Benzaldehyde Knoevenagel condensation

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

To evaluate properties of basic catalysts, the Knoevenagel condensation over aluminophosphate oxynitrides was investigated [13]. In this reaction usually catalysed by amines, the solid catalysts function by abstraction of a proton from an acid methylene group, which is followed by nucleophilic attack on the carbonyl by the resultant carbanion, re-protonation of oxygen and elimination of water. The condensation between benzaldehyde and malononitrile is presented below. 

The Knoevenagel condensation of a-lithiosulphoxides with hemiacetal 437 has been used to synthesize PGI2 analogues 438 (equation 261). The Knoevenagel-type condensation of dithioacetal monoxides with substituted benzaldehydes has been performed using Triton B as a base and gave the corresponding ketene dithioacetal monoxides 4395 2,513 (equation 262). 

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

It is assumed that in the formation of 2-509, a Knoevenagel condensation of the benzaldehydes 2-511 and tetronic acid 2-512 initially takes place, and this is followed by the generation of a hemiaminal with the aniline 2-510 and an electrophilic substitution. 

Because a base-catalyzed reaction involves the abstraction of a proton by the catalyst, one approach to measurement of the total number of basic sites and also the base strength distribution is to use the reactions of molecules with various values (96-100). For instance, the basic site distribution in calcined MgAl hy-drotalcites was determined by Corma et al. (99), who used the Knoevenagel condensation (Scheme 7) between benzaldehyde and methylene active compounds with various pKa values, i.e., ethyl cyanoacetate (pKa = 9), diethyl malonate (pKa = 13.3), and ethyl bromoacetate (pKa = 16.5). The authors found that this material has basic sites with pKa values up to 16.5, although most of the basic sites... 

A convenient synthesis of lonchocarpin (206) and similar compounds is the Knoevenagel condensation of a 6-acetylchromene (207) with benzaldehyde (7iJCS(C)796, 71JCS(C)8U>. Carbonyl groups present in chromenes as aldehydes or ketones form oximes and 2,4-dinitrophenylhydrazones <77HC(31)11). 

Hybrid organic/mineral solid base catalysts bearing primary and tertiary amino functions have been used as catalysts in the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate at 375 K in the presence of DMSO as solvent. Both catalysts exhibited a selectivity of approximately 100 % in ethyl trans-a-cyanocinnamate and could be recycled several times, after filtration and washing, without decrease in their catalytic performance.11711 The activity was found to be... 

The proton sponge, l,8-bis(dimethylaminonaphthalene) (DMAN), has been anchored onto amorphous and pure silica MCM-41.[182] DMAN supported on MCM-41 is an excellent base catalyst for the Knoevenagel condensation between benzaldehyde and different active methylene compounds, as well as for the Claisen-Schmidt condensation of benzaldehyde and 2 -hydroxyacetophenone to produce chalcones and flavanones. It was found that the activity of the supported catalyst is directly related to the polarity of the inorganic support. Moreover, the support can also preactivate the reagents by interaction of the carbonyl groups with the weakly acidic silanol groups of MCM-41. This preactivation step enables DMAN, anchored onto MCM-41, to abstract protons with a higher pK than that of the DMAN. 

The catalytic properties were checked in the transesterification of ethyl propionate with n-butanol and in the Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate ... 

Excellent results were also obtained using activated hydrotalcite as a solid base catalyst in the Knoevenagel condensation of benzaldehyde with ethylcya-noacetate [110], ethylacetoacetate [111] or malononitrile [112] (see Fig. 2.34). Similarly, citronitrile, a perfumery compound with a citrus-like odor, was synthesized by hydrotalcite-catalyzed condensation of benzylacetone with ethyl-cyanoacetate, followed by hydrolysis and decarboxylation (Fig. 2.34) [113]. 

In contrast with the widespread application of zeolites as solid acid catalysts (see earlier), their use as solid base catalysts received scant attention until fairly recently [121]. This is probably because acid-catalyzed processes are much more common in the oil refining and petrochemical industries. Nonetheless, basic zeolites and related mesoporous molecular sieves can catalyze a variety of reactions, such as Knoevenagel condensations and Michael additions, which are key steps in the manufacture of flavors and fragrances, pharmaceuticals and other specialty chemicals [121]. Indeed, the Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate (Fig. 2.36) has become a standard test reaction for solid base catalysts [121]. 

Cesium-exchanged zeolite X was used as a solid base catalyst in the Knoevenagel condensation of benzaldehyde or benzyl acetone with ethyl cyanoacetate [121]. The latter reaction is a key step in the synthesis of the fragrance molecule, citronitrile (see Fig. 2.37). However, reactivities were substantially lower than those observed with the more strongly basic hydrotalcite (see earlier). Similarly, Na-Y and Na-Beta catalyzed a variety of Michael additions [122] and K-Y and Cs-X were effective catalysts for the methylation of aniline and phenylaceto-nitrile with dimethyl carbonate or methanol, respectively (Fig. 2.37) [123]. These procedures constitute interesting green alternatives to classical alkylations using methyl halides or dimethyl sulfate in the presence of stoichiometric quantities of conventional bases such as caustic soda. 

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]. 

A study of the Knoevenagel condensation of cyclohexanone and benzaldehyde with three active-methylene components showed that rubidium fluoride and cesium fluoride are more effective catalysts than potassium fluoride and that lithium fluoride... 

Nonetheless some examples using neat TSIL turned out to be successful, such as the application of the Knoevenagel condensation on supported benzaldehyde [30], Using piperidine as a catalyst under microwave heating conditions, olefins could be... 

The Aldol condensation and Knoevenagel condensation (eqn. 1) was carried out as follows. The powder catalyst was added to toluene (2.5 ml) solution of benzaldehyde (0.7 mmol, 1) and reactant (0.5 mmol, 2), then the reaction mixture was stirred at 323 K, Products 3 were analyzed by gas chromatography employing dodecane as an internal standard. 

The catalytic activity of the NHs-grafted mesoporous silica, FSMN, was examined in some base-catalysed condensations (eqn. 1). The results were listed in Table 1. The FSMN catalyst used here was FSMN-5 that was prepared by the pre-activation at 1073 K followed by NH3-treatment at 973 K. The Aldol condensation of benzaldehyde and acetone did not proceed in this condition (entry 1). The Knoevenagel condensation of benzaldehyde and diethyl malonate (entry 2) did not occurred. On the other hand, the reactions with malononitrile (entry 3) and with ethyl cyanoacetate (entry 4) were catalysed by the FSMN-5. This shows that the NHa-grafted mesoporous silica would function as base catalyst. 

Table 2 shows the results of the Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate on the FSM-16 and the FSMN samples prepared in various conditions. The reaction occurred on all FSMN samples (entry 1-5), while reaction did not occur over unmodified FSM-16 (entry 7). H-NMR and GC did not detect any by-products, confirming the progress of the selective reaction. Moreover, it was confirmed that basic species would not elute during the reaction, since the filtrate after the reaction over active catalyst did not exhibit the activity. 

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