Development of Carbonyl Functionalization Methods Towards Sustainable Synthetic Strategies Method Development in Organic Chemistry Sara Bacaicoa García Department of Chemistry and Molecular Biology 2025 Doctoral Thesis Submitted to fulfill the requirements for the degree of Doctor of Philoso- phy in Natural Science with a specialization in Chemistry Doctoral Dissertation in Organic Chemistry Department of Chemistry and Molecular Biology University of Gothenburg May 2025 © Sara Bacaicoa García Cover layout: Oil on canvas titled 1800s Chemist. Author: Sara Bacaicoa García Printing: Kompendiet AB, Gothenburg, Sweden, 2025 ISBN: 978-91-8115-234-0 (PRINT) ISBN: 978-91-8115-235-7 (PDF) Series name: SL05 Dedicated to my mother, Esperanza García, my father, Luis Bacaicoa, my brother, Asier Bacaicoa, and all my grandparents, aunts, uncles and cousins for their endless support during my doctoral thesis. Also dedicated to my wonderful friends that accompanied me during these times. Abstract Carbonyl compounds represent a fundamental and versatile class of organic mole- cules that play a central role in both synthesis and biology. In synthetic chemistry, traditional methods for carbonyl functionalization generally involve the use of haz- ardous reagents or the production of large amounts of waste all of which contribute to environmental problems. Consequently, the development of sustainable strategies for carbonyl functionalization is of utmost importance. This thesis explores two strategies for carbonyl functionalization: aerobic oxidative N-heterocyclic carbene (NHC) catalysis and the visible-light induced Zimmerman- O’Connell-Griffin (ZOG) rearrangement. The objective is to develop efficient carbonyl functionalization methods that contribute to the advancement of sustainable chemis- try through the investigation of these strategies. Aerobic oxidative NHC catalysis is a synthetic strategy for the direct conversion of al- dehydes to activated carbonyl species known as acyl azolium intermediates. These in- termediates are pivotal for the synthesis of various substances, including highly sub- stituted benzene derivatives. Within this approach, aerial oxygen is the terminal oxi- dant, a desirable choice due to its cost-effectiveness and the production of water as the sole byproduct. However, the low reactivity of oxygen necessitates the develop- ment of a specialized catalytic system. By incorporating electron transfer mediators to the reactions (ETMs), mild aerobic oxidation conditions can be achieved. These ETM-assisted, aerobic NHC-catalyzed transformations demonstrate high selectivity and reduced waste generation. The ZOG rearrangement represents a strategy for the generation ketenes another form of an activated carbonyl species. In this reaction we use visible light to trigger a rearrangement of a photosensitive substrate leading to in situ formation of the ketene. Ketenes are highly reactive intermediates capable of engaging with a diverse array of substrates, thereby enabling broad synthetic utility. Remarkably, no additional rea- gents or catalysts are needed to trigger this photochemical reaction. With only the re- actants and visible light, a broad range of products can be obtained under mild condi- tions and generating a minimal amount of waste. Key words: acyl azolium, aerobic oxidations, aldehydes, amides, benzene ring con- struction, carbonyl compounds, esters, ETMs, ketenes, NHC, nucleophilic, organoca- talysis, photochemical rearrangement, redox-NHC, sustainable, visible light, ZOG re- arrangement. Sammanfattning Karbonylföreningar är en viktig grupp av organiska molekyler som spelar en central roll inom både kemi och biologi. Traditionella metoder för att förändra dessa molekyler innebär ofta användning av farliga kemikalier och leder till stora mängder avfall, vilket gör dem problematiska ur ett miljöperspektiv. Därför är utvecklingen av mer hållbara strategier en högprioriterad uppgift inom modern kemi. Denna avhandling undersöker två innovativa metoder för att modifiera karbonylföreningar på ett mer miljövänligt sätt: aerob oxidativ N-heterocyklisk karben (NHC)-katalys och den synligt ljusinducerade Zimmerman-O’Connell-Griffin (ZOG)-omlagringen. Målet är att ut- veckla effektiva och hållbara syntesmetoder genom att utnyttja syre från luften och synligt ljus som drivkrafter. Den första metoden, aerob oxidativ NHC-katalys, gör det möjligt att omvandla aldehyder till reaktiva karbonylföreningar med hjälp av luftens syre. Eftersom syre är både billigt och endast producerar vatten som biprodukt, erbjuder detta en grönare lösning än traditionella oxidationsmetoder. Dock krävs specialdesignade katalysatorer och elektronöverföringsme- diatorer (ETM) för att göra processen effektiv. Den andra metoden, ZOG-omlagring, använder synligt ljus för att få en substans att genomgå en omlagringsreaktion och bilda en keten. Ketener är mycket reaktiva och kan användas som mellansteg i reaktioner för att syntetisera en mängd olika moleky- ler med potentiellt olika egenskaper. En av de stora fördelarna med denna metod är att den inte kräver några ytterligare reagens eller katalysatorer, endast ljus och de reaktiva ämnena. Detta minskar avfall och gör processen både energieffektiv och håll- bar. Genom dessa två metoder öppnar forskningen upp nya möjligheter för mer miljövänlig or- ganisk syntes, där naturliga resurser som luftens syre och synligt ljus utnyttjas för att driva kemiska reaktioner på ett hållbart sätt. Nyckelord: acylazolium, aeroba oxidationer, aldehyder, amider, bensenringkon- struktion, karbonylföreningar, estrar, ETM, ketener, NHC, nukleofil, organoka-talys, fotokemisk omarrangemang, redox-NHC, hållbart, synligt ljus, ZOG omarrangemang. Contents 1. Introduction and background: Sustainability in organic synthesis and carbonyl group functionalization .......................................................................... 1 1.1. Sustainability in Synthetic Chemistry ........................................................ 2 1.2. Carbonyl Compounds: Structure and Reactivity ........................................ 6 1.3. Carbonyl functionalization enabled by organocatalysis and aerobic oxidations .......................................................................................................... 9 1.3.1. Organocatalysis ................................................................................................ 9 1.3.2. NHC Organocatalysis: Structure and Reactivity ............................................. 10 1.3.3. Oxidative NHC catalysis ................................................................................ 13 1.3.4. Aerobic oxidative NHC catalysis .................................................................... 15 1.4. Carbonyl functionalization enabled by photochemically generated ketenes ........................................................................................................................ 19 1.4.1. Ketene carbonyl group. Characteristics, generation and reactivity. ................ 19 1.4.2. Photochemically generated ketenes ................................................................ 21 2. Overall objectives .......................................................................................... 23 3. Paper I. Aerobic Oxidative N-Heterocyclic Carbene-Catalyzed [3+3] Cyclization for the synthesis of Trisubstituted Benzene Derivatives ................. 25 3.1. Introduction .............................................................................................. 25 3.2. Results and discussion .............................................................................. 26 3.3. Summary .................................................................................................. 32 4. Paper II. Redox Active N-Heterocyclic Carbenes in Oxidative NHC Catalysis ............................................................................................................................ 33 4.1. Introduction ....................................................................................... 33 4.2. Results and discussion ...................................................................... 34 4.3. Summary ................................................................................................. 43 5. Paper III. Visible-Light-Mediated Late-Stage N-functionalization of Unprotected Peptides: Introducing the aza-Zimmerman-O’Connell-Griffin Reaction .............................................................................................................. 45 5.1. Introduction .............................................................................................. 45 5.2. Results and discussion .............................................................................. 46 5.3. Summary .................................................................................................. 52 6. Conclusion and outlook ................................................................................ 53 7. References ...................................................................................................... 54 Publications This thesis is based on the following publications: I. Aerobic Oxidative N-Heterocyclic Carbene-Catalyzed Formal [3+3] Cy- clization for the Synthesis of Tetrasubstituted Benzene Derivatives. Bacaicoa S.; Goossens, E.; Sundén, H. Org. Lett. 2022, 24, 9146-9150. II. Redox Active N-Heterocyclic Carbenes in Oxidative NHC Catalysis. Bacaicoa S.; Stenkvist, S.; Sundén, H. Org. Lett. 2024, 26, 3114-3118. III. Visible-Light-Mediated Late-Stage N-functionalization of Unprotected Peptides: Introducing the aza-Zimmerman-O’Connell-Griffin Reaction. Bacaicoa S.; Martos, M.; Yhlen Graf, W.; Runemark, A.; Shinde, G.; Ghotekar, G.; Sundén, H. Manuscript, 2025. Publication by the author not included in the thesis: IV. Aerobic Oxidative N-Heterocyclic Carbene Catalysis. Stenkvist S.; Bacaicoa, S.; Goossens, E. Sundén, H. Chem. Rec. 2023, 23, e202300091. Contribution Report Paper I Contributed to the outline of the project. Carried out the experimental work together with Ellymay Goossens, a master student under my supervision. Contributed to the design of the scope of the reaction. Analyzed the results. Wrote the manuscript and SI with Henrik Sundén. Paper II Conducted the experimental work together with Simon Stenkvist, a master student under my supervision. Designed and implemented the kinetic experiments. Contrib- uted to the design of the substrate scope of the reaction. Analyzed the results. Wrote the manuscript and SI with Henrik Sundén. Paper III Participated in the project design. Performed the majority of the experimental work aided by Mario Martos, Wilma Yhlen Graf, August Runemark, Ganesh Shinde and Ganesh Ghotekar. Designed the scope of the reaction. Analyzed the results. Wrote the manuscript and SI with Mario Martos and Henrik Sundén. The contribution report is hereby approved by Prof. Henrik Sundén, supervisor and corresponding author of all papers included in the thesis. iv Acknowledgements Throughout my PhD journey, I have grown not only as a researcher but also as a per- son, and I am grateful for the new experiences that doing a PhD outside my home country has brought me. First and foremost, I would like to express my sincere gratitude to my supervisor, Prof. Sundén, for selecting me as a PhD student and for the opportunity to be part of his research group. His guidance, trust, and scientific insight have been invaluable throughout this work. I am also thankful to my examiner, Prof. Grötli, and to my co-supervisor, Prof. Wallen- tin, for their support and mentorship during my studies. I also wish to acknowledge Prof. Kahn from Chalmers, for being my opponent during my half time seminar, who helped me with an outside perspective of my chemistry. I would like to express my sincere gratitude to the mentors who guided me throughout my academic journey in Spain. To Prof. Navarro Blasco, my bachelor thesis supervisor, for his invested guidance and for introducing me to analytical chemistry. During my undergraduate studies, the inspiring teaching of Dr. Plano Amatriain sparked my pas- sion for organic chemistry and made it my preferred discipline. Dr. Razkin Lizarraga, thanks for being a patient and dedicated mentor during my master thesis and for your support during my PhD. During my doctoral work, I had the opportunity to co-supervise several bachelor and master students. I am proud to have worked alongside Ellymay Goossens, Simon Stenkvist, Madushani Bandara, Wilma Yhlen Graf, Judith Söderlund, and Isabell Johan- son, each of whom demonstrated commitment, curiosity, and perseverance in their projects. It was truly a rewarding experience to see their growth as young scientists. I would also like to thank