Synthesis of Highly Functionalized N,N-Diarylamides by an Anodic C,N-Coupling Reaction.

We report an innovative, sustainable and straightforward protocol for the synthesis of N,N-diarylamides equipped with nonprotected hydroxyl groups by using electrosynthesis. The concept allows the application of various substrates furnishing diarylamides with yields up to 57 % within a single and direct electrolytic protocol. The method is thereby easy to conduct in an undivided cell with constant current conditions offering a versatile and short-cut alternative to conventional pathways.

Direct Metal- and Reagent-Free Sulfonylation of Phenols with Sodium Sulfinates by Electrosynthesis.

A novel electrochemical strategy for the synthesis of aryl sulfones by direct sulfonylation of phenols with sodium sulfinates has been developed. The C,S-coupling products are of particular interest for chemical synthesis, material sciences and pharmaceutical sciences. By using this metal- and reagent-free electrochemical method, aryl and diaryl sulfones can be obtained directly in good yields. The established one-step protocol is easy to perform, scalable, inherently safe, and enables a broad scope, which is not limited by quinoid-forming substrates.

Regioselective Metal- and Reagent-Free Arylation of Benzothiophenes by Dehydrogenative Electrosynthesis.

A novel strategy for the synthesis of biaryls consisting of a benzothiophene and a phenol moiety is reported. These heterobiaryls are of utmost interest for pharmaceutical, biological, and high-performance optoelectronic applications. The metal- and reagent-free, electrosynthetic, and highly efficient method enables the generation of 2- and 3-(hydroxyphenyl)benzo[b]thiophenes in a regioselective fashion. The described one-step synthesis is easy to conduct, scalable, and inherently safe. The products are afforded in high yields of up to 88 % and with exquisite selectivity. The reaction also features a broad scope and tolerates a large variety of functional groups.

Electrochemical Arylation Reaction.

Arylated products are found in various fields of chemistry and represent essential entities for many applications. Therefore, the formation of this structural feature represents a central issue of contemporary organic synthesis. By the action of electricity the necessity of leaving groups, metal catalysts, stoichiometric oxidizers, or reducing agents can be omitted in part or even completely. The replacement of conventional reagents by sustainable electricity not only will be environmentally benign but also allows significant short cuts in electrochemical synthesis. In addition, this methodology can be considered as inherently safe. The current survey is organized in cathodic and anodic conversions as well as by the number of leaving groups being involved. In some electroconversions the reagents used are regenerated at the electrode, whereas in other electrotransformations free radical sequences are exploited to afford a highly sustainable process. The electrochemical formation of the aryl-substrate bond is discussed for aromatic substrates, heterocycles, other multiple bond systems, and even at saturated carbon substrates. This survey covers most of the seminal work and the advances of the past two decades in this area.

Metal- and Reagent-Free Anodic C-C Cross-Coupling of Phenols with Benzofurans leading to a Furan Metathesis.

Heterobiaryls consisting of a phenol and a benzofuran motif are of significant importance for pharmaceutical applications. An attractive sustainable, metal- and reagent-free, electrosynthetic, and highly efficient method, that allows access to (2-hydroxyphenyl)benzofurans is presented. Upon the electrochemical dehydrogenative C-C cross-coupling reaction, a metathesis of the benzo moiety at the benzofuran occurs. This gives rise to a substitution pattern at the hydroxyphenyl moiety which would not be compatible by a direct coupling process. The single-step protocol is easy to conduct in an undivided electrolysis cell, therefore scalable, and inherently safe.

Unexpected high robustness of electrochemical cross-coupling for a broad range of current density.

Electro-organic synthesis is a powerful technique for the sustainable preparation of compounds. However, many electrosynthetic reactions require complex equipment, are limited to a very narrow current density range, or have very long reaction times; some also involve nonselective transformations and bad scalability. The robust and selective synthesis of nonsymmetric biphenols and partially protected derivatives is established by anodic C-C cross-coupling. The setup is simple, involving constant current conditions and undivided cells. Its key is a unique electrolyte system based on fluorous alcohols and mixtures, particularly 1,1,1,3,3,3-hexafluoroisopropanol. This allows variations of the current density of more than two orders of magnitude without decreasing selectivity or product yield. This exceptional effect is unknown for electro-organic synthesis of products that have similar oxidation potentials as the starting materials. It potentially paves the way for industrial electrolyzers with variable current consumption, which could enable the flexible use of energy surplus in the electricity supply.

Single and Twofold Metal- and Reagent-Free Anodic C-C Cross-Coupling of Phenols with Thiophenes.

The first electrochemical dehydrogenative C-C cross-coupling of thiophenes with phenols has been realized. This sustainable and very simple to perform anodic coupling reaction enables access to two classes of compounds of significant interest. The scope for electrochemical C-H-activating cross-coupling reactions was expanded to sulfur heterocycles. Previously, only various benzoid aromatic systems could be converted, while the application of heterocycles was not successful in the electrochemical C-H-activating cross-coupling reaction. Here, reagent- and metal-free reaction conditions offer a sustainable electrochemical pathway that provides an attractive synthetic method to a broad variety of bi- and terarylic products based on thiophenes and phenols. This method is easy to conduct in an undivided cell, is scalable, and is inherently safe. The resulting products offer applications in electronic materials or as [OSO]2- pincer-type ligands.

Synthesis of meta-Terphenyl-2,2''-diols by Anodic C-C Cross-Coupling Reactions.

The anodic C-C cross-coupling reaction is a versatile synthetic approach to symmetric and non-symmetric biphenols and arylated phenols. We herein present a metal-free electrosynthetic method that provides access to symmetric and non-symmetric meta-terphenyl-2,2''-diols in good yields and high selectivity. Symmetric derivatives can be obtained by direct electrolysis in an undivided cell. The synthesis of non-symmetric meta-terphenyl-2,2''-diols required two electrochemical steps. The reactions are easy to conduct and scalable. The method also features a broad substrate scope, and a large variety of functional groups are tolerated. The target molecules may serve as [OCO](3-) pincer ligands.

Inhibition of macrophage fatty acid ß-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses.

AIMS/HYPOTHESIS: Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid ß-oxidation (FAO) affects macrophage responses to SFA. METHODS: We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. RESULTS: To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. CONCLUSIONS/INTERPRETATION: Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.

Detailed structure-activity relationship of indolecarboxamides as H4 receptor ligands.

A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H(4)R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H(4)-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H(4)R protein.