Salicylaldehyde Knoevenagel reaction

Scheme 4.15 Knoevenagel reaction of salicylaldehyde with diethyl malonate.

Bose et al. [18] reported that the Knoevenagel reaction between salicylaldehyde 27 and ethyl malonate 28 in the presence of piperidine gave a high yield of 3-carbethox-ycoumarin 29 in 3 min in an open vessel in a MW oven (Scheme 4.15). 

Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhancements when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide supra, Scheme 4.15) was performed in toluene than when ethanol was used as the solvent. The calculated rate constants in toluene solution were more than three times higher under MW irradiation than under conventional conditions, whereas the rate constants of the reaction in ethanol were the same, within experimental error, under both heating methods. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

Table 7 Synthesis of Coumarins by a Knoevenagel Reaction on Salicylaldehyde...

Under aqueous conditions, after 12 min of irradiation, 3-carboxycoumarin was obtained from salicylaldehyde in a 60% yield by a Knoevenagel reaction and lactonisation (Scheme 9.9)113. 

Salicylaldehydes and some o-hydroxyaryl ketones react with Meldrum s acid to give coumarin-3-carboxylic acids <03TL1755>. 3-Cyanocoumarins, and thus the 3-carboxylic acids, are available in high yield from a Knoevenagel reaction between salicylaldehydes and malononitrile in water <0382331>. 3-Chlorocoumarins result from the cathodic reduction of trichloroacetyl esters of o-hydroxyacetophenones <03T9161>. 

Knoevenagel reactions between triethyl phosphonoacetate and salicylaldehyde or its derivatives (Scheme 11)(r1 = H or Br, = H, OMe or OEt) in the presence of piperidine acetate/ -alanine in refluxing toluene resulted in condensation followed by cyclization to give 3-coumtuinylphosphonic esters, reducible to the dihydro derivatives. 

Reaction of salicylaldehydes (488) with the tetraethyl ester of methylene-bisphosphonic add (489), under Knoevenagel reaction conditions, has provided the corresponding l,2-benzoxaphosphorin-3-phosphonates (490) in good yields. The [3 -I- 2] regio- and stereoselective cycloaddition reaction of (490), (491) and (492) with ethyl diazoacetate produced the corresponding epiineric pyrazoline bisphosphonate tetraethyl esters (Scheme 125). ... 

The Knoevenagel reaction has been carried out between aldehydes and acetonitrile in water. Thus, salicylaldehydes react with malononitrile at room temperature in the heterogeneous aqueous alkaline medium to give... 

Ethyl cyanoacetate in the presence of piperidine may also be used as the carbanionic component in reactions with salicylaldehyde. The initial Knoevenagel condensation is followed by a [l,7]-sigmatropic shift and cyclization to the 2-iminochromene derivative which adds another cyanoacetate molecule (67AP1). 

Quaternary ammonium hydroxides anchored on MCM-41 provide stronger base catalysts than amine analogues11731 and were able to catalyse the same reaction as previously reported namely for the intermolecular Michael reaction leading to flavanone.[181] Moreover, this catalyst induced the successive intramolecular olefinic attack of the phenolic group from the Knoevenagel condensation product of salicylaldehyde and diethyl glutaconate (Scheme 9.6). This fast cyclization leads to chromene derivatives (1) from which subsequent conversions induced by proton abstraction from the alpha position of the ester function gives coumarin... 

Usually the Knoevenagel condensation yields the unsaturated product, but, with appropriate aldehydes, 3-hydroxymalonates can be isolated.62 The unusual formation of an a-naphthol (74) has been reported from the reaction of diphenylacetaldehyde (73) with diethyl malonate under Knoevenagel conditions.115 Condensation of salicylaldehydes and other aromatic o-hydroxy aldehydes with malonates is still in use for the synthesis of the corresponding coumarin-3-carboxylic esters (75).3<116-118 Reduction... 

A variety of 2-substituted 2//-chromenes can be obtained from the facile reaction of 2-hydroxybenzaldehydes with vinylboronic acids in ionic liquid solvents <04SL2194>. In a one-pot sequence also in an ionic liquid, a Knoevenagel condensation between O-prenylated salicylaldehydes and 4-hydroxycoumarins is followed by an intramolecular hDA reaction to yield ci5-fused chromano[4, 3 4,5]pyrano[3,2-c]coumarins e.g. 20 small amounts of the corresponding chromone are also formed <04S1783>. In like manner, cii-fused furopyranopyran derivatives have been obtained from sugar aldehydes <04TL3493>. 

The synthesis of pentacyclic indole derivatives, 9-phenyl-9,13c-dihydro-6//-chromeno[4, 3 4,5]-thiopyrano[2,3-( ]indoles (Scheme 2.3), has been achieved via domino Knoevenagel-hetero-Diels-Alder reactions of indolin-2-thiones and O-propargylated salicylaldehyde derivatives in the presence of 10 mol% of ZnO as a heterogeneous catalyst in CH3CN (Kiamehr and Moghaddam 2009). When the... 

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