the past and present members of the Sundén lab: Andrea Ruiu, Savannah Zacharias, Ganesh Ghotekar, August Runemark, Ganesh Shinde, Ekata Saha, Martin Nigríni, Yogesh Patil, and Mario Martos for their camaraderie, scientific discussions, and support throughout the PhD. I truly enjoyed the lunch breaks and conversations shared with Savannah and August about climbing, birds, and other cu- riosities. Mario has also been an incredibly helpful and supportive colleague, always bringing a sense of humor to the lab and group meetings. Within the Department of Chemistry and Molecular Biology, I want to acknowledge Carlos, who not only became a coworker but also a close friend and an important connection to my home country. Andrew, thanks for making the journey more enjoy- able with your British sense of humor. Ishan, it has been a pleasure to share lunch breaks, climbing days, and laughter. Finally, I would like to acknowledge the many others whose presence added to this journey: Luisa, Helal, Anna, Oscar, Hampus, Alex, Alica, Amalyn, Diego, Yeersen, Aishi, Charity, Emil, and Jonathan. Whether it was through shared teaching duties, course- work, or climbing near Chalmers, your company helped make this experience richer and more meaningful. Dr. Lettius, hopefully soon, when someone asks if there’s a doctor in the room, we’ll both be able to say yes (though I can’t promise I’ll be much help). Thank you for the moments we shared, for your trust and friendship, and for making life beyond the uni- versity brighter. Peter, thanks for your support through hard times, for believing in me and for making the time outside the university my best. También reservo mi agradecimiento a mi familia y mis amigos en España, sin vuestro apoyo este viaje habría sido imposible. Muchas gracias a mis padres, Esperanza y Luis, a mi hermano Asier, mis tíos y tías, Ana, Miguel, Maite y Ramón, y a mi querido amigo Pablo por venir a Suecia a ver la defensa de mi tesis doctoral. List of Abbreviations AE Atom Economy CC Circular Chemistry DBE 1,2-dibenzoylethylene DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene DCC N,N′-Dicyclohexylcarbodiimide DCM Dichloromethane DMF Dimethylformamide DMSO Dimethyl Sulfoxide d.r. Diastereomeric ratio ee Enantiomeric Excess EPA Environmental Protection Agency ETM Electron Transfer Mediator FePc Iron phthalocyanine GC-FID Gas Chromatography – Flame Ionization Detector HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HBTU Hexafluorophosphate Benzotriazole Tetramethyl Uronium HCTU 2-(6-Chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylamin- ium hexafluorophosphate hETM Hybrid Electron Transfer Mediator HOBt Hydroxybenzotriazole HOMO Highest Occupied Molecular Orbital HQ Hydroquinone HRMS High Resolution Mass Spectrometry LC-MS Liquid Chromatography – Mass Spectrometry LUMO Lowest Unoccupied Molecular Orbital MW Molecular Weight m. s. Molecular sieves NHC N-heterocyclic carbene NMR Nuclear Magnetic Resonance Q Quinone SI Supplementary Information TBD Triazabicyclodecene TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetra- methylpiperidin-1-yl)oxidanyl TFA Trifluoroacetic Acid THF Tetrahydrofuran TLC Thin Layer Chromatography ZOG Zimmerman O’Connell Griffin 1. Introduction and background: Sustaina- bility in organic synthesis and carbonyl group functionalization Method development. The demand for more efficient use of resources and en- ergy continues to drive the evolution of the chemical industry. Given its significant influence on both society and the environment, the industry faces ongoing pres- sure to implement processes that minimize energy consumption, reduce waste, utilize safer reagents, and rely on sustainable raw materials. In parallel with these economic and environmental goals, the pursuit of new materials and pharmaceu- ticals compels organic chemists to explore novel areas of chemical space. Advance- ments in these areas are linked to the progress in method development within or- ganic synthesis. Method development is fundamental to organic chemistry, enabling the creation of new reactions that expand the synthetic toolbox required to access structurally diverse molecules. A synthetic method can be viewed as a "recipe", a defined se- quence of steps that transforms starting materials into a target compound. The choice of method often depends on factors such as production scale, raw material availability, and energy efficiency. Thus, maintaining a diverse repertoire of syn- thetic strategies is essential to address varying needs across different contexts. Importantly, the development of environmentally benign reactions, as promoted by the principles of green chemistry, is a central objective in modern method de- velopment. Green chemistry aims to reduce the environmental footprint of chem- ical synthesis by minimizing hazardous substances and waste generation. By driv- ing innovation in reaction design and process efficiency, green chemistry plays a pivotal role in shaping safer, more sustainable, and economically viable chemical manufacturing practices. 1 Introduction and Background 1.1. Sustainability in Synthetic Chemistry Paul T. Anastas, an organic chemist involved with the Environmental Protection Agency (EPA), and the chemist John C. Warner introduced the Twelve Principles of Green Chemistry (Table 1) in their book titled "Green Chemistry: Theory and Practice." in 1998.1 The 12 principles were developed to guide the development of sustainable chemical processes in industry. These principles have been founda- tional in promoting sustainable chemistry practices and reducing the environ- mental impact of chemical production. Table 1. The twelve principles of green chemistry. 7. Use of Renewable Feedstocks. Raw materi- 1. Waste Prevention. Preventing waste genera- als or feedstocks should preferably be renewa- tion is better than managing after it occurs. ble rather than derived from finite resources. 8. Reduce Derivatives. The formation of deriv- 2. Maximize Atom Economy. Chemical pro- atives should be minimized, as these steps often cesses should aim to utilize all input materials demand extra reagents and lead to increased as fully as possible in the final product. waste. 3. Less Hazardous Chemical Syntheses. 9. Catalysis. Catalysts are preferred over stoi- Chemical processes should minimize the use chiometric reagents, as they enable reactions and generation of substances that are harmful with greater efficiency and less waste. to human health and the environment. 4. Designing Safer Chemicals. Chemicals 10. Design for degradation. Chemical products should be engineered to perform their intended should be designed to break down after use, function effectively while reducing toxicity to preventing long-term persistence in the envi- the lowest possible level. ronment. 11. Real-time Analysis for Pollution Preven- 5. Safer Solvents and Auxiliaries. Whenever tion. Analytical techniques should enable real- feasible, the use of auxiliary substances should time monitoring and control during processing be avoided, and when necessary, they should be to prevent the formation of hazardous sub- non-hazardous. stances 12. Inherently Safer Chemistry for Accident 6. Design for Energy Efficiency. Chemical pro- Prevention. Chemicals selected for a process cesses should be designed to require the least should minimize the risk of accidents such as amount of energy possible. leaks, explosions, or fires. The first of the twelve principles states that it is preferrable to avoid the formation of waste rather than disposing of it once it has been produced. The first principle may be the most important of the twelve principles, and the following ones can be considered as a guideline of how to achieve it. Traditionally, the efficiency of a reaction has been measured by calculating the yield, which is calculated dividing the amount of product generated by the 2 Introduction and Background maximum theoretical yield possible of that reaction as indicated in equation (1). A high yield is always desirable, which means that the amount of product obtained is close to the theoretical maximum yield of the reaction. actual yield Yield % = ( ) × 100 (1) theoretical yield However, yield alone does not provide a complete picture of the efficiency of a reaction. Additional insight can be gained by calculating the atom economy (AE), term that was introduced by M. Trost.2 The second principle of green chemistry, related to maximizing AE, can be met by designing synthetic protocols that opti- mize the incorporation of all materials used in the process into the final product. As an example, we can assume that both hypothetical reactions (a) and (b) render a 100% yield of benzaldehyde (Scheme 1, 2). Scheme 1. Comparation of AE between reactions (a) oxidation of 1 with stoichiometric manganese dioxide and reaction and (b) catalytic aerobic oxidation of 1. We can calculate the AE of reactions with the following equation: MWproduct AE = × 100 (2) ΣMWstarting materials Where the calculated AE of reactions (a) and (b) will be: 106 AEreaction (a)= ( ) ×100=54% (3) 108+87 106 AEreaction (b)= ( 1 ) ×100=85% (4) 108+(32×2) This example demonstrates that, despite both reactions achieving a 100% yield of 2, the calculation of the AE allows for a distinction between the efficiency of the two reactions. Specifically, the reaction (b), which is a catalytic aerobic oxidation with its AE calculated in equation (4), is superior in efficiency to reaction (a) in terms of AE. Whether homogeneous or heterogeneous catalysts, they are not in- cluded in the calculation of AE because catalysts increase the rate of a chemical reaction without being consumed in the process. As a result, catalytic reactions are 3 Introduction and Background inherently more desirable than those relying on stoichiometric reagents, as they minimize waste generation and improve overall reaction efficiency. A complementary metric employed for evaluating waste production in a chemical process is the E-factor, introduced by Roger Sheldon in 1992.3 The E-factor quan- tifies the amount of waste generated relative to the mass of the desired product. The E-factor is calculated using the following equation: Mass of components−Mass of product E-Factor= (5) Mass of product This measure provides insight into the efficiency of a process by highlighting the amount of waste produced per unit of valuable product. As can be observed from equation (5), the amount of product produced ‘total product’ is in the denominator with respect to the mass of components, indicating that lower E-factor numbers will refer to less contaminating processes. Generally, the tolerance for E-factor val- ues within the chemical industry depends on the added value of the products (Ta- ble 2).4 Table 2. Target E-factor values for the chemical industry. Chemical industry Targeted E-factor range Oil refining <0.1 Bulk chemicals 1 to 5 Fine chemicals 5 to 50 Pharmaceuticals 25 to 100 However, there are more factors that need to be considered to make a more accu- rate evaluation of the greenness of a reaction. A broader assessment should take into account variables such as the cost and toxicity of materials, safety, technical complexity, reaction conditions, and work-up procedures. To address these as- pects, the EcoScale, developed by Van Aken, Strekowski, and Patiny,5 serves as a comprehensive qualitative scoring system for chemical reactions. It assigns a score from 100 (ideal) to 0, penalizing synthetic methods based on the aforemen- tioned criteria. The EcoScale thus enables a rapid yet thorough evaluation of the overall sustainability of a reaction. It is important to note, however, that this tool was specifically designed for small-scale, laboratory-based applications. When a pharmaceutical company applies sustainability principles to the produc- tion design of an active pharmaceutical ingredient, dramatic reductions in waste are often achieved. As an example, in 2002 the pharmaceutical company Pfizer re- ceived the Presidential Green Chemistry Challenge award for improving its man- ufacturing process of sertraline. Their new process doubled the overall product yield, reduced raw material use, eliminated the generation of approximately 1.8 4 Introduction and Background million pounds of hazardous materials, reduced energy and water use, and in- creased worker safety.6 However, significant technological advancements are required to address the in- dustrial practices which still heavily depend on the extraction of fossil fuels, such as coal, oil, and natural gas, or the extraction of rare-earth elements. This reliance stresses the urgent need for sustainable alternatives to minimize environmental impacts as these resources are depleted. Tom Keijer, Vincent Bakker, and J. Chris Slootweg emphasize the need for an up- date to green chemistry, which has been in practice since 1990s. They argue that while green chemistry currently focuses on optimizing linear production, the emerging concept of a circular economy requires a re-evaluation of what consti- tutes a sustainable chemical process. In 2019, the authors established the twelve principles of circular chemistry (CC).7 In contrast to green chemistry, circular chemistry promotes cyclic chemical processes in which products are continuously reused with minimal energy input. This redefinition of sustainable practices pri- marily aims to address the dependence on finite materials, such as fossil fuels and rare elements. 