Multicomponent Tandem Reaction Of Biginelli Reaction/Vinylogous Aldol Condensation And Its Application

Dihydropyrimidin-2(1H)-ones (DHPMs) display a broad range of biological activitie in clinicalmedicine and biological science. To date, as the major method for the synthesis of DHPMs, the Biginellireaction has received much attention. In the past decade, there have been nearly500publicationsconcerning this reaction. However, these reports have mostly focused on the improvement of the reactioncatalyst. Relatively, it is rare to focus on the derivatization of DHPMs, especially on the functionalizationof the C-6methyl group; in general, acetoacetates are employed in the Biginelli reaction, and, therefore, inmost cases, a methyl group is introduced at the C-6position of the pyrimidine ring. To the best of ourknowledge, very few reports have appeared in the literatures concerning the functionalization of the C-6methyl group, which is reported to proceed through (i) bromination and a subsequent nucleophilicreplacement reaction, or (ii) electrophilic substitution reaction in the presence of base. In contrast,vinylogous aldol reaction of cyclic compounds has received much attention, although vinylogous aldolreaction of Biginelli products has not yet been achieved to date. We present here the first report ofvinylogous aldol reaction of Biginelli products, an effective and practical Lewis acid-catalyzed approach to6-arylvinyl DHPMs, and its further application to generate additional drug-like complex derivatives,including pyrido[4,3-d]pyrimidines.Multi-component reactions (MCRs) offer numerous benefits over traditional chemical synthesis. AMCR is a process in which three or more easily accessible components，rapidly and efficiently providing anovel molecule that contains the fragments derived from all the building blocks employed in the MCRs in asingle step. They are particularly suitable for diversity-oriented synthesis because they can take fulladvantage of the desired functional groups and the inert present in the building blocks in the rapidtransformation process. Over the past decade, iron-catalyzed MCRs have drawn much attention due to thenontoxicity, low cost, sustainability, ready availability, stability, and environmentally friendly properties.There are also many articles about iron-catalyzed Biginelli reaction. Based on our previous work, a noveliron-catalyzed vinylogous aldol condensation of amide group at the5-position of the Biginelli productswith aryl aldehydes has been developed for the syntheses of potential bioactive (E)-6-arylvinyl-dihydropyrimidin-2(1H)-ones. Herein, we report a new MCR consists of a Biginellireaction of acetoacetamide, arylaldehyde, and urea, and subsequent a novel vinylogous aldol condensationof the Biginelli product with an additional molecule of arylaldehyde. The use of a single catalyst for theabove processes could significantly enhance the operational convenience with good yields.