Chromone-2-carboxylic acids reactions

Chromone-2-carbaldehyde, 3-methyl-synthesis, 3, 709 Chromonecarbaldehydes Knoevenagel condensation, 3, 711 Chromone-3-carbaldehydes mass spectra, 3, 615 oxidation, 3, 709 reactions, 3, 712 Schiff bases, 3, 712 synthesis, 3, 821 Chromone-2-carbonyl chloride Grignard reaction, 3, 711 Chromonecarboxamide, N-tetrazolyl-antiallergic activity, 3, 707 Chromone-2-carboxylic acid, 3-chloro-ethyl ester... 

Grignard reaction, 3, 711 Chromone-2-carboxylic acid, 7-phenyl-ethyl ester reduction, 3, 704... 

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

The reaction of chromone-2-carboxylic acid with thionyl chloride or phosphorus halides gives the trihalide (400). This compound readily loses one of its geminal chlorine atoms and with water, for example, affords 4-chlorocoumarin through the simultaneous loss of carbon monoxide (Scheme 131) (63JGU1806). 

The reaction between a phenol and an unsaturated carboxylic ester has been widely used for the synthesis of chromone-2-carboxylic acids (00JCS1119,1179). There is little restriction on the substituents which may be present in the phenol and the necessary basic conditions have been achieved in various ways. 

Dimethylamino)vinyl)chromones 813 undergo a [2+2] cycloaddition reaction with DMAD to form the intermediate 814, which rearrange to afford xanthones in modest yield (Scheme 229) <1997J(P1)2167, 1999J(P1)3005>. ( )-2-(2-(Dimethylamino)vinyl)chromones 813 can also react with iV-phenylmaleimide 815 and chromone-3-carboxylic acid 816 to afford xanthones in modest yield (Scheme 230) <1997J(P1)2167, 1999J(P1)3005>. 

The reaction between the acid chloride of chromone-2-carboxylic acid and ethyl ethoxymagnesioacetoacetate probably leads to the expected fi-diketone which enolizes and cyclizes spontaneously to spirofuranone(52).127 A different approach was made by Hungarian workers in their synthesis of tachrosin (53), an unusual kind of flavone isolated from Tephrosia poly-stachyoides and one of the earliest natural furanones to be isolated. They subjected an unsaturated ketone (Scheme 32) to oxidative rearrangement by thallium(III) salts, a reaction well known in chalcone chemistry, and eliminated methanol from the product to obtain the necessary starting material.128... 

The acid chlorides of several chromone-2-carboxylic acids have been used in the Freidel-Crafts reaction to prepare 2-aroyl-chromones which were pharmacologically active.Decarboxylation of a heterocyclic acid is often a facile reaction but removal of an aldehyde group is unusual. Chromone-3-carboxaldehyde (156) has been decarbonylated by heating with piperidine to give the acrylophenone (157), which cyclized again, with loss of piperidine and one carbon atom. ... 

Similar results have been obtained for some reactions between phosphite triesters and the chlorides from heterocyclic carboxylic acids. The first of these to be reported were for the pyridinylcarbonyl chlorides. Here, 270 from 2-pyridinylcarbonyl chloride, and 271 from the 3- and 4-pyridinyl chlorides, were obtained presumably via the betaines Similarly, the acylphosphonate 274, from 273, reacted with more trialkyl phosphite (R = Me or Et), possibly via structures 275 and 276 (together with, in the latter case, the geometrically isomeric form) to give the isolated products, 277 and 278 (again as geometric isomers) With 4,4-dichloro-4//-benzopyran-2-ylcarbonyl chloride, a similar mechanism was postulated but with the loss of one chlorine atom (as in 279) to restore electron redistribution within the chromone system" the E structure was confirmed by X-ray crys-tallography ... 

Cyanochromone exhibits high stereoselectivity in [4+2]-cycloaddition reactions with electron-rich dienes which lead to partially reduced xanthones <97JOC7904>. The dienamine (44) affords xanthones on reaction with N-phenylmaleimide and with chromone-3-carboxylic acid through loss of dimethylamine from the [4+2]-cycloadduct. However, more reactive dienophiles such as DMAD undergo a [2+2] cycloaddition followed by an intramolecular [4+2] reaction to give the xanthone (Scheme 13) <97JCS(P1)2167>. 

Replacement of a pyrone thioxo by an oxo group has been described [63] but no yield is given. The process consists of heating the thioxo compound under reflux for 10 hours with a mixture of acetic and dilute sulphuric acids. Heating chromone-2-carboxylic acid with phosphorus pentasulphide at 110°C reverses this reaction [63]. 

MeO, R = Me, R = H) have been prepared in moderate yields by oxidation of the benzopyrano[3,2-c]coumarins (32) to the chromones (33) whose lactone group was then simultaneously hydrolysed and methylated [121], The methyl ester (31, R = Me) of the flavone-3-carboxylic acids was obtained when sufficient dimethyl sulphate was present. By a similar sequence of reactions, a 5,6-benzo-homologue of the 3-carboxylic acid ester was prepared. 

Until recently, no mass spectrometric study had been made of chromone-2-carboxylic acids or esters. The technique was first applied to this class of compounds by Holmberg, Malmstrom and Blom [144] in an attempt to identify the product formed from the reaction of ethyl chromone-2-carboxy-late with an aryl magnesium bromide. Elemental analysis and infrar spectroscopy showed that the product had structure (46) or (47). N.M.R. spectroscopy would now enable these two structures to be distinguished but the Scandinavian workers used mass spectrometry to produce evidence for structure (46). The fragmentation pattern is summarised in Figure 2.8. 

Reactions—Esters of chromone-2-carboxylic acids readily undergo transesterification in the presence of a trace of alkali or sodium methoxide [36]. Thus, when the chromone ester (49) is hydrogenated in the presence of Raney nickel and using methanol as solvent, transesterification occurs to give the methyl ester (50). The ethyl ester (49) is quantitatively converted into the corresponding methyl ester (51) on standing over a small amctunt of Raney nickel or sodium methoxide in methanol [36]. 

The products of catalytic reduction of chromone-2-carboxylic acids or esters depend partly on the catalyst used, the amount of hydrogen present and the conditions of reaction. Ethyl chromone-2-carboxylate is reduced (in 86 per cent yield) to the corresponding chromanone in the presence of Raney nickel and hydrogen at a pressure of 50 Ib/in [184]. The 5-hydroxy analogue is similarly reduced at 80°C and 30 Ib/in in 44 per cent yield [8]. A nitro group on the benzene ring is more readily hydrogenated than the pyrone double bond (10 atmospheres, platinum-charcoal or palladium-charcoal catalyst) [24,40]. 

Deactivation of C-3 by the carboxyl group at C-2 prevents attack by electrophiles, for example, the Mannich reaction results in substitution at C-3 in many chromones [16] but not with chromone-2-carboxylic acid or ester. Radical (homolytic) chlorination of the ester or nitrile using sulphuryl chloride and a trace of benzoyl peroxide gives the 3-chloro derivative (84) [57, 149, 167]. 

There is no record of a successful Friedel-Crafts acylation of a chromone-2-carboxylic acid the 6-acetyl acid was prepared from 2,4-diacetyl phenol and the acetyl group undergoes the usual Mannich and Claisen reactions [32]. 

Chlorocoumarin may be prepared by the reaction of chromone-2-carboxylic acid with thionyl chloride [169] or oxalyl chloride [55]. 4,4-Dichlorochromen-2-carbonyl chloride which is formed first, reacts with water to give a 91 per cent yield of 4-chlorocoumarin (92) with simultaneous release of carbon monoxide [161]. 

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