2-Pyrone-2-carboxylate

Both 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5 can also be prepared from 2-pyrone-3-carboxylic acid 40 and coumalic acid 39 in one step, albeit in moderate yields, utilizing the same protocol, varying only the equivalents of NBS employed in the reaction (Scheme 14). 

With bromine, 2-pyrone forms an nnstable addnct that gives the substitution product 3-bromo-2-pyrone on warming," however this can also be obtained satisfactorily by bromodecarboxylation of 2-pyrone-3-carboxylic acid coumalic acid (2-pyrone-5-carboxylic acid) gives 5-bromo-2-pyrone"" or 3,5-dibromo-2-pyrone" (See also 11.2.2.3 and 11.4.2 for syntheses of halo-2-pyrones). 

The MS-free BINOL-Ti complex 21 catalyzes the inverse-electron-demand Diels Alder reaction of methyl 2-pyrone-3-carboxylate (23) with vinyl ethers 24, yielding adducts 25 in 95-98% ee and excellent yields39. The adducts are converted into an important synthon for la-hydroxyvitamin D3. 

This ability of ethyl and methyl l//-azepine-l-carboxylate to participate as an enophile and a dienophile is demonstrated in a further report describing their reactions with methyl pyrone-3-carboxylate and its 5-isomer <84BCJ3483>. On heating at 80°C for 68 hours, methyl 1/f-azepine-l-carboxylate and the pyrone-3-isomer yielded the [2 + 4]7t adduct (23) and the azepine [6 + 4]tc dimer. Under similar conditions ethyl 1/f-azepine-l-carboxylate and the corresponding pyrone-5-isomer gave a mixture of the [2 + 4]7t and [6 + 4]7t adducts (24) and (25) in yields of 25% and 20%, respectively. At 110°C the products consisted of the azepine [6 + 6[n dimer and a small amount of 3-ethyl 7-methyl 3/7-3-benzazepine-3,7-dicarboxylate (26), arising from (24) by extrusion of carbon dioxide. In a further reaction the same authors have demonstrated the formation of (27) by reaction with tetrachlorocyclopentadienone dimethyl acetal. 

Treatment of 2-bromo-6-hydfoxymethyl-3-methoxy-4-pyrone with aqueous ammonia or aqueous methylamine gives 4-hydroxy-2-pyridones. 6-Chloro-4 hydroxy-2-pyrone-3-carboxylic acid and m-anisidine give iV,Mdi-m-methoxy-phenylacetonedicarboxamide, which can be converted to 4-hydroxy-iV-(m-methoxyphenyl)-6-(OT-methoxyanilino)-2-pyridone (XII-258) by heating with phosphorus oxychloride. ... 

The ethyl 6-(trifluoromethyl)-2-pyrone-3-carboxylate (61) was prepared by condensation of trifluoroacetone with diethyl ethoxymethylenemalonate, followed by cyclization of intermediate diethyl p-acylethylidenemalonate. This pyrone was used for the preparation of cage derivatives to explore their usefulness as antiviral agents. Reaction of 61 with ethylene at high pressure afforded ester 62. Hydrogenation of 62 yielded the corresponding alkyl bicyclo[2.2.2]octane-l-carboxylate, which was hydrolyzed to 63. The latter was converted into bicyclo[2.2.2]octan-l-amine hydrochloride 64 via the Schmidt reaction [29] (Scheme 21). 

In addition decarboxylation of the (2 + 4)-adduct occurs to give a diene that is trapped as (175) by a second addition of maleimide. A further report by the same group states that the cycloaddition of maleimides with 2-pyrone carboxylates in the solid-state yields endo adducts. This is in contrast to the sensitized cycloaddition that leads exclusively to the exo products. 

The intramolecular reaction oF allcenes with various O and N functional groups offers useful synthetic methods for heterocycles[13,14,166]. The reaction of unsaturated carboxylic acids affords lactones by either exo- or endo-cyclization depending on the positions of the double bond. The reaction of sodium salts of the 3-alkenoic acid 143 and 4-alkenoic acid 144 with Li2PdCl4 affords mostly five-membcrcd lactones in 30-40% yields[167]. Both 5-hexe-noic acid (145) and 4-hexenoic acid (146) are converted to five- or six-mem-bered lactones depending on the solvents and bases[168]. Conjugated 2,4-pentadienoic acid (147) is cyclized with Li2PdCl4 to give 2-pyrone (148) in water[i69]. 

