amines is reported. Employing highly electron-poor trifluoromethyl aldimines in their stable hemiaminal form was key to enable both a fast and complete aminal formation as well as the palladium-catalyzed carboamination step. The conditions developed allow the introduction of a wide variety of alkynyl, vinyl, aryl, and hetereoaryl groups with complete regioselectivity and high diastereoselectivity. The reaction exhibits a high functional-group tolerance. Importantly, either nitrogen atom of the imidazolidine products can be selectively deprotected, while removal of the aminal tether can be achieved in a single step under mild conditions to reveal the free diamine. We expect that this work will promote the further use of mixed aminal tethers in organic synthesis

Palladium-Catalyzed Vicinal Amino Alcohols Synthesis from Allyl Amines by In Situ Tether Formation and Carboetherification

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

Decarboxylative Alkynylation and Cyanation of Carboxylic Acids using Photoredox Catalysis and Hypervalent Iodine Reagents

Alkynes and nitriles are important functional groups that serve as versatile building blocks in organic synthesis and find applications in material and medicinal sciences. A convenient and straightforward access to both classes of compounds under mild conditions is, therefore, highly desirable. Herein, we disclose the decarboxylative alkynylation and cyanation of broadly available carboxylic acids using photoredox catalysis and hypervalent iodine reagents. Choices of both catalysts and reagents were crucial. Computational and experimental studies revealed two different possible mechanisms that are dictated by the oxidation potential of the reagents: radical for alkynylation, ionic for cyanation

Room temperature alkynylation of H-phosphi(na)tes and secondary phosphine oxides with ethynylbenziodoxolone (EBX) reagents

Highly efficient protocols for the alkynylation of H-phosphi(na)tes and secondary phosphine oxides with silyl, aryl and alkyl ethynyl-benziodoxolone (EBX) reagents are reported. Alkynyl phosphorus compounds were obtained in 69-93% yield without the need for a transition metal catalyst at room temperature under open flask conditions

Cyclic Hypervalent Iodine Reagents and Iron Catalysts: The Winning Team for Late-Stage C-H Azidation

1+1=3: by combining the exceptional properties of benziodoxolone reagents and iron catalysts, Sharma and Hartwig have achieved an important breakthrough for the late-stage C-Hazidation of complex molecules. Nevertheless, moderate yields and selectivities were still observed for some substrates, and our understanding of the reaction mechanism remains underdeveloped. Indeed, the potential of combining base-metal catalysts and cyclic hypervalent iodine reagents for the discovery of new reactions has just begun to be investigated, and many more exciting discoveries await us in the future. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim