Supporting Information. Indole Synthesis via Cobalt(III)-Catalyzed Oxidative Coupling of N-Arylureas and Internal Alkynes

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1 Supporting Information Indole Synthesis via Cobalt(III)-Catalyzed Oxidative Coupling of N-Arylureas and Internal Alkynes Zhuo-Zhuo Zhang, Bin Liu, Jing-Wen Xu, Sheng-Yi Yan, Bing-Feng Shi * Department of Chemistry, Zhejiang University, Hangzhou , China. bfshi@zju.edu.cn Table of Contents: 1. General Information S2 2. Experimental Section S3 2.1 Optimization of Reaction Conditions S3 2.2 General Procedure for C H Activation Experiments S7 2.3 General Procedure for Mechanistic Experiments S13 3. References S16 4. Spectra S17 S1

2 General Information AgSbF 6 was obtained from Alfa Aeser. Ag 2 CO 3 was purchased from Adamas and NaH 2 PO 4 was purchased from Energy. The other materials and solvents were purchased from Adamas or other commercial suppliers and used without additional purification. [CoCp * (CO)I 2 ], [1] substituted N-arylureas, [2] alkynes [3] were prepared according to the literature. Reactions for the synthesis of indoles was carried out under O 2. NMR spectra were recorded on a Bruke Avance operating for 1 H NMR at 400 MHz, 13 C NMR at 100 MHz, using TMS as internal standard. Chemical shifts were given relative to CDCl 3 (7.26 ppm for 1 H NMR, ppm for 13 C NMR). The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet. Mass spectroscopy data of the products were collected on an HRMS-TOF instrument using EI ionization and ESI ionization. S2

3 1. Experimental Section 2.1 Optimization of Reaction Conditions Screening of Different Directing Groups a,b a Reaction Conditions: 1a (0.1 mmol), 2a (0.15 mmol), [CoCp * (CO)I 2 ] (0.01 mmol), AgSbF 6 (0.02 mmol), Na 2 CO 3 (0.04 mmol), CuBr Me 2 S (0.04 mmol), solvent (1 ml), under O 2 for 24 h. b Yield was determined by 1 H NMR using 1,3,5-trimethoxybenzene as an internal standard S3

4 Screening of Oxidants and Additives a a Reaction Conditions: 1a (0.1 mmol), 2a (0.15 mmol), [CoCp * (CO)I 2 ] (0.01 mmol), AgSbF 6 (0.02 mmol), salt (0.04 mmol), additive (0.04 mmol), DCE (1 ml), under O 2 for 24 h. b Yield was determined by 1 H NMR using 1,3,5- trimethoxybenzene as an internal standard. c salt (0.1 mmol). d additive (0.10 mmol). S4

5 Screening of Different Co salts a Ph O NMe 2 Co salt (10 mol %) Ph N + Ph Ph AgSbF 6 (20 mol %) H NaH N 2 PO 4 (1.0 equiv) Ag 2 CO 3 (1.0 equiv) H O Me 2 N DCE, 110 篊, O 2, 24 h 1ab 2a 3ab Entry Co salt Yield [%] b [CoCp * (CO)I 2 ] Co(OAc) 2 4H 2 O Co(acac) 2 Co 2 C 2 O 4 CoCO 3 CoSO 4 7H 2 O Co(acac) 3 CoCl Co(SCN) 2 Co(NO 3 ) 6H 2 O 0 0 a Reaction Conditions: 1a (0.1 mmol), 2a (0.15 mmol), [CoCp * (CO)I 2 ] (0.01 mmol), AgSbF 6 (0.02 mmol), NaH 2 PO 4 (0.1 mmol), Ag 2 CO 3 (0.1mmol), DCE (1 ml), under O 2 for 24 h. b Yield was determined by 1 H NMR using 1,3,5- trimethoxybenzene as an internal standard. S5

6 Screening of Temperature a a Reaction Conditions: 1a (0.1 mmol), 2a (0.15 mmol), [CoCp * (CO)I 2 ] (0.01 mmol), AgSbF 6 (0.02 mmol), NaH 2 PO 4 (0.1 mmol), Ag 2 CO 3 (0.1mmol), DCE (1 ml), under O 2 for 24 h. b Yield was determined by 1 H NMR using 1,3,5- trimethoxybenzene as an internal standard. c NaH 2 PO 4 (0.2 mmol), Ag 2 CO 3 (0.10 mmol). d NaH 2 PO 4 (0.2 mmol), Ag 2 CO 3 (0.12 mmol). e 1a (0.15 mmol), 2a (0.1 mmol), NaH 2 PO 4 (0.2 mmol), Ag 2 CO 3 (0.12 mmol). f Isolated product. S6