The base-promoted ring contraction of 3-bromo-2-pyrones to 2-furoic acids cf. Scheme llOd) is a well exemplified reaction 01CB1992,69JCS(C)1950,73JCS(P1)1130> which has also been applied to the obtention of benzofuran-2-carboxylic acids frorn 3-bromocoumarins 08CB830,70KGS(S2)166), Similar base treatment of 3-amino-2-pyrones provides pyrrole-2-carboxylic acids (Scheme IlOe) 75JHC129). 

The straightforward construction of substituted pyrone 4 proceeded as follows (see Scheme 6c). Alkylation of the monoanion of 2,4-pentanedione (8) with methyl iodide furnishes 3-methyl-2,4-pentanedione. Conversion of this substance into the corresponding dianion with sodium amide followed by selective carboxylation of the more basic site provides intermediate 7. Pyrone 4 is obtained after cyclization with l,l -carbonyldiimidazole and methylation of the resulting enol with dimethyl sulfate. 

The only example of the preparation of a benzazepine from a l//-azepine involves the loss of carbon dioxide from the initially formed [4 + 2] cycloadduct of methyl 2-pyrone-5-carboxylate (8) with ethyl l//-azepine-l-carboxylate (7).106 3-Ethyl 7-methyl 3//-3-benzazepine-3,7-dicar-boxylate (9) is formed as the minor product along with the [6 + 6] 7i-dimer 10 of the l//-azepine. 

Dihydro-2f/-pyran-2-one has been prepared by reductive cycliza-tion of 5-hydroxy-2-pentynoic acid [2-Pentynoic acid, 5-hydroxy-], which is obtained in two steps from acetylene [Ethyne] and ethylene oxide [Oxirane] 3 and by the reaction of dihydropyran [277-Pyran, 3,4-dihydro-] with singlet oxygen [Oxygen, singlet].4,5 2ff-Pyran-2-one has been prepared by pyrolysis of heavy metal salts of coumalic acid [2//-Pyran-5-carboxylic acid, 2-oxo-],8 by pyrolysis of a-pyrone-6-carboxylic acid [211 - Pyran-6-carboxyl ic acid, 2-oxo-] over copper,7 and by pyrolysis of coumalic acid over copper (66-70% yield).8... 

Whole cells of Rhodococcus opacus strain Icp were used to study the metabolism of fluorophenol isomers (Finkelstein et al. 2000), in which both fluorocatechols and fluoro-pyrogallols were produced (Figure 9.35a). Both 3- and 4-fluorophenol produced 5-fluoro-pyrogallol, which was transformed into 2-pyrone-4-fluoro-6-carboxylate (Figure 9.35b). 

Ring contractions of pyran derivatives are occasionally valuable. The contraction of 3-halo-2-pyrones to 2-furoic acids under the influence of alkali has been studied and the conditions defined.58112113 The method is adaptable to the preparation of 3-furoic acid via furan-2,4-dicarboxylic acid58 and of 3,4,5-triphenylfuran-2-carboxylic acid.113 Another ring contraction involving halides is the conversion of 4-chloromethylpyrylium salts into furylmethyl ketones as indicated in Scheme 21.114 Pyridine oxides may be transformed with unexpected ease into furans through treatment with a thiol (Scheme 22).115... 

Scheme 6.108 Products ofthe interception of 1,2,4,6-cyclohepta-tetraene (5) with 1,3-diphenylisobenzofuran, anthracenes, 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dien-l-one, methyl 2-pyrone-5-carboxylate, tropones, 8,8-dicyanoheptafulvene and 1,3,5-cycloheptatrienes.

Diynes have already been used for building polycylic compounds in the presence of CO2 and a stoichiometric amount of Ni(0) bicyclic pyrones were obtained [117]. With the electrocarboxylation method, linear or cyclic mono-carboxylic acids were obtained as main products from non-conjugated diynes depending on the ligand associated to Ni [118, 119]. Thus ring-fomation occurred with the Ni-bipyridine complex at normal pressure of CO2 on the other hand, in the presence of PMDTA as ligand and with a 5 atmosphere pressure of CO2, linear adducts were mainly formed as illustrated in Eq. (16) ... 

