Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2014
Copper-Catalyzed Arylation of Nitrogen Heterocycles from Anilines under Ligand-Free Conditions Dounia Toummini,[a] Anis Tlili,[a] Julien Bergs,[a] Fouad Ouazzani,[b] and Marc Taillefer*[a] chem_201404982_sm_miscellaneous_information.pdf
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Synthetic Methods
Supporting Information General Experimental Procedures. All reactions were carried out in 35 mL Schlenk tubes or in Carousel “reaction stations RR98030” Radley tubes, under a pure and dry argon atmosphere. Methanol was distilled from magnesium/iodine and stored under argon atmosphere. Other solvents were distilled and stored under argon atmosphere with classical technics. Tert-butylnitrite 90% (Acros), glacial acetic acid 99.5% (Carlo Erba), BF3.OEt2 (48% BF3 -Acros), CuI 99.5% (Aldrich), CuI metal basis 99.998% (Alfa Aesar), CuCl2 99% (Acros), CuBr2 pure anhydrous 99% (Acros), Cu(acac)2 98% (Alfa Aesar), Cu(OTf)2 98% (Stream Chemicals), Cu(acetate) 99% (Stream Chemicals), Cu(acetate) anhydous 98% (Alfa Aesar), Cu(acetate)2 99.999% (Aldrich) and all other solid materials were stored in the presence of P4O10 in a bench-top desiccator under vacuum at room temperature and weighed in the air without further purification. Arylamines and nitrogene heterocycles were purchased from commercial sources. Column chromatography was performed with SDS 60 A C.C silica gel (35-70 µm). Thin layer chromatography was carried out using Merck silica gel 60 F254 plates. All products were characterized by NMR and GC/MS spectra. NMR spectra were recorded at 20°C on a Bruker AC 400 MHz or on a DRX-250 spectrometer working respectively at 400 MHz for 1H and at 100 MHz for 13 C. Chemical shifts are reported in ppm/TMS for 1H and {1H}13C (δ 77.00 for CDCl3 signal). The first-order peak patterns are indicated as s (singulet), d (doublet), t (triplet), q (quadruplet). Complex non-first-order signals are indicated as m (multiplet). Gas chromatography – mass spectra GC-MS were recorded on a Shimadzu QP2012-SE instrument with a Zebron ZB-5ms (20m x 0 ,18mm) capillary apolar column (stationary phase : 5% phenyl-arylene, 0.18µm). GC/MS method: Initial temperature: 45°C; Initial time: 2 min; Ramp: 2°C/min until 50°C then 10 °C/min; Final temperature: 250°C; Final time: 10 min. General procedure for synthesis of N-aryl heterocycles. Protocol A (Table 2-3). Standard procedure for the synthesis of arylazoles via in situ formation of arenediazonium salts intermediates: After standard cycles of evacuation and back-filling with dry and pure argon, a Schlenk tube equipped with a magnetic stirring bar was charged with aniline derivatives (1.5 mmol) under an atmosphere of dry argon. Methanol (3 ml) was added by syringe. The solution was cooled at 0°C AcOH (0.2 equiv, 17µl) and t-BuONO (1.1 equiv, 176.6µl) were then added dropwise by syringe. The resulting mixture was stirred at 0°C for 30 min, and was added to a mixture of pyrazole derivatives (1 mmol) and copper acetate (20 mol%, 36,4 mg) in methanol (1.5 ml). The reaction mixture was stirred at 20°C for 18 h, filtered through a pad of celite (5 g) and rinsed with ethyl acetate (20 ml). The resulting organic solution was washed with brine (3 x 10 ml). The organic layer was dried over MgSO4, filtered, and concentrated (700 mbar, 40°C). The residue was further purified by flash chromatography (SiO2, petroleum ether / ethyl acetate), yielding the corresponding arylazole. Protocol B (Table 4). Standard procedure for the synthesis of arylazoles via in situ formation of arenediazonium salts intermediates: After standard cycles of evacuation and back-filling with dry and pure argon, a Schlenk tube equipped with a magnetic stirring bar was charged with aniline derivatives (1.5 mmol) under an atmosphere of dry argon. Methanol (700 µl) was added by syringe. The solution was cooled at 0°C and t-BuONO (1.1 equiv, 176.6µl) and AcOH (0.2 equiv, 17µl) were then added dropwise by syringe. The resulting mixture was stirred at 0°C for 30 min and copper acetate (20 mol%, 36,4 mg) and Bu4NI (0.8 mmol) were added in the medium. After 20 min at 90°C the nitrogen heterocycle (1 mmol) and Cs2CO3 (2 mmol, 2 equiv, 650 mg) were added and the resulting reaction mixture was stirred at 120°C for 18 h. The resulting mixture was filtered through a pad of celite (5 g) and rinsed with ethyl acetate (20 ml). The resulting organic solution was washed with brine (3 x 10 ml). The organic layer was dried over MgSO4, filtered, and concentrated (700 mbar, 40°C). The residue was further purified by flash chromatography (SiO2, dichloromethane / ethyl acetate), yielding the corresponding arylazole.
