Active Methylene Compounds with Aldehydes

Condensation of Active Methylene Compounds with Aldehydes Condensation of compounds containing active methylene group can be made to react with the aromatic aldehydes to give corresponding arylidene derivatives (Scheme 20). 

The aldol, Perkin, and Knoevenagel condensations of active methylene compounds with aldehydes give olefins which are probably derived from the intermediate alcohols, as is true in the aldol condensation shown above. The Perkin, Knoevenagel, and Claisen reactions are described in further detail in Chapter 9, Carboxylic Acids. 

Vinylpyrroles and vinylindoles are extremely sensitive to acid-catalyzed dimerization and polymerization and it is significant that much of the early research was conducted on systems which were produced in situ. Even by this approach, the dimerization of, for example, 2-(3-indolyl)propene and l-(3-indolyl)-l-phenylethylene was difficult to prevent (see the formation of 110 and 120, Section 3.05.1.2.8). Similarly, although it is possible to isolate ethyl 2-(2- and 3-indolyl)propenoates, they appear to be extremely unstable at room temperature even in the absence of acid (81UP30500) to give [ 4 + 2] cycloadducts of the type (348) (cf. 77JCS(P1)1204>. For many years simple vinylpyrroles also eluded isolation, on account of their facile acid-catalyzed polymerization. Application of the Wittig reaction, however, permits the synthesis of vinyl-pyrroles and -indoles under relatively mild and neutral conditions (see Section 3.05.2.5). In contrast, heteroarylvinyl ketones, esters, nitriles and nitro compounds, obtained by condensation of the appropriate activated methylene compound with the heteroaryl aldehydes (see Section 3.05.2.5), are thermally stable and... 

The C-H bond cleavage of active methylene compounds with a transition metal catalyst is another method for the functionalization of these C-H bonds. To date, several reactions have been developed. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers. One of the most attractive research subjects is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. The mthenium-catalyzed reaction active methylene compounds with carbonyl compounds involving aldehyde, ketones, and a,y3-unsatu-rated ketones and esters is described in this section. 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

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. 

In contrast to facile a-alkylation of carbonyl compounds, a-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth a-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now a-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for a-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct a-arylation of acetate or propionate. 

Knoevenagel Condensation. The condensation of active methylene compounds with the structure Z1-CH2-Z2 (Z = electron-withdrawing groups) with aldehydes or ketones is termed as Knoevenagel condensation (Fig. 12) (48). Knoevenagel condensation is one of the most important C—C bond-forming reactions... 

The Knoevenagel reaction is the condensation of an active methylene compound with an aldehyde or ketone, to give an a,p-unsaturated dicarbonyl compound.(l + 2 —> 3). ... 

Useful but rarely exploited is the use of [ " C]acetic anhydride as an active methylene compound with aromatic aldehydes to produce labeled cinnamic acids (Perkin reaction, Figure 6.18). This adol-type reaction is limited to aromatic aldehydes, and in many cases malonic acid ester methods are superior, being more flexible and giving higher yields. The reaction of [l- " C]acetic anhydride with o-nitrobenzaldehyde is one of the very few examples published in the literature". ... 

Knoevenagel condensation is a classic C-C bond formation reaction. It occurs between aldehydes or ketones and active methylene compounds with ammonia or another amine as a catalyst in organic solvents. The Knoevenagel reaction is considered to be a modification of the aldol reaction. The main difference between these approaches is the higher acidity of the active methylene hydrogen as compared to a carbonyl hydrogen. 

The possible general mechanism for the enolate-mediated synthesis of 1,2,3-triazoles from active methylene compounds, enolizable aldehydes 69, enolizable ketones 71, and substituted acetonitriles 73 is illustrated in Scheme 4.26. First, the reaction of the catalyst (base) with the CH acid 76 generated the enolate A, which on in situ treatment with Ar-Ng 2 selectively furnished the adduct 1,2,3-triazolines B through a concerted [3-1-2]-cycloaddition or stepwise amination-cyclization reaction. Adduct B further transformed into the 1,2,3-triazole 77 through the rapid elimination of water under ambient conditions induced by the basic nature of the catalyst. 

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. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Condensation of an aldehyde or ketone with an active methylene compound... 

The imide nitrogen atom was also most reactive to a variety of electrophilic species (hydrogen halides, pseudohalogens, and alkyl halides) in the parent Rimidophosphazenes, R(C—NH)-N=PPh3. With t-butyl hypochlorite the /V-chloro-derivatives, R(C=NCl)-N=PPh3, were obtained. R/ -Vinyl-phenylphosphazenes have been prepared by condensation of aldehydes with active methylene compounds ... 

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 condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

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. 

Quantitative Knoevenagel condensations of aldehydes with active methylene compounds are most desirable due to the frequent use of the electron-poor alkenes that arise [107]. But previous techniques use catalysts and produce dangerous wastes even if highly energy-consuming microwave irradiation upon polar solid supports is additionally used. 

The aldehyde moiety of 50 can be condensed with either amines or active methylene compounds. In the case of reactions with amines, the aldehyde 50 (presumably obtained by reduction of the cyano group with diisobutyl-aluminium hydride (DIBAL-H)) forms simple Schiff bases 51 (Equation 20) <1998J(P1)3557>. 

Although less reactive than many aromatic aldehydes, formyl-pyrroles and -indoles undergo base-catalyzed reactions with a variety of activated methylene compounds to yield compounds of the type (431) and (432), where, for example, X, Y = C02Et, C02Et COMe,... 

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