In the Knoevenagel reaction

Virtually any aldehyde or ketone and any CH-acidic methylene compound can be employed in the Knoevenagel reaction however the reactivity may be limited due to steric effects. Some reactions may lead to unexpected products from side-reactions or from consecutive reactions of the initially formed Knoevenagel product. 

Actually NHx surface species are not the only active species in the Knoevenagel reaction. Indeed the catalysts with 2.8, 17.5 and 20 wt.% bulk nitrogen have the same NHx surface species content but their activities are... 

Previous work [111] by our group has demonstrated that RTIL-catalyzed 1,3-dipolar cycloaddition under the action of microwave irradiation leads to dramatically shorter reaction times with better yields of isolated products. We have recently investigated the reactivity of the formyl group covalently grafted on the ionic liquid phase 75 in the Knoevenagel reaction with malonic derivatives 76 [112], as shown in Scheme 8.76. 

Tellurium tetrachloride is an efficient catalyst in the Knoevenagel reaction of non-enoUz-able aldehydes with active methylene compounds. ... 

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). 

Problem 17.35 In the Knoevenagel reaction, aldehydes or ketones condense with compounds having a reactive CHj between two C=0 groups. The cocatalysts are both a weak base (RCOO ) and a weak acid (R,NH,). Outline the reaction between C<,H,CH==0 and H2C(COOEt)2. d... 

Ito and Hayashi noticed that Au(I)-chiral fenocenylphosphine complexes are remarkably efficient in the Knoevenagel reaction between aldehydes and isocyanoacetic esters to form 5-alkyl-2-oxazoline-4-car-boxylates with high enantio- and diasteieoselectivity (Scheme 116)... 

The catalyst derived from chlorine displacement was effective in the base catalysed ring-opening of epoxides to form monoglycerides.[16] The other TBD-derived catalyst (from epoxide ring-opening) was also found to be active in the Knoevenagel reaction, the Michael addition and the base catalysed epoxidation of alkenones.[15] Results in the epoxidation reaction were of particular interest, as this leads to highly labile and... 

Scheme 3 Deactivation mechanism of aminopropyl-grafted silicas in the Knoevenagel reaction...

When a compound containing an activated methylene group is the proton-donating catalyst, the presence of a secondary amine is required for easy isolation of the desired ketose derivative in crystalline form. The conditions resemble those requisite for a Knoevenagel reaction. - A condensation of the Knoevenagel type evidently does not occur, as the dehydrated product would be too stable for practical reversibility. However, the addition compound which is an intermediate in the Knoevenagel reaction, such as V, couW be formed from IV. Splitting of V to yield the ketose de-... 

The catalytic activity of proton sponge in the Knoevenagel reaction has been studied227. It was shown that benzaldehyde, in the presence of 2 mol% of 1, reacts with ethyl cyanoacetate and ethyl acetoacetate (equation 22). The condensation is accelerated in polar solvents (especially in DMSO) and does not occur in the case of diethyl malonate, as its CH-acidity is too low (pK = 13.3). 

The important point, however, is that no reasonable mechanism for the elimination of water can be written until step 5 is complete, and step 5 requires the presence of a proton donor (an acid). These considerations have been nicely verified in the Knoevenagel reaction (pp. 182, 183), where it has been found that a base alone is not as effective a catalyst as it is in the presence of acetic acid. 

In the Knoevenagel reaction, the thermodynamically more stable compounds are usually formed. However, a closely related transformation provides access to compounds of opposite stereochemistry. Condensation of phosphonoacetate (40) with aliphatic and aromatic aldehydes in the presence of N-methylmorpholine/TiCU yields product (41) with the thermodynamically more stable ( )-configura-tion. In contrast, titanated (40), obtained from the reaction of the sodium salt of (40) with ClTi(OCHMe2)3 reacts with aldehydes to give preferentially the thermodynamically less stable (Z)-isomer (42). ... 

Pyrazolones (154) and isoxazolones (155) can also be used in the Knoevenagel reaction. Thus condensations with aliphatic aldehydes, aromatic aldehydes and ketones in the presence of ethylenediammon-ium diacetate or other typical catalysts provide the corresponding alkylidene and benzylidene compounds in good yields (for stereochemistry see Section 1.1A new method involves the use of dicyclohexylcarbodiimide at 20 C without an additional catalyst. ... 

There is almost no restriction in the choice of an appropriate electrophile in the Knoevenagel reaction. Aldehydes, ketones, thioketones, imines, enamines, acetals and orthoesters have been used. With less reactive methylene groups, however, drastic reaction conditions may be necessary. Steric effects have a significant influence on the rate and unexpected compounds are often obtained as a result of secondary reactions. Reaction of 1,3-dicarbonyl compounds with carbon disulfide followed by dialkylation with an alkyl halide give diacylketene-S,5-acetals (159). However, even with highly acidic dicarbonyl com-... 

Steroidal ketones have been used extensively in the Knoevenagel reaction. Thus, die transformation of 17-oxoandrostane derivatives (309), which are readily available by microbiological degradation of sitosterin, are employed for the synthesis of enantiomerically pure cardiotonic steroids such as bufa-dienolide and cardenolide (311). In toth syntheses the substitutent at C-17 is introduced by a Knoevenagel reaction of the 17-oxoandrostane derivative (309) with ethyl cyanoacetate in the presence of ammonium acetate to give the cyano ester (310), presumably as a mixture of the ( )- and (Z)-isomers, in 89% yield.5 5... 

Figure 4.20 Solvent effects in the Knoevenagel reaction using (a) aminopropyl silica and (b) aminopropyl HMS catalysts...

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