General cross-coupling reactions with adaptive dynamic homogeneous catalysis.

Cross-coupling reactions are among the most important transformations in modern organic synthesis1-3. Although the range of reported (het)aryl halides and nucleophile coupling partners is very large considering various protocols, the reaction conditions vary considerably between compound classes, necessitating renewed case-by-case optimization of the reaction conditions4. Here we introduce adaptive dynamic homogeneous catalysis (AD-HoC) with nickel under visible-light-driven redox reaction conditions for general C(sp2)-(hetero)atom coupling reactions. The self-adjustive nature of the catalytic system allowed the simple classification of dozens of various classes of nucleophiles in cross-coupling reactions. This is synthetically demonstrated in nine different bond-forming reactions (in this case, C(sp2)-S, Se, N, P, B, O, C(sp3, sp2, sp), Si, Cl) with hundreds of synthetic examples under predictable reaction conditions. The catalytic reaction centre(s) and conditions differ from one another by the added nucleophile, or if required, a commercially available inexpensive amine base.

Light-Activated Agonist-Potentiator of GABAA Receptors for Reversible Neuroinhibition in Wildtype Mice.

Gamma aminobutyric acid type A receptors (GABAARs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABAARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABAAR potentiators, despite their high efficacy, good biodistribution, and favorable molecular properties. One solution to this problem is to use drugs with light-dependent activity (photopharmacology) in combination with on-demand, localized illumination. However, a suitable light-activated potentiator of GABAARs has been elusive so far for use in wildtype mammals. We have met this need by developing azocarnil, a diffusible GABAergic agonist-potentiator based on the anxiolytic drug abecarnil that is inactive in the dark and activated by visible violet light. Azocarnil can be rapidly deactivated with green light and by thermal relaxation in the dark. We demonstrate that it selectively inhibits neuronal currents in hippocampal neurons in vitro and in the dorsal horns of the spinal cord of mice, decreasing the mechanical sensitivity as a function of illumination without displaying systemic adverse effects. Azocarnil expands the in vivo photopharmacological toolkit with a novel chemical scaffold and achieves a milestone toward future phototherapeutic applications to safely treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy.

Towards a General Access to 1-Azaspirocyclic Systems via Photoinduced, Reductive Decarboxylative Radical Cyclizations.

A convenient and versatile approach to important 1-azaspirocyclic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.

In-situ Monitoring of Photocatalysis on Polymeric Carbon Nitride Thin Films.

Polymeric carbon nitride has attracted significant interest in heterogeneous photocatalysis due to its activity under visible-light irradiation. Herein, we report on using carbon nitride-coated NMR tubes for in-situ studies of photocatalytic reaction mechanisms. In a first step, we exploited carbon nitride-coated crimp vials as batch photoreactors for visible photocatalytic fluorinations of unactivated C(sp3)-H bonds, with moderate to excellent yields and reusability over multiple cycles. Eventually, carbon nitride-coated NMR tubes were used as a photoreactor by coupling them with optical fiber irradiation directly inside the spectrometer. This enabled us to follow the reaction with in-situ NMR spectroscopy identifying reactive intermediates otherwise elusive in conventional analyses. The method provides advantages for the study of photocatalytic mechanisms of complex reactions and substantially reduces the need of comparative tests for depicting reaction intermediates and conversion pathways.

Reversible Radical Addition Guides Selective Photocatalytic Intermolecular Thiol-Yne-Ene Molecular Assembly.

In modern organic chemistry, harnessing the power of multicomponent radical reactions presents both significant challenges and extraordinary potential. This article delves into this scientific frontier by addressing the critical issue of controlling selectivity in such complex processes. We introduce a novel approach that revolves around the reversible addition of thiyl radicals to multiple bonds, reshaping the landscape of multicomponent radical reactions. The key to selectivity lies in the intricate interplay between reversibility and the energy landscapes governing C-C bond formation in thiol-yne-ene reactions. The developed approach not only allows to prioritize the thiol-yne-ene cascade, dominating over alternative reactions, but also extends the scope of coupling products obtained from alkenes and alkynes of various structures and electron density distributions, regardless of their relative polarity difference, opening doors to more versatile synthetic possibilities. In the present study, we provide a powerful tool for atom-economical C-S and C-C bond formation, paving the way for the efficient synthesis of complex molecules. Carrying out our experimental and computational studies, we elucidated the fundamental mechanisms underlying radical cascades, a knowledge that can be broadly applied in the field of organic chemistry.