5 Introduction and Background 1.2. Carbonyl Compounds: Structure and Reactivity Carbonyl compounds are ubiquitous in both natural and synthetic systems. They are essential components of pharmaceuticals, materials, and biological macromol- ecules, including proteins. This widespread presence underscores the importance of carbonyl chemistry, making its study particularly compelling. Characterized by the presence of a C=O bond, carbonyl compounds are versatile intermediates in organic synthesis and play a crucial role in numerous chemical transformations. In the carbonyl functional group, both the carbon and oxygen atoms are sp²-hy- bridized. One of the sp² orbitals from each atom overlaps to form a σ bond, while the unhybridized p orbitals combine to generate a π bond, constituting the char- acteristic double bond of the carbonyl group. This hybridization results in a trigo- nal planar geometry around the carbon atom, with bond angles close to 120°. The C=O bond is relatively short, strong, and highly polarized, making it particularly reactive in a wide range of chemical transformations. The polarity of the carbonyl bond arises from the significantly higher electronegativity of oxygen, which in- duces a partial positive charge (δ⁺) on the carbon atom and a partial negative charge (δ⁻) on the oxygen (Scheme 2). Scheme 2. Structural and electronic features of carbonyls. The carbonyl group family is very diverse (Scheme 3), highlighting its broad ap- plicability and versatility in organic synthesis. The structures depicted in red (per- oxyacids, anhydrides, carbonyl halides, carbonyl azides, ketenes) represent exam- ples of activated carbonyl compounds, which are typically synthesized as interme- diates in reaction sequences to facilitate the preparation of other carbonyl deriv- atives. Scheme 3. Examples of carbonyl functionalities. 6 Introduction and Background Typically, when preparing the majority of the listed carbonyls from scheme 3, the starting material is a carboxylic acid. For instance, the synthesis of esters from carboxylic acids and alcohols is one of the most fundamental and important pro- cesses for producing useful compounds in organic chemistry. The Fischer esterifi- cation, a fundamental reaction in organic synthesis, involves the condensation of a carboxylic acid and an alcohol under acidic conditions.8 However, this classical method presents several challenges. The reaction necessitates heating, which may be incompatible with temperature-sensitive substrates. Additionally, achieving satisfactory yields often requires the use of an excess of one reactant to shift the equilibrium towards product formation, a constraint that becomes problematic when the availability of starting materials is limited. These challenges can be mit- igated by using coupling reagents that facilitate acylation under milder conditions (Scheme 4a). An example is the Steglich esterification, where a stoichiometric amount of DCC is employed in combination with a catalytic amount of DMAP to efficiently synthesize esters and thioesters.9 Scheme 4. a) Carbonyl functionalization using coupling reagents. b) Carbonyl functionaliza- tion using halogenating reagents. Coupling reagents are also employed in amide synthesis, a key functionality espe- cially prevalent in biomolecules such as peptides. A significant challenge in pep- tide synthesis is the activation of the carboxylic acid prior to amide bond for- mation between amino acid residues. While coupling reagents like DCC, HATU, HBTU, and HCTU offer high efficiency in peptide, ester, and thioester synthesis, they present substantial drawbacks. For example, health risks including anaphy- laxis, and in the case of HOBt, potential for explosiveness.10 More importantly, the frequent need to use these coupling reagents in excess to drive reactions to com- pletion results in the generation of at least a stoichiometric amount of waste. 7 Introduction and Background An alternative strategy for carboxylic acid functionalization involves the conver- sion of the carboxylic acid into a more reactive carbonyl halide via halogenation (Scheme 4b). A common example is the reaction of a carboxylic acid with thionyl chloride, producing an acyl chloride, which exhibits significantly enhanced reac- tivity toward nucleophilic attack. However, thionyl chloride is often avoided when working with sensitive substrates due to the generation of HCl as a byproduct. In addition to carboxylic acids, aldehydes represent an abundant and versatile class of carbonyl-containing starting materials. When aldehydes serve as precur- sors in carbonyl functionalization, they typically require oxidation to carboxylic acids before further modification. A widely used method for this transformation is the Pinnick oxidation,11 which efficiently converts aldehydes into carboxylic acids (Scheme 5a). Subsequently, the use of a coupling reagent or a halogenating rea- gent is necessary to activate the carboxylic acid and react it with various nucleo- philes. Alternatively, aldehydes can be directly functionalized through oxidative coupling reactions, offering a more efficient alternative to multi-step synthetic routes. This approach eliminates the need for separate oxidation steps, as well as the use of coupling or halogenating reagents (Scheme 5b). In oxidative couplings, the alde- hyde is oxidized in situ and then undergoes direct coupling with a nucleophile, all in a single step. This strategy is particularly advantageous when the correspond- ing carboxylic acid is less readily available than the aldehyde precursor. In this thesis, coupling reactions involving aldehydes will be investigated to ex- plore the synthetic utility of this approach. Scheme 5. a) Multi-step synthesis of carbonyl derivatives from aldehydes. b) Oxidative cou- plings on aldehydes for the synthesis of carbonyl derivatives. 8 Introduction and Background 1.3. Carbonyl functionalization enabled by organo- catalysis and aerobic oxidations 1.3.1. Organocatalysis A catalyst is a substance that accelerates a chemical reaction by reducing the Gibbs free energy of activation, without affecting the overall Gibbs free energy or being consumed during the process. Catalysis is integral to many technological pro- cesses and daily life. One prominent example is in the synthesis of ammonia, an essential component of nitrogen-based fertilizers. This process, known as the Ha- ber-Bosch reaction, converts nitrogen and hydrogen into ammonia using a heter- ogeneous iron catalyst, which allowed to greatly enhance global food produc- tion.12 Historically, catalysis has been largely dominated by transition metal and Brønsted acid catalysis. However, more than a century ago, other organic mole- cules beyond Brønsted acids were also recognized as effective catalysts. In 1896, Knoevenagel introduced the condensation of 1,3-dicarbonyl compounds and alde- hydes using amines as catalysts, one of the first examples of organocatalysis.13 Though aminocatalysis using amino acids has been in use for over a century, it was not until the 1970s that asymmetric organocatalysis was demonstrated in the L- proline catalyzed Hajos-Parrish-Eder-Saur-Wiechert reaction.14, 15 Organocatalysis has since become an integral part of synthetic chemistry, with various activation modes developed, such as enamine and iminium catalysis, chi- ral Brønsted acids,16 hydrogen bond donors,17 organic superbases,18 and phase- transfer catalysts. The popularity of organocatalysts can be attributed to their gen- erally lower cost and reduced toxicity compared to transition metal catalysts. Fur- thermore, implementing organocatalysis address the need for intensive mining of precious metals and the challenges of metal contamination in the end product,19 making it a more sustainable alternative to transition metal catalysis. Among the various classes of organocatalysts, N-heterocyclic carbenes (NHCs) have garnered significant attention due to their ability to efficiently catalyze a wide range of reactions, including those requiring high selectivity and functional group tolerance. Their ability to perform under mild conditions make NHCs par- ticularly valuable within the context of green chemistry, further advancing the principles of sustainability in synthetic methodologies. 9 Introduction and Background 1.3.2. NHC Organocatalysis: Structure and Reactivity Carbenes are bivalent species that contain a carbon atom with six valence elec- trons. The carbenes can possess a singlet or a triplet ground state (Scheme 6a). In a singlet carbene, four out of six valence electrons are involved in covalent bond- ing and the remaining pair of electrons are ubicated in the sp2 hybridised orbital, leaving an empty 2pz orbital. Carbenes can be both nucleophilic, via the lone pair in the sp2 orbital, and electrophilic, via its empty 2pz orbital. Reflecting their sim- ultaneous electron-donating and electron-accepting capabilities, singlet carbenes have been described as 1,1-dipoles by H. W. Wanzlick.20 Depending on the struc- ture of the molecule and on the functional groups in the vicinity of the carbenic center, its stability and predominant reactivity can change considerably (Scheme 6b).21 Scheme 6. (a) Singlet and triplet electronic configurations of carbenes. (b) Examples of re- activity and stability of different carbenes depending on their molecular structure. In 1991, A. J. Arduengo reported an stable and isolable carbene incorporated into a N-heterocyclic structure(Scheme 7).22 These carbenes are commonly referred to as NHCs. Scheme 7. NHC reported by A. J. Arduengo in 1991. By incorporating the carbene into a cyclic structure, it forces the carbenic carbon into a sp2-like hybridization, stabilizing the singlet state. In addition, the nitrogen heteroatoms stabilize the empty p-orbital of the carbene by donating electronic density from their lone pairs, while the electron-withdrawing effects of the 10 Introduction and Background electronegative atoms further contribute to its stability by removing electronic density from the sp2 orbital (Scheme 8). Scheme 8. Stabilization of the singlet carbene by -electron-donating and -electron with- drawing effect of the flanking nitrogen heteroatoms. Another feature that contributes to the stability of NHC 5, are the bulky adamantyl substituents adjacent to the carbenic carbon, which help stabilize the carbene ki- netically preventing its dimerization (Scheme 9). The dimerization process is known as the Wanzlick equilibrium described by H. W. Wanzlick in 196220 who observed the dimer 7 from diphenyl imidazolinylidene carbene 6. This phenom- ena was corroborated by V. P. W. Böhm and W. A. Herrmann in 2000.23 Regarding carbene 5 (Scheme 7), having two bulky N-adamantyl substituents difficult the di- merization, shifting the equilibrium to the carbene and stabilizing it kinetically. Scheme 9. Wanzlick equilibrium. H. W. Wanzlick also proposed that aromatic stabilization plays a role in the stabil- ity of NHCs, suggesting that delocalization of electron density through the aro- matic system can contribute to the stabilization of the empty p-orbital on the car- bene.20 Scheme 10. Summary of stabilization features of NHCs. In synthesis, NHCs are typically generated in situ from a stable precursor, with the most common method being deprotonation of a precursor azolium salt. The pre- cursor salts can be classified based on their cyclic skeletons, such as imidazolium, triazolium and thiazolium salts (Scheme 11). The base used for deprotonation de- pends on the pKa of the precursor salt. The pKa values are approximately 16.5 for 11 Introduction and Background thiazolium, 17–28 for imidazolium, and 12–15.5 for triazolium precursors (in DMSO).24 Scheme 11. Generation of NHC by deprotonation of a precursor azolium salt and typical structures of precursors employed in NHC catalysis. Carbenes are known to catalyze a number of chemical transformations, being the most notable examples the Benzoin condensation and the Stetter reaction. While stable carbenes were not isolated until 1989,25 the catalytic potential of NHCs was recognized much earlier. In 1958, Breslow proposed a carbene mediated mecha- nism (Scheme 12) for the benzoin condensation.26 Mechanistically, the initial step of the benzoin condensation involves the generation of carbene 9 through depro- tonation of the carbene precursor 8 by a base. Once formed, carbene 9 undergoes a nucleophilic attack on the benzaldehyde, resulting in the formation of adduct 10. Deprotonation of the tetrahedral adduct leads to the formation of the Breslow in- termediate 11, a key species that serves as the starting point for various NHC-cat- alyzed reactions. An important aspect of this reaction is the nucleophilic nature of the Breslow intermediate. This is an example of umpolung, a reversal of reactivity, where the normally electrophilic carbonyl carbon of benzaldehyde is transformed into a nucleophilic centre, ultimately forming molecule 11. This allows the Bres- low intermediate to react with a second molecule of benzaldehyde to form species 12. This adduct subsequently undergoes fragmentation to yield benzoin 13 and regenerate carbene 9. Scheme 12. Mechanism of the benzoin condensation proposed by Breslow (1958) in which the central reactive species is the Breslow intermediate. 