In the last decade photoredox catalysis has emerged as an important new tool for organic chemists. The especially mild conditions and the broad range of reactions accessible using this methodology had a beneficial effect on the exploitation of radical reactions on otherwise labile substrates. Herein we report our work in this fast developing area and our efforts into the double functionalisation of styrenoid double bonds. We disclosed a new methodology for the room temperature photoredox catalysed alkoxy- and amino-arylation of styrenes using diaryl iodonium tetrafluoroborates and diazonium salts as aryl radical precursors. This methodology allows the successful regioselective coupling of three disparate components together and can be expanded to a wide range of alcohol nucleophiles, nitriles and water in moderate to good yields. The mild conditions employed permit the effective reaction of electron-rich styrenes and the tolerance of halogen functionalities, thus opening the possibility to further molecular elaboration. We then moved to explore the possibility of oxymethylnitrilation of styrenes and of the sysnthesis of heterocyclic cores via internal trapping with a nucleophile. Pleasingly, we were able to develop a mild and general methodology for the methylnitrilation of styrenes using simple and cheap bromoacetonitrile and photoredox catalysis. Furthermore, the synthesis of tetrahydrofuran and dihydrofuran cores was achieved in a single step, allowing us to synthesise tricyclic cores, maintaining functionisable handles such as halogens and ester groups. Finally, we decided to explore the possibility to add an azide functionality. After extensive optimisation, we were pleased to discover reaction conditions allowing for a switchable reactivity: under light irradiation we could perform an azidation reaction followed by addition of a nucleophile of choice; excluding the light from the reaction conditions, we could perform a double azidation reaction. The mild reaction conditions ensured the previously observed tolerance of functional groups; furthermore, we used a more sustainable copper-based photoredox catalyst.

Over the past decade, the field of photoredox catalysis has garnered increasing amounts of attention in the organic chemistry community due to its wide applicability in sustainable free radical-mediated processes. Several examples have demonstrated that under carefully optimized conditions, efficient and highly selective processes can be developed through excitation of a photosensitizer using inexpensive, readily available light sources. Furthermore, these reactions can generally be performed under milder conditions than thermal reactions, as all the energy required to overcome the reaction barrier is supplied by light. Despite all these recent advancements in the field, many of these discoveries often lack in depth investigations into the excited state kinetics and underlying mechanisms. Furthermore, the vast majority of these transformations are photocatalyzed by ruthenium and iridium polypyridyl complexes. Not only are these precious metal catalysts extremely costly, but these metals are also known to be toxic, limiting their potential use in the development of pharmaceutical protocols. Herein, we present our solutions to these shortcomings, which involve a three-prong approach in the development of novel protocols, understanding the underlying mechanisms through detailed kinetic analysis, and by the development of new tools to facilitate mechanistic investigation for practitioners who may not possess specialized photochemical equipment. In this work, we were the first to demonstrate that radicals derived from amines, commonly employed as “sacrificial” electron-donors, can also act as reducing agents in photoredox transformations. We also present examples in which Methylene Blue, an inexpensive, non-toxic organic dye, can be employed as a viable alternative to ruthenium complexes for photoredox transformations. By employing a photosensitizer with more favourable excited state kinetics for electron-transfer, we successfully demonstrated that Methylene Blue could be used to increase the efficiency of a previously developed photoredox transformation. While employing organic dyes is an excellent strategy to lowering the cost of photoredox transformations, another viable strategy is to employ heterogeneous semiconductors. Titanium dioxide is an example of a semiconductor which is often employed in photocatalytic applications due to its low cost, desirable redox properties, and high chemical stability which allows for continued use. However, titanium dioxide has seen limited use in organic synthesis due to the requirement of UV irradiation for excitation. Herein, we present a process which led to the discovery of visible light photochemistry with titanium dioxide, generated through the adsorption of indole substrates creating a new, visible light absorbing complex. Employing this strategy, we were able to promote the photocatalytic Diels–Alder reaction of indoles with electron-rich dienes, giving access to valuable tetrahydrocarbazole scaffolds. Finally, in order to facilitate the characterization of chain processes in photoredox catalysis, we have successfully developed a visible light actinometer based on the ubiquitous photocatalyst, Ru(bpy)3Cl2. This actinometer offers many advantages compared to other visible light actinometers, such as completely eliminating the need for spectral matching, as the actinometer is also the photocatalyst. This technique should provide researchers with a mechanistic tool to properly characterize chain propagation in the transformation of interest.

