Tobias Ritter

Alcohols are readily converted to electrophiles on a large scale, while deaminative functionalization of aliphatic amines is less developed. Aromatic amines are readily used as versatile synthetic intermediates through diazonium chemistry, but analogous aliphatic diazonium chemistry is currently not as useful because of the instability and explosiveness of aliphatic diazonium intermediates. Here, we develop aliphatic diazonium chemistry through nitrate reduction-based diazotization with substoichiometric hydroquinone as a chemically competent reductant. As a consequence, the deamination allows Sandmeyer-type reactivity to convert aliphatic amines into alkyl (pseudo)halides. Because all of the reagents are inexpensive, aliphatic diazonium chemistry provides potential access to alkyl halides and alkyl nitrate esters on scale.

Oxetanes are strained four-membered oxygen heterocycles that are valuable motifs for modulating lipophilicity, metabolic stability and three-dimensional structure of pharmaceuticals. Diaryloxetanes with 3,3-substitution are recognized as bioisosteres of diaryl ketones that preserve key electronic features while exhibiting distinct reactivity. However, synthesis of this motif largely relies on Lewis acid-promoted Friedel–Crafts reactions, which are restricted to electron-rich arenes and often suffer from low functional-group tolerance and competing side reactions. Here we report a method for the synthesis of 3,3-substituted diaryloxetanes from readily available 3-oxetanone through a cross-coupling reaction with tetrafluoropyridone as leaving group. The difunctionalization through subsequent addition of two aryl groups, one from an aryl halide, the other from an arylboronic ester, provides access to a variety of benzophenone bioisosteres. The nickel-catalysed cross-coupling at a fully substituted carbon centre is enabled through oxetanyl C–O bond oxidative addition and establishes programmable entry to 3,3-diaryloxetane bioisosteres that are synthetically challenging to access via traditional polar bond disconnection strategies. Mechanistic studies support a Ni(0)-mediated oxidative addition of the oxetanyl tetrafluoropyridine ester.

Carbenes are reactive divalent carbon intermediates that serve as one-carbon synthons to access cyclopropanes. The synthetic utility of these three-membered carbocycles has led chemists to accept the dangers associated with the explosive starting materials ¹ or intermediates ² required for both conventional and modern cyclopropanation reactions. Sulfonium salts, although safer, have not been competitive for cyclopropanation because they typically do not function as efficient carbene donors ³ . In all cyclopropanation reactions reported, diversity can be obtained through either the olefin or carbene partner, but not both; for example, several modern reactions are limited to activated olefins, such as styrenes ^4–7 . Here we report how alkylthianthrenium salts differ conceptually from all other carbene precursors and allow for carbene-transfer chemistry, including the synthesis of cyclopropanes, in which both the olefin and the carbene partner can be diverse. The steric bulk and low Lewis basicity of thianthrene can rationalize the superior reactivity of the thianthrenium salts for cyclopropanation because undesired energetically low-lying local minima on the potential energy surface, as present for other sulfonium salts, are avoided. Despite high reactivity, thianthrenium salts exhibit a desirable safety profile that allows scale up, also in the solid state through ball-milling, which is dangerous with many other cyclopropanation reactions. The combination of reactivity and safety highlights thianthrenium ylides as a general compound class for metal–carbene reactivity that extends beyond cyclopropanation to diverse carbene-transfer reactions, including σ -bond insertion and sigmatropic rearrangements.

Alkenes are widely used functional groups in synthetic chemistry, important for producing polymers, detergents, agrochemicals and pharmaceuticals. When treated with electrophiles, alkenes typically undergo addition, not substitution, reactions ¹ . As a consequence, the intuitive retrosynthetic disconnection to form a substituted alkene from the parent alkene does not exist in the toolbox of the chemist. For example, conversion of tri-substituted into tetra-substituted alkenes, or late-stage alkylation of complex alkenes, would provide access to molecules that are currently difficult to construct. Alkene cross-metathesis can formally alkylate appropriately substituted alkenes, but diastereoselectivity and alkene–alkyl combinations are restricted to specific cases ² , and several classes of alkenes, such as internal or cyclic alkenes, cannot be readily alkylated with known methods ³ . Here we report a formal regio- and diastereoselective C−H alkylation of alkenes with carboxylic acids as alkyl source, readily available in large diversity. Key to the development is a polar decarboxylative alkylation that deviates from the current model of radical-mediated C−C bond formation from carboxylic acid derivatives, enabled by a previously unappreciated access to persistent alkylzinc intermediates from redox-active esters. A Pd-catalysed cross-coupling of the alkylzinc species with alkenyl thianthrenium salts accessed from alkenes affords the substituted alkenes in high diastereoselectivity. The transformation offers alkylation of cyclic, acyclic, terminal, internal, mono-substituted, di-substituted and tri-substituted alkenes with diverse alkyl groups.

Herein, we show the conversion of alkenes into functionalized 1,3-dienes in two steps. First, C-H thianthrenation is used to access a wide pool of alkenyl electrophiles directly from alkenes. Second, the alkenyl thianthrenium salts undergo a Pd-catalyzed three-component coupling reaction with allene gas and nonorganometallic nucleophiles to afford 1,3-dienes. This method provides a robust and modular platform for accessing structurally complex 1,3-dienes that would be challenging to access otherwise.

