Catalyst-free formation of isocoumarins and α-pyrones from the corresponding alkynyl esters is realized. The resulting γ- and δ-lactones are isolated as the pinacolboronic esters, boronic acids or potassium trifluoroborate salts, which provide a variety of methods for downstream functionalization of the newly formed B−C σ bond. Reaction conditions have been optimized and a substrate table has been constructed to show tolerance of various functional groups incompatible with other borylation techniques. A mechanism has been proposed as a result of mechanistic studies and downstream functionalization is in progress to show the versatility of the methodology.

Chapter 1. This chapter introduces both the importance of generating organometallic reagents through oxidative addition to metal powders, and the prior analytical limitations that created difficulties studying the mechanisms of their synthesis through these routes. My thesis research developed fluorescence microscopy as a tool to overcome these prior difficulties, with a focus on the reaction of organohalides with zinc metal to form organozinc complexes. Fluorescence microscopy methods for the observation of organozinc intermediates under reaction conditions, originally developed by Dr. Chao Feng and Dr. Kristof Jess in our laboratory, have now been expanded, harnessed, and further developed to provide insight into four systems: 1) An origin of batch-to-batch variation in organoindium synthesis, 2) Solvent effects in organozinc synthesis, 3) Salt effects in Rieke zinc systems, 4) Effect of TMSCl pretreatment on commercial zinc powder, and 5) Environment heterogeneity of commercial zinc powder during oxidative addition. To enable insight into the mechanisms of activators with zinc metal, imaging experiments were taken into a new direction—fluorescence lifetime imaging microscopy (FLIM)—which had not previously been used to study oxidative addition of organohalides to metal surfaces. Together, the findings in this dissertation could lead to targeted improvement of the synthesis of organozinc reagents and to the activation of currently unreactive metals beyond zinc.Chapter 2. Yields of organoindium reagents synthesized from indium metal were previously reported to be highly dependent on metal batch and supplier due to the presence or absence of anticaking agent. Here, single-particle fluorescence microscopy established that magnesium oxide, an additive in some batches nominally for anticaking, is able to accomplish physisorption of small-molecule organics, and Aldrich-brand indium (which does not have a magnesium oxide coating) contains no detectable physisorption of organic molecules. An inert and relatively nonpolar boron dipyrromethene fluorophore with a hydrocarbon tail provided a sensitive probe for this surface physisorption. Further documented was the incomplete commercial bottle labeling regarding the presence and composition of this anticaking agent, both within our laboratory and previously in the literature, which may complicate reproducibility between laboratories. Adapted with permission from Jess, K.; Hanada, E. M.; Peacock, H.; Blum, S. A. Origins of Batch-to-Batch Variation: Organoindium Reagents from Indium Metal. Organometallics, 2020, 39, 2575–2579. Chapter 3. Solvent effects are often difficult to understand in cases where reaction intermediates, and thus their differential behaviour in different solvents, are not directly observable by traditional ensemble analytical techniques. Herein, the sensitivity of single-particle fluorescence microscopy uniquely enables direct observation of organozinc intermediates and solvent effects on their build-up and persistence. When combined with NMR spectroscopy, these imaging data pinpoint the previously elusive mechanistic origin of solvent effects in the synthesis of widely used organozinc reagents. These findings characterize the acceleration of oxidative addition of the starting organoiodide to the surface of zinc metal in DMSO relative to THF, but once formed, surface intermediates display similar persistence in either solvent. The current studies are the first demonstration of a highly sensitive, single-particle fluorescence microscopy technique to pinpoint otherwise elusive solvent effects in synthetic chemistry. Copyright 2020 Wiley. Used with permission from Hanada, E. M.