Rhodium-Catalyzed Direct Bis-cyanation of. Arylimidazo[1,2-α]pyridine via Double C-H Activation

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1 Supporting Information Rhodium-Catalyzed Direct Bis-cyanation of Arylimidazo[1,2-α]pyridine via Double C-H Activation Xinju Zhu, Xiao-Jing Shen, Zi-Yao Tian, Shuai Lu, Lu-Lu Tian, Wen-Bo Liu, Bing Song,* Xin-Qi Hao* College of Chemistry and Molecular Engineering, School of Life Sciences, Zhengzhou University, No. 100 of Science Road, Zhengzhou, Henan , P. R. China (B. Song); (X.-Q. Hao) Table of contents Experimental section....s1 1. Optimization of reaction conditions....s1 2. Mechanistic studies..s3 3. X-ray crystal structure of 2a S6 4. Theoretical calculations S8 NMR spectra of compounds.. S14 IR Spectra of 2a and 2t.. S57 S0

2 Experimental section 1. Optimization of reaction conditions Table S1. Optimization of catalyst loading a Entry X Y Yield Entry X Y Yield trace a Reaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl 2 ] 2 (X mol%), AgSbF 6 (Y mol%), DCE (1 ml), 120 o C, 24 h, air atmosphere. Table S2. Optimization of solvents a Entry Solvent Yield Entry X Yield b 1 toluene 20 8 ethyl acetate 25 2 EtOH trace 9 n-hexane 46 3 DCM DMF N.R. 4 dioxane DMSO N.R. 5 acetone THF chloroform DCE t AmOH N.R. a Reaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl 2 ] 2 (5 mol%), AgSbF 6 (40 mol%), solvent (1 ml), 120 o C, 24 h, air atmosphere. Table S3. Optimization of temperature and time a S1

3 Entry temp time Yield Entry temp time Yield N.R a Reaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl 2 ] 2 (5 mol%), AgSbF 6 (40 mol%), DCE (1 ml), temperature, time, air atmosphere. Table S4. Optimization of additives a Entry Additive N Yield Entry Additive N Yield 1 CF 3 COOH K 2 CO 3 1 trace 2 CH 3 COOH Na 2 CO NaHCO NaOAc t-buona NaHCO t-buoli NaHCO t-buok 1 N.R. 12 NaHCO a Reaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl 2 ] 2 (5 mol%), AgSbF 6 (40 mol%), DCE (1 ml), additive (N equiv), 120 o C, 24 h, air atmosphere. S2

4 2. Mechanistic experiments: (a) Procedure for preparation of 1a-d 5 : (b) H/D exchange experiment: S3

5 (c) Parallel experiment between 1 and 1-d 5 : Time (min) H NMR Yield of 2a(%) y = x H NMR Yield (%) Time (min) S4

6 Time (min) H NMR Yield of 2a-d 3 (%) y = 0.16x H NMR Yield (%) Time (min) KIE = K H /K D = 0.193/0.16= 1.23 (d) Competitive experiment between 1 and 1-d 5 : KIE = K H/K D = 0.534/0.466 =1.146 S5

7 3. X-ray crystal structure of 2a Table S5. Crystal data and structure refinement of 2a Sturcture 2a Identification code Empirical formula C 15 H 8 N 4 Formula weight Temperature/K 293(2) Crystal system monoclinic Space group P 21/c a/å (4) b/å (9) c/å (7) α/ 90 β/ (5) γ/ 90 Volume/Å (13) Z 4 ρ calc g/cm μ/mm F(000) 504 Crystal size/mm Radiation Cu Kα (λ = ) 2Θ range for data collection/ o to Index ranges -7 h 9, -12 k 9, -16 l 14 Reflections collected 4242 Independent reflections 2110 [Rint = , Rsigma = ] Data/restraints/parameters 2110 / 0 / 173 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å /-0.27 S6

8 Figure S1. ORTEP views of the molecular structures of 2a with ellipsoids drawn at the 30% probability level S7

9 4. Theoretical calculations Computational details: All density functional theory (DFT) calculations were performed using Gaussian 09 program. 1 The structures of all the stationary points were fully optimized and characterized as minima at the M06-2X/6-31++G(d, p) level at K and 1 atm, 2,3 with the salvation effects of DCE included and simulated by the IEFPCM model. 4,5 Results and discussion: To explain the formation of bis-cyanated product 2a is more favorable compared with that of mono-cyanated product 2a', theoretical calculations using the density functional theory (DFT) method was performed. The general C-H cyanation process was illustrated in Scheme S1, which underwent mon-cyanation and bis-cyanation sequences. The starting materials (1a and NCTS) were denoted as stage A, the mono-cyanated products (2a', NCTS, and NCTS-H) denoted as stage B, and the bis-cyanated products (2a' and NCTS-H) denoted as stage C. Also, the relative free energy of stage A was defined as 0.0 kcal/mol. As shown in Table S6 and Figure S2, stage C has lower ΔG (-27.7 kcal/mol) compared with stage B (-15.7 kcal/mol), which indicates that the bis-cyanated product 2a is much more stable than the mono-cyanated product 2a' from the thermodynamic perspective, and that s why it is difficult to capture the mono-cyanated product 2a'. The Cartesian coordinates of all optimized structures for 1a, NCTS, NCTS-H, 2a', and 2a were also included (Table S7-S11). Scheme S1. The general C H cyanation process. Table S6. Relative energies of stage A, B, and C. Stage ΔE (kcal/mol) ΔG (kcal/mol) A B C S8

