Tritiation of aryl thianthrenium salts with a molecular palladium catalyst

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 labels from tritium gas is commonly achieved by heterogeneous transition-metal-catalysed tritiation of aryl (pseudo)halides. However, heterogeneous catalysts such as palladium supported on carbon operate through a reaction mechanism that also results in the reduction of other functional groups that are prominently featured in pharmaceuticals3. Homogeneous palladium catalysts can react chemoselectively with aryl (pseudo)halides but have not been used for hydrogenolysis reactions because, after required oxidative addition, they cannot split dihydrogen4. Here we report a homogenous hydrogenolysis reaction with a well defined, molecular palladium catalyst. We show how the thianthrene leaving group—which can be introduced selectively into pharmaceuticals by late-stage C–H functionalization5—differs in its coordinating ability to relevant palladium(II) catalysts from conventional leaving groups to enable the previously unrealized catalysis with dihydrogen. This distinct reactivity combined with the chemoselectivity of a well defined molecular palladium catalyst enables the tritiation of small-molecule pharmaceuticals that contain functionality that may otherwise not be tolerated by heterogeneous catalysts. The tritiation reaction does not require an inert atmosphere or dry conditions and is therefore practical and robust to execute, and could have an immediate impact in the discovery and development of pharmaceuticals.

Nickel-catalyzed electrochemical carboxylation of unactivated aryl and alkyl halides with CO2

Electrochemical catalytic reductive cross couplings are powerful and sustainable methods to construct C−C bonds by using electron as the clean reductant. However, activated substrates are used in most cases. Herein, we report a general and practical electro-reductive Ni-catalytic system, realizing the electrocatalytic carboxylation of unactivated aryl chlorides and alkyl bromides with CO2. A variety of unactivated aryl bromides, iodides and sulfonates can also undergo such a reaction smoothly. Notably, we also realize the catalytic electrochemical carboxylation of aryl (pseudo)halides with CO2 avoiding the use of sacrificial electrodes. Moreover, this sustainable and economic strategy with electron as the clean reductant features mild conditions, inexpensive catalyst, safe and cheap electrodes, good functional group tolerance and broad substrate scope. Mechanistic investigations indicate that the reaction might proceed via oxidative addition of aryl halides to Ni(0) complex, the reduction of aryl-Ni(II) adduct to the Ni(I) species and following carboxylation with CO2.

Heme Peroxidases at Unperturbed and Inflamed Mucous Surfaces

In our organism, mucous surfaces are important boundaries against the environmental milieu with defined fluxes of metabolites through these surfaces and specific rules for defense reactions. Major mucous surfaces are formed by epithelia of the respiratory system and the digestive tract. The heme peroxidases lactoperoxidase (LPO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO) contribute to immune protection at epithelial surfaces and in secretions. Whereas LPO is secreted from epithelial cells and maintains microbes in surface linings on low level, MPO and EPO are released from recruited neutrophils and eosinophils, respectively, at inflamed mucous surfaces. Activated heme peroxidases are able to oxidize (pseudo)halides to hypohalous acids and hypothiocyanite. These products are involved in the defense against pathogens, but can also contribute to cell and tissue damage under pathological conditions. This review highlights the beneficial and harmful functions of LPO, MPO, and EPO at unperturbed and inflamed mucous surfaces. Among the disorders, special attention is directed to cystic fibrosis and allergic reactions.

A Ball Milling Enabled Cross-Electrophile Coupling

<div><div><div><p>The nickel-catalyzed cross-electrophile coupling of aryl (pseudo)halides and alkyl (pseudo)halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C–C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive set-ups, in reaction times of 2 hours. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the catalytic cycle of nickel. A library of 28 cross- electrophile coupled building blocks has been constructed to exemplify this technique.</p></div></div></div>

A Ball Milling Enabled Cross-Electrophile Coupling

<div><div><div><p>The nickel-catalyzed cross-electrophile coupling of aryl (pseudo)halides and alkyl (pseudo)halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C–C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive set-ups, in reaction times of 2 hours. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the catalytic cycle of nickel. A library of 28 cross- electrophile coupled building blocks has been constructed to exemplify this technique.</p></div></div></div>

Iron-Catalyzed Cross-Coupling of Thioesters and Organomanganese Reagents

We report a Fukuyama-type coupling of thioesters with aliphatic organomanganese reagents utilizing a cheap and easily available iron(III) catalyst. The reactions exhibit a wide tolerance of solvents and functional groups (e.g. ketones, esters, aryl(pseudo)halides) allowing for the conversion of thioesters derived from natural products and pharmaceutical compounds. Investigations showed a strong steric influence from each reaction component (carboxylic moiety, thiol substituent and manganese reagent), which enabled regioselective transformation of dithioesters. Tandem transformations combining the coupling with an additional step were observed. Our experiments provide insights into the potential of the employed aliphatic manganese reagents, such as the interaction between iron, manganese and oxygen, which allows for a smooth conversion.

Iron-Catalyzed Cross-Coupling of Thioesters and Organomanganese Reagents

We report a Fukuyama-type coupling of thioesters with aliphatic organomanganese reagents utilizing a cheap and easily available iron(III) catalyst. The reactions exhibit a wide tolerance of solvents and functional groups (e.g. ketones, esters, aryl(pseudo)halides) allowing for the conversion of thioesters derived from natural products and pharmaceutical compounds. Investigations showed a strong steric influence from each reaction component (carboxylic moiety, thiol substituent and manganese reagent), which enabled regioselective transformation of dithioesters. Tandem transformations combining the coupling with an additional step were observed. Our experiments provide insights into the potential of the employed aliphatic manganese reagents, such as the interaction between iron, manganese and oxygen, which allows for a smooth conversion.

Acylboronates in Polarity-Reversed Generation of Acyl Palladium(II) Intermediates

We report a catalytic cross-coupling process between aryl (pseudo)halides and boron-based acyl anion equivalents. This mode of acylboronate reactivity represents polarity reversal, which is supported by the observation of tetracoordinated boronate and acyl palladium(II) species by ¹¹B, ³¹P NMR, and mass spectrometry. A broad scope of aliphatic and aromatic acylboronates has been examined, as well as a variety of aryl (pseudo)halides.