Oxazole, formation

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

Despite the above, there is also considerable evidence to suggest that oxazole formation proceeds via an intermediate nitrile ylide, particularly in the catalysed reactions (see below). Nitrile ylides have been detected in laser flash photolysis studies of diazo compounds in the presence of nitriles, and stable nitrile ylides can be isolated in some cases.<94CRV1091>... 

Although 2-acyl-2//-azirines are known to give oxazoles upon irradiation, the reaction is wavelength dependent, and isoxazoles are formed at some wavelengths, as they are in the thermal rearrangement of 2-acyl-2//-azirines.<74TL29,75JA4682> Since the thermal reaction of diazocarbonyl compounds with nitriles leads to oxazole formation, it would seem that mechanistic path C is unlikely in these reactions. 

Corey s retrosynthetic concept (Scheme 9) is based on two key transformations a cationic cyclization and an intramolecular Diels-Alder (IMDA) reaction. Thus, cationic cychzation of diene 50 would give a precursor 49 for epf-pseudo-pteroxazole (48), which could be converted into 49 via nitration and oxazole formation. Compound 50 would be obtained by deamination of compound 51 and subsequent Wittig chain elongation. A stereocontroUed IMDA reaction of quinone imide 52 would dehver the decaline core of 51. IMDA precursor 52 should be accessible by amide couphng of diene acid 54 and aminophenol 53 followed by oxidative generation of the quinone imide 52 [28]. 

Polymerization of terephthalic acid with 4,6-diamino-l,3-benzenediol via oxazole formation (Eq. 2-219) proceeds with a sharp and continuous decrease in reaction rate with increasing polymer molecular weight [Cotts and Berry, 1981]. Reaction becomes progressively more diffusion-controlled with increasing molecular size due to the increasing rigid-rod structure of the growing polymer. 

Proposed mechanism for intramolecular catalysis of oxazole formation by pyrrole NH. 

In isomer 1, where catalytic redox functions are retained, a facilitated inactivation reaction such as oxazole formation, which can take place even nonenzymatically in any cell, results in potential toxicity. 

Scheme 9 Proposed Mechanism for Peptide-Based Oxazole Formation via Dehydration of an /V-fS-Oxo Amide1631...

The mechanism of this oxazole formation is identical to that of the Hantzch thiazole synthesis. However, because of the reduced nucleophilicity of a carbonyl group as compared to a thiocarbonyl (due to the higher electronegativity of oxygen), this synthesis only proceeds under vigorous conditions (high temperatures, amide component as solvent, etc). 

Imidazole formation runs closely parallel to oxazole formation.243 That the A-alkyl groups are derived from the amino acid was shown by the use of [2-13C]Gly and Ala. 

V. A. Yaylayan and L. J. W. Haffenden, Mechanism of imidazole and oxazole formation in [13C-2]-labelled glycine and alanine model systems, Food Chem., 2003, 81, 403 109. 

Isoxazoles are photolabile. The first step in the reaction is believed to be fission of the N—O bond with formation of a diradical which may recyclize. In the case of the isoxazolopyridine (4) the reaction is rationalized as taking place via a 2ZZ-azirine (5) and a carbenoid structure (6) before formation of an oxazole ring (7). A high pressure mercury lamp is used, and the reaction can be run on a preparative scale (79CB3282). Photolysis of the isoxazole (8), which is fused to an azine ring with a different order of its azole heteroatoms, also leads to oxazole formation (10) (78CPB2497), but in this instance another type of intermediate is postulated (9). 

In order to install a benzophenone at the bicyclic scaffold we relied on the previously used oxazole linkage. To this end, the known amino-hydroxybenzophenone 37 (Aichaoui et al. 1990) was coupled to the free acid rac-38, which is available from Kemp s triacid in five synthetic steps. Remarkably, an 0-aeylation instead of the expected /V-acylalion was observed resulting in ester rac-39. As a consequence, oxazole formation was less straightforward but could eventually be achieved under more forceful conditions. The reaction sequence led to the racemic benzophenone rac-40, i.e. to a 1/1 mixture of the enantiomers (+)-40 and (-)-40, which was separated by chiral HPLC (Daicel Chiralpak AD). It is important to mention that a separation of enantiomers at an earlier stage is not sensible. While carboxylic acid 38 can be obtained in enantiomerically pure form, racemisation occurs upon activation, presumably due to a bridged symmetrical intermediate (Kirby et al. 1998) (Scheme 16). 

ADDITIONAL EXAMPLES OF OXAZOLE FORMATION USING DIMETHYL DIAZOMALONATE 1 AND DIAZO FORMYLACETATE 2a... 

Benzynes, 3-acylamino-, oxazole formation via, 56, 221 Beryllium-containing four-membered rings, 56, 339, 381 Betaines... 

It is usual for the reaction of or-acyloxy ketones with ammonium acetate to give mixtures of oxazoles and imidazoles, with the result that the method may not be the one of choice if the product mixture complexity can become too great (Scheme 77) (70AHC(12)103). Excess ammonia may help depress oxazole formation, although the oxazoles can be converted into imidazoles (Section 4.08.2.2). 

A one-pot/two-reaction sequential ruthenium- and gold-catalyzed oxazole formation has been reported <2004CC2712>. The reaction of a propargylic alcohol and a primary amide in the presence of a Ru catalyst facilitates the formation of the intermediate propargyl amide which cyclizes upon treatment with AuCls (Scheme 61). 

Meinwald obser ed, besides oxazole formation, an adduct from two molecules of 2-butyne and one molecule of methoxycarbonylnitrene. Acetylnitrene also gave an oxazole when generated in the presence of phenylacetylene... 

Spirodienones 1410, 1411—see also Bis-spirodienones, Tris-spirodienones Spiro-oxazoles, formation of 1172 Square-wave voltammetry 982 S vl reactious 1073... 

Under similar conditions, no cyclopropanation of allyl phenyl sulfones takes place, but rather [2,3] rearrangement of a primarily formed sulfur ylide. With but-2-enenitrile, oxazole formation rather than cyclopropanation occurs. " ... 

Kawano and Togo introduced an ionic liquid group into iodoarenes, to form ionic liquid-supported iodoarenes, and used them for the promotion of the synthesis of oxazoles [24]. The results of the reactions of acetonitrile, m-chloroperbenzoic acid (mCPBA), trifluoromethanesulfonic acid (TfOH), and acetophenone are shown in Table 12.1, using various IL-supported iodoarenes (IL-supported Phis). The reactivities of IL-supported iodoarenes (Phis) 17-25 are shown in entries 1-9, and IL-supported Phi 20 showed the best reactivity. Instead of acetonitrile as solvent, room temperature ILs, such as [emim][OTs], [bmim][PFg], and [bmpyjlNTf ], were used in the presence of IL-supported Phi 20 (entries 10-12). However, [emim][OTs] did not promote the oxazole formation at all, while [bmimJPF and [bmpy][NTfJ provided the oxazole in moderate to low yields. Thus, use of acetonitrile as solvent yielded the best reactivity as compared with these ILs. 

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