Some selected spectra 1-Phenyl-1H-pyrazole (1) [1] Follow the procedure A with: aniline (136.5 µL), pyrazole (68 mg). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.45-6.46 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.25-7.30 (m, 1H), 7.42-7.46 (m, 2H), 7.667.72 (m, 3H), 7.92 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.59 (CH), 119.24 (CH), 126.45 (CH), 126.74 (CH), 129.43 (CH), 140.24 (C), 141.08 (CH). GC/MS: rt = 7.24 min, M/Z = 144. 1 H NMR
13
C NMR
1-(4-tolyl)-1H-pyrazole (4)[2] Follow the procedure A with: 4-methylaniline (160.74 mg), pyrazole (68 mg)
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 3H), 6.44-6.45 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.25 (d, 2H, J = 8.8 Hz), 7.57 (d, 2H, J = 8.4 Hz), 7.70 (d, 1H, J = 1.6 Hz), 7.88 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 20.95 (CH3), 107.33 (CH), 119.22 (CH), 126.72 (CH), 129.95(CH), 136.34 (C), 137.50 (C), 140.79 (CH). GC/MS: rt = 7.35 min, M/Z = 158. 1 H NMR
13
C NMR
1-(4-methoxy-phenyl)-1H-pyrazole (6) [3] Follow the procedure A with: 4-methoxyaniline (184.72 mg), pyrazole (68 mg). MeO
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 3.84 (s, 3H), 6.43 (dd, 1H, J = 2 Hz, J = 1.6 Hz ), 6.98 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 9.2 Hz), 7.69 (d, 1H, J = 1.6 Hz), 7.82 (d, 1H, J = 2 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 55.58 (CH3), 107.18 (CH), 114.51 (CH), 120.90 (CH), 126.82 (CH), 134.44 (C), 140.63 (CH), 158.62 (C). GC/MS: rt = 8.25 min, M/Z = 174. 1
H NMR
13
C NMR
1-(3-chloro-phenyl)-1H-pyrazole (10)[9] Follow the procedure A with: 3-chloroaniline (191.25 mg), pyrazole (68 mg). N N Cl 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.47-6.48 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz ), 7.23-7.26 (m, 1H), 7.34-7.38 (t, 1H, J = 8.4 Hz), 7.57 (dd, 1H, J = 8 Hz, J = 1.2 Hz), 7.72 (d, 1H, J = 1.6 Hz), 7.72-7.75 (m, 1H), 7.90 (d, 1H, J = 2.8 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 108.14 (CH), 117.02 (CH), 119.47 (CH), 126.42 (CH), 126.81(CH), 130.48 (CH), 135.31(C), 141.13 (C), 141.53 (CH). GC/MS: rt = 7.63 min, M/Z = 178. 1
H NMR
13
C NMR
1-(4-chloro-phenyl)-1H-pyrazole (11) [3] Follow the procedure A with: 4-chloroaniline (191.25 mg), pyrazole (68 mg). Cl
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.48 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.41-7.44 (m, 2H), 7.63-7.65 (m, 2H), 7.72 (d, 1H, J = 1.6 Hz), 7.89 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.92 (CH), 120.33 (CH), 126.70 (CH), 129.53 (CH), 132.39 (C), 139.68 (C), 141.38 (CH). GC/MS: rt = 7.66 min, M/Z = 178. 1
H NMR
13
C NMR
1-(4-fluoro-phenyl)-1H-pyrazole (12) [3] Follow the procedure A with: 4-fluoroaniline (142.5 µl), pyrazole (68 mg). F
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.45-6.46 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.11-7.15 (m, 2H), 7.62-7.66 (m, 2H), 7.71 (d, 1H, J = 1.6 Hz), 7.85 (d, 1H, J = 2 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.73 (CH), 116.10 (CH), 121.03 (CH), 126.89 (CH), 136.04 (C), 141.14 (CH), 162.65 (C). GC/MS: rt = 6.56 min, M/Z = 162. 1
H NMR
13
C NMR
4-(1H-pyrazol-1-yl)benzonitrile (13) [6] Follow the procedure A with: 4-aminobenzonitrile (177.23 mg), pyrazole (68 mg). NC
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.52-6.54 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.73-7.76 (m, 2H), 7.77 (d, 1H, J = 1.2 Hz), 7.82-7.85 (m, 2H), 7.99 (d, 1H, J = 2.8 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.06 (CH), 109.71 (C), 118.46 (C), 118.96 (CH), 126.83 (CH), 133.68 (CH), 142.44 (CH), 143.13 (CH). GC/MS: rt = 8.29 min, M/Z = 169. 1
H NMR
13
C NMR
N-(4-(1H-pyrazol-1-yl)phenyl)acetamide (16) Follow the procedure A with: 4’-aminoacetanilide (225 mg), pyrazole (68 mg). O HN
