6-Substituted 2-pyrones

Bromo-2-pyrone is not only a valuable precursor for the synthesis of various 3-substituted 2-pyrones,7 but it is also a reactive unsymmetrical diene.8 3-Bromo-2-pyrone undergoes Diels-Alder cycloadditions with a regioselectivity and stereoselectivity that is superior to that of 2-pyrone. Furthermore, 3-bromo-2-pyrone is a chameleon (i.e., ambiphilic) dienophile, undergoing cycloaddition to both electron deficient and electron rich dienophiles. The cycloadducts of bromopyrone with dienophiles are isolable and are useful in the synthesis of diastereomerically pure cyclohexene carboxylates (Scheme 2).8... 

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. 

Intramolecular [4+4] cycloaddition of 2-pyrones with furans has been studied by West and coworkers (Sch. 39). Irradiation of 172, with a furan tethered to C6 of the pyrone, leads to a mixture of trans 173 and cis 174 [115]. Interestingly, the Cope rearrangement of the cis isomer 174 yields an equilibrium mixture with cyclobutane 175. The effect of a stereogenic center on the tether was also determined in this study. With the furan tethered to C3 of the triflate-substituted pyrone 176, the trans isomer 177 was formed with good selectivity and isolated in very good yield [116]. 

A series of tris(3-hydroxy-4-pyranato)gaUium(in) complexes has been prepared by the neutralization of solutions of GaCls and substituted pyrones (15a-d). The complexes of larixinic acid (15b) and kojic acid (15c) are water soluble but retain their neutral charge. 

Thomas, A. D., Josemin, K. N. N., Asokan, C. V. Viismeier-Haack reactions of carbonyl compounds synthesis of substituted pyrones and pyridines. Tetrahedron 2004, 60, 5069-5076. 

We also found that the C3 carbon of 38 (Scheme 26) can be selectively coupled with various organotin reagents 93 to produce the 3-substituted pyrones 81 in good yields <02TL5779>. 

This chapter focuses on recent advances in the scope, stereocontrol, and synthetic utility of 2-pyrones in Diels-Alder reactions. Special attention is given to the development of new, mild reaction conditions and electronically matched reaction partners which allow isolating the initially formed bicyclic lactone adducts. Relative reactivities and selectivities of differently substituted pyrones are compared. Finally,... 

The [4+3] cycloaddition reaction offers a convenient way to prepare relatively complex seven-membered rings from simple starting materials. Using MBH adducts 352 as C3 component, a phosphine-catalyzed [4 + 3] annulation has been developed to construct the bicyclo[3.2.2]nonadiene skeleton (Scheme 4.112). The reactions proceeds smoothly with various MBH adducts as well as various substituted pyrones 353 such as ester, nitrile and amide substituted pyrones, resulting in compounds 354 in moderate to good yields. 

Comparable to the dienes (see Figure 14) also alkynes may react with carbon dioxide yielding both chain or cyclic products. As shown in Figure 30 a 1 1 reaction should result alkynoic acids or substituted pyrones. As a further possibility Figure 30 shows the hypothetical combination of acetylene and two moles of carbon dioxide giving alky-nedioic acids or pyronic acids. Once again the reactions will be considered according to the transition metal applied. 

Already in 1977 Inoue discovered the reaction of hexynes with carbon dioxide catalyzed by nickel complexes [86]. 1-Hexyne reacted with CO2 in the presence of a nickel/dppe-catalyst to give the butyl-substituted pyrone in 50 % yield (Figure 31). As by-products the oligomers of 1-hexyne were formed. Similar reactions proved to be possible with alkynes containing internal double bonds, such as 3-hexyne and 4-octyne [87,88], giving tetrasubstituted pyrones. Yields up to 60 % could be obtained. 

Asymmetric synthesis of a substituted pyrone was reported by Evans group. They performed a Lewis acid-catalyzed [2 - - 2] cycloaddition... 

Wolf, P.A. Westveer, W.M. (1950) The antimicrobial activity of several substituted pyrones. Arch. Biochem. Vol.28, pp.201-206. 

