Secondary catalyst, Knoevenagel reaction

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

The manufacture of alkyl cyanoacrylate monomers, 1, involves the Knoevenagel reaction of formaldehyde, 2, with an alkyl cyanoacetate, 3, and a base, such as a secondary amine, as the catalyst, shown in Eq. 1. 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

When a compound containing an activated methylene group is the proton-donating catalyst, the presence of a secondary amine is required for easy isolation of the desired ketose derivative in crystalline form. The conditions resemble those requisite for a Knoevenagel reaction. - A condensation of the Knoevenagel type evidently does not occur, as the dehydrated product would be too stable for practical reversibility. However, the addition compound which is an intermediate in the Knoevenagel reaction, such as V, couW be formed from IV. Splitting of V to yield the ketose de-... 

On the other hand the catalyst is of great importance primary, secondary or tertiary amines or their corresponding ammonium salts are usually used, but many other catalysts such as phase transfer catalysts, Lewis acids or potassium fluoride can also be applied. The most widely employed catalysts are pyridine, with or without added piperidine, and ammonium salts, such as ammonium or piperidinium acetate. Condensations that employ strong bases or preformed metal salts of the methylene component are not covered here since transformations under these conditions are not usually considered to be Knoevenagel reactions. 

The Knoevenagel reaction [3] is one of the most important C-C bond-forming reactions available to synthetic chemists. It is widely used in the synthesis of important intermediates or end-products for perfumes [4], pharmaceuticals [5], e. g. antihypertensive and calcium antagonists [6], and polymers [7]. The reaction is catalyzed by bases, acids, or catalysts containing acid-base sites [8], e. g. bases such as ammonia, primary and secondary amines and their salts [1], and Lewis acids such as CUCI2 [9], ZnCl2 [10], and Sml3 [11]. 

Amino acids may also be applied as catalysts in the Knoevenagel reaction 914,915 thus ethyl 2-cyano-4-methyl-2-pentenoate has been prepared in 87% yield from 2-butanone and ethyl cyanoacetate in the presence of /9-alanine.916 Other catalysts that have been recommended are benzylamine (additional to the salt of a secondary amine), 917 ion-exchangers,918 and alkali fluorides.919... 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Most aldehydes easily undergo Knoevenagel condensation using secondary amines or their salts as a catalyst. Under standard conditions, reaction of simple unbranched aliphatic aldehydes and of most ketones is difficult. However, the use of TiCWamine allows reaction even of refractory aldehydes and a multitude of ketones in good to very good yields." -" For example, the synthesis of Knoevenagel adducts (72) from 5-formyl-octaethylporphyrin (71) and different malonic esters in the presence of TiCU/pyridine at 0 "C has been achieved in 75-94% yield." ... 

It is pertinent to mention here that Knoevenagel condensation is new invariably employed more widely and rationally to include malonic acid analogues, namely diethyl monoethyl-malonate, ethyl cyanoacetate etc. Interestingly, a host of heterocyclic secondary amines may be used as catalysts and frequently the most effective is piperidine (hexahydrop3rridine) besides, a mixture of piperidine and pyridine or pyridine alone, is also often utilized for the said condensation reactions. 

Despite these mechanistic and theoretical studies, intermolecular amine-catalyzed aldolizations have only rarely been used on a preparative scale. A few note vorthy exceptions in vhich aldehydes are used as donors are sho vn in Scheme 4.6 [51-55]. These reactions are often performed neat or in the presence of small amounts of an organic solvent. The catalyst usually used is either a primary or secondary amine, a combination of an amine vith a carboxylic acid, or simply an amino acid. These catalyst systems have previously been used in the Knoevenagel condensation and it is apparent that synthetic amine-catalyzed aldolizations originate from Knoevenagel s chemistry [56]. 

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