Room-Temperature Palladium-Catalyzed Coupling of Heteroaryl Amines with Aryl or Heteroaryl Bromides

Abstract

Heteroaryl amines readily undergo Buchwald-Hartwig amination reactions with a range of aryl and heteroaryl bromides at room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu. The pharmaceutically attractive biaryl amines are generally formed in short reaction times (0.5-16 h) and in good to excellent yields.

Key words

amination - biaryl amine - coupling - heteroaryl amine - palladium

References and Notes

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14

Representative General Procedure; Coupling of Pyrazole 2 and 2-Bromopyridine: 3-Methylpyrazol-
5-amine (2; 1.50 mmol, 146 mg), t-BuXPhos Pd(II) phenethylamine chloride 1 (0.015 mmol, 10.3 mg), t-BuXPhos (0.015 mmol, 6.4 mg) and NaOt-Bu (3.15 mmol, 303 mg) were charged into a round-bottom flask which was evacuated and back-filled with nitrogen (3 ×), then purged with a stream of nitrogen for 10 min. t-BuOH (5 mL) and
2-bromopyridine (1.88 mmol, 296 mg) were added via syringe and the reaction was stirred at r.t. for 4 h. The solvent was removed then H₂O, sat. aq NH₄Cl and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (EtOAc-MeOH, 9:1) to give the biaryl amine as a white solid (229.5 mg, 88%); mp 177-179 ˚C. IR: 3521 (br), 2995 (m), 1525 (s), 1503 (m), 1495 (m), 1420 (s), 1281 (m) cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 2.19 (s, 3 H, Me), 6.04 (s, 1 H, CH_pyrazole), 6.68 (m, 1 H, CH_Ar), 7.22 (m, 1 H, CH_Ar), 7.52 (dd, 1 H, J = 7.2, 7.0 Hz, CH_Ar), 8.09 (d, 1 H, J = 4.1 Hz, CH_Ar), 9.00 (s, 1 H, NH), 11.73 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 10.95, 94.12, 109.22, 113.60, 137.12, 138.87, 147.40, 149.06, 155.39. MS (ES): m/z (%) = 175 [M + H]⁺(100), 158 (100), 134 (80), 107 (25). HRMS: m/z [M + H]⁺ calcd for C₉H₁₁N₄: 175.09782; found: 175.09778.