Palladium-Catalyzed Couplings of Heteroaryl Amines with Aryl Halides Using Sodium Phenolate as the Stoichiometric Base

Abstract

Heteroaryl amines are efficiently coupled (in two hours) to aryl halides with catalytic Pd₂(dba)₃ and Xantphos to provide the corresponding biaryl amines under microwave and standard thermal conditions. The use of organic-soluble sodium phenolate (NaOPh) as the stoichiometric base promotes facile coupling of a variety of substrates in excellent yields.

Key words

palladium-catalyzed - sodium phenolate - C-N bond-forming - biaryl amine - heteroaryl amine

References and Notes

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8

At the time of this manuscript’s preparation, a search via ACD and ACX failed to find any commercially available arylnonaflates.

12

All microwave reactions were conducted in a 2-5 mL Biotage Microwave Vial Kit with sealable cap (code no. 351521) using a magnetic stirbar. Microwave heating was performed with a single-mode cavity Emrys SmithCreator.

13

General Procedure for Compounds Shown in Table 3
A 2-5 mL Biotage microwave vial was charged with the aryl halide (1.10 mmol), sodium phenolate (191 mg, 1.65 mmol), Pd₂(dba)₃ (12.6 mg, 0.0137 mmol, 2.5 mol% of Pd), and Xantphos (19.1 mg, 0.0330 mmol, 3.0 mol%) followed by degassed 1,4-dioxane (6.50 mL). The mixture was stirred while degassing with argon for 1 min. The heteroaryl amine (1.21 mmol) was added last, the vial was immediately capped and sealed, then heated at 80 °C for 2 h. After cooling to r.t., the mixture was diluted with EtOAc (400 mL), washed with 1 N aq NaOH (3 × 100 mL) and brine (100 mL), dried over anhyd Na₂SO₄, filtered, and the solvent removed under vacuum. The resulting residue was purified over silica gel (12 g, hexanes-EtOAc) and the product was freeze-dried from MeCN-H₂O to provide the pure product.