Pd(II) Catalyzed C3-selective arylation of pyridine with (hetero)arenes Guo-Lin Gao,, Wujiong Xia, Pankaj Jain and Jin-Quan Yu *, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA The Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin 150080, China SUPPORTING INFORMATION Table of Contents General Information:... 2 Experimental method:... 3 Experimental data:... 6 References:... 10 NMR Spectra... 11 1
General Information: Unless otherwise noted, all reactions were run under air and were heated on hot plates with oil baths calibrated to an external thermometer. Prior to starting experiments, the hot plate was turned on, and the oil bath was allowed to equilibrate to the desired temperature over 30 minutes. All materials were used as received from commercial sources without further purification and all reagents were handled in air. 1 H and 13 C NMR spectra were recorded on Varian Inova or Bruker AV (400 MHz and 100 MHz, respectively) instrument internally referenced to SiMe4 signals. The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. High resolution mass spectra were recorded at the Center for Mass Spectrometry, The Scripps Research Institute. 2
Experimental method: 1. Optimization of reaction conditions: Table S1: Solvent screening without ligand a Table S2: Solvent screening with 1,10-phenanthroline a 3
Table S3: Reaction condition screening for substituted pyridines (2,6- dimethoxypyridine was used as model) a 2. General procedure for Pd(II)-catalyzed dimerization of pyridine derivatives: To a 50 ml screw-top sealed tube, Pd(OAc)2 (11.2 mg, 0.05 mmol, 10 mol %), 1,10- phenanthroline (9.0 mg, 0.05 mmol, 10 mol %), Ag2CO3 (276 mg, 1.0 mmol, 2 equiv), K2CO3 (138mg, 1.0 mmol, 2 equiv), pyridine (0.3 ml, 4 equiv), substituted pyridine (2.7 ml, 20 32 equiv, depents on density and formula weight of 1) were added in sequence. The tube was capped and stirred at 130 o C for 48 h. The reaction mixture 4
was cooled to room temperature, diluted with EtOAc, filtered through a short pad of Celite, washed with EtOAc, and concentrated in vacuo. The resulting residue was analyzed by 1 H NMR (CH2Br2 as internal standard) and the isomer ratio was determined. Then all resulting product were collected, concentrated in vacuo and purified by PTLC using hexanes : ethyl acetate (5:1 to 1:1, depending on the substrate) as the eluant. Known compounds were characterized by 1 H NMR and 13 C NMR. Unknown compounds are characterized by 1 H NMR, 13 C NMR and HRMS. 3. Arylation condition screening (see Table S2). Table S4: Arylation condition screening a 4. General procedure for Pd(II)-catalyzed arylation of pyridine derivatives: To a 50 ml screw-top sealed tube, Pd(OAc)2 (11.2 mg, 0.05 mmol, 10 mol %), 1,10- Phenanthroline (9.0 mg, 0.05 mmol, 10 mol %), Ag2CO3 (276 mg, 1.0 mmol, 2 equiv), K2CO3 (138mg, 1.0 mmol, 2 equiv), arene (1.5 ml, benzene 30 equiv, p-xylene 22 equiv), substituted pyridine (1.5 ml, 26-32 equiv, depents on density and formula weight of 1) were added in sequence. The tube was capped and stirred at 130 o C for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, 5
filtered through a short pad of Celite, washed with EtOAc, and concentrated in vacuo. The resulting residue was analyzed by 1 H NMR (CH2Br2 as internal standard) and the isomer ratio was determined. Then all resulting product were collected, concentrated in vacuo and purified by PTLC using hexanes : ethyl acetate (5:1 to 1:1, depending on the substrate) as the eluant. Known compounds were characterized by 1 H NMR and 13 C NMR. Unknown compounds are characterized by 1 H NMR, 13 C NMR and HRMS. Experimental data: 3,3'-Bipyridine (2a) 1. 1 H NMR TON was 11.2, and isolated TON was 10.3. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 8.66 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.43 (dd, J = 8.0, 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 149.28, 148.15, 134.45, 133.50, 123.79. 