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

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.

Development of New Strategies of Umpolung with Cyclic Hypervalent Iodine Reagents

Paola Caramenti

Organic chemistry is essential for the development of a modern society and technical progress requires the continuous development of synthetic methodologies Novel, efficient, selective and flexible protocols are employed to access complex frameworks from simple starting materials. However, classical synthetic methods often relies on the intrinsic reactivity of functional groups, reducing the portfolio of available reactions for synthetic chemists. The reversal of classical reactivity of functional groups allows alternative disconnection pathways and can improve synthetic efficiency. The research presented in this thesis was aimed at the development of new strategies of Umpolung with hypervalent iodine reagents. Three new Umpolung methods have been investigated. First a strategy for the synthesis of enantioenriched Î±-cyano Î±-allyl ketones has been developed. Second, novel indole- and pyrrole-based hypervalent iodine reagents have been synthesized and applied in the context of metal-catalysis ad metal-free transformations. Third, a new class of umpoled enamides and enol ethers have been prepared from simple starting materials. Î±-Cyano carbonyls are important structural motifs of bioactive compounds and natural products. Nitriles are also versatile building blocks that undergo a plethora of transformations, which are usually accessed by transfer of the nucleophilic cyanide anion to electrophiles. The reactivity of cyanide can be reversed by the use of hypervalent iodine reagents. Part I focus on the application of umpoled nitriles for the functionalization of carbonyls. With these reagents, a variety of Î²-keto esters were successfully cyanated in racemic fashion. Inspired by previous results obtained in our group, a decarboxylative asymmetric allylic alkylation strategy was applied for the synthesis of enantioenriched quaternary Î±-cyano Î±-allyl ketones embedded in an indanone framework. Cyclic indanone derivatives were accessed in good yields and enantioselectivities. Indole and pyrrole heterocycles are often embedded in relevant drugs, natural products and materials. Their ubiquity inspired decades of intensive research for both their synthesis and functionalizations. Especially functionalization methods mainly focused on their intrinsic nucleophilic properties. The field exploiting their electrophilic derivatization was severely underdeveloped. An alternative strategy to access electrophilic indole and pyrrole synthons takes advantage of the unique properties of hypervalent iodine. In Part II of this thesis, indole- and pyrrole-based benziodoxoles were prepared and used for the metal-catalyzed direct indole transfer on aromatic CâH bonds. A large variety of indole-aryl frameworks, previously elusive or accessed via multi-step syntheses, were accessed in a straightforward manner, starting from simple commercially available building blocks. A direct oxidative metal-free cross-coupling for the synthesis of mixed bi-(hetero)aryl-indoles was then developed. The reaction worked well with our previously synthesized reagents, and a new class of electrophilic indoles (activated at the C2 carbon) was specifically developed for this transformation, further expanding the pool of available benziodoxoles.

EPFL2019

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.

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

Development of New Strategies of Umpolung with Cyclic Hypervalent Iodine Reagents

Paola Caramenti

EPFL2019

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

Franck Le Vaillant

EPFL2019

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

EPFL2020