7 2.2 General Procedure for C H Activation Experiments N-arylureas 1 (0.15 mmol, 1.5 equiv), alkyne 2 (0.10 mmol, 1.0 equiv), [CoCp * (CO)I 2 ] (0.01 mmol, 10 mol %), AgSbF 6 (0.02 mmol, 20 mol %), NaH 2 PO 4 (0.20 mmol, 2.0 equiv), Ag 2 CO 3 (0.12 mmol, 1.2 equiv) and 1,2-dichloroethane (1 ml) were charged into a pressure tube. The reaction mixture was stirred for 24 h at 130 under O 2 followed by cooling. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using EA/PE=1/6 to afford the product such as 3aa. 1-(2,3-diphenyl-1H-indol-1-yl)ethanone (3aa) [4] 3aa was obtained according to the general procedure as a yellow solid (9.0 mg, 29%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), (m, 10H), (m, 2H), 2.01 (s, 3H). N,N-dimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ab) [5] 3ab was obtained according to the general procedure as a yellow solid (32.0 mg, 94%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), (m, 10H), 7.22 (m, 2H), 2.98 (brs, 3H), 2.53 (brs, 3H). 5-fluoro-N,N-dimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ba) [5] 3ba was obtained according to the general procedure as a yellow solid (15.4 mg, 43%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (dd, J = 8.9, 4.3 Hz, 1H), (m, 11H), 7.05 (td, J = 9.0, 2.5 Hz, 1H), 2.97 (brs, 3H), 2.50 (brs, 3H). 5-bromo-N,N-dimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ca) [5] S7

8 3ca was obtained according to the general procedure as a yellow solid (18.8 mg, 45%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (s, 1H), 7.32 (d, J = 1.0 Hz, 2H), (m, 10H), 2.90 (brs, 3H), 2.42 (brs, 3H). methyl 1-(dimethylcarbamoyl)-2,3-diphenyl-1H-indole-5-carboxylate (3da) [5] 3da was obtained according to the general procedure as a yellow solid (23.8 mg, 60%). 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.95 (d, J = 8.7, 1H), 7.45 (d, J = 8.7 Hz, 1H), (m, 10H), 3.84 (s, 3H), 2.92 (s, 3H), 2.44 (s, 3H). N,N,6-trimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ea) [5] 3ea was obtained according to the general procedure as a yellow solid (22.7 mg, 64%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 8.1 Hz, 1H), (m, 10H), 7.25 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 2.97 (brs, 3H), 2.49 (s, 6H). methyl 1-(dimethylcarbamoyl)-2,3-diphenyl-1H-indole-6-carboxylate (3fa) [5] 3fa was obtained according to the general procedure as a yellow solid (15.5 mg, 39%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.83 (dd, J = 8.4, 1.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), (m, 10H), 3.87 (s, 3H), 2.94 (s, 3H), 2.46 (s, 3H). N,N,7-trimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ga) [5] 3ga was obtained according to the general procedure as a yellow solid (17.0 mg, 48%). S8

9 1 H NMR (400 MHz, CDCl3) δ (m, 1H), (m, 2H), (m, 7H), (m, 1H), (m, 2H), 2.92 (s, 3H), 2.52 (s, 3H), 2.44 (s, 3H). 7-methoxy-N,N-dimethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ha) [5] 3ha was obtained according to the general procedure as a yellow solid (27.0 mg, 73%). 1 H NMR (400 MHz, CDCl3) δ 7.38 (brs, 1H), 7.34 (d, J = 8.4 Hz, 1H), (m, 10H), 7.08 (d, J = 8.4, 1H), 2.89 (brs, 2H), 2.48 (brs, 3H), 2.37 (s, 3H). N,N,5,6-tetramethyl-2,3-diphenyl-1H-indole-1-carboxamide (3ia) [5] 3ia was obtained according to the general procedure as a yellow solid (21.5 mg, 58%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (s, 1H), (m, 11H), 2.88 (brs, 3H), 2.40 (brs, 3H), 2.32 (s, 3H), 2.26 (s, 3H). (2,3-diphenyl-1H-indol-1-yl)(pyrrolidin-1-yl)methanone (3ja) [6] 3ja was obtained according to the general procedure as a yellow solid (27.1 mg, 74%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), (m, 2H), (m, 9H), (m, 1H), 3.58 (s, 1H), 3.33 (s, 1H), 2.90 (s, 1H), 2.75 (s, 1H), (m, 4H). 2-methyl-3,4-diphenylquinoline (4aa) [7] 4aa was obtained according to the general procedure as a yellow solid (4.7 mg, 16%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), (m, 6H), (m, 5H), 2.54 (s, 3H). N,N-dimethyl-2,3-di-p-tolyl-1H-indole-1-carboxamide (5a) S9

10 5a was obtained according to the general procedure as a yellow solid (27.6 mg, 75%). 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), (m, 9H), 2.91 (s, 3H), 2.47 (s, 3H), 2.28 (d, J = 7.7 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ , , , , , , , , , , , , , , , , , 38.10, 36.58, 21.48, HRMS (EI-TOF) calcd for C 25 H 24 N 2 O (M+): , found: ,3-bis(4-methoxyphenyl)-N,N-dimethyl-1H-indole-1-carboxamide (5b) 5b was obtained according to the general procedure as a yellow solid (16.8 mg, 42%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), (m, 5H), (m, 1H), (m, 4H), 3.76 (s, 3H), 3.74 (s,3h), 2.93 (brs, 3H), 2.46 (brs, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 55.35, 55.33, 38.04, HRMS (EI-TOF) calcd for C 25 H 24 N 2 O 3 (M+): , found: ,3-bis(4-butylphenyl)-N,N-dimethyl-1H-indole-1-carboxamide (5c) 5c was obtained according to the general procedure as a yellow solid (20.8 mg, 46%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), (m, 10H), 2.89 (s, 3H), 2.54 (m, 4H), 2.42 (s, 3H), (m, 4H), (m, 4H), (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 35.57, 35.55, 33.67, 33.