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

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.

Room-Temperature Decarboxylative Alkynylation of Carboxylic Acids Using Photoredox Catalysis and EBX Reagents

Thibaut Christian Courant, Franck Le Vaillant, Jérôme Waser

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 alpha-amino and alpha-oxo acids derived from biomass.

Wiley-Blackwell2015

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

New Strategies for the Functionalization of Alkenes Exploiting Tethering Chemistry and Ring Strain

Bastian Antoine Rodolphe Claude Muriel

Amino alcohols, cyclopropanes and nitriles are privileged structural motifs found in the scaffold of natural products and bioactive compounds. In addition, they are versatile building blocks in organic chemistry. The development of new and increasingly efficient synthetic methods to access these chemical motifs from readily available feedstocks is therefore highly desirable. In this context, alkenes have been substrates of choice to rapidly access complex molecules, as two new functionalities can be installed across their double bond. To achieve such transformations, palladium catalysis and radical chemistry stand as two of the most efficient strategies. In this thesis, a new palladium-catalyzed carboamination of allylic alcohols using a trifluoroacetaldehyde-based tether was first investigated. The tether could be easily installed on diverse allylic alcohol substrates, the formed hemiaminals underwent in high yield and diastereoselectivities the desired transformation under optimized conditions. Both alkynyl- and aryl-bromides could be used as electrophilic partners in the reaction. For the latter, in order to supress a competitive Heck-pathway, a new phosphine-based ligand âFuXPhosâ had to be developped and was key to reach high yields for the aminoarylation in combination with CsOTf as additive. The tether in the obtained products could be cleaved under acidic conditions delivering valuable amino alcohol derivatives. This difunctionalization strategy mediated by palladium was then applied to the strained alkene of cyclopropenes. While preliminary results for the intramolecular carbo-amination and carbo-etherification of cyclopropenes could be obtained, the difficulty to access the starting materials for these transformations led to consider a more convergent approach to access functionalized cyclopropanes. Using radical chemistry, a novel synthesis of bicyclo[3.1.0]hexanes could be developed, by a (3+2) annulation of cyclopropylanilines with cyclopropenes mediated by photoredox. The scope of the transformation was broad for both reaction partners, but the products were obtained with low diastereoselectivities. It was found that by combining difluorocyclopropenes with a bulky aromatic N-substituent on the cyclopropylamine, the corresponding fluorinated bicyclo[3.1.0]hexanes could be accessed in good yields and diastereoselectivities under slightly re-optimized conditions. Finally, the possibility to achieve an amination reaction of cyclopropenes using N-centered radicals was investigated. It was discovered that the addition of azidyl radicals to the double bond of cyclopropenes under photoredox conditions led to the formation of two new products coming from an unexpected ring cleavage: an alkenyl nitrile and a quinoline. While the formation of the quinoline product could not be optimized above 47% yield, conditions could be found for the selective formation of the alkenyl nitrile in high yields using cheap and commercial reagents. Through the scope investigations it was discovered that an aryl-substituent on the double bond of the cyclopropene substrates was necessary for the transformation to proceed. Despite this limitation various substrates could be engaged in the transformation and delivered the corresponding alkenyl nitriles in high yields. With 1,2-diaryl substituted cyclopropenes a synthesis of valuable polycyclic aromatic compounds could be developed, through a one pot radical amination / oxidative cyclization.