Construction of the Isoxazole Ring

In 1888, Claisen reported that condensation of p-ketoesters with hydroxylamine provided a mixture of 3-hydroxyisoxazoles and 5-oxazolones. The product distribution was largely dependent on the substitution of the initial P-ketoester and the pH of the reaction mixture. The differentiation occurs due to the initial attack of the hydroxylamine at either the ester carbonyl or the ketone carbonyl. Krogsgaard-Larsen has prepared isoxazoles selectively starting with Meldrum s acid in a three-step procedure. When acetyl chloride (R = CH3) is used in this procedure, the soil fungicide 5-methyl-3-oxazazolol is prepared in 57% overall yield. 

Oxazoles are acidic at C2 with a theoretical pKg value of 21 Metalation is facile at C2 with strong bases. C2-metalated oxazoles are in equilibrium with their ring-opened isonitrile. Due to this equilibrium, C2-metalated oxazoles are nucleophilic at either C2 or C4, and care must be taken when quenching the C2-metalated oxazole to ensure proper chemoselectivity (see Section 6.3.3). Benzoxazoles are acidic at C2 like oxazoles (experimental pKa 24.8), and the metalated benzoxazole is also in equilibrium with its ring opened isonitrile. Isoxazoles, without a C-H group flanked by two heteroatoms, are acidic at the C5 position with a theoretical pKa value of 27 however, in practice, deprotonation with hydroxide occurs at C3 to give a ring-opened P-ketonitrile intermediate. All of these heterocycles can be deprotonated with metal amides or carbanion bases. 

Protonation of all three heterocycles occurs at the nitrogen atom, which is weakly basic. The resulting oxazole and benzoxazole conjugate acids have a pK, value of—1, and the conjugate acid of isoxazole has a pKa value of —3. 

As mentioned previously, examples of electrophilic substitution to the oxazole nucleus are relatively rare, especially in the modem synthetic literature. Introduction of an electron-donating substituent substantially increases the rate of substitution. An early example was demonstrated by Wiley, wherein 2-phenyloxazole was brominated with NBS to give 5-bromooxazole as expected. More recently, efforts toward the synthesis of molecules with a high affinity for the GABA receptor made use of this reaction to give the fully substituted 5-bromooxazole.  

Electron-rich isoxazoles are also known to undergo electrophilic substitution under similar conditions. The bromination of 5-aminoisoxazole provided the 4-bromo derivative that was utilized as part of a synthesis of a library of compounds screened for their ability to act as bradykinin B2 receptor antagonists.  

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