Diels-Alder reactions of oxazoles

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

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder 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 heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

The retro-Diels-Alder reaction is a valuable tool for the synthesis of heterocycles <2003COR1423>. The Diels-Alder/ retro-Diels-Alder reaction of oxazoles with acetylenedicarboxylates has been extensively applied for the synthesis of 3,4-disubstituted furans. In a total synthesis of the alkaloid colchicine, such a reaction has been carried out in an intramolecular mode to yield a [ ]-annulated furan, which served as a synthetic key intermediate (Equation 30) <2000T10175>. 

Diels-Alder reactions of oxazoles have proven to be quite versatile and continue to attract attention. Oxazoles have traditionally been used as the diene component and react with alkyne dienophiles to give furan products after extrusion of a nitrile molecule via a reverse-cycloaddition process. This method has been used to access highly substituted furans and has been utilized in numerous natural product syntheses. The reaction typically requires the use of high temperatures for efficient conversion. The furan intermediate 67 was obtained by a thermal intermole-cular Diels-Alder reaction between oxazole 66 and an acetylene. Furan 67 was a key intermediate for the synthesis of (—)-teubrevin G (Scheme 10) <2000JA9324>. Similarly, furan 68, obtained from a Diels-Alder reaction between 4-phenyloxazole and an acetylene, served as an intermediate in the total synthesis of the natural product cornexistin (Scheme 10) <20030L89>. 

It is well known that Diels-Alder reaction of oxazoles as azadienes with acetylenic dienophiles result in the formation of furan derivatives via elimination of a nitrile from the adduct in a retro Diels-Alder process... 

An intramolecular Diels-Alder reaction of oxazoles with alkenes has not been investigated (83T2869). Recently, Levin and Weinreb (83JA1397 84JOC4325) applied an intramolecular Kondrat va pyridine synthesis (74AHC(17)99 81MI1) to the total synthesis of azaphenanthrene alkaloids eupolauramine (506). Independently, some examples of intramolecular... 

Since their discovery in 1957, Diels-Alder reactions of oxazoles have proven useful for the synthesis of a variety of compounds and consequently have been a constant focus of attention <57MI 304-01 >. Reaction fundamentals and generalities were discussed in <84CHEC-I(6)177>. Alkynes and alkenes are the usual dienophiles. 

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)]. 

Extensive studies on the mechanism342 343 of the Diels-Alder reaction of oxazoles have clearly demonstrated that the formation of pyridine bases fundamentally involves two (or possibly three) steps the condensation of oxazoles with dienophiles giving the bicyclic adducts (183), and... 

Liotta Tandem DIels-Alder/retro Diels-Alder reaction of oxazoles [83112473]... 

Oxazoles readily participate in cycloaddition reactions as dienophiles and as dienes in Diels-Alder reactions, and suitably substituted oxazoles participate in sigmatropic rearrangements (e.g., aza-Claisen rearrangements). In particular, the Diels-Alder reaction of oxazoles is one of the most widely explored and synthetically useful reactions, and as such, it has been used extensively both in natural product syntheses and to convert oxazoles to other heterocyclic ring systems. For example, a partial list of heterocyclic systems readily accessible from oxazoles via Diels-Alder reactions or other cycloadditions include pyridines hydroxy-pyridines isoindoles pyridazines tetrahydronaphthyridines benzo[h]-l,6-naphthyridines benzopyrano[3,4-b]pyridines 2-substituted, 2,4-disubstituted,... 

Iwase and Aoki reported a very efficient synthesis of 3- or 4-substitufed pyridines via high-pressure Diels-Alder reaction of oxazole 1. For example, 1 reacted with acrylonitrile at 1.1 Mpa to produce 3-cyanopyridine 1652 in 95% yield (Scheme 1.425). Kondrat eva and co-workers described cycloaddition reactions of 2-aminoox-azoles 1653 with maleimide (Scheme 1.425). The authors isolated several different... 

The Diels-Alder reaction of oxazoles with alkenes, alkynes, and heterodieno-philes has become a valuable tool for the construction of highly substituted pyridines, furans, and other heterocycles and has now been exploited for the synthesis of diverse compounds from pharmaceuticals to complex natural products. These reactions have been extensively reviewed. The purpose of this chapter is to provide an introduction to the use of oxazoles in Diels-Alder cycloadditions and an update on these reactions since 1985. 

In addition, the Diels-Alder reactions of oxazoles 3 bearing alkoxy substituents at the 5 position were disclosed by Kondrat eva and Huang in 1961 (Fig. 3.2). In contrast to the alkyloxazoles, the cycloadditions of derivatives such as maleimide with 3 resulted in the formation of pyridinols 4 rather than the expected 3 - alkoxypyridines. 

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. 

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 synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

The Diels-Alder reaction of oxazoles with alkynes has become a preferred method for the synthesis of substituted furans with diverse applications. A large number of early examples of this reaction have been tabulated. Activated dienophiles such as acetylenic ketones and esters can be used, although unactivated alkyl, aryl, and silyl alkynes have been used as well. In particular, the reaction of 4-phenyloxazole with substituted acetylenes is frequently used for preparing 3,4-disubstimted furans. Cycloadducts derived from 4-phenyloxazole typically decompose under milder conditions than 4-alkyloxazoles, allowing the synthesis of a wider range of functionalized furans. Several examples are shown below. 

The bicyclic intermediate arising from Diels-Alder reaction of oxazoles with alkynes extrudes nitriles (comprised of the nitrogen atom and C4 of the oxazole) to form furans as the ultimate product of the cycloaddition. The same regioselectivity seen in alkene Diels-Alder reactions is noted here. 

Intramolecular Diels-Alder Reaction of Oxazoles. A catalytic amount of copper(II) trillate promotes the intramolecular Diels-Alder addition of uj-unsaturated oxazoles, as in 6 (eq 26) and 8 (eq 27), to afford the corresponding cyclopenta[c]pyridines (7) and respectively 9. ... 

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