+; Jess, K.+; Blum, S. A. Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis. Chem. Eur. J. 2020, 26, 15094–15098. Chapter 4. Contrary to prevailing thought, the salt content of the supernatants is found to dictate reactivity differences of different preparation methods of Rieke zinc toward oxidative addition of organohalides. This conclusion is established through combined single-particle microscopy and ensemble spectroscopy experiments, coupled with careful removal or keeping of the supernatants during Rieke zinc preparations. Fluorescence microscopy experiments with single-Rieke-zinc-particle resolution determined the microscale surface reactivity of the Rieke zinc in the absence of supernatant, thus pinpointing its inherent reactivity independent of convoluting supernatant composition. In parallel experiments, SEM, EDS, XPS, and ICP-MS characterized zinc metal chemical composition at the bulk and single-particle levels. 1H NMR spectroscopy kinetics characterized bench-scale Rieke zinc reactivity in the presence and absence of different supernatants and exogenous salt additives. Together, these experiments show that the differences in reactivity from sodium-reduced vs. lithium-reduced Rieke zinc arise from the residual salts in the supernatant rather than the differing salt compositions of the solids. This supernatant salt also determines the structure of the ultimate organozinc product, generating either the diorganozinc or monoorganozinc halide complex. That different organozinc complexes formed upon direct insertion to different preparations of Rieke zinc was not previously reported, despite Rieke zinc’s widespread use. These findings impact organozinc-reagent and nanomaterial synthesis by showing that, unexpectedly, desired Rieke zinc reactivity can be achieved through simple addition of soluble salts to solutions that were used to prepare the metals—a substantially easier synthetic manipulation than solid composition and morphology control. Reprinted with permission from Hanada, E. M.; Tagawa, T. K. S.; Kawada, M.; Blum, S. A. J. Am. Chem. Soc. 2022, 144, 12081–12091. Copyright 2022 American Chemical Society. Chapter 5. Trimethylsilyl chloride (TMSCl) is commonly used to “activate” metal(0) powders toward oxidative addition of organohalides, but knowledge of its mechanism remains limited by the inability to characterize chemical intermediates under reaction conditions. Here, fluorescence lifetime imaging microscopy (FLIM) overcomes these prior limitations and shows that TMSCl aids in solubilization of the organozinc intermediate from zinc(0) metal after oxidative addition, a previously unknown mechanistic role. This mechanistic role is in contrast to previously known roles for TMSCl before the oxidative addition step. To achieve this understanding, FLIM, a tool traditionally used in biology, is developed to characterize intermediates during a chemical reaction—thus revealing mechanistic steps that are unobservable without fluorescence lifetime data. These findings impact organometallic reagent synthesis and catalysis by providing a previously uncharacterized mechanistic role for a widely used activating agent, an understanding of which is suitable for revising activation models and for developing strategies to activate currently unreactive metals. Adapted with permission from Hanada, E. M.; McShea, P. J.; Blum, S. A. Angew. Chem. Int. Ed. 2023, e202307787. Copyright 2023 Wiley. Chapter 6. Zinc metal powder commonly requires activation for consistent and reliable use as a reductant for organohalides in the formation of organozinc reagents, and for associated avoidance of batch-to-batch variability. Here, fluorescence lifetime imaging microscopy (FLIM) reveals and provides a method to quantify the heterogeneity of environments on the surface of different zinc particles. Different activation methods (i.e., none/stirring/TMSCl) produced different surface environments and different degrees of heterogeneity. Without the fluorescence lifetime information available through FLIM, the heterogeneity of the different chemical environments is undetectable.