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.07 (s, 3H), 6.37 (m, 1H), 7.24-7.28 (m, 1H), 7.33-7.36 (m, 2H), 7.63 (s, 1H), 7.83 (d, 1H, J = 2.4 Hz), 7.87-7.89 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 110.4 (CH), 121.3 (CH), 121.5 (CH), 122.7 (CH), 125.4 (C), 126.6 (CH), 127.17 (CH), 129.4 (CH), 135.4 (CH), 138.8 (C), 140.3 (C). GC/MS: rt = 10.41 min, M/Z = 201. HRMS: calc. for [M+H]+ C11H12N3O: 202.0980 found: 202.0980 IR (cm-1): 743.1, 870.9, 1043.2, 1270.5, 1299.1, 1317.4, 1487.1, 1564.2, 1601.7, 1663.2, 2923.7, 3102.9, 3205.7, 3260.9 1
H NMR
13
C NMR
1-(4-pyrazole-1-yl-phenyl)-ethanone (18) [4,5] Follow the procedure A with: 4’-aminoacetophenone (202.7 mg), pyrazole (68 mg). N O 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 2.53 (s, 3H), 6.42 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.67-7.72 (m, 3H), 7.92-7.97 (m, 3H). C NMR (100 MHz, CDCl3) δ (ppm): 26.58 (CH3), 108.57 (CH), 118.35 (CH), 128.88 (CH), 129.96 (CH), 135.09 (C), 142.02 (CH), 143.67 (C), 196.44 (C). GC/MS: rt = 8.87 min, M/Z = 186. 13
1
H NMR
13
C NMR
3-methyl-1-phenyl-1H-pyrazole (19a) [11] Follow the procedure A with: aniline (136.5 µL), 3-methylpyrazole (80.5 µl). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 3H), 6.24 (d, 1H, J = 2.4 Hz), 7.22-7.26 (m, 1H), 7.40-7.44 (m, 2H), 7.63-7.66 (m, 2H), 7.80 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 13.75 (CH3), 107.51 (CH), 118.84 (CH), 125.92 (CH), 127.34 (CH), 129.35 (CH), 140.39 (C), 150.98 (C). GC/MS: rt = 7.24 min, M/Z = 158. 1
H NMR
13
C NMR
4-methyl-1-phenyl-1H-pyrazole (20)[10] Follow the procedure A with: aniline (136.5 µL), 4-methylpyrazole (82 mg). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 2.12 (s, 3H), 7.19-7.23 (m, 1H), 7.37-7.40 (m, 2H), 7.51 (s, 1H), 7.61-7.66 (m, 3H). C NMR (100 MHz, CDCl3) δ (ppm): 8.95 (CH3), 118.22 (C), 118.70 (CH), 125.35 (CH), 125.95 (CH), 129.36 (CH), 140.39 (CH), 141.79 (CH). GC/MS: rt = 7.38 min, M/Z = 158. 13
1
H NMR
13
C NMR
4-iodo-1-phenyl-1-H-pyrazole (22) [7] Follow the procedure A or B with: aniline (136.5 µL), 4-iodopyrazole (194 mg). I N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.14-7.21 (m, 1H), 7.31-7.35 (m, 2H), 7.52 (d, 2H, J = 7.6 Hz), 7.60 (s, 1H), 7.83 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 59.75 (CH), 119.09 (C), 127.08 (C), 129.56 (CH), 131.32 (CH), 139.68 (CH), 145.94 (CH). GC/MS: rt = 8.69 min, M/Z = 269. 1
H NMR
13
C NMR
Ethyl-3-methyl-1-phenyl-1H-pyrazole-5-carboxylate (24)[12] Follow the procedure A with: aniline (136.5 µL), ethyl-3-methylpyrazole-5-carboxylate (154 mg) O
EtO N
N 1
H NMR (400 MHz, CDCl3) δ (ppm): 1.22 (t, 3H), 2.35 (s, 3H), 4.22 (q, 2H), 6.80 (s, 1H), 7.25-7.46 (m, 5H). C NMR (100 MHz, CDCl3) δ (ppm): 13.39 (CH3), 14.01 (CH3), 61.03 (CH2), 112.06 (CH), 125.98 (CH), 128.37 (CH), 128.51 (CH), 133.87 (C), 140.36 (C), 148.86 (C), 159.40 (C). GC/MS: rt = 8.75 min, M/Z = 230.
13
1
H NMR
13
C NMR
4-iodo-1-(4-methoxyphenyl)-1H-pyrazole (26) Follow the general procedure with: aniline (136.5 µL), 4-iodopyrazole (194 mg). I MeO
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.07 (s, 3H), 6.37 (m, 1H), 7.24-7.28 (m, 1H), 7.33-7.36 (m, 2H), 7.63 (s, 1H), 7.83 (d, 1H, J = 2.4 Hz), 7.87-7.89 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 55.61 (CH3), 58.29 (C), 114.58 (CH), 128.83 (CH), 131.34 (CH), 133.28 (C), 145.49 (CH), 158.63 (C). GC/MS: rt = 10.17 min, M/Z = 300. HRMS: calc. for [M+H]+ C11H12N3O: 300.9838 found: 300.9836 IR (cm-1): 832.2, 939.4, 1021.4, 1241.4, 1519.5, 1615.7, 2834.5, 2963.1, 3118.9 1
H NMR
13
C NMR
1-Phenyl-1H-imidazole (28)[15] Follow the general procedure A or B with: aniline (136.5 µL), imidazole (68 mg). N 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 7.19 (s, 1H), 7.27 (s, 1H), 7.32-7.40 (m, 3H), 7.43-7.49 (m, 2H), 7.84 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 118.3 (CH), 121.6 (2 CH), 127.6 (CH), 129.9 (CH), 130.5 (2 CH), 135.7 (CH), 137.5 (C). GC/MS: rt = 7.53 min, M/Z = 144.
