2-Chloropyridine → N-pyridin-2-yl-1,3-oxazol-2-amine

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Objective: Comparison of the reactivity of 2-aminooxazole in the coupling with 2-chloropyridine using three different catalyst systems ( previously shown to be the best performers in a 96-well Process Research and Development Screen) To an oven-dried microwave vial was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.107 g, 0.2 mmol) and the vial was capped and purged with nitrogen. dioxane (2 mL) (degassed) was added and the reaction [Reactants]mixture was heated to 50 °C for 40 min followed by heating to 90 °C for a further 15 min (Solution 1). To an oven dried microwave vial was added 2-chloropyridine (0.095 mL, 1 mmol), oxazol-2-amine (0.187 g, 2.00 mmol), potassium carbonate (0.207 g, 1.50 mmol) and 4,4'-di-tert-butylbiphenyl (0.027 g, 0.1 mmol). The vial was then capped and purged with nitrogen. To this was added the activated catalyst solution (Solution 1). The reaction mixture was then heated to 90 °C for 16 h under an inert atmosphere. LCMS of the crude reaction mixture (Base) showed the mass peak for the desired product, however, this peak co-elutes with the Cl-pyridine starting material. LCMS of the crude reaction mixture using an acidic method showed no peak in the UV which had a mass corresponding to that of the product, however, the desired mass was observed in the MS at Rt= 0.27 min. A peak in the UV of a mass corresponding to the homocoupled bipyridine product was observed under both acidic and basic methods. Dichloromethane was added to the crude reaction mixture together with silica (2 g). The solvent was removed under reduced pressure and the resulting residue was placed in a dry-load tube prior to chromatography. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanolic ammonia (7 M) in DCM. 2-aminooxazole (103 mg) was recovered. The fraction containing the mass of the desired product produced 33 mg of impure material (see attached proton NMR, the desired product **_may_** be present (but it's hard to say). If this sample was to be pure it would correspond to an isolated yield of ~ 20% of the desired product, due to the fact that this is a really impure sample the real value is probably less than 10%. Conclusion: Reaction not progressed.

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