A field in bloom: photoredox catalysis has allowed chemists access to highly reactive intermediates via the photo-mediated excitation of transition metal complexes and organic dyes for the mild generation of free radicals. These complexes and dyes are designed based on Nature’s blueprints of light-harvesting biomolecules that transform solar energy (photons) into chemical energy during photosynthesis. Light-mediated chemical activation is regarded as one of the most sustainable forms of chemical activation being that the energy provided by the sun is considered renewable and largely underutilized and presents an attractive avenue for research and development of new transformations that are mild, efficient, and waste-limiting in organic synthesis. Radical chemistry and photochemistry are united in their inherent ability to undergo single (or photoinduced) electron transfers by one-electron reaction modes. Combining these unique fields, photoredox catalysis has emerged as a mild and efficient alternative to classic alkyl radical generation using hazardous initiators and organostannanes. Photoredox catalysis has been dominated by ruthenium- and iridium-based polypyridyl complexes. These complexes are limited by their inherent redox potentials, restricting their reactivity towards relatively activated bonds. Nonactivated bromoalkanes and arenes are considered challenging substrates to engage using redox chemistry and typically only accessible in the realm of organostannane chemistry. Described herein are the efforts towards the discovery of free radical based organic transformations derived from nonactivated bromoalkanes and arenes mediated by photochemical excitation of polynuclear gold(I) complexes as photoredox catalysts. This work represents some of the first uses of a photoredox catalyst in the reduction of substrates having such high reduction potentials and offers a practical and useful alternative to classic radical reactions mediated by initiators (peroxides, persulfates, and azo compounds) and toxic organostannanes (Bu3SnH). Using gold based photoredox catalysts, the research conducted has provided many methodological advancements for the mild and efficient formation of carbon-carbon bonds using nonactivated bromoalkanes and a large collection of radical acceptors. Establishing the use of these photoexcited polynuclear gold(I) complexes in the context of classic radical reactions in organic synthesis was important for their validation as useful photocatalysts. First, the Ueno-Stork cyclization of nonactivated bromoalkanes was used to demonstrate the powerful reducing capabilities of the excited-state gold(I) complexes. Next, a photo-mediated variant of the Appel reaction was described, where the transformation of an alcohol to a bromoalkane was achieved using carbontetrabromide and N,N-dimethylformamide through the intermediacy of a Vilsmeier-Haack reagent. In combination with the hydrodebromination chemistry developed with photoexcited polynuclear gold(I) complexes, a photo-mediated one-pot formal deoxygenation reaction of alcohols was described; a useful alternative to the organostannane mediated Barton-McCombie deoxygenation reaction. Finally, in the field of medicinal chemistry, the functionalization of heteroarenes is of high interest for the discovery of drug candidates and bioactive molecules. In this respect, one of the most useful reactions for the functionalization of heteroarenes by alkyl radicals is the Minisci reaction using silver salts, carboxylic acids, and persulfates. Detailed are the efforts for the development of a photo-mediated redox-neutral improvement of the Minisci reaction, needing only gold(I) photocatalyst and nonactivated bromoalkane in the presence of heteroarenes. Overall, the work described in this thesis represents the push for mild and efficient alternatives to the relatively harsh conditions and/or toxic reagents and byproducts associated with classic radical chemistry. These studies demonstrate the ability to control highly reactive alkyl radical intermediates with the goal of their broader application in synthetic organic chemistry. The use of photoexcited polynuclear gold(I) complexes as potent reductants compared to ruthenium- and iridium-based polypyridyl complexes is illustrated through the genesis of highly reactive alkyl radicals from nonactivated bromoalkanes.