13
1
H NMR
13
C NMR
1-p-tolyl-1H-imidazole (29)[14] Follow the general procedure B with: p-toluidine (162 mg), imidazole (68 mg). N 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 1.84 (s, 3H), 6.57-6.78 (m, 6H), 7.26 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 21.1 (CH), 118.5 (CH), 121.6 (2 CH), 130.3 (2 CH), 130.4 (CH), 135.1 (C), 137.6 (C), 141.3 (CH). GC/MS: rt = 8.14 min, M/Z = 158. 13
1
H NMR
13
C NMR
1-Phenyl-1H-pyrrole (31)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), pyrrole (70 µL). N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.26 (t, 2H, J=2.2 Hz), 7.00 (t, 2H, J=2.2 Hz), 7.11-7.17 (m, 1H), 7.19-7.34 (m, 4H). C NMR (100 MHz, CDCl3) δ (ppm): 110.5 (CH), 119.5 (2 CH), 120.7 (2 CH), 125.7 (CH), 129.7 (2 CH), 141.2 (C). GC/MS: rt = 6.66 min, M/Z = 144.
13
1
H NMR
13
C NMR
1-phenyl-1H-indazole (32)[13] Follow the general procedure A or B with: aniline (136.5 µL), indazole (118 mg).
N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.18-7.22 (m, 1H), 7.32-7.35 (m, 1H), 7.38-7.42 (m, 1H), 7.49-7.53 (m, 2H), 7.70-7.73 (m, 3H), 7.77-7.79 (m, 1H), 8.19 (d, 1H, J = 0.8Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 110.4 (CH), 121.3 (CH), 121.5 (CH), 122.7 (CH), 125.4 (C), 126.6 (CH), 127.17 (CH), 129.4 (CH), 135.4 (CH), 138.8 (C), 140.3 (C). GC/MS: rt = 9.18 min, M/Z = 194. 1
H NMR
13
C NMR
1-phenyl-1H-indole (33)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), Cs2CO3 (1.3 g), indole (117 mg). N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.72 (dd, 1H, J=3.3Hz, J=0,9Hz), 7.19-7.28 (m, 2H), 7.35-7.42 (m, 2H), 7.52-7.57 (m, 4H), 7.58-7.63 (m, 1H), 7.70-7.76 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 103.7 (CH), 110.6 (CH), 120.4 (CH), 121.2 (CH), 122.4 (CH), 124.5 (2CH), 126.6 (CH), 128.0 (CH), 129.4 (C), 129.7 (2CH), 135.9 (C), 139.9 (C). GC/MS: rt = 9.32 min, M/Z = 193 1
H NMR
13
C NMR
1-phenyl-1H-benzo[d]imidazole (34)[14] Follow the general procedure B with: aniline (136.5 µL), benzimidazole (120 mg). N
1
N
H NMR (400 MHz, CDCl3) δ (ppm): 8.11 (s, 1H), 7.86-7.92 (m, 1H), 7.42-7.61 (m, 6H), 7.29-7.38 (m, 2H). C NMR (100 MHz, CDCl3) δ (ppm): 110.5 (CH), 120.7 (CH), 122.9 (2CH), 123.8 (CH), 124.1 (CH), 128.1 (CH), 130.1 (2CH), 136.4 (CH), 144.1 (C). GC/MS: rt = 9.87 min, M/Z = 194.
13
1
H NMR
13
C NMR
1-phenyl-1H-[1,2,4]triazole (35)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), Cs2CO3 (1.3 g), 1,2,4-triazole (69 mg). N
N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.34-7.43 (m, 1H), 7.46-7.54 (m, 2H), 7.62-7.74 (m, 2H), 8.09 (s, 1H), 8.55 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 120.2 (2CH), 128.4 (CH), 129.9 (2CH), 137.2 (C), 141.2 (CH). GC/MS: rt = 7.16 min, M/Z =145 1 H NMR 13
13
C NMR
1-phenylpyrrolidin-2-one (36)[15] Follow the general procedure B with: aniline (136.5 µL), 2-pyrrolidinone (77.5 µL). O N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.55-7.64 (m, 2H), 7.30-7.39 (m, 2H), 7.38-7.42 (m, 1H), 3.82 (t, 2H, J=7.0Hz), 2.57 (t, 2H, J=8.1Hz), 2.07-2.19 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 17.9 (CH2), 32.8 (CH2), 48.8 (CH2), 119.9 (2CH), 124.4 (CH), 128.8 (2CH), 139.4 (C), 174.2 (C). GC/MS: rt = 8.59 min, M/Z = 161. 1 H NMR
13
C NMR
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Annex 1
Various applications of arenediazonium salts
Annex 2 A possible mechanism for the Cu catalysed C-N bond formation from anilines via the in situ generation of catalytic amounts of ArI. Step 1: Synthesis of the aryldiazonium C from the aniline A; Step 2: in situ copper catalyzed generation of catalytic amounts of ArI D; Step 3: Activation of ArI by the anionic [NuCu]- intermediate F; regeneration of the copper (Cun) and formation of the expected product ArNu (G).
