Carbon Knoevenagel condensation

The condensation of aldehydes and ketones with active hydrogen atoms is called Knoevenagel condensation. It is related to an aldol condensation and commonly is used to produce enones (a compound with a carbon-carbon double bond adjacent to a carbonyl). The process requires a weak base (an amine). A typical excimple and mechanism eire presented in Figure 15-22. 

Ethyl E7E -2,4-dienoutes.1 These diunsaturaled esters can be prepared by Knoevenagel condensation (piperidine catalyzed) of ethyl 2-phenylsulfinylacetate with aldehydes and thermolysis of the product in the presence of potassium carbonate (equation I). 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

A large number of catalytic asymmetric MCR are based on deoxo-bisubstitution reactions of carbonyl compounds such as the Mannich and Strecker reactions in which an oxo-group is displaced by two new cr-bonds, one to a nitrogen atom and one to a carbon atom. Other examples of deoxo-bisubstitutions include tandem processes that involve an initial Knoevenagel condensation followed by either a nucleophilic or a cycloaddition. These processes are characterized by the conversion of a C O-K-bond into two new C-C-cr-bonds and have been termed carba-acetalizations. 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

For a number of processes, reactive distillation is not possible, as some of the reactants are destroyed or degraded in side reactions by heating them up to boiling temperature. Examples of such processes are the Knoevenagel-condensation of aldehydes or ketones with components of high CH-acidity, the production of enam-ines or carbonic acid amides, or the esterification of fatty acids with fatty alcohols to fatty esters [7]. 

Among the most important reactions in organic synthesis are those that form carbon-carbon bonds. Classically this was accomplished using base-catalyzed reactions such as the aldol, Claisen, and Knoevenagel condensation reactions. Modem versions of these reactoins often display remarkable stereoselectivity.1 Unfortunately, many types of carbon atoms cannot be joined together by these reactions, for example, an aryl carbon to another aryl carbon. It took the development of transition metal-catalyzed reactions before new types of carbon-carbon and carbon-heteroatom bonds could be created. Of particular note in this regard are the reactions catalyzed by palladium, usually in its 0 or +2 oxidation state.2,3,4,5... 

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. 

Milder reaction conditions have been developed for the HWE reaction of phosphonate-stabilized carbanions to increase yields, accommodate sensitive substrates and to minimize undesired side reactions such as double bond migrations, the Cannizzaro reaction, Knoevenagel condensation and Michael addition. For example, a number of different bases have been employed to generate the carbanion. These include sodium hydroxide under phase-transfer conditions, potassium carbonate, barium hydroxide, diisopropylethylamine and l,8-diazabicyclo[5.4.0]undec-7-ene (see Protocol 10).22... 

Titanium tetrachloride and a tertiary amine are a useful catalyst for Knoevenagel condensation [149] as shown in Eq. (45) [150]. Because the reaction can be performed under mild conditions, acid-sensitive functional groups survive the reaction conditions and the optically active center at the enolizable position did not racemize (Eq. 45). More examples of the titanium-catalyzed Knoevenagel condensation are shown in Table 5. Alkylation of an (unsaturated) (iV,0)-acetal with active methylene compounds was performed analogously in the presence of TiCU and NEts (Eq. 46) [154]. Depending on the structure of the active methylene compounds, carbon-carbon bond... 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

Matsumoto and co-workers reported in 1978 that simply heating a solution of 4-chlorobenzaldehyde (6), methyl a-isocyanoacetate (7), and piperidine (8) in MeOH led to the formation of an amidine (9) in about 50% yield (Scheme 5.6) [19]. The reaction is suggested to be initiated by the Knoevenagel condensation followed by a formal a-addition of the secondary amine to the isocyano group. It is evident from this work that the a-proton of a-isocyanoacetate 7 is relatively acidic and is readily deprotonated under even weakly basic conditions [20]. The nucleophilicity of the a-carbanion of the enolate 12 produced is apparently higher than that of the terminal divalent carbon of the isonitrile, thus initiating the overall reaction sequence by the Knoevenagel condensation. 

In connection with a synthesis of the hydroazulenic sesquiterpene kessanol (304), Knoevenagel condensation of photocitral-A (302) with ethyl cyanoacetate was found to give (303) as a single isomer. The following sequence includes an intramolecular Prins reaction initiated with SnCU. In Isobe s synthesis of vemolepin (307) the two carbons of the -y-iactone are introduced by a Knoevenagei condensation. Reaction of ketone (305) with di-f-butyl maionate followed by treatment with DBU affords (306), which is transformed to the a,a -dihydroxy compound (308). Hydrolysis of the esters foliowed by decarboxy-iation, formation of the y-lactone, Mannich reaction and elimination yields vemolepin (307 Scheme 58).3"... 

Related condensations involving the replacement of the anhydride component with succinic acid (Fit-tig synthesis) or with malonic acid (Knoevenagel condensation, see Volume 2, Qiapter 1.11) provide complementary preparative methods which are useful for both aromatic and aliphatic systems. The Fittig extension of the Perkin transformation involves heating an aliphatic or aromatic aldehyde with sodium succinate and acetic anhydride to give the condensation products (17), which lose carbon dioxide to afford p,7-unsaturated cartoxylic acids (18), accompanied by small amounts of the corresponding 7-buty-rolactones (19 Scheme 7)P... 

Alkali metal-exchanged zeolites have been used to prepare activated alkenes of interest as prepolymers by Knoevenagel condensation of malononitrile with ketones having different positive charge density on the carbon of the carbonyl group benzophenone, cyclohexanone, and p-aminoacetophenone [85]. The reactivity depends both on ketone structure (the order of reactivity was benzophenone > cyclohexanone > p-aminoacetophenone) and on the catalyst used. For instance, when malononitrile is condensed with cyclohexanone in the presence of a CsY zeolite conversion was very low. CsX zeolite, however, which has a substantial number of basic sites with pX in the range 9 < P a < 10.7 and some with 10.7 < < 13.3 could be used to perform... 

A one-carbon homologation method for converting various aldehydes and ketones (110) into a-halo-esters (112) (Scheme 8) consists of sequential Knoevenagel condensation with malononitrile and oxidation (NaCIO) to give epoxide (111) followed by treatment with HX-EtOH... 

Aramendia, MA Borau. V Jimenez, C Marinas, JM Romero. FJ. New aspects of Knoevenagel condensation and Michael addition reactions on alkaline carbonates. Chemisrrv Letters 2000 514-575. 

Knoevenagel condensation [22] is a commonly used synthetic method for forming carbon-carbon bonds. Amines, ammonium salts, or various Lewis acids usually catalyze the reaction, which is strongly solvent-dependent. An improved Knoevenagel condensation reaction of aromatic aldehydes and malononitrile was reported by Ren et al [23]. The experimental protocol entails grinding the aldehydes with malononitrile using a glass mortar and pestle at room temperature for 1 h and alio-... 

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