Knoevenagel product

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. 

When the reaction is run with potassium fert-butoxide in THF at -5°C, one obtains (after hydrolysis) the normal Knoevenagel product (32), except that the isocyano group has been hydrated (16-65). With the same base but with DME as solvent the product is the nitrile (33). When the ketone is treated with 31 and thallium(I) ethoxide in a 4 1 mixture of absolute ethanol and DME at room temperature, the product is a 4-ethoxy-2-oxazoline (34). Since 33 can be hydrolyzed to a carboxylic acid and 34 to an a-hydroxy aldehyde, this versatile reaction provides a means for achieving the conversion of RCOR to RCHR COOH, RCHR CN, or RCR (OH)CHO. The conversions to RCHR COOH and to RCHR CN have also been carried out with certain aldehydes (R = H). 

Reaction of the enatiopure aldehyde 2-800, obtained from the corresponding imine by enantioselective hydrogenation, with Meldrum s acid (2-801) and the enol ether 2-802a (E/Z= 1 1) in the presence of a catalytic amount of ethylene diammonium diacetate for 4h gave 2-805 in 90 % yield with a 1,3 induction of >24 1. As intermediates, the Knoevenagel product 2-803 and the primarily produced cycloadduct 2-804 can be supposed the latter loses C02 and acetone by reaction with water formed during the condensation step (Scheme 2.178). 

The residue is washed with diethyl ether (4 x 30 mL), and the combined organic layers are washed with water (3 x 30 mL), 1 N hydrochloric acid (3 x 30 mL), saturated sodium bicarbonate solution (3 x 30 mL), water (30 mL), and brine (3 x 30 ml), and finally dried over anhydrous sodium sulfate. Filtration and removal of the solvent on a rotary evaporator at 25°C yields 24.1-25.5 g (90-95%) of the Knoevenagel product as a colorless oil. The crude product is pure enough to be used in the ene reaction. An analytically pure sample of 3 (Note 8) is obtained by column chromatography (SI02) (Note 9) with petroleum ether/acetone, 98 2. Compound 3 is acid and base sensitive and should be stored under argon in a freezer. 

Pyrrolizinones have also been synthesized by ring closure of the Knoevenagel product from 2-formylpyrroles and diethyl malonate (B-77MI30505). 

In the transformation of a-carbonylated phosphonate 183a and benzaldehyde 184a using a catalytic amount of piperidine as base, enol ether 88a had to be added after complete formation of the Knoevenagel product (NMR-monitoring) other-... 

While zeolites are mostly used in acid catalysts, there are various procedures to introduce basic sites with variable strength into these materials. Depending on the nature of the active site, one is able to selectively catalyze reactions with different basicity requirements, and this is probably the main virtue of base catalysis with zeolites. For instance, in a classical Knoevenagel condensation, the reaction selectivity can be decreased by a consecutive Michael reaction, since the Knoevenagel product can serve itself as a Michael receptor -. 

Substituted tetrahydropyridines 134 have been recently prepared via an interesting one-pot transformation involving the Aza Diels-Alder reaction of imines 132 with enamines 133 (Scheme 26) [62]. The enamine adducts were prepared from the reaction of anilines 129 with the Knoevenagel products of 130 and 131. 

A useful extension of sulfoxide-sulfenate rearrangements exploits the greater stability of allylic vs. vinylic sulfoxides.For example, the Knoevenagel product (202) is deconjugated under the conditions of its formation. This sets the stage for a 2,3-rearrangement in the same pot (equation 66). Optically active condensation products give hydroxy esters (201) with 64-72% 50-80% ee were reported for... 

The total synthesis of the marine-derived diterpenoid sarcodictyin A was accomplished in the laboratory of K.C. Nicolaou. The most challenging part of the synthesis was the construction of the tricyclic core, which contains a 10-membered ring. This macrocycle was obtained by the intramolecular 1,2-addition of an acetylide anion to an a, 3-unsaturated aldehyde. This unsaturated aldehyde moiety was installed by utilizing the Knoevenagel condensation catalyzed by (3-alanine. The Knoevenagel product was exclusively the ( )-cyanoester. 

The first step of this process involves the Knoevenagel condensation of an aldehyde with malononitrile to form the corresponding Knoevenagel product (5). The second molecule of malononitrile then undergoes Michael addition to 5 followed by simultaneous thiolate addition to C N of the adduct and cyclization to dihydropyridine (6) which on aromatization and oxidation (air) under the reaction conditions leads to pyridine. 