10 Figure S2. Free energy profiles of C-H cyanation with stage A, B, and C. Table S7. The Cartesian coordinates of all optimized structures for 1a Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z S9

11 Table S8. The Cartesian coordinates of all optimized structures for NCTS Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z Table S9. The Cartesian coordinates of all optimized structures for NCTS-H Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z S10

12 Table S10. The Cartesian coordinates of all optimized structures for 2a' Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z S11

13 Table S11. The Cartesian coordinates of all optimized structures for 2a Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z S12

14 Reference 1. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision C. 01; Gaussian, Inc.: Wallingford, CT, Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, Sang-Aroon, W.; Ruangpornvisuti, V. Int. J. Quantum Chem. 2008, 108, Tomasi, J.; Mennucci, B.; Cance.s, E. J. Mol. Struct. (THEOCHEM) 1999, 464, S13

15 NMR spectra of synthesized compounds 1 H NMR of compound 2a 13 C NMR of compound 2a S14

16 1 H NMR of compound 2b 13 C NMR of compound 2b S15

17 1 H NMR of compound 2c 13 C NMR of compound 2c S16

18 1 H NMR of compound 2d 13 C NMR of compound 2d S17

19 1 H NMR of compound 2e 13 C NMR of compound 2e S18

20 1 H NMR of compound 2f 13 C NMR of compound 2f S19

21 19 F NMR of compound 2f 1 H NMR of compound 2g S20

22 13 C NMR of compound 2g 1 H NMR of compound 2h S21

23 13 C NMR of compound 2h 1 H NMR of compound 2i S22

24 13 C NMR of compound 2i 19 F NMR of compound 2i S23

25 1 H NMR of compound 2j 13 C NMR of compound 2j S24

26 1 H NMR of compound 2k 13 C NMR of compound 2k S25

27 1 H NMR of compound 2l 13 C NMR of compound 2l S26

28 1 H NMR of compound 2m 13 C NMR of compound 2m S27

29 1 H NMR of compound 2n 13 C NMR of compound 2n S28

30 1 H NMR of compound 2o 13 C NMR of compound 2o S29

31 19 F NMR of compound 2o 1 H NMR of compound 2p S30

32 13 C NMR of compound 2p 1 H NMR of compound 2q S31

33 13 C NMR of compound 2q 1 H NMR of compound 2r S32

34 13 C NMR of compound 2r 1 H NMR of compound 2s S33

35 13 C NMR of compound 2s 19 F NMR of compound 2s S34

36 1 H NMR of compound 2t 13 C NMR of compound 2t S35

37 1 H NMR of compound 2u 13 C NMR of compound 2u S36

38 1 H NMR of compound 2v 13 C NMR of compound 2v S37

39 1 H NMR of compound 2w 13 C NMR of compound 2w S38

40 19 F NMR of compound 2w 1 H NMR of compound 2x S39

41 13 C NMR of compound 2x 1 H NMR of compound 2y S40

42 13 C NMR of compound 2y 19 F NMR of compound 2y S41

43 1 H NMR of compound 2z 13 C NMR of compound 2z S42

44 19 F NMR of compound 2z 1 H NMR of compound 2aa S43

45 13 C NMR of compound 2aa 1 H NMR of compound 2ab S44

46 13 C NMR of compound 2ab 1 H NMR of compound 2ac S45

47 13 C NMR of compound 2ac 19 F NMR of compound 2ac S46

48 1 H NMR of compound 2ad 13 C NMR of compound 2ad S47

49 1 H NMR of compound 2ae 13 C NMR of compound 2ae S48

50 1 H NMR of compound 2af 13 C NMR of compound 2af S49

51 1 H NMR of compound 2ag 13 C NMR of compound 2ag S50

52 19 F NMR of compound 2ag 1 H NMR of compound 2ah S51

53 13 C NMR of compound 2ah 1 H NMR of compound 2ai S52

54 13 C NMR of compound 2ai 1 H NMR of compound 2aj S53

55 13 C NMR of compound 2aj 1 H NMR of compound 2ak S54

56 13 C NMR of compound 2ak 1 H NMR of compound 2al S55

57 13 C NMR of compound 2al S56

58 %T %T c m c m c m c m c m - 1 IR spectra of 2a cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm-1 Name Description Administrator 41-2 Sample 041 By Administrator Date Friday, February IR spectra of 2t cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm-1 Name Description Administrator 40-1 Sample 040 By Administrator Date Friday, February S57