Knoevenagel synthesis

Bigi F, Chesini L, Maggi R, Sartori G (1999) Montmorillonite KSF as an inorganic, water stable, and reusable catalyst for the knoevenagel synthesis of coumarin-3-carboxylic acids. J Org Chem 64 1033-1035... 

An indication of the scope of the Knoevenagel synthesis of coumarins is apparent from Table 7, but some further examples utilizing the conventional procedure are worthy of mention partly because some of the products are naturally occurring compounds. Graveolone (375), a benzodipyran, is obtained from the chroman-4-one shown by cyclization of the acrylic acid (Scheme 117) (78IJC(B)570). 

Synthesis of the benzopyran ring has also been performed by microwave-assisted copper-catalysed cross coupling of an aryl iodide with terminal alkynes, in the presence of copper(I) iodide/triphenylphosphine (Scheme 3.35)56. An alternative approach involving microwave heating of mixtures of salicylaldehyde and various derivatives of ethyl acetate in the presence of piperidine has enabled rapid Knoevenagel synthesis of coumarin derivatives (Scheme 3.35)57. 

Side Note 13.6. Knoevenagel Synthesis of Conjugated (Mono-) Carboxylic Acids... 

One of the most common strategies for the preparation of thiophenes involves the intramolecular condensation of -thioglycolates with adjacent carbonyls (Knoevenagel synthesis) a representative example is shown in Scheme 103. 

Cyclocondensation of o-hydroxybenzaldehydes with reactive methylene compounds (malonic ester, cyanoacetic ester, malononitrile) in the presence of piperidine and other bases (Knoevenagel synthesis) ... 

King-Ortoleva reaction 380 Knoevenagel synthesis (coumarin) 323... 

Knoevenagel reaction Knorr pyrrole synthesis. Kolbe>Schmitt reaction Leuckart reaction Mannich reaction... 

Phenyl-7-aminocoumarin is obtained by a Knoevenagel reaction of substituted saUcylaldehydes with phenylacetic acid or ben2yl cyanide. Further synthesis of the individual end products is carried out by usual procedures. 

Uses. Malonic acid is used instead of the less expensive malonates for the introduction of a CH—COOH group under mild conditions by Knoevenagel condensation and subsequent decarboxylation. The synthesis of 3,4,5-trimethoxycinnaniic acid, the key intermediate for the coronary vasohdator Cinepa2et maleate [50679-07-7] (5) involves such a pathway (13). 

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). 

Knoevenagel condensation, 3, 674 2H-Chromene, 4-alkyl-prototropy, 3, 642 2H-Chromene, 3-bromo-synthesis, 3, 668... 

Chromone-2-carbaldehyde, 3-methyl-synthesis, 3, 709 Chromonecarbaldehydes Knoevenagel condensation, 3, 711 Chromone-3-carbaldehydes mass spectra, 3, 615 oxidation, 3, 709 reactions, 3, 712 Schiff bases, 3, 712 synthesis, 3, 821 Chromone-2-carbonyl chloride Grignard reaction, 3, 711 Chromonecarboxamide, N-tetrazolyl-antiallergic activity, 3, 707 Chromone-2-carboxylic acid, 3-chloro-ethyl ester... 

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... 

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 ... 

Many dihydropyridines that are of therapeutic interest are unsymmetrically substituted at C-3 and C-5. The synthesis of such compounds is possible from separately prepared Knoevenagel condensation products 6, as is outlined in the following scheme for nitrendipine 8, which is used in the medical treatment of high blood pressure." ... 

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. 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

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>. 

However, an almost classical attempt to generate an a, -unsaturated e-capro-lactam 87 involved a Knoevenagel condensation of 86 as the ring forming step. The material was employed in a synthesis of conformationally restricted analogs of some anti cancer agents (tetrahydrofolate analog) (Scheme 17) [24]. 

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