NMR spectroscopy is the most widely used method to investigate both the configuration and conformation of Knoevenagel products. The configuration of acrylic or cinnamic acids obtained by condensation of aldehydes with malonic acid and other 1,2-disubstituted alkenes can be determined from the value of the vicinal coupling constant Vh,h (between the protons of the double bond) on the basis of the relationship > Vh.h-hi. If only one isomer is available, the electronegativity of the substituents has... 

The acidity of these products cannot be determined by means of direct pH determination. However, the virtual acidity constant, AT l, is accessible from optical and electrochemical measurements. Comparison of the pX i values of selected Knoevenagel products and the pX values of some typical carboxylic acids in methanol establishes that they exhibit comparable acidity (Scheme 7). Using the o -values, the pX i values of benzylidene derivatives of Meldrum s acid are in good accordance with the Hammett equation. The Lewis acidity of Knoevenagel products is due to the formation of labile pseudobase adducts, the so-called anbadons (10), upon reaction with nucleophiles. Structures of the anbadons have... 

The rate of the hydrolytic cleavage of Knoevenagel products (retro-Knoevenagel reaction) strongly depends on the pH of the aqueous solution - as well as on cosolvents such as DMSO and additional nucleophiles such as amines. The hydrolysis of these alkenes to CH2XY can be presented by equation (3) at pH < and by equation (4) at pH > Although the kinetics are related to the na-... 

Knoevenagel products of cyclic ketones such as cyclohexanone show a pronounced preference in adopting a chair conformation with an axial orientation of substituents in the a-position. Condensation of rranj-2,5-dimethylcyclohexanone (50) with malonodinitrile under neutral or weakly basic conditions leads, as expected, to (51) under the same conditions the dj-2,5-dimethylcyclohexanone (52) affords (53). It is remarkable that the cis product (53) is thermodynamically more stable than (51), whereas the ketone (50) with trans orientated methyl groups is more stable than (52). The unexpected difference in stability is due to the necessity of the a-substituent in the Knoevenagel products (51) and (53) to adopt an axial orientation. In the conformation with an equatorial a-methyl group a severe steric interaction would occur because of a coplanar arrangement of the methyl and the dicyanomethylene moiety. ... 

The 1,4-addition of nucleophiles to Knoevenagel products of Meldrum s acid has been widely used synthetically. The products of the addition of Grignard reagents can be degraded to yield monocarbox-ylic acids and monocarboxylic esters, respectively. Although hydrolysis of Knoevenagel products in aqueous methanol yields Meldrum s acid and the corresponding aldehyde or ketone, with a trace of hydrochloric acid in ethanol half-esters of 2-methylenemalonates are obtained. - "... 

An interesting route to a-carboxy-8-lactones (81) and a-methylenelactones (80), based on hydrolysis of Knoevenagel products (79) of Meldrum s acid with cyclic aliphatic ketones (78), has been developed (Scheme 14). Reduction of 5-methylene derivatives of Meldrum s acid has been performed catalyti-caiiyi30 or by use of LAH. Imidoylation reaction of Meldrum s acid and subsequent solvolysis of the resulting (82) yields -enamino esters (83) in good yields.Flash vacuum pyrolysis of alkylidene derivatives of Meldrum s acid can be used to prepare methylene ketenes (84), a class of compounds difficult to prepare by conventional methods. By this procedure, methylene ketenes are obtained from aromatic aldehydes and ketones and from aliphatic ketones in only two steps. Intramolecular trapping of the methylene ketene obtained from the ketone (85) has been used successfully in the synthesis of the naphthol (86). ... 

Malonomonoamides can be condensed with aldehydes to give acrylamides or cinnanamides, but condensation with malonodiamides is of only minor impjortance. In contrast to Meldrum s acid (58), Knoevenagel reactions of barbituric acid (56) and A A -dimethylbarbituric acid have been less explored. However, several aliphatic, aromatic and heteroaromatic aldehydes are known to react easily and with high yields in most cases. Reactions of 1,2-dimethyl-3,5-pyrazolidinedione (93) with several aliphatic and aromatic aldehydes using standard conditions yield Knoevenagel products in good yield. A similar reactivity is observed with 2-phenyl-3,5-dioxoisoxazolidine (94) and oxazepanediones (45 see Section 1.11.2.5). Recently, the oxidations of alcohols to carbonyl compxiunds and thiols to disulfides with 5-arylidene-l,3-dimethylbarbituric acids (95) have been described Mechanistically (95) mimics enzymic oxidation by flavin adenine dinucletide (FAD). ... 

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