Chapter 1. This chapter describes the importance and application of metalated heterocycles, specifically borylated and silylated heterocycles, in various fields. A general comparison of traditional preparation methods versus Lewis acid-cyclization routes and radical-cyclization routes is also described. In addition, the previous methods from both the Blum Laboratory and other laboratories that serve as precedents for the work presented this thesis are also summarized.

Chapter 2. An oxyboration reaction that employs B–O σ bonds as addition partners to C–C π bonds to form 4-borylated isochromenes has been developed. By nature of the mechanism, the reaction produces exclusively one borylated regioisomer, complementary to alternative routes that produce 3-borylated isochromenes via C–H activation. Access to the borylative heterocyclization route is demonstrated from alcohols directly or from a hydroboration–oxyboration sequence starting from the corresponding ketone, forming the heterocylic core and installing the boron in one synthetic step.

Chapter 3. In contrast to previously reported borylative heterocyclization methods, a reaction here proceeds without the need for air-free techniques, to access synthetically useful borylated thiophenes, benzothiophenes, and isocoumarins. A comparison of stability/decomposition rates in air of several catecholboronic ester (Bcat) compounds derived from different heterocycle cores showed a strong dependence on heterocycle structure. Lessons learned from this comparison were then harnessed for the development of borylative heterocyclization reactions under ambient-atmosphere conditions and with wet solvent. In contrast to literature reports suggesting general moisture sensitivity, a subset of Bcat products resulting from this technique were chromatography-stable and directly isolable, obviating the requirement for an extra synthetic transformation into more stable boron species, such as pinacolboronic esters (Bpin) for isolation. The isolated Bcat products were amenable to various downstream functionalization reactions, including reactions that were not accessible with their better-known Bpin counterparts, showing the complementarity of Bcat reaction partners and expanding their known chemistry. These results suggest the value of conceptual revisitation of substitution and solvent influence on stability and isolability of organo-Bcat compound classes, and lay groundwork for additional practical borylative methods development in air.

Chapter 4. A demethylative silyl radical cascade cyclization of 2-isocyanothioanisoles toward 2-silylated benzothiazole building blocks has been developed. The development of a “radical initiator–inhibitor symbiosis” system solves the challenge of otherwise dominant methyl-radical triggered side reactions brought about by kinetically unfavored generation of reactive silyl radical species. The products accessed in this protocol are amendable to various downstream functionalization reactions, including the quick construction of a topoisomerase II inhibitor via a Hiyama cross-coupling reaction and of an antiviral agent via a fluoride-/hydroxide-free nucleophilic substitution to acyl chloride.

Chapter 5. This chapter summarizes unpublished projects including: 1) Attempted borylative and silylative heterocyclization for synthesis of borylated and silylated furans; 2) Attempted intermolecular boration of benzynes; 3) Base-induced cyclative hydrosilylation toward benzoxasiloles. 4) Photoinduced radical route to borylative heterocyclization toward borylated benzosilolines; 5) Borylative radical cyclization for 2-borylated indoles; 6) 2-Silylative radical cyclization for 2-silylated indoles; 7) Indium-mediated group-transfer reaction. Among the aforementioned projects, some of them have obtained preliminary results, but efforts toward reaction optimization have failed, and/or the reproducibility of the targeted reaction is challenging. Outlooks and comments on potentials for these projects are also discussed in each individual section.

Organoboron compounds and borylated heterocycles are in general versatile building blocks and precursors for organic synthesis. The common strategy for the synthesis of borylated heterocycles involves initial formation of the heterocyclic core and subsequent borylation of this unit through established methods. This dissertation describes our laboratory’s development of formal borylative heterocyclization reactions that access borylated heterocycles in one synthetic step. The dissertation starts with the development of a formal borylation reaction that makes borylated lactones (Chapter 2). This class of reactions takes advantage of bifunctional B-chlorocatecholborane (ClBcat) as a carbophilic carbon−carbon π-bond activator and eventual dealkylating agent. Our motivation in developing this new class of catalyst-free borylation reactions and subsequently expanding the formal borylation strategy is described. The thioboration of o-alkynylthioanisole substrates to form borylated benzothiophenes is presented next. Our investigations into the details of the mechanism of this formal thioboration reaction are also discussed (Chapter 3). These collaborative mechanistic studies included

experimental and computational findings that elucidated the rate-determining step and likely intermediates of the reaction. These studies further compared different boron sources as electrophiles, including those used in other known reactions, providing fundamental knowledge about the capabilities of commercially available boron reagents toward borylative heterocyclization. Our findings from these investigations next provided us with guiding principles for the design of a new class of electrophilic heterocyclization/group transfer reactions, wherein the heterocyclic core from formal borylative heterocyclization is generated and intercepted. Specifically, the cationic

heterocycle serves as a key intermediate, yet effectively blocks the pathway toward established electrophilic cyclization reactions through substrate hybridization strategies. These hybridization strategies result in a ring-opening pathway that produces

trisubstituted olefins (Chapter 4). Mechanistic studies of the group-transfer reactivity indicate that this stereo- and regiocontrolled pathway can be influenced by subtle variations in the starting material to generate different substitution patterns. The new

developments provided us with information leading toward the design of a diverse set of formal addition reactions that proceed through analogous electrophilic heterocyclization/group-transfer strategies, the preliminary results for which are presented in this dissertation (Chapter 5). This new direction from my dissertation research has generated a project now being pursued by other group members.