Thesis advisor: Matthias M. Waegele / Studying the visible light-driven photoredox catalysis coupled with transition-metal complexes is of overriding importance in the development of synthetic strategy. Comparing to conventional thermal catalysis, reactions catalyzed and/ or initiated by photon energy are not only attractive for establishing a more sustainable system, but also for their unique reactivity that has previously been inaccessible. However, one issue draws our attention is that such photoredox catalytic schemes often suffer from a limited substrate scope. To develop more efficient and effective synthetic strategies applicable to broader range of substrates, it is of our interest to construct an functional and reliable instrument to identify the critical mechanistic steps that lead to low product yield. To this end, we designed a time-resolved visible-pump/ infrared-probe spectroscopic measurement technique to monitor reaction dynamics in-situ. Using our transmission infrared setup, we effectively demonstrated in-situ photoexcitation and decay process of Tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate in deuterated acetonitrile. In addition, to optimize signal resolution, an electronic filter was installed in one of the data-collecting channels to allow for concurrent AC-coupled and DC-coupled signal recording. A series of chopper wheel experiments was conducted to assure the functionality of the system and reliability of obtained data. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Nitrogen-centred radicals (NCRs) are powerful reaction intermediates that allow key bonds to nitrogen to be formed. However, the generation of NCRs typically requires pre-functionalised precursors that can be difficult to access and harsh reaction conditions in the formation of the NCR itself which has limited synthetic application. In this thesis, the application of visible-light mediated photoredox catalysis towards the generation of iminyl and amidyl radicals is demonstrated and the advances to NCR chemistry this has facilitated. Initial work developed electron-poor O-aryl oximes as suitable precursors for hydroimination reactions, activated via single-electron reduction under photoredox conditions. These precursors are accessible by a simple condensation reaction with the commercially available hydroxylamine and can be purified by recrystallization. The realisation of a transition metal-free protocol was made possible by using the organic dye eosin Y as the photocatalyst. This activation mode was then extended to the generation of (carb)amidyl-radicals from easy-to-make O-aryl hydroxylamides. Similar transition metal-free photoredox reaction conditions could be applied in intramolecular hydroamidation reactions allowing the preparation of lactams and cyclic (thio)carbamates. For the first time N-Boc and N-Cbz protected amidyl-radicals were utilised despite the very high electrophilic nature of these species. Finally, one of the big challenges associated with NCR chemistry was addressed; the development of multicomponent reactions for the divergent synthesis of complex N-containing molecules. Previously developed O-aryl precursors proved unsuitable and instead a novel class of alpha-imino acid precursors were identified that can be activated via oxidation under photoredox conditions. This activation mode was also rendered transition metal-free by using the Fukuzumi photoredox catalyst. These new NCR precursors proved crucial in developing a divergent methodology that allows the synthesis of up to fifteen iminofunctionalised products from a single starting material. Moreover, this methodology could be applied to the modification of complex natural products such as immunosuppressant drug mycophenolic acid and alkaloid thebaine. One could envisage such an approach may be ideal for a drug discovery type situation where changes in functionality can greater alter drug activity.

