Alkynylation with Hypervalent Iodine Reagents

Alkynes are among the most versatile functional groups in organic synthesis. They are also frequently used in chemical biology and materials science. Whereas alkynes are traditionally added as nucleophiles into organic molecules, hypervalent iodine reagents offer a unique opportunity for the development of electrophilic alkyne synthons. Since 1985, alkynyliodonium salts have been intensively used for the alkynylation of nucleophiles, in particular soft carbon nucleophiles and heteroatoms. They have made an especially strong impact in the synthesis of highly useful ynamides. Nevertheless, their use has been limited by their instability. Since 2009, more stable ethynylbenziodoxol(on)e (EBX) reagents have been identified as superior electrophilic alkyne synthons in many transformations. They can be used for the alkynylation of acidic C–H bonds with bases or aromatic C–H bonds using transition metal catalysts. They were also highly successful for the functionalization of radicals or transition metal-catalyzed domino processes. Finally, they allowed the alkynylation of a further range of heteroatom nucleophiles, especially thiols, under exceptionally mild conditions. With these recent developments, hypervalent iodine reagents have definitively demonstrated their utility for the efficient synthesis of alkynes based on non-classical disconnections.

Photoredox-Catalyzed Decarboxylation for the Transfer of Alkynes and Nitriles Using Hypervalent Iodine Reagents

Franck Le Vaillant

Aliphatic alkynes and nitriles are privileged motifs in organic chemistry. Therefore, alkynes and nitriles have played a central role for the exploration and development of novel strategies to forge C-C bonds in efficient manner. They are broadly used as versatile building blocks for applications in every fields of chemistry, from pharmaceuticals to material sciences. Alkynes are also of paramount importance in chemical biology for labelling experiments due to their bio orthogonality. In this context, radical chemistry provides endless alternatives to nucleophilic and electrophilic alkynylation and cyanation reactions. For decades, organic chemists have designed and improved the structure of alkynylating reagents in order to enhance the efficiency of group transfer process. Methods enabling alkynylation and cyanation of alkyl radicals have emerged and while providing useful tools, they set the basis for further improvements. Notably, the formation of alkyl radicals is limited to harsh conditions using peroxides, elevated temperature and radical initiators. To overcome these major limitations, photoredox catalysis has emerged as a powerful tool for the generation of alkyl radicals under ambient conditions. The combination of photocatalysts and alkynylating reagents allowed the photoredox-catalyzed alkynylation of organoboron trifluoroborates salt and N-phtalimide esters. In this regard, the goal of my PhD was first to extend the photoredox catalyzed alkynylation to carboxylic acids. Indeed, carboxylic acids are broadly available from biomass, and widely occurring in drugs and fine chemicals, thus making them attractive starting materials. Their conversion to alkynes would provide efficient disconnections for the construction of Csp3-Csp, and find useful applications in chemical biology. Ethynyl Benziodoxolone (EBX) reagents, CsOBz and iridium photocatalysts were identified as a promising combination for the development of this novel transformation, in which silyl, aryl and alkyl substituted alkynes were transferred. ï¡ïamino, ï¡ïoxy and non-heteroatom stabilized radicals could be alkynylated in good to excellent yields upon visible light irradiation. This strategy was next applied to the decarboxylative cyanation of carboxylic acids. In that regard, Cyano Benziodoxolone CBX was introduced for the first time in photoredox-catalyzed cyanation. The combination of CBX, CsOBz and the same iridium photocatalyst allowed the smooth conversion of amino and oxy acids to their corresponding nitriles, and this novel method was applied to the synthesis of important intermediates in the synthesis of APIs. During scope investigations, hydantoins were isolated as side products. This background reaction was further optimized as a novel and efficient synthesis of chiral hydantoins starting from amino acids and CBX. Finally, investigations of the reaction mechanisms of the photoredox-catalyzed decarboxylations revealed that the cyanation followed a divergent mechanism compared to alkynylation. A additional redox step between CBX and ï¡-amino radical allows the generation of cyanide and iminium, which upon recombination affords the nitrile product. Then, the second goal of my PhD was to implement the photoredox mediated alkynylation and cyanation to other starting materials. In this regard, the use of carboxylic acids as starting materials to initiate photoredox catalyzed radical fragmentations was an appealing strategy.

