Experimental and DFT analysis of the reaction between isocyanides and Meldrum's acid with pyridinecarboxaldehydes in the presence of alcohols or amines

A facile and efficient one-pot synthesis of novel pyridine-embedded amidodiester, triamide and diamidoacid conjugates from the reaction of pyridinecarboxaldehydes with Meldrum 's acid and isocyanides in the presence of alcohols or amines is described. To explore the mechanism for this pseudo five-component reaction, three possible reaction pathways represented below by red (first route), green (second route), and purple (third) have been suggested and investigated in detail using density functional theory (DFT) in a solvent medium. For the mechanistic investigation, a reaction involving 3-pyridinecarboxaldehyde, Meldrum 's acid, tert -butyl isocyanides, and methanol was selected. The red (first route) and green (second route) pathways are initiated by the nucleophilic attack of methanol, while the purple (third) pathway begins with the elimination of acetone. The results indicate that the third reaction pathway (purple) is the most energetically favorable, and the amidoester product (P1) was calculated as the most stable in agreement with the experimental yield. This study provides the first computational insight into the reaction mechanism of this pseudo-five-component system.