Revisiting Biginelli-like reactions: solvent effects, mechanisms, biological applications and correction of several literature reports.

This study critically reevaluates reported Biginelli-like reactions using a Kamlet-Abboud-Taft-based solvent effect model. Surprisingly, structural misassignments were discovered in certain multicomponent reactions, leading to the identification of pseudo three-component derivatives instead of the expected MCR adducts. Attempts to replicate literature conditions failed, prompting reconsideration of the described MCRs and proposed mechanisms. Electrospray ionization (tandem) mass spectrometry, NMR, melting points, elemental analyses and single-crystal X-ray analysis exposed inaccuracies in reported MCRs and allowed for the proposition of a complete catalytic cycle. Biological investigations using both pure and "contaminated" derivatives revealed distinctive features in assessed bioassays. A new cellular action mechanism was unveiled for a one obtained pseudo three-component adduct, suggesting similarity with the known dihydropyrimidinone Monastrol as Eg5 inhibitors, disrupting mitosis by forming monoastral mitotic spindles. Docking studies and RMSD analyses supported this hypothesis. The findings described herein underscore the necessity for a critical reexamination and potential corrections of structural assignments in several reports. This work emphasizes the significance of rigorous characterization and critical evaluation in synthetic chemistry, urging a careful reassessment of reported synthesis and biological activities associated with these compounds.

In Melting Points We Trust: A Review on the Misguiding Characterization of Multicomponent Reactions Adducts and Intermediates.

We discuss herein the problems associated with using melting points to characterize multicomponent reactions' (MCRs) products and intermediates. Although surprising, it is not rare to find articles in which these MCRs final adducts (or their intermediates) are characterized solely by comparing melting points with those available from other reports. A brief survey among specialized articles highlights serious and obvious problems with this practice since, for instance, cases are found in which as many as 25 quite contrasting melting points have been attributed to the very same MCR adduct. Indeed, it seems logical to assume that the inherent non-confirmatory nature of melting points could be vastly misleading as a protocol for structural confirmation, but still many publications (also in the Q1 and Q2 quartiles) insist on using it. This procedure contradicts best practices in organic synthesis, and articles fraught with limitations and misleading conclusions have been published in the MCRs field. The drawbacks inherent to this practice are indeed serious and have misguided MCRs advances. We therefore suggest some precautions aimed at avoiding future confusions.