Copper-Catalyzed N-Arylation of Amides and Azoles Using Phosphine-Free Hydrazone Ligands

Abstract

Phosphine-free hydrazone such as 1c was found to be an efficient ligand for the copper-catalyzed Goldberg-type N-arylation of amides and Ullmann-type N-arylation of azoles with aryl halides under mild conditions. A variety of N-arylamides and N-arylazoles were synthesized in good to high yields.

copper - arylations - hydrazones - amides - amines

References and Notes

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<A NAME="RU11907ST-11">11</A>

General Procedure for Copper-Catalyzed N-Arylations of Amides with Aryl Iodides (Table 2)
Under an atmosphere of argon, aryl iodide (1.2 mmol) was added to the mixture of amide (1 mmol), K₃PO₄ (2 mmol), ligand (0.10 mmol), and CuI (0.05 mmol) in DMSO (1 mL) at r.t. The mixture was stirred at 110 °C. After 5 h, the mixture was cooled to r.t, diluted with EtOAc, and filtered through Celite, eluting with additional EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography using a mixture of hexane and EtOAc to provide the desired product. All prepared compounds 2 were known and identified by ¹H NMR, ¹³C NMR, and MS.

<A NAME="RU11907ST-12">12</A>

General Procedure for Copper-Catalyzed N-Arylations of Azoles with Aryl Halides (Table 4)
Under an atmosphere of argon, aryl halide (1.5 mmol) was added to the mixture of azole (1 mmol), Cs₂CO₃ (2 mmol), ligand (0.10 mmol), and CuI (0.05 mmol) in DMF (1 mL) at r.t. The mixture was stirred at 110 °C. After 24 h, the mixture was cooled to r.t., diluted with EtOAc, and filtered through Celite, eluting with additional EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography using a mixture of hexane and EtOAc to provide the desired product. All prepared compounds 3 except for 3j were known and identified by ¹H NMR, ¹³C NMR, and MS.
Analytical Data of Compound 3j
¹H NMR (CDCl₃): δ = 6.69 (d, J = 3.3 Hz, 1 H), 7.00-7.03 (m, 1 H), 7.15-7.21 (m, 3 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.66-7.70 (m, 2 H), 7.88 (d, J = 7.7 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 103.2, 110.3, 120.3, 120.8, 122.3, 123.1 (q, J = 273.7 Hz), 127.4 (q, J = 5.1 Hz), 128.3, 128.6 (q, J = 30.7 Hz), 128.6, 129.7 (d, J = 1.4 Hz), 131.0, 132.8, 137.5 (d, J = 1.8 Hz), 138.5. MS (EI): m/z (rel intensity) = 261 (100) [M⁺]. HRMS-FAB: m/z calcd for C₁₅H₁₀NF₃: 261.0765; found: 261.0786.

<A NAME="RU11907ST-13">13</A>

Preparation of Hydrazone-Copper Complex 4
To a solution of ligand 1c (127.3 mg, 0.51 mmol) in PhMe (10 mL) and MeCN (6 mL) was added CuI (48.2 mg, 0.25 mmol). After the mixture was heated to 80 °C, a yellow solid, precipitated from the mixture with addition of H₂O (10 mL), was isolated, washed with Et₂O, and dried under reduced pressure: 74.2 mg, 0.069 mmol, 83% as a yellow solid; mp 189-191 °C. ¹H NMR (DMSO-d ₆): δ = 1.49 (s, 8 H), 1.66 (s, 8 H), 3.49 (s, 8 H), 6.85 (s, 2 H). Anal. Calcd for C₂₈H₅₂N₈Cu₃I₃: C, 31.37; H, 4.89; N, 10.45. Found: C, 31.30; H, 4.86; N, 10.35. The filtrate was concentrated under reduced pressure. And the resulting residue was purified by silica gel chromatography to provide the recovered ligand 1c (61.1 mg, 0.24 mmol).

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X-ray Diffraction Analysis Data of 4
Yellow plate crystals from PhMe-MeCN-H₂O, monoclinic space group C2/c, a = 20.787(2) Å, b = 10.7489(12) Å, c = 16.6982(19) Å, α = 90°, β = 107.6570(10)°, γ = 90°, V = 3555.3(7) ų, Z = 4, r = 2.003 g cm^-3, m (Mo Kα) = 0.4415 cm^-1. The structure was solved by the direct method of full-matrix least-squares, where the final R and Rw were 0.0258 and 0.0998 for 4053 reflections, respectively.

<A NAME="RU11907ST-15">15</A>

Copper-Catalyzed N-Phenylation of 2-Pyrrolidone Using Hydrazone-Copper Complex 4 (Scheme 1)
Under an atmosphere of argon, PhI (244 mg, 1.2 mmol) was added to the mixture of 2-pyrrolidone (83.8 mg, 0.99 mmol), K₃PO₄ (425 mg, 2 mmol), and copper complex 4 (17.7 mg, 16.6 mmol) in DMSO (1 mL) at r.t. The mixture was stirred at 110 °C. After 5 h, the mixture was cooled to r.t., diluted with EtOAc, and filtered though Celite, eluting with additional EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane-EtOAc = 1:1) to provide the desired product (143 mg, 0.89 mmol, 90%).