Oxazole production

Williams and McClymont have observed that acylation reactions of the dianion of 2-(5-oxazolyl)-l,3-dithiane (15) lead to formation of 4,5-disubstituted oxazole products through a Comforth rearrangement pathway under base-induced, low-temperature conditions. For example, deprotonation of 15 with LiHMDS (3.0 equivalents) at -78°C, followed by addition of benzoyl chloride or p-chlorobenzoyl chloride and warming to 0°C, provided 16 in 74% and 47% yield, respectively. 

Ingham proposed the following sequence to explain the formation of oxazole products following his study of the reaction of benzaldehyde with mandelonitrile and hydrogen chloride. In the event, addition of hydrogen chloride to the cyanide is the first step providing the intermediate iminochloride 5 (Ari = Ph), which upon reaction with benzaldehyde affords oxazole 2 (Ari, Ar2 = Ph) via intermediate 6 (Ari, Ar2 = Ph). 

A highly efficient and interesting method of oxazole production was described by Lee et al. [57]. Scheme 13 describes the synthesis of compounds 59 and 58 using solvent-free microwave irradiation in yields of 70% and 68%, respectively. 

Because of the presence of the extra phenyl substituent in the present case, further enolization is prevented, and therefore ring closure to an oxazole cannot occur. Thus, prevented from further reaction, the adduct undergoes a slow breakdown to reproduce the original enolate, and the 2-oxazole anion, which is then able to react irreversibly with the benzaldehyde to produce the observed 2-substituted oxazole product. 

Propargylamine amides can readily undergo cycloisomerization to oxazole products using a number of conditions. Conjugated alkynyl amide 176 was converted into oxazole 177 with the aid of silica gel (Equation 10) <2004OL3593>. 

Tosylmethylisocyanide (TosMIC) reacts with aldehydes via a [3+2] pathway, under basic conditions, to give 5-substituted oxazoles. In one example, the resulting oxazole product was used in the synthesis of a key intermediate for the hepatitis C drug candidate VX-497 (Scheme 56) <20020PD677>. K2CO3 is usually the base of choice for this reaction since stronger bases such as KO/-Bu lead to a cyanide product. 

A polymer-supported TosMIC reagent 196 has been developed in which the isocyanide is attached to a ringopening metathesis polymer (ROMP gel) (Scheme 57). The use of this reagent significantly simplified the purification of the oxazole products <20010L271>. 

Oxazoles 240 have also been prepared by flash vacuum pyrolysis or photolysis of A -acylisoxazol-5-ones 239 (Scheme 70) <1996TL675>. The acylisoxazol-5-ones were in turn prepared by the acylation of the corresponding isoxazol-5-ones 238. This method of oxazole production has been reported to give significantly better yields than the rearrangement of the acyltriazole precursors. 

Although oxazoles follow the pattern and lithiate at C-2, 4-substituted products are produced with some electrophiles this is explained by a ring opening of the anion, to produce an enolate, which after C-electrophilic attack, recloses. An estimate by NMR spectroscopy showed the ring-cleaved tautomer to dominate the equilibrium." Some electrophiles produce good yields of oxazole products reaction of lithi-ated oxazole with hexachloroethane produces 2-chlorooxazole in good yield." The open enolates can be... 

In 1982, Hamada and Shioiri reported that carboxylic acids could be directly employed as acyl donors in the Schollkopf reaction via in situ activation (presumably via a mixed anhydride or azidocarbonyl species) using diphenyl phosphorazidate (DPPA). Thus reaction of a mixture of carboxylic acid, isocyanide, DPP A, and potassium carbonate in DMF afforded the anticipated oxazole product in good yield cf, 14 + 15 —> 16). Notably, this reaction was compatible with iV-protected a-amino acid starting materials and proceeded with minimal epimerization. Although diethyl phosphorocyanidate (DEPC) has found similar use in... 

The Schollkopf reaction additionally serves as a useful method for the preparation of a-amino ketones (c/, 14 32 33). Aeid-eatalyzed hydrolysis of the oxazole products of the Schollkopf reaction (e.g., 18) leads initially to a-amino ketone intermediates cf, 32), which can either be isolated or—in the case of intermediates derived from oxazoles bearing C-4 ester substituents—de-alkylated and deearboxylated to provide the related a-amino ketones cf, 33). ... 

Schregenberger and Seebach have alternatively suggested that the tetrahedral intermediate initially obtained from the reaction of metalated isocyanide and amide is stable to the reaction conditions and decomposes only on workup to afford the oxazole product Schregenberger, C. Seebach, D. Liebigs Ann. Chem. 1986,2081-2103. 

Optional domains can be incorporated into a module for further modification to the intermediate. For example, a cylisation (Cy) domain can be used to produce thiazoline or oxazoline intermediates, which can be further modified by an oxidation (Ox) domain to yield the thiazole and oxazole products [40, 41]. Epimierisation (E) domains are also a common feature, which catalyse the stereochemical inversion of L-amino acids to D-amino adds [42]. Einally, following the last module, a thioesterase (TE) domain either hydrolyses or cyclises the intermediate to yield the NRP product [16]. 

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