2,2',6,6'-Tetramethoxy-3,3'-bipyridine (2b) 2. 1 H NMR TON was 9.8, and isolated TON was 9.3. White solid. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 8.0 Hz, 2H), 3.94 (s, 6H), 3.91 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 162.05, 159.62, 142.50, 110.54, 100.42, 53.44, 53.36. 5,5'-Difluoro-3,3'-bipyridine (2c). 1 H NMR TON was 7.3, and isolated TON was 6.5. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 8.56 (d, J = 4.0 Hz, 2H), 7.40 (dd, J = 8.0, 4.0 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 156.12 (d, J = 259 Hz), 145.95 (t, J = 2.7 Hz), 139.39-138.94 (m), 128.26 (dd, J = 8.3, 3.5 Hz), 124.65. HRMS (ESI-TOF) m/z Calcd for C10H7F2N2 + [M+H] + 193.0572, found 193.0581. 2,2',6,6'-Tetrafluoro-3,3'-bipyridine (2d). 1 H NMR TON was 7.0, and isolated TON was 6.0. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.03-7.97 (m, 2H), 7.00 (dd, J = 8.0, 2.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 161.43 (dd, J = 248, 14.1 Hz), 158.13 (dd, J = 248, 14.4 Hz), 145.90 (dt, J = 8.0, 4.0 Hz), 112.20 (dd, J = 22.6, 6.0 Hz), 106.78 (dt, J = 34.6, 3.0 Hz). HRMS (ESI-TOF) m/z Calcd for C10H5F4N2 + [M+H] + 229.0383, found 229.0390. 6
5,5'-Dimethyl-3,3'-bipyridine (2e). 1 H NMR TON was 6.0, and isolated TON was 5.6. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 8.48 (s, 2H), 7.68 (s, 2H), 2.43 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 149.71, 145.38, 134.95, 133.27, 133.10, 18.44. HRMS (ESI-TOF) m/z Calcd for C12H13N2 + [M+H] + 185.1073, found 185.1082. Dimethyl 6,6'-dimethoxy-[3,3'-bipyridine]-5,5'-dicarboxylate (2f). 1 H NMR TON was 5.6, and isolated TON was 4.8. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.4 Hz, 2H), 8.34 (d, J = 2.4 Hz, 2H), 4.10 (s, 6H), 3.95 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 165.23, 161.99, 148.26, 139.43, 125.72, 114.02, 54.47, 52.48. HRMS (ESI- TOF) m/z Calcd for C16H17N2O6 + [M+H] + 333.1081, found 333.1087. 2,2'-Difluoro-5,5'-dimethyl-3,3'-bipyridine (2g). 1 H NMR TON 9.3, and isolated TON was 8.3. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 2H), 7.70-7.67 (m, 2H), 2.39 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 158.72 (d, J = 237 Hz), 147.31 (t, J = 7.2 Hz), 142.33 (t, J = 3.2 Hz), 131.11 (t, J = 2.4 Hz), 115.82 (dd, J = 34.1, 8.6 Hz), 17.36. HRMS (ESI-TOF) m/z Calcd for C12H11F2N2 + [M+H] + 221.0885, found 221.0893. 2,2',5,5'-Tetrafluoro-4,4'-bipyridine (2h). 1 H NMR TON was 8.3, and isolated TON was 7.3. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 2H), 7.07 (dd, J = 5.6, 3.2 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 159.24 (dd, J = 237, 1.9 Hz), 153.99 (ddd, J = 256, 5.0, 1.1 Hz), 136.26-135.81 (m), 132.75-132.53 (m), 110.62 (dt, J = 42.2, 1.7 Hz). HRMS (ESI-TOF) m/z Calcd for C10H5F4N2 + [M+H] + 229.0383, found 229.0390. 2,6-Dimethoxy-3,3'-bipyridine (2i) 3. 1 H NMR TON was 1.0, and isolated TON was 0.6. Yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 4.8 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 3.97 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 162.82, 159.49, 149.68, 147.65, 141.15, 136.07, 132.68, 122.94, 111.98, 101.56, 53.62, 53.45. 7
