Oxazole cross-coupling reactions

The 2-aryloxazoles have also been synthesized under microwave activation by the direct Stille and Suzuki cross-coupling reactions of 1,3-oxazoline (OXT) [17]. Nolt et al. [18] utilized the microwave-assisted Cornforth rearrangements for the preparation of substituted 5-amino-oxazole-4-carboxylate (v). 

An improved and scalable method for the Pd-catalyzed cross-coupling reaction of oxazole-2-ylzinc derivatives with aryl bromides was reported [27]. Zinc chloride (ZnC ) was used in the couphng reactions and the products were obtained in exceUent yields, tolerating an array of functional groups on the aryl ring [27]. 

A novel oxazole building block, 4-bromomethyl-2-chlo oox lzole, has been synthesised and exploited in palladium-catalysed cross-coupling reactions to give a range of 2,4-disubstituted oxazoles in satisfactory yields <04TL3797>. The synthesis of previously inaccessible 2-amino-4-benzyloxeizoles has also been reported <04TL867>. 

The 1,3-disposition of the heteroatoms also imparts differential acidities to the ring positions, enabling sequential deprotonation. This rich acid-base chemistry permits selective functionalization of each ring-carbon atom. The synthesis of other organometaUic oxazoles and transition-metal-catalyzed cross-coupling reactions are also described. Applications of new cross-coupling methods for preparing polyoxazoles in the context of the syntheses of natural products are described in Section 1.5. 

This section details some recent examples of regioselective ring metalation and regioselective lateral metalation and subsequent functionalization. The examples were arbitrarily selected to demonstrate the versatility of such analogues. There is no attempt to include every metalated oxazole and the reader should consult the primary literature for additional examples. The synthesis and cross-coupling reactions of stannyloxazoles, silyloxazoles, and other organometallic oxazole analogues are discussed in Sections 1.4.8 and 1.4.9, respectively. 

Hughes and co-workers " studied the lithiation of 5-(3-methyl-5-isoxazolyl) oxazole 891 as part of their program to prepare suitable species for cross-coupling reactions (Scheme 1.239). They investigated the equilibrium of the 2-lithiooxazole 892 and the acyclic isocyanovinyUithium alkoxide 893 using H-NMR and C-NMR spectroscopy. The authors concluded that 893 was the predominant species under the reaction conditions investigated based on comparison of the H-NMR and C-NMR spectra with the spectra of 894 together with an extensive series of deuterium quenches. However, they also cautioned that the results of deuterium quenches of systems where dynamic equilibria are possible or expected must be interpreted with care. ... 

In contrast, if the mixture of 892 893 was transmetalated at —78°C with ZnCli and the resulting organozinc species quenched with D4-acetic acid, > 85% of the deuterium incorporation was found at C(2). The authors concluded that this organozinc species was best represented as the oxazole 895, which was subsequently used in palladium-catalyzed cross-coupling reactions (see Section 1.4.8). 

Appropriately substituted oxazoles can participate in transition metal-catalyzed cross-coupling reactions either as the organometaUic reagent or as the coupling partner. Halide-, OTf-, or SCHs-substituted oxazoles have been employed quite successfully as coupling partners to prepare 2-, 4-, and 5-substituted analogs. Examples of each type of reaction from the recent literature are discussed. Additional examples are described in Section 1.5. 

TABLE 1.71. 4-( 0-ALKENYL-2-PHENYLOXAZOLES FROM PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF 2-PHENYL-4-OXAZOLE TRIFLATE"... 

To prepare 4-iodooxazoles, Vedejs protocol with DMPU cosolvent allows for efficient synthesis. When DMF is used as the solvent, 2,4-unsubstituted oxazoles can be regioselectively brominated at the 4-position widi NBS on kilogram scale. Hunsdiecker reaction of a C4-carboxylic acid also provides the C4 bromide. With a substituted C2 position, Nicolaou and co-workers achieved chlorination of the C4 position using NCS to prepare an intermediate in the partial synthesis of diazonamide Similar to C2 trifloyloxazole synthesis, trapping of 4-oxazolones with triflic anhydride yields 4-trifloyloxazoles. These triflates, in contrast to 2- or 5-trifloyloxazoles are stable and can generally be utilized in cross-coupling reactions. 

The Suzuki-Miyaura cross-coupling reaction between oxazole-4-yl boronate and 2-iodo-oxazole derivatives was carried out under microwave irradiation at 150 W maximum power for 20 min to afford bis-oxazoles in good to excellent yields. A two fold increase in the yield and a six fold decrease in the reaction time were observed as compared to conventional heating (Flegeau et al., 2008). 

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