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Palladium-catalysed hydrogenolysis with molecular hydrogen a, Heterogeneous Pd-catalysed hydrogenolysis with H2. b, Homogeneous Pd-catalysed hydrogenolysis of aryl halide. L, neutral 2-electron ligand. c, Homogeneous Pd-catalysed hydrogenolysis of aryl thianthrenium salt. d, Chemo- and site-selective C–H tritiation via arylthianthrenium salt by homogeneous palladium catalysis. X, conventional (pseudo)halide.
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Tritium labelling is a critical tool for investigating the pharmacokinetic and pharmacodynamic properties of drugs, autoradiography, receptor binding and receptor occupancy studies¹. Tritium gas is the preferred source of tritium for the preparation of labelled molecules because it is available in high isotopic purity². The introduction of tritium...
Citations
... Among these compounds, aryl thianthrenium (TT) salts are particularly renowned for their exceptional versatility as reactive intermediates [31][32][33][34][35][36][37][38] . Recently, Ritter and coworkers have successfully utilized these compounds for halogenation (F 39 , Cl, Br, and I 40 and hydrogen isotope labeling 41 by breaking carbon-sulfur bonds with the assistance of transition metals catalysis (Fig. 1c). Furthermore, alkyl TT salts have been investigated by our group 42,43 and other researchers 44,45 , resulting in a noteworthy expansion of the chemical landscape for alkyl (pseudo)halides. ...
Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks, allowing for the incorporation of deuterium atoms and functional groups into a target molecule in a single step. Unfortunately, the limited availability of synthetic approaches to deuterated synthons has impeded progress in this field. Here, we present an approach utilizing alkyl-substituted thianthrenium salts that efficiently and selectively introduce deuterium at the α position of alkyl chains through a pH-dependent HIE process, using D2O as the deuterium source. The resulting α-deuterated alkyl thianthrenium salts, which bear two deuterium atoms, exhibit excellent selectivity and deuterium incorporation in electrophilic substitution reactions. Through in situ formation of isotopically labelled alkyl halides, these thianthrenium salts demonstrate excellent compatibility in a series of metallaphotoredox cross-electrophile coupling with (hetero)aryl, alkenyl, alkyl bromides, and other alkyl thianthrenium salts. Our technique allows for a wide range of substrates, high deuterium incorporation, and precise control over the site of deuterium insertion within a molecule such as the benzyl position, allylic position, or any alkyl chain in between, as well as neighboring heteroatoms. This makes it invaluable for synthesizing various deuterium-labeled compounds, especially those with pharmaceutical significance.
... Carbon-14 and tritium are the most common elements used in these studies 4 . Tritiation is typically the first method employed because it can be directly incorporated into the structure via exchange reactions (for example, acid equilibration or metal-catalysed C-H functionalization reactions), and therefore requires little manipulation of an existing drug candidate [5][6][7][8][9] . However, the sites on the molecule that are easiest to tritiate often coincide with metabolic instability, and substantial kinetic isotope effects with tritium can result in misleading data on the stability or fate of a drug in biological systems 3 . ...
The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [¹⁴C]CO and [¹⁴C]CO2. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming ¹⁴C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid ¹⁴C source. To enable this process, a functional group metathesis of carbon–carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon–chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the ¹⁴C label or ¹³C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.
... This novel approach involves the utilization of tetra-fluorothianthrene sulfoxide (TFT=O) or thianthrene sulfoxide (TT=O), which react with arenes under mild conditions, exhibiting exclusive regioselectivity. Significant advancements in the synthesis of arylthianthrenium salts have prompted a growing interest in their utilization as versatile precursors for the conversion of C-H bonds in arenes into C-C/X bonds through transition-metal-catalyzed cross-coupling processes [12][13][14][15][16][17][18][19][20]. On the other hand, sulfonium salts have emerged as appealing sources of aryl radicals for a wide range of transformations aimed at creating novel chemical bonds driven by their distinctive structural attributes and chemical tendencies (Scheme 1a) [9,[21][22][23][24][25][26]. ...
