Aldehydes reaction with active methylene compounds

Aldehyde 7.28 is another useful synthetic intermediate, readily undergoing condensation reactions with active methylene compounds such as malonic acid and nitromethane to produce 7.29 and 7.30. 

Various aromatic aldehydes react with active methylene compounds in the presence of piperidine to give the corresponding dipiperidines (18), which are in equilibrium with the iminium ion (16) under the reaction conditions (Scheme 8). In addition, the primary reaction products (17) of iminium ions (16) with the active methylene compound (11) can also be isolated. In the reaction of V,iV-dimethylbarbituric acid and citronellal using catalytic amounts of ethylenediammonium diacetate, the 3-hydroxy-1,3-dicarbonyl has been identified by NMR spectroscopy. ... 

Imines are more versatile than preformed iminium salts in reactions with active methylene compounds because the product, a secondary Mannich base, has an additional site on the nitrogen for further elaboration (equation 11). Imine condensation reactions are also superior to the classical method for the synthesis of secondary Mannich bases because cross-condensation reactions do not occur, due to the absence of free aldehyde in solution. The major side reactions occurring in imine condensation reactions are abstraction of enolizable ot-protons and self-condensation reactions of enolizable imines at elevated temperature. 

Enders triple cascade reaction for the formation of three new C—C bonds and providing enantiopure cyclohexane derivatives 152 through reaction of a,p-unsaturated aldehydes 95 with activated methylene compounds 151 using his famous Jprgensen-Hayashi catalyst (5)-97 (Scheme 2.45) [75]. 

Aldehydes can also be converted to olefins by reaction with active methylene compounds [Eq. (4)] by the Knoevenagel, Perkin, Claisen, and aldol condensation reactions... 

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

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

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

A basic ionic liquid, l-butyl-3-methyl imidazolium hydroxide, [bmImjOH, was found to catalyze the Knoevenagel condensation of aliphatic aldehydes and ketones with active methylene compounds elSciently in the absence of any organic solvent (Scheme 5.58). Coumarins have been obtained in one step from the reaction of o-hydroxy aldehydes following this procedure. ... 

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. 

The products of aldol/dehydration reactions of active methylene compounds with unsaturated aldehydes undergo in situ hetero-IMDA reaction. Reaction of 2-phenyl-5-methyl-2.4-di-hydro-3//-pyrazol-3-one with 2-(3-methyl-2-butenyloxy)benzaldehyde in acetonitrile containing catalytic 1,2-ethanediammonium diacetate gave the products of a highly stereoselective IMDA reaction82. 

Ozonolysis of benzo[h]thiophene yields mainly the aldehydes 46 (34%) and 47 (22%).204 Aldehyde 46, which may also be obtained from benzenoid precursors, reacts with active methylene compounds of the type RCH2C02H (e.g, R = C02H, CN, Ph) or RCH3 (e.g R = N02), to give a 2-(R-substituted) benzo[b] thiophene. The reaction is of synthetic value in cases where the substituent R cannot easily be introduced by more conventional routes (e.g., R = N02). 

The properties of 2-phosphinoylacetaldehydes have attracted much attention. Typically for aldehydes, condensation occurs with active methylene compounds in the presence of piperidine as catalyst (Scheme 41), although side reactions predominate for those aldehydes with unbranched chains and it is then not possible to isolate a dicarbonyl product in some cases cyclization to l,2-oxaphosph(V)orin derivatives has been observed". ... 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

Highly thermally stable, three-dimensional, spongelike mesoporous Ce Zri 02 nanocrystallines acted as acid-base bifunctional solid solutions for the Knoevenagel condensation of aldehydes with active methylene compounds [44]. This catalyst can be recycled at least twice for the reaction of benzaldehyde with malononitrile. 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

It consists in the condensation of aldehydes or ketones with active methylene compounds in the presence of a base [288]. The first organocatalytic enantiose-lective domino multicomponent reaction, which was developed by Barbas et al. 

Nanoparticulate ZnO was used as an efficient catalyst for the synthesis of cou-marins (84) by the reaction of o-hydroxy benzaldehydes (82) and 1,3-dicarbonyl compounds (83) via Knoevenagel condensation under microwaves and thermal conditions (Scheme 9.24) in moderate to excellent yields (Kumar et al. 2011). This protocol differs from the previous methods for the synthesis of coumarins (84) in terms of simplicity and effectiveness. The application of ZnO/MgO in ionic liquid [bmim] [BF4] was carried out successfully for the synthesis of 4//-pyrans (85) and coumarins (88) at ambient temperature via Knoevenagel condensation reaction of aldehydes (8) or 2-hydroxybenzaldehyde derivatives (86) with active methylene compounds (16, 43, 87) (Schemes 9.25 and 9.26) (Valizadeha and Azimib 2011). The method has several advantages in terms of mild reaction conditions, reusability of the catalyst, high yields of the products, and short reaction times. In comparison with methods mentioned in the literature for the synthesis of 4F(-pyrans (85) and coumarins (88), this protocol has better yield and eco-friendly advantages. 

Knoevenagel condensation is the addition of a nucleophile from active methylene compound to a carbonyl group followed by dehydration to form a P-conjugated enone. The Knoevenagel condensation between different aldehydes (15), including various aliphatic, aromatic, and heterocyclic aldehydes with active methylene compounds (119) in the presence of nano-ZnO under solvent-free conditions (Scheme 9.37) has been reported (Hosseini-Sarvari et al. 2008). Most of the aldehydes investigated reacted smoothly to afford the corresponding products in excellent yields (90%-98%) in a reaction time of 5 min to 3 h. 

The condensation of aldehydes or ketones, with active methylene compounds (especially malonic ester) in presence of a weak base like ammonia or amine (primary or secondary) is known as Knoevenagel reaction. However, when condensation is carried out in presence of pyridine as a base, decarboxylation usually occurs during the condensation. This is known as Doebner modification. Some examples are given (Scheme 37). 

Hu Y, Wei P, Huang H, Le ZG, Chen ZC (2005) Organic reactions in ionic liquids ionic liquids ethylammonium nitrate promoted knoevenagel condensation of aromatic aldehydes with active methylene compounds. Synth Commun 23(35) 2955-2960... 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

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