Unsaturated synthesis, Knoevenagel reaction

J,V-Unsaturated carboxylic acids and their derivatives are valuable synthetic intermediates for various natural products. Two typical multi-step processes for the synthesis of p.y-unsaturated acids, Knoevenagel reaction/isomerization with base and allylic cyanide/hydrolysis,3 are those most commonly used. Other new methods have been developed 4-7 however, there is a problem with E/Z stereoselectivity. One straightforward way to obtain p,y-unsaturated acids is by the carboxylation of an allyl metal Intermediate. In the substituted allylic series, the reaction usually occurs at the more sterically hindered terminus. A stereospecific route for the synthesis of homogeranlo acid and homoneric acid by carboxylation of the lithiated allylic sulfone... 

Knoevenagel reaction is the synthesis of a, p-unsaturated acids by reaction of aldehydes and compounds with active methylene groups in the presence of an organic base... 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

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. 

An interesting approach to the substituted 6,8-bisdehydro[13]annulenone (238) includes a double Knoevenagel reaction of the mixed acetonedicarboxylic ester (235) with aldehyde (236) in the presence of piperidine to give (237). Oxidative coupling of the acetylene moieties in (237) with Cu(OAc)2 in pyridine affords (238) in 10% yield (Scheme 47).2 a,p-Unsaturated malonodinitriles are suitable intermediates for the synthesis of a variety of carbocyclic systems. Cyclization of the benzylidene malonodinitrile (239) to form a five-membered carbocyclic ring (240) can be achieved upon treatment with acid and subsequent hydrolysis (Scheme 48). A similar cyclization of (241) affords six-mem-bered carbocyclic ring systems. ... 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

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 . 

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 ... 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

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. 

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