Diels-Alder-type oxazole

The Michael type reaction of (3R)-5-t-butyldimethysiloxy-3-phenyl-17/-pyrrolo[ 1,2-c]oxazole with nitroethylene proceeds in the presence of Lewis acid to give the alkylated product in good chemical yield and diastereoselectivity. In the case of nitroethylene, the Diels-Alder type transition state is favored to give the yy/i-adduct selectively (Eq. 4.72).91... 

Oxazoles readily undergo Diels-Alder type cycloaddition across the 2,5-positions, in parallel with the behaviour of furans (18.7). Thiazole and imidazole do not show this mode of reactivity, however they do react with highly electrophilic alkynes via initial electrophilic addition to the nitrogen, then nucleophilic intramolecular cyclising addition (cf the comparable reactivity of quinohnes, 9.13). ... 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

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. 

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. 

Although oxazole possesses a sextet of 7r-electrons, all its properties indicate that the delocalization is quite incomplete hence it has but little aromatic character. There is considerable bond fixation (see Section 4.18.2.3.1), hydroxyoxazoles are unstable relative to their oxo tautomers, oxazolediazonium salts are unknown, oxazoles function as dienes in the Diels-Alder reaction (see Section 4.18.3.1.2(vii)) and electrophilic substitution is rare. The chemistry of oxazole is dominated by its tendency to undergo ring-opening rather than preserve its type. 

There have been reports on the reaction of oxazoles with heterodienophiles, including N=N, C=N, C=0, and types, to give new heterocycles <89X3535, 88JOO 663>. In most cases, the products may be envisioned to arise from ring opening and rearrangement of Diels-Alder adducts followed by reclosure, but so far no proof of this mechanism has appeared. A reaction of 5-ethoxy-... 

The formation of a 7-pyrone (203) from the reaction of 5-ethoxyoxazoles (199) with diphenylcyclopropenone constitutes an example of a retro-homo-Diels-Alder reaction.353 364 In no case were adducts of the types 200 or 202 isolated. But, nevertheless, stable adducts (204, R = H or Me) have been isolated from the oxazoles (199, R = H or Me) and diethyl azodicarboxylate in 65-66% yield, whereas 199 (R = Me) gives adduct 205... 

Benzoxazolo[3,4-a]pyridinium salts (116) are known to give cycloadditions of the [4-1-2] and [3 -I- 2] type with alkenes and alkynes. The primary adducts were readily converted to alternative heterocyclic systems (121) and (122) which were usually the isolated major products (Scheme 24) <79JOCill, 82JOC3098>. The formation of oxazoles from the reaction of alkynic aldehydes with (116) was claimed to result from the Diels-Alder pathway with the carbonyl group acting as the dienophile <93JCS(P1)1839>. 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

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