Fused oxazoles

Formation of ring-fused systems by this procedure is not as common. If the vicinally substituted hydroxyamino derivative is available, then Pb(OAc)4 treatment will lead to a ring-fused oxazole as in the conversion of (272) into (273) (71JCS(C)1482). In a different approach the CH=N— functional group is generated in situ. The 2-(l-pyrrolidinyl)ethanol... 

In this section coverage follows the general order of Part I [93AHC (57)271] in that heterocycles fused to furan will precede those fused to thiophene and pyrrole fused oxazoles will precede fused thiazoles, etc. 

Additional heterocyclic ring systems, such as benzofurans [125], dihydropyrroles and dihydroazepines [41], piperidines and dihydropyrimidines 36 [126], and fused oxazole derivatives [127], have been described (Eq. 7). The formation of epoxides and aziri-dines, formally emanating from ylides, was recently reported by Doyle et al. [77]. Rho-dium(II)-catalyzed isomiinchnone cycioaddition followed by Lewis acid-mediated ring opening has been used as an entry into the protoberberine azapolycyclic ring structure [128]. 

Nitro-2-phenyloxazole 271a undergoes Diels-Alder [4 + 2] cycloaddition with both electron-rich and electron-poor dienophiles to give an oxazoline 273 that may not be isolable due to the facile aromatization to a fused oxazole 274. Examples are shown in Table 8.22 (Scheme 8.77). 

Considerable knowledge on oxazoloazine chemistry has been built up over the last 15 or so years. A major emphasis has been on the preparation of compounds for biological purposes oxazolopyrimidines may be regarded as purine analogues. Oxazoloazine ring systems are also found in antibiotics and alkaloids. Fluorescent whitening properties have also stimulated interest in azine-fused oxazoles. 

Nucleophilic substitution in the azine ring is a normal reaction. The fused oxazole ring, however, is susceptible to nucleophilic ring opening reactions, especially in oxazolium salts and dihydro derivatives. When fused to pyrimidine, substituents in the pyrimidine ring may promote a Dimroth rearrangement of the latter. 

Nitrogen heterocycles are attacked by cyanogen halides at the nitrogen. In the reaction of cyanogen bromide with the saturated, fused oxazole (182), a fused medium-ring heterocycle (183) is formed when the reaction is carried out under solvolytic conditions... 

Fused oxazoles are susceptible to ring opening reactions. In appropriately substituted systems, however, nucleophilic substitutions in the azine ring are possible. Thus, in the 7-pyrimidinone (190) chlorination is effected in the usual manner by means of phosphorus oxychloride. The chlorine can be substituted by amino or sulfur nucleophiles (71JHC503). 

Azine approach. Reissert compounds such as (222) on treatment with acid form transient cyclic intermediates containing the 3,4-fused oxazole ring. When the acid is tetrafluoroboric acid, the Reissert salt (223) can be isolated (73JA2392). 

Fused oxazoles have been prepared by heating aryl azides containing electron-withdrawing groups at the para position with czurboxylic acids in polyphosphoric acid. j -Nitrophenyl azide and acetic acid yielded (83%) 2-methyl-6-nitrobenzoxazole (203)... 

Many of the methods available for the synthesis of fused oxazoles lead to... 

MPhenacyl-2-pyridinium salts cyclize on heating in pyridine, the methylthio group being lost (cf. Chapter 36, Section 1.3). Simultaneous Beckmann rearrangement, demethylation and cyclization converts an o-alkoxy-ketoxime into a fused oxazole ring. 

When 2-oxocyclohexanecarboxaldehyde reacts with hydroxylamine, a mixture of the 1,2- and the 2,1-isoxazole is formed these can be difficult to separate, but when the ketal-carboxaldehyde is used, the product is the 1,2-isoxazole. A similar method was effective on 2-acetylcyclohexanone but some of the 2,1-isomer was formed. A high yield of a pert-fused oxazole is obtained by treating the acridinone (30.4) with PPA at 80 C for 4h. The product is a derivative of an antimalarial drug. 

Thermolysis of an azide with PPA and an alkanoic acid can lead (through a rearrangement) to a fused oxazole ring being formed. 

Hydroxy and ester groups (the latter being formed in situ from a nitrile) react at ambient temperature with a nucleophile to form a fused oxazole ring. 

An efficient conversion of a hydroxy-imine into a fused oxazole ring under relatively mild conditions is effected by either silver oxide or thionyl chloride. Ekirium manganate is claimed to be more efficient than manganese dioxide in this cyclization. 

Tsveniashvili and co-workers acquired polarographic data for series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles and investigated the effects of substituents on the electrochemical reduction potential. They explained their results by two one-electron reversible steps to produce a dianion, which was then protonated. Rogers and co-workers described anion-pi radicals formed during electrochemical reduction of fused oxazoles, e.g., 2-phenylbenzox-azole. 

The fused oxazole derivative 100 was synthesized from 3-azido-3-deoxy-l,2 5,6-di-O-isopropylidene-a-D-allofuranose, the key final step being the reaction of methyl 3-amino-3-deoxy-5,6-0-isopropylidene-p-D-alloside with DMF dimethyl acetal. The annelated pyranoside 101 was obtained by cyclization of a branched chain hexosulose derivative, and the fused triazole-piperidinoses such as 102 were made by a radical cyclization of a 3-pyrazolo-6-iodo-sugar derivative. The spiro-isoxazohne 103 and related isomers have been synthesized by dipolar cycloadditions of mesitonitrile oxide to 2-deoxy-2-C-methyl-ene-pentonic acids, themselves available in five steps from D-mannitol. Intra-... 

Scheme 44 Iodide-catalyzed oxidative amination of fused oxazoles...

Fused oxazoles, particularly tetrahydrofuro[3,2-d]oxazoles, are abundandy present in natural products, modified sugar derivatives, and important bioactive molecules. Ahmed and coworkers have reported a highly efficient, novel, microwave-assisted, metal-free, diastereoselective synthesis of... 

Conjugated BBO-containing polymers with type-2 positioning of fused oxazole units were synthesized using the Sonogashira coupling protocol. ... 

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