Isoxazoles Diels-Alder reactions

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

Keywords Diels-Alder reactions of isoxazoles, isoxazolines, isoxazolidines, oxazoles and oxazolines... 

Isoxazole ring systems play an important role in organic synthesis, and 4-nitroisoxazoles have been used as dienophiles in Diels-Alder reactions, as shown in Eq. 8.23.36... 

The gas-phase Diels-Alder reaction between butadiene and ethene follows a synchronous pathway, while the 1,3-dipolar cycloaddition of fulminic acid to ethyne proceeds in a concerted, almost synchronous fashion, in spite of the different nature of the two bonds closing the isoxazole cycle. 

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. 

Furo[3,4-d]isoxazoles have also been used as transients in inter- and intramolecular Diels-Alder reactions (see Section IV). 

Oxazole A is often used as a diene in Diels-Alder reactions. However, isoxazole B appears to be inert. Their different reactivities are surprising, considering that their MOs are similar. Propose an explanation. Bond lengths and strengths CC 1.54 A and 82.6 kcalmoU1 C=C 1.34 A and 144 5 kcalmoU1 CN 1.47 A and 72.8 kcalmol-1 C=N 1.27 A and 147 kcal/mol-1 NO 1.40 A and 48 kcalmol-1.86... 

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). 

Somewhat less dramatic changes are observed for orbital i /4, which undergoes rehybridization that is reminiscent of orbital /6 in the Diels-Alder reaction. Ultimately, the (i /2,i /4) pair describes one of the two new bonds that close the isoxazole ring, as shown in the right-hand column of Figure 5. 

An intramolecular aza Diels-Alder reaction of as well electronically neutral N-aryl imines useful for the synthesis of novel tetrahydropyridine derivatives has been introduced by our group [268]. The reactive intermediate 3-43 exhibiting the 2-aza-l,3-butadiene subunit was generated in situ from the aldehyde 3-41 and the amino isoxazole 3-42 and led directly to the diastereomerically pure cycloadduct 3-44 (Fig. 3-14). In contrast to the reactions studied by Barlu-enga, the 2-aza-1,3-butadiene acts as electron-deficient component in this case. 

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. ... 

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... 

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... 

TTie synthesis of oxepino[2,3-d]isoxazole system from dimethyl acetylenedicarboxylate and substituted furo(3,4-Diels-Alder reaction as the key step (Scheme 27) <91TLI 161). 

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