12 Introduction and Background Another classic NHC catalyzed transformation is the Stetter reaction, where the Breslow intermediate reacts with Michael acceptors.27 Traditional NHC catalysis primarily utilizes umpolung to transform aldehydes, as demonstrated in the Benzoin and Stetter reactions. However, the electron-rich Breslow intermediate, in addition to reacting with electrophiles, can also be oxi- dized using external oxidants. This branch of NHC catalysis, known as oxidative NHC catalysis, has significantly expanded the synthetic toolbox of organic chemis- try and will be reviewed in the following section. 1.3.3. Oxidative NHC catalysis In oxidative NHC catalysis, the Breslow intermediate (14) is oxidized by an exter- nal oxidant, resulting in the formation of the acyl azolium intermediate (Scheme 13, 15). This process can be described as a double umpolung, where the carbonyl carbon of an aldehyde, originally electrophilic, gets turned into the nucleophilic Breslow intermediate, and upon oxidation it returns to be an electrophilic acyl az- olium. Due to its electrophilic nature, 15 readily undergo substitution reactions with nucleophiles. Scheme 13. Oxidative NHC catalytic cycle in which the central reactive species is the acyl azolium. When an NHC reacts with an α,β-unsaturated aldehyde (16), a conjugated Breslow intermediate, also known as the homoenolate (17), is formed (Scheme 14a). Upon oxidation, 17 is converted into an α,β-unsaturated acyl azolium (18), which pos- sesses electrophilic character at both the carbonyl carbon and the β-position of the conjugated system. This intermediate plays a pivotal role in oxidative NHC ca- talysis, acting as a key platform for a wide range of synthetically valuable trans- formations.28 If the α,β-unsaturated acyl azolium contains an enolizable proton at the γ-position, a nucleophilic azolium dienolate 19 can be generated by deproto- nation with a base. This allows for γ-carbon activation, which can be utilized in reactions such as formal (3 + 3) annulation.29 13 Introduction and Background Several external oxidants are known to facilitate the oxidation of the Breslow in- termediate. Common stoichiometric oxidants employed in oxidative NHC catalysis include 20,30 21,31 and metal-based oxidants such as MnO2 (Scheme 14b).32, 33 Scheme 14. (a) -unsaturated aldehyde 16 reacting with an NHC, subsequent oxidation to -unsaturated acyl azolium 18 and deprotonation leading to azolium dienolate 19. (b) Examples of stoichiometric oxidants commonly employed in oxidative NHC catalysis. In 2010, A. Studer demonstrated that quinone 22, a mild stoichiometric oxidant first introduced by M. S. Kharasch in 1957,34 could be effectively utilized in the NHC catalyzed oxidative esterification of unsaturated aldehydes (Scheme 15a).35 Since then, 22 has become one of the most frequently employed oxidants in NHC- catalysis, owing to its high selectivity in the oxidation of the Breslow intermediate. Oxidative esterification of aldehydes has been applied in later studies, including selective carbohydrate functionalization by A. Studer36 and polyester oligomer (PEs) synthesis by Massi (Scheme 15a).37 Scheme 15. Selected examples of products derived from oxidative NHC catalysis. 14 Introduction and Background It is also possible to use nitrogen-based nucleophiles to participate in nucleophilic addition to the acyl azolium. In this context, A. Studer and coworkers reported the first example of oxidative NHC-catalyzed synthesis of carbonyl azides and amides. (Scheme 15b).38 Oxidative NHC catalysis also facilitates reactions involving multi- ple bond formation, as demonstrated in the synthesis of dihydropyranones39 and trisubstituted benzenes (Scheme 15c).29 T. Rovis reported the addition of car- benes to imines giving access to an analogue of the Breslow intermediate, denom- inated the aza-Breslow intermediate.40 The aza-Breslow intermediate can be oxi- dized to an imidoyl azolium species, leading to the formation of products such as 2-arylbenzoxazoles (Scheme 15d).41 The syntheses described above represent a few selected examples aimed at demonstrating the rich reactivity and versatility of oxidative NHC catalysis. In all these reactions, the Kharasch oxidant has been employed in stoichiometric amounts. However, its high molecular weight and the generation of equimolar waste can limit the scalability and practicality of these protocols. This limitation may be overcome by using molecular oxygen as the terminal oxidant. 1.3.4. Aerobic oxidative NHC catalysis In the pursuit of more environmentally conscious oxidation methods, atmospheric oxygen (O₂) has emerged as a highly attractive oxidant. Oxygen is non-toxic, read- ily available, cost-effective and has a high efficiency of weight per oxidant. Im- portantly, its reduction product is water, a benign and easily removable byprod- uct, which minimizes environmental impact and simplifies purification. These at- tributes position atmospheric oxygen as an ideal terminal oxidant in green chem- istry applications. Nevertheless, in large-scale aerobic oxidation processes, safety concerns may arise due to the use of oxygen in conjunction with flammable organic solvents. To address these concerns, strategies such as continuous flow systems offer im- proved control over reaction parameters, thereby minimizing associated risks.42 Additionally, employing low-volatility solvents, such as deep eutectic solvents or ionic liquids, can further enhance safety by reducing the potential for hazardous vapor formation during the reaction process.43 Molecular oxygen exists in a triplet ground state, making it a diradical molecule.44 Although radicals are typically short-lived and highly reactive, O₂ is kinetically sta- ble under ambient conditions, accounting for its abundance in the atmosphere. Despite its thermodynamic inclination as an oxidant, the high activation energy associated with oxygen often requires elevated temperatures, which may compro- mise selectivity by favoring side reactions. In catalysis, this issue is referred to as the "oxidation problem", where the electron transfer between the catalyst and ox- ygen occurs too slowly relative to the rapid deactivation of the catalyst.45 15 Introduction and Background In aerobic oxidative NHC catalysis,46 aerobic oxidation of the Breslow intermedi- ate can occur through two distinct pathways: the oxidative pathway and the oxy- genative pathway (Scheme 16).47 Both mechanisms initiate with a single electron transfer (SET) from the Breslow intermediate 14 to molecular oxygen, generating a radical ion pair 23. This species recombines to form either a hydroperoxide 27 or a peroxide ion 24, leading to two distinct pathways. In the oxidative pathway, hydroperoxide 27 undergoes fragmentation to yield the acyl azolium intermedi- ate 15, which reacts with a nucleophile to afford the carbonyl substitution product and regenerate the carbene. In the oxygenative pathway, peroxide ion 24 reacts with a second aldehyde to form carboxylate ion 25, which undergoes a Criegee- type fragmentation to produce a carboxylic acid and the oxo-Breslow intermedi- ate 26. Fragmentation of 26 gives a second equivalent of carboxylic acid along with carbene regeneration. Scheme 16. The two primary mechanistic pathways for the oxidation of Breslow intermedi- ate 14: the oxidative pathway (left) and the oxygenative pathway (right). Direct oxidation of the Breslow intermediate by oxygen (Scheme 16) is challeng- ing due to the competing oxidative and oxygenative reaction pathways, leading to low selectivity and acid byproducts. Thus, carrying out aerobic oxidative NHC re- actions often require high temperatures or long reaction times leading to sluggish reaction with mainly carboxylic acid formation (Scheme 17a).48 The addition of a redox catalysts can improve this (Scheme 17b), but still the reactions often need 16 Introduction and Background heat or have limited substrate scope and face challenges such as poor selectivity,47 the necessity for high reaction temperatures,49 the need for anhydrous conditions or a pure oxygen atmosphere.50, 51 The high temperatures required for these reac- tions stem from the high energy barrier associated with the triplet ground state of molecular oxygen. In the context of NHC catalysis, this high activation barrier often results in inefficient aerobic oxidation of the Breslow intermediate. However, this challenge can be addressed by employing electron transfer mediators (ETMs) in aerobic oxidation processes (Scheme 17c). Scheme 17. (a) Direct oxidation of the Breslow intermediate with air renders carboxylic ac- ids. (b) Esterification reactions using a metal catalyst results in reactions restricted by scope and/or yield. (c) Aerobic oxidations using an ETM strategy. The concept of ETMs for controlled aerobic oxidation processes is inspired from the aerobic oxidations occurring in living organisms, such as those found in the electron transport chain within the respiratory system. In the cells, electrons are transferred through a series of redox donors and acceptors (ETMs), ultimately leading to the oxidation of NADH by oxygen to generate energy in the form of ATP. By utilizing a multistep electron transfer process, large activation energies can be redistributed along several catalytic redox cycles, turning aerobic oxidations more kinetically favorable and possible under mild conditions (Scheme 17c). One of the earliest examples of aerobic oxidation utilizing ETMs is the Wacker pro- cess, developed in 1956. 52 In this reaction, CuCl₂ functions as an ETM to regener- ate Pd(II) from Pd(0), enabling the oxidation of ethylene to acetaldehyde on an industrial scale (Scheme 18a). However, the use of chloride ions can lead to unde- sired byproducts. To overcome this limitation, Bäckvall and co-workers developed a chloride-free variant utilizing Pd(OAc)₂ in combination with hydroquinone and either iron(II) phthalocyanine (29) or cobalt(salophen) (30) as ETMs, achieving 17 Introduction and Background enhanced efficiency and selectivity in the oxidation of terminal alkenes (Scheme 18b).53 Scheme 18. (a) Wacker oxidation. (b) ETM system for aerobic oxidations reported by J. E. Bäckvall and coworkers. Systems employing ETMs have been successfully applied in aerobic oxidative NHC-catalyzed reactions, including esterifications (Scheme 19),54 N-acylations,55 and lactonizations,56 demonstrating their potential to enhance both the efficiency and selectivity of oxidative transformations in organic synthesis. Scheme 19. NHC catalyzed aerobic esterification of aldehydes using an ETM system. The incorporation of ETMs facilitates the electron transfer from the Breslow in- termediate to oxygen along a low energy pathway, enabling the reactions to pro- ceed under mild conditions, and improving the selectivity of these reactions, pro- moting the formation of desired products while minimizing side reactions. 