This thesis concerns the development of novel catalytic approaches for the construction of stereocentres bearing a nitrogen atom. In 2011, the Dixon group reported a Ag(I)/cinchona-derived amino phosphine catalytic system for the activation of isocyanoacetates in asymmetric aldol and Mannich reactions. During this thesis work it was sought to extend the scope of this catalytic system to Mannich additions of other isocyanide pronucleophiles, then the focus was broadened to include Reformatsky and α-alkylation reactions of ketimine substrates. Chapter 1 gives an overview of the state of the art with particular emphasis on catalytic enantioselective additions to ketimines and the use of activated isocyanides as pronucleophiles. Chapter 2 describes the application of the Ag-catalysed enantio- and diastereoselective aldol reaction of isocyanoacetates to the concise asymmetric synthesis of the antibiotic chloramphenicol, which possesses a chiral stereodefined α-amino β-hydroxy motif. Chapter 3 details our efforts to expand the scope of the Ag(I)/amino phosphine catalytic system to the activation of more challenging isocyanides lacking an electron-withdrawing group in the α-position by investigating aldol and Mannich reactions of benzyl isocyanide. Chapter 4 describes how the scope of the Ag(I)/amino phosphine catalytic system was successfully extended to another pronucleophile, the versatile p-toluenesulfonylmethyl isocyanide (TosMIC). The first catalytic enantio- and diastereoselective addition of TosMIC to N-diphenylphosphinoyl (N-DPP) ketimines was developed, affording 2-imidazolines possessing two contiguous stereocentres with high yields and excellent levels of stereocontrol. Chapter 5 describes the development of a Ni(II)-catalysed Reformatsky reaction of N-DPP ketimines with ethyl bromoacetate and diethylzinc, providing racemic amines bearing a quaternary stereocentre in the α-position in good yields. Chapter 6 reports the serendipitous discovery of the α-alkylation of N-DPP ketimines with ethyl bromoacetate using visible light photoredox catalysis. The transformation, catalysed by ruthenium(II) and nickel(II) complexes under mild conditions, was optimised, its scope assessed and the mechanism investigated.

L’atome de fluor est un élément essentiel de notre quotidien. Il est indispensable pour le développement des batteries, de la réfrigération (Fréon), des cristaux liquides qui constituent nos écrans de téléphone ou encore des matériaux (Téflon®). Mais c’est surtout dans les sciences du vivant que le fluor joue un rôle primordial. L’introduction d’un atome de fluor modifie les propriétés physico-chimiques d’une molécule, permettant ainsi de moduler et d’améliorer profondément son activité biologique. Son introduction dans les molécules organiques représente donc un défi majeur pour les chimistes, qui nécessite sans cesse le développement de nouveaux réactifs de fluoration et perfluoroalkylation.Parmi ceux-ci, les sulfoximines perfluorées sont des réactifs de perfluoroalkylation électrophile, nucléophile ou radicalaire. De plus, les sulfoximines perfluorées possèdent des propriétés singulières ayant des applications en sciences des matériaux et du vivant.Mes travaux de thèse s’inscrivent dans la volonté de notre laboratoire de mettre au point une nouvelle voie d’accès générale aux sulfoximines fluorées ainsi qu’à la synthèse de sulfoximines hautement fonctionnalisées. Ma thèse a également pour but l’étude des sulfilimino iminiums, dont la synthèse dérive de celle des sulfoximines et qui sont des réactifs très efficaces et polyvalents pour des réactions perfluoroalkylation par catalyse photoredox. / Fluorine atom is essential in our everyday life. It is necessary for the development of battery, refrigeration (Fréon), liquid crystals which constitute the screens of phones, or materials (Téflon®). But its main role is in life sciences. The introduction of a fluorine atom modifies the physical and chemical properties of organic molecules, allowing to modulate and to enhance their biological activities. Its introduction in organic molecules constitutes a key challenge for chemists, which necessitates continually the development of new reagents for fluoration or perfluoroalkylation reactions. Among these, perfluorinated sulfoximines are electrophilic, nucleophilic or radical perfluoroalkylating reagents. Moreover, perfluorinated sulfoximines have peculiar properties with uses in material or life sciences.My PhD work falls within the project of our laboratory to develop a new general acces to perfluorinated sulfoximines and the synthesis of highly functionalized sulfoximines. My PhD work also deals with the synthesis of sulfilimino iminiums, derived from sulfoximines, which are efficient and versatile reagents for visible light-induced perfluoroalkylation reactions.

Développement de méthodes d'α,β-fonctionnalisation d'amines et formation d'hétérocycles optiquement actifs via l'utilisation de l'organocatalyse et de la catalyse photoredox. / Development of methods α,β-functionalization of amines andformation of optically active heterocycles via the use of the organocatalysis and thephotoredox catalysis.

