An approach to a series of new 5-amino-4-cyanoxazoles is described. Synthesis of the title compounds relied on a twostep sequence including heterocyclization of 2-amido-3,3dichloroacrylonitriles with aliphatic secondary amines (dimethylamine, morpholine), primary aliphatic amines with active functional groups (2-aminoethanol and glycine ethyl ester), and aniline. An efficient and straightforward protocol introduces a carboxylate group at the C-2 position of 5-amino-4-cyanoxazoles, connected to the heterocycle directly or through an aliphatic linker. This carboxylic group is an attractive motif that can be found in a variety of drug-relevant compounds and also used for further modifications. Furthermore, efficient transformations of selected trisubstituted compounds were used to demonstrate their rich synthetic potential -e. g., as precursors to 2-(4-cyano-5-(dimethylamino)oxazol-2-yl)acetamides, oxazole-containing macrocyclic structures, 2-(oxazol-2-yl) acetamides, amino pyrazoles, 3-(4-cyano-5-aminoxazol-2-yl) coumarins, and oxazole amino acids.[a] D.
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.
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., aldehydes, ketones, esters, amides, O-benzoyl hydroxylamine, chlorosilane, borate ester) to assemble C–C, C–N, C–Si, and C–B bonds. In contrast to the classic two-step Grignard synthesis, the mechanochemical approach has the advantage of being essentially solvent-free, single step, operationally simple, immune to air, and surprisingly tolerant to water and other proton donors. Mechanistic studies have clarified the role of mechanochemistry in the process, indicating that the reaction predominantly proceeds via the generation of transient organometallics, which occurs rapidly due to improved mass transfer and activation of the surface of magnesium metal
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