Isoxazoles Diels-Alder reaction with

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. ... 

Oxazole itself, in contrast to isoxazole, thiazole, and imidazole has been found to undergo Diels-Alder reaction with dienophiles.340 341 Isonicotinic acid esters (182, R = COOR ) and isonicotinonitriles (182, R = CN) are... 

The idea of employing the reaction of a nitroarene or nitroheterocycle with a mtinchnone to synthesize a fused pyrrole ring system has been developed by two groups. Nesi et al. (109) found that mtinchnone 38 reacts with 3-methyl-4-nitroisoxazole (196) and 4-nitro-3-phenylisoxazole (197) to give the corresponding 5//-pyrrolo[3,4-tf]isoxazoles 198 and 199, respectively, in good yield. Presumably loss of carbon dioxide in a retro-Diels-Alder reaction follows loss of nitrous acid. 

A new synthesis of isoxazoles is by successive treatment of a ketoxime with butyllithi-um, the ester of a carboxylic acid and sulfuric acid, e.g. 1 -> 2 (94S989). Hitrovinyl oximes 3 (R1, R3 = alkyl or aryl) undergo oxidative cyclization to isoxazoles 4 by the action of DDQ or iodine/potassium iodide (94JHC861). Flash-vacuum pyrolysis of the 1,3-dipolar cycloadduct 5 of acrylonitrile oxide to norbornadiene results in a retro-Diels-Alder reaction to give cyclopentadiene and 3-vinylisoxazole 6 (94CC2661). 

Other reactions. Microwave irradiation of 3-phenyl-2-isoxazolin-5-one (159) in the presence of KF on alumina, without any solvent, reacted with aromatic aldehydes (160) to afford 4-(arylmethylene) derivatives (161) (Equation (31)) <93SC16>. The fused bicyclic-isoxazoline (162) underwent a thermal retro-Diels-Alder reaction and resulted in a mixture of 3-phenyl isoxazole (163) and norborn-eneadduct (164) (Equation (32)) <90MRC1023>. 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

There are no reports of simple isoxazoles participating in [4 + 2] cycloadditions in which the isoxazole nucleus functions as a heteroaromatic 1-azadiene system. However, one of the early reports of the successful participation of a 1-azadiene system in [4 + 2] cycloadditions does include the Diels-Alder reactions of benzisoxazoles (Chapter 9, Section 1, Table 9-1, entries 1-7).61 An additional report has detailed the participation of substituted 4,5-dihydro-3-vinylisoxazoles in [4 + 2] cycloadditions (Chapter 9, Section 1, Table 9-1, entry 8).62a Isoxazolium salts react with enamines to provide pyridinium salts via a [4+ + 2] reaction (Chapter 9, Section 10).62b... 

Accordingly, the reaction of203 with benzonitrile oxide (204) led to the isoxazolines 205 and 206. Subsequent retro Diels-Alder reaction of 205 afforded the desired pyrrole 207 in 52 % yield by ehmination of the isoxazole 208. The isomeric isoxa-zoline 206 gave the pyrrole If in very low yield [48],... 

Photochemical addition of dimethyl acetylenedicarboxylate to the enamine H2Ca C -NH-CE=>CH2 (E => COOMe) yields the bridged cyclohexene (90), irtiich decomposes at 90 °C in a retro-Diels-Alder reaction to ethylene and the ester (91). The adducts (92 R = PhCO or COOBu ") of perf luorobut-2-yne, CP CHCCF, to N-substituted pyrroles have been degraded to 3,4-bls(trlfluoromethyl)pyrroles (93) by two methods in the former, the adducts were first hydrogenated at the unsubstituted double bond and then heated to eliminate ethylene,idille in the latter, the adducts were treated with mesitonitrile oxide, 2,4,S-Me C H CEN -0, which removed the ethylene unit in the form of the isoxazole (94). ... 

The reactions of isoxazoles differ considerably from those of oxazoles, although both systems are aromatic. The reason for this lies in the relatively weak N-0 bond in the isoxazole molecule, which is cleaved in all ring-opening reactions. Moreover isoxazoles, unlike oxazoles, do not react with dieno-philes to form Diels-Alder adducts [82]. 

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