Copper-Catalyzed Arylation of Nitrogen Heterocycles from Anilines under Ligand-Free Conditions Dounia Toummini,[a] Anis Tlili,[a] Julien Bergs,[a] Fouad Ouazzani,[b] and Marc Taillefer*[a] chem_201404982_sm_miscellaneous_information.pdf
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Synthetic Methods
Supporting Information General Experimental Procedures. All reactions were carried out in 35 mL Schlenk tubes or in Carousel “reaction stations RR98030” Radley tubes, under a pure and dry argon atmosphere. Methanol was distilled from magnesium/iodine and stored under argon atmosphere. Other solvents were distilled and stored under argon atmosphere with classical technics. Tert-butylnitrite 90% (Acros), glacial acetic acid 99.5% (Carlo Erba), BF3.OEt2 (48% BF3 -Acros), CuI 99.5% (Aldrich), CuI metal basis 99.998% (Alfa Aesar), CuCl2 99% (Acros), CuBr2 pure anhydrous 99% (Acros), Cu(acac)2 98% (Alfa Aesar), Cu(OTf)2 98% (Stream Chemicals), Cu(acetate) 99% (Stream Chemicals), Cu(acetate) anhydous 98% (Alfa Aesar), Cu(acetate)2 99.999% (Aldrich) and all other solid materials were stored in the presence of P4O10 in a bench-top desiccator under vacuum at room temperature and weighed in the air without further purification. Arylamines and nitrogene heterocycles were purchased from commercial sources. Column chromatography was performed with SDS 60 A C.C silica gel (35-70 µm). Thin layer chromatography was carried out using Merck silica gel 60 F254 plates. All products were characterized by NMR and GC/MS spectra. NMR spectra were recorded at 20°C on a Bruker AC 400 MHz or on a DRX-250 spectrometer working respectively at 400 MHz for 1H and at 100 MHz for 13 C. Chemical shifts are reported in ppm/TMS for 1H and {1H}13C (δ 77.00 for CDCl3 signal). The first-order peak patterns are indicated as s (singulet), d (doublet), t (triplet), q (quadruplet). Complex non-first-order signals are indicated as m (multiplet). Gas chromatography – mass spectra GC-MS were recorded on a Shimadzu QP2012-SE instrument with a Zebron ZB-5ms (20m x 0 ,18mm) capillary apolar column (stationary phase : 5% phenyl-arylene, 0.18µm). GC/MS method: Initial temperature: 45°C; Initial time: 2 min; Ramp: 2°C/min until 50°C then 10 °C/min; Final temperature: 250°C; Final time: 10 min. General procedure for synthesis of N-aryl heterocycles. Protocol A (Table 2-3). Standard procedure for the synthesis of arylazoles via in situ formation of arenediazonium salts intermediates: After standard cycles of evacuation and back-filling with dry and pure argon, a Schlenk tube equipped with a magnetic stirring bar was charged with aniline derivatives (1.5 mmol) under an atmosphere of dry argon. Methanol (3 ml) was added by syringe. The solution was cooled at 0°C AcOH (0.2 equiv, 17µl) and t-BuONO (1.1 equiv, 176.6µl) were then added dropwise by syringe. The resulting mixture was stirred at 0°C for 30 min, and was added to a mixture of pyrazole derivatives (1 mmol) and copper acetate (20 mol%, 36,4 mg) in methanol (1.5 ml). The reaction mixture was stirred at 20°C for 18 h, filtered through a pad of celite (5 g) and rinsed with ethyl acetate (20 ml). The resulting organic solution was washed with brine (3 x 10 ml). The organic layer was dried over MgSO4, filtered, and concentrated (700 mbar, 40°C). The residue was further purified by flash chromatography (SiO2, petroleum ether / ethyl acetate), yielding the corresponding arylazole. Protocol B (Table 4). Standard procedure for the synthesis of arylazoles via in situ formation of arenediazonium salts intermediates: After standard cycles of evacuation and back-filling with dry and pure argon, a Schlenk tube equipped with a magnetic stirring bar was charged with aniline derivatives (1.5 mmol) under an atmosphere of dry argon. Methanol (700 µl) was added by syringe. The solution was cooled at 0°C and t-BuONO (1.1 equiv, 176.6µl) and AcOH (0.2 equiv, 17µl) were then added dropwise by syringe. The resulting mixture was stirred at 0°C for 30 min and copper acetate (20 mol%, 36,4 mg) and Bu4NI (0.8 mmol) were added in the medium. After 20 min at 90°C the nitrogen heterocycle (1 mmol) and Cs2CO3 (2 mmol, 2 equiv, 650 mg) were added and the resulting reaction mixture was stirred at 120°C for 18 h. The resulting mixture was filtered through a pad of celite (5 g) and rinsed with ethyl acetate (20 ml). The resulting organic solution was washed with brine (3 x 10 ml). The organic layer was dried over MgSO4, filtered, and concentrated (700 mbar, 40°C). The residue was further purified by flash chromatography (SiO2, dichloromethane / ethyl acetate), yielding the corresponding arylazole.
