Monosubstituted oxazoles

A short route to 5-monosubstituted oxazoles is based on the flash vacuum pyrolysis of azolides of 1,2,4-triazole (169) <89H(29)103>. 5-Aryloxazoles are obtained in excellent yield, but the formation of ketene is a major side reaction for alkyl analogues with an a hydrogen. The rearrangement is believed to proceed by [1,5] sigmatropic shift of the acyl substituent followed by loss of nitrogen and cyclization of a diradical intermediate (Scheme 79). 

Ferrini and Marxer186 observed that the condensation of equimolar amounts of acid amides and vinylene carbonate (128) in the presence of polyphosphoric acid leads to 2-monosubstituted oxazoles, but generally... 

Monosubstituted oxazoles (or oxazole itself) in this way may offer a route to 3-mono- or 3,4-disubstituted furans by reaction with appropriate... 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

A number of recent papers have appeared in the literature related to the synthesis of saturated 5(477)-oxazolones that were not yet covered in our contribution. 4-Acyl-2,4-dialkyl-5(477)-oxazolones 776 have been obtained from A-acylglycines. Thus, cyclization of an A-acylglycine in the presence of thionyl chloride affords a monosubstituted 5(477)-oxazolone 775. Acylation of 775 with an aroyl chloride in the presence of magnesium chloride occurred at C-4 to produce 776. Hydrolysis and decarboxylation of 776 gave the A-acylamino ketones 777 that are valuable intermediates to prepare oxazoles 778 (Scheme 7.236). 

The primary adducts (156) and (157) of oxazoles with alkenes and alkynes, respectively, are usually too unstable to be isolated. An exception is compound (158), obtained from 5-ethoxy-4-methyloxazole and 4,7-dihydro-l,3-dioxepin, which has been separated into its endo and exo components. If the dienophile is unsymmetrical the cycloaddition can take place in two senses. This is usually the case in the reactions of oxazoles with monosubstituted alkynes with alkenes on the other hand, regioselectivity is observed. Attempts to rationalize the orientation of the major adducts by the use of various MO indices, such as 7r-electron densities or localization energies and by Frontier MO theory (80KGS1255) have not been uniformly successful. A general rule for the reactions of alkyl- and alkoxy-substituted oxazoles is that in the adducts the more electronegative substituent R4 of the dienophile occupies the position shown in formula (156). The primary adducts undergo a spontaneous decomposition, whose outcome depends on the nature of the groups R and on whether alkenes or alkynes have been employed. 

C—C—O+N—C. a-Hydroxy ketones react with monosubstituted cyanamides under the influence of sodium hydroxide to yield derivatives of 2-aminooxazole (equation 125) (76S591). Oxazoles are obtained by the action of nitriles on a-diazo carbonyl compounds in the presence of Lewis acids, such as aluminum chloride or boron trifluoride, and the reaction is thought to involve the intermediacy of nitrilium salts (equation 126). Nitrilium salts are also the effective agents in the formation of oxazoles from a-chloro ketones and nitriles in the presence of tin(IV) chloride (equation 127). 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

The use of Lindlar s catalyst and aqueous acidic conditions allowed the generation of /3-hydroxy ketone 62 from oxazole 61 with the disubstituted olefin remaining intact (Scheme 22).A yield of 65% was obtained even when a monosubstituted olefin was present. 

Photocycloadditions have also been observed between 2/f-azirines and acyl chlorides. The primary cycloadducts 70 are quite labile and cannot be isolated directly. The 5-chloro substituent of the photoproduct could readily be exchanged for an alkoxyl group. Cycloadducts 70, which are monosubstituted at C-2, undergo a 1,4 elimination of hydrogen chloride on treatment with tertiary amines to form oxazoles in moderate yield. ... 

Zhao F, Liu X, Qi R, Zhang-Negrerie D, Huang J, Du Y, Zhao K (2011) Synthesis of 2-(tri-fluoromethyl)oxazoles from p-monosubstituted enamines via PhI(OCOCF3) 2-mediated tri-fluoroacetoxylation and cyclization. J Org Chem 76 10338-10344... 

An interesting PlFA-promoted )S-trifluoroacetoxylation and intramolecular cyclization of monosubstituted enamines 52 led to various 2-(trifluoromethyl)oxazoles 53. The interesting part of the reaction is to transfer of a... 

F. Zhao, X. Liu, R. Qi, D. Zhang-Negrerie, J. Huang, Y. Du, K. Zhao, Synthesis of 2-(trifluoromethyl)oxazoles from p-monosubstituted enamines via PhI(OCOCF3)2-mediated trifluoroacetoxylation and cyclization, J. Org. Chem. 76 (2011) 10338-10344. 

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