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Piperazine cores have long been identified as privileged scaffolds in the development of pharmaceutical compounds. Despite this, the facile synthesis of diverse C-substituted piperazines remains a challenge without prefunctionalized substrates/cores. Herein, we describe a programmable approach to highly diversifiable piperazine cores, which circumvents the typical need for radical precursors. The use of organic photoredox catalysis renders this method operationally simple, as direct substrate oxidation followed by 6- endo-trig radical cyclization with in situ generated imines may furnish the product. Additionally, the photoredox-catalyzed anti-Markovnikov hydroamination of readily accessible ene-carbamates provides a modular approach to functionalized diamine starting materials which are shown to generate more complex piperazine cores. A wide range of both carbonyl and amine condensation partners were shown to be compatible with this system in good to excellent yield.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [ 18 F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [ 18 F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with 18 F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [ 18 F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination. Here, we report a general and simple method to generate a variety of highly reactive 18 F-labeled electrophiles via one-step organophotoredox-mediated radiofluorination. The method benefits from high step-economy, reaction efficiency, functional group tolerance, and easily accessible precursors. The obtained prosthetic groups have been successfully applied in PET agent construction and subsequent imaging studies, thereby demonstrating the feasibility of this synthetic method in promoting imaging and biomedical research., Competing Interests: The authors declare the following competing financial interest(s): We have filed a provisional patent on the invention in this manuscript., (© 2024 The Authors. Published by American Chemical Society.)

The C-H functionalization of remote, unactivated C-H bonds offers a unique method of garnering structural complexity in a synthesis. The use of directing groups has provided a means of enacting C-H functionalization on these difficult-to-access bonds; however, the installation and removal of directing groups on a substrate require additional synthetic manipulations, detracting from both the efficiency and economic feasibility of a transformation. The use of alkoxy radicals as transient directing groups for the functionalization of remote C-H bonds allows access to the synthesis of complex molecules without the need for additional functionality. Herein, we report a method for alkoxy radical formation from unactivated alcohols and reactivity mediated by photoredox-generated sulfoxide cation radicals. This protocol leverages the unique reactivity of alkoxy radicals to implement different reaction manifolds: 1,5-hydrogen atom transfer (HAT), cyclization, and β-scission. Furthermore, it was discovered that this methodology could be utilized to impose radical group transfer reactions via the β-scission pathway. Stern-Volmer analysis supports the formation of an alkoxy radical via the intermediacy of a sulfurane radical rather than a proton-coupled electron transfer (PCET) mechanism.

In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[ 18 F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.0% radiochemical purity (RCP) and enantiomeric excess (ee), notably by a simple cartridge-based purification. The flow chemistry-enhanced photolabeling method supplies an efficient and versatile solution for the synthesis of 6-[ 18 F]FDOPA and for more PET tracer development.

The β-amino nitrile moiety and its derivatives frequently appear in natural product synthesis, in drug design, and as ligands in asymmetric catalysis. Herein, we describe a direct route to these complex motifs through the amino- and oxycyanation of olefins utilizing an acridinium photooxidant in conjunction with copper catalysis. The transformation can be rendered asymmetric by using a serine-derived bisoxazoline ligand. Mechanistic studies implicate olefin-first oxidation. The scope of amines for the aminocyanation reaction has been greatly expanded by undergoing a cation radical intermediate as opposed to previous N -centered radical-initiated aminocyanations. Furthermore, alkyl carboxylic acids were included as nucleophiles in this type of transformation for the first time without any decarboxylative side reactions.

Direct functionalization of alkynes under oxidative conditions is challenging, as alkynes are usually recalcitrant towards typical oxidants. Herein, we communicate a strategy for the divergent functionalization of alkynes with photoexcited acridinium organic dyes, presumably via the formation of vinyl cation radicals as key intermediates. Based on the nature of the nucleophiles, different types of difunctionalized products were obtained in moderate to good yields. Addition of lithium Lewis acids resulted in a surprising reversal of diastereocontrol., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12 C and 13 C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [ 11 C]nitriles into arenes. The aryl [ 11 C]nitriles can be further derivatized to [ 11 C]carboxylic acids, [ 11 C]amides, and [ 11 C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents., Competing Interests: DECLARATION OF INTERESTS The authors Z.L., D.A.N. and W.C. have filed a WO patent (patent applicant, the University of North Carolina at Chapel Hill, USA; inventors, Z.L, D.A.N and W.C.; patent no. WO 2020176804) related to part of the labelling methodology in this manuscript and is under review. Z.L. and D.A.N. are the cofounders of LED Radiofluidics. D.A.N. is a member of Chem’s advisory board. The remaining authors declare no competing interests.

