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 450001, P. R. China E-mail: bingsong@zzu.edu.cn (B. Song); xqhao@zzu.edu.cn (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
Experimental section 1. Optimization of reaction conditions Table S1. Optimization of catalyst loading a Entry X Y Yield Entry X Y Yield 1 5 10 trace 5 5 50 53 2 5 20 15 6 5 60 53 3 5 30 44 7 2.5 20 50 4 5 40 60 8 10 80 12 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 42 10 DMF N.R. 4 dioxane 29 11 DMSO N.R. 5 acetone 32 12 THF 19 6 7 chloroform DCE 32 60 13 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
Entry temp time Yield Entry temp time Yield 1 120 12 48 5 60 24 N.R. 2 120 18 50 6 100 24 38 3 120 24 60 7 110 24 51 4 120 36 60 8 130 24 60 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 1 24 7 K 2 CO 3 1 trace 2 CH 3 COOH 1 45 8 Na 2 CO 3 1 75 3 NaHCO 3 1 84 9 NaOAc 1 35 4 t-buona 1 80 10 NaHCO 3 0.3 65 5 t-buoli 1 24 11 NaHCO 3 0.5 89 6 t-buok 1 N.R. 12 NaHCO 3 1.5 85 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
2. Mechanistic experiments: (a) Procedure for preparation of 1a-d 5 : (b) H/D exchange experiment: S3
(c) Parallel experiment between 1 and 1-d 5 : Time (min) 60 75 90 105 120 1 H NMR Yield of 2a(%) 9 11 14 18 20 25 20 y = 0.1933x - 3 1 H NMR Yield (%) 15 10 5 0 0 20 40 60 80 100 120 140 Time (min) S4
Time (min) 60 75 90 105 120 1 H NMR Yield of 2a-d 3 (%) 2 6 8 10 12 14 12 y = 0.16x - 6.8 1 H NMR Yield (%) 10 8 6 4 2 0 0 20 40 60 80 100 120 140 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
3. X-ray crystal structure of 2a Table S5. Crystal data and structure refinement of 2a Sturcture 2a Identification code 201609132 Empirical formula C 15 H 8 N 4 Formula weight 244.25 Temperature/K 293(2) Crystal system monoclinic Space group P 21/c a/å 8.2318(4) b/å 10.7603(9) c/å 13.7380(7) α/ 90 β/ 90.712(5) γ/ 90 Volume/Å 3 1216.77(13) Z 4 ρ calc g/cm 3 1.333 μ/mm -1 0.673 F(000) 504 Crystal size/mm 3 0.19 0.14 0.13 Radiation Cu Kα (λ = 1.54184) 2Θ range for data collection/ o 10.444 to 134.106 Index ranges -7 h 9, -12 k 9, -16 l 14 Reflections collected 4242 Independent reflections 2110 [Rint = 0.0249, Rsigma = 0.0357] Data/restraints/parameters 2110 / 0 / 173 Goodness-of-fit on F 2 1.069 Final R indexes [I>=2σ (I)] R 1 = 0.0552, wr 2 = 0.1701 Final R indexes [all data] R 1 = 0.0700, wr 2 = 0.1919 Largest diff. peak/hole / e Å -3 0.34/-0.27 S6
Figure S1. ORTEP views of the molecular structures of 2a with ellipsoids drawn at the 30% probability level S7
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 393.15 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 0.0 0.0 B -15.0-15.7 C -26.5-27.7 S8
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 ---------------------------------------------------------------------------------------------------------- 1 6 0-1.751990-0.695083-0.041273 2 6 0-3.044602 1.356216 0.079522 3 6 0-4.198526 0.635241 0.039674 4 6 0-4.154295-0.789223-0.043757 5 6 0-2.955051-1.446161-0.083896 6 6 0 0.259397 0.059439-0.001448 7 6 0-0.554346 1.175412 0.064095 8 1 0-2.997102 2.436142 0.142525 9 1 0-5.146543 1.157495 0.072474 10 1 0-5.082550-1.348723-0.075478 11 1 0-2.884977-2.525694-0.146901 12 1 0-0.349391 2.231878 0.134625 13 7 0-1.841480 0.694269 0.037956 14 7 0-0.484777-1.087319-0.064301 15 6 0 1.732115 0.023778-0.003600 16 6 0 2.403099-1.201517 0.092259 17 6 0 2.484155 1.202441-0.099536 18 6 0 3.795651-1.245898 0.096552 19 1 0 1.820369-2.113731 0.164546 20 6 0 3.875535 1.156802-0.092868 21 1 0 1.982341 2.161855-0.186432 22 6 0 4.537670-0.068136 0.005340 23 1 0 4.302434-2.203020 0.172662 24 1 0 4.443863 2.078569-0.168856 25 1 0 5.622476-0.103295 0.008866 ----------------------------------------------------------------------------------------------------------- S9
