Knoevenagel condensations pyridine

Titanium tetrachloride pyridine Knoevenagel condensation Improved procedure... 

Titanium tetrachloride pyridine Knoevenagel condensation s. 26, 814 s. a. Tetrahedron 28, 663 (1972)... 

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 ... 

With the aid of a Knoevenagel condensation and a Staudinger reaction, 2-azidocyclopent-l-ene 1-carbaldehydes (195) can be converted into suitable products for a cyclopenta[b]pyridine synthesis [89JCS(P1)1369], as shown in Scheme 72. In order to bring the ester carbonyl function and the imino-phosphorane group into close proximity suitable for cyclization reactions, the 1,3-diene system 196 should possess the s-cis conformation. Furthermore, the exocyclic double bond should show a cis conformation. To achieve... 

Numerous condensation polymers such as polyamides (75MI11103) containing the pyridine nucleus in the backbone have been prepared from the corresponding pyridine diesters or diacid chlorides. The Knoevenagel condensation (Scheme 32) has provided another way of incorporating the pyridine nucleus into a condensation framework. Poly(styrylpyridines) (116) have been found to exhibit exceptional flame resistance and are useful in reinforced composites (79USP4163740). 

Phenylcoumarins are conveniently prepared by the Knoevenagel condensation of salicylaldehyde with a benzyl cyanide, in the presence of base such as sodium hydroxide or piperidine, followed by acid hydrolysis of the resultant imine. A second convenient synthesis is via condensation of 2-methoxybenzaldehyde with benzyl cyanide and cyclization of the 2-methoxy-a-phenylcinnamic nitrile in pyridine (Scheme 12). 

Treatment of 2-methyldibenzo[ /]thiepin-ll(677)-one 5,5-dioxide 79 with aromatic aldehydes 138 in pyridine and piperidine produced the Knoevenagel condensation products 139 in 53-96% yields (Equation 20) <2005MI524>. 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

The Doebner Modification (or Knoevenagel Condensation), which is possible in the presence of carboxylic acid groups, includes a pyridine-induced decarboxylation. 

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). 

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

Fig. 13.56. Mechanism of the Knoevenagel condensations in Figure 13.55. The C,H( )-acidic reaction partneris malonicacidin the form of the malonic acid enolate D (malonic acid "monoanion"). The decarboxylation proceeds as a fragmentation of the pyridinium-substituted malonic acid carboxylate F to furnish the ,/Tunsaturated ester (G) and pyridine. This fragmentation resembles the decomposition of the sodium salts H of ,/Tdibrominated carboxylic acids to yield the a,/Tunsaturated bromides I and sodium bromide.

Isatins fail to yield Knoevenagel condensation products with malonic acid419. However, malonic acid can be condensed with isatin in a mixture of ethanol and pyridine, in which the initial condensation product suffers decarboxylation, furnishing an acetic acid derivative. This can be converted to the acid chloride and submitted to a Friedel-Crafts acylation reaction, yielding acetophenone derivatives420. Alternatively the oxoindolinylidene acetic acid derivative can be treated with an arene in the presence of AICI3 to yield. sy />o[indoline-3,3 -indan]-2,l-dione derivatives. ... 

Knoevenagel condensation. The combination of titanium tetrachloride and pyridine in THF is useful for Knoevenagel condensations. For example, ethyl aceto-acetate and ethyl nitroacetate undergo condensation readily under these conditions... 

The Knoevenagel condensation of hexanal and malonic acid to give 2- and 3-octenoic acids (341 and 342) was investigated in the presence of different bases (83H1541). The amines used could be classified into two groups. Bases containing a basic center with no steric hindrance (e.g., pyridine) afforded predominantly 2-octenoic acid (341), whereas bases containing a sterically crowded basic center (e.g., DBU or triethylamine) yielded mainly 3-octenoic acid (342). When DBU was applied, the ratio of 341 and 342 was 6 94. 

Lehnert, W. Improved varients of the Knoevenagel condensation with titanium tetrachloride-THF-pyridine. I. Alkylidene- and arylideremalonic esters at 0-25.deg. Tetrahedron Lett. 1970, 4723-4724. 

Knoevenagel condensation Doebner modification. Condensation of aldehydes or ketones with active methylene compounds (specifically malonic ester) in the presence of ammonia or amines the use of malonic acid and pyridine is known as the Doebner modification. 

The first step of this process involves the Knoevenagel condensation of an aldehyde with malononitrile to form the corresponding Knoevenagel product (5). The second molecule of malononitrile then undergoes Michael addition to 5 followed by simultaneous thiolate addition to C N of the adduct and cyclization to dihydropyridine (6) which on aromatization and oxidation (air) under the reaction conditions leads to pyridine. 

Knoevenagel condensation. The most generally used catalyst for the condensation of aldehydes with malonic ester is pyridine with or without piperidine.1 Lehnert2 has reported recently that yields of alkylidenemalonates are improved considerably if a combination of titanium tetrachloride (0.1 mole) and pyridine (0.2 mole) is used for the condensation of the aldehyde (0.05 mole) and malonic... 

As a new generally applicable catalyst for the Knoevenagel condensation, a mixture of titanium tetrachloride and a tertiary organic base in solvents like tetrahydrofuran or dioxane was introduced by Lehnert. " The procedure is often superior to standard methods in reactions of sensitive compounds because it can be performed at low temperature. As an example, the reaction of the aldehyde (4) with malonate or cyanoacetate in the presence of titanium tetrachloride and pyridine gives the desired products (5) in high yield, whereas the classical method using piperidine acetate fails (Scheme 3). ... 

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." ... 

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... 

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

Unsaturated 8-lactones are biologically active structural elements in many natural products. The synthesis of this heterocyclic moiety can be achieved by a Knoevenagel condensation of 3-hydroxy aldehydes with active methylene in the presence of TiCU/pyridine or under standard conditions. ° " ... 

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