Knoevenagel condensation, coumarin

Watson BT, Christiansen GE (1998) Solid phase synthesis of substituted coumarin-3-carbox-ylic acids via the knoevenagel condensation. Tetrahedron Lett 39 6087-6090... 

Song A, Wang X, Lam KS (2003) A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum s acid with ortho-hydroxyaryl aldehydes or ketones. Tetrahedron Lett 44 1755-1758... 

In the second investigation [34], involving a coumarin synthesis by Knoevenagel condensation, supported by rate constant measurements and activation energy calculations, it was found that the effect of MW was more important when the reaction was conducted in xylene - it was noticeably reduced in ethanol (Eq. (5) and Tab. 3.3). 

Elaboration of the side-chain of the salicylaldehyde (376) coupled with a Knoevenagel condensation enabled a number of naturally occurring coumarins such as xanthyletin (377) to be prepared (71CJC2297). The use of C-labelled malonic acid leading to coumarins labelled at C-3 enhances the potential of this route. 

Bogdal, D., Coumarins fast synthesis by knoevenagel condensation under microwave irradiation, /. Chem. Res. (S), 1998, 468-469. 

Keywords Meldrum s acid, o-vanillin, Knoevenagel condensation, 3-carboxy-coumarin... 

Keywords hydroxybenzaldehyde, ethyl acetate, Knoevenagel condensation, microwave irradiation, coumarin... 

Attempted Knoevenagel condensation of the coumarin aldehydes 1 using piperidine as base led in a number of cases to formation of significant amounts of Mannich-type products 2 (R2,R3 =... 

In practise a Knoevenagel condensation reaction yields coumarin 9.16 directly, without isolation of diester 9.17. The mechanism is shown below. ... 

Horing, E.C. et al. (1955). Organic synthesis, Coll. Vol. Ill, 165 (experimental details of a Knoevenagel condensation to give a coumarin ester). 

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... 

Solventless, Microwave-Assisted Synthesis of Coumarins via a Tandem Knoevenagel Condensation and an Intramolecular Nucleophilic Acyl Substitution... 

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... 

A basic ionic liquid, l-butyl-3-methyl imidazolium hydroxide, [bmImjOH, was found to catalyze the Knoevenagel condensation of aliphatic aldehydes and ketones with active methylene compounds elSciently in the absence of any organic solvent (Scheme 5.58). Coumarins have been obtained in one step from the reaction of o-hydroxy aldehydes following this procedure. ... 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

The general approach can be enlarged and conditions for condensation made milder by the use of further-activated esters, thus condensation with methyl nitroacetate produces 3-nitro-coumarins, condensations with Wittig ylides " allow orffto-hydroxyaryl ketones to be used ° and the use of diethyl malonate (or malonic acid ) (a 3-ester can be removed by hydrolysis and decarboxylation ), malononitrile, ethyl trifluo-roacetoacetate, or substituted acetonitriles in a Knoevenagel condensation, produces coumarins with a 3-ester, 3-trifluoroacetyl, " 3-cyano, or 3-alkyl or -aryl substituent. Condensation with IV-acetylglycine generates 3-acetylamino-coumarins. ... 

Usually the Knoevenagel condensation yields the unsaturated product, but, with appropriate aldehydes, 3-hydroxymalonates can be isolated. The unusual formation of an a-naphthol (74) has been reported from the reaction of diphenylacetaldehyde (73) with diethyl malonate under Knoevenagel conditions." Condensation of stdicyl dehydes and other aromatic o-hydroxy aldehydes with malonates is still in use for the synthesis of the corresponding coumarin-3-carboxylic esters (75). - " 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 classical Pechmann approach for synthesis of coumarins via the microwave-promoted reaction [75] has been extended to a solvent-free system in which salicyl-aldehydes undergo Knoevenagel condensation with a variety of ethyl acetate derivatives in the presence of piperidine to afford coumarins (Scheme 8.23) [76]. 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

In a review on the intramolecular DA reaction as a key step in tandem or sequential processes, versatile syntheses of tetrahydro-2H-pyrans, chro-mans, heterocycle-fused 2H-benzopyrans and related compounds were considered (14T2857). Although many examples of the synthetic methods of O- and S-6-membered heterocycles are based on the tandem use of the Knoevenagel condensation and a hDA reaction, a review described only domino reactions with Knoevenagel condensation as a step and without the DA step in the synthesis of several types of chromones and coumarins (14T551) and of only coumarins (14SC2756). 

Nanoparticulate ZnO was used as an efficient catalyst for the synthesis of cou-marins (84) by the reaction of o-hydroxy benzaldehydes (82) and 1,3-dicarbonyl compounds (83) via Knoevenagel condensation under microwaves and thermal conditions (Scheme 9.24) in moderate to excellent yields (Kumar et al. 2011). This protocol differs from the previous methods for the synthesis of coumarins (84) in terms of simplicity and effectiveness. The application of ZnO/MgO in ionic liquid [bmim] [BF4] was carried out successfully for the synthesis of 4//-pyrans (85) and coumarins (88) at ambient temperature via Knoevenagel condensation reaction of aldehydes (8) or 2-hydroxybenzaldehyde derivatives (86) with active methylene compounds (16, 43, 87) (Schemes 9.25 and 9.26) (Valizadeha and Azimib 2011). The method has several advantages in terms of mild reaction conditions, reusability of the catalyst, high yields of the products, and short reaction times. In comparison with methods mentioned in the literature for the synthesis of 4F(-pyrans (85) and coumarins (88), this protocol has better yield and eco-friendly advantages. 

Kumar, B.V., Naik, H.S.B., Girija, D. and Kumar, B.V. 2011. ZnO nanoparticle as catalyst for efficient green one-pot synthesis of coumarins through Knoevenagel condensation. J. Chem. Sci. 123 615-621. 

Knoevenagel condensation between aromatic aldehydes and active methylene compounds has also been induced by Lewis acid ionic liquids leading to the generation of electrophilic alkenes as major products. Extension of this methodology to o-hydroxybenzaldehydes resulted in the formation of coumarins (Harjani et al. 2002). 

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