Amides Knoevenagel condensation

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. 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

The TEMPO moiety (2,2,6,6-tetramethylpiperidine-l-oxyl) has been incorporated into acetoacetic derivatives to achieve E-selective Knoevenagel condensations, exploiting the steric hindrance that it causes.269 In contrast, acylacetoamides (including Weinreb amides) produce Z-adducts. Downstream reductions of carbonyl groups in the products allow access to a variety of useful materials. 

The first -selective Knoevenagel condensation of acetoacetic derivatives has been developed by using TEMPO for the acylated substituent.21 Alternatively, Z-selective Knoevenagel condensation was achieved by use of amide analogues including the Weinreb amide. 

Compound 85 was dehydrogenated at 300° over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86) was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92) was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-cinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol 94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53). 

Lewis base sites in PCPs have the potential to show different catalytic properties from Lewis acid sites.52 165 166 The three-dimensional PCP, [Cd(NC>3)2(4-btapa)2] 6H20 2DMF (4-btapa = 1,3,5-benzenetricarboxylic acid tris[/V-(4-pyridyl)-amide]), has amide groups that act as guest interaction sites on the surfaces of channels with dimensions of 4.7 x 7.3 A2165 A Knoevenagel condensation reaction catalyzed by this PCP demonstrates its selective heterogeneous base catalytic properties, which depend on the size of the reactants. This solid catalyst maintains its crystalline framework after the reaction and is easily recycled. 

For a number of processes, reactive distillation is not possible, as some of the reactants are destroyed or degraded in side reactions by heating them up to boiling temperature. Examples of such processes are the Knoevenagel-condensation of aldehydes or ketones with components of high CH-acidity, the production of enam-ines or carbonic acid amides, or the esterification of fatty acids with fatty alcohols to fatty esters [7]. 

This stereochemistry is the opposite of that found in the j3-cyanostibazoles (XI-43) obtained from a Knoevenagel condensation of arylacetonitriles with pyridinealdehydes (see Table XI-25). Unfortunately, these results do not provide syntheses for both the ds- (XI-41) and the tram- (XI-4S) carboxystilbazoles because, although the nitriles can be hydrolyzed to the tram amides (XI-44), these amides isomerize when hydrolyzed further to yield the cis acids. ... 

Kossmehl (1979) et at have described the polymerization of the benzothiazohum salts by the Knoevenagel condensation of 2,3,6-trimethylthiazolo[4,S- benzothiazohum perchlorate (117, X = CIO4-) and iodide (117, X = 1-) with dialdehydes such as p-phenylenedicarbaldehyde, 2,5-dimethoxy-p-phenylenedicarbaldehyde, thiophene-2,3 dicarbaldehyde (scheme-33) (Kossmehl et at 1979). In the same year Mukaiyama (1979) studied that the benzothiazolium compounds can be used to activate the carboxyhc adds or alcohols to give 2-acyloxy or 2-alkoxy intermediates, which can be converted into esters, thioesters, amides, lactones, add fluorides, isocyanates, etc (Mukaiyama 1979). 

Butylation of phenylacetonitrile with aqueous NaOH, as shown in Scheme 25, proceeds faster by use of high DF (>0.5) anion exchange resins.The strongly alkaline conditions degrade the quaternary ammonium ions of the catalyst. Catalyst (64) (1% DVB) is active for alkylation of phenylacetonitrile and benzyl phenyl ketone, and for Williamson ether synthesis, and it is much more stable in base than AERs. AERs in OH form are catalysts for dichlorocyclopropane syntheses from alkenes, chloroform and solid sodium hydroxide, and for dehydration of amides to nitriles. AERs in the appropriate hydroxide, acetate, or cyanide form are catalysts for aldol condensations, Michael reactions, Knoevenagel condensations, cyanoethylations and cyanohydrin syntheses. " ... 

Abell et al. [288] reported the reaction of 5-formyl-lH-pyrrole-2-carboxylic amides bound to the polymeric support via their amide linkage (249) and dihydrocinna-moyl chloride. The acid chloride is believed to acylate the pyrrole nitrogen prior to an intramolecular Knoevenagel type condensation. The resulting bicycle (251) is deeply colored and was suggested by the authors to be used as a tag for combinatorial libraries. Upon treatment with NaOCHs, the bicycHc structure can be reverted to a 1-benzyl 3-pyrrolyl acrylic ester (Scheme 55). 

The Knoevenagel and Wittig type reactions have been used for the creation of the 6-bond. The condensation of octadecanal with methyl p-(chlorophenyl)sulfinyl acetate in the presence of piperidine afforded the corresponding acetate after acetylation of the hydroxy group which, after subsequent molibdenum-catalyzed elimination, gives the dienic ester as a 4 1 E,E E,Z mixture. After final amidation, the amide trichonine (13) [40] is obtained (Scheme 2). A similar strategy has been used for the synthesis of piperovatine (21) with total E,E-stereoselectivity [41]. 

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). 

The second target, 4-oxo-4H-l-benzopyran-3-carboxylic acids (3) were obtained by Jones oxidation of or hydrolysis of the 3-carbonitrile derivatives ( ) described below (14). The third target, 3-(4-oxo-4H-1-benzopyran-3)acrylic acids (4) were synthesized generally by the Knoevenagel reaction of 3-carboxaldehydes (2) with malonic acid ( 1 ). In the meantime, it was found that the 3-carboxaldehydes ( ), which were able to function as P-dialdehyde compounds, were attacked by amide groups in some cases, to give 2(IH)-pyridone derivatives after condensation with malonic acid derivatives. Thus, condensation of 2 with malonodiamide in pyridine gave initially acrylamide derivatives which were converted into 3-carbamoyl-5-(2-hydroxybenzoyl)-2(IH)-pyridones ( ) (24) ... 

Iminium triflates can also undergo nucleophilic addition with a broad spectrum of nucleophiles. For example, the activated amide can react with malonates in a Knoevenagel-t)tpe condensation reaction (96). Other nucleophiles include, but are not limited to, Grignard reagents to form ketones 56 qj. alkylamines, phosphites, amino acids, pyridines, and pyridine oxydes or alcohols to afford lactones via intramolecular cyclization (97). ... 

It has been shown recently that the condensation of an allylsilane, of which a double bond is conjugated to an amide (silylacrylamide), onto aldehydes in the presence of TBSOTf and NEts gives direct access to dienamides after a p-eliminati(Mi on the intermediate aldol product [120]. Another paper based on a Knoevenagel craidensa-tion involves p-diketones or P-ketoesters and enals. Proline catalysis leads to the expected conjugated dienones in good yields and after short reaction times [121],... 

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