This dissertation introduces the importance of surfactant-based organic chemical reactions and summarizes key development milestones and reaction applications by global laboratories. However, the limitations of current analytical techniques prevent understanding of these multiphasic systems. Though experiments detailed in later chapters, fluorescence microscopy emerged as a technique to examine surfactant-based reactions. A powerful feature of fluorescence microscopy is its ability to obtain subensemble information about chemical reactions and processes that are unobtainable through other analytical techniques. For example, fluorescence microscopy methods, developed by the Blum Laboratory, provide advantages over other methods due to their ability to spatiotemporally resolve effects under synthetic reaction conditions. Herein, a summary of influential studies is included, highlighting the capability of fluorescence microscopy to answer mechanistic questions in complex, multiphasic systems under many different conditions.

The syntheses of borylated S- and O- heterocycles are reported via mechanistically distinct borylative cyclizations. These methods can proceed with a Au(I) catalyst (direct borylation, formation of B–X bond) or without (formal borylation). Commercially-available B-chlorocatecholborane was the boron source used in these studies. The borylated products furnished from these methods provide complementary functional group tolerance to existing borylation methods, as well as complementary regioselectivity. Borylated benzofurans, dihydrofurans, isocoumarins, alpha-pyrones, benzothiophenes, and dihydrothiophenes were synthesized using this borylative cyclization methodology. In the direct borylative cyclization pathway (chapter 2), the mechanism is proposed to proceed via Au(I)-induced cyclization via a boric ester, follow by transmetalation of the organogold intermediate to furnish the desired borylated heterocycle. In the formal borylative cyclization pathway (chapters 3–5), mechanistic studies revealed that B chlorocatecholborane preferentially coordinated with the C–C pi system instead of the heteroatom to induce cyclization. These methods generate borylated building blocks that can be further functionalized through various C–B sigma-bond transformations.

Chapter 1. This chapter introduces fluorescence microscopy methods towards investigations in synthetic chemistry, with particular attention to polymer synthesis and polymer–catalyst dynamics, the topic of this dissertation. A powerful feature of fluorescence microscopy is its ability to obtain subensemble information about synthetic reactions that would otherwise be obscured by ensemble-averaging effects. A highlight of influential studies is provided herein, outlining how fluorescence microscopy was used to answer mechanistic questions in chemistry and inform on chemical dynamics.Chapter 2. Synthetic polymers, derived from transition metal-catalyzed polymerization, are some of the most ubiquitous materials used in contemporary society. Rates of these transition-metal catalyzed reactions are important to understand, given that there is direct relation between polymer structures and reaction rates; however, obtaining kinetic information at the single-catalyst and -polymer particle level is a challenge due to ensemble averaging present in traditional measurements. Kinetic information at the single-catalyst and -polymer particle level is vital for understanding the dynamic microenvironments of catalysts and developing a physical model for polymer particle growth. To address these gaps in knowledge, polymer structure modification techniques, crosslinking and spin coating, in tandem with fluorescence microscopy, were employed to observe the effect of polymer composition and morphology on molecular catalyst activity with single-polymer-particle sensitivity. These experiments exemplify the capabilities of fluorescence microscopy at the single polymer-particle level to elucidate a plausible model for particle growth during ROMP polymerization. A relation between polymerization rate and linear growth duration was found and provided a basis for interpreting particle growth rate data. Adapted with permission from Easter, Q. T.; Garcia IV, A.; Blum, S. A. Single-Polymer–Particle Growth Kinetics with Molecular Catalyst Speciation and Single-Turnover Imaging ACS Catal. 2019, 9, 3375−3383. Copyright 2019 American Chemical Society.

Chapter 3. The chemoselectivity of molecular catalysts underpins much of modern synthetic organic chemistry. However, little is known about the selectivity of individual catalysts because this single-catalyst-level behavior is hidden by the bulk catalytic behavior. Here, for the first time, the selectivity of individual molecular catalysts for two different reactions is imaged in real time at the single-catalyst level. This imaging is achieved through fluorescence microscopy paired with spectral probes that produce a snapshot of the instantaneous chemoselectivity of a single catalyst for either a single-chain-elongation or a single-chain-termination event during ruthenium-catalyzed polymerization. Superresolution imaging of multiple selectivity events, each at a different single-molecular ruthenium catalyst, indicates that catalyst selectivity may be unexpectedly spatially and time-variable. Copyright 2021 Wiley. Used with permission from Garcia IV, A.; Saluga, S. J.; Dibble, D. J.; López, P.; Saito, N.; Blum, S. A. Does Molecular Catalyst Selectivity Change with Time? Polymerization Imaged by Single-Molecule Spectroscopy. Angew. Chem. Int. Ed. 2021, 60, 1550−1555.