18 Introduction and Background 1.4. Carbonyl functionalization enabled by photo- chemically generated ketenes 1.4.1. Ketene carbonyl group. Characteristics, generation and reactivity. Ketenes57 are a highly reactive subclass of carbonyl compounds. Due to their re- activity, ketenes are typically not stored but generated and immediately reacted, often in situ. Ketenes can be unequivocally identified in the reaction media by IR spectroscopy, where they exhibit a sharp and intense absorbance band around 2100 cm-1.58 The existence of ketenes was first reported over a century ago, with H. Staudinger’s discovery in 1905, which involved the dehalogenation of 2-chloro- 2,2-diphenylacetyl chloride using zinc (Scheme 20).59 Scheme 20. First ketene generated by Herman Staudinger. Ketenes exhibit significant electrophilicity at the α-carbon, which is adjacent to the oxygen atom, due to their unique electronic and structural properties. The α-car- bon in ketenes is sp-hybridized, resulting in a linear geometry with two orthogo- nal π-bonds (C=C=O). This sp hybridization reduces electron density at the α-car- bon, enhanced by the electron-withdrawing effect of the carbonyl oxygen. Addi- tionally, the highest occupied molecular orbital (HOMO) is oriented perpendicu- larly to the ketene plane, while the lowest unoccupied molecular orbital (LUMO) lies within the plane. This arrangement places substantial electron density on both the oxygen and β-carbon, while the α-carbon carries a significant positive charge.60, 61 In addition, the α-carbon of the ketene is more accessible for nucleo- philic attack, as bulky substituents on the β-carbon partially shield it. These factors collectively contribute to the electrophilic reactivity of ketenes. The simplest ketene, ethenone, is produced in commercial scale via the thermal dehydration of acetic acid at temperatures between 700-750°C. This process has been utilized in the commercial synthesis of acetic anhydride.62 Ketenes can also be thermally generated via flash vacuum pyrolysis (FVP) of N-(2-pyridyl)acetam- ides (32) (Scheme 21a), which are usually synthesized by the condensation of a carboxylic acid with N-(2-pyridyl)amine (31) employing DCC.63 A classical method for ketene formation involves the elimination of hydrogen chloride (HCl) from carbonyl chlorides through base-mediated processes (Scheme 21b). Addi- tionally, ketenes can be produced through the reaction of carbon monoxide with 19 Introduction and Background cobalt(III)-carbene radicals, which are generated by the metallo-radical activation of diazo compounds using cobalt(II) porphyrin complexes (Scheme 21c).64 Scheme 21. (a) Thermal synthesis of ketenes via FPV of N-(2-pyridyl)acetamides. (b) Syn- thesis of ketenes via elimination of HCl from an acyl chloride. (c) Synthesis of ketenes via cobalt carbene radicals using carbon monoxide. Nucleophiles readily engage in reactions with the electrophilic α-carbon of a ke- tene, leading to the formation of an enolate intermediate. This enolate is subse- quently prone to react with electrophilic species (Scheme 22). Scheme 22. (a) Synthesis of spiro pyrazolidinones. (b) Stereoselective synthesis of -lac- tams combining ketene chemistry with asymmetric NHC catalysis. A representative example of this mechanism is the synthesis of spiro pyrazolidin- 3-ones (Scheme 22a).65 In this reaction, the deprotonated hydrazone 34 reacts with the -carbon of the ketene 33, creating an enolate. Subsequently, the zwit- terionic species undergoes cyclization resulting in the formation of the spiro 20 Introduction and Background pyrazolidin-3-one 35. Another notable example is the Staudinger reaction, wherein β-lactams are synthesized via the [2+2] cycloaddition of ketenes and imines. Similarly, β-lactones can be synthesized through a [2+2] cycloaddition be- tween ketenes and aldehydes. These reactions exhibit excellent diastereoselectiv- ity, typically yielding the corresponding anti-cycloadducts when conducted under thermodynamic control.61 Furthermore, an asymmetric Staudinger synthesis has been reported, which combines ketene chemistry with asymmetric NHC catalysis (Scheme 22b), providing β-lactams with good enantiomeric excess.66 However, the reaction mechanism remains unclear, with uncertainty as to whether NHC cat- alyst 39 first interacts with ketene 36 to form an enolate, or with imine 37 to form an NHC–imine adduct. 1.4.2. Photochemically generated ketenes The ability to access highly reactive transient species without additional reagents can be achieved through photochemistry. The activation of photosensitive sub- strates often occurs without the necessity for additional reagents, thereby mini- mizing waste formation and resulting in a valuable strategy for the development of sustainable methodologies. This approach facilitates the generation of activated species, such as ketenes, under mild conditions. The most widely employed light-induced method for the generation of ketenes oc- curs via the Wolff rearrangement of α-diazo ketones (Scheme 23)67. Unlike con- ventional Wolff rearrangement reactions, which typically require heating or tran- sition metal catalysis, visible-light-induced α-diazo ketone rearrangement reac- tions offer several advantages, including mild reaction conditions and the release of nitrogen gas as the sole byproduct. Mechanistically, these reactions yield highly reactive ketene species through alkyl 1,2-migration of carbene intermediates, which can be utilized for various synthetic applications. Although the mechanistic details of the Wolff rearrangement remain a subject of debate, there is substantial evidence supporting the notion that light-induced ketene formation favors a step- wise process. During this process, nitrogen extrusion and 1,2-shift occurs, and the presence of the acyl carbene intermediate can be detected.68 Scheme 23. Photogeneration of ketenes via the Wolf rearrangement. However, ketenes generated via the Wolff rearrangement require pre-functional- ization of substrates with a diazo group, typically involving hazardous reagents such as hydrazine or azide-bearing chemicals. Additionally, the resulting α-diazo ketones are potentially explosive, limiting their scalability for industrial 21 Introduction and Background applications. The Zimmerman O'Connell Griffin (ZOG) reaction69-71 is an alterna- tive method for the photogeneration of ketenes. In 1962, the ZOG reaction was simultaneously reported in two communications by the three authors that gave name to the reaction. The reaction was described as the formation of 1:1 adducts resulting from the irradiation of Z-1,2-dibenzoyleth- ylene (Z-DBE) (Scheme 24, I) in the presence of alcohols. It was also demonstrated that compound 41 could be obtained by irradiating E-1,2-dibenzoylethylene (E- DBE) (40a), wherein the reaction initiates via E/Z isomerization. In 1967, E. Zim- merman published a comprehensive mechanistic study of the reaction, further in- vestigating the rearrangement using two additional DBE derivatives (40b, 40c). Scheme 24. (a) ZOG reaction. (b) Synthesis of -lactams and -lactones via the ZOG rear- rangement. In the originally described mechanism, the E-DBE 40a undergoes isomerization to Z-DBE (I), and upon further excitation performs an intramolecular ipso attack from one of the oxygen atoms to a phenyl ring leading to intermediate II, which upon electronic rearrangement forms the ketene III. Finally, the ketene is inter- cepted by an alcohol rendering products of type 41. In 2023, Sundén and coworkers introduced the visible-light induced ketene gen- eration through the ZOG rearrangement to access -lactones and -lactams in a very efficient manner (Scheme 24b).72 Notably, this reaction could proceed utiliz- ing the inherently safer visible light as the source of irradiation, and 40 was re- acted with a broad variety of aldehydes and imines, successfully affording cyclic esters and amides. 22 2. Overall objectives ❖ To explore the feasibility of γ-carbon functionalization of α,β-unsatu- rated aldehydes under aerobic oxidative NHC catalyzed conditions for the synthesis of tetrasubstituted arenes. ❖ To evaluate and apply hybrid catalytic systems in aerobic oxidative NHC catalysis, aiming to enhance the efficiency of aerobic oxidation pro- cesses. For this purpose, the synthesis of carbonyl derivatives such as esters and amides serve as model reactions. ❖ To develop an efficient synthetic route to amides via the reaction of pho- togenerated ketenes with nitrogen-based nucleophiles, utilizing the ZOG rearrangement. 23 3. Paper I. Aerobic Oxidative N-Heterocyclic Carbene-Catalyzed [3+3] Cyclization for the synthesis of Trisubstituted Benzene Deriva- tives 3.1. Introduction Within the dynamic field of catalysis employing NHCs, various methodologies that require the oxidation of the Breslow intermediate (Scheme 25, I) to generate the versatile α,β-unsaturated acyl azolium (Scheme 25, II) have been developed, as highlighted in Chapter 1 of this doctoral thesis, section 1.3.3. Typically, these oxi- dation processes rely on the addition of a stoichiometric high-molecular-weight oxidant.73, 74However, the use of such oxidants results in the production of large amounts of waste and potential purification challenges, thereby restricting the scalability of these protocols. Scheme 25. Oxidation of the homoenolate to the -unsaturated acyl azolium and -carbon activation. In 2014, Chi and co-workers reported the synthesis of highly substituted benzene rings from unsaturated aldehydes and ketones (Scheme 26).29, 75, 76 This transfor- mation proceeds via NHC-catalyzed γ-activation of the aldehyde (Scheme 25, III) and involves two sequential oxidation steps, necessitating the use of 2 equivalents of Kharasch oxidant 22 (Scheme 26). Scheme 26. Chi’s oxidative NHC catalyzed synthesis of tetrasubstituted benzenes using stoichiometric 22. To circumvent the reliance on stoichiometric amounts of high-molecular-weight oxidants, atmospheric oxygen can be used as a terminal oxidant. To enable this 25 Paper I aerobic oxidation under mild conditions, it was decided to utilize the ETM strat- egy, which would allow to perform the oxidation under mild conditions. Previ- ously, ETM-based aerobic NHC-catalyzed transformations had been limited in ap- plication to perform reactivity on the carbonyl carbon for the formation of esters and amides (Scheme 27a), or to synthesize dihydropyranones via activating the - carbon of -unsaturated aldehydes (Scheme 27b).54-56 Scheme 27. (a) Activation of the carbonyl carbon for aerobic esterification reactions. (b) Activation of the -carbon for the synthesis of dihydropyranones using aerial oxygen as the terminal oxidant. (c) Activation of -carbon for the aerobic synthesis of tetrasubstituted benzenes. In this study, we expand the scope of the ETM strategy to facilitate aerobic, oxida- tive NHC-catalyzed γ-activation for the synthesis of functionalized arenes (Scheme 27c). 3.2. Results and discussion Optimization studies using α,β-unsaturated aldehyde 42 and diketone 43 demon- strated that a [3+3] cyclization via γ-carbon activation is efficiently promoted un- der aerobic conditions. The reaction proceeds in the presence of 30 mol % NHC precatalyst NHC B, cesium carbonate, and both redox-active catalysts 22 and 29 (each at 10 mol %), affording the desired substituted benzene 44 in 76% yield under standard conditions. Efficient conversion to product 44 was found to critically depend on the presence of both ETMs 22 and 29, as omission or reduced loading of the catalysts signifi- cantly decreased yields (Table 3, entries 2-6). While 29 alone could mediate the oxidation at elevated loading (20 mol %), the reaction proceeded with reduced 26 Paper I efficiency yielding 17% of 44 (Table 3, entry 7). Additional evaluation of reaction parameters revealed that lower temperature, reduced NHC or base loading, sub- stoichiometric aldehyde, or excess diketone all negatively impacted the outcome (Table 3, entries 8-13). Substitution of THF with the greener solvent 2-methylTHF also led to decreased performance (Table 3, entry 14), underscoring the standard conditions. Table 3. Optimization of the aerobic NHC catalyzed [3+3] cyclization. Yield of 44b Entry Change from standard conditions (%) 1 No changea 76c 2 Without 22 8 3 Without 29 8 4 Without 22 and 29, only atmospheric O2 as oxidant 7 5 22 (5 mol%) and 29 (5 mol%) 52c 6 29 (5 mol%) 30 7 Without 22 and with 29 (20 mol%) 17 8 19 °C 70c 9 0 °C 27 10 NHC B (20 mol%) 56 11 Cs2CO3 (1.5 equiv.) 68c 12 42 (1.5 equiv.) 