In recent years, S-(alkyl)thianthrenium salts have become an important means of functionalizing alcohol compounds. However, additional transition metal catalysts and/or visible light are required. Herein, a direct thioetherification/amination reaction of thianthrenium salts is realized under metal-free conditions. This strategy exhibits good functional-group tolerance, operational simplicity, and an extensive range of compatible substrates.
... We envisioned that a Cys-selective reagent that, upon conjugation, results in formation of a more reactive electrophile in situ would enable reactions with various nucleophiles that are not reactive enough to be used with current methods. Our group has previously reported the synthesis and reactivity of several thianthrenium-based compounds, for example, aryl-27 and trifluoromethyl 28 thianthrenium salts, which can access reactivity that goes beyond what has been possible with conventional halides or pseudohalides 29,30 . Based on the promising and distinct reactivity that the thianthrenium substituent can impart, we hypothesized that vinyl thianthrenium salts can be used to achieve versatile functionalization of biomolecules with different complexity at biocompatible conditions, and provide the opportunity to install a stable linker that is shorter than other methods allow. ...
Cysteine conjugation is an important tool in protein research and relies on fast, mild and chemoselective reactions. Cysteinyl thiols can either be modified with prefunctionalized electrophiles, or converted into electrophiles themselves for functionalization with selected nucleophiles in an independent step. Here we report a bioconjugation strategy that uses a vinyl thianthrenium salt to transform cysteine into a highly reactive electrophilic episulfonium intermediate in situ, to enable conjugation with a diverse set of bioorthogonal nucleophiles in a single step. The reactivity profile can connect several nucleophiles to biomolecules through a short and stable ethylene linker, ideal for introduction of infrared labels, post-translational modifications or NMR probes. In the absence of reactive exogenous nucleophiles, nucleophilic amino acids can react with the episulfonium intermediate for native peptide stapling and protein–protein ligation. Ready synthetic access to isotopologues of vinyl thianthrenium salts enables applications in quantitative proteomics. Such diverse applications demonstrate the utility of vinyl-thianthrenium-based bioconjugation as a fast, selective and broadly applicable tool for chemical biology.
... Gratifyingly, we observed excellent selectivity for substrates that contained an additional sulfur atom in the structure. Thus, thianthrene selectively generated product 2c, which is an important precursor for the synthesis of thianthrene salts [37]. ...
Sustainable oxidation protocols aim to provide an environmentally friendly and cost-effective method for the production of various chemicals and materials. The development of such protocols can lead to reduced energy consumption, fewer harmful byproducts, and increased efficiency in industrial processes. As such, this field of research is of great importance and interest to both academia and industry. This work showcases a sustainable and catalyst-free oxidation method for heteroatoms (e.g., S, P, and Se) using only air, water and light. An additional reaction pathway is proposed in which the incorporated oxygen on the heteroatoms originates from water. Furthermore, the addition of certain additives enhances productivity by affecting kinetics. The industrial potential is demonstrated by conveniently transferring the batch protocol to continuous flow using the HANU flow reactor, indicating scalability and improving safety.
... Therefore, the most attractive approach became the hydrogen isotope exchange (HIE) of selected hydrogen atoms of the active pharmaceutical ingredient (API) in a single reaction step. [7,8] Many HIE methods have already been reported following mainly three general concepts of a) pH-controlled HIE, b) homogeneous catalysis or c) heterogeneous catalysis. [9,10] Other than functional group-directed and non-directed approaches, there are several HIE systems that describe capitalizing on distinct reactivities to obtain high selectivity. ...
We have studied the photoredox‐catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre‐catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox‐catalyzed and CH‐functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.