Chapter 4. The ability to directly observe chemical reactions at the single-molecule and single-particle level has enabled the discovery of behaviors otherwise obscured by ensemble averaging in bulk measurements. However powerful, a common restriction of these studies to date has been the absolute requirement to surface tether or otherwise immobilize the chemical reagent/reaction of interest. This constraint arose from a fundamental limitation of conventional microscopy techniques, which could not track molecules or particles rapidly diffusing in three dimensions, as occurs in solution. However, many chemical processes occur entirely in the solution phase, leaving single-particle/-molecule analysis of this critical area of science beyond the scope of available technology. Here, we report the first kinetics studies of freely diffusing and actively growing single polymer−particles at the single particle level freely diffusing in solution. Active-feedback single-particle tracking was used to capture three-dimensional (3D) trajectories and real-time volumetric images of freely diffusing polymer particles (D ≈ 10−12 m2 /s) and extract the growth rates of individual particles in the solution phase. The observed growth rates show that the average growth rate is a poor representation of the true underlying variability in polymer−particle growth behavior. These data revealed statistically significant populations of faster and slower-growing particles at different depths in the sample, showing emergent heterogeneity while particles are still freely diffusing in solution. These results go against the prevailing premise that chemical processes in freely diffusing solution will exhibit uniform kinetics. We anticipate that these studies will launch new directions of solution-phase, nonensemble-averaged measurements of chemical processes. Collaboration between the Blum Laboratory and the Welsher Laboratory at Duke University. Adapted with permission from Yu, D.; Garcia IV, A.; Blum, S. A.; Welsher, K. D. Growth Kinetics of Single Polymer Particles in Solution via Active-Feedback 3D Tracking J. Am. Chem. Soc. 2022, 9, 14698−14705. Copyright 2022 American Chemical Society.

Chapter 5. Control of polymer molecular weight is critical for tailoring structure−function properties; however, traditional molecular weight characterization techniques have limited ability to determine the molecular weight of polymers in real time without sample removal from the reaction mixture, with spatial resolution, and of insoluble polymers. In this work, a fluorescence lifetime imaging microscopy (FLIM) method was developed that overcomes these limitations. The method is demonstrated with polynorbornene and polydicyclopentadiene, polymers derived from ruthenium-catalyzed ring-opening metathesis polymerization (ROMP). The polymer Mw, ranging from 35 to 570 kg/mol as determined by gel permeation chromatography, was quantitatively correlated with the fluorescence lifetime. The revealed correlation then enabled time-resolved measurement of Mw during an ongoing ROMP reaction, requiring only 1 s per measurement (of a 45 μm × 45 μm polymer sample area), and provided spatial resolution, resulting in simultaneous characterization of polymer morphology. To provide the fluorescence signal, the initial reaction solutions contained a very low doping of a reactive norbornene monomer labeled with fluorescent boron dipyrromethene (BODIPY), such that 1 in every 107 monomers contained a fluorophore. The resulting FLIM visualization method enables the rapid determination of the molecular weights of growing polymers without removal from the reaction mixture and regardless of polymer solubility. Garcia IV, A.; Blum, S. A. Polymer Molecular Weight Determination via Fluorescence Lifetime. J. Am. Chem. Soc. 2022, 144, 22416−22420. Copyright 2022 American Chemical Society.

Chapter 6. This chapter summarizes unpublished projects including three research aims: 1) Investigating a universal approach to polymer molecular weight determination via fluorescence lifetime with non-covalently bound fluorescence dyes; 2) Developing FLIM based molecular weight determination through natively autofluorescent polymers and/or reaction systems; 3) Development of single-molecule FLIM methods to probe spatiotemporal heterogeneity in polymer molecular weight in real-time. These projects are inspired by the investigations from Chapter 5, where the overarching research goal is to address the current limitations to FLIM based molecular weight determination as well as provide information on molecular weight dispersity (PDI) in real-time.