57c 13 42 (0.2 mmol) and 43 (0.4 mmol) 54 14 2-methylTHF as solvent 52c aStandard reaction conditions: 43 (0.2 mmol), 42 (0.4 mmol, 2 equiv.), 29 (0.02 mmol, 10 mol%), 22 (0.02 mmol, 10 mol%), NHC B (0.06 mmol, 30 mol%), cesium carbonate (0.4 mmol, 2 equiv.), THF (4 mL), 25 °C, air and 14 h. b GC-FID yield. c Isolated yield. With optimized conditions in hand, the substrate scope was evaluated using vari- ous enals (as E/Z mixtures) and unsaturated ketones (Scheme 28). Electron-rich enones bearing p-methyl and p-methoxy substituents afforded products 49 and 55 in 54% and 50% yields, respectively. Halogenated enones, including m-bromo and p-chloro derivatives, were well tolerated, yielding products 46 and 48 in 98% and 86% yields. An o-fluorinated enone also performed efficiently, providing 45 in 70% yield. A substrate containing ethyl ketone moiety successfully reacted with 42, rendering 47 in modest 46% yield. The heteroaromatic thiophene-derived enone was also compatible with the reaction, rendering 50 in 85% yield. Extended 27 Paper I aromatic systems and a vinyl aromatic dienone also participated successfully, yielding 51 and 52 in 71% and 60% yields, respectively. Scheme 28. Substrate scope of the diketone moiety. aIsolated yield of 1 mmol scale experi- ment. β-Keto esters were effective electrophiles, affording aryl benzoates in moderate to good yields (53-56). However, dienone substrates consistently provided higher yields, likely due to their greater electrophilicity compared to β-keto esters. This reactivity trend also accounts for the reduced yield observed for product 49, bear- ing a p-electron-donating group. The highest yield (98%) was obtained with a m- bromo-substituted enone, yielding product 46 as the major product. Next, the scope of enal substrates was explored using two dienones, 3-benzyli- denepentane-2,4-dione and 3-(3-phenylallylidene)pentane-2,4-dione, resulting in the synthesis of products 57-71 (Scheme 29). Electron-rich enals bearing m-me- thyl or p-methoxy substituents were favorable to the reaction, rendering products 57, 58, and 66 in 96%, 78%, and 73% yields, respectively. Halogenated enals, in- cluding m-substituted and p-substituted derivatives, also performed well (59-61, 67) with yields between 53-82%. However, the o-chloro substituted enal gave sig- nificantly lower yield (62, 40%) due to steric hindrance. Enals with extended aro- matic and heteroaromatic systems (63-65, 82-89% yields) were well tolerated. Overall, reactions with electron-deficient dienone 43 afforded higher yields, ex- cept in sterically hindered cases. Enals also reacted with more conjugated 28 Paper I dienones (66-69) resulting in moderate yields (53-73%). However, non-aromatic α,β-unsaturated enals and γ-substituted enals were incompatible (70, 71), indi- cating the limitations of the method with non-aromatic or sterically hindered al- dehydes. Scheme 29. Substrate scope of the enal moiety. To further elucidate the role of the different ETMs, the reaction progress was mon- itored over time by GC-FID analysis (Figure 1). When the reaction was performed under nitrogen with 2 equivalents of ETM 22 (Figure 1b), the yield closely matched that observed under the catalytic aerobic conditions (Figure 1a). Omis- sion of ETM 22 resulted in the early cessation of the reaction, yielding only 8% of the desired product (Figure 1d). A comparable outcome was observed upon exclu- sion of ETM 29 (Figure 1c), indicating that both redox active catalysts are critical for an efficient electron transfer. In the absence of both ETMs (22 and 29), with atmospheric oxygen as the sole oxidant, the reaction proceeded with reduced ef- ficiency, affording less than 7% yield (Figure 1e). These results demonstrate the essential role of ETMs in facilitating effective aerobic oxidation under the optimal reaction conditions. 29 Paper I 100 90 80 70 (a) 60 (b) 50 (c) 40 (d) 30 (e) 20 10 0 0 5 10 15 time (hours) Figure 1. Reaction profiles under varying conditions: (a) Optimized conditions. (b) 2 equiv- alents of ETM 22 under nitrogen atmosphere. (c) 10 mol% of ETM 22 exposed to atmos- pheric oxygen. (d) 10 mol% of ETM 29 exposed to atmospheric oxygen. (e) atmospheric oxygen as the sole oxidant, in the absence of ETMs. Further analysis of the reaction mixture revealed complete consumption of the enal substrate within 5 hours, indicating the presence of competing kinetic side reactions that likely compromise the overall efficiency of the transformation. The proposed mechanism (Scheme 30) begins with cesium carbonate-assisted deprotonation of imidazolium salt NHC B to generate the active NHC catalyst. Nu- cleophilic addition to α,β-unsaturated aldehyde 42 forms Breslow intermediate I, which is oxidized to acyl azolium II via oxidant 22, regenerated by the ETM system using molecular oxygen as the terminal oxidant. Subsequent γ-deprotonation yields intermediate III, which undergoes Michael addition with diketone 43, fol- lowed by a second γ-deprotonation (intermediate IV) and intramolecular aldol condensation to form intermediate VI. Final lactonization, decarboxylation, and an ETM-mediated oxidation furnish the tetrasubstituted arene 44. To further demonstrate the relevance of this protocol, products obtained through this methodology were used to access high value molecular scafffolds with broad applicability across medicinal chemistry, materials science, and photochemical re- search (Scheme 31). Notably, biologically active indenes and photochemically rel- evant fluorenones can be obtained through one or two derivatization steps.29, 77, 78 30 yield % 3a Paper I Scheme 30. Proposed reaction mechanism for the aerobic NHC-catalyzed [3+3] cyclization. Tetrasubstituted acetophenones such as 44 can be transformed into oxotriphenyl- hexanoates (OTHOs, 72), supramolecular gelators, via a four-component reaction achieving an overall yield of 38%, and with a yield per bond-forming step of 72% (Scheme 31a).79-83 Additionally, aromatic ester 52 can be converted into pharma- cologically relevant isocoumarin84 73 through sequential hydrolysis and sele- nium-catalyzed lactonization,85 yielding 73 in 52% (Scheme 31b). Scheme 31. (a) Synthetic application of the methodology toward the preparation of the gelator OTHO. (b) Derivatization strategy for the synthesis of isocoumarins. 31 Paper I 3.3. Summary The synthesis of polysubstituted benzenes remains a challenging objective in or- ganic chemistry. There are few established methods available, primarily limited to the oxidative Diels–Alder reaction,86 Dötz benzannulation,87 and alkyne trimeriza- tion.88 In this context, the reported aerobic NHC-catalyzed transformation offers a valuable alternative, enabling the efficient synthesis of functionalized arenes up to 98% yield. These arene products possess high synthetic versatility and can be readily derivatized for use in various areas of applied chemistry. Importantly, this novel aerobic NHC-catalyzed methodology unlocks γ-carbon ac- tivation via a multistep electron transfer process. These findings provide a strong foundation for future advancements in aerobic oxidative NHC catalysis, expanding its potential for new reactivities under mild and sustainable conditions by utilizing ETM systems. 32 4. Paper II. Redox Active N-Heterocyclic Car- benes in Oxidative NHC Catalysis 4.1. Introduction One limitation of the methodology developed in Paper I, was the complexity asso- ciated with the optimization and implementation of the ETM aerobic oxidative strategy. This challenge arises from the necessity of optimizing the catalytic amounts of multiple redox-active catalysts, whose quantity is interdependent and must be precisely balanced to achieve an orchestrated electron transfer process. As an illustrative example of this, in Scheme 32 is represented an ETM system where the electrons get transferred from one redox active catalyst to the next re- dox active catalyst externally. Scheme 32. External oxidation within the catalytic cycles of the ETM system. Specifically, once the Breslow intermediate I has been formed, the electrons get transferred externally from I to catalyst 74, rendering the oxidized acyl azolium II. Subsequently, the electrons get transferred from ETM 74 to ETM 29 and finally to the oxygen (Scheme 32). We have denominated the afore described electron transfer between discrete redox active catalysts as an external oxidation. Im- portantly, in this ETM system the quantities of catalysts NHC B, and ETMs 29 and 74 need to be carefully adjusted, as the mol percentage of all the catalysts is critical to avoid side reactivity. A redox-active NHC precursor was reported in the literature (Scheme 33), previ- ously employed as a ligand in metal catalysis,89 with its redox properties exten- sively studied by Bielawski and co-workers.90 This redox active NHC ligand (NHC D) is the result of the combination of an NHC precursor moiety which is covalently linked to a quinone moiety giving NHC D redox properties. Here we envisioned the opportunity to test NHC D in oxidative NHC catalysis. 33 Paper II Scheme 33. Redox active NHC precatalyst NHC D as a combination of an NHC precatalyst and a quinone. The hybrid NHC D is capable of transferring the electrons internally from the Bres- low intermediate to the quinone, a process that we refer to as internal oxidation (Scheme 34). Due to the collision theory, we hypothesized that by using NHC D the electron transfer could be enhanced and would result in an improved overall effi- cacy of the oxidative reaction. Additionally, the use of redox active NHCs like NHC D could help to implement this aerobic oxidative strategy to more oxidative NHC catalyzed reactions. Scheme 34. Internal oxidation within the catalytic cycles of the hybrid ETM system. 4.2. Results and discussion Our investigation began by exploring the dual role of NHC D as both an NHC cata- lyst and oxidant in the oxidative esterification of aldehydes. Notably, when NHC D was utilized in a stoichiometric amount, it effectively converted cinnamaldehyde (75) into methyl cinnamate (77) with a 90% yield (Table 4, entry 1). Consequently, an experiment was conducted to test the hypothetically enhanced electron transfer in the oxidation of the Breslow intermediate when occurring in- ternally, compared to when occurring externally. For this purpose, the reaction profile of two simultaneous reactions was monitored comparing the internal oxi- dation (reaction a) to the external oxidation (reaction b). 34 Paper II Figure 2: Comparison of reaction profiles of reactions a) internal oxidation and b) external oxidation. Conditions of reaction a): 75 (0.3 mmol, 1 equiv.), 76 (8 equiv.), NHC D (1.2 equiv.), cesium carbonate (1.2 equiv.), dry and degassed THF (2ml), nitrogen atmosphere, room temperature. Conditions of reaction b): 75 (0.3 mmol, 1 equiv.), 76 (8 equiv.), 74 (1.2 equiv.), 29 (1.2 equiv.), cesium carbonate (1.2 equiv.), dry and degassed tetrahydrofuran (2ml), nitrogen atmosphere, room temperature. Selectivity (300 min.) = (yield 77 /75 con- sumed)×100. The quantification of 77 and 75 was measured by GC-FID, using dodecane as internal standard. The reaction profiles in Figure 2 offer key insights into the performance of the two systems. In reaction (a), product 77 reaches 80% yield after 240 minutes, followed by a reduction in reaction rate. In contrast, reaction (b) stalls below 60% yield after 150 minutes, likely due to full consumption of enal 75 through competing side reactions. The α,β-unsaturated aldehydes like 75 are prone to side reactivity in NHC-cata- lyzed reactions with alcohols. Common parasitic pathways include non-oxidative dimerization of cinnamaldehyde,91 reduction to saturated esters,92 and overoxida- tion to carboxylic acids under strongly oxidative conditions. In this case, NMR analysis of the crude reaction mixture confirmed that the major side product was saturated ester 78, formed via reduction of 75. This outcome suggests inefficient 35 Paper II oxidation of the Breslow intermediate by quinone 74, allowing competing non- oxidative pathways to dominate. Figure 3: Graph II: consumption of cinnamaldehyde in percentage over time. Graph III: Se- lectivity of internal oxidation versus external oxidation. Graphs in figure 3 provide a comparative overview of the overall selectivity ob- served during the reactions (a) and (b). In reaction (a), selectivity remains con- sistently high throughout the course of the reaction, maintaining values between 0.8 and 0.9. In contrast, reaction (b) exhibits lower selectivity, typically ranging between 0.6 and 0.7. Notably, a sharp decline in selectivity is observed at the 90- minute mark, dropping to 0.4. This decrease is attributed to the consumption of cinnamaldehyde through its interaction with the NHC catalyst, leading to the for- mation of reactive intermediates, such as the Breslow intermediate. It is proposed that the sudden increase in Breslow intermediate concentration at this point ex- ceeded the oxidative capacity of oxidant 74, resulting in inefficient oxidation. The lack of a coordinated electron transfer process contributed to the reduced selec- tivity and the formation of side product 78. This limitation was overcome by em- ploying catalyst NHC D, hypothetically due to the promotion of intramolecular ox- idation of the Breslow intermediate. Under these conditions, no non-oxidative NHC-catalyzed side products were detected in the crude NMR analysis. To address the need for stoichiometric amounts of redox-active NHC D, efforts were made to achieve its aerobic regeneration. Using atmospheric oxygen alone resulted in