Copper-catalyzed transformations of carboradicals generated by electrochemical and photochemical methods: oxidative amination and polyfluoroarylation

Organic radicals are highly active species that can undergo various transformations. Electrochemistry and photochemistry are efficient methods for the generation of these species of high energy, through single electron transfer processes under mild conditions. These methods have been frequently used to form various carboradical intermediates, for example, via the addition of N-centered radicals to alkenes (Section 1.4). Copper is a versatile transition metal that can transform carboradicals for the formation of various chemical bonds (Section 1.6). Combining electrochemistry or photochemistry for the generation of carboradicals with the copper-catalyzed carboradical functionalization will potentially lead to a large chemical space of useful organic reactions. So far, this intersection of electrochemistry or photochemistry with copper chemistry is still highly underdeveloped. In this thesis, we have developed three useful reactions, testifying the practicability of this concept.In Chapter 2, we describe an intramolecular oxidative amination reaction by integrating electrochemical oxidation with Cu catalysis. Electrochemical oxidation facilely generates N-radical from N-H for the intramolecular cyclization to double bonds, and then the resultant carboradicals are transformed into a new double bond via copper-catalyzed oxidative elimination (Section 1.6.1). A wide range of 5-membered N-containing heterocycles bearing a pendant, functionalizable alkene moiety can be synthesized under mild conditions. Mechanistic studies revealed that direct oxidation on the electrode couldn't efficiently convert primary and secondary alkyl radical intermediates into alkenes, and that the assistance of copper was indispensable.In Chapter 3, an intermolecular oxidative amination reaction of unactivated alkenes by integrating photoredox with Cu catalysis is described. This method relied on photochemical reduction of a hydroxyamine derivative to generate amidyl radical which then adds to unactivated alkenes. The obained carboradicals are trapped by the copper catalyst to form allylic amines. The reaction exhibited a broad scope and excellent tolerance for functional groups including highly polar groups. In Chapter 4, we report a decarboxylative coupling reaction of aliphatic acids with polyfluoroaryl nucleophiles by integrating photoredox with copper catalysis. A set of polyfluoroaryl zinc reagents were prepared and applied to the coupling. The aliphatic esters of N-hydroxyphthalimide (NHPI esters) were transformed into alkyl radicals by photoreduction. Then, the trapping of the radical by the copper catalyst and subsequent reductive elimination render the alkyl polyfluoroarenes as products. This method allows the installation of polyfluoroaryls with variable F-content (2F -5F) and F-substitution patterns on primary or secondary alkyl groups, with good compatibility of functional groups. In summary, this thesis demonstrates the combination of electrochemistry and photochemistry with copper catalysis to construct useful synthetic methods. Considering the diversity of radicals that could be generated by electrochemical and photochemical methods, and the versatility of copper catalyzed functionalization of carboradicals, we believe that this combination has far more potential than these three reactions.

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

Nickel-catalyzed Hydrosilylation of Alkenes and Transition-Metal-Free Intermolecular α-C-H Amination of Ethers

Ivan Buslov

Transition-metal-catalyzed hydrosilylation of olefins is one of the most important methods for the preparation of organosilicon compounds, which have broad applications in both synthetic and material chemistry. For decades, precious metals, principally platinum-based complexes, have been utilized as catalysts for olefin hydrosilylation. However, due to the high and volatile cost and low abundance of Pt, the development of active and selective catalysts based on Earth-abundant metals is highly desirable. In the first chapter, a short overview of state-of-the-art Pt catalysts and recent advances in development of Fe, Co and Ni-catalysts for olefin hydrosilylation is given. The applications, mechanisms and remaining challenges of transition-metal-catalyzed hydrosilylation are discussed. In the chapter 2, chemoselective anti-Markovnikov hydrosilylation of functionalized alkenes using well-defined bis(amino)amide nickel pincer complexes is described. The catalysts exhibit both high turnover frequencies and turnover numbers. Alkenes containing amino, ester, amido, ketone, and formyl groups are selectively hydrosilylated with Ph2SiH2. Chemoselective hydrosilylation of carbon-carbon double bond in the presence of formyl group using a base metal catalyst is reported for the first time. A modification of reaction conditions allows tandem isomerization-hydrosilylation reactions of internal alkenes to give terminal alkyl silanes. Hydrosilylation of alkenes with tertiary silanes is more attractive from practical point of view. The screening of various nickel alkoxide complexes with reduced steric bulk led us to discovery of an efficient heterogeneous catalyst for alkene hydrosilylation with commercially relevant tertiary silanes (chapter 3). The catalyst exhibits high activity in anti-Markovnikov hydrosilylation of unactivated terminal alkenes and isomerizing hydrosilylation of internal alkenes. The catalyst can be applied to synthesize a single terminal alkyl silane from a mixture of internal and terminal alkene isomers. Furthermore, the same catalyst can be used to remotely functionalize an internal alkene derived from a fatty acid. Chapter 4 describes a catalytic system composed of a nickel amido(bisoxazoline) complex and NaOtBu for an unexpected synthetic transformation, leading to the synthesis of functionalized alkyl hydrosilanes from readily available alkenes and alkoxysilanes. This method provides a convenient and safe alternative to hydrosilylation using flammmable and potentially dangerous Me2SiH2, MeSiH3 and SiH4. The reaction mechanism was also described. Efficient and atom-economical creation of C-N bond is one of the major tasks in synthetic organic chemistry. Direct C-H amination has emerged as an attractive method for the construction of new C-N bonds. In the chapter 5 a new transition-metal free method for the intermolecular amination of the alpha-C-H bonds of ethers is described. Using a hypervalent iodine reagent as oxidant the amination of cyclic and acyclic alkyl ethers with a wide range of amides, imides, and amines was achieved. The utility of this method was demonstrated in the synthesis of Tegafur and its analogues. This transition-metal-free method provides a rapid access to a large number of nitrogen-containing organic molecules that may serve as useful synthetic intermediates or biologically active agents.

