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Synlett 2008(4): 614-620  
DOI: 10.1055/s-2008-1042763
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Takashi Mino*, Yoshikazu Harada, Hiroaki Shindo, Masami Sakamoto, Tsutomu Fujita
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax: +81(43)2903401; e-Mail: tmino@faculty.chiba-u.jp;
Further Information

Publication History

Received 27 November 2007
Publication Date:
12 February 2008 (online)

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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.

Key words

copper - arylations - hydrazones - amides - amines

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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.

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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.

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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) Å3, 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.

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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%).