low efficiency (33% yield, Table 4, entry 2), indicating its insufficiency as a sole oxidant. Implementation of the ETM strategy enabled successful catalytic aerobic oxidation (Table 4, entry 3), consistent with findings reported in previous studies.46, 54-56, 93, 94 36 Paper II Table 4. Optimization of reaction conditions for the redox-active NHC-catalyzed aerobic oxidative esterification. ETM Yield % Entry Pre-NHC (mol%) Solvent Base (mol%) (mol%) 77a 1b NHC D (110) - THF DBU (120) 90 2 NHC D (20) - EtOAc K2CO3(50) 33 3 NHC D (20) 29 (3) MeCN DBU (25) 82 4 NHC D (20) 30(3) MeCN DBU (25) 90 5 NHC D (20) 29 (3) 2-Me-THF DBU (25) 74 6 NHC D (20) 29 (3) CHCl3 DBU (25) 62 7 NHC D (20) 29 (3) DMC DBU (25) 69 8 NHC D (20) 29 (3) EtOAc DBU (25) 75 9 NHC D (20) 29 (3) MeOH DBU (25) 91c 10 NHC D (20) 29 (3) Toluene DBU (25) 64 11 NHC D (20) 29 (3) EtOAc DBU (50) 66 12 NHC D (20) 29 (3) EtOAc Et3N (50) 74 13 NHC D (20) 29 (3) EtOAc TBD (50) 44 14 NHC D (20) 29 (3) EtOAc Na2CO3 (50) 55 15 NHC D (20) 29 (3) EtOAc K2CO3(25) 83 16 NHC D (20) 29 (3) EtOAc K2CO3(50) 90d 17e NHC D (20) 29 (3) EtOAc K2CO3(50) 25 18 NHC D (15) 29 (3) EtOAc K2CO3(50) 76 19 NHC E (20) 29 (3) EtOAc K2CO3(50) 78% General conditions: 0.25mmol 75, 500 L solvent, 24 hours, 21°C. aYield determined by GC- FID. bUnder N2 atmosphere, 5 hours, 0.1 mmol 75, 300 L dry THF, 21°C. cReaction time: 6 hours. dIsolated yield. eUsed 4 equivalents of 76. The complex cobalt(II) salophen (30) was evaluated as an alternative redox-active catalyst for the aerobic reaction, yielding promising results (Table 4, entry 4). However, 29 was preferred due to its environmentally benign properties. Solvent screening revealed that polar aprotic solvents such as acetonitrile and ethyl ace- tate gave the highest yields, 82% and 75%, respectively (Table 4, entries 3 and 8). Conducting the reaction neat in methanol shortened reaction time and increased yield of 77 to 91% (Table 4, entry 9), likely due to enhanced nucleophile 37 Paper II concentration. Base optimization showed that potassium carbonate was superior, providing optimal yields with 0.5 equivalents (Table 4, entry 16). Other bases, in- cluding DBU, TEA, TBD, and sodium carbonate, were less effective (Table 4, entries 11-14). Lowering methanol equivalents or NHC D loading negatively impacted yield of 77 (Table 4, entries 17 and 18). A bulkier redox-active NHC (NHC E) gave inferior results under identical conditions (Table 4, entry 19). With optimized conditions (Table 4, entry 16), the method was applied to a range of α,β-unsaturated aldehydes and benzaldehydes (Scheme 35). Halogenated sub- strates p-Cl, p-F and o-Br yielded the corresponding methyl esters (79-81) in 83- 87% yields. An electron-rich p-methoxy-substituted aldehyde afforded product 82 in 62% yield. Notably, an o-nitro-substituted aldehyde significantly enhanced reactivity, delivering 83 in 98% yield. Scheme 35. Substrate scope of aldehydes for the aerobic redox-NHC catalyzed esterifica- tion. aIsolated yield obtained from a 1 mmol scale experiment. Benzaldehydes were also evaluated as substrates for the oxidative esterification under the optimized conditions. Heteroaromatic and extended aromatic alde- hydes provided products 84 and 85 in 79% and 63% yields, respectively. Halo- genated benzaldehydes were well tolerated, affording esters 86-88 in yields up to 98%. Disubstituted benzaldehyde also gave good results (89, 85%). Electron- withdrawing groups, particularly p-cyano, further enhanced reactivity, yielding 90 in 99%. In contrast, electron-donating substituents led to poor or no conver- sion under these conditions. 38 Paper II To explore the diversity of compatible nucleophiles, various hydroxyl-containing molecules were tested with cinnamaldehyde (Scheme 36). Phenols and methoxy- phenols proved to be excellent nucleophiles, yielding phenyl esters in 94% and 66% yields (92 and 93, respectively). Glycerol 1,2-carbonate also reacted well, providing ester 94 in 78% yield. Furthermore, the bicyclic natural product myr- tenol successfully reacted with 75 to give 74% of the corresponding ester 95. Scheme 36. Substrate scope of alcohols for the aerobic redox-NHC catalyzed esterification. The hybrid catalyst NHC D could also be employed for the oxidative amidation of aldehydes. For instance, the a one pot synthesis of amide 96 was achieved by using a stoichiometric amount of NHC D in conjunction with hexafluoroisopropanol (HFIP), 75 and pyrrolidine (Scheme 37a).38 The reaction (a) courses via the for- mation of a reactive ester during 24 hours in the first step, which is subsequently attacked by pyrrolidine in the second step yielding 96 in 78%. Additionally, 2-ox- azolidinone (97) was utilized as a nucleophile, affording compound 98 with a 54% yield. Scheme 37. Amide synthesis using stoichiometric amount of NHC D. To further explore the applicability of the redox-active NHC D in aerobic transfor- mations, it was investigated its use in the aerobic oxidative NHC-catalyzed [3+3] cyclization for the synthesis of tetrasubstituted benzenes (Scheme 38). In this study, NHC D was employed in place of NHC B and 22. However, the reaction did not proceed as expected, and the desired product 44 was not detected. A plausible explanation for this outcome could be that the second oxidation step, responsible 39 Paper II for aromatization, is predominantly facilitated by the Kharasch oxidant. The ab- sence of the Kharasch oxidant in this experiment likely resulted in the failure to obtain product 44. Scheme 38. Aerobic oxidative NHC catalyzed [3+3] cyclization using NHC D. In a new effort to implement the applicability of NHC D to more aerobic oxidative reactions, it was performed an aerobic oxidative NHC catalyzed [2+4] cyclization for the synthesis of dihydropyranones (Scheme 39).56 In this experiment, NHC D was utilized in place of the NHC A and 22. The targeted product 99 was success- fully obtained with a yield of 36%. Scheme 39. Aerobic oxidative NHC catalyzed [2+4] lactonization using NHC D. Furthermore, the developed aerobic method is applicable to the synthesis of pol- ymer precursors, including diesters of type 102 and oligomers such as 104 (Scheme 40). These compounds are of particular interest due to their potential use in the production of polyethylene terephthalate (PET).37, 95 Scheme 40. Oligomer synthesis by aerobic redox active NHC D catalyzed acylation. A mechanistic pathway was proposed for the internal oxidative esterification of aldehydes (Scheme 41). The redox-active carbene species NHC Dox is generated in situ via deprotonation of NHC D. Nucleophilic attack of NHC Dox on the carbonyl carbon of the aldehyde yields the Breslow intermediate I. Subsequent intramolec- ular electron transfer from the enamine moiety to the quinone unit of the NHC facilitates the formation of intermediate II and ultimately the acyl azolium 40 Paper II intermediate III. Nucleophilic attack on III affords the ester product and regener- ates the reduced carbene species NHC Dred. Finally, NHC Dred is reoxidized to NHC Dox by molecular oxygen, with iron(II) phthalocyanine (29) acting as an ETM. Scheme 41. Proposed mechanism for the internal oxidative esterification of aldehydes us- ing catalytic redox NHC D. Continuing in this line of investigation, it was decided to explore a complementary type of hybrid catalyst in which the ETM would be covalently attached to a qui- none (Scheme 42). The hybrid catalyst 105, is an organometallic hybrid redox ac- tive catalyst, which could potentially facilitate the electronic transfer from the Breslow intermediate to the atmospheric oxygen. This kind of hybrid ETMs have been previously reported by Bäckvall and coworkers, using them to perform aer- obic oxidations in palladium and ruthenium chemistry.96-102 Scheme 42. Hybrid ETM 105. To evaluate the efficacy of the hybrid catalyst 105 as an oxidant, different loadings were tested maintaining a loading of NHC B of 2 mol%. The optimization graph in Table 4 illustrates the relationship between the yield of 77 and the molar percent- age of 105 (Table 5, entries 1-4). The data indicate a slight increase in the yield of 77 with increasing 105 loading (Table 5, entries 1 and 2). However, this trend shifts when the loading of 105 is further increased (Table 5, entries 3 and 4). Anal- ysis of the crude reaction mixtures by NMR and TLC revealed that at lower 105 41 Paper II loadings (Table 5, entries 1 and 2), side products 78 and 106 were formed due to non-oxidative NHC-catalyzed side reactions. The observed decline in the yield of 77 at higher 105 loadings (6 mol% and 10 mol%) was attributed to excessive ox- idative conditions, which led to the oxidation of cinnamaldehyde to cinnamic acid 107 (Table 5, entries 3 and 4). Based on these findings, a significant increase in the loading of both NHC B and 105 was attempted to enhance the yield of 77. However, this substantial increase in catalyst concentrations resulted in only a moderate yield of 56% for 77 (Table 5, entry 5). After careful evaluation of the hybrid ETM 105 for the aerobic esterification of 75, it was concluded that the required high loadings of both NHC B and 105 renders an inherently non-efficient oxidative strategy when compared to using redox NHC D together with 29, as described in paper II, or to using non-hybrid ETM systems applied in aerobic oxidative NHC catalysis.46 Additionally, a high loading of 105 is troublesome even for small scale reactions due to the difficult and time-consuming 6-step synthesis of hybrid ETM 105, in contrast to the rapid and easy 2-step syn- thesis of NHC D that can also easily be scaled up. Table 5. Optimization of amount of hybrid ETM 105 for the aerobic oxidative NHC cata- lyzed esterification of aldehydes. Pre-NHC ETM Yield Entry 50 (mol%) (mol%) 77a 39 40 40 32 1 NHC B (2) 105 (2) 39% 30 2 NHC B (2) 105 (4) 40% 20 20 3 NHC B (2) 105 (6) 32% 4 NHC B (2) 105 (10) 20% 10 0 NHC B 0 5 105 (10) 56% (10) 0 2 4 6 8 10mol% 105 Reaction conditions: 75 (1 equiv., 0.25 mmol, 33.08 mg), 76 (4 equiv, 1.00 mmol, 41 uL), NHC B, 105, TBD (0.5 equiv., 0.125 mmol, 17.42 mg), and 0.5 mL of acetonitrile at room temperature and under open atmosphere during 24h. aYields quantified by GC-FID using dimethyl sulfone as internal standard. 42 yield% of 77 Paper II 4.3. Summary In summary, a novel internal oxidation strategy has been developed utilizing the hybrid redox-active NHC D within oxidative NHC catalysis, enabling oxidative ac- ylation reactions. This approach facilitates the efficient synthesis of esters and am- ides through the aerobic regeneration of NHC D, achieving yields of up to 99% for esters and 78% for amides. The successful implementation of the redox-active NHC D highlights the feasibility of internal oxidation in oxidative NHC catalysis, providing a new perspective for the future development of efficient coupling reac- tions with aldehydes. 43 5. Paper III. Visible-Light-Mediated Late- Stage N-functionalization of Unprotected Peptides: Introducing the aza-Zimmerman- O’Connell-Griffin Reaction 5.1. Introduction Amides are a fundamental class of compounds, prevalent in biologically active molecules such as peptides, proteins, and pharmaceuticals, making their synthesis a subject of ongoing interest. Traditionally, amides are synthesized through the coupling of carboxylic acids with amines, employing stoichiometric coupling rea- gents. An alternative synthetic strategy involves the reaction of amines with ketenes, which are typically generated through the prior conversion of carboxylic acids into acyl halides, followed by base-induced elimination of HCl. However, ketenes can also be accessed without the use of additional reagents through photochemi- cal methods. The ZOG reaction offers such an alternative, enabling ketene genera- tion via light-induced rearrangement of a photosensitive substrate. In the original description of the reaction, the ketene formed in the ZOG rearrangement was in- tercepted by an oxygen nucleophile. Here, it was hypothesized that nitrogen nu- cleophiles could similarly engage the photogenerated ketene to afford a variety of amides (Scheme 43). Scheme 43. Aza-Zimmerman O'Connell Griffin reaction (aza-ZOG). The reaction investigated in this work involves the construction of amide bonds through the photogeneration of ketenes enabled by the ZOG rearrangement. This strategy would eliminate the need for pre-functionalized reagents and stoichio- metric waste, offering a sustainable alternative for amide synthesis. 