Photochemical Alkynylations with Hypervalent Iodine Reagents

Over the past twenty years, photochemical transformations have gained in importance in organic chemistry. Indeed, the development of photocatalysts has allowed the use of visible light as an energy source for chemical transformations. More specifically, photoredox chemistry has emerged as a valuable tool for the generation of free radical intermediates, enabling the organic chemist to envisage new bond disconnections and bond formations.For the organic chemist, the triple CïºC bond, or alkyne, is a versatile functional group. Alkynes are valuable building blocks for accessing more complex scaffolds. They also have multiple applications in medicinal chemistry, materials science, and chemical biology. Hence, the development of strategies that give access to alkynes is highly relevant. Due to the innate electronics of the alkyne, its transfer was initially limited to the alkynylation of electron-poor positions (electrophiles), however the development of alkyne transfer reagents have allowed the alkynylation of electron-rich positions (nucleophiles), and, more recently, the alkynylation of radicals. Specifically, ethynylbenziodoxolones (EBXs), hypervalent iodine (III) reagents bearing an alkyne, have frequently been used for the alkynylation of radicals. In combination with photochemical conditions they have enabled the activation of multiple functional groups (for example: carboxylates, potassium alkyl trifluoroborates salts, or Î±-oxo C-H bonds) for the introduction of an alkyne.The first objective of this research was to enable the photochemical difunctionalisation of double bonds to allow the introduction of an alkyne and a second functional group using EBXs. Indeed, difunctionalisation strategies are highly valuable as they can allow a rapid increase in molecular complexity in a single step. We found that enamides and enol ethers could undergo an alkynylative difunctionalisation with EBXs in presence of a photocatalyst and a hypervalent iodine additive. This method gave access to 1-alkynyl-1,2-aminoalcohols and diols scaffolds, which can be selectively deprotected to deliver the free alcohol or free amine.The second objective of this thesis was to develop a deoxyalkynylation strategy to allow the conversion of alcohols into alkynes. Starting from cesium oxalates, in presence of a photocatalyst and the EBX reagent, we could access a broad scope of aliphatic arylalkynes. Interestingly, the key to success for this project was found in the choice of light source: to ensure high yields, two high intensity blue LED lamps (440 nm, ca. 80 W) were required. During our mechanistic studies we discovered that this light source could also generate an excited state EBX species. We then decided to explore this discovery: we were delighted to find that the EBX alone under irradiation could promote the photomediated alkynylation of carboxylates, trifluoroborates, enamides, imines and Î±-oxo C-H bonds. Although the understanding of this process is still in the preliminary stages, we believe that the discovery of the direct photoexcitation of EBXs will enable facile reaction discovery and complement photocatalysed strategies.

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

C-C and C-N bonds are some of the most common structures in molecules ranging from drugs to catalysts and to food additives. Many coupling reactions were developed to form these types of bonds with excellent selectivity and good performance. Still, the synthesis of some of those species either depends on traditional methods or requires expensive and rare reagents and catalysts. The use of precious metals in chemistry, and particularly in the industry, can make molecular synthesis expensive and energy-intensive since the extraction of those materials is costly. Moreover, in homogeneous catalysis, the recovery of metal-based catalysts is almost impossible, making these processes unsustainable for the future. Thus, the discovery of chemical reactions that donât involve precious materials is indispensable. This thesis concentrates on the development of two chemical transformations, one performing an sp2-sp3 radical reductive coupling, one performing a photocatalyzed alkyl amination, involving inexpensive reagents and catalysts. The first chapter reviews the existing methodologies which use alkyl radicals to form carbon-carbon and carbon-nitrogen bonds. Alkyl radicals are formed from alkyl halides and pseudo-halides (Acids, esters, tosylates, etc.) via oxidation or reduction performed by metal or photoredox catalyst. The wide variety of available methodologies was illustrated, highlighting the advantages and weaknesses of each reaction. The second chapter of this dissertation is devoted to the development of a new iron-based catalytic method to form stereoselectively Z-alkene boron species from the corresponding boron-alkyne. This novel stereoselective method opens a new way to obtain these types of molecules with cheap reagents, in high yields, with excellent stereoselectivity (Z:E ratio >10:1), and with good tolerance of functional group. The reaction is radical based, avoiding the problem of beta-hydride elimination, which usually occurs in ionic reactions involving metal centers. In order to prove the versatility of this method, the vinyl boron compound formed from this reaction was used for further functionalizations. The formal total synthesis of a 5-HT2c receptor agonist was successfully performed, improving the overall yield of the process, and avoiding the use of expensive and polluting chemicals. The third chapter of this thesis is concentrated on the development of a tandem photoredox/metal base catalyzed functionalization of anilines and imines with alkyl carboxylic esters. In this reaction, no late transition metal is used, and the traditional metal-based photocatalyst is substituted with an inexpensive and more efficient organic dye. The alkylation of amines is a challenging topic in organic chemistry and classical nucleophilic substitution lacks selectivity and scope. Harvesting visible light with a photoredox catalyst opens the possibility to a radical pathway, making this coupling easy and with high tolerance for functional groups. In order to understand the catalytic cycle of the reaction, additional mechanistic studies were conducted, leading to some insight on how this reaction works.

EPFL2020

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.