Reactivity of Superbasic Carbanions Generated via Reductive Radical-Polar Crossover in the Context of Photoredox Catalysis.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides.

Postsynthetic diversification of peptides through selective modification of endogenous amino acid side chains has enabled significant advances in peptide drug discovery while expanding the biological and medical chemistry space. However, current tools have been focused on the modification of reactive polar and ionizable side chains, whereas the decoration of aromatic systems (e.g., the N(in) of the tryptophan) has been a long-standing challenge. Here, we introduce metallaphotocatalysis in solid-phase peptide synthesis for the on-resin orthogonal N-arylation of relevant tryptophan-containing peptides. The protocol allows the chemoselective introduction of a new C(sp2)-N bond at the N(in) of tryptophan in biologically active protected peptide sequences in the presence of native redox-sensitive side chains. The fusion of metallaphotocatalysis with solid-phase peptide synthesis opens new perspectives in diversifying native amino acid side chains.

Divergent Functionalization of Styrenes via Radical/Polar Crossover with CO2 and Sodium Sulfinates.

Sulfones and carboxylic acids are prominent motifs widely present in the chemical structure of agrochemicals, pharmaceuticals and many other highly valuable compounds. Herein, we describe a conjunctive strategy for the precise installation of these functionalities onto styrenes using sodium sulfinates and CO2 as coupling partners. The protocol allowed the preparation of carboxy-sulfonylated compounds in good yields and broad functional group tolerance. Additionally, taking advantage of the leaving group ability of the sulfone moiety, a one-pot photocatalytic carboxy-sulfonylation-elimination strategy was developed for the synthesis of α-aryl-acrylates.

Tuning the Photocatalytic Performance of Ruthenium(II) Polypyridine Complexes Via Ligand Modification for Visible-Light-Induced Phosphorylation of Tertiary Aliphatic Amines.

Tuning the redox potential of commonly available photocatalyst to improve the catalytic performance or expand its scope for challenging synthetic conversions is an ongoing demand in synthetic chemistry. Herein, the excited state properties and redox potential of commercially available [Ru(bpy)3 ]2+ photocatalyst were tuned by modifying the structure of the bipyridine ligands with electron-donating/withdrawing units. The visible-light-mediated photoredox phosphorylation of tertiary aliphatic amines was demonstrated under mild conditions. A series of cross-dehydrogenative coupling reactions were performed employing the RuII complexes as photocatalyst giving the corresponding α-aminophosphinoxides and α-aminophosphonates via carbon-phosphorus (C-P) bond formation.

Riboflavin Photocatalyzed Dearomative Spiro-Etherification of Naphthols.

The dearomative spiro-etherification of naphthols is achieved using catalytic amounts of riboflavin tetracetate (RFTA) as a photosensitizer and molecular oxygen as a terminal oxidizing agent under blue light (440 nm) irradiation in the presence of acid. The presence of acid increases the photooxidation power of RFTA and facilitates the dearomatization reaction.

Hybrid Catalysts for Enantioselective Photo-Phosphoric Acid Catalysis.

The syntheses of two novel, organic, and chiral photocatalysts are presented. By combining donor-acceptor cyanoarene-based photocatalysts with a chiral phosphoric acid, bifunctional catalysts have been designed. In preliminary proof-of-concept reactions, their use in both enantioselective energy transfer and photoredox catalysis is demonstrated.

Light-Controlled Biocatalysis by Unspecific Peroxygenases with Genetically Encoded Photosensitizers.

Fungal unspecific peroxygenases (UPOs) have gained substantial attention for their versatile oxyfunctionalization chemistry paired with impressive catalytic capabilities. A major drawback, however, remains their sensitivity towards their co-substrate hydrogen peroxide, necessitating the use of smart in situ hydrogen peroxide generation methods to enable efficient catalysis setups. Herein, we introduce flavin-containing protein photosensitizers as a new general tool for light-controlled in situ hydrogen peroxide production. By genetically fusing flavin binding fluorescent proteins and UPOs, we have created two virtually self-sufficient photo-enzymes (PhotUPO). Subsequent testing of a versatile substrate panel with the two divergent PhotUPOs revealed two stereoselective conversions. The catalytic performance of the fusion protein was optimized through enzyme and substrate loading variation, enabling up to 24300 turnover numbers (TONs) for the sulfoxidation of methyl phenyl sulfide. The PhotUPO concept was upscaled to a 100 mg substrate preparative scale, enabling the extraction of enantiomerically pure alcohol products.