... The drugs' metabolism and pharmacokinetic properties will be profoundly modified by the presence of the deuterium (D) atom due to its kinetic isotope effect [1][2][3][4][5][6] . Since the first deuterated drug, deutetrabenazine (Austedo), has been approved by the US Food and Drug Administration (FDA) 7 , tremendous efforts have been devoted to synthesizing and patenting D-labeled pharmaceuticals [8][9][10][11][12][13][14][15][16] . Aryl ethylamines can serve as both important drug molecules and ubiquitous scaffolds in biologically active compounds ( Fig. 1a and Supplementary Fig. 1) [17][18][19][20][21] . ...
Developing a step-economical approach for efficient synthesis of α,β-deuterio aryl ethylamines (α,β-DAEAs) with high deuterium ratios using an easy-to-handle deuterated source under ambient conditions is highly desirable. Here we report a room-temperature one-pot two-step transformation of aryl acetonitriles to α,β-DAEAs with up to 92% isolated yield and 99% α,β-deuterium ratios using D2O as a deuterium source. The process involves a fast α-C − H/C − D exchange and tandem electroreductive deuteration of C ≡ N over an in situ formed low-coordinated Fe nanoparticle cathode. The moderate adsorptions of nitriles/imine intermediates and the promoted formation of active hydrogen (H*) on unsaturated Fe sites facilitate the electroreduction process. In situ Raman confirms co-adsorption of aryl rings and the C ≡ N group on the Fe surface. A proposed H*-addition pathway is confirmed by the detected hydrogen and carbon radicals. Wide substrate scope, parallel synthesis of multiple α,β-DAEAs, and successful preparation of α,β-deuterated Melatonin and Komavine highlight the potential.
... In 2021, Ritter and coworkers reported palladium-catalysed reductive deuteration and tritiation of aryl thianthrenium salts (1) (Scheme 9). 75 Ritter used aryl thianthrenium salts on the micromole scale in 2 H 2 / 3 H 2 gas at atmospheric pressure. A proposed mechanism showed that a monoligated Pd 0 catalyst generated from Pd [(P t Bu 3 )] 2 would undergo reversible association with H 2 and oxidative addition with aryl thianthrenium salts (1) to afford A. Then A went through dihydrogen splitting and reductive elimination to furnish the nal product (9) and regenerate the Pd 0 catalyst. ...
Organothianthrenium salts are a class of compounds containing a positively charged sulfur atom and a neutral sulfur atom. Over the past years, organothianthrenium salts have been emerging as attractive precursors for a myriad of transformations to forge new C-C and C-X bonds due to their unique structural characteristics and chemical behaviors. The use of the thianthrenation strategy selectively transforms C-H, C-O, and other chemical bonds into organothianthrenium salts in a predictable manner, providing a straightforward alternative for regioselective functionalizations for arenes, alkenes, alkanes, alcohols, amines and so on through diverse reaction mechanisms under mild conditions. In this review, the preparation of different organothianthrenium salts is summarized, including aryl, alkenyl and alkyl thianthrenium salts. Moreover, the utilization of organothianthrenium salts in different catalytic processes and their synthetic potentials are also discussed.
... to the feasible accessibility of aryl sulfonium salts from simple arenes via regioselective electrophilic thianthrenation or phenoxathiination (Figure 1b) [22][23][24] . In comparison with aryl halides and their analogues, the corresponding arylthianthrenium salts present unique reactivities in both transition metal catalyzed cross-coupling reactions as an aryl electrophile 23,[25][26][27][28][29][30][31][32] and photoredox catalyzed radical coupling reactions as an aryl radical precursor 24,[34][35][36][37][38][39][40] . Most importantly, several novel reaction processes with arylthianthrenium salts, including Pd-catalyzed tritiation 32 , photocatalyzed radical coupling, 24,[34][35][36][37][38][39][40] and electron donor-acceptor complex photoactivation 39,40 etc., have been proven to be inert or inefficient with aryl halides and their analogues. ...