Innovative labeling methods to incorporate the short-lived positron emitter carbon-11( 11 C) into bioactive molecules are attractive for positron emission tomography (PET) tracer discovery. Herein, we report a direct C-H radiocyanation method that incorporates [ 11 C]cyanide ( 11 CN - ) to a series of functional electron-rich arenes via photoredox catalysis. This photoredox-mediated radiocyanation can proceed in an aerobic environment and is not moisture sensitive, which allows for ease of reaction setup and for scalable synthesis of 11 C-aryl nitriles from readily available precursors.

A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using organic photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addition into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic aromatic substitution (CRA-S N Ar). Electrochemistry and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidation in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophysical studies. An alternative catalyst scaffold with improved turnover numbers is presented.

The alkylation and heteroarylation of unactivated tertiary, secondary, and primary C(sp 3 )-H bonds was achieved by employing an acridinium photoredox catalyst along with readily available pyridine N oxides as hydrogen atom transfer (HAT) precursors under visible light. Oxygen-centered radicals, generated by single-electron oxidation of the N oxides, are the proposed key intermediates whose reactivity can be easily modified by structural adjustments. A broad range of aliphatic C-H substrates with electron-donating or -withdrawing groups as well as various olefinic radical acceptors and heteroarenes were well tolerated., Competing Interests: The authors declare no competing financial interest.

Ketone-olefin coupling reactions are common methods for the formation of carbon-carbon bonds. This reaction class typically requires stoichiometric or super stoichiometric quantities of metal reductants, and catalytic variations are limited in application. Photoredox catalysis has offered an alternative method toward ketone-olefin coupling reactions, although most methods are limited in scope to easily reducible aromatic carbonyl compounds. Herein, we describe a mild, metal-free ketone-olefin coupling reaction using an excited-state acridine radical super reductant as a photoredox catalyst. We demonstrate both intramolecular and intermolecular ketone-olefin couplings of aliphatic and aromatic ketones and aldehydes. Mechanistic evidence is also presented supporting an " olefin first " ketone-olefin coupling mechanism.

Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C- 18 F bonds through direct halide/ 18 F conversion in electron-rich halo(hetero)arenes. [ 18 F]F - is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct 19 F/ 18 F exchange method enables rapid PET probe diversification through the preparation and evaluation of an [ 18 F]-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent L-[ 18 F]FDOPA from a readily available L-FDOPA analogue., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The fields of C-H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C-H functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C-H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction class─either sp 2 or sp 3 C-H functionalization─lends perspective and tactical strategies for use of these methods in synthetic applications.

The use of carbon dioxide as a C1 chemical feedstock remains an active field of research. Here we showcase the use of milled dry ice as a method to promote the availability of CO 2 in a reaction solution, permitting practical synthesis of arylcarboxylic acids. Notably, the use of milled dry ice produces marked increases in yields relative to those obtained with gaseous CO 2 , as previously reported in the literature.

The direct β -functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of β -C-H bonds in these motifs. Herein, we demonstrate the β -functionalization of saturated aza-heterocycles enabled by a two-step organic photoredox catalysis approach. Initially, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C-C, C-O, and C-N aza-heterocycles at the β -position., Competing Interests: The authors declare no competing financial interest.

A pair of 9-mesityl-10-phenyl acridinium (Mes-Acr + ) photoredox catalysts were synthesized with an iodoacetamide handle for cysteine bioconjugation. Covalently tethering of the synthetic Mes-Acr + cofactors with a small panel of thermostable protein scaffolds resulted in 12 new artificial enzymes. The unique chemical and structural environment of the protein hosts had a measurable effect on the photophysical properties and photocatalytic activity of the cofactors. The constructed Mes-Acr + hybrid enzymes were found to be active photoinduced electron-transfer catalysts, controllably oxidizing a variety of aryl sulfides when irradiated with visible light, and possessed activities that correlated with the photophysical characterization data. Their catalytic performance was found to depend on multiple factors including the Mes-Acr + cofactor, the protein scaffold, the location of cofactor immobilization, and the substrate. This work provides a framework toward adapting synthetic photoredox catalysts into artificial cofactors and includes important considerations for future bioengineering efforts., (© 2020 Wiley-VCH GmbH.)

