Knoevenagel reaction pyridine derivatives

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

An intramolecular variant of this cycloaddition process is combined with a Knoevenagel reaction in a total synthesis of the insectan leporin A, a pyrano[3,2-c]pyridine derivative <96JOC2839>. 

Knoevenagel reaction. Hydrogenation of the double bond, desilylation and oxidation of the released primary alcohol group to the aldehydic function with PCC in dichloromethane in the presence of molecular sieves, gives the branched chain L-riho-hepturonic acid derivative 31. Treatment with acetic anhydride and pyridine results in cyclization, and acetylation of the resulting alcohol affords the acetate 32 in 69% yield. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

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. 

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). 

Among the condensed heterocycles prepared by condensation reactions of 10 are many pyridine derivatives. So Knoevenagel condensation of two mol 10 with 19 gave 73. ... 

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) ... 

Because of the huge importance of pyridine derivatives, a considerable amoimt of effort has been directed to the development of multicomponent routes for their synthesis, including reactions performed in water. For instance, a one-pot four-component condensation of aldehydes, malononitrile and thiophenols in the presence of boric acid as catalyst in aqueous medium afforded high yields of 2-amino-3,5-dicaibonitrile-6-thiopyridines 46 [29], either by conventional heating or under ultrasound-aided conditions (Scheme 1.21). This reaction can also be performed in an aqneons snspension of basic almnina [30] or in water with microporous mo-lecnlar sieves as catalysts [31]. Mechanistically, this transformation involves an initial Knoevenagel condensation of the aldehyde with a molecule of malononitrile, followed by the Michael addition of the second molecule of malononitrile, reaction of one of the nitrile groups with the thiol, cyclization and a final air oxidation step. 

Malononitrile reacts with acetone in water in the presence of KF-alumina to give 2-aza[2.2.2]octane in high yield via Knoevenagel condensation followed by double cyclization [15]. The bicyclo adduct heated directly or refluxed in tetralin releases 2-methylpropene (retro Diels-Alder reaction), giving the corresponding pyridine derivative. 

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. ... 

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