Knoevenagel condensation solvent effects

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

Kinetic solvent effect (KSE), on antioxidant activity 877-881 Knoevenagel condensation 1405 Kohn-Sham method 68 Koilands 1427 Koilates 1427... 

The Knoevenagel condensation reaction of benzaldehyde with ethylcyanoacetate (Scheme 1) was first studied on CsNaY 7Cs in order to check the better conditions to control the different reaction parameters (solvent effect on the rate and on the selectivity of the uncatalyzed and catalyzed reactions, mass effect of the catalyst, concentration effect of both reactants) [21],... 

Interestingly, although Knoevenagel demonstrated the effectiveness of amine bases in promoting aldol-type reactions and though, as noted above, he was particularly interested in pyridine, he overlooked this material s potential application to aldol condensations. It was left to Verley (1899) and Doebner (1900) to introduce successful modifications of the condensation in which pyridine appears to play a number of roles as a solvent, as a base, and assisting in the decarboxylation. 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

Cinnamoyl-4-hydroxy-6-methyl-2-pyrone was synthesized via Knoevenagel condensation of dehydroacetic acid with benzaldehyde derivatives (Baziz et al., 2008). The reaction rate was dramatically enhanced by a specific microwave effect, when the reaction was performed under solvent-free conditions, in a microwave reactor. Excellent isolated yields (upto 90%) were obtained within short reaction times (typically 2 to 10 min). They concluded that Knoevenagel condensation assisted by solvent-free microwave procedure was better than conventional procedure in terms of energy saving, rapidity, yield and cleanliness. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

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