Herein, we describe an organic photoredox system for direct arene C-H radiofluorination, using a peroxide oxidizing agent and LEDs as the light source. In conjunction with an optimized photocatalyst and a microtubing reactor, this system is applicable to a range of electron-rich aromatics and heteroaromatics. We also demonstrate the feasibility of C-H radiofluorination without an azeotropic drying step, which greatly simplifies the workflow of the labeling process.

Nucleophilic aromatic substitution (S N Ar) is a classical reaction with well-known reactivity toward electron-poor fluoroarenes. However, electron-neutral and electron-rich fluoro(hetero)arenes are considerably underrepresented. Herein, we present a method for the nucleophilic defluorination of unactivated fluoroarenes enabled by cation radical-accelerated nucleophilic aromatic substitution. The use of organic photoredox catalysis renders this method operationally simple under mild conditions and is amenable to various nucleophile classes, including azoles, amines, and carboxylic acids. Select fluorinated heterocycles can be functionalized using this method. In addition, the late-stage functionalization of pharmaceuticals is also presented. Computational studies demonstrate that the site selectivity of the reaction is dictated by arene electronics.

Nucleophilic aromatic substitution (S N Ar) is routinely used to install 19 F - and 18 F - in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C-F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated nucleophilic aromatic substitution (CRA-S N Ar) enables the fluorination of electron-rich arenes with 19 F - and 18 F - under mild conditions, thus complementing the traditional arene polarity requirements necessary for S N Ar-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [ 18 F]5-fluorouracil ([ 18 F]FU). Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical S N Ar strategies, with the potential for use in the synthesis and discovery of PET radiopharmaceuticals., Competing Interests: Competing Interests: The authors declare no competing interests.

Polysubstituted bicyclic acetals are a class of privileged pharmacophores with a unique 3D structure and an adjacent pair of hydrogen bond acceptors. The key, fused acetal functionality is often assembled, via intramolecular cyclization, from linear substrates that are not readily available. Herein, we report a formal cycloaddition between cinnamyl alcohols and cyclic enol ethers under ambient photoredox catalysis conditions. Polysubstituted bicyclic acetals can be prepared in one step from readily available building blocks. Employment of sugar-derived enol ethers allows easy access to a library of scaffolds with intriguing conformation and medicinal chemistry potential., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nucleophilic aromatic substitution (S N Ar) is a common method for arene functionalization; however, reactions of this type are typically limited to electron-deficient aromatic halides. Herein, we describe a mild, metal-free, cation-radical accelerated nucleophilic aromatic substitution (CRA-S N Ar) using a potent, highly oxidizing acridinium photoredox catalyst. Selective substitution of arene C-O bonds on a wide array of aryl ether substrates was shown with a variety of primary amine nucleophiles. Mechanistic evidence is also presented that supports the proposed CRA-S N Ar pathway.

Activation of aliphatic C(sp 3 )-H bonds in the presence of more activated benzylic C(sp 3 )-H bonds is often a nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp 3 )-H bonds to achieve reactivity at the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups, achieving valuable reactivity that traditionally would require multiple chemical transformations.

Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C-H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C-H functionalization reactions with diazoacetate derivatives, furnishing sp 2 -sp 3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Photoinduced electron transfer (PET) is a phenomenon whereby the absorption of light by a chemical species provides an energetic driving force for an electron-transfer reaction 1-4 . This mechanism is relevant in many areas of chemistry, including the study of natural and artificial photosynthesis, photovoltaics and photosensitive materials. In recent years, research in the area of photoredox catalysis has enabled the use of PET for the catalytic generation of both neutral and charged organic free-radical species. These technologies have enabled previously inaccessible chemical transformations and have been widely used in both academic and industrial settings. Such reactions are often catalysed by visible-light-absorbing organic molecules or transition-metal complexes of ruthenium, iridium, chromium or copper 5,6 . Although various closed-shell organic molecules have been shown to behave as competent electron-transfer catalysts in photoredox reactions, there are only limited reports of PET reactions involving neutral organic radicals as excited-state donors or acceptors. This is unsurprising because the lifetimes of doublet excited states of neutral organic radicals are typically several orders of magnitude shorter than the singlet lifetimes of known transition-metal photoredox catalysts 7-11 . Here we document the discovery, characterization and reactivity of a neutral acridine radical with a maximum excited-state oxidation potential of -3.36 volts versus a saturated calomel electrode, which is similarly reducing to elemental lithium, making this radical one of the most potent chemical reductants reported 12 . Spectroscopic, computational and chemical studies indicate that the formation of a twisted intramolecular charge-transfer species enables the population of higher-energy doublet excited states, leading to the observed potent photoreducing behaviour. We demonstrate that this catalytically generated PET catalyst facilitates several chemical reactions that typically require alkali metal reductants and can be used in other organic transformations that require dissolving metal reductants.

