2-amino-4-substituted oxazoles

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... 

Kidwai and Kumar ° reported a microwave-accelerated reaction of urea 232 with phenacylbromide to yield the iminooxazoline 233 (Scheme 1.64). In this case, the total reaction time required was only 1.0-1.5 min. Patel and Fernandes prepared the 2-amino-4-substituted oxazoles 235 as precursors to novel oxa-zolo[5,4-c]pyrazoles and oxazolo[5,4-c]pyridazines, which were evaluated as antibacterial agents. Cyclization of a-bromoketones 234 with urea in refluxing DMF afforded 235 (Scheme 1.65). 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Reaction of Ser-OMe with benzimino ethyl ester resulted in the formation of an oxazoline without racemization (Scheme 27) (85T2379). After forming an amide with 2-amino-l-phenylethanol, Af-phthalimido AAs were oxidized with CrOs and dehydrated by POCI3 to give substituted oxazoles (91JHC1241). 

Oxazoles. N-Aroyl-a-amino ketones (I) can be cyclized to substituted oxazoles (2) in high yield by use of anhydrous hydrogen fluoride. ... 

The S-OT o-cyclization of amino-ketene dithioacetals such as 183 is also a viable method for the synthesis of sulfur-substituted oxazoles 184 (Scheme 51) <2002RJC1714>. 

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. 

In the rearrangement of allyl-substituted oxazoles, derived from Ar-benzoyl protected x-amino acids by cyclization with phosgene524, 525 or with triphenylphosphane/carbon tetrachloride502 as dehydrating agent, high selectivity is more of an exception, e.g., for the geranyl derivative 10524. 

Various preparation methods have been described. Wiley (1945, 1947) converted a-amino acids to acetdmido ketones by reaction with acetic anhydride in pyridine and obtained 2,5-dimethyl-4-substituted oxazoles after dehydration of the enol form of the intermediate. Theilig (1953) applied the reaction of a-bromoketones with the appropriate amides. 

Infrared absorption spectral data for several oxazole derivatives,86 90 including alkyl-98 186 and aryl-263 264 substituted oxazoles, 2-amino- and substituted-amino derivatives109 112 136, 5-amino179 198-201 and 5-alkoxy-oxazoles,66 carboxylic acids,112 147 esters,126 179 184 carboxamides,199 200 4-acetyloxazoles,147 halogenoalkyl oxazoles,91 oxazolines,262 and benzoxazoles262 have been reported. 

Freeman s group ° prepared a series of 5-amino-4-cyano-2-substituted oxazoles 517 from carboxylic acids and aminomalononitrile tosylate (AMNT) (Scheme 1.140). Presumably, AMNT is acylated by a carboxylic acid using DCC, which produces an intermediate A-acylamino nitrile 516 that is cyclized under the reaction conditions to yield 517. The yields of 517 are fair to excellent, and the reaction tolerates a wide variety of functional groups. This further extended the scope of their earlier work. ° Representative examples are shown in Table 1.35. 

Bromination of substituted oxazoles can yield normal aromatic substitution products or 4,5- and 2,5-addition products, depending on the reaction conditions. For example, Hassner and Fischer " brominated 2,5-diphenyloxazole 111 with bromine in acetic acid and sodium acetate to prepare 4-bromo-2,5-diphenyloxazole 595 (Scheme 1.163). Similarly, Belen kii and co-workers isolated a mixture of 5-bromo-2-phenyloxazole 596 and 4,5-dibromo-2-phenyloxazole 597 from treatment of 2-phenyloxazole 5 with bromine in refluxing benzene. Lawson and VanSant " isolated 2-amino-5-bromo-4-(trifluoromethyl)oxazole 599a and 5-bromo-2-(methylamino)-4-(trifluoromethyl)oxazole 599b from bromination of 2-amino-4-(trifluoromethyl)oxazole 598a and 2-(methylamino)-4-(trifluoromethyl) oxazole 598b, respectively, with bromine in acetic acid and sodium acetate. 

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... 

TABLE 1.35 5-AMINO-4-CYANO-2-SUBSTITUTED OXAZOLES FROM AMINOMALONONI-TRILE TOSYLATE AND CARBOXYLIC ACIDS, 110... 

This reaction can be used for the preparation of substituted oxazoles and amino acid and even imidazole and oxazolo[4,5-d]pyrimidin-7-one. ... 

In addition to intermolecular carbonylations, there are intramolecular reactions that allow for the synthesis of various heterocycles. As a prime example, the intramolecular alkoxy- or aminocarbonylation (cyclocarbonylation) of hydroxyl-or amino-substituted aryl/vinyl halides enables the synthesis of lactones, lactams, oxazoles, thiazoles, imidazoles, etc. [229]. 

C4-Alkenylation of 2,5 -substituted oxazoles was reported by Antilla and coworkers [59] (Scheme 18.61). The alkenylated products can be converted to functionalized amino alcohol and amino acid derivatives. 

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). 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

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

The thermally induced Cornforth rearrangement can be rationalized by postulating the dicarbonylnitrile ylid 103 as intermediate. It is especially the natures of the substituents R and R" that determine the direction of the rearrangement. For example, heating of 5-alkoxy-4-(aminocarbonyl)oxazole (102, R = OAlkyl, R" = NR2) readily gives in a good yield rearrangement into the isomeric 5-(substituted amino)-4-(alkoxycarbonyl) oxazole (104, R = OAlkyl, R" = NR2) (Scheme IV.40). 

Descriptor frequence values (cm )] are claimed to be helpful in predicting the direction of these rearrangements (96ZOK1742). These values were developed for oxazoles, 1,2,4-oxadiazoles, and furazanes. The calculated descriptor values [v sr(cm )] for the E- and Z-isomers of 4-aminofurazan 3-carboxamidoximes [E-I and Z-I, = (CH2)4, (013)2] and their rearranged 3-(substituted amino)furazan 4-carboxamidoximes [II,... 

---