Pd-Catalyzed Nucleophilic Fluorination of Aryl Bromides

Reaction Scheme

Abstract

The first palladium-catalyzed amidation of five-membered heterocyclic bromides with multiple heteroatoms was achieved using the Pd/1�catalyst system. N-Arylated imidazoles, pyrazoles, thiazoles, pyrroles, and thiophenes were synthesized in moderate to excellent yield. Experimental results and DFT calculations point to the need for an electron-rich and sterically demanding biaryl phosphine ligand to promote these difficult reactions.

Substrates

Procedure

General procedure: An oven-dried test tube was equipped with a magnetic stir bar and charged with [{(allyl)PdCl}2] (0.75 mol %), AdBrettPhos (3.0 mol %), Cs2CO3 (2 mmol), and amide (2 mmol ; the heteroaryl bromide (1 mmol), if solid, is added at this point). The test tube was sealed with a screw-cap septum, and then evacuated and backfilled with argon (this process was repeated a total of 3 times). 2-Methyl-2- butanol (2 mL) and heteroaryl bromide (1 mmol) were then added by syringe. The reaction mixture was heated at 90�C for 21h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with a saturated solution of sodium bicarbonate, dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography on silica gel (see the Supporting Information for details) to give pure products.

Products

Materials

     
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