The use of microscopy techniques to uncover the heterogeneity of molecular catalysts is herein reported. Prior to this work, molecular catalysts were detected and quantified through traditional ensemble analytical techniques, such as 1H NMR spectroscopy and mass spectrometry, but no information existed on molecular catalyst activity of single catalysts or small ensembles. Although appearing efficient on the bulk scale, microscopy techniques (Chapter 2) indicated that despite a uniform distribution of catalyst, the catalytic activity of molecular catalysts was poorly distributed. Surface intermediates were transformed by LiCl into soluble organozinc reagents (Chapter 3). Using fluorescence microscopy, spatiotemporal resolution of single active molecular polymerization catalysts was achieved (Chapter 4), which was the first single-turnover fluorescence microscopy imaging at any molecular catalyst. These molecular polymerization catalysts were found to exhibit time-variant chemical kinetics (Chapter 5), rather than continue to exhibit uniform polymerization activity at all time points, in contrast to their traditional textbook depictions. Finally, boundary conditions were established through fluorescence microscopy on when unique subensemble and single-turnover catalytic activity could be detected (Chapter 6). These studies redefine the concept of a “uniform” or “average” catalyst and suggest broad applicability to understanding the full picture of catalysis.

Chapter 1. This chapter provides a very brief introduction to the field of homogeneous gold(I) catalysis and discusses the context of the Blum group's previous studies in this area.

Chapter 2: Organogold compounds undergo stoichiometric cross-coupling reactions with aryl and vinyl bromides in high yield under mild, nickel-catalyzed conditions. The reaction tolerates both electron-rich and electron-poor organogold complexes, and vinyl bromides undergo cross-coupling with high stereoselectivity. This novel transformation links well-established nickel catalysis with more recent developments in organogold transformations.

Chapter 3: A vinyl aziridine activation strategy cocatalyzed by Pd(0) and a Au(I) Lewis acid was developed. This rearrangement installs a C-C and a C-N bond in one synthetic step to form pyrrolizidine and indolizidine products. Two proposed mechanistic roles for the gold cocatalyst were considered: (1) carbophilic gold catalysis or (2) azaphilic gold catalysis. Mechanistic studies support an azaphilic Lewis acid activation of the aziridine over a carbophilic Lewis acid activation of the alkene.

Chapter 4: A borylation reaction cocatalyzed by Au and Rh was proposed as a means of isolating catalytic organogold intermediates as the corresponding organoboron derivatives for use in subsequent functionalization steps. Products consistent with the proposed reactivity were obtained, but control experiments indicated no role for Rh in the reaction; organogold complexes were found to undergo facile thermal reactivity with electrophilic B without Rh. Electronic effects in the chemoselective borylation of heterocyclic organogold complexes were studied, suggesting design parameters used in the development of the Au-catalyzed borylation reactions discussed in Chapters 5 and 6.

Chapter 5: For nearly 70 years, the addition of boron-X sigma bonds to carbon-carbon multiple bonds has been employed in the preparation of organoboron reagents. However, the significantly higher strength of boron-oxygen bonds has thus far precluded their activation for addition, preventing a direct route to access a potentially valuable class of oxygen-containing organoboron reagents for divergent synthesis. Herein is discussed an alkoxyboration reaction, the addition of boron-oxygen sigma bonds to alkynes. Functionalized O-heterocyclic boronic acid derivatives are produced using this transformation, which is mild and exhibits broad functional group compatibility. Our results demonstrate activation of this boron-oxygen bond using a gold catalysis strategy that is fundamentally different from that used previously for other boron addition reactions.

Chapter 6: Four additional investigations stemming from the benzofuran-forming alkoxyboration reaction (Chapter 5) are described. Discussed are electronic effects in the B/Au transmetalation reaction, progress towards an intermolecular alkoxyboration reaction, and the expansion of the alkoxyboration concept to two additional substrate classes for intramolecular B-O sigma-bond activation reactivity.

Chapter 1. This chapter introduces the concept of electrophilic-cyclization–group-transfer reactions and explains each expansion in methodology. Context is first provided for the initial discovery and development of this class of reactions by our research group. Subsequently, the chapter explains the logical progression from the initial borylative electrophilic-cyclization–group transfer reaction development to iodination–group-transfer reactions. Finally, the chapter discusses the logical conceptual leaps taken from these initial group transfer reactions that employed stoichiometric electrophiles, to the development of a thioarylation cyclization using gold(I)/(III) catalysis in place of stoichiometric electrophiles.

