Synthesis and Application of Palladium Precatalysts that Accommodate Extremely Bulky Di-tert-butylphosphino Biaryl Ligands

Reaction Scheme


An umpolung approach to the synthesis of diaryl ketones has been developed based on in situ generation of acyl anion equivalents and their catalytic arylation. This method entails the base-promoted, palladium-catalyzed direct C-H arylation of 2-aryl-1,3-dithianes with aryl bromides. Use of MN-(SiMe3)2 (M = Li, Na) base results in reversible de- protonation of the weakly acidic dithiane. In the presence of a Pd(NiXantphos)-based catalyst and aryl bromide, cross-coupling of the metallated 2-aryl-1,3-dithiane takes place under mild conditions (2 h at rt) with yields as high as 96%. The resulting 2,2-diaryl-1,3-dithianes were converted into diaryl ketones by either molecular iodine, N-bromosuccinimide (NBS) or Selectfluor in the presence of water. The dithiane arylation/hydrolysis can be performed in a one-pot procedure to yield a variety of diaryl ketones in good to excellent yields. This method is suitable for rapid and large-scale synthesis of diaryl ketones. A one-pot preparation of anti-cholesterol drug fenofibrate (TriCor?) has been achieved on 10.0 mmol scale in 86 % yield.



An oven-dried 10 mL reaction vial equipped with a stirring bar was charged with 2-aryl-1,3-dithiane (0.2 mmol, 1.0 equiv.) and aryl bromide -if it was solid-(0.4 mmol, 2.0 equiv.) and the vial was brought into a glovebox. The reaction vial was charged with base [LiN(SiMe3)2 or NaN(SiMe3)2] (0.4 mmol, 2.0 equiv.), 1.4 mL THF, 0.4 mL THF solution (0.025 M) of NiXantphos and 0.2 mL THF solution of (0.025 M) [PdCl(allyl)]2, respectively. The vial was sealed with a rubber septa, wrapped with a strip of Parafilm, and taken out of the glovebox. The sealed vial was charged with aryl bromide -if it was liquid- (0.4 mmol, 2.0 equiv.) by a syringe. The resulting solution was stirred for the given time at the stated temperature. The reaction mixture was quenched with 0.1 mL of water and filtered through a small pad of Celite. The pad was then rinsed additional CH2Cl2. The combined organic solution was mixed with 0.5 g of deactivated silica gel and the solvent was removed in a rotatory evaporator. The remaining solid residue was loaded onto a deactivated silica gel column and purified by flash chromatography. The silica gel was deactivated by flushing with 5% triethylamine/hexanes solution (3 times) followed by 20:1 hexanes/ethyl acetate solution (3 times) to remove excess triethylamine.



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