Diels-Alder oxazole-olefin

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. 

Flassner A., Fischer B. New Chemistry of Oxazoles Heterocydes 1993 351441-1465 Keywords Diels-Alder reactions of oxazoles with olefins or acetylenes, het-erodienophiles... 

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. 

Oxazole Olefin Diels-Alder Reactions Employed in the Total Synthesis of Pyridoxol... 

Thiazoles have been shown to be much more reluctant than oxazoles to participate in Diels-Alder reactions, and only two successful intermolec-ular Diels-Alder reactions have been described. Like oxazoles, olefinic dienophiles provide pyridine products via a Kondrat eva dehydration [Eq. (9)].60... 

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)]. 

Despite the early recognition that heterocyclic azadiene systems are typically electron-deficient,1 little effort has been devoted to the exploration of the potential participation of electron-deficient oxazoles in inverse electron demand (LUMOdiene controlled) Diels-Alder reactions with electron-rich or simple olefinic dienophiles. One study has demonstrated the potential of such investigations (Table 10-1, entry 26).34 Breslow and coworkers have adapted the oxazole olefin Diels-Alder reaction for the preparation of a tetrahydroquinoline-based analog of pyridoxamine with the stereochemically defined placement of a catalytic group [Eq. (2)].37b... 

Since the early demonstrations of the participation of substituted 1,2,4,5-tetrazines and oxazoles in Diels-Alder reactions with olefinic and acetylenic dienophiles, the potential utilization of the [4 + 2] cycloaddition reactions of heteroaromatic systems possessing a suitable azadiene arrangement has been the focus of extensive investigations. In general, the heteroaromatic systems which possess an electron-deficient azadiene... 

That these reactions proceed via the intermediacy of a Diels-Alder cycloaddition adduct has been affirmed by the isolation of a variety of the 1 1 Diels-Alder adducts.For example, the reaction of 5-ethoxy-4-methyloxazole 8 with cis-2,5-dimethoxy-2,5-dihydrofuran 9 provided the isolable endo and exo adducts 10 and 11 respectively, in a 2 1 ratio (Fig. 3.4). Similarly, 5-ethoxy-4-oxazoleacetic acid ethyl ester 12 reacted with maleic anhydride to provide the stable endo and exo adducts 13 and 14, in which the olefin has moved into conjugation with the ester moiety. In this case, compound 13 was the sole product when the reaction proceeded at 10°C, but only the exro-adduct 14 was isolated if the cycloaddition was conducted at 80°C. Heating at 50°C for 3h converted 13 into 14. The 2-carboethoxy analog of oxazole 12 behaved similarly. ... 

Although the regiochemistry of oxazole-olefin cycloadditions has not been extensively studied, some generalizations can be made. The major product is the 4-substituted pyridine in those instances when the alkene dienophile bears an electron-withdrawing substituent. This regioselectivity is exemplified by the Diels-Alder reaction used in a synthesis of the natural product ellipticine by Kozikowski and Hasan," starting from the reaction of oxazole 21 with acrylonitrile to give 4-cyanopyridine 22 (Fig. 3.6). 

The rate of Diels-Alder reactions of oxazoles with electron-deficient olefins and acetylenes depends on the electron-donating ability of the oxazole substituent Rates decrease in the order OR > NR1R2 > alkyl > 4-phenyl > COCH3 > CO2CH3 3> 2-,5-phenyl 5-aIkoxy oxazoles have reactivity roughly equivalent to an all-carbon diene. 

An oxazole-olefin Diels-Alder reaction was also used in an approach to nonpeptide neurokinin-3 receptor antagonists. Thus when 4-phenyloxazole 55 is melted together with maleic acid at 110°C for 15 min, 2-phenyl-4-pyridinecar-boxylic acid 56 is obtained in 18% yield after decarboxylation (Fig. 3.16). This compound is then coupled with methyl phenylglycinate to give the desired final product 57. 

TABLE 3.1. INTERMOLECULAR OXAZOLE-OLEFIN DIELS-ALDER REACTIONS... 

The azaphenanthrene alkaloid eupolauramine appeared to be an ideal target for exploring the applicability of an intramolecular Kondrat eva pyridine synthesis in the construction of natural products. Despite the fact that 2-phenyloxazoles are unreactive in intermolecular cycloadditions, the Diels-Alder reaction of oxazole-olefin 97 was expected to provide the tricyclic framework of eupolauramine... 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

The intermolecular oxazole-olefin Diels-Alder reactions are summarized in Table 3.1, p. 431. 

Several additional examples of oxazole Diels-Alder reactions applied to the synthesis of natural products have appeared. Using the same synthetic strategy that resulted in the total synthesis of normalindine, " Ohba and co-workers adapted the oxazole-olefin Diels-Alder cycloaddition for the synthesis of the mono-terpene alkaloids plectrodorine and oxerine. The synthesis of (-)-plectrodorine began with the requisite Diels-Alder precursor 262a, prepared from (5)-(-)-malic acid (Fig. 3.78). The intramolecular Diels-Alder reaction of this 2-alkyloxazole... 

Several esters (Xl-3) were obtained from a Diels-Alder cycloaddition between the oxazole XI-1 and the activated olefins XI-2... 

The use of the CFs-substituted oxazole as an aza-diene for a Diels-Alder reaction was briefly examined. Thus, prolonged heating of the mixture of 5-ethoxy-4-trifluoromethyloxazole and an excess of acrylic acid afforded the CFs-substituted pyridine derivative in reasonable yield [61], However, cycloaddition with other olefins, such as ethyl acrylate, N-phenylmaleimide, 2,5-dihydrofuran, maleic anhydride, and 2-buten-4-olide did not take place to any appreciable extent presumably because of the deactivation of the oxazole ring by a strongly electron-withdrawing CF3 group. 

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