Piperazine-containing compounds serve as one of the most important classes of compounds throughout all fields of chemistry. Alas, current synthetic methods have fallen short of providing a general method for the synthesis of highly decorated piperazine fragments. Herein, we present a site-selective approach to the C-H functionalization of existing piperazine compounds using photoredox catalysis. This manifold relies on the predictable differentiation of electronically distinct nitrogen centers within the piperazine framework, granting access to novel C-alkylated variants of the starting piperazines.

Organic azides serve as synthetically useful surrogates for primary amines, a functional group which is ubiquitous in bioactive and medicinally relevant molecules. Historically, the formal hydroazidation of simple activated olefins and styrenes has proven difficult due to the inherent propensity of these compounds to oligomerize. Herein is disclosed a method for the anti-Markovnikov hydroazidation of activated olefins, catalyzed by an organic acridinium salt under irradiation from blue LEDs. This method is applicable to a variety of substituted and terminal styrenes and several vinyl ethers, yielding synthetically versatile hydroazidation products in moderate to excellent yield.

Herein we describe a cation radical-accelerated-nucleophilic aromatic substitution (CRA-S N Ar) of alkoxy arenes utilizing a highly oxidizing acridinium photoredox catalyst and acetone cyanohydrin, an inexpensive and commercially available cyanide source. This cyanation is selective for carbon-oxygen (C-O) bond functionalization and is applicable to a range of methoxyarenes and dimethoxyarenes. Furthermore, computational studies provide a model for predicting regioselectivity and chemoselectivity in competitive C-H and C-O cyanation of methoxyarene cation radicals.

Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C-H bonds, which limits advancements in PET radiotracer development. Here, we disclose a mild method for the fluorine-18 ( 18 F)-fluorination of aromatic C-H bonds by an [ 18 F]F - salt via organic photoredox catalysis under blue light illumination. This strategy was applied to the synthesis of a wide range of 18 F-labeled arenes and heteroaromatics, including pharmaceutical compounds. These products can serve as diagnostic agents or provide key information about the in vivo fate of the labeled substrates, as showcased in preliminary tracer studies in mice., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Photoredox catalysis is a rapidly evolving platform for synthetic methods development. The prominent use of acridinium salts as a sustainable option for photoredox catalysts has driven the development of more robust and synthetically useful versions based on this scaffold. However, more complicated syntheses, increased cost, and limited commercial availability have hindered the adoption of these catalysts by the greater synthetic community. By utilizing the direct conversion of a xanthylium salt into the corresponding acridinium as the key transformation, we present an efficient and scalable preparation of the most synthetically useful acridinium reported to date. This divergent strategy also enabled the preparation of a suite of novel acridinium dyes, allowing for a systematic investigation of substitution effects on their photophysical properties.

Strategies for the direct C-H functionalization of amines are valuable as these compounds comprise a number of pharmaceuticals, agrochemicals and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, organic acridinium photoredox catalyst allows for direct oxidation of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Additionally, we were able to showcase the utility of this methodology through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.

Control of absolute stereochemistry in radical and ion radical transformations is a major challenge in synthetic chemistry. Herein, we report the design of a photoredox catalyst system comprised of an oxidizing pyrilium salt bearing a chiral N- triflyl phosphoramide anion. This class of chiral organic photoredox catalysts is able to catalyze the formation of cation radical-mediated Diels-Alder transformations in up to 75:25 e.r. in both intramolecular and intermolecular examples.

Synthetic transformations that functionalize unactivated aliphatic C-H bonds in an intermolecular fashion offer unique strategies for the synthesis and late-stage derivatization of complex molecules. Herein we report a general approach to the intermolecular functionalization of aliphatic C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradiation. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes.

