MCRs Involving Meldrums Acid

SCHEME 13.85 Four-component Yonemitsu-type reactions [163,164], 

SCHEME 13.86 Proposed structures 421 and 112 of Meldrum s acid and its acidic, nucleophilic, and electrophihc properties. 

C-2 modification of the 1,3-dicarbonyl compound is possible by deprotonation in the 2-position followed by electrophilic capture (path A). Depending on the type of electrophile used, oxygen modification is also possible (path B). Nucleophilic attack on one of the Meldrum s adds carbonyl groups leads to a tetrahedral intermediate, which decomposes easily to generate carbon dioxide, acetone, and an enolate product, which is protonated either by addic leadion media or in a separate work-up step. This nucleophilic displacement reaction equals the use of Meldrum s acid as a —CH CCO) equivalent. Indeed, this is a very common application of Meldrum s acid in multicomponent syntheses (vide infra). 

The following chapter will give an overview on the hter-ature dealing with the application of Meldrum s acid in multicomponent syntheses since 2(X)5. The hterature will be summarized in three main categories depending on the products formed. Reactions in which the Meldrum s acid moiety is intact in the product will be followed by reactions in which 112 serves as a —CH CIO) equivalent. At the end, the hterature that does not fit into the first two categories will be discussed. As Meldrum s acid is an extensively apphed CH-acidic 

SCHEME 13.87 Synthesis of benzo[/]quinolin-3-ones 423 with spirocyclic by-product 424 by Wang et al. Three-component reaction for the generation of dispiro[4.2.5.2]pentadecanes 427 by Tu et al. [170, 171]. 

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The mechanism of these MCRs involving Meldrum s acid should include Knoevenagel condensation and Michael addition cascade process [100, 113] (Scheme 37). To form positional isomeric reaction product, arylliden derivatives of Meldrum s acid are attacked by exocyclic NH2-group instead of endocyclic nucleophilic center. 

In MCRs involving aminoazoles and carbonyl compounds, Meldrum s acid can also be used as reagent. The comprehensive review of the application of Meldrum s acid in the synthesis of pyridine and pyrimidine derivatives including reactions with aminoazoles was recently published [113]. In this connection, further we give only few selected facts concerning positional selectivity of such reactions. 

Significant contribution in the studying of the MCRs based on aminoazoles, aldehydes, and Meldrum s acid was made by Lipson and co-authors in their publications [ 114—119]. It was established that in some cases these multicomponent treatments can yield positional isomers. For example, refluxing of 3-amino-l,2,4-triazole with aldehydes and Meldrum s acid gave only triazolopyrimidinones 82 [114] (Scheme 36). On the other hand, MCRs involving 3-amino-5-methylthio-1,2,4-triazoles in boiling DMF yielded solely 5-pyrimidinones 83, while the... 

In another example, Kurth has reported the use of a novel three-component MCR (3CR) involving a Meldrum s acid-like substrate (182), an aldehyde equivalent (183) and a nitrile oxide (generated from the oxime 184) in the assembly of spiromaerolaetams (185, Seheme 11.32). Similar results were observed with non-aromatie-eontaining counterparts of 182. Generally, MCRs are eondueted under fairly eoneentrated conditions to overcome en-tropic barriers. For this partieular proeess, however, the use of a highly reactive, but transient, acyl ketene intermediate permitted short reaction times... 

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