Oxazoles ring transformations

Closely related to the aldoxime fragmentation is the base-catalyzed ring cleavage of C(3)-substituted isoxazoles. Quite recently a novel base-catalyzed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate (61) into ethyl 4-cyano-5-methyloxazol-2-ylacetate (62 Scheme 5). ... 

Ring transformations heterocyclic compounds reviews, 1, 70 Ring-chain tautomerism polyheteroatom six-membered rings, 3, 1056 Ripariochromene A synthesis, 3, 751, 755 Robinson-Gabriel synthesis oxazoles, 6, 216... 

Acid-catalyzed ring transformation of the 2-aminomethyl-2,3-dihydro-77/-pyrimido[2,TA [l,3]oxazol-7-one 193 resulted in the pyrimido[l,2- ]pyrimidine 194 (Equation 19) <2000NN1381>. 

The reaction of a-diazocarbonyl compounds with nitriles produces 1,3-oxazoles under thermal (362,363) and photochemical (363) conditions. Catalysis by Lewis acids (364,365), or copper salts (366), and rhodium complexes (367) is usually much more effective. This latter transformation can be regarded as a formal [3 + 2] cycloaddition of the ketocarbene dipole across the C=N bond. More than likely, the reaction occurs in a stepwise manner. A nitrilium ylide (319) (Scheme 8.79) that undergoes 1,5-cyclization to form the 1,3-oxazole ring has been proposed as the key intermediate. 

The presence of electron-withdrawing substituents at C(4) facilitates reactions with nucleophiles, which may well be initiated by attack at C(5). Thus oxazole-4-aldehydes undergo ring-fission on treatment with aqueous alkali to form (acylamino)malondialdehydes (equation 3), and 2-pentyloxazole-4-carboxylic acid yields 2-pentylimidazole, with concomitant decarboxylation, when heated with ammonia at 150 °C. An example of a more complex ring transformation is the formation of 3-aminopyridines (131) by the action of malononitrile on 4-acetyloxazoles under alkaline conditions (equation 4). 

The original photoproduct of these reactions has a hydrated oxazolic ring formed by the interaction of the carbonyl group with the neighboring N-alkylated amino group. This photoproduct was transformed into anthra 2,1 -J oxazoline derivatives, which form following oxidative cleavage. 

In this case the isoxazole ring is transformed to an oxazole ring. 

Control experiment indicated that template effect (in the presence of different metal salts) [108] was not operating for this transformation. The presence of NH function in 86 that could potentially form a H-bond with oxazole ring, thus preorganizing the cyclization precursor [109], was not an obligation. Indeed, compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant 88% yield per chemical bond created, including the macrocyclization step. 

While the so-called halogen dance reaction had been reported for aromatic and heteroaromatic systems, it had never been described for the oxazole ring. This approach was used for an efficient transformation of 5-bromo-2-phenyloxazole, 114, into several 5-substituted 4-bromo-2-phenyloxazoles 115 <05SL1433>. The electrophiles used were water, benzaldehyde, TMSCl, halogens, and CO2 affording the final compounds in good yields (66-78%). 

The a-(benzoxazol-2-ylsulfanyl) ketone 15 reacts with hydrazine hydrate in acetic acid to yield Ar-(2-hydroxyphenyl)-5-phenyl-6//-l,3,4-thiadiazin-2-amine (16). When the a-(l,3-oxazol-2-yl-sulfanyl) ketones 17 are heated under similar conditions, ring transformation to afford the 2//-imidazo[2,l-h][l,3,4]thiadiazines 18 occurs. 

Catalytic transformation of alkyl- or aryloxazoles into the corresponding thiazoles330 381 in low yields is possible by passage over alumina in a stream of hydrogen sulfide at 350°. This indicates that the oxazole ring is more stable towards attack by hydrogen sulfide than is furan.880... 

A fiiran synthesis which cannot easily be deduced from retrosynthetic considerations is the ring transformation of oxazoles by a Diels-Alder reaction with activated alkynes. For example, 4-methyloxazole 20 reacts with dimethyl acetylenedicarboxylate to provide furan-3,4>dicarboxylic ester 22 [6] via a nonisolable adduct 21 ... 

On heating with ammonia, formamide or primary amines, oxazoles thereby undergo a ring transformation into imidazoles. 

As for quinolines, isoquinoline derivatives can be prepared by ring transformation of other heterocycles. For instance, oxazole-4-carboxylic ester 74, obtained from phthalic anhydride and isocyanoacetic ester, is converted into the l-isoquinolone-3-carboxylic ester 75 in an acidic medium, probably by hydrolysis to the enaminocarboxylic acid 76 followed by cyclization. 

The reader is directed to several excellent reviews for further details. Hassner and Fischer s general review of oxazoles covers both electrophilic aromatic substitution (EAS) reactions and addition reactions. Belen kii and Chuvylkin surveyed EAS reactions of oxazoles as part of a larger review for azoles. Larina and co-workers published two extensive reviews of nitration of azoles, including oxazoles. The articles cover kinetics and the mechanism of nitrations as well as the synthesis of nitroazoles via heterocyclization and ring transformations and direct methods of nitration. In light of these reviews, only a few selected examples of EAS reactions of oxazoles are described in this section. 

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