Knoevenagel reaction scope

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

The Nokami hydroxylative Knoevenagel reaction has been expanded from the initial report using phenylsulfmylacetonitrile 42 to the use of phenylsulfinylacetates and phenylsulfinylketones. The scope of the carbonyl compound has also been expanded to include ketones as well as aldehydes, but the use of ketones with available a-hydrogens on both sides adds the obvious potential complications in terms of mixtures of products. 

In addition, also spiro compounds can be synthesized using alkylidene-cyclo-alkenes as a dienophile moiety [56]. Finally, as an immense enlargement of the scope of this protocol, the domino Knoevenagel hetero Diels-Alder reaction can be run as a three component transformation mixing an aldehyde such as 2-99, a... 

It must be emphasized that the scope and limitations of many of the new Knoevenagel catalysts have not been explored sufficiently. From the practising chemist s point of view the situation is somewhat confusing and the search for the appropriate reaction conditions is still largely a process of trial and error. 

The corresponding enantiopure spirocyclic ketones were remarkably obtained in high yields, as shown in Scheme 10.31. These products constitute attractive starting materials for the synthesis of natural and biologically active products. Later, these authors extended the scope of this reaction by performing hetero-domino Knoevenagel/Diels-Alder/epimerization reactions which provided access to highly... 

In 1970, Willy Lehnert showed that in the presence of titanium tetrachloride and a tertiary amine such as pyridine or triethylamine, the Knoevenagel condensation of both aldehydes and ketones with diethylmalonate proceeded under mild conditions (0 °C to room temperature) to provide the condensation products in good yield (e.g., 47—>48). The scope of the reaction was therefore increased as hindered ketones could be coupled with malonate esters in reasonable yield. ... 

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