Palladium-Catalyzed Amination of Unprotected Five-Membered Heterocyclic Bromides

Reaction Scheme


An efficient method for the palladium-catalyzed amination of unprotected bromoimidazoles and bromopyrazoles is presented. The transformation is facilitated by the use of our newly developed Pd precatalyst based on the bulky biarylphosphine ligand tBuBrettPhos (L4). The mild reaction conditions employed allow for the preparation of a broad scope of aminoimidazoles and aminopyrazoles in moderate to excellent yields.



To an oven-dried re-sealable screw-cap test tube, equipped with a magnetic stir bar, was added tBuBrettPhos-Pd-G3 (1.0 mol %), tBuBrettPhos (1.0 mol %, Pd:L = 1:1), heteroaryl halide (1.0 mmol, 1.0 equiv), amine (if it is a solid) (1.2 mmol, 1.2 equiv). The vial was sealed with a teflon screw- cap, evacuated and backfilled with argon (this process was repeated a total of 3 times). Under argon, amine (if it is a liquid) (1.2 mmol, 1.2 equiv) was added followed by LHMDS (1M in THF) (2.2 mL, 2.2 equiv) via syringe. The argon source was removed and the sealed test tube was placed into a pre-heated 50 �C oil bath with vigorous stirring. After stirring for 6 h at 50 �C, the vessel was cooled to room temperature, then quenched by the careful addition of 1M HCl (4 mL), diluted with EtOAc and poured into saturated aqueous NaHCO3. After extracting with 3 portions of EtOAc and 1 portion of CH2Cl2, the combined organic layers were dried over Na2SO4, concentrated in vacuo and purified via flash column chromatography.



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