4-amino-2,5-disubstituted oxazoles

Tanaka and Kuriyama " prepared cii-4,5-disubstituted-oxazolines by catalytic hydrogenation of 2-amino-4,5-disubstituted oxazoles using PtOa or Pd/C. The authors isolated ring cleavage products from reactions employing a high catalyst load. 

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. ... 

The tosyl compound reacts with aldehydes in the presence of potassium carbonate to yield 5-alkyl- or 5-aryl-oxazoles, the intermediate dihydrooxazoles (which can be isolated) eliminating toluene-p-sulfinic acid (Scheme 30). Use of acyl chlorides in place of aldehydes leads to 4-tosyloxazoles (288). Furthermore, alkylation of tosylmethyl isocyanide with an alkyl halide RfX, followed by treatment with an aldehyde R2CHO, yields a 4,5-disubstituted oxazole (289). A related reaction is that of A-tosylmethyl-iV -tritylcarbodiimide with aromatic aldehydes under phase-transfer catalysis to yield 2-tritylaminooxazoles which are readily converted into 2-amino-5-aryloxazoles (equation 117) (81JOC2069). 

A novel oxazole building block, 4-bromomethyl-2-chlo oox lzole, has been synthesised and exploited in palladium-catalysed cross-coupling reactions to give a range of 2,4-disubstituted oxazoles in satisfactory yields <04TL3797>. The synthesis of previously inaccessible 2-amino-4-benzyloxeizoles has also been reported <04TL867>. 

Cyclization of an amide or urea with an a-haloketone is a well-established and still widely used method to prepare oxazoles. Both 2,4-disubstituted oxazoles 197 and 2-amino-4-substituted oxazoles 198 are readily available from this methodology (Scheme 1.53). The commercial availability of the starting materials and the... 

P Wipf, H Heimgartner. Coupling of peptides with C-terminal a,a-disubstituted a-amino acids via oxazol-5(4//)-onc. Ilelv Chim Acta 69, 1153, 1986. 

The oxazolo[4,5-/z]quinolin-2(3//)-ones (89) and 2,5-disubstituted oxazolo[4,5-/i]quinolines (90) were prepared as new antiallergic agents by oxazole ring annelation conducted by condensing 7-amino-8-hydroxyquinoline intermediates with phosgene, o-ester, or imidate reagents (Scheme 7)... 

Rearrangement of alkoxycarbonyl imidazole acryl azides in diphenyl ether at high temperatures afforded imidazo[l,5-c]pyrimidinone or imidazo[4,5-c]pyridinone derivatives <02TL5879>. Efficient synthesis of imidazopyridodiazepines from peri annulation in imidazo[l,2-a]pyridine has been described <02TL9119>. A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[l, 2-a]pyridines has been published <02TL9051>. Novel 2,3-dihydroimidazo[2,l-h][l,3]oxazoles were prepared from intramolecular nucleophilic i/wo-substitution of 2-alkylsulfonylimidazoles <02S2691>. 4,4 -Bi-l//-imidazol-2-ones were efficiently synthesized from 5-amino-ot-imino-1 //-imidazole-4-acetonitriles and isocyanates <02JOC5546>. 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

Kawase described a direct and general synthesis of 2,4-disubstituted 5-(trifluoromethyl)oxazoles 500 from reaction of an A -acyl-A-benzyl amino acid 499 with trifluoroacetic anhydride in pyridine (Scheme 1.136). In general, the best... 

TABLE 1.34. 2,4-DISUBSTITUTED-5-(TRIFLUOROMETHYL)OXAZOLES EROM A-ACYEATED AMINO ACIDS AND TEAA... 

Mohapatra and Datta isolated a series of 2,4-disubstituted-5-(f-butoxycarbon-yloxy)oxazoles 546 by treating A -acyl amino acids 544 with di-ferf-butyl pyroca-bonate (Boc)20 (Scheme 1.150). The authors proposed that (Boc>20 effected cyclodehydration of 544, producing a 2,4-disubstituted 5(4//)-oxazolone 545. However, enolization of 545 under the reaction conditions and trapping with (Boc)20 then led to 546. Attempts to isolate 545 were unsuccessful. This one-pot reaction was quite general and afforded the oxazoles in good yield. 

TABEE 1.34 2,4-DISUBSTITUTED-5-(TRlFEUOROMETHYL)OXAZOLES FROM Af-ACYLATED AMINO ACIDS AND TFAA, 107... 

Oxazoloquinazolines 1134 and oxazoles 1135 have been prepared from o-amino-N-(l,l-disubstituted-propynyl)benzamides 1133 with triphosgene by angular cydi-zation, promoted by either the initial exothermic reaction on the addition of triphosgene and/or by refluxing in pyridine [805]. 

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