Aldehydes are among the most versatile functional groups for synthetic chemistry. However, access to polysubstituted alkyl aldehydes is very limited and requires lengthy synthetic routes that involve multiple-step functional-group conversion. This paper reports a one-step synthesis of polysubstituted aldehydes from readily available olefin substrates using visible-light photoredox catalysis. Despite a number of competing reaction pathways, commercial styrenes react with vinyl ethers selectively in the presence of an acridinium salt photooxidant and a disulfide hydrogen-atom-transfer catalyst under blue LED irradiation. Alkyl aldehydes with different substitution patterns are prepared in good yields. This strategy can be applied to structurally sophisticated substrates., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The direct catalytic C-H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C-H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C-N bonds, using primary amines, by direct C-H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron-rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nucleophilic aromatic substitution (S N Ar) is a direct method for arene functionalization; however, it can be hampered by low reactivity of arene substrates and their availability. Herein we describe a cation radical-accelerated nucleophilic aromatic substitution using methoxy- and benzyloxy-groups as nucleofuges. In particular, lignin-derived aromatics containing guaiacol and veratrole motifs were competent substrates for functionalization. We also demonstrate an example of site-selective substitutive oxygenation with trifluoroethanol to afford the desired trifluoromethylaryl ether.

We describe here a surface-bound, oxide-based procedure for the photooxidation of a family of aromatic hydrocarbons by a phosphate-bearing flavin mononucleotide (FMN) photocatalyst on high surface area metal-oxide films., Competing Interests: The authors declare no conflict of interest.

Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes.

We report a formal [4+2] cycloaddition reaction of styrenes under visible-light catalysis. Two styrene molecules with different electronic or steric properties were found to react with each other in good yield and excellent chemo- and regioselectivity. This reaction provides direct access to polysubstituted tetralin scaffolds from readily available styrenes. Sophisticated tricyclic and tetracyclic tetralin analogues were prepared in high yield and up to 20/1 diasteroselectivity from cyclic substrates., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Methods for the direct C-H functionalization of aromatic compounds are in demand for a variety of applications, including the synthesis of agrochemicals, pharmaceuticals, and materials. Herein, we disclose the construction of aromatic nitriles via direct C-H functionalization using an acridinium photoredox catalyst and trimethylsilyl cyanide under an aerobic atmosphere. The reaction proceeds at room temperature under mild conditions and has proven to be compatible with a variety of electron-donating and -withdrawing groups, halogens, and nitrogen- and oxygen-containing heterocycles, as well as aromatic-containing pharmaceutical agents.

Halofunctionalization of alkenes is a classical method for olefin difunctionalization. It gives rise to adducts which are found in many natural products and biologically active molecules, and offers a synthetic handle for further manipulation. Classically, this reaction is performed with an electrophilic halogen source and leads to regioselective formation of the halofunctionalized adducts. Herein, we demonstrate a reversal of the native regioselectivity for alkene halofunctionalization through the use of an acridinium photooxidant in conjunction with a copper cocatalyst., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The development of methods for anti-Markovnikov alkene hydrofunctionalization has been a focal point of catalysis research for several decades. The vast majority of work on the control of regioselectivity for this reaction class has hinged on transition metal catalyst activation of olefin substrates. While progress has been realized, there are significant limitations to this approach, and a general solution for catalysis of anti-Markovnikov hydrofunctionalization reactions of olefins does not presently exist. In the past several years, this research lab has focused on alkene activation by single electron oxidation using organic photoredox catalysts to facilitate anti-Markovnikov hydrofunctionalization. By accessing reactive cation radical intermediates, we have realized a truly general approach to anti-Markovnikov olefin hydrofunctionalization reactions. We have identified a dual organic catalyst system consisting of an acridinium photooxidant, first reported by Fukuzumi, and a redox-active hydrogen atom donor that accomplishes a wide range of hydrofunctionalization reactions with complete anti-Markovnikov regiocontrol. This method relies on single electron oxidation of the alkene to reverse its polarity and results in the opposite regioselectivity for hydrofunctionalization. In 2012, we disclosed the anti-Markovnikov hydroetherification of alkenols employing an acridinium photocatalyst and a hydrogen atom donor that proceeds via interwoven polar and radical steps. This general catalyst system has enabled several important reactions in this area, including anti-Markovnikov alkene hydroacetoxylation, hydrolactonization, hydroamination, and hydrotrifluoromethylation reactions. More recently, we have also delineated conditions for intermolecular anti-Markovnikov hydroamination reactions of alkenes using either triflamide or nitrogen-containing heteroaromatic compounds such as pyrazole, indazole, imidazole, and 1,2,3-triazole. Further development led to a method for the anti-Markovnikov addition of mineral acids to olefins using lutidinium halide salts as convenient reagents to deliver the mineral acids. Acids including HCl, HF, H3PO4, and MeSO3H all participate in the hydrofunctionalization reactions, even with alkenes that are highly prone to polymerization. A combination of transient and steady-state absorption spectroscopy tools were employed to observe alkene cation radicals and the resultant acridine radical, lending support for an electron transfer mechanism. The origin of the anti-Markovnikov selectivity in these reactions is likely the result of a reversible addition of the nucleophile to the alkene cation radical resulting in a greater population of the more stable radical. Loss of a proton followed by reaction of the radical intermediate with the hydrogen atom donor completes the transformations. Again, by means of transient absorption spectroscopy, oxidative turnover of the acridine radical was observed to complete the dual catalytic cycle mechanistic picture.

