Knoevenagel-condensation

Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines. 

Example 2, using ionic liquid ethylammonium nitrate (EAN) as solvent  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 138, Springer-Verlag Berlin Heidelberg 2009 

Julia-Lythgoe ol nation. In Name Reactions for Homologations-Part / Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 474-501. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979 147, Springer International Publishing Switzerland / 

Example 3, Using ionic liqnid ethylammoninm nitrate (EAN) as solvenf 

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. 

Hann-Lapworth mechanism with tertiary amines as catalysts  

The total synthesis of the marine-derived diterpenoid sarcodictyin A was accomplished in the laboratory of K.C. Nicolaou. The most challenging part of the synthesis was the construction of the tricyclic core, which contains a 10-membered ring. This macrocycle was obtained by the intramolecular 1,2-addition of an acetylide anion to an a, 3-unsaturated aldehyde. This unsaturated aldehyde moiety was installed by utilizing the Knoevenagel condensation catalyzed by (3-alanine. The Knoevenagel product was exclusively the ( )-cyanoester. 

TMSOTf (5 equiv), i-Pr2NEt (10 equiv), DCM, -78 °C, lOmin 71% for 3 steps 

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

The Knoevenagel Condensation. Another classical reaction called the Knoevenagel condensation involves malonate enolates in a condensation reaction with aldehydes, usually a non-enolizable aldehyde. An aldehyde or ketone can be condensed with an active methylene compounds such as a malonic 

Other derivatives containing two electron-withdrawing groups can be used in the reaction, including malononitrile (200). When condensed with 2,3-benzocycloheptanone (199), the dicyanoalkylidene product (201) was isolated in 46% yield. Cyanoacetic acid derivatives (such as ethyl 2-cyanoacetate) are also common partners in the Knoevenagel condensation. 120 

Note that nitro enolates have other synthetic uses. When nitrobutane was treated with sodium hydroxide, nitro-enolate 205 was formed. Rather than addition of an aldehyde or a ketone, 205 was treated with concentrated sulfuric acid to form butanal, with loss of N2O, in what is known as the Nef reaction. 28 Modern versions of this reaction use bases such as LDA and less vigorous oxidizing agents such as MoOPh. 29 The Knoevenagel disconnection is  

SCHEME 13.5 Knoevenagel condensation reactions to prepare septanosides [16,17]. 

An organic base in an ionic liquid was also found to be effective for a Knoevenagel reaction. Glycine was added to the ionic liquid [HMIMjPFs as the base catalyst. The reaction proceeded at room temperature in air without the need for rigorous drying of the ionic liquid. Glycine and the reactants malononitrile and benzaldehyde dissolved readily in the ionic liquid. The product was extracted from the ionic liquid phase with an immiscible co-solvent, toluene 110). 

In 1885, Arthur Hantzsch showed that the condensation of ethylacetoacetate, benzaldehyde and ammonia provided the symmetrical dihydropyridine 6. 1,5-Diketone 7 was also isolated from the reaction mixture and it was shown that it could be converted to 6 by treatment by resubjecting it to ethanolic ammonia. Subsequent experiments showed that if a primary amine such as methyl, ethyl or allyl amine was used, 7 was isolated as the sole product. Hantzsch showed that the amine was an essiential part of the condensation, as no reaction occurred between ethylacetoacetate and benzaldehde in the absence of amine, but even a catalytic amount of amine was an effective promoter of this condensation. Hantzsch s synthesis of 7 was probably the first reported instance of what was to become known as the Knoevenagel condensation. 

In 1894, Emil Knoevenagel expanded on Hantzsch s work in two significant ways. First, he showed that this reaction could be promoted by any primary or secondary amine, not just the few primary amines demonstrated by Hantzsch. (In ICnoevenagel s hands, tertiary amines, such as pyridine, quinoline, diethylaniline or dimethylaniline were ineffective, although this was to be later revisited by Hann and Lapworth, vide infra). 

Knoevenagel also showed that the synthesis of 7 could be carried out in a stepwise manner, first by condensation of ethylacetoacetate with benzaldehyde, followed by Michael addition of an additional equivalent of acetoacetate. This method allowed for the possibility of synthesizing unsymmetrical pyridines, which were not otherwise available using the 

Hantzsch procedure. In his initial work, Knoevenagel used Claisen s method (anhydrous HCl) for the synthesis of the alkylidine acetoacetates, and used sodium ethoxide to catalyze the Michael addition of the second equivalent of acetoacetate. 

Later that same year, Knoevenagel expanded the scope of this transformation in showing that diethylmalonate (10) could take the place of ethylacetoacetate as the active methylene component in Hantzsch s procedure, condensing with formaldehyde in the presence of diethylamine to form a bis-adduct, 11.  

Reproduced from Mack J, Shumba M. Rate enhancement of the Morita-Bayiis-Hiiiman reaction through mechanochemistry. Green Chem 2007 9 328-30. with permission from the Royai Society of Chemistry. 