EPFL2016

Suzuki-Miyaura cross-coupling of non-activated alkyl halides catalyzed by well-defined nickel pincer complexes

Thomas Clément Di Franco

Metal-catalyzed cross-coupling reactions are powerful and widespread methods for the carbon-carbon bond formation. Among the electrophile partners, non-activated alkyl halides remain challenging substrates because of their reluctance towards oxidative addition and their tendency to undergo the competitive ß-hydride elimination reaction. Due to the stability, availability and low toxicity of boron reagents, the Suzuki-Miyaura reaction is one of the most advantageous cross-coupling reaction. This dissertation is devoted to the development of Ni-catalyzed Suzuki-Miyaura reactions of non-activated alkyl halides. Chapter 2 describes the alkyl¿alkyl and alkyl¿aryl Suzuki¿Miyaura reactions of unactivated alkyl halides catalyzed by a well-defined pincer complex, Nickamine (1). The coupling of 9-alkyl-9-borabicyclo[3.3.1]nonane and 9-phenyl-9-borabicyclo[3.3.1]nonane (9-BBN) reagents with primary alkyl halides was achieved in modest to good yields. The reactions tolerated a variety of useful functional groups including ester, ether, furan, thioether and acetal. Reaction attempts with other boron reagents are also presented. In chapter 3, the first Ni-catalyzed Suzuki¿Miyaura coupling of alkyl halides with alkenyl-(9-BBN) reagents is reported. Both primary and secondary alkyl halides including alkyl chlorides can be coupled. The coupling method can be combined with hydroboration of terminal alkynes, allowing the expedited synthesis of functionalized alkyl alkenes from readily available alkynes with complete (E)-selectivity in one-pot. The method was successfully applied to the total synthesis of (±)-Recifeiolide, a natural macrolide. Replacement of a dimethyl amino group of the amidobis(amine) nickel(II) pincer complex (1), [(MeN2N)Ni¿Cl], by a pyrrolidino group resulted in a new nickel(II) pincer complex (2), [(PyrNMeNN)Ni¿Cl]. As shown in chapter 4, complex 2 is an efficient catalyst for Suzuki-Miyaura cross-coupling of non-activated secondary alkyl halides, while complex 1 is largely inactive. In contrast to the dimethylamino group in 1, the pyrrolidino group in 2 appears to be ¿hemilabile¿, which explains the significant activity difference towards the coupling of secondary alkyl halides. Synthesis and characterization of a new series of Ni-NNN pincer complexes are presented in chapter 5. No major structural difference was found between the new complexes except for the C-N-C angle of the various substituents of the side arm amino groups. The influence of these substituents on the catalytic performance of the Ni-complexes in alkyl-alkyl Kumada and Suzuki-Miyaura cross-coupling reactions was systematically investigated. No correlation was found between the catalytic activity and the key structural parameter (C-N-C angle), redox properties or Lewis acidity of the complexes. The cross-coupling of secondary alkyl halides is highly desirable since a stereogenic carbon center can be created during the process. Chapter 6 resumes the synthesis of new chiral pincer ligands in order to develop an enantioselective cross-coupling. Chiral centers were first introduced in the pyrrolidino group of the pincer ligand but the resulting Ni-complexes did not succeed in achieving a stereoconvergent reaction. The introduction of an oxazolino group in the pincer ligand structure resulted in more promising Ni-catalysts, efficient for both primary and secondary alkyl halides.

EPFL2016

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

Guido Barzanò

EPFL2020

Nickel-catalyzed Hydrosilylation of Alkenes and Transition-Metal-Free Intermolecular α-C-H Amination of Ethers

Ivan Buslov

EPFL2016

Suzuki-Miyaura cross-coupling of non-activated alkyl halides catalyzed by well-defined nickel pincer complexes

Thomas Clément Di Franco

EPFL2016