The cycloaddition reaction can also proceed smoothly with carbon dioxide [143] or isocyanate [144] to yield the corresponding substituted pyrones or pyridones, respectively. 

For the preparation of 4-substituted coumarins, a phenol may be condensed with ethyl acetoacetate under the influence of sulphuric acid. Thus resorcinol (II) readily undergoes this condensation (which is represented diagrammatically above) to give 7-hydroxy-4-methyl-coumarin (III). Note that the coumarins, like all 2 pyrones, are systematically lactones. 

The Pechmaim reaction has found extensive appHcations for the synthesis of numerous coumarin derivatives (39). Coumarin derivatives substituted in the pyrone ring can be obtained by condensing phenol with beta-ketoesters. For example, 4-methylcoumarin (3) is obtained with ethyl acetoacetate... 

The mass spectrum of 2-pyrone shows an abundant molecular ion and a very prominent ion due to loss of CO and formation of the furan radical cation. Loss of CO from 4-pyrone, on the other hand, is almost negligible, and the retro-Diels-Alder fragmentation pathway dominates. In alkyl-substituted 2-pyrones loss of CO is followed by loss of a hydrogen atom from the alkyl substituent and ring expansion of the resultant cation to the very stable pyrylium cation. Similar trends are observed with the benzo analogues of the pyrones, although in some cases both modes of fragmentation are observed. Thus, coumarins. 

The use of trifluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [I/Sj (equation 98)... 

Thiopyrones and selenopyrones can be alkylated more readily than pyrones. Thus 2,6-dimethyl-4/f-pyran-4-thionc (4,6-dimethyl-4-thiopyrone) (23, Y = S) reacts rapidly with methyl iodide yielding a 4-methylmercaptopyrylium iodide (24, Y = S, R = Me, X = I). Many alkylating agents were investigated by King et al. The kinetics of the reaction between 2,6-dimethyl-4-thiopyrone and substituted phenacyl bromides was found to be described by the Hammett... 

So far, this reaction finds application for the conversion of 4-pyrone into 4-substituted pyrylium salts with free a-positions, for which few... 

Propionic acid, 2-iodo-3-nitro-, ethyl ester [Propanoic acid, 2-iodo-3-mtro-, ethyl ester], 65 2//-Pyran, 3,4-dihydro-, 51 2//-PYR AN-2-ONE, 49 2H Pyran 2-one, 5 bromo 5,6-dihydro, 50 27/-PYRAN-2-ONE, 5,6 DIHYDRO-, 49 PYRIDINE, 2,3,4,5 TETRAHYDRO, 118 Pyridines, -substituted, 34 a Pyrone-6-carboxyhc acid [2H Pyran-6-Larboxyhc acid 2-oxo ], 51 Pyrroles, 34... 

Dipoles can be embedded in heterocyclic structures, just as dieneunits are present in pyrones and other ring structures (see p. 491). N-Substituted pyridinium-3-ols can be deprotonated to give 3-oxidopyridinium betaines that have 1,3-dipolar character.142... 

Lia DJ, Mariko K, Hiromitsu T, Sjamsul AA, Norio A. A 6-substituted-5,6-dihydro-2-pyrone from Cryptocarya strictifolia. Phytochemistry 2000 54 989-993. 

Cyclic dienes also react readily with ADC compounds although in many cases the initial adducts are not isolable. 1-Substituted pyrid-2-ones give Diels-Alder adducts with ADC compounds, although 2-pyridone itself gives only the substitution product (e.g., 113).174 2-Pyrone gives a 1 2 adduct with PTAD, since the initial adduct (114) rapidly loses C02 to generate a diene which then reacts with more PTAD.175 The initial adducts of ADC compounds with cyclopentadienones,176 and 3,4-dimethyl-1-phenylphos-phole 1-sulfide (115)177 also regenerate a diene by loss of CO and PhP=S, respectively. 

Coumarins belong to a group of compounds known as the benzopyrones, all of which consist of a benzene ring joined to a pyrone. They may also be found in nature, in combination with sugars, as glycosides. They can be categorized as simple fura-nocoumarins, pyranocoumarins, and coumarins substituted in the pyrone ring (Murray and others 1982). 

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