Some selected spectra 1-Phenyl-1H-pyrazole (1) [1] Follow the procedure A with: aniline (136.5 µL), pyrazole (68 mg). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.45-6.46 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.25-7.30 (m, 1H), 7.42-7.46 (m, 2H), 7.667.72 (m, 3H), 7.92 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.59 (CH), 119.24 (CH), 126.45 (CH), 126.74 (CH), 129.43 (CH), 140.24 (C), 141.08 (CH). GC/MS: rt = 7.24 min, M/Z = 144. 1 H NMR
13
C NMR
1-(4-tolyl)-1H-pyrazole (4)[2] Follow the procedure A with: 4-methylaniline (160.74 mg), pyrazole (68 mg)
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 3H), 6.44-6.45 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.25 (d, 2H, J = 8.8 Hz), 7.57 (d, 2H, J = 8.4 Hz), 7.70 (d, 1H, J = 1.6 Hz), 7.88 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 20.95 (CH3), 107.33 (CH), 119.22 (CH), 126.72 (CH), 129.95(CH), 136.34 (C), 137.50 (C), 140.79 (CH). GC/MS: rt = 7.35 min, M/Z = 158. 1 H NMR
13
C NMR
1-(4-methoxy-phenyl)-1H-pyrazole (6) [3] Follow the procedure A with: 4-methoxyaniline (184.72 mg), pyrazole (68 mg). MeO
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 3.84 (s, 3H), 6.43 (dd, 1H, J = 2 Hz, J = 1.6 Hz ), 6.98 (d, 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 9.2 Hz), 7.69 (d, 1H, J = 1.6 Hz), 7.82 (d, 1H, J = 2 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 55.58 (CH3), 107.18 (CH), 114.51 (CH), 120.90 (CH), 126.82 (CH), 134.44 (C), 140.63 (CH), 158.62 (C). GC/MS: rt = 8.25 min, M/Z = 174. 1
H NMR
13
C NMR
1-(3-chloro-phenyl)-1H-pyrazole (10)[9] Follow the procedure A with: 3-chloroaniline (191.25 mg), pyrazole (68 mg). N N Cl 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.47-6.48 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz ), 7.23-7.26 (m, 1H), 7.34-7.38 (t, 1H, J = 8.4 Hz), 7.57 (dd, 1H, J = 8 Hz, J = 1.2 Hz), 7.72 (d, 1H, J = 1.6 Hz), 7.72-7.75 (m, 1H), 7.90 (d, 1H, J = 2.8 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 108.14 (CH), 117.02 (CH), 119.47 (CH), 126.42 (CH), 126.81(CH), 130.48 (CH), 135.31(C), 141.13 (C), 141.53 (CH). GC/MS: rt = 7.63 min, M/Z = 178. 1
H NMR
13
C NMR
1-(4-chloro-phenyl)-1H-pyrazole (11) [3] Follow the procedure A with: 4-chloroaniline (191.25 mg), pyrazole (68 mg). Cl
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.48 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.41-7.44 (m, 2H), 7.63-7.65 (m, 2H), 7.72 (d, 1H, J = 1.6 Hz), 7.89 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.92 (CH), 120.33 (CH), 126.70 (CH), 129.53 (CH), 132.39 (C), 139.68 (C), 141.38 (CH). GC/MS: rt = 7.66 min, M/Z = 178. 1
H NMR
13
C NMR
1-(4-fluoro-phenyl)-1H-pyrazole (12) [3] Follow the procedure A with: 4-fluoroaniline (142.5 µl), pyrazole (68 mg). F
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.45-6.46 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.11-7.15 (m, 2H), 7.62-7.66 (m, 2H), 7.71 (d, 1H, J = 1.6 Hz), 7.85 (d, 1H, J = 2 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.73 (CH), 116.10 (CH), 121.03 (CH), 126.89 (CH), 136.04 (C), 141.14 (CH), 162.65 (C). GC/MS: rt = 6.56 min, M/Z = 162. 1
H NMR
13
C NMR
4-(1H-pyrazol-1-yl)benzonitrile (13) [6] Follow the procedure A with: 4-aminobenzonitrile (177.23 mg), pyrazole (68 mg). NC
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 6.52-6.54 (dd, 1H, J = 2.4 Hz, J = 1.6 Hz), 7.73-7.76 (m, 2H), 7.77 (d, 1H, J = 1.2 Hz), 7.82-7.85 (m, 2H), 7.99 (d, 1H, J = 2.8 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 107.06 (CH), 109.71 (C), 118.46 (C), 118.96 (CH), 126.83 (CH), 133.68 (CH), 142.44 (CH), 143.13 (CH). GC/MS: rt = 8.29 min, M/Z = 169. 1
H NMR
13
C NMR
N-(4-(1H-pyrazol-1-yl)phenyl)acetamide (16) Follow the procedure A with: 4’-aminoacetanilide (225 mg), pyrazole (68 mg). O HN
