5-heteroaryl-substituted oxazoles

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

Finally, 2-iodonitrobenzene has also been effectively utilized in the heteroaryl Heck reaction to provide a fully substituted oxazole ring. ... 

Activity. Our structure-activity studies involved the evaluation of oxazoles and thiazoles as the central component, aryl and heteroaryl substitution about the azole heterocycle and optimization of substituents on the peripheral aryl/heteroaryl moieties. 

Ducept and Marsden described a general synthesis of 5-ethoxy-2-substituted 4-(triethylsilyl)oxazoles 176 from the rhodium(II)octanoate-catalyzed diazo-transfer reaction of ethyl (triethylsilyl)diazoacetate 175 and nitriles (Scheme 1.48). The reaction conditions tolerate a wide variety of functional groups on the nitrile, including alkyl, aryl, heteroaryl, vinyl, carbonyl, sUyloxy, and dialkylamino. Desilylation of 176 with TBAF afforded the corresponding 2-alkyl(aryl)-5-ethoxy-oxazoles 177, which are normally inaccessible from diazoesters using conventional rhodium-carbene methodology. The authors noted that carbonyl groups in the 2 position of 176 are not compatible with TBAF deprotection. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reaction, whereby the alkyl halide or aryl halide is coupled to the unfunctionalized oxazole. First developed by Ohta and colleagues, it was demonstrated that a diverse array of aromatic heterocycles can be substrates in the reaction with chloropyrazines. While substitution was expected to occur at the 2-position, the reaction with chloropyrazine as the aryl halide resulted in substitution at the 5-position. When benzoxazole is used as the coupling partner, substitution is effected at the 2-position. More recently, a systematic study by Strotman and co-workers has demonstrated that slight modifications of the reaction conditions can allow completely regioselective coupling at either the 2- or 5-position. ... 

Shao and coworkers employed a [NHC-Pd(II)-Im] catalyst in the C-2 arylation of oxazoles and benzoxazoles with less-expensive and readily available aryl chlorides (2014OL1984). Consequently, 5-aryloxazoles (16 examples 77—97% yield) and 5-(un)substituted benzoxazoles (26 examples 53—96% yield) readily coupled to aryl chlorides bearing an assortment of different functional groups with no significant impact on the reaction. Examples of coupled products using the heteroaryl chlorides and 2-chloropyr-idine, 3-chloropyridine, or 2-chlorothiophene are illustrated below. 

Using alpha-terthienyl as the model for this third class of photoactivated miticides, an azole heterocycle was incorporated as the central anchor ring of molecule 3. Both oxazole and thiazole heterocycles were examined. Aryl and heteroaryl moieties were substituted about the azole. 

Direct Carbonylative Coupling. Unsymmetrical diaryl ketones were synthesized via the direct carbonylative coupling of aryl iodides and heteroarenes in the presence of catalytic [PdCl(cinnamyl)]2, l,3-bis(diphenylphosphino)propane (dppp) as the ligand, and stoichiometric Cul. Thus, heterocycles such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, and imidazoles reacted, with 4-iodoanisole in 56-75% yields (eq 1). Aryl iodides containing a variety of electron-donating or electron-withdrawing substitutents were tolerated in the reaction (eq 2) however, aryl bromides provided only traces of products. The role of the stoichiometric copper salt was to form a heteroaryl-Cu species, which could easily transmetallate to Pd. No reaction was observed in the absence of the Cul additive. 

The construction of 2-substituted 5-formyl-oxazoles was performed starting from aryl, heteroaryl, and alkyl propargylamides through treatment with Pd(ll) salts with tolerance of various functional groups [103] (Scheme 53). 

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