Table S8. The Cartesian coordinates of all optimized structures for NCTS. ------------------------------------------------------------------------------------------------------------- Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------------------------------------------------------------------------------------------------------------- 1 16 0 0.024494 0.258924 1.090723 2 8 0 0.112945 1.567057 1.718304 3 8 0 0.560137-0.916013 1.751770 4 6 0-1.618655-0.015782 0.520750 5 6 0-2.517283 1.045739 0.509013 6 6 0-3.809501 0.811293 0.044460 7 6 0-4.196740-0.455906-0.401242 8 6 0-3.260278-1.502105-0.376292 9 6 0-1.967896-1.294291 0.081848 10 1 0-2.211914 2.027037 0.856350 11 1 0-4.524680 1.627736 0.029404 12 1 0-3.553460-2.490098-0.719037 13 1 0-1.243226-2.102351 0.104470 14 6 0-5.593620-0.710662-0.899526 15 1 0-6.092596-1.456917-0.274218 16 1 0-6.191123 0.202379-0.889753 17 1 0-5.572136-1.100460-1.921261 18 7 0 0.898692 0.310622-0.423111 19 6 0 0.513017 1.286986-1.260905 20 7 0 0.140748 2.110027-1.990785 21 6 0 2.301453-0.054401-0.394213 22 6 0 3.277011 0.932950-0.281795 23 6 0 2.629687-1.404679-0.470654 24 6 0 4.617785 0.554269-0.261139 25 1 0 2.988227 1.978064-0.217989 26 6 0 3.972306-1.772191-0.434266 27 1 0 1.840097-2.143815-0.553797 28 6 0 4.963920-0.795106-0.333287 29 1 0 5.388601 1.313260-0.181901 30 1 0 4.243414-2.820917-0.491509 31 1 0 6.008921-1.086268-0.312151 -------------------------------------------------------------------------------------------------------------- Table S9. The Cartesian coordinates of all optimized structures for NCTS-H. -------------------------------------------------------------------------------------------------------------- Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z -------------------------------------------------------------------------------------------------------------- S10
1 16 0 0.083480 0.237033 0.853735 2 8 0 0.299220 1.595224 1.353414 3 8 0 0.452175-0.882811 1.714374 4 6 0-1.600109 0.084916 0.331268 5 6 0-2.392638 1.223817 0.247595 6 6 0-3.715462 1.086943-0.171208 7 6 0-4.240743-0.165272-0.501158 8 6 0-3.412678-1.294770-0.403795 9 6 0-2.093486-1.181019 0.011576 10 1 0-1.982681 2.193302 0.510012 11 1 0-4.346272 1.968076-0.239094 12 1 0-3.812303-2.273170-0.655150 13 1 0-1.453929-2.054502 0.090561 14 6 0-5.671309-0.316110-0.945624 15 1 0-6.235640-0.914109-0.223675 16 1 0-6.160712 0.654613-1.043050 17 1 0-5.724839-0.829882-1.909621 18 7 0 0.884184-0.010850-0.615248 19 6 0 2.317844-0.058601-0.543766 20 6 0 3.082272 1.016131-1.000852 21 6 0 2.936371-1.206741-0.045201 22 6 0 4.473366 0.935394-0.970402 23 1 0 2.589361 1.907200-1.379534 24 6 0 4.326876-1.268391 0.003961 25 1 0 2.324581-2.033973 0.296666 26 6 0 5.098269-0.202541-0.461652 27 1 0 5.066328 1.767847-1.335011 28 1 0 4.808539-2.158499 0.395524 29 1 0 6.181334-0.260506-0.431065 30 1 0 0.558678 0.695179-1.276330 ------------------------------------------------------------------------------------------------------------ Table S10. The Cartesian coordinates of all optimized structures for 2a'. ------------------------------------------------------------------------------------------------------------ Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------------------------------------------------------------------------------------------------------------- 1 6 0-2.000738-0.828908-0.149119 2 6 0-3.176174 1.238891 0.341170 3 6 0-4.366909 0.604908 0.167883 4 6 0-4.402668-0.781807-0.175192 5 6 0-3.244186-1.489725-0.332538 6 6 0 0.048696-0.210035 0.030826 7 6 0-0.702265 0.921033 0.297313 S11
8 1 0-3.066844 2.284719 0.599193 9 1 0-5.284500 1.166102 0.292648 10 1 0-5.361251-1.270210-0.310286 11 1 0-3.234523-2.541689-0.592126 12 1 0-0.444128 1.931958 0.566071 13 7 0-2.011777 0.524465 0.181943 14 7 0-0.759422-1.282999-0.239310 15 6 0 1.511939-0.383282 0.040635 16 6 0 2.031154-1.679124 0.156838 17 6 0 2.432435 0.679304-0.064899 18 6 0 3.402108-1.909996 0.178700 19 6 0 3.815245 0.447288-0.040033 20 6 0 4.301729-0.846932 0.083743 21 1 0 3.771435-2.925927 0.273800 22 1 0 4.493802 1.289221-0.125162 23 1 0 5.371239-1.024423 0.102250 24 6 0 2.004294 2.043293-0.226139 25 7 0 1.699001 3.153509-0.356184 26 1 0 1.332194-2.504022 0.233341 ------------------------------------------------------------------------------------------------------------- Table S11. The Cartesian coordinates of all optimized structures for 2a. ------------------------------------------------------------------------------------------------------------- Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------------------------------------------------------------------------------------------------------------- 1 6 0-2.045420-0.536116-0.437788 2 6 0-3.332605 1.097453 0.818658 3 6 0-4.485263 0.531277 0.372750 4 6 0-4.445225-0.597324-0.503283 5 6 0-3.250345-1.124405-0.904755 6 6 0-0.041463 0.052795 0.026549 7 6 0-0.844610 0.944875 0.708450 8 1 0-3.282092 1.952819 1.480327 9 1 0-5.432512 0.948584 0.690651 10 1 0-5.375868-1.034015-0.847809 11 1 0-3.181912-1.979627-1.566435 12 1 0-0.625647 1.772426 1.364811 13 7 0-2.129532 0.566195 0.412405 14 7 0-0.780579-0.856990-0.675189 15 6 0 1.428874 0.007754 0.008959 16 6 0 2.118486-1.214335 0.110416 17 6 0 2.209244 1.170627-0.124902 18 6 0 3.516507-1.270275 0.069942 S12
19 6 0 3.608225 1.118415-0.156438 20 6 0 4.261175-0.104062-0.064395 21 1 0 4.010083-2.232199 0.155072 22 1 0 4.170981 2.038982-0.265242 23 1 0 5.343365-0.148412-0.094898 24 6 0 1.417333-2.456226 0.325644 25 6 0 1.587378 2.462728-0.268953 26 7 0 0.941700-3.490239 0.536490 27 7 0 1.134105 3.521369-0.388219 ------------------------------------------------------------------------------------------------------------- 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, 2010. 2. Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215 241. 3. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157 167. 4. Sang-Aroon, W.; Ruangpornvisuti, V. Int. J. Quantum Chem. 2008, 108, 1181 1188. 5. Tomasi, J.; Mennucci, B.; Cance.s, E. J. Mol. Struct. (THEOCHEM) 1999, 464, 211 226. S13
NMR spectra of synthesized compounds 1 H NMR of compound 2a 13 C NMR of compound 2a S14
1 H NMR of compound 2b 13 C NMR of compound 2b S15
1 H NMR of compound 2c 13 C NMR of compound 2c S16