Substituted heterocycles are common building-blocks for biologically relevant molecules and represent challenging synthetic targets. Due to limited methods available for their preparation and derivatization, direct C-H functionalization protocols offer considerable advantages. Radical chemistry has shown great potential in this regard; however traditional approaches are unattractive due to poor selectivity and harsh reaction conditions. Visible light photoredox catalysis, on the other hand, is a mild alternative for alkyl radical generation and has proven its utility in organic synthesis. The work encompassed in this thesis details the efforts towards the development of practical photoredox-based functionalizations of heterocycles. Specific focus is placed upon overcoming obstacles pertaining to H-atom abstraction, back electron transfer, and redox strength of photocatalysts to achieve efficient C-Br bond reductions, amine oxidations, and C-C bond formations. In pursuit of these objectives, a C2-selective malonation of indoles and other electron-rich heteroarenes was accomplished in high yields using photocatalyst Ru(bpy)3Cl2, p-CH3OC6H4NPh, and blue LEDs as the light source. Use of a triarylamine over a trialkylamine suppressed H-atom abstraction and promoted C-C bond formation. Subsequent exploitation of the reductive quenching cycle of Ru(bpy)3Cl2 and use of Cl3CBr as an alternative oxidant led to an oxidative nucleophilic trapping of tetrahydroisoquinolines to provide a diverse set of analogues. Finally, photoredox catalysis was utilized for the creation of C-C bonds in the context of complex molecule synthesis. A variety of bromopyrroloindolines and indoles were coupled to furnish C3-C3' and C3-C2' bisindole alkaloids, which was successfully applied to the total synthesis of gliocladin C and related analogues. Moreover, fine-tuning of the redox cycle with photocatalyst Ir(ppy)2(dtbbpy)PF6 and LiB(cat)2 as the reductive quencher enabled the coupling less-reactive substrates and suppression of back electron transfer.

Indiana University-Purdue University Indianapolis (IUPUI) / Alkyl radicals are powerful intermediates for the generation of carbon-carbon bonds, which play an indispensable role in the synthesis of natural products, pharmaceuticals, and pesticides. Traditionally, there are two main methods for the generation of alkyl radicals. The first is C-H bond functionalization via hydrogen-atom-transfer (HAT). HAT processes have been used as an effective approach for selectively activating C-H bonds via radical pathways. The other strategy to explore the generation of alkyl radicals is C-X bond functionalization via halogen-atom-transfer (XAT). Alkyl halides are one of the largest classes of building blocks in synthesis and they can be obtained from the corresponding alcohols. The most straightforward and effective way to form such alkyl radicals is the direct homolytic cleavage of C-X bonds. In past decades, photoredox catalysis has emerged as a powerful and greener tool for the synthesis of radicals under mild reaction conditions, which has brought tremendous attention. Although remarkable success has been made in this field, some methods still require costly transition metal catalysts or toxic reagents. Herein, we display a series of visible light-induced approaches under transition-metal free conditions or using earth-abundant metals. These novel photo-induced transformations and corresponding mechanistic work will be discussed in the following order: We will first present our work on metal-free visible-light-promoted C(sp3)-H functionalization of aliphatic cyclic ethers using trace O2. This reaction uses a trace amount of aerobic oxygen as the sole green oxidant under blue light at room temperature to achieve the synthesis of sulfone and phosphate derivatives in good to excellent yields using cyclic ethers and vinyl sulfones. Then, we report on a photo-induced C(sp3)-H chalcogenation of amide derivatives and ethers via a ligand-to-metal charge-transfer. This reaction converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-N,S-acetal derivatives in good yields, using an earth abundant metal catalyst under mild conditions. Finally, we present a photoredox polyfluoroarylation of alkyl halides via halogen atom transfer. This method converts primary, secondary, and tertiary unactivated abundant alkyl halides into the corresponding polyfluoroaryl compounds in good yields and has good functional group compatibility.