Chapter 2. A metal-free regio- and stereocontrolled group-transfer route toward the synthesis of trisubstituted alkenes is described. In this route, an electrophilic heterocyclization is followed by ring-opening group transfer. Specifically, a thioboration reaction transforms readily available alkynyl sulfide precursors into alkenyl boronates and alkenyl sulfides with defined regio- and stereochemistry in one synthetic step using commercially available B-chlorocatecholborane (ClBcat). Mechanistic studies identified the likely pathway as proceeding through zwitterionic rather than haloborated intermediates. The regio- and stereochemistry set in the initial cyclization step is preserved in the final acyclic alkene product, producing alkenes with up to four modifiable substituents with predictable regio- and stereochemistry. Downstream functionalization reactions showcase the versatility of the substitutions of the resulting alkenes. The mechanistic concept maps onto future reaction designs, given the abundance of known electrophiles and nucleophiles for electrophilic heterocyclization/dealkylation sequences. This chapter features work from Adena Issaian, a senior PhD-student member of the Blum Laboratory, who initiated this project based on a starting mechanistic hypothesis. She mentored me on my first sets of experiments on this project. After her graduation, I took the task of completing this scientific work. Our co-contributions were recognized with co-first author status on the published version of this report. Specific contributions are noted in the main body of the thesis chapter. Reprinted with permission from Kaplan, J. A.+; Issaian, A.+; Stang, M.; Gorial, D.; Blum, S. A. Repurposing π Electrophilic Cyclization/Dealkylation for Group Transfer. Angew. Chem., Int. Ed. 2021, 60, 25776–25780.

Chapter 3. The regio- and stereodefined synthesis of trisubstituted alkenes remains a significant synthetic challenge. Herein, a method is developed for producing regio- and stereodefined trisubstituted iodoalkenes by diverting intermediates from an iodination–electrophilic-cyclization mechanism. Specifically, cyclized sulfonium ion-pair intermediates are diverted to alkenes by ring-opening with nucleophilic iodide. Alternatively, scavenging of the iodide by AgOTf prevents ring-opening, enabling isolation of the sulfonium ion-pair intermediate. Isolation of the ion pair enables access to complementary reactivity, including ring-opening by alternative nucleophiles (i.e., amines), yielding trisubstituted acyclic alkenes and an example tetrasubstituted alkene. X-ray crystallographic determination of reaction intermediates and products confirm the initial electrophilic-cyclization step sets the stereo- and regiochemistry of the product. The products serve as synthetic building blocks by readily participating in downstream functionalization reactions, including oxidation, palladium-catalyzed cross-coupling, and nucleophilic displacement. Reprinted with permission from Kaplan, J. A.; Blum, S. A. Iodination–Group-Transfer Reactions to Generate Trisubstituted Iodoalkenes with Regio- and Stereochemical Control. J. Org. Chem. 2023, 88, 13236–13247.

Chapter 4. A thioarylation method is developed for the synthesis of 2,3-dihydrothiopheniums through an electrophilic-cyclization–cross-coupling mechanism, harnessing the gold(I)/(III) cycle of the recently developed MeDalPhosAuCl catalyst. Single-crystal X-ray crystal structural analysis of the dihydrothiophenium products characterized the anti-addition of the sulfur and Csp2 group to the alkyne and a preference for 5-endo dig cyclization. The dihydrothiophenium products are demonstrated as synthetic building blocks for stereodefined acyclic tetrasubstituted alkenes upon ring-opening reaction with amines. Intramolecular competition experiments show the favorability of Csp3 tether cyclizations over Csp2 tethers, preferentially generating dihydrothiopheniums over thiopheniums. Intermolecular competition experiments of alkyne aryl groups and an intermolecular aryl iodide competition suggest a rate-determining reductive elimination step in the gold(I)/gold(III) catalytic cycle. This rate-determining step is further supported by HRMS analysis of reaction intermediates that identify the catalyst resting state under turnover conditions. Catalyst poisoning experiments provide evidence of substrate inhibition, further consistent with these conclusions.