Knoevenagel reactions with formaldehyde

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. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

The cyanoacryhc esters are prepared via the Knoevenagel condensation reaction (5), in which the corresponding alkyl cyanoacetate reacts with formaldehyde in the presence of a basic catalyst to form a low molecular weight polymer. The polymer slurry is acidified and the water is removed. Subsequendy, the polymer is cracked and redistilled at a high temperature onto a suitable stabilizer combination to prevent premature repolymerization. Strong protonic or Lewis acids are normally used in combination with small amounts of a free-radical stabilizer. 

Di-tert-butyl methylenemalonate was originally prepared by phenyl-sulfenylation of di-tert-butyl methylmalonate and thermal elimination of the related sulfoxide.8 Because methylenemalonate esters are customarily prepared by Knoevenagel-type condensation of malonic esters with formaldehyde equivalents, the considerably more convenient procedure described herein was subsequently adapted from Bachman and Tanner s study using paraformaldehyde under metal ion catalysis.39 The approximately 6% di-tert-butyl malonate accompanying the product has presented no interference in the aforementioned reactions with nucleophilic alkenes under neutral or acidic conditions, but its presence should be taken into consideration in other applications. 

The dicyclohexylammonium salt of diethyl l-(hydroxycarbonyl)methylphosphonate and formaldehyde in the presence of EtjN undergoes a Knoevenagel reaction to give the dicyclohexylammonium salt of l-(hydroxycarbonyl)vinylphosphonate (70%) This compound is able to react readily with a variety of secondary amines,-- 1,3-dicarbonyl and monocarbonyl nucleophiles, to give the corresponding Michael adducts. 

Alkyl-2-cyanoacrylates can be prepared by several synthetic procedures. The only method of importance involves the Knoevenagel condensation of an alkylcyanoacetate with formaldehyde. As this is a base-catalysed reaction, the monomer is rapidly polymerized to give a low-molecular-weight poly(alkyl-2-cyanoacrylate). The resulting polymer is retropolymer-ized by heating under controlled conditions to yield monomeric cyanoacrylate (Scheme 1). 

Tietze reported a domino-Knoevenagel-hetero-Diels-Alder reaction involving a three-component reaction between an a-nitroketone, formaldehyde, and an alkyl vinyl ether. In one example, a Knoevenagel condensation between ketone 105 and formaldehyde (106) yields electron-poor hetero-diene 108 that undergoes an inverse electron demand Diels-Alder reaction with ethyl vinyl ether to furnish dihydropyran 109. Tietze subsequently converted 109 into the deoxysugar (+)-forosamin. ... 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

Cavaleiro et al. reported the reaction of vinyl-substituted zinc porphyrins 76 with Knoevenagel products of formaldehyde 72 with several quinones 75 in refluxing 1,4-dioxane and ort/jo-dichlorobenzene (Scheme 13.22) [37]. The desired products 77 could be obtained in moderate to high yields where the exclusive formation of the para-benzoquinone is noteworthy (see also [36]). A catalytic amount of acetic acid reduces the reaction time and increases the product yield. 

The second and today most commercially favored method involves the Knoevenagel condensation reaction of an alkyl cyanoacetate with formaldehyde in the presence of a base to yield a poly(alkyl-2-cyanoacrylate) as follows ... 

Nair and coworkers reported a [2+4] cycloaddition reaction of coumarin quinone methide 59 (generated in situ by Knoevenagel condensation between formaldehyde and 4-hydroxycoumarm 58) with pentafulvenes such as 27, providing a facile synthesis of pyranocoumarins 60 (Scheme 7.14) [16]. A computational study was performed to shed light on the process. 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

The thermal Yonemitsu-type reaction of ethyl 2-nitroace-tate with variably substituted indoles and formaldehyde in toluene led to the formation of various tryptophan precursors in moderate to high yields [134]. Molecular sieves supported the Knoevenagel condensation step. A closely related catalyst-free version was published by Jerdme et al. in 2009 [43]. P-Ketoesters represent the CH-acidic component that undergoes a Yonemitsu-type reaction at slightly elevated temperatures to provide the desired products in moderate yields within 6-20 h. 

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