1 H NMR of compound 2d 13 C NMR of compound 2d S17
1 H NMR of compound 2e 13 C NMR of compound 2e S18
1 H NMR of compound 2f 13 C NMR of compound 2f S19
19 F NMR of compound 2f 1 H NMR of compound 2g S20
13 C NMR of compound 2g 1 H NMR of compound 2h S21
13 C NMR of compound 2h 1 H NMR of compound 2i S22
13 C NMR of compound 2i 19 F NMR of compound 2i S23
1 H NMR of compound 2j 13 C NMR of compound 2j S24
1 H NMR of compound 2k 13 C NMR of compound 2k S25
1 H NMR of compound 2l 13 C NMR of compound 2l S26
1 H NMR of compound 2m 13 C NMR of compound 2m S27
1 H NMR of compound 2n 13 C NMR of compound 2n S28
1 H NMR of compound 2o 13 C NMR of compound 2o S29
19 F NMR of compound 2o 1 H NMR of compound 2p S30
13 C NMR of compound 2p 1 H NMR of compound 2q S31
13 C NMR of compound 2q 1 H NMR of compound 2r S32
13 C NMR of compound 2r 1 H NMR of compound 2s S33
13 C NMR of compound 2s 19 F NMR of compound 2s S34
1 H NMR of compound 2t 13 C NMR of compound 2t S35
1 H NMR of compound 2u 13 C NMR of compound 2u S36
1 H NMR of compound 2v 13 C NMR of compound 2v S37
1 H NMR of compound 2w 13 C NMR of compound 2w S38
19 F NMR of compound 2w 1 H NMR of compound 2x S39
13 C NMR of compound 2x 1 H NMR of compound 2y S40
13 C NMR of compound 2y 19 F NMR of compound 2y S41
1 H NMR of compound 2z 13 C NMR of compound 2z S42
19 F NMR of compound 2z 1 H NMR of compound 2aa S43
13 C NMR of compound 2aa 1 H NMR of compound 2ab S44
13 C NMR of compound 2ab 1 H NMR of compound 2ac S45
13 C NMR of compound 2ac 19 F NMR of compound 2ac S46
1 H NMR of compound 2ad 13 C NMR of compound 2ad S47
1 H NMR of compound 2ae 13 C NMR of compound 2ae S48
1 H NMR of compound 2af 13 C NMR of compound 2af S49
1 H NMR of compound 2ag 13 C NMR of compound 2ag S50
19 F NMR of compound 2ag 1 H NMR of compound 2ah S51
13 C NMR of compound 2ah 1 H NMR of compound 2ai S52
13 C NMR of compound 2ai 1 H NMR of compound 2aj S53
13 C NMR of compound 2aj 1 H NMR of compound 2ak S54
13 C NMR of compound 2ak 1 H NMR of compound 2al S55
13 C NMR of compound 2al S56
%T %T 2 2 3 1. 0 5 c m - 1 1 5 5 0. 0 4 c m - 1 1 3 6 6. 6 4 c m - 1 1 0 8 9. 4 2 c m - 1 7 2 7. 5 2 c m - 1 IR spectra of 2a 96 94 92 90 3146.64cm-1 88 86 3036.75cm-1 84 82 80 2955.20cm-1 78 76 2849.72cm-1 74 72 2917.30cm-1 70 1976.66cm-1 1835.56cm-1 908.99cm-1 1920.88cm-1 1578.47cm-1 1321.84cm-1 941.53cm-1 612.37cm-1 1636.93cm-1 1499.94cm-1 1231.91cm-1 923.91cm-1 622.93cm-1 1060.74cm-1 670.87cm-1 1712.79cm-1 1197.39cm-1 1285.48cm-1 1107.17cm-1 695.90cm-1 1158.78cm-1 685.02cm-1 1258.09cm-1 1437.35cm-1 805.43cm-1 68 750.70cm-1 66 757.36cm-1 65 4000 3500 3000 2500 2000 1500 1000 600 cm-1 Name Description Administrator 41-2 Sample 041 By Administrator Date Friday, February 17 2017 IR spectra of 2t 97 95 1363.13cm-1 1167.90cm-1 90 85 80 3153.73cm-1 3094.12cm-1 2987.70cm-1 2941.92cm-1 2231.43cm-1 1809.35cm-1 1577.55cm-1 1635.45cm-1 1450.38cm-1 1393.78cm-1 1462.28cm-1 954.30cm-1 938.02cm-1 610.80cm-1 912.94cm-1 623.96cm-1 858.25cm-1 1006.80cm-1 888.85cm-1 690.77cm-1 837.76cm-1 782.59cm-1 682.56cm-1 75 1422.58cm-1 1342.64cm-11228.38cm-1 1136.81cm-1 731.45cm-1 811.08cm-1 70 1193.50cm-1 1709.30cm-1 1321.46cm-1 1088.22cm-1 767.45cm-1 65 1296.07cm-1 749.85cm-1 61 4000 3500 3000 2500 2000 1500 1000 600 cm-1 Name Description Administrator 40-1 Sample 040 By Administrator Date Friday, February 17 2017 S57