ConspectusThianthrenium (TT) salts have emerged as versatile reagents with utility across transition-metal (TM) catalysis, photochemistry, biocatalysis, electrochemistry, and polar transformations. Initially introduced as an aryl (pseudo)halide surrogate in traditional TM-catalyzed cross-coupling reactions, thianthrenium salts have since demonstrated conceptually distinct advantages over their (pseudo)halide analogues in single-electron mediated processes, particularly under visible-light irradiation.The positively charged thianthrenium group raises the substrate's reduction potential into the range accessible to common photocatalysts, and upon single-electron transfer, the exocyclic C-S_TT bond undergoes ultrafast mesolytic cleavage to generate aryl or alkyl radicals while avoiding the back-electron-transfer often observed with halide substrates. This combination of favorable redox properties and rapid bond fragmentation distinguishes thianthrenium salts as efficient radical precursors in photoredox catalysis.Beyond the electron transfer mechanism in photoredox catalysis, thianthrenium salts have distinct advantages in triplet energy transfer (EnT) catalysis. In contrast to simple aryl (pseudo)halides, which possess high triplet energies (E_T ≈ 78-82 kcal/mol), Ar-TT⁺ salts exhibit consistently lower triplet energies (E_T ≈ 60-66 kcal/mol), largely independent of the arene substitution pattern. This energy range allows for efficient triplet-triplet energy transfer from photosensitizers such as thioxanthone (TXO, E_T = 65.5 kcal/mol) for radical generation via EnT in high quantum yield.In addition to photocatalytic pathways, direct photolysis of thianthrenium salts has emerged as a third mode of activation. This reactivity was initially employed to homolyze the CF₃-S_TT bond of trifluoromethyl thianthrenium (CF₃-TT⁺) triflate that has a low bond dissociation energy (BDE), with blue LEDs. A more general, biocompatible approach emerged through the development of selenonium-based TT analogues. TT-like selenonium-based reagents have been designed to realize site-selective selenylation of electron-rich aromatic residues on biomacromolecules in aqueous media. While the C-Se bond in these selenonium salts remains stable under ambient conditions, it undergoes efficient homolytic cleavage upon irradiation due to their visible light absorption and low BDE of ∼70 kcal/mol for the C-Se bond. Therefore, photochemical late-stage modifications of peptides, proteins, and nucleic acids can be achieved under physiologically compatible conditions.This Account retraces the conceptual evolution of thianthrenium chemistry in our laboratory─from its origins in aromatic C-H functionalization to its diverse applications in photochemistry. We highlight conceptual and practical advances enabled by thianthrenium salts in photocatalysis, which are classified into two categories: photocatalytic SET (photoredox catalysis) and photocatalytic EnT. Within photoredox catalysis, three mechanistic modes are distinguished: (i) conventional photoredox catalysis; (ii) dual photoredox/transition-metal catalysis; and (iii) photoinduced transition-metal catalysis. In addition, we discuss the direct homolytic cleavage of thianthrenium and selenium salts under visible-light irradiations. By contrasting these strategies, we explain how thianthrenium chemistry provides practical and mechanistically distinct solutions to modern radical chemistry.

We developed a synthetically readily accessible dicationic thianthrenium reagent for reliable identification of protein-protein interactions (PPIs) in cellulo. Cysteine (Cys)-selective Michael addition to in situ generated alkenyl thianthrenium salts leads to formation of reactive episulfonium intermediates on protein surfaces that covalently trap all nucleophilic amino acids of interacting proteins. Short and chemically stable ethylene linkages are introduced in a single step and thereby provide short distance restraints for reliable modeling of PPI interfaces. The fundamental advance described in this work is the development of a reagent for identification of low-abundant interprotein cross-links via episulfonium chemistry enabled by the introduction of an alkyne tag for downstream enrichment of cross-linked products without an extension of the linkage length between the two cross-linked amino acids. Based on the fast single-step cross-linking, we show that our method allows for more accurate structure prediction of reported PPIs compared to data produced by commonly used bifunctional cross-linking reagents. We further demonstrate that our approach enables identification of previously undocumented PPIs in human cancer cells by targeting native Cys residues and that the obtained short distance restraints provide valuable information for modeling of PPI surfaces.

Proteome-wide intramolecular cross-linking of amino acids allows for protein structure probing and is often achieved by reactive intermediates generated in situ. For example, carbene insertion chemistry forms versatile products but relies on two-step protocols that first introduce a photoreactive group and then generate a reactive intermediate via UV light irradiation. Alternatively, direct cross-linking with bifunctional electrophilic reagents enables modification of natural amino acids in a single transformation but proceeds via intermediates with a sufficiently long half-life in solution to capture unfavorable protein conformations. Herein, we report the use of commercially available vinyl thianthrenium tetrafluoroborate (VTT) for a single-step cross-linking strategy based on the umpolung of native cysteinyl thiols to electrophilic episulfonium ions in cells. We demonstrate that the umpolung reaction proceeds within minutes in various cell types. Even when competing with cysteine-reactive maleimide or iodoacetamide reagents, the fast cellular uptake of VTT enables efficient intracellular labeling and ensures the formation of products with a short and stable ethylene linker between cysteine and nucleophilic natural amino acids. We anticipate that the fast generation of episulfonium ions, which enable cross-linking without exogenous activation, will assist researchers in predicting protein structures based on quantitative proteome-wide information generated in cellulo.

C-N cross coupling reactions are widely employed for the construction of carbon-nitrogen bonds. However, control of chemoselectivity in the presence of the amino functionality in oligonucleotides remains a challenge. Here, we report the development of a new ruthenium reagent that enables the chemoselective N-arylation of amine-DNA conjugates with distinct chemoselectivity when compared to conventional palladium-based C-N bond-forming catalysts. The ruthenium reagent activates commercially available haloarenes in situ via η⁶ π-arene coordination for subsequent S_NAr with the amine. The method is compatible with various commercially available haloarenes and aliphatic amines, and the reaction proceeds under mild conditions.