5-Bromo-2-phenyloxazole

Condensation of 2-bromoethylamine hydrobromide with benzoyl chloride in benzene in the presence of 5 equivalents of EtsN gave 2-phenyl-4,5-dihydrooxazole (1) in 67% yield [1]. Treatment of 1 with 3 equivalents of NBS in boiling CCL in the presence of AIBN led to 5-bromo-2-phenyloxazole (2). Presumably, sequential bromination and dehydrobromination of 1 led to 2-phenyloxazole, which underwent further bromination to afford 2. 

While the so-called halogen dance reaction had been reported for aromatic and heteroaromatic systems, it had never been described for the oxazole ring. This approach was used for an efficient transformation of 5-bromo-2-phenyloxazole, 114, into several 5-substituted 4-bromo-2-phenyloxazoles 115 <05SL1433>. The electrophiles used were water, benzaldehyde, TMSCl, halogens, and CO2 affording the final compounds in good yields (66-78%). 

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 simple two-step synthesis of 5H-alkyl-2-phenyloxazol-4-ones has been reported by Trost and coworkers (Scheme 6.209) [377]. a-Bromo acid halides were condensed with benzamide in the presence of pyridine base at 60 °C to form the corresponding imides. Microwave irradiation of the imide intermediates in N,N-dimethylacetamide (DMA) containing sodium fluoride at 180 °C for 10 min provided the desired 5H-alkyl-2-phenyloxazol-4-ones (oxalactims) in yields of 44—82%. This class of heterocycles served as excellent precursors for the asymmetric synthesis of a-hydroxycar-boxylic acid derivatives [377]. 

The halogenated derivatives of oxazoles, thiazoles80 and benzothiazoles81 were also the subject of palladium catalyzed coupling with terminal acetylenes. 5-Bromo-2-methyl-4-phenyloxazole for example coupled efficiently with phenylacetylene using a conventional catalyst system to give an excellent yield of the desired product (6.53.),82... 

A systematic study of substitution reactions of oxazole itself has not been reported. Bromination of 2-methyl-4-phenyloxazole or 4-methyl-2-phenyloxazole with either bromine or NBS gave in each case the 5-bromo derivative, while 2-methyl-5-phenyloxazole was brominated at C(4). Mercuration of oxazoles with mercury(II) acetate in acetic acid likewise occurs at C(4) or C(5), depending on which position is unsubstituted 4,5-di-phenyloxazole yields the 2-acetoxymercurio derivative. These mercury compounds react with bromine or iodine to afford the corresponding halogenooxazoles in an electrophilic replacement reaction (81JHC885). Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole with the DMF-phosphoryl chloride complex yields the 4-aldehyde. 

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. ... 

Further evidence for involvement of an iV-acyl-l//-azirine intermediate is supported by isolation of both 5-bromo-4-methyl-2-phenyloxazole 113 and 4-bromo-5-methyl-2-phenyloxazole 114 from the photolysis of 2-benzoyl-4-bromo-3-methylisoxazol-5-one 112 (Scheme 1.31). In addition, the presence of a 4-halo substituent in 112 seriously limited the synthetic utility of this reaction. Despite extensive and substituent labeling, the authors concluded that further studies were necessary to elucidate fully the mechanism of this rearrangement. 

Cleavage of 171 with TEA was accompanied by desilylation to afford 2-aryl-5-(4-hydroxyphenyl)oxazoles 172. Bromodesilylation of 171 yielded the corresponding resin-bound 4-bromo-2,5-diaryloxazole 173, which was used in a Suzuki coupling to prepare 5-(4-hydroxyphenyl)-4-(4-methylphenyl)-2-phenyloxazole 174 (Ar = C6H5). Selected examples are shown in the Table 1.11. 

The reactions of 2,5-disubstituted 3-furyl bromides with butyllithium and OFCP in anhydrous THF at -78° afforded bisfurylethenes 76 [84]. Photochrome 77 [85, 86] (29 6 % yield) and a series of its derivatives 78 (55-65 % yield) with various substituents in position 6 of the benzofuran ring [87] were obtained from 3-bromo-2-methyl-1 -benzofuran. 1,2-Bis(5-n-aIkyl-2-phenyloxazol-4-yl)perfluorocyclopent-enes... 

Silver(I) acetate was the optimal oxidant however, TFA was also needed as an acidic additive to improve conversions. For 2-phenyloxazole, electron-donating substrates afforded better yields compared with electron-withdrawing substrates (eq 43). Bromo and chloro substitution were also compatible. Additionally, 2-alkyl and 2-carbonyl substrates could be employed. Other triarylphosphines could also be employed however, orf/zo-substituted triarylphosphines were unreactive. Electron-withdrawing substituents such as trifluoromethyl on the phosphine produced diminished yields (25% with 2-phenylthiazole). 

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