Coumarin-3-carboxylic acid synthesis

Coumarin brightening agents, 1, 339-340 Coumarin-4-carboxylic acid methyl ester synthesis, 3, 806 synthesis, 3, 809... 

Coumarin-3-carboxylic acid, 6-nitro-ethyl ester reduction, 3, 691 Coumarinic acid synthesis, 3, 685 Coumarinoisocoumarin synthesis, 3, 834 Coumarins acetoxylation, 3, 680 acylation, 3, 689 annelated... 

Bigi F, Chesini L, Maggi R, Sartori G (1999) Montmorillonite KSF as an inorganic, water stable, and reusable catalyst for the knoevenagel synthesis of coumarin-3-carboxylic acids. J Org Chem 64 1033-1035... 

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... 

Kwakman et al. [65] described the synthesis of a new dansyl derivative for carboxylic acids. The label, N- (bromoacetyl)-A -[5-(dimethylamino)naphthalene-l-sulfonyl]-piperazine, reacted with both aliphatic and aromatic carboxylic acids in less than 30 min. Excess reagent was converted to a relatively polar compound and subsequently separated from the derivatives on a silica cartridge. A separation of carboxylic acid enantiomers was performed after labeling with either of three chiral labels and the applicability of the method was demonstrated by determinations of racemic ibuprofen in rat plasma and human urine [66], Other examples of labels used to derivatize carboxylic acids are 3-aminoperylene [67], various coumarin compounds [68], 9-anthracenemethanol [69], 6,7-dimethoxy-l-methyl-2(lH)-quinoxalinone-3-propionylcarboxylic acid hydrazide (quinoxalinone) [70], and a quinolizinocoumarin derivative termed Lumarin 4 [71],... 

The formation of 2-oxopyran-5 -carboxylic acid (coumalic acid) from 2-hydroxybutanedioic acid (malic acid) is described in detail (63OSC(4)20l) and involves the decarbonylation and dehydration of the hydroxy acid. The formylacetic acid so formed then undergoes selfcondensation. This synthesis is an example of the Pechmann reaction usually associated with the synthesis of coumarins (benzopyran-2-ones). It will be observed that this route leads to pyran-2-ones which carry identical substituents at the 4- and 6-positions. 

The synthesis consists of heating a mixture of the o-hydroxybenzaldehyde with the sodium salt and anhydride of a carboxylic acid, usually acetic acid. Generally, a temperature in the range 150-200 °C is required and a prolonged reaction time is often necessary. A 1 2 molar ratio of aldehyde to anhydride gives optimum yields of coumarin (Scheme 124). 

Song, A. M. Zhang, J. H. Lam, K. S. Synthesis and reaction of 7-fluoro-4-methyl-6-nitro-2-oxo- 2H l-benzopyran-3-carboxylic acid A novel scaffold for combinatorial synthesis of coumarins. J. Com. Chem., 2004, 6(1) 112-120. 

Li et al. [30] gave the solvent free synthesis of 2-aryl-5-(coumarin-3 -yl)-l,3,4-oxadiazoles (xxv) in high yields by reacting the coumarin-3-carboxylic acid (xxiii) with (un)substituted benzoic acid hydrazides (xxiv) in presence of PEG supported dichlorophosphate under microwave irradiation. 

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... 

Boehm [363] has described for the first time the synthesis of oxygen-bridged tetrahydropyridones by a three-component condensation among coumarin-3-carboxylic acid, ketones, and primary amines. A solid-phase version of this reaction has recently been reported [364]. 1,3-Propylenediamine was immobilized onto chloro-trityl polystyrene resin (loading of 0.65 mmol g ). The supported amine (470) was then treated with coumarin-3-carboxylic acid and 8 different ketones in NMP/THF... 

A fluorine atom adjacent to a carbonyl group in a benzenoid compound is labile, as is exemplified in the synthesis of a coumarin from 2-fluorobenzaldehyd and a reactive methylene-containing carboxylic acid. 

The Perkin reaction involves the condensation of a carboxylic acid anhydride and an aldehyde in the presence of a weak base, often the sodium or potassium salt of the acid or triethylamine, to give unsaturated carboxylic acids (equation 1). The first example of this reaction was described by Perkin in 1868 and involves a synthesis of coumarin by heating the sodium salt of salicylaldehyde with acetic anhydride (equation 2). The reaction is generally applicable only to aromatic aldehydes and is particularly useful for the preparation of substituted cinnamic acids, as illustrated by equation (3). ... 

In the course of this reaction, derivatives of coumarin-3-carboxylic acid are produced. This synthesis proceeds under much milder conditions than the condensation based on the Perkin reaction which involves condensation of salicylaldehydes with acetic anhydride/acetate. 

The synthesis of Coumarin-3-carboxylic acid is often accomplished in two steps, namely (i) Preparation of 3-Carbethoxycoumarin, and Hi) Preparation of Coumarin-3-carboxylic acid. 

FIGURE 11.83 Solid-phase synthesis of psoralen analogs. (From Song, A., Zhang, J., and Lam, K.S., Synthesis and reactions of 7-fluoro-4-methyl-6-nitro-2-oxo-27f-l-benzopyran-3-carboxylic acid a novel scaffold for combinatorial synthesis of coumarins, J. Comb. Chem., 6,112, 2004 Song, A. et al.. Solid-phase synthesis and spectral properties of 2-alkylthio-6//-pyrano[2,3-/ benzimidazole-6-ones a combinatorial approach for 2-aUcylthioimidazo coumarins, J. Comb. Chem., 6, 604, 2004 Song, A. and Lam, K.S., Parallel sohd-phase synthesis of 2-arylamino-6H-pyrano [2,3-f] benzimidazole-6-ones, Tetrahedron, 60, 8605, 2004.)... 

B. T. Watson, G. E. Christiansen, Solid phase synthesis of substituted coumarin-3-carboxylic acids via the Knoevenagel condensation. Tetrahedron Lett. 1998, 39, 6087-6090. 

The major part of this review concerns chromones which possess a carboxyl or related group at C-2 but a few derivatives of the 3-carboxylic acids are known and discussed. Compounds in which the heterocyclic oxygen or the pyrone carbonyl oxygen is replaced by sulphur are also mentioned. The chemistry of chromones has been reviewed up to 1948 [1] and a survey (without references) of the synthesis of coumarins and chromones of therapeutic interest appeared in 1970 [2], Naturally-occurring chromones are covered in a chapter of a book by Dean [3]. The chromone-2- and -3-carboxylic acids have not been reviewed previously, although an early review of chromones [4] contains a short section on chromone carboxylic acids. 

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) ... 

Trkovnik M, Ivezic Z (2000) Synthesis of some new coumarin-quinolone carboxylic acids. J Heterocycl Chem 37 137-141... 

Back to our tenacity and purpose, he reported the synthesis of coumarins from the reaction of phenols with a carboxylic acid or ester containing a /1-carbonyl group (Scheme 1). 

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