Knoevenagel condition

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group sufficiently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is... 

The selective nucleophilic displacement of one ortho nitro group from 2,4,6-trinitrotoluene by esters of mercap-toacetic acid followed by oxidation leads to 2-(alkoxycarbonyl)methylsulfonyl compounds. These sulfones react with aromatic aldehydes under Knoevenagel conditions to produce thiochroman 1,1-dioxides 477, probably via a stilbene and a subsequent intramolecular Michael addition. Activating groups other than nitro are compatible with the route (Scheme 167) <2003RJ0397>. 

The synthesis of the derivatives (339)-(346) was carried out as shown in Scheme 28. Metalation of the acetal (336), followed by thiolation and alkylation, gave the ester derivative (337). Acetal deprotection to form (338) and subsequent treatment under Knoevenagel conditions with piper-idinium acetate in benzene afforded the desired ester (339). Reduction of compound (339) gave alcohol (340), which was converted to aldehyde (341) and protected as its acetal (342) under standard conditions. Deprotonation was effected by Bu"Li in THF at — 78 °C and subsequent conversion to the sulfonyl chloride was carried out by sequential treatment with sulfur dioxide and A-chloro-succinimide. Treatment of the sulfonyl chloride (343) with concentrated NH4OH in acetone provided the sulfonamide (344), which was deprotected (345) and subjected to reductive amination to provide compounds in the aminomethyl sulfonamide series (346). 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

Usually the Knoevenagel condensation yields the unsaturated product, but, with appropriate aldehydes, 3-hydroxymalonates can be isolated. The unusual formation of an a-naphthol (74) has been reported from the reaction of diphenylacetaldehyde (73) with diethyl malonate under Knoevenagel conditions." Condensation of stdicyl dehydes and other aromatic o-hydroxy aldehydes with malonates is still in use for the synthesis of the corresponding coumarin-3-carboxylic esters (75). - " Reduction... 

Cyanoacetamides yield a-cyanoacrylamides (124) stereoselectively upon reaction with aldehydes and nonselectively with ketones under standard Knoevenagel conditions. a-Cyanoacrylamides (124) are also obtained by partial hydrolysis of methylenemalonodinitriles. With 1,3-diketones, e.g. acetyl-acetone, pyridones like (125) are formed upon reaction with cyanoacetamides. Base-catalyzed dimerization of a-cyanoacrylamides (124) yields piperidones. ... 

Condensations of aryiacetic acids, arylacetates and arylacetonitriles with aromatic aldehydes and ketones proceed under standard Knoevenagel conditions, providing access to stilbenes or substituted stil-benes. - Thus 3-nitrobenzaldehyde and 4-nitrophenylacetic acid react in the presence of different amines to give (130), (131) and (132). The ratio of the products varies greatly with the amine used. (131) and (132) could easily be transformed into (130) in high yield. Reaction of arylacetates with o-hydroxybenzaldehydes yields the corresponding coumarins. The condensation of 2-hydroxy-4-meth-oxybenzaldehyde (133) with pyridylacetates like (134) yields 7-methoxy-3-pyridylcoumarins like (135) (Scheme 20). 

Cinnamaldehyde (39), which is a vinylog of benzaldehyde, gives excellent yields of p-styrylacrylic acid (40) under Perkin reaction conditions3 or Knoevenagel conditions.9... 

A malonic acid derivative of Wang resin has been prepared by reaction with Meldrum s acid and the product converted to a malonamide via the acid chloride. Condensation with an aldehyde under Knoevenagel conditions gave methylene malonic acid-amides that were cleaved from the resin with TFA-H2O [193] (Scheme 7). 

Condensation of a retinaldehyde with a 1,3-diketone under Knoevenagel conditions in the presence of piperidinium acetate gave a retinylidene 1,3-diketone. Thus, for example, (607) was formed from retinaldehyde (2) and dimedone (606) (Acton and Brossi, 1980b Acton et aL, 1980). 

Considering the structures of the reaction products 4 and 5 we notice that tricyclic alcohol 5 resembles the expected Knoevenagel product (although it has been oxidized), but in the case of 4 the structure is completely different. It is very unlikely that two products, so different from each other, would come from a single reaction pathway. Hence, a much more reasonable option is to consider two competing reaction pathways when 2 was treated under Knoevenagel conditions. 

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