Mechanochemical Birch Reduction with Low Reactive Alkaline Earth Metals.

Birch reduction and similar dissolved metal-type transformations hold significant importance in the organic synthesis toolbox. Historically, the field has been dominated by alkali metal reductants. In this study, we report that largely neglected, low-reactive alkaline earth metals can become powerful and affordable reductants when used in a ball mill under essentially solvent-free conditions, in the presence of ethylenediamine and THF as liquid additives. Calcium can reduce both electron-deficient and electron-rich arenes, with yields of products similar to those obtained with lithium metal. Magnesium reveals enhanced reducing power, enabling the reduction of benzoic acids while keeping electron-rich aromatic moieties intact and allows for chemoselective transformations. The developed mechanochemical approach uses readily available and safer-to-handle metals, operates under air and ambient temperature conditions, and can be used for gram-scale preparations. Finally, we demonstrate that the developed conditions can be used for other dissolved metal-type reductive transformations, including reductive amination, deoxygenation, dehalogenation, alkene and alkyne reductions.

Mechanochemistry-Amended Barbier Reaction as an Expedient Alternative to Grignard Synthesis.

Organomagnesium halides (Grignard reagents) are essential carbanionic building blocks widely used in carbon-carbon and carbon-heteroatom bond-forming reactions with various electrophiles. In the Barbier variant of the Grignard synthesis, the generation of air- and moisture-sensitive Grignard reagents occurs concurrently with their reaction with an electrophile. Although operationally simpler, the classic Barbier approach suffers from low yields due to multiple side reactions, thereby limiting the scope of its application. Here, we report a mechanochemical adaptation of the Mg-mediated Barbier reaction, which overcomes these limitations and facilitates the coupling of versatile organic halides (e.g., allylic, vinylic, aromatic, aliphatic) with a diverse range of electrophilic substrates (e.g., aromatic aldehydes, ketones, esters, amides, O-benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C-C, C-N, C-Si, and C-B bonds. The mechanochemical approach has the advantage of being essentially solvent-free, operationally simple, immune to air, and surprisingly tolerant to water and some weak Brønsted acids. Notably, solid ammonium chloride was found to improve yields in the reactions of ketones. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating the generation of transient organometallics facilitated by improved mass transfer and activation of the surface of magnesium metal.

Design, Synthesis, and Xanthine Oxidase Inhibitory Activity of 4-(5-Aminosubstituted-4-cyanooxazol-2-yl)benzoic Acids.

Xanthine oxidase is a known therapeutic target for the treatment of hyperuricemia and related diseases. Despite the availability of current drugs such as allopurinol and febuxostat, the search for new compounds to effectively inhibit this enzyme remains relevant. In our study, 75 virtual structures of 4-(5-aminosubstituted-4-cyanooxazol-2-yl)benzoic acids with structural similarity to febuxostat were designed for evaluation of their potency against xanthine oxidase. After molecular docking simulations, eight compounds were selected for synthesis and in vitro testing. The synthesized compounds were found to exhibit in vitro xanthine oxidase inhibitory activity in the nanomolar concentration range. The most effective inhibitors with 4-benzylpiperidin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl substituents at position 5 of the oxazole ring had IC50 values close to that of febuxostat. The kinetic data suggest a mixed-type inhibition when the inhibitor binds preferentially to the free enzyme rather than to the enzyme-substrate complex. Molecular docking and molecular dynamic simulations were carried out to get insight into the key interactions of the inhibitors bound to the xanthine oxidase active site.