Synthesis Knoevenagel reaction

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. 

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. 

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 Knorr p3rrrole synthesis. Kolbe-Schmitt reaction Leuckart reaction Mannich reaction Mccrwein-Ponndorf-Verley reduction Michael reaction Oppenauer oxidation... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

Microwave activation and solvent-free PTC have been shown to be of prime efficiency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by the Knoevenagel reaction. When performed classically by use of KOH in ethanol at room temperature for 12 h (Eqs. 43 and 44) the yield was 30%. This was improved to 90-94% within 2-6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28],... 

An efficient solventless synthesis of imidazolones via the Knoevenagel reaction using microwave irradiation has appeared recently in Green Chemistry [76] (Scheme 8.52). 

Knoevenagel reaction org chem The condensation of aldehydes with compounds containing an activated methylene (=Cff2) group. ka ne va.nag al re.ak shan ) Knorr synthesis orgchem Acondensation reaction carried out In either glacial acetic acid or an aqueous alkali in which an a-aminoketone combines with an a-carbonyl compound to form a pyrrole possibly the most versatile pyrrole synthesis. nor, sin-th3-s3s ... 

Tietze LF, Beifuss U (1991) The knoevenagel reaction. In Trost B (ed) Comprehensive organic synthesis, vol. 2. Pergamon Press, Oxford, pp 341-394... 

Mettler and colleagues reported an alternative synthesis of malonate 16 in the same paper (Griffiths et al., 1991) in which they condensed cyclohexanone with ethyl cyano-acetate instead of diethyl malonate in the Knoevenagel reaction to give ethyl cyano(cyclohexylidene)-acetate (18). In the presence of a catalytic amount of sodium cyanide, the Michael addition of HCN to cyanoacetate 18 proceeded in good yield at room temperature to generate the dicyanoester 19. Intermediate 19 was selectively converted to malonate 16 with pressurized HCI treatment in ethanol (Scheme 16.4). 

An attractive method to generate C5-monoalkyl-substituted Meldrum s acids consists of a two-step synthesis (Scheme 10). In the first step, a Knoevenagel reaction between Meldrum s acid (22) and an aldehyde (or sometimes a ketone) yields the C5-alkylidene derivative 23. In the following step, the alkylidene derivative 23 is reduced, to generate the C5-monoalkyl-substituted Meldrum s acid 24.[43 71 104 1051 Alternatively, in the second step, Michael addition of a nucleophile to the conjugated C=C bond in the C5-alkylidene derivative generates a Meldrum s acid 25 monosubstituted on C5 by a more elaborated alkyl.t106 ... 

Use of the Knoevenagel reaction (67OR(l5)204), in which a benzaldehyde reacts with an activated methylene compound in the presence of an amine, goes some way to overcoming the inherent difficulties of the Perkin synthesis of coumarins (see later). In order to obtain the coumarin rather than the usual cinnamic acid, a 2-hydroxy substituent must be present... 

Table 7 Synthesis of Coumarins by a Knoevenagel Reaction on Salicylaldehyde...

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. 

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