Ethyl cyanoacetate condensation with ketones

Ethyl cyanoacetate condenses with ketones and ammonia in absolute ethanol at 0-5° to give 44-73% yields of cyclic dicyanoimides. Endocyclic ketones may be used, giving imides in which the two radicals are p>art of an alicyclic ring. The imides are hydrolyzed and decarboxylated in almost theoretical yields to yS,/S-disubstituted glutaric acids. A similar reaction takes place between aldehydes or ketones and cyanoacetamide, NCCHjCONHj, in the presence of piperidine or potassium hydroxide. When aldehydes are used, the condensation products are dicyanoamides, RCH[CH(CN)CONHj]j, rather than cyclic imides. 

The condensation of active methylene compounds such as malononitrile, ethyl cyanoacetate, etc., with phenyl isocyanate followed by alkylation and cyclization gives 3-aminothiophenes 304 (Scheme 51) <2003T1557>. Dihydrothienopyrimidine-4(/7T)ones 306 are prepared by the reaction of 305 with a-halo ketones <2006HAC104>. 

Functionalized 5-alkoxymethyl- and 5-phenoxymethyl-2(5//)-furanones 44-46 were obtained starting from 3-alkoxy- and 3-phenoxy-2-hydroxy ketones 40 (98T1801). Condensation of the hydroxy ketones 40 with a slight excess of diethyl malonate 41 (Z = COOMe R = Me), ethyl cyanoacetate 42 (Z = CN R = Me),... 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

In a 500-ml. round-bottomed flask attached to a modified Dean and Stark constant water separator 1 (Note 1) which is connected to a reflux condenser are placed 67.8 g. (0.60 mole) of ethyl cyanoacetate (Note 2), 56.8 g. (0.66 mole) of diethyl ketone (Note 3), 9.2 g. (0.12 mole) of ammonium acetate, 30 g. (0.48 mole) of glacial acetic acid, and 100 ml. of benzene. The flask is heated in an oil bath at 160-165°, and the water which distils out of the mixture with the refluxing benzene is removed from the separator at intervals. Refluxing is continued for 24 hours (several hours after the separation of water has ceased) (Note 4). 

A number of ketones have been condensed with ethyl cyanoacetate by this procedure. Reactive ketones such as aliphatic methyl ketones and cyclohexanone condense with ethyl cyanoacetate much more rapidly and give better yields of alkyli-dene esters. It is advantageous with such ketones to use a lower ratio of ammonium acetate-acetic acid catalyst.1... 

The above procedure is a very slight modification of a recently described 1 general method for condensing ketones with ethyl cyanoacetate. Ethyl (l-ethylpropylidene)-cyanoacetate also has been prepared by condensing diethyl ketone with ethyl cyanoacetate in the presence of piperidine or acetic anhydride and zinc chloride,5 or piperidine and anhydrous sodium sulfate in a pressure bottle at 100°.6... 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

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. 

Diamines grafted on MCM-41 revealed higher base catalytic activity because they were able to catalyse condensation between benzaldehyde and ethyl malonate which is usually less active than ethyl cyanoacetate. The catalytic activity was also high with less reactive carbonyl derivatives, such as cyclic or aliphatic ketones. Moreover, aldolization between acetone and aromatic aldehyde was also possible.11721... 

Condensation of ethyl cyanoacetate, cyanoacetamide, or malono-nitrile with unsaturated ketones leads to 8-oxonitriles (34) from which, in turn, dihydropyridones (35) may be obtained.194... 

Cyclohexenylacetonitrile has been prepared by the decarboxylation of cyclohexylidenecyanoacetic acid 4-5 by the dehydration of 1-cyclohexenylacetamide 5 by the condensation of cyclohexanone and cyanoacetic acid in the presence of piperidine 6 by the condensation of cyclohexanone and ethyl cyano-acetate in the presence of sodium ethoxide 4-7 and by the condensation of cyclohexanone and cyanoacetic acid in the presence of ammonium acetate followed by decarboxylation.8 Ammonium acetate also has been used as a catalyst for the condensation of ketones with ethyl cyanoacetate.3-9... 

Alkali-exchanged mesoporous molecular sieves are suitable solid base catalysts for the conversion of bulky molecules which cannot access the pores of zeolites. For example, Na- and Cs-exchanged MCM-41 were active catalysts for the Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate (pKa=10.7) but low conversions were observed with the less acidic diethyl malonate (pKa=13.3) [123]. Similarly, Na-MCM-41 catalyzed the aldol condensation of several bulky ketones with benzaldehyde, including the example depicted in Fig. 2.38, in which a flavonone is obtained by subsequent intramolecular Michael-type addition [123]. 

Condensation catalyst. Ammonium acetate is recommended as catalyst for the condensation of ketones with cyanoacetic acid or ethyl cyanoacetate. ... 

The Knoevenagel condensation was also performed with MCM-41-(6112)3-NH-(CH2)2-NH2 catalyst prepared through post-modification methodology/ utilizing (2-aminomethylaminopropyl)trimethoxysilane. Various aldehydes and ketones were reacted with malononitrile and ethyl cyanoacetate (Scheme 3.21, R =R = CN and R CN, R = EtOCO) in all the reactions total conversions were achieved in toluene with exclusive formation of dehydrated products (75-100% yield). Interestingly, both aliphatic and aromatic carbonyl compounds showed identical reactivity in the reaction with ethyl cyanoacetate and the substitution on the aromatic ring did not influence the reactivity. 

Knoevenagel condensation of aldehydes/ketones with malonitrile and ethyl cyanoacetate. The reactions were carried out under homogeneous and biphasic conditions, including the use of liquid-silica supported IL, with the biphasic system employing cyclohexene as the second phase. Although supported ILs showed a reduced initial activity, in general an excellent recyclability was observed, with the reaction repeated over five times without leaching of the IL into the extractant phase or reduction in activity. 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

Compound (329), a potent inhibitor of dihydrofolate reductase, was synthesized by a Knoevenagel condensation of the ketone (326) with ethyl cyanoacetate to afford (327) in 28-81% yield. Catalytic hydrogenation of (327) over Pd/C gave almost exclusively the undesired endo isomer, whereas with lithium in liquid ammonia and phenol as proton donor the desired exo compound (328) was obtained in 71% yield.222 Knoevenagel condensation of benzaldehydes with malonodinitrile in the presence of a base leads to benzylidenemalonodinitriles. These compounds, especially the 2-chlorobenzylidenemalonodini-trile (CS, 330), are used as riot-control agents (sneeze and tear gas). 2,324... 

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