102 CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

Reproduced from Wada S, Suzuki H. Calcite and fluorite as catalyst for the Knoevenagel condensation of malononitrile and methyl cyanoacetate under solvent-free conditions. Tetrahedron Lett 2003 44 399-401. Copyright (2003), with permission from Elsevier. 

The role of calcite and fluorite used in ball-milling process was proposed. When the minerals are mechanically crushed, the newborn solid surface is activated with the naked ionic species in situ generated. The naked carbonate and fluoride anions act as a strong base capable of deprotonating the active methylene compounds, with the consequent formation of a carbanion stabilized via the coordination with calcium cation, which combines with a carbonyl compound, eventually leading to the Knoevenagel product. 

Ondruschka commented later on their observation that the reaction proceeded to high yields when the mineral reagent was mechanically cmshed to 1-3 mm pieces prior to use, but no reaction occurred when fine powder was used [43]. It appears more likely that the added minerals did not act as a catalyst but merely served as additional grinding stones during milling of the reactants. When mineral powder was used instead, the reaction mixtures became effectively diluted and the grinding less effective. 

When malononitrile was used as a substrate, a high conversion of 98% was obtained after 12 h, whereas almost no activity was observed in the conversion of ethyl cyanoacetate and cyano-acetic acid tert-butyl ester, suggesting that the catalyst was size selective. The observation of reactant shape selectivity revealed that the catalytic turnovers take place in the MOF channels rather than at the outer surface of the MOF particles. Upon desolvation, for example, by the removal of water 

Gascon et al. [61] reported that IRMOF-3 and Am-functionalized MIL-53, both made from the 2-aminoterephthalic acid Hnker, were active as base catalysts in the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate in dimethylformamide at 60°C. The IRMOF-3 catalyst showed higher performance than the homogeneous anihne reference catalyst, with a conversion of 90% achieved compared to 55%, respectively. After the removal of the IRMOF-3 catalyst from the liquid reaction product mixture, no further conversion was observed, demonstrating the stability of the heterogeneous catalyst. The Am-MIL-53 catalyst was found to be less active in this reaction probably because of a strong adsorption and a slow diffusion of the reaction substrates and products inside the pores of this particular MOF. 

Catalytically active sites can also be introduced through the postsynthetic functionalization of the MOF framework, while keeping its structure intact. Functionalization of the dehydrated MIL-101 through grafting of amine molecules, such as ethylene diamine (ED), diethylenetriamine (DETA), and 

The catalytic performance of the functionalized MIL-101 was evaluated in the condensation of benzaldehyde and ethyl cyanoacetate in cyclohexane as solvent at 80 °C. A high conversion was obtained with all the ED-, DETA-, and APS-MIL-101 MOF catalysts having a high selectivity for traws-ethyl cyanocinnamate (turnover 

In addition, measurements of the intrinsic reaction rate (free of external and internal diffusion limitations) were achieved by the strict control of the thickness of SIM shell on SIM/alumina beads. The Hnearity observed between the variation of the MOF layer thickness and the conversion observed for the Knoevenagel condensation demonstrated that the reaction takes place inside the whole MOF layer through the porosity and not just at the external surface. 

Paquette, L. A. Kern, B. E. Mendez-Andino, J. Tetrahedron Lett 1999, 40, 4129. 

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The term Knoevenagel Condensation was originally applied to the base-catalysed condensation of the carbonyl ( CO) group of aldehydes and ketones with the reactive methylene group of malonic acid, with loss of w ater ... 

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

In a sophisticated variation of the Knoevenagel condensation ("Panizzi ) methyl 3,3-dimethoxypropanoate (from ketene and dimethoxymethenium tetrafluoroborate D.J. Crosby, 1962) is used as a d -reagent. Because only one carbonyl group activates the methylene group, a strong base with no nucleophilic properties (p. 10) has to be used. A sodium-sand mixture, which presumably reacts to form silicate anions in the heat, was chosen... 

The only acid-resistant protective group for carbonyl functions is the dicyanomethy-lene group formed by Knoevenagel condensation with malononitrile. Friedel-Crafts acylation conditions, treatment with hot mineral acids, and chlorination with sulfuryl chloride do not affect this group. They have, however, to be cleaved by rather drastic treatment with concentrated alkaline solutions (J.B. Basttis, 1963 H. Fischer, 1932 R.B. Woodward, 1960, 1961). 

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. 

Uses. Malonic acid is used instead of the less expensive malonates for the introduction of a CH—COOH group under mild conditions by Knoevenagel condensation and subsequent decarboxylation. The synthesis of 3,4,5-trimethoxycinnaniic acid, the key intermediate for the coronary vasohdator Cinepa2et maleate [50679-07-7] (5) involves such a pathway (13). 

Knoevenagel condensation of malonic acid with heptaldehyde [111-71-7] followed by ring closure, gives the fragrance y-nonanoic lactone [104-61-0] (6) (14). Beside organic synthesis, malonic acid can also be used as electrolyte additive for anodization of aluminum [7429-90-5] (15), or as additive in adhesive compositions (16). 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Otherwise, the main reactions at the methylene group are the dialkylation with alkyl haUdes (77), the acetylation with acetyl chloride which yields acetylma1 ononitrile [1187-11-7] (78), the Knoevenagel condensation, as well as the condensation with triethyl orthoformate, gives... 