Enforced Electronic-Donor-Acceptor Complex Formation in Water for Photochemical Cross-Coupling.

The amino alcohol meglumine solubilizes organic compounds in water and enforces the formation of electron donor acceptor (EDA) complexes of haloarenes with indoles, anilines, anisoles or thiols, which are not observed in organic solvents. UV-A photoinduced electron transfer within the EDA complexes induces the mesolytic cleavage of the halide ion and radical recombination of the arenes leading, after rearomatization and proton loss to C-C or C-S coupling products. Depending on the substitution pattern selective and unique cross-couplings are observed. UV and NMR measurements reveal the importance of the assembly for the photoinduced reaction. Enforced EDA aggregate formation in water allows new activation modes for organic photochemical synthesis.

Monitoring the Reversibility of GPCR Signaling by Combining Photochromic Ligands with Label-free Impedance Analysis.

G protein-coupled cell surface receptors (GPCR) trigger complex intracellular signaling cascades upon agonist binding. Classic pharmacological assays provide information about binding affinities, activation or blockade at different stages of the signaling cascade, but real time dynamics and reversibility of these processes remain often disguised. We show that combining photochromic NPY receptor ligands, which can be toggled in their receptor activation ability by irradiation with light of different wavelengths, with whole cell label-free impedance assays allows observing the cell response to receptor activation and its reversibility over time. The concept demonstrated on NPY receptors may be well applicable to many other GPCRs providing a deeper insight into the time course of intracellular signaling processes.

Ion-Pairing Catalysis in Stereoselective, Light-Induced Transformations.

With the rapid development of photoredox catalysis, numerous concepts for asymmetric induction were successfully and broadly adapted from polar two-electron transformations to radical chemistry. While this applies to organocatalysis or transition metal chemistry, asymmetric ion-pairing catalysis remains a niche application within light-driven reactions today. This perspective gives an overview of recent examples, strategies, and their application in stereoselective transformations at the interface of ion-pairing and photo(redox) catalysis.

Strategies for the Photocatalytic Generation of Carbanion Equivalents for Reductant-Free C-C Bond Formations.

ConspectusThe use of photocatalysis in organic chemistry has encountered a surge of novel transformations since the start of the 21st century. The majority of these transformations are driven by the generation and subsequent reaction of radicals, owing to the intrinsic property of common photocatalysts to transfer single electrons from their excited state. While this is a powerful and elegant method to develop novel transformations, several research groups recently sought to further extend the toolbox of photocatalysis into the realm of polar ionic reactivity by the formation of cationic as well as anionic key reaction intermediates to furnish a desired product.Our group became especially interested in the photocatalytic formation of anionic carbon nucleophiles, as the overall transformation resembles classical organometallic reactions like Grignard, Barbier, and Reformatsky reactions, which are ubiquitous in organic synthesis with broad applications especially in the formation of valuable C-C bonds. Although these classical reactions are frequently applied, their use still bears certain disadvantages; one is the necessity of an (over)stoichiometric amount of a reducing metal. The reducing, low-valent, metal is solely applied to activate the starting material to form the organometallic carbanion synthon, while the final reaction product does generally not contain a metal species. Hence, a stoichiometric amount of metal salt is bound to be generated at the end of each reaction, diminishing the atom economy. The use of visible light as mild and traceless activation agent to drive chemical reactions can be a means to arrive at a more atom economic transformation, as a reducing metal source is avoided. Beyond this, the vast pool of photocatalytic activation methods offers the potential to employ easily available starting materials, as simple as unfunctionalized alkanes, to open novel and more facile retrosynthetic pathways. However, as mentioned above, photocatalysis is dominated by open-shell radical reactivity. With neutral radicals showing an intrinsically different reactivity than ionic species, novel strategies to form intermediates expressing a polar behavior need to be developed in order to achieve this goal.In the last couple of years, several methods toward this aim have been reported by our group and others. This Account aims to give an overview of the different existing strategies to photocatalytically form carbon centered anions or equivalents of those in order to form C-C bonds. As the main concept is to omit a stoichiometric reductant source (like a low-valent metal in classical organometallic reactions), only redox-neutral and reductant-free transformations were taken into closer consideration. We present selected examples of important strategies and try to illustrate the intentions and concepts behind the methods developed by our group and others.

