2-methyl-4-substituted oxazoles

Evans and co-workers developed a regioselective lithiation protocol of 2-methyl-4-substituted oxazoles 945 during their synthesis of phorboxazoles. In particular, the authors required a general method to generate regioselectively a 2-(lithiomethyl)oxazole and to functionalize the intermediate without competitive lithiation and reaction at C(5). Among the bases investigated, lithium diethylamide was particularly effective and selective for the required transformation (Scheme 1.253, p. 206). 

The similarity of the ultraviolet spectrum of 4,5-diphenyloxazol-2-one (91) with those of both alternative methyl derivatives preclude application of the spectral comparison method to the elucidation of their structures, but the fluorescence spectra of these compounds indicate that 91 exists in the oxo form. ° Infrared data for a number of substituted oxazol-2-ones support this conclusion. ... 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

N,N-bis-trimethylsilyl enamines (e.g. 269) obtained by sequential addition of methyl-lithium and acyl chlorides to acetyltrimethylsilane cyanohydrin 267, cyclize under thermolysis or by trimethylsilyl trifluoromethanesulfonate treatment to give substituted oxazoles (e.g. 270) (equation 57)140. 

It is interesting to note that 5-butyloxazole has a very distinct bacon-fatty aroma and could be an important flavor constituent of fried bacon. 5-Pentyloxazole also possesses a similar aroma characteristic. Both 5-butyloxazole and 5-pentyloxazole have no alkyl group on carbon 2 or A of the oxazole ring. When a methyl group is substituted on carbon-2 (e.g., 2-methyl-5-pentyloxazole), the fatty aroma decreases and a sweet-floral aroma becomes more characteristic. The sweet-floral character is further enhanced by additional methyl substitution on carbon-A (38). 

For a closely related method for the synthesis of a-substituted a-amino acids via rearrangement of allyloxy-substituted oxazoles (derived from At-benzoyl-protected a-amino acids) see p 3448. For the synthesis of substituted 2-aminopent-4-enals by Claisen rearrangement of substituted (l-methyl-3-oxahexa-l,5-dienyl)amines see ref 85. 

Fig. 2. Plots of pXa values for 4-methyl-(A) and 2,4-dimethyl-5-substituted oxazoles (B) against the Hammett (meta)-a constants. [Reproduced with permission from D. J. Brown and P. B. Ghosh, J. Chem. Soc. B, 270 (1969).]...

Although electrophilic substitution reactions are possible with oxazoles, they are frequently accompanied by addition reactions, as in furan. The bromination of 4-methyl-2-phenyloxazole with bromine or A/-bromosuccinimide yields 5-bromo-4-methyl-2-phenyloxazole, and that of 2-methyl-5-phenyloxazole gives 4-bromo-2-methyl-5-phenyloxazole. Mercury(II) acetate in acetic acid acetoxymercurates 4-sub-stituted oxazoles in the 5-position, 5-substituted oxazoles in the 4-position, and 4,5-disubstituted oxazoles in the 2-position. The acetoxymercury group can be substituted by electrophiles, e.g. ... 

Short and Ziegler employed propargylamides as precursors to (E)-p-iodo (vinyl)sulfones, which were key intermediates in their synthesis of 5-[(phenylsul-fonyl)methyl]-2-substituted oxazoles (Scheme 1.73). Here, a propargylamide 274 was iodosulfonated photolytically to afford the key ( )-p-iodo(vinyl)sulfones 275. 

TABLE 1.21. 5-[(PHENYLSULFONYL)METHYL]-2-SUBSTITUTED OXAZOLES FROM PROPARGYL AMIDES VIA ( )-P-IODO(VINYL)SULFONES ... 

Recently, Addie and Taylor extended the synthetic utility of TosMIC by developing conditions to effect desulfonylation of a 5-substituted 4-tosyloxazole 405 (Scheme 1.109, p. 90). Their plan was to generate the dianion of 5-methyl-4-tosyloxazole 402 followed by quenching with an electrophile to produce a 5-substituted-4-tosyloxazole 404. Desulfonylation of 404 would provide a novel entry to 5-substituted oxazoles 405, thereby avoiding the use of toxic methyl isocyanide. In addition, desulfonylation of the 5-substituted 4-tosyloxazoles 406 normally obtained from reaction of TosMIC with an ester, acid chloride, or acid anhydride would further broaden the scope and use of this reaction. 

Jacobi s group cyclodehydrated iV-carbobenzyloxy-D-prolyl-L-alanine methyl ester 438 using POCVpyridine to prepare large quantities (50 g) of the 5-methoxy-4-methyl-2-substituted oxazole 439 (Scheme 1.121). Both 439 and ent-439 were key starting points for their enantiospecific syntheses of (+)-norsecurinine and (—)-norsecurinine. 

A mechanistic rationale that explains the formation of acyl isocyanates, mixed anhydrides, and A-acylamides from ozonolysis of substituted oxazoles was pre-sented by Kashima s group. In addition, Kashima and co-workers adapted their methodology for peptide synthesis (Scheme 1.204). Here, the starting amino acid was readily converted to a 5-phenyloxazole analogue 740 in several straightforward steps. Ozonolysis of 740 followed by reaction with glycine methyl ester... 

Methyl-4-(1 -hydroxy-1 -methylethyl) benzene. See Tri methyl benzyl alcohol Methyl hydroxymethyl oleyl oxazoline CAS 14408-42-5 EINECS/ELINCS 238-387-5 Synonyms 2-(8-Heptadecenyl)-4-methyl-2-oxazol i ne-4-methanol 2-Oxazol i ne-4-methanol, 2-(8-heptadecenyl)-4-methyl-Classification Substituted heterocyclic compd. Empirical C22H41NO2 Uses Antistat in cosmetics... 

Jefferys has modified the Davidson oxazole synthesis by using phenacyl bromides and ammonium acetate to yield 2-methyl-4-(or 4,5-di-)-substituted oxazoles. He was also able to extend the syntheses outlined by Japp and Davidson to obtain 4,5-dialkyl and 4-aryl oxazoles. These oxazoles together with 2-methyloxazole were then quatemized and transformed into cyanine and merocyanine dyes. 

The first iodine-catalyzed synthesis of 2-alkyl substituted oxazoles 130 by a decarboxylative domino reaction was reported. Aryl methyl ketones 128 were transformed in situ into a-iodo ketones and then, by the Kornblum oxidation, into 1,2-diketones. After the addition of the a-amino acid 129, an l2-mediated cyclization/decarboxylation gave oxazoles 130. The reaction proceeds better if the Ar has electron-donating substituents and if the R group is a branched alkyl chain or phenyl residue. The reaction used oxone to regenerate iodine (13JOC6065). 

The 2 -I- 2-photocycloaddition reaction of substituted oxazoles, 2-methyl-5-methoxyoxazoles (23), with isoquinoline-1,3,4-triones (22) yielded spirooxetanes (24) with high regio- and diastereo-selectivity. The chemoselectivity of the photoreaction is greatly influenced by the substituent on the C(5) of the oxazole ring (Scheme 7) ... 

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... 

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