In this review, we highlight the use of organic photoredox catalysts in a myriad of synthetic transformations with a range of applications. This overview is arranged by catalyst class where the photophysics and electrochemical characteristics of each is discussed to underscore the differences and advantages to each type of single electron redox agent. We highlight both net reductive and oxidative as well as redox neutral transformations that can be accomplished using purely organic photoredox-active catalysts. An overview of the basic photophysics and electron transfer theory is presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds.

The Newman-Kwart rearrangement is perhaps the quintessential method for the synthesis of thiophenols from the corresponding phenol. However, the high thermal conditions required for the rearrangement of the requisite O-aryl carbamothioates often leads to decomposition. Herein, we present a general strategy for catalysis of O-aryl carbamothioates to S-aryl carbamothioates using catalytic quantities of a commercially available organic single-electron photooxidant. Importantly, this reaction is facilitated at ambient temperatures.

A direct catalytic synthesis of substituted α-benzyloxyamino-γ-butyrolactones is reported, starting from simple oxime acids and alkenes. The substituted O-benzyloxime acid starting materials are cyclized with oxidizable alkenes, via Polar Radical Crossover Cycloaddition (PRCC) reactions. The catalytic reaction is carried out using the Fukuzumi acridinium photooxidant and substoichiometric amounts of a redox-active cocatalyst. The utility of this method has been demonstrated through the use of 3 oxime acids and 19 oxidizable olefins.

Over the past several decades, organometallic cross-coupling chemistry has developed into one of the most reliable approaches to assemble complex aromatic compounds from preoxidized starting materials. More recently, transition metal-catalyzed carbon-hydrogen activation has circumvented the need for preoxidized starting materials, but this approach is limited by a lack of practical amination protocols. Here, we present a blueprint for aromatic carbon-hydrogen functionalization via photoredox catalysis and describe the utility of this strategy for arene amination. An organic photoredox-based catalyst system, consisting of an acridinium photooxidant and a nitroxyl radical, promotes site-selective amination of a variety of simple and complex aromatics with heteroaromatic azoles of interest in pharmaceutical research. We also describe the atom-economical use of ammonia to form anilines, without the need for prefunctionalization of the aromatic component., (Copyright © 2015, American Association for the Advancement of Science.)

A direct, catalytic hydrodecarboxylation of primary, secondary, and tertiary carboxylic acids is reported. The catalytic system consists of a Fukuzumi acridinium photooxidant with phenyldisulfide acting as a redox-active cocatalyst. Substoichiometric quantities of Hünig's base are used to reveal the carboxylate. Use of trifluoroethanol as a solvent allowed for significant improvements in substrate compatibilities, as the method reported is not limited to carboxylic acids bearing α heteroatoms or phenyl substitution. This method has been applied to the direct double decarboxylation of malonic acid derivatives, which allows for the convenient use of dimethyl malonate as a methylene synthon. Kinetic analysis of the reaction is presented showing a lack of a kinetic isotope effect when generating deuterothiophenol in situ as a hydrogen atom donor. Further kinetic analysis demonstrated first-order kinetics with respect to the carboxylate, while the reaction is zero-order in acridinium catalyst, consistent with another finding suggesting the reaction is light limiting and carboxylate oxidation is likely turnover limiting. Stern-Volmer analysis was carried out in order to determine the efficiency for the carboxylates to quench the acridinium excited state.

Metal-free, visible light-initiated, living cationic polymerization of 4-methoxystyrene using 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate and methanol is demonstrated. Molecular weight and dispersity are controlled by the concentration of methanol. Initial mechanistic analysis suggests that methanol likely serves to regulate propagation of the cation chain end via reversible chain transfer in a manner analogous to reversible addition-fragmentation chain transfer polymerization.

In this work we present a direct catalytic synthesis of γ-lactams and pyrrolidines from alkenes and activated unsaturated amides or protected unsaturated amines, respectively. Using a mesityl acridinium single electron photooxidant and a thiophenol cocatalyst under irradiation, we are able to directly forge these important classes of heterocycles with complete regiocontrol.