Oxazoles acidity

Significant producers include Daiichi, Hoffmann-La Roche, Takeda, and several factories in mainland China. Takeda and Daiichi practice processes based on alanine by ethoxyoxazole (12), at least one Chinese producer from alanine by oxazole acid (13), and Roche from ketene via cyanooxazole (15). 

Benzoxazole dyes exhibit irreversible degradations that involve opening of the oxazole (66). Oxacarbocyanines, eg, 3,3 -dimethyloxacarbocyariine iodide [48198-86-3] (42), react most readily with aqueous acid, whereas benzoxazole merocarbocyanines (43) react with sulfite or hydroxide ion to produce ring-opened products such as (44). 

Oxazoles give acylamino ketones (158) by acid-catalyzed ring scission, although they are somewhat more stable than furans. The oxazole ring is also moderately stable to alkali (74AHCU7)99) as expected, reaction with hydroxide ions is facilitated by electron-with-drawing substituents and fused benzene rings. 

Oxazoles are easily cleaved. 2,5-Dialkyl-l,3,4-oxadiazoles (159) in aqueous solution with acid or base give hydrazides (if suitable substituents are present, further reaction can occur see Section 4.02.3.5.1). 3-Methyl-l,2,4-oxadiazole (160) is easily hydrolyzed to acetamidoxime (61CKL)292). 

Azolecarboxylic acids can be quite strongly acidic. Thus l,2,5-thiadiazole-3,4-dicar-boxylic acid has first and second values of 1.6 and 4.1, respectively <68AHC(9)107). The acidic strengths of the oxazolecarboxylic acids are in the order 2>5>4, in agreement with the electron distribution within the oxazole ring <74AHC( 17)99). Azolecarboxylic acids are amino acids and can exist partly in the zwitterionic, or betaine, form e.g. 394). 

Azoleacetic acids with a carboxymethyl group also decarboxylate readily, e.g. all three thiazole isomers, by a mechanism similar to that for the decarboxylation of /3-keto acids cf. Section 4.02.3.1.2. The mechanism has been investigated in the oxazole case, (396) (397) (398) <72JCS(P2)1077). 

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

Thieno[3,4-d]oxazole-3a(4H)-carboxylic acid, dihydro-2-methyl-synthesis, 6, 1020 Thieno[2,3-d Joxazoles synthesis, 6, 990 Thieno[3,2-g]pteridine structure, 3, 284 lH-Thieno[3,4-c]pyran-2-ones synthesis, 4, 1032 Thienopyrazines synthesis, 4, 1022-1024 Thieno[2,3-6]pyrazines, 4, 1023 electrophilic substitution, 4, 1024 Thieno[3,4-6]pyrazines, 4, 1024 Thieno[3,4-c]pyrazole, 4,6-dihydro-3-hydroxy-carbamates... 

Oxazoles, prepared from carboxylic acids (benzoin, DCC NH4OAC, AcOH, BOSS % yield), have been used as carboxylic acid protective groups in a variety of synthetic applications. They are readily cleaved by singlet oxygen followed by hydrolysis (ROH, TsOH, benzene or K2CO3, MeOH ). 

In contrast to other acids, anhydrous hydrogen fluoride does not cause hydroly SIS and decarboxylation of the malonic acid residues in these reactions [5]. It is a good reagent for the cyclization of a-benzamidoacetophenones to 2,5 diphenyl-oxazoles [6] (equation 7) The same reaction with concentrated sulfuric acid gives cyclic product with only a 12% yield [6]... 

The Fisher oxazole synthesis involves condensation of equimolar amounts of aldehyde cyanohydrins (1) and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid. ... 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

More recent examples have employed a milder reagent system, triphenyl-phosphine and dibromotetrachloroethane to generate a bromo-oxazoline, which is subsequently dehydrohalogenated. Wipf and Lim utilized their method to transform intermediate 11 into the 2,4-disubstituted system of (+)-Hennoxazole k Subsequently, Morwick and coworkers reported a generalized approach to 2,4-disubstituted oxazoles from amino acids using a similar reagent combination, triphenylphosphine and hexachloroethane. ... 

Workers at Lilly prepared the oxazole-containing, dual PPAR ot/y agonist 23, through Robinson-Gabriel cyclodehydration of ketone 22 with acetic anhydride and sulfuric acid in refluxing ethyl acetate. ... 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

Thus attack of the TosMlC anion 9 on a carbonyl carbon is followed (or accompanied) by ring closure of the carbonyl oxygen to the electrophilic isocyano carbon to form an oxazoline (12). Loss of p-tolylsulfinic acid provides the 5-substituted oxazole 13. ... 

TosMIC reagents. For example, glyoxylic acid ethyl ester undergoes cycloaddition with (2-naphthyl) tosylmethyl isonitrile (17) to produce oxazole 18 in good yield. ... 

---