The second example described here is dormant seeds from Rosa canina. Extracts of these seeds also inhibit germination of seeds of several plants (10). In Figure 5 a scheme is given for extraction and separation oF"three different inhibitor compounds. All these are present in the acid fraction. The first essential step is chromatography on Sephadex LH-20, which separates inhibitor I from inhibitor II and III. Inhibitor I was identified as abscisic acid. The other two inhibitors were separated by methylation with diazomethane, fractional distillation, and column chromatography. The second inhibitor is the a-pyrone 1 . Reaction with diazomethane transforms it into the bi-cyclic compound 19. This bicyclic compound is even more active than the parent a-pyrone 1 . Since we sought structural requirements for bioactivity here also,we tested several synthetic a-pyrones ( 0 - 22) for bioactivity. These compounds had no inhibitory activity. We alio tested the cyclopropane derivatives 23 and 24 In Table II, the bioactivity of the bicyclic compound T9 and two such derivatives is compared. The presence of several carboxylic acid groups seems to be essential (or at least helpful) for bioactivity in this case also. 

Kraut, L. et al., Carboxylated a-pyrone derivatives and flavonoids from the liverwort Dumortiera hirsuta. Phytochemistry, 42, 1693, 1996. 

Pyridine, pyrone and pyridone carboxylic acids undergo decarboxylation when heated, and the general order of reactivity is a > y > p. In pyridine, the carboxylic acids, as expected, exist mainly in the zwitterionic forms and decarboxylation of the a and y isomers under fairly mild conditions is a consequence of the relative stability of the ions of the type (48). 

The Lewis acid-mediated condensation reaction of a,/3-unsaturated carboxylic acids with 4-hydroxy-2-pyrones has been utilized to prepare Fleischmann s a,a-bispyrone 2 and Praill s a,7-bispyrone 3 and confirm their assignments <2000TL1901>. 

Attempts to effect cycloadditions with a-pyrone as the diene system failed (78JOC315). However, the more electron-deficient a-pyrone-5- (or 6-) carboxylates add slowly (5 days in boiling toluene) to the l//-azepine to furnish a mixture of the [2+4]7t (25%) and the [6 + 4]7r (20%) adducts (153) and (154) respectively. On prolonged heating (7 days) in toluene solution adduct (153) extrudes CO2 to form the benzazepine (155 R1 = CC Me R2 = Et) <78H(11)401). 

The cumulation reactions, which start from carboxylic acids and esters usually lead to the formation of pyrone derivatives. Methyl (Z)-3-iodoacrylate and 3-hexyne gave, for example, 5,6-diethyl-2-pyrone in acceptable yield (4.38.). Inclusion of the acrylate into a six membered ring starting from ethyl 2-bromocyclohexen-l-carboxylate, led to a condensed ring system, giving a partially reduced isocoumarin derivative.50... 

The analogous open chain carboxylic acid, Z-non-2-en-4-ynoic acid, when treated with 4-iodoanisole in the presence of a palladium-triphenylphosphine catalyst and potassium carbonate gave a mixture of three products, two of which were isolated (4.41.) z) the pyrone derivative arising from the attack of the anisylpalladium complex at the 4-position, followed by ring closure //) the furane derivative (major product) arising from the... 

Bromo-2-pyrones and 3-bromocoumarins give furan- and benzofuran-2-carboxylic acids by ring fission and subsequent closure, e.g. (228) — (229) (116) or (117) — (230). Pyrone rings are opened by aqueous acid in some cases, probably by successive protonation and attack of a water molecule, e.g. dehydroacetic acid (231) gives (233) which immediately forms (232) or (234) with HC1 or H2S04, respectively. 

Azinecarboxylic acids lose C02 significantly more easily than benzoic acid. Pyridinecarboxylic acids decarboxylate on heating with increasing ease in the order (3 < < y < a. 2-Pyridazinecarboxylic acid gives pyrazine at 200°C, and 4,5-pyrimidinedicarboxylic acid forms the 5-mono-acid on vacuum distillation. Pyrone- and pyridone-carboxylic acids also decarboxylate relatively easily thus, chelidonic acid (680 Z = O) at 160°C over copper powder and chelidamic acid (680 Z=NH) at 260°C give (681 Z = 0, NH). 

---