Pd(II) Catalyzed C3-selective arylation of pyridine with (hetero)arenes SUPPORTING INFORMATION

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1 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, N. Torrey Pines Road, La Jolla, California 92037, USA The Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin , China SUPPORTING INFORMATION Table of Contents General Information:... 2 Experimental method:... 3 Experimental data:... 6 References: NMR Spectra

2 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

3 Experimental method: 1. Optimization of reaction conditions: Table S1: Solvent screening without ligand a Table S2: Solvent screening with 1,10-phenanthroline a 3

4 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, 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

5 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, 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

6 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 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 , , , , ,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 , , , , , 53.44, ,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 (d, J = 259 Hz), (t, J = 2.7 Hz), (m), (dd, J = 8.3, 3.5 Hz), HRMS (ESI-TOF) m/z Calcd for C10H7F2N2 + [M+H] , found ,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 (m, 2H), 7.00 (dd, J = 8.0, 2.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ (dd, J = 248, 14.1 Hz), (dd, J = 248, 14.4 Hz), (dt, J = 8.0, 4.0 Hz), (dd, J = 22.6, 6.0 Hz), (dt, J = 34.6, 3.0 Hz). HRMS (ESI-TOF) m/z Calcd for C10H5F4N2 + [M+H] , found

7 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 , , , , , HRMS (ESI-TOF) m/z Calcd for C12H13N2 + [M+H] , found 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 , , , , , , 54.47, HRMS (ESI- TOF) m/z Calcd for C16H17N2O6 + [M+H] , found ,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), (m, 2H), 2.39 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ (d, J = 237 Hz), (t, J = 7.2 Hz), (t, J = 3.2 Hz), (t, J = 2.4 Hz), (dd, J = 34.1, 8.6 Hz), HRMS (ESI-TOF) m/z Calcd for C12H11F2N2 + [M+H] , found ,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 (dd, J = 237, 1.9 Hz), (ddd, J = 256, 5.0, 1.1 Hz), (m), (m), (dt, J = 42.2, 1.7 Hz). HRMS (ESI-TOF) m/z Calcd for C10H5F4N2 + [M+H] , found ,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 , , , , , , , , , , 53.62,

8 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), (m, 2H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl3) δ , , , , , , , , , ,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 , , , , , , , , , , 18.42, HRMS (ESI-TOF) m/z Calcd for C12H13N2 + [M+H] , found ',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), (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 (d, J = 237 Hz), (d, J = 236 Hz), , , (d, J = 7.4 Hz), (d, J = 4.1 Hz), (d, J = 4.8 Hz), (d, J = 4.7 Hz), , , (dd, J = 5.4, 1.6 Hz), (d, J = 1.2 Hz). HRMS (ESI-TOF) m/z Calcd for C12H11F2N2 + [M+H] , found 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 , , , , , , , , (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 (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),

9 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ , , , , , , , , , , , 20.85, 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), (m, 3H), 7.40 (dd, J = 6.8, 4.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ (d, J = 256 Hz), (d, J = 5.2 Hz), (d, J = 25.7 Hz), (d, J = 10.7 Hz), (d, J = 1.4 Hz), , , , HRMS (ESI-TOF) m/z Calcd for C11H9FN + [M+H] , found 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), (m, 2H), (m, 2H), (m, 1H), 2.41 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ , , , , , , , , , 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), (m, 2H), (m, 2H), (m, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ (d, J = 236 Hz), (d, J = 14.3 Hz), (d, J = 4.3 Hz), (d, J = 5.2 Hz), (d, J = 4.7 Hz), (d, J = 3.0 Hz), , , (d, J = 28.5 Hz), (d, J = 1.2 Hz). HRMS (ESI-TOF) m/z Calcd for C12H11FN + [M+H] , found 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 , , , References: (1) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, (2) Dayaker, G.; Chevallier, F.; Gros, P. C.; Mongin, F. Tetrahedron 2010, 66,

10 (3) Fu, X.-L.; Wu, L.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Eur. J. Org. Chem. 2009, (4) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, (5) Alacid, E.; Nájera, C. Org. Lett. 2008, 10, (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, (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,

11 NMR Spectra 2a 11

12 2b 12

13 2c 13

14 2d 14

15 2e 15

16 2f 16

17 2g 17

18 2h 18

19 2i 19

20 3a 20

21 3e 21

22 3g 22

23 5a 23

24 5b 24

25 5c 25

26 5d 26

27 5e 27

28 6a 28