2,3'-Bipyridine (3a) 4. 1 H NMR TON was 2.8, and isolated TON was 2.2. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.20 (S, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.34 (dt, J = 8.0, 2.0 Hz, 1H), 7.83-7.75 (m, 2H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 7.32-7.28 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 154.74, 150.03, 149.82, 148.15, 136.97, 134.87, 134.36, 123.59, 122.82, 120.59. 5,5'-Dimethyl-2,3'-bipyridine (3e). 1 H NMR TON was 1.0, and isolated TON was 0.6. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.13 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 152.22, 150.43, 150.08, 145.19, 137.44, 134.64, 134.41, 133.11, 132.40, 120.13, 18.42, 18.20. HRMS (ESI-TOF) m/z Calcd for C12H13N2 + [M+H] + 185.1073, found 185.1083. 2',6-Difluoro-3,5'-dimethyl-2,3'-bipyridine (3g). 1 H NMR TON was 1.5, and isolated TON was 1.0. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.74 7.69 (m, 2H), 6.92 (dd, J = 8.0, 4.0 Hz, 1H), 2.39 (s, 3H), 2.25 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.48 (d, J = 237 Hz), 158.50 (d, J = 236 Hz), 147.80, 147.66, 143.45 (d, J = 7.4 Hz), 142.75 (d, J = 4.1 Hz), 131.32 (d, J = 4.8 Hz), 130.16 (d, J = 4.7 Hz), 109.22, 108.85, 17.79 (dd, J = 5.4, 1.6 Hz), 17.37 (d, J = 1.2 Hz). HRMS (ESI-TOF) m/z Calcd for C12H11F2N2 + [M+H] + 221.0885, found 221.0889. 3-Phenylpyridine (5a) 5. 1 H NMR TON was 7.0, and isolated TON was 6.5. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.0 Hz, 1H), 8.58 (dd, J = 4.8, 1.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 148.35, 148.21, 137.71, 136.52, 134.23, 128.97, 127.99, 127.03, 123.43. 3-(2,5-Dimethylphenyl)pyridine (5b) 6. 1 H NMR TON was 6.0, and isolated TON was 5.6. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.59-8.57 (m, 2H), 7.64 (dt, J = 8.0, 2.0 Hz, 1H), 7.33 (dd, J = 8.0, 4.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 2.36 (s, 3H), 2.23 8
(s, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.92, 147.98, 137.88, 137.55, 136.40, 135.53, 132.36, 130.51, 130.45, 128.75, 122.91, 20.85, 19.80. 3-Fluoro-5-phenylpyridine (5c). 1 H NMR TON was 6.3, and isolated TON was 5.7. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.51-7.45 (m, 3H), 7.40 (dd, J = 6.8, 4.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 156.60 (d, J = 256 Hz), 145.93 (d, J = 5.2 Hz), 138.98 (d, J = 25.7 Hz), 136.00 (d, J = 10.7 Hz), 132.87 (d, J = 1.4 Hz), 129.21, 128.78, 128.75, 124.17. HRMS (ESI-TOF) m/z Calcd for C11H9FN + [M+H] + 174.0714, found 174.0717. 3-Methyl-5-phenylpyridine (5d) 7. 1 H NMR TON was 5.1, and isolated TON was 4.5. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.43 (s, 1H), 7.68 (s, 1H), 7.58-7.56 (m, 2H), 7.49-7.45 (m, 2H), 7.41-7.37 (m, 1H), 2.41 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 148.85, 145.43, 137.86, 136.20, 135.07, 133.05, 128.98, 127.97, 127.12, 18.44. 2-Fluoro-5-methyl-3-phenylpyridine (5e). 1 H NMR TON was 7.0, and isolated TON was 6.5. Colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.66 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 7.56-7.54 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.83 (d, J = 236 Hz), 145.74 (d, J = 14.3 Hz), 141.28 (d, J = 4.3 Hz), 133.96 (d, J = 5.2 Hz), 131.21 (d, J = 4.7 Hz), 128.68 (d, J = 3.0 Hz), 128.58, 128.24, 122.93 (d, J = 28.5 Hz), 17.38 (d, J = 1.2 Hz). HRMS (ESI-TOF) m/z Calcd for C12H11FN + [M+H] + 188.0870, found 188.0878. Biphenyl (6a) 8. 1 H NMR TON was 1.0, and isolated TON was 0.6. White solid. 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 4H), 7.44 (t, J = 8.0 Hz, 4H), 7.35 (t, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 141.20, 128.72, 127.22, 127.14. References: (1) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358. (2) Dayaker, G.; Chevallier, F.; Gros, P. C.; Mongin, F. Tetrahedron 2010, 66, 8904. 9
(3) Fu, X.-L.; Wu, L.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Eur. J. Org. Chem. 2009, 2051. (4) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282. (5) Alacid, E.; Nájera, C. Org. Lett. 2008, 10, 5011. (6) Ye, M.; Gao, G.-L.; Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19090. (7)Xin B. J. Chem. Res. (S.) 2008, 412. (8) Yang, L.; Zeng, T.; Shuai, Q.; Guo, X.; Li, C.-J. Chem. Commun. 2011, 47, 2161. 10
NMR Spectra 2a 11
2b 12
2c 13
2d 14
2e 15
2f 16
2g 17
2h 18
2i 19
3a 20
3e 21
3g 22
5a 23
5b 24
5c 25
5d 26
5e 27
6a 28