Silica Knoevenagel condensation

Aminosilicas have been widely studied for use in catalysis, either as a base catalyst or as a support for metal complexes (12). For example, amine functionalized silica can be used to catalyze the Knoevenagel condensation, an important C-C bond forming reaction. Also, the amine sites on the silica can be further functionalized to form supported imines, guanidine, and other species... 

Knoevenagel condensation of the corresponding 3-methylfuran-2-carbaldehyde 379 and 3-methybenzo[4]furan-2-carbaldehyde 382 with diethyl malonate followed by bromination with iV-bromosuccinimide (NBS) in the presence of dibenzoyl peroxide afforded bromides 380 and 383, respectively. Treatment of 380 and 383 with benzylamine, isopropylamine, /-butylamine 3-hydroxypropylamine, aniline and -toluidine in ethanol yielded furo[2,3-c]pyrroles 381 and benzo[4,5]furo[2,3-c]pyrroles 384, respectively (Scheme 41). The yields of furopyrroles 381 are only moderate (16-46%), because these compounds are highly sensitive to acid, and partially polymerized upon silica... 

Base catalysis is one of the less-well developed areas of heterogeneous catalysis. We have developed novel bases derived from amines via the one-step process outlined above. A range of supported amines have been prepared and evaluated in a series of reactions We have also investigated the nature of the amine groups attached to the surface in comparison with those formed by grafting onto pre-formed silica. While many workers have studied the use of basic catalysts for the Knoevenagel condensation of aldehydes, with three articles on the use of MCM derivatives[ 12], little has been done on the more demanding condensation of ketones. 

Further projects dealt with the fabrication of heterogeneous, basic or acidic solid-state catalysts or adsorbents carrying, for instance, amino or sulfonic acid groups. Amino-functionalized silicas were prepared and analyzed for the catalytic activity in Knoevenagel condensation reactions of aldehydes or ketones with ethyl cyanoace-tate ions by Macquarrie et al.154 155 Recently, Zhang et al.156,157 reported on the successful preparation of amino-functionalized silica thin films by means of the EISA approach. 

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. 

However, more interesting from an application point of view are silylation reactions which introduce new functions into the materials. These can be created either directly or in subsequent further steps after silylation. Most simple is the direct conversion of the silica to a basic material by reaction, for instance, with 3-aminopropyltriethoxysilane [17]. Also two-step processes have been employed to synthesize basic materials, where first chloropropyl groups are anchored to the surface with subsequent conversion of the chloro group into an amine. In order to remove the residual, unreacted silanol groups, a second silylation with hexamethyldisilazane can be used. Such materials were found to be reasonably active in different base-catalyzed reactions, such as Knoevenagel condensations and Michael additions. A survey of the catalyzed reactions and the types of modification used can be found in Ref. [5]. 

Since silica is such a common support for immobilization, the effect of the weakly acidic silanol groups has been studied. A cooperative silanol effect is thought to improve the catalytic activity of mesoporous silica-supported amines in base-catalyzed reactions such as the nitroaldol (Henry) condensation [6, 7], Knoevenagel condensation [6, 8,9], and Michael addition [6]. Thus immobilizing amines onto supports with stronger acid groups could be expected to further increase the catalytic activity. 

Angeletti E, Canepa C, Martinetti G, Venturello P (1989) Amino groups immobilized on silica gel An efficient and reusable heterogeneous catalyst for the knoevenagel condensation. J Chem Soc Perkin Trans 1 105... 

Primary amines anchored to silica have been utilized as catalysts for Knoevenagel condensation reactions. For example, silica gel functionalized with a propylamino moiety [SiO2-(CH2)3-NH2] was employed in the reaction of different methylene active compounds with aldehydes and ketones for the production of electron-poor olefins 73 (Scheme 3.21). ... 

Knoevenagel condensation of aldehydes/ketones with malonitrile and ethyl cyanoacetate. The reactions were carried out under homogeneous and biphasic conditions, including the use of liquid-silica supported IL, with the biphasic system employing cyclohexene as the second phase. Although supported ILs showed a reduced initial activity, in general an excellent recyclability was observed, with the reaction repeated over five times without leaching of the IL into the extractant phase or reduction in activity. 

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. 

The NHa-grafted mesoporous silica, FSMN, exhibited the base catalytic activity for some reactions. The catalytic active site was clarified to be the surface Si-NHa group. The highest activity in Knoevenagel condensation was obtained on the FSMN sample that pre-activated at 1073 K and NHa-treated at 923 K since the catalyst possessed the largest amount of Si-NHa. 

MTS silicas functionalized with amino groups exhibit interesting base catalytic properties in condensation reaction which are well-correlated with their physico-chemical characteristics. The greater activity of the immobilized primary amine sites compare to the tertiary amine sites in the Knoevenagel condensation is explained by the imine intermediate formation which is much more reactive than the parent carbonyl group of the reactant. 

Besides this early example another application was reported in 1988 by Ven-turello and coworkers [10]. They disclosed the use of aminopropyl-function-alized silica gel as a suitable catalyst in Knoevenagel condensations under continuous flow conditions (Scheme 4). Good yields were obtained when aromatic aldehydes, cyclohexanone, and acetophenone were condensed with ethyl acetoacetate, ethyl cyanoacetate or malononitrile [11,12]. The concept was based on a conventional column reactor which was equipped with a vertical double-jacket thermostat. The catalyst was introduced into the column while the reactants were placed on the top of the column. Toluene was passed through the column and the products were conveniently obtained by evaporation of the solvent. 

Polymer- or mesoporous silica-supported TBD reagents have also been shown to catalyse efficiently Knoevenagel condensations and, in some cases, be feasible for continuous-flow synthesis in a microreactor [36,37,43,44]. 

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