Cascade Knoevenagel/hetero-Diels—Alder

A domino Knoevenagel/hetero-Diels-Alder cycloaddition cascade was developed by Tietze (96CR115) and has continued to attract considerable attention. For... 

One pot domino (cascade) reactions like tandem Knoevenagel-hetero Diels-Alder, Knoevenagel-ene, Pictet-Spengler-ene, Sakurai carbonyl-ene reactions. 

The tandem Knoevenagel-Diels-Alder sequence is well known, and has been extensively studied by Tietze and others. The Knoevenagel products have been shown to be active as dienophiles in normal-electron-demand Diels-Alder reactions, as well as heterodienes in inverse-electron-demand hetero-Diels-Alder reactions. One of the most elegant examples of a tandem Knoevenagel-hetero-Diels—Alder sequence is Tietze s synthesis of hirsutine 76. In this sequence, a mixture of aldehyde 70, Meldrum s acid 71, enol ether 73 (a mixture of isomers) and a catalytic amount of ethylenediamine diacetate were sonicated in Benzene for 12 h at 60 °C. This effected a cascade sequence that began with Knoevenagel condensation to form the heterodiene 72, followed by intermolecular hetero-Diels-Alder reaction with enol ether 73 to lead to 74, which underwent in situ hydrolysis and decarboxylation to yield intermediate 75 in 84% yield. 

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