... In comparison with aryl halides and their analogues, the corresponding arylthianthrenium salts present unique reactivities in both transition metal catalyzed cross-coupling reactions as an aryl electrophile 23,[25][26][27][28][29][30][31][32] and photoredox catalyzed radical coupling reactions as an aryl radical precursor 24,[34][35][36][37][38][39][40] . Most importantly, several novel reaction processes with arylthianthrenium salts, including Pd-catalyzed tritiation 32 , photocatalyzed radical coupling, 24,[34][35][36][37][38][39][40] and electron donor-acceptor complex photoactivation 39,40 etc., have been proven to be inert or inefficient with aryl halides and their analogues. Accordingly, the direct functionalization of arenes via corresponding arylthianthrenium salts has become an appealing approach for the late-stage modification of drug molecules and bioactive molecules. ...
... Our initial efforts were focused on the preparation the arylthianthrenium salts using aryl halides as the starting materials in the presence of a transition metal catalyst (Pd, Ni etc.), inspiring by the transition metalcatalyzed phosphonium salts formation reaction 46,47 (Figure 2a). However, the desired arylthianthrenium salts could not be obtained after systematical investigation of the reaction parameters, probably due to the weak coordinating ability of thianthrene in comparison to phosphine compounds and the high reactivity of arylthianthrenium salts in the presence of palladium and nickel catalysts [24][25][26][27][28][29][30][31][32] . Although no desired arylthianthrenium salts were observed with simple aryl halides (only the homocoupling of aryl halides were observed), we were delighted to find the Cu(I)-mediated thianthrenation of aryl bromide is feasible in the presence of a pyridine directing group 48 (Figure 2b). ...
Great success in synthetic chemistry is motivated by the development of novel and reactive linchpins for carbon-carbon and carbon-heteroatom bond formation reactions, that has dramatically altered chemists’ approach to building molecules. Herein, we report the readily synthesis of aryl sulfonium salts, a novel versatile electrophilic linchpin, via an unprecedented Cu-mediated thianthrenation and phenoxathiination of commercially available arylborons with thianthrene and phenoxathiine, providing a series of aryl sulfonium salts in high efficiency. More importantly, by leveraging the sequential Ir-catalyzed C–H borylation and Cu-mediated thianthrenation of arylborons, the formal thianthrenation of arenes are also achieved. As the Ir-catalyzed C–H borylation with undirected arenes normally occurred at the less steric hindrance position, thus providing a complementary method for thianthrenation of arenes in comparison with the electrophilic thianthrenation. This process is capable of late-stage functionalization of a series of pharmaceuticals, which might find wide synthetic applications in both industry and academic sectors.
... 4 Tritiation is typically the rst method employed because it can be directly incorporated into the structure via exchange reactions (e.g., acid equilibration or metal-catalyzed C-H functionalization reactions), and therefore requires little manipulation of an existing drug candidate. [5][6][7][8][9] However, the sites on the molecule that are easiest to tritiate often coincide with metabolic instability, and signi cant kinetic isotope effects with tritium can result in misleading data on the stability or fate of a drug in biological systems. 3 Due to these factors, carbon-14 labeling is ultimately required for most molecules in clinical development. ...
The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs required to probe these features presents a significant hurdle, since it typically requires synthesis with toxic, radioactive gases such as ¹⁴ CO 2 and ¹⁴ CO. Here, we describe a straightforward alternative approach to directly carbon-label carboxylic acid-containing pharmaceuticals: via a metal catalyzed functional group exchange reaction. This provides a general route to ¹⁴ C-labeled carboxylic acid-containing drugs without radioactive gases, in one pot, and using an easily available and handled carboxylic acid ¹⁴ C-source. To enable this process, a new class of functional group metathesis of carbon-carbon covalent bonds in acid chloride functionalities is developed that exploits the ability of earth abundant nickel catalysts to both reversibly activate carbon-chloride bonds and exchange functionalities between organic molecules. The applicability of this system to drug development is illustrated by the direct incorporation of ¹⁴ C- or ¹³ C-label into an unprecedented array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or special apparatus, at simply ambient conditions, and without loss of the radiolabel.