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.07 (s, 3H), 6.37 (m, 1H), 7.24-7.28 (m, 1H), 7.33-7.36 (m, 2H), 7.63 (s, 1H), 7.83 (d, 1H, J = 2.4 Hz), 7.87-7.89 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 110.4 (CH), 121.3 (CH), 121.5 (CH), 122.7 (CH), 125.4 (C), 126.6 (CH), 127.17 (CH), 129.4 (CH), 135.4 (CH), 138.8 (C), 140.3 (C). GC/MS: rt = 10.41 min, M/Z = 201. HRMS: calc. for [M+H]+ C11H12N3O: 202.0980 found: 202.0980 IR (cm-1): 743.1, 870.9, 1043.2, 1270.5, 1299.1, 1317.4, 1487.1, 1564.2, 1601.7, 1663.2, 2923.7, 3102.9, 3205.7, 3260.9 1
H NMR
13
C NMR
1-(4-pyrazole-1-yl-phenyl)-ethanone (18) [4,5] Follow the procedure A with: 4’-aminoacetophenone (202.7 mg), pyrazole (68 mg). N O 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 2.53 (s, 3H), 6.42 (dd, 1H, J = 2 Hz, J = 1.6 Hz), 7.67-7.72 (m, 3H), 7.92-7.97 (m, 3H). C NMR (100 MHz, CDCl3) δ (ppm): 26.58 (CH3), 108.57 (CH), 118.35 (CH), 128.88 (CH), 129.96 (CH), 135.09 (C), 142.02 (CH), 143.67 (C), 196.44 (C). GC/MS: rt = 8.87 min, M/Z = 186. 13
1
H NMR
13
C NMR
3-methyl-1-phenyl-1H-pyrazole (19a) [11] Follow the procedure A with: aniline (136.5 µL), 3-methylpyrazole (80.5 µl). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 3H), 6.24 (d, 1H, J = 2.4 Hz), 7.22-7.26 (m, 1H), 7.40-7.44 (m, 2H), 7.63-7.66 (m, 2H), 7.80 (d, 1H, J = 2.4 Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 13.75 (CH3), 107.51 (CH), 118.84 (CH), 125.92 (CH), 127.34 (CH), 129.35 (CH), 140.39 (C), 150.98 (C). GC/MS: rt = 7.24 min, M/Z = 158. 1
H NMR
13
C NMR
4-methyl-1-phenyl-1H-pyrazole (20)[10] Follow the procedure A with: aniline (136.5 µL), 4-methylpyrazole (82 mg). N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 2.12 (s, 3H), 7.19-7.23 (m, 1H), 7.37-7.40 (m, 2H), 7.51 (s, 1H), 7.61-7.66 (m, 3H). C NMR (100 MHz, CDCl3) δ (ppm): 8.95 (CH3), 118.22 (C), 118.70 (CH), 125.35 (CH), 125.95 (CH), 129.36 (CH), 140.39 (CH), 141.79 (CH). GC/MS: rt = 7.38 min, M/Z = 158. 13
1
H NMR
13
C NMR
4-iodo-1-phenyl-1-H-pyrazole (22) [7] Follow the procedure A or B with: aniline (136.5 µL), 4-iodopyrazole (194 mg). I N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.14-7.21 (m, 1H), 7.31-7.35 (m, 2H), 7.52 (d, 2H, J = 7.6 Hz), 7.60 (s, 1H), 7.83 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 59.75 (CH), 119.09 (C), 127.08 (C), 129.56 (CH), 131.32 (CH), 139.68 (CH), 145.94 (CH). GC/MS: rt = 8.69 min, M/Z = 269. 1
H NMR
13
C NMR
Ethyl-3-methyl-1-phenyl-1H-pyrazole-5-carboxylate (24)[12] Follow the procedure A with: aniline (136.5 µL), ethyl-3-methylpyrazole-5-carboxylate (154 mg) O
EtO N
N 1
H NMR (400 MHz, CDCl3) δ (ppm): 1.22 (t, 3H), 2.35 (s, 3H), 4.22 (q, 2H), 6.80 (s, 1H), 7.25-7.46 (m, 5H). C NMR (100 MHz, CDCl3) δ (ppm): 13.39 (CH3), 14.01 (CH3), 61.03 (CH2), 112.06 (CH), 125.98 (CH), 128.37 (CH), 128.51 (CH), 133.87 (C), 140.36 (C), 148.86 (C), 159.40 (C). GC/MS: rt = 8.75 min, M/Z = 230.
13
1
H NMR
13
C NMR
4-iodo-1-(4-methoxyphenyl)-1H-pyrazole (26) Follow the general procedure with: aniline (136.5 µL), 4-iodopyrazole (194 mg). I MeO
N N
1
H NMR (400 MHz, CDCl3) δ (ppm): 2.07 (s, 3H), 6.37 (m, 1H), 7.24-7.28 (m, 1H), 7.33-7.36 (m, 2H), 7.63 (s, 1H), 7.83 (d, 1H, J = 2.4 Hz), 7.87-7.89 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 55.61 (CH3), 58.29 (C), 114.58 (CH), 128.83 (CH), 131.34 (CH), 133.28 (C), 145.49 (CH), 158.63 (C). GC/MS: rt = 10.17 min, M/Z = 300. HRMS: calc. for [M+H]+ C11H12N3O: 300.9838 found: 300.9836 IR (cm-1): 832.2, 939.4, 1021.4, 1241.4, 1519.5, 1615.7, 2834.5, 2963.1, 3118.9 1
H NMR
13
C NMR
1-Phenyl-1H-imidazole (28)[15] Follow the general procedure A or B with: aniline (136.5 µL), imidazole (68 mg). N 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 7.19 (s, 1H), 7.27 (s, 1H), 7.32-7.40 (m, 3H), 7.43-7.49 (m, 2H), 7.84 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 118.3 (CH), 121.6 (2 CH), 127.6 (CH), 129.9 (CH), 130.5 (2 CH), 135.7 (CH), 137.5 (C). GC/MS: rt = 7.53 min, M/Z = 144.
