Knoevenagel condensation, coumarin synthesis

Fig. 2 Representative traditional methods for coumarins synthesis, (a) Perkin synthesis (b) Pechmann-type condensation (c) Knoevenagel-type condensation...

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). 

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

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

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... 

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... 

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]. 

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. 

Chizhov DL, Sosnovskikh VY, Pryadeina MV, Burgart YV, Saloutin VI, Charushin VN (2008) The first synthesis of 4-unsubstituted 3-(trifluoroacetyl)coumarins by the Knoevenagel condensation of salicylaldehydes with ethyl trifluoroacetoacetate followed by chromene-coumarin recyclization. Synlett 2008 281-285... 

Nair and coworkers reported a [2+4] cycloaddition reaction of coumarin quinone methide 59 (generated in situ by Knoevenagel condensation between formaldehyde and 4-hydroxycoumarm 58) with pentafulvenes such as 27, providing a facile synthesis of pyranocoumarins 60 (Scheme 7.14) [16]. A computational study was performed to shed light on the process. 

The Knoevenagel condensation is one of the most useful C-C bond forming reaction in organic synthesis. This reaction is often the key catalytic step in the synthesis of heterocyclic compounds followed by intramolecular hetero-cyclization. Porous catalytic systems have been reported to be in use in the preparation of O-heterocycles through Knoevenagel condensation, particularly in the synthesis of chromenes, coumarins, and xanthenediones. 

Coumarins Aider et al. have recently published the synthesis of coumarins 18 from different substituted salicylaldehydes and ethyl acetoacetate catalyzed by amino-grafted SBA-15 via Knoevenagel condensation followed by a noncatalytic lactonization step (Scheme 10) [70]. Additionally, the authors reported therein a theoretical density fxmctional theory (DPT) study which demonstrated that the amino moiety of methyl aminopropyl/SBA-15 shows a dual acid-base catalytic behavior as H-donor/H-acceptor when used in the synthesis of the coumarins. 

Valizadeh, H. Shockravi, A. Gholipur, H. Microwave assisted synthesis of coumarins via potassium carbonate catalyzed Knoevenagel condensation in l-n-butyl-3-methylimidazolium bromide ioiuc liquid. J. Heterocycl. Chem. 2007,44, 867-870. 

Harishkumar, H. N. Mahadevan, K. M. Kiran Kumar, H. C. Satyanarayan, N. D. A facile, choline chloride/urea catalyzed solid phase synthesis of coumarins via Knoevenagel condensation. Org. Commun. 2011,4, 26-32. 

Cyclocondensation of 2-hydroxybenzaldehydes (saHcylaldehydes) with reactive methylene compounds (malonic esters, cyanoacetic esters, malononitrile) in the presence of pyridine and other bases also leads - via lactonization of the primary condensation product 19 - to derivatives of coumarin-2-carboxylic acid 20 (Knoevenagel synthesis) ... 

Coumarin synthetic routes include Perkin, Knoevenagel, Reformatsky, and Pechmann reactions. Among them Pechmann reaction has been proven to be superior regarding different issues and aspects. Pechmann found that coumarin derivatives are synthesized when the P-ketonic esters are condensed with phenols in the presence of concentrated sulfuric acid. The process and course of this reaction depends on the nature of the phenols, the beta-ketonic esters, and the catalyst. Since then, the use of this superior and practical protocol has become a vibrant area of study, and it has found applications as central strategic choice in the synthesis of an extensive selection of coumarin derivatives. 

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