Knoevenagel condensation, 3, 674 2H-Chromene, 4-alkyl-prototropy, 3, 642 2H-Chromene, 3-bromo-synthesis, 3, 668... 

Chromone-2-carbaldehyde, 3-methyl-synthesis, 3, 709 Chromonecarbaldehydes Knoevenagel condensation, 3, 711 Chromone-3-carbaldehydes mass spectra, 3, 615 oxidation, 3, 709 reactions, 3, 712 Schiff bases, 3, 712 synthesis, 3, 821 Chromone-2-carbonyl chloride Grignard reaction, 3, 711 Chromonecarboxamide, N-tetrazolyl-antiallergic activity, 3, 707 Chromone-2-carboxylic acid, 3-chloro-ethyl ester... 

Trimethylsilyloxy-p-nitrostyrene was the target of Knoevenagel condensation of 2-trimethyl-siloxybenzaldehyde with nitromethane in the presence of -butylamine as base. NMR spectra 20 were obtained from the product of the reaction. What has happened ... 

The first step in the Gewald reaction is a Knoevenagel condensation of an activated nitrile with a ketone or aldehyde to produce an acrylonitrile 8, which is then thiolated at the methylene position with elemental sulfur. The sulfurated compound 9 initially decays... 

The initial step of the Hantzsch synthesis is likely to be a Knoevenagel condensation reaction of aldehyde 2 and /3-ketoester 1 to give the a ,/3-unsaturated ketoester 6 ... 

Many dihydropyridines that are of therapeutic interest are unsymmetrically substituted at C-3 and C-5. The synthesis of such compounds is possible from separately prepared Knoevenagel condensation products 6, as is outlined in the following scheme for nitrendipine 8, which is used in the medical treatment of high blood pressure." ... 

If a Knoevenagel condensation with malonic acid is conducted in refluxing pyridine, a subsequent decarboxylation often occurs. It has been shown that the decarboxylation of a ,/3-unsaturated diesters 3 under these conditions is slow the decarboxylation of the corresponding free dicarboxylic acid is formulated as follows ... 

The following example is a sequence consisting of a Knoevenagel condensation and a subsequent hetero-Diels-Alder reaction. An aromatic... 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

The observation that a carboxyl derivative of a pyrimidinoquinol ine shows mediator release inhibiting activity is in consonance with the earlier generalization. Knoevenagel condensation of nitroaldehyde 138 with cyano-acetamide gives the product 139. Treatment with iron in... 

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

Scheme 5.1-33 The Knoevenagel condensation and the Robinson annulation in [HMIM][PFg],...

It would be preferable to incorporate both fluorescent and electron transport properties in the same material so as to dispense entirely with the need for electron-transport layers in LEDs. Raising the affinity of the polymer facilitates the use of metal electrodes other than calcium, thus avoiding the need to encapsulate the cathode. It has been shown computationally [76] that the presence of a cyano substituent on the aromatic ring or on the vinylene portion of PPV lowers both the HOMO and LUMO of the material. The barrier for electron injection in the material is lowered considerably as a result. However, the Wessling route is incompatible with strongly electron-withdrawing substituents, and an alternative synthetic route to this class of materials must be employed. The Knoevenagel condensation... 

The cyano-substituted five-ring oligomers were formed in good yields in a Knoe-venagel condensation between an aldehyde and a cyanomethyl-substituted compound, according to a procedure previously reported by Greenham el at. [6. The Knoevenagel condensation needs careful control of reaction conditions in order to... 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

The thermolabile, unsubstituted 3-benzothiepin (3) can be synthesized by a double Wittig reaction, in analogy to the Knoevenagel condensation (vide supra). This is achieved by condensation of phthalaldehyde with the bis(triphenylphosphonium) salt of bis(bromomethyl) sulfide in the presence of lithium methoxide as base at — 30"C.68... 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

TABLE 23. Knoevenagel condensation of a-sulphinylacetates 435a and a-ketosulphoxides 435b with aldehydes... 

Reactions in which the number of molecules decreases when starting materials are converted to products cycloadditions such as the Diels-Alder (15-58), condensations such as the Knoevenagel condensation (16-41). 

Another publication is the Index of Reviews in Organic Chemistry , complied by Lewis, Chemical Society, London, a classified listing of review articles. The first volume, published in 1971, lists reviews from 1960 (in some cases much earlier) to 1970 in alphabetical order of topic. Thus four reviews are listed under Knoevenagel condensation , five under Inclusion compounds , and one under Vinyl ketones. There is no index. A second volume (1977) covers the literature to 1976. Annual or biannual supplements appeared from 1979 until the publication was terminated in 1985. Classified lists of review articles on organometallic chemistry are found in articles by Smith and Walton and by Bruce.A similar list for heterocyclic chemistry is found in articles by Katritzky and others.See also the discussion of the Index of Scientific Reviews, page 1638. 

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