Dienophiles oxazoles

The course of and facility with which the Diels-Alder reaction of oxazoles proceed are dependent on the dienophile structure, the oxazole/dienophile substitution, as well as the reaction conditions. Olefinic dienophiles provide pyridine products derived from the fragmentation of the initial [4 + 2] cycloadducts 2 to provide 3 which subsequently aromatize to provide the substituted pyridines [Eq. (1)]. 

Nitro-2-phenyloxazole 271a undergoes Diels-Alder [4 + 2] cycloaddition with both electron-rich and electron-poor dienophiles to give an oxazoline 273 that may not be isolable due to the facile aromatization to a fused oxazole 274. Examples are shown in Table 8.22 (Scheme 8.77). 

Ring opening of the cycloadducts (172) from oxazoles (171) and dienophiles (XCH=CHY) gives dihydropyridines and frequently pyridines (172 — 173 — 174) entities such as XR3, HR3 or XOH can also be lost in the aromatization of intermediate (173). 

Oxazoles and dienophiles give pyridines in good yield as discussed in Section 3.4.1.10.1. 

The oxazoles and their derivatives have played a variety of fascinating roles in the preparation of new molecular systems. Much of this chemistry stems from their ability to serve as diene components (azabutadiene equivalents) in reactions with a variety of dienophilic agents, to undergo nuclear metallation, to activate attached aryl or alkyl groups to deprotonation (thus functioning as masked aldehydes, ketones or carboxylic acid groups), and to serve as useful electrophiles on conversion to AT-alkylated salts. 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

A synthesis of the furanoeremophilane ( )-ligularone has been accomplished via the intramolecular Diels-Alder reaction of an oxazole with an alkynic dienophile (81JA4611). The lactone (359) was treated with lithium methylisocyanide to yield the oxazole (360). Oxidation of alcohol to aldehyde and reaction of this unstable aldehyde with lithiopropyne gave a 55 45 mixture of diastereomeric alcohols (361). Oxidation of the mixture gave a single alkynic ketone (362) which when refluxed in ethylbenzene afforded the desired furanosesquiterpene (363 Scheme 78). 

Oxazoles with alkynes as dienophiles give furans by a spontaneous fragmentation of the intermediate with loss of a nitrile <74AHC(17)99) (see Section 3.12.3.3). 

The expected adduct (430) from the Diels-Alder reaction of the oxazole (429) with diphenylcyclopropenone could not be isolated (Scheme 145) (70JCS(C)552). Instead the pyran-4-one (431) is obtained, resulting from elimination of acetonitrile. This process is essentially irreversible because the pyranone lacks diene properties and nitriles are poor dienophiles. 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

The primary adducts (156) and (157) of oxazoles with alkenes and alkynes, respectively, are usually too unstable to be isolated. An exception is compound (158), obtained from 5-ethoxy-4-methyloxazole and 4,7-dihydro-l,3-dioxepin, which has been separated into its endo and exo components. If the dienophile is unsymmetrical the cycloaddition can take place in two senses. This is usually the case in the reactions of oxazoles with monosubstituted alkynes with alkenes on the other hand, regioselectivity is observed. Attempts to rationalize the orientation of the major adducts by the use of various MO indices, such as 7r-electron densities or localization energies and by Frontier MO theory (80KGS1255) have not been uniformly successful. A general rule for the reactions of alkyl- and alkoxy-substituted oxazoles is that in the adducts the more electronegative substituent R4 of the dienophile occupies the position shown in formula (156). The primary adducts undergo a spontaneous decomposition, whose outcome depends on the nature of the groups R and on whether alkenes or alkynes have been employed. 

Pathways C and D are less well documented, mainly because oxazoles lacking a 5-alkoxy substituent show reduced reactivity towards the usual dienophiles. An example of reaction C is the formation of 3-hydroxy-2-methylpyridine from 4-methyloxazole and acrylonitrile (equation 13). Dehydrogenation (path D) is rare but proceeds in the presence of a hydride acceptor. Thus 4-methyloxazole reacts with ethyl acrylate in the presence of hydrogen peroxide to give ethyl 3-hydroxy-2-methylpyridine-5-carboxylate in 27% yield (equation 14). 

DielsAlder reactions of oxazoles afford useful syntheses of pyridines (Scheme 80). A study of the effect of substituents on the DielsAlder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with dienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type 394 have been isolated they can also decompose to yield furans (Scheme 81). With benzyne, generated at 0C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g., 395) in essentially quantitative yields. The adducts can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran (Scheme 82). 

Oxazoles are well-investigated compounds. The occurrence, uses, and synthesis of oxazole derivatives have been the subjects of extensive reviews.5 The heterocyclic oxazole unit is seen with various substitution-patterns in a large number of naturally occurring compounds. Furthermore, oxazoles serve as synthetic intermediates leading to many other systems.5 6 7 In this context, oxazoles have seen, for example, numerous applications as "2-azadiene" components in 4+2 cycloadditions with several types of dienophiles. Further transformations of the products then lead to a number of other nitrogen- or oxygen-containing heterocyclic products.6... 

Five-membered heteroaromatic systems that possess an electron-deficient azadiene substructure, e.g., oxazoles and thiazoles, are suitable for participation in Diels-Alder reactions with inverse electron-demand [49JA3062 59JA4342 62AG(E)329]. The introduction of strongly electron-donating substituents in many cases is sufficient to overcome the electron-deficient nature of the azadiene moiety and permits normal HOMO diene/ LUMO dienophile controlled Diels-Alder reactions (87MI6). 

Acetylenic dienophiles react with oxazoles to provide furans, which arise from the retro Diels-Alder reaction with loss of RCN from the initially formed alkyne/oxazole Diels-Alder adduct. Olefinic dienophiles and oxazoles react to give pyridine derivatives resulting from a fragmentation of the initial [4 + 2] cycloadducts with subsequent aromatization. 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

Oxazoles are anodier class of heteroaromatic dienes which readily undergo Diels-Alder reactions with benzynes. For example, slow, simultaneous injection of solutions of triazole (483) and lead tetraacetate to a solution of oxazole (515) in CH2CI2 at 0 C afforded cycloadduct (516) in essentially quantitative yield. The latter is a convenient source for the unstable isobenzofiiran (517), which can be trapped by [4 + 2] cycloaddition to a variety of dienophiles, e.g. by -methylmaleimide (Scheme 121). 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

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