Benz oxazole

Fig. 8.13. Cyclization a) of Y -(2-hydroxyphenyl)carbamates as potential prodrugs of benz-oxazoles and phenols, and b) of N-(2-hydroxypropyl)carbamates as potential prodrugs of oxazolidinones and phenols [175]... 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other -sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines T22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[ >]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Similar results were observed for the heteroaryl Heck reactions of chloropyrazines with tc-electron-rich hetcroaryls including oxazole, thiazole, benz[ >]oxazole, benz[fc ]thiazole and N-... 

The tetrahydro-derivatives of the oxazole and isoxazole system are unstable. As a consequence, only acyclic products have been reported from the reductions with complex metal hydrides. 2,5-Diphenyl-oxazole (119) gave 2-benzylamino-l-phenylethanol (120),141 and 3,5-diphenyl-2-isoxazoline (121) was converted to 3-amino-l,3-diphenylpropanol (122)142 on reduction with lithium aluminum hydride. 3-Phenylbenzisoxazole was resistant to reduction with lithium aluminum hydride and sodium borohydride,143 but benz-oxazole (123), benzoxazol-2-one (124), and benzoxazol-2-thione (125) have been reported 141 to yield 2-methylaminophenol (126) on reduction with lithium aluminum hydride. 

Ethyl chloroacetate converts 2-hydrazinobenzoxazole (286) into 2//-[l,2,4]triazolo[3,4-6]benz-oxazol-3-ones (291) <88BCJ1339>. Also 2,9-dihydro[l,2,4]triazolo[4,3-/>]benzimidazol-3-ones (292) and 2//-[l,2,4]triazolo[3,4-/>]benzthiazol-3-ones (293) are formed from the respective 2-hydra-zinobenzimidazole (28" and 2-hydrazinobenzthiazole (290) (Equation (81)) <88BCJ1339>. 

Phenyloxazole (38) is regioselectively phenylated at C-5 to afford 2,5-diphenyl-oxazole with bromobenzene, and arylation of benz[ ]oxazole (39) with 26 gives the C-2 arylation product 40 as expected [3]. 

The first example of C—H arylation of (benz)oxazoles (20 examples 23—92% yield) and (benzo)thiazoles (3 examples 43—97% yield) with easily accessible aryltrimethylammonium triflates was recendy reported by Wang and coworkers (2015OL4926). The researchers evaluated a catalyst system... 

Decarboxylative benzoylation of (benz)oxazoles (220) and (benzo)thia-zoles (221) with a-oxocarboxyHc acids (222) was observed to be catalyzed... 

Miura and Hirano reported a copper-mediated cross-couphng reaction between 2-arylazines 102 and 1,3-azoles 100 including (benz)oxazoles and xanthines giving the products 103 (Scheme 45) (2011JA2160). The corresponding arylated heteroarenes were obtained in moderate yields under rather harsh conditions (high temperature in the presence of superstoichiometric... 

Scheme 70 Copper-catalyzed/mediated thiolation of heterocycles including (benz) oxazoles, (benzo)thiazoles, (benz)-1H-imidazoles, IH-indoles, and IH-pyrroles with ar-ene- and alkanethiols.

An alternative to the use of benzyl hahdes in direct C-H benzylations was disclosed by Ackermaim and coworkers. These authors optimized conditions for the C-H arylation and alkenylation of (benz)oxazoles with phosphate and sulfamate electrophiles and extended their results to the C-2 benzylation of (benz)oxazoles with benzyl phosphate (Scheme 19.21) [35]. More recently, the same group reported the use of a palladium catalyst containing an air- and moisture-stable secondary phosphine oxide ligand for this reaction [36]. 

Scheme 19.21 Palladium-catalyzed benzylation of (benz)oxazoles with benzyl phosphate.

The same group reported an extension of the direct alkylation of (benz)oxazoles with various alkyl bromides and chlorides by using the stronger base lithium tert-butoxide (Scheme 19.23) [38]. 5-Aryloxazoles containing electronically diverse substituents such as CFj and OMe were also alkylated successfully. Various linear alkyl chains were introduced, such as phenylpropyl, citronellyl, or octyl, affording interesting lipophilic molecules. The optimized reaction conditions failed to apply to benzothiazoles, and the authors had to turn their attention to nickel catalysis to achieve the corresponding alkylation (Section 19.2.3). Experiments were run to understand the reaction mechanism that presumably involves Sj 2-type oxidative addition of the alkyl halide to palladium(O) followed by transmetallation by the in situ-lithiated (benz)oxazole (Scheme 19.24). 

Scheme 19.23 Palladium-catalyzed direct alkylation of (benz)oxazoles.

The oxidation products were the corresponding 2-substituted benz-oxazoles (Box), formed in yields higher than 90% (Figure 47). 

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