45 Paper III 5.2. Results and discussion The investigation commenced with the optimization of reaction conditions with the identification of a suitable reaction solvent. For this purpose, the reaction be- tween E-DBE and 1,2,4-triazole was selected as the model reaction (Table 6). Table 6. Optimization of the aza-ZOG. Entry Deviation from standard conditions Yield % 110a 1 none 95b 2 Toluene as solvent 97 3 n-hexane as solvent n.r. 4 Acetonitrile as solvent 67 5 Dichloromethane as solvent 85 6 Tetrahydrofuran as solvent 98 7 Diethyl ether as solvent 91 aThe yield was quantified by quantitative NMR against internal standard dimethylsulfone. bThe yield was quantified by isolation. n.r. = no reaction Initial tests identified that the reaction progressed in ethyl acetate, affording prod- uct 110 in 95% yield, and stablishing this as the standard conditions (Table 6, en- try 1). Consequently, a range of aprotic solvents was evaluated. Among less polar solvents, toluene provided a slightly higher yield of 97% (Table 6, entry 2), while no conversion was observed in hexane, likely due to poor solubility of the starting materials (Table 6, entry 3). Polar aprotic solvents such as tetrahydrofuran were well tolerated, delivering up to 98% yield (Table 6, entry 6). Despite these varia- tions, ethyl acetate was chosen for subsequent studies owing to its low toxicity, biodegradability, and overall favorable performance. The standard conditions were thus employed as optimal conditions in the investigation of the substrate scope of the aza-ZOG reaction. Following the establishment of optimal conditions for the aza-ZOG reaction, the scope was expanded to assess the reactivity of various nitrogen-based nucleo- philes, including amino acids (Scheme 44). Reaction of E-DBE (108) with the me- thyl ester of L-phenylalanine yielded 111 in 63% after chromatographic purifica- tion, whereas unprotected L-phenylalanine provided 112 in quantitative yield via simple filtration. L-Proline also reacted efficiently, affording 113 in quantitative yield, and the reaction was successfully scaled up to 3 mmol without loss of effi- ciency or need for chromatography (97% yield). 46 Paper III Pipecolic acid afforded 114 in 58% yield. In contrast, unprotected alanine gave a significantly lower yield (15%), likely due to the formation of an electron donor– acceptor (EDA) complex with DBE. This behavior is consistent with previous ob- servations,103, 104 where DBE has been shown to form EDA complexes with elec- tron-rich, sterically unhindered amines. To suppress such side reactivity, the bulk- ier L-tert-butyl leucine was employed, yielding 115 quantitatively. Scheme 44. Substrate scope of amino acids. aYield from the 3 mmol experiment. b1.05 equivalents of nucleophile were employed. c 2 equivalents of nucleophile were employed. d4 equivalents of nucleophile were employed. Following this trend, other sterically hindered amino acids bearing tert-butyl es- ters consistently delivered products 116-119 and 127-128 in quantitative yields. For L-tyrosine, the O-tert-butyl ether was used to protect the phenolic group, af- fording 120 in 99% yield. For di-tert-butyl esters of L-aspartic acid and L-glutamic acid, reducing their equivalents from 1.2 to 1.05 afforded a cleaner reaction mix- ture due to increased solubility in ethyl acetate, yielding 121 and 122 in 95% and 94%, respectively. In contrast, substrates containing a competing nucleophilic am- ide group such as glutamine and asparagine required increased equivalents (2.0 and 4.0, respectively) to suppress undesired side reactions, affording 123 and 47 Paper III 124. Use of a tert-butyl protecting group on the secondary alcohol of L-threonine prevented competing nucleophilic reactivity, affording 125 in quantitative yield. Remarkably, unprotected serine, bearing a primary alcohol, still afforded exclu- sive amine functionalization, yielding 126 in 99%. Scheme 45. Substrate scope with amines as nucleophiles. a0.2 mmol of 108 and 1.07 equiv- alents of 1H-1,2,4-triazole. b0.2 mmol of 108 and 4.2 equivalents of 1H-benzo[d][1,2,3]tria- zole. c0.11 mmol of 108 and 6.62 equivalents of 1H-pyrazole. dIn this reaction, 1.4 equiva- lents of nucleophile where used. The scope of the rearrangement was further explored with a range of amines (Scheme 45). 1,2,4-triazole afforded products gave compound 110 in 95% yield and benzotriazole gave compound 129 in 76% yield. Pyrazole is also compatible with the reaction delivering 130 in 84% yield. Phenyl substituted pyrazoles also work well and compounds 131-134 can be isolated in very good to excellent yields. Electron-deficient anilines were effective reaction partners, yielding 135 and 136 in 80% and 73%, respectively. The tert-butyl ester of N-phenyl glycine, a known EDA donor,105 delivered 137 in 56% yield, supporting the notion that ste- ric bulk induced by the tert-butyl ester diverts reactivity from EDA pathways to the ZOG mechanism. In agreement, bulky amines and aliphatic tert-butyl amine afforded 138 and 139 in 92% and 78% yields, respectively. Additionally, DBE re- acted with ammonium acetate to furnish primary amide 140 in 85% yield. The reactivity of DBE derivatives bearing diverse electronic and steric substitu- ents was examined to evaluate the scope of the ZOG rearrangement (Scheme 46). 48 Paper III Electron-rich and electron-deficient para-substituted DBEs reacted efficiently with L-proline, affording 141 and 142 in 98% and high yield, respectively. Steri- cally hindered derivatives, such as di-naphthyl DBE, gave 143 in 61% yield with tert-butyl L-alaninate. Reaction of DBE bearing an additional phenyl group (R´=Ph), yielded 144 in 99% yield with a 6:1 diastereomeric ratio. Scheme 46. Substrate scope of DBE. Substrate containing a tert-butyl group instead of aromatic, afforded 145 in 67% yield, albeit requiring prolonged irradiation time (48 h). Mono-p-methoxy-substi- tuted DBE exhibited complete regioselectivity for migration of the unsubstituted phenyl group, yielding 146 in 99% with a 5:1 d.r., attributed to stabilization of the intermediate radical by the migrating aryl group (Scheme 47, II’). This regioselec- tivity was also observed for 147 and 148 (63% and 65% yield, d.r. = 7:5 in both cases). In contrast, the mono-p-bromo-substituted DBE, lacking a stabilizing aryl 49 Paper III ring, produced a 1:1 mixture of regioisomers (149), indicating non-selective aryl migration. The proposed mechanism of the aza-ZOG rearrangement is depicted in Scheme 47. Upon irradiation, E-DBE rapidly isomerizes to the Z-isomer (I) within 30 minutes. Continued light exposure promotes excitation, triggering an intramolecular ipso- attack from one oxygen atom to an aryl ring to form intermediate II, forming a new C–O bond. Subsequent aryl migration generates the reactive ketene intermediate III, which is then intercepted by a nitrogen nucleophile, affording the final product. Scheme 47. Reaction mechanism of visible-light-driven aza-ZOG. To further extend the scope of the aza-ZOG, the reaction was successfully em- ployed in unprotected peptide functionalization (Scheme 48). Reaction of diphe- nylalanine under standard conditions of table 8 yielded functionalized peptide 150 in 73%. L-alanyl-L-phenylalanine failed to react in ethyl acetate due to solu- bility limitations; however, switching to DMF enabled formation of 151 in 57% yield. L-leucyl-L-proline and diglycine also underwent efficient functionalization, yielding 152 and 154 in 71% and 61%, respectively. For L-alanyl-L-glutamine, modifying the stoichiometry to 1.0 equivalent of E-DBE prevented undesired pri- mary amide reactivity, affording 153 in 73% after 48 h irradiation. Similarly, tri- glycine was converted to 155 in 91% yield with extended irradiation. Notably, 155 was obtained pure after merely washing with ether and centrifuging. The re- action was scalable to 2.5 mmol, delivering 155 in 70% yield without chromatog- raphy. It was hypothesized that the Z-4-phenoxy-4-phenylbut-3-en fragment remaining after DBE-mediated N-functionalization of peptides under visible light could serve as a versatile linker for late-stage modification (Scheme 49). Treatment of 155 with trifluoroacetic acid (TFA) enabled hydrolysis of the O-phenyl enolate, afford- ing ketene-containing peptide 156 in 80% yield. This N-functionalized, unpro- tected peptide features a reactive ketene moiety amenable to further transfor- mations, including imine, hydrazone, or oxime formation (Scheme 49, 157), keto- enol tautomerism, or reduction to enable macro-lactonization with carboxylic acid termini. 50 Paper III As a proof of concept, compound 156 was reacted with stoichiometric biotin hy- drazide to form hydrazone-linked bifunctional molecule 157 in 93% yield (Z/E = 1:6). Given biotin’s significance in chemical biology and therapeutic develop- ment,106 this strategy offers a promising platform for the late-stage functionaliza- tion of unprotected peptides and the generation of novel bioactive molecules.107, 108 Scheme 48. Scope of functionalized peptides. To evaluate the environmental impact of the aza-ZOG reaction, a sustainability as- sessment was conducted using gram-scale syntheses of 113 and 155 as repre- sentative examples. Metrics including E-factor, AE, and ecoscale scores are some metrics that give indications of the sustainability of the reaction (Table 2).5, 109 For the gram synthesis of 113, the results demonstrated excellent sustainability: a low E-factor (within the ideal range for bulk chemicals), perfect AE (1.00) and the EcoScale score (>75) also classified the protocol as excellent, with minor deduc- tions due to ethyl acetate flammability and the need for dry conditions. In the case of the gram scale synthesis of 155, the metrics remained favorable despite greater synthetic complexity. The E-factor fell within the acceptable range for pharmaceu- tical synthesis (25–100), and AE remains 1.00. Nonetheless, chromatographic pu- rification was avoided, significantly improving environmental performance. Fur- ther enhancements in sustainability could be achieved through adjustments such as replacing toluene for DMF removal. 51 Paper III Scheme 49. Application of the aza-ZOG in the synthesis of bifunctional molecules. 5.3. Summary The aza-ZOG reaction enables efficient N-functionalization of diverse substrates, including N-heterocycles, aromatic and aliphatic amines, and ammonium salts. Ad- ditionally, the methodology is applicable to amino acids and unprotected peptides, affording yields of up to 99% and 92%, respectively, with scalability and without the need for chromatographic purification. The use of traditional reagents for ke- tene generation is circumvented by employing a photogenerated ketene. Moreo- ver, the protocol exhibits excellent sustainability metrics, particularly in the func- tionalization of amino acids and peptides. This approach also facilitates the syn- thesis of bifunctional molecules via the incorporation of ketone linkers on pep- tides, offering a valuable platform for late-stage peptide modification. 52 6. Conclusion and outlook Throughout this thesis, novel methodologies for the synthesis of carbonyl deriva- tives have been presented, with a particular emphasis on the sustainability of the processes. Paper I demonstrates γ-carbon activation of α,β-unsaturated aldehydes via aero- bic NHC catalysis, enabling the formation of tetrafunctionalized benzenes. This protocol avoids the use of stoichiometric Kharasch oxidant replacing it by molec- ular oxygen as the terminal oxidant, facilitated by ETMs. In Paper II, a novel oxidative NHC catalytic pathway is introduced through the use of a redox-active hybrid NHC catalyst, regenerated via aerobic oxidation using iron phthalocyanine as an ETM. This strategy enables the aerobic synthesis of esters and amides from aldehydes under mild conditions. Paper III reports a visible-light-mediated synthesis of amides via the ZOG rear- rangement. By using visible light it is possible to generate ketenes in situ, without the need for additional reagents. The photogenerated ketene can react with a broad range of nitrogen nucleophiles, including aromatic amines, N-heterocycles, aliphatic amines, ammonium salts, amino acids, and unprotected peptides. Collectively, these studies demonstrate the utility of aerobic oxidations and pho- toinduced methods in minimizing reliance on stoichiometric oxidants and auxil- iary reagents, thereby preventing the production of waste derived from carbonyl functionalization reactions. In this context, the environmental impact of these transformations can be further reduced through combination with emerging strategies such as electrocatalysis or mechanochemistry. For instance, the use of electricity could enable the regeneration of redox-active NHCs, thereby eliminat- ing the need for stoichiometric chemical oxidants. Similarly, mechanochemical methods can minimize the use of flammable organic solvents, reducing waste and increase the reaction rate. 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