13
1
H NMR
13
C NMR
1-p-tolyl-1H-imidazole (29)[14] Follow the general procedure B with: p-toluidine (162 mg), imidazole (68 mg). N 1
N
H NMR (400 MHz, CDCl3) δ (ppm): 1.84 (s, 3H), 6.57-6.78 (m, 6H), 7.26 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 21.1 (CH), 118.5 (CH), 121.6 (2 CH), 130.3 (2 CH), 130.4 (CH), 135.1 (C), 137.6 (C), 141.3 (CH). GC/MS: rt = 8.14 min, M/Z = 158. 13
1
H NMR
13
C NMR
1-Phenyl-1H-pyrrole (31)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), pyrrole (70 µL). N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.26 (t, 2H, J=2.2 Hz), 7.00 (t, 2H, J=2.2 Hz), 7.11-7.17 (m, 1H), 7.19-7.34 (m, 4H). C NMR (100 MHz, CDCl3) δ (ppm): 110.5 (CH), 119.5 (2 CH), 120.7 (2 CH), 125.7 (CH), 129.7 (2 CH), 141.2 (C). GC/MS: rt = 6.66 min, M/Z = 144.
13
1
H NMR
13
C NMR
1-phenyl-1H-indazole (32)[13] Follow the general procedure A or B with: aniline (136.5 µL), indazole (118 mg).
N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.18-7.22 (m, 1H), 7.32-7.35 (m, 1H), 7.38-7.42 (m, 1H), 7.49-7.53 (m, 2H), 7.70-7.73 (m, 3H), 7.77-7.79 (m, 1H), 8.19 (d, 1H, J = 0.8Hz). 13 C NMR (100 MHz, CDCl3) δ (ppm): 110.4 (CH), 121.3 (CH), 121.5 (CH), 122.7 (CH), 125.4 (C), 126.6 (CH), 127.17 (CH), 129.4 (CH), 135.4 (CH), 138.8 (C), 140.3 (C). GC/MS: rt = 9.18 min, M/Z = 194. 1
H NMR
13
C NMR
1-phenyl-1H-indole (33)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), Cs2CO3 (1.3 g), indole (117 mg). N 1
H NMR (400 MHz, CDCl3) δ (ppm): 6.72 (dd, 1H, J=3.3Hz, J=0,9Hz), 7.19-7.28 (m, 2H), 7.35-7.42 (m, 2H), 7.52-7.57 (m, 4H), 7.58-7.63 (m, 1H), 7.70-7.76 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 103.7 (CH), 110.6 (CH), 120.4 (CH), 121.2 (CH), 122.4 (CH), 124.5 (2CH), 126.6 (CH), 128.0 (CH), 129.4 (C), 129.7 (2CH), 135.9 (C), 139.9 (C). GC/MS: rt = 9.32 min, M/Z = 193 1
H NMR
13
C NMR
1-phenyl-1H-benzo[d]imidazole (34)[14] Follow the general procedure B with: aniline (136.5 µL), benzimidazole (120 mg). N
1
N
H NMR (400 MHz, CDCl3) δ (ppm): 8.11 (s, 1H), 7.86-7.92 (m, 1H), 7.42-7.61 (m, 6H), 7.29-7.38 (m, 2H). C NMR (100 MHz, CDCl3) δ (ppm): 110.5 (CH), 120.7 (CH), 122.9 (2CH), 123.8 (CH), 124.1 (CH), 128.1 (CH), 130.1 (2CH), 136.4 (CH), 144.1 (C). GC/MS: rt = 9.87 min, M/Z = 194.
13
1
H NMR
13
C NMR
1-phenyl-1H-[1,2,4]triazole (35)[15] Follow the general procedure B with: aniline (136.5 µL), AcOH (85 µL), Cs2CO3 (1.3 g), 1,2,4-triazole (69 mg). N
N N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.34-7.43 (m, 1H), 7.46-7.54 (m, 2H), 7.62-7.74 (m, 2H), 8.09 (s, 1H), 8.55 (s, 1H). C NMR (100 MHz, CDCl3) δ (ppm): 120.2 (2CH), 128.4 (CH), 129.9 (2CH), 137.2 (C), 141.2 (CH). GC/MS: rt = 7.16 min, M/Z =145 1 H NMR 13
13
C NMR
1-phenylpyrrolidin-2-one (36)[15] Follow the general procedure B with: aniline (136.5 µL), 2-pyrrolidinone (77.5 µL). O N 1
H NMR (400 MHz, CDCl3) δ (ppm): 7.55-7.64 (m, 2H), 7.30-7.39 (m, 2H), 7.38-7.42 (m, 1H), 3.82 (t, 2H, J=7.0Hz), 2.57 (t, 2H, J=8.1Hz), 2.07-2.19 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 17.9 (CH2), 32.8 (CH2), 48.8 (CH2), 119.9 (2CH), 124.4 (CH), 128.8 (2CH), 139.4 (C), 174.2 (C). GC/MS: rt = 8.59 min, M/Z = 161. 1 H NMR
13
C NMR
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Annex 1
Various applications of arenediazonium salts
Annex 2 A possible mechanism for the Cu catalysed C-N bond formation from anilines via the in situ generation of catalytic amounts of ArI. Step 1: Synthesis of the aryldiazonium C from the aniline A; Step 2: in situ copper catalyzed generation of catalytic amounts of ArI D; Step 3: Activation of ArI by the anionic [NuCu]- intermediate F; regeneration of the copper (Cun) and formation of the expected product ArNu (G).