Photochromic Fentanyl Derivatives for Controlled µ-Opioid Receptor Activation.

Photoswitchable ligands as biological tools provide an opportunity to explore the kinetics and dynamics of the clinically relevant µ-opioid receptor. These ligands can potentially activate or deactivate the receptor when desired by using light. Spatial and temporal control of biological activity allows for application in a diverse range of biological investigations. Photoswitchable ligands have been developed in this work, modelled on the known agonist fentanyl, with the aim of expanding the current "toolbox" of fentanyl photoswitchable ligands. In doing so, ligands have been developed that change geometry (isomerize) upon exposure to light, with varying photophysical and biochemical properties. This variation in properties could be valuable in further studying the functional significance of the µ-opioid receptor.

Highly Chemoselective Catalytic Photooxidations by Using Solvent as a Sacrificial Electron Acceptor.

Catalyst recovery is an integral part of photoredox catalysis. It is often solved by adding another component-a sacrificial agent-whose role is to convert the catalyst back into its original oxidation state. However, an additive may cause a side reaction thus decreasing the selectivity and overall efficiency. Herein, we present a novel approach towards chemoselective photooxidation reactions based on suitable solvent-acetonitrile acting simultaneously as an electron acceptor for catalyst recovery, and on anaerobic conditions. This is allowed by the unique properties of the catalyst, 7,8-dimethoxy-3-methyl-5-phenyl-5-deazaflavinium chloride existing in both strongly oxidizing and reducing forms, whose strength is increased by excitation with visible light. Usefulness of this system is demonstrated in chemoselective dehydrogenations of 4-methoxy- and 4-chlorobenzyl alcohols to aldehydes without over-oxidation to benzoic acids achieving yields up to 70 %. 4-Substituted 1-phenylethanols were oxidized to ketones with yields 80-100 % and, moreover, with yields 31-98 % in the presence of benzylic methyl group, diphenylmethane or thioanisole which are readily oxidized in the presence of oxygen but these were untouched with our system. Mechanistic studies based on UV-Vis spectro-electrochemistry, EPR and time-resolved spectroscopy measurements showed that the process involving an electron release from an excited deazaflavin radical to acetonitrile under formation of solvated electron is crucial for the catalyst recovery.

Photo-Induced Homologation of Carbonyl Compounds for Iterative Syntheses.

We describe a photo-induced reaction for the in situ generation of highly reactive alkyl diazo species from carbonyl precursors via photo-excitation of N-tosylhydrazone anions. The diazo intermediates undergo efficient C-H insertion of aldehydes, leading to the productive synthesis of aldehydes and ketones. The method is applicable to the iterative synthesis of densely functionalized carbonyl compounds through sequential trapping of the diazo species with various aldehydes. The reaction proceeds without the need of any catalyst by light irradiation and features high functional group tolerance. More than 70 examples, some performed on a gram-scale, demonstrate the broad applicability of this reaction sequence in synthesis.

Intermolecular Photocatalytic Chemo-, Stereo- and Regioselective Thiol-Yne-Ene Coupling Reaction.

The first example of an intermolecular thiol-yne-ene coupling reaction is reported for the one-pot construction of C-S and C-C bonds. Thiol-yne-ene coupling opens a new dimension in building molecular complexity to access densely functionalized products. The employment of Eosin Y/DBU/MeOH photocatalytic system suppresses hydrogen atom transfer (HAT) and associative reductant upconversion (via C-S three-electron σ-bond formation). Investigation of the reaction mechanism by combining online ESI-UHRMS, EPR spectroscopy, isotope labeling, determination of quantum yield, cyclic voltammetry, Stern-Volmer measurements and computational modeling revealed a unique photoredox cycle with four radical-involving stages. As a result, previously unavailable products of the thiol-yne-ene reaction were obtained in good yields with high selectivity. They can serve as stable precursors for synthesizing synthetically demanding activated 1,3-dienes.