Knoevenagel condensation with malonic acid

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 ... 

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). 

The phenanthrenequinone oxime 54 was built in four steps from the two benzenoid precursors 52 and 53. Beckmann rearrangement of 54 furnished the cyano-acid 55. The latter, after reduction to the corresponding cyano-aldehyde, was homologated by Knoevenagel condensation with malonic acid to give, after reduction, hydrolysis and esterification, the diester 56. This compound underwent Dieckmann condensation, installing the seven-membered C-7 ketone 57 in 69% yield after hydrolysis and decarboxylation of the intermediate (3-ketoester. 

Selenophene-2-aldehyde takes part in the Hantzsch synthesis [Eq. (I)]108 and reacts readily with ammonia, aromatic amines and diamines,109 hippuric, barbituric, and malonic acids, malononitrile,70 and rhodanine.109 /3-(Selenien-2-yl)acrylic acid has been obtained from selenophene-2-aldehyde by the Perkin reaction and by Knoevenagel condensation with malonic acid.70 Esters of /9-(selenien-2-yl)acrylic acid are easily formed by condensation of the aldehyde... 

Aldehyde functions have been used as such to synthesize Schiff bases °, various stilbene derivatives by Wittig-Homer-type olefination or cinnamic acids or by Knoevenagel condensation with malonic acid . They can also be reduced to or oxidized to As examples for derivatives obtained via alcohol functions,... 

The synthesis of bixin (533) requires the regiospecific introduction of a Z double bond. Attention was first focused on the total synthesis of (all- )-methylbixin (534) [35]. (3-Methylepichlorohydrin (180) was treated with sodium acetylide (68) to give the alcohol 181 which was transformed with dihydropyran and phosphorus oxychloride to the acetylenic compound 182. Condensation of two moles of 182 with oct-4-ene-2,7-dione (5) in the presence of PhLi resulted in the C2o-diol 183. Treatment with p-toluenesulphonic acid first in toluene gave the diether 184 and afterwards in ethanol led to the diol 185, which was oxidized with Mn02 to the dial 186. The Knoevenagel condensation with malonic acid (187) and methylation with diazomethane gave the diester 188, which was hydrogenated in the presence of Lindlar catalyst and isomerized with iodine to (all- )-methylbixin (534) in an overall yield of 0.04% referred to 180 (Scheme 41). 

Rhodium-catalyzed decarboxylative hydroformylation has been used to generate a substrate for a Knoevenagel condensation with malonic acid. This interesting sequence results in two carbon homologation of carboxylic acids (Scheme 26.17) [97]. 

Literature procedures were employed in the synthesis of 4-amlno-3-hydroxybenzoic acid 1 (9) and 3-amlno-4-hydroxyphenylace-tic acid (10). The propanoic and propenoic compounds were obtained as outlined in Figure 1. In both Isomeric systems, the intermediate hydroxynitrobenzaldehydes were cleanly converted to the cinnamic acid derivatives by Knoevenagel condensation with malonic acid followed by spontaneous decarboxylation. Reduction of the nitro groups with sodium dithionate then gave the alkene... 

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). 

The second reaction type investigated is the Linstead-Knoevenagel condensation of malonic acid with heptanal (Scheme 4). The product from this is a precursor to the lactone, a component of coconut oil. 

Malonic acid undergoes Knoevenagel condensations with nearly every type of aldehyde and with very reactive ketones. If condensations with malonic acid are performed in ethanolic ammonia below 70 C, the methylenemalonic acids are usually obtained. If, however, the condensations are performed in pyridine (Doebner modification), decarboxylation normally takes place and the acrylic or cinnamic acid is... 

Ketones can also be condensed with malonic acid by the Knoevenagel method for example, 3-methyl-2-butenoic acid is formed in 60% yield when malonic acid is heated with acetone in pyridine containing a little piperidine 909 when diethyl ketone is used in this synthesis the yield falls to 35%, and the reaction fails (yield 5%) with cyclohexanone. However, in such cases condensation of ketones with malonic acid is successful if piperidine acetate is used as catalyst. 

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) ... 

In 1898 Knoevenagel showed that benzylidine aminal 20 condensed with malonic acid proceeded with decarboxylation to give cinnamic acid (22). This was found to be a fairly general method for the condensation of malonic acid with aromatic aldehydes, but was not efficient for aliphatic aldehydes. 

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. 

The Knoevenagel-type condensation of salicylaldehydes with malonic acid [14, 27], malonic ester [28], cyanoacetic ester [29], or Meldrum s acid [30], is... 

Trimethoprim has also been synthesized by condensing 3,4,5-trimethoxybenzaldehyde with malonic acid dinitrile in a Knoevenagel reaction, which forms the derivative (33.1.53), which is partially reduced to the enamine (33.1.54) by hydrogen using a palladium on carbon catalyst, which upon being reacted with guanidine is transformed into trimethoprim [52,53]. 

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 synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

This reaction type leading to oc,/ -unsaturated acids and esters is exemplified in the Perkin reaction (Section 6.12.3, p. 1036) and the Knoevenagel reaction (Section 5.11.6, p. 681). The Doebner reaction, which is illustrated in this section, is the condensation of an aldehyde with malonic acid in pyridine solution, often in the presence of a trace of piperidine. The reaction mechanism involves the addition of a malonate anion to the aldehydic carbonyl carbon atom followed by the elimination of water accompanied by decarboxylation. 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

NMR spectroscopy is the most widely used method to investigate both the configuration and conformation of Knoevenagel products. The configuration of acrylic or cinnamic acids obtained by condensation of aldehydes with malonic acid and other 1,2-disubstituted alkenes can be determined from the value of the vicinal coupling constant Vh,h (between the protons of the double bond) on the basis of the relationship > Vh.h-hi. If only one isomer is available, the electronegativity of the substituents has... 

As part of a project to synthesize stable analogs of the indole-2,3-quinodimethane system, the 2,4-di-hydropyrrolo[3,4]indole (251) has been prepared from formylindole (249). Knoevenagel condensation with ethyl malonate followed by bromination and nucleophilic substitution of the bromide with azide yields (250), which immediately undergoes intramolecular 1,3-dipolar cycloaddition to give the triazoline (252). Treatment of (252) with toluene-p-sulfonic acid affords diethyl diazomalonate and (251 ... 

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