Solvent‐Free Ball‐Milling Biginelli Reaction by Subcomponent Synthesis

Abstract

We report here an understanding of systems chemistry on small molecules through covalent mechanochemistry. As a proof‐of‐concept, the multicomponent Biginelli reaction by subcomponent synthesis was considered as a model system. Reactions were performed under solvent‐free, metal‐free, mechanochemical (ball milling) and ambient laboratory conditions. Br+‐catalyzed oxidation of benzyl alcohols led to the product benzaldehydes and byproduct H+ which were further promoted as component and catalyst, respectively, for a cascade transformation to dihydropyrimidones within the same reaction pot. Remarkably, in solution, the reaction system could not be reproduced at room temperature even after 24 h.

Green High-Yielding One-Pot Approach to Biginelli Reaction under Catalyst-Free and Solvent-Free Ball Milling Conditions

“…Recently, Mal et al [41] showed that the 3,4-dihydropyrimidines can be accessed in two steps under ball milling through a combination of a catalytic amount of potassium bromide (KBr), oxone and TEMPO (2,2,6,6-Tetramethyl-1-piperidinyloxy).…”

Mechanochemical Strecker Reaction: Access to α‐Aminonitriles and Tetrahydroisoquinolines under Ball‐Milling Conditions

“…Particularly interesting are the reports on mechanochemical multicomponent reactions (MCRs), which allow the efficient coupling of several building blocks in a single step to afford highly functionalized organic molecules. Recently, examples of the mechanochemically induced Biginelli, Ugi, and Passerini reactions have exemplified some of the advantages of mechanochemistry, such as the reduction or elimination of the solvent, shorter reaction times, clean reaction mixtures, and simple work‐up procedures. Consequently, the combination between MCRs and mechanochemistry clearly strengthen the known advantages of both approaches in the effort to develop environmentally friendly synthetic strategies, because the generation of large amounts of waste, especially from solvents used in the reactions or during the purification of the intermediates is avoided.…”

Mechanochemistry for Synthesis

“…An umber of multi-component reactions have been adapted to mechanochemistry,including Biginelli, [105] Strecker, [106] Ugi and Passerini reactions, [67] validating orthogonal and cascade reaction designs in as olvent-free environment. Thep otential of mechanochemistry in that sense was ex-plored by Hernµndez et al [107] who developed ao ne-step 5component route to build Re I complexes from asimple metal carbonyl, based on orthogonal oxidative addition and ligand exchange (Figure 11 a).…”