EPFL2019

Cyclopropanes and Hypervalent Iodine Reagents: High Energy Compounds for Applications in Synthesis and Catalysis

Jonathan Brand, Filippo De Simone, Stefano Nicolai, Jérôme Waser

One of the major challenges faced by organic chemistry is the efficient synthesis of increasingly complex molecules. Since October 2007, the Laboratory of Catalysis and Organic Synthesis (LCSO) at EPFL has been working on the development of catalytic reactions based on the Umpolung of the innate reactivity of functional groups. Electrophilic acetylene synthons have been developed using the exceptional properties of ethynyl benziodoxolone (EBX) hypervalent iodine reagents for the alkynylation of heterocycles and olefins. The obtained acetylenes are important building blocks for organic chemistry, material sciences and chemical biology. The ring-strain energy of donor-acceptor cyclopropanes was then used in the first catalytic formal honno-Nazarov cyclization. In the case of aminocyclopropanes, the method could be applied in the synthesis of the alkaloids aspidospermidine and goniomitine. The developed methods are expected to have a broad potential for the synthesis and functionalization of complex organic molecules, including carbocycles and heterocycles.

2011

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

Nitrogen-containing compounds are an important class of molecules in medicinal chemistry, chemical biology, biochemistry, material sciences or environmental sciences. Organic nitrogen occurs in many forms, ranging from small building blocks such as urea, amino acids, nucleotides, to complex natural products, drug molecules, proteins, nucleic acids, among others. The transformation of easily-accessed nitrogen-containing building blocks into more complex nitrogen-containing structures is therefore important for the synthesis of bioactive compounds or functional materials. Interested in donor-acceptor aminocyclopropanes and aminocyclobutanes, we first developed a Lewis-acid catalyzed formal [4+1] cycloaddition of donor-acceptor aminocyclobutanes with isocyanides, which resulted in the formation of cyclopentene-1,2-diamines. We then attempted to develop a formal [3+2] cycloaddition of donor-acceptor aminocyclopropanes with electron-deficient alkenes, which was mechanistically inspired by the Morita-Baylis-Hillman reaction. Apart from the donor-acceptor system, we were also attracted by simple aminocyclopropanes without electron-withdrawing group at vicinal position. We anticipated that the incorporation of cyclopropylamine into carboxylic-containing compounds followed by ring opening functionalization reactions could be used for the synthesis of more complex products. Therefore, we first disclosed an oxidative ring-opening strategy to transform acyl, sulfonyl or carbamate protected aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal. Replacing the alkoxy group of the N,O-acetal was achieved under acidic conditions via an elimination-addition pathway, while substitution of the halides by nucleophiles was done under basic conditions via a SN2 pathway, generating a wide range of 1,3-difunctionalized propylamines. Based on the transformation described above, we further discovered an efficient synthesis of 4-amino thiochromans starting from simple aminocyclopropanes and thiophenols through a formal [3+3] annulation reaction. Next, we developed an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the terminal position. Both cheap benzophenone with UV A light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry. Finally, we turned our attention to the synthesis of diamines, which are essential building blocks for the synthesis of agrochemicals, drugs and organic materials, yet their synthesis remains challenging, as both nitrogen moieties need to be differentiated and diverse substitution patterns (1,2-, 1,3 or 1,4) are required. We described a new strategy giving access to 1,2-, 1,3- and 1,4- amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes and cyclobutanes.Other unsuccessful efforts over the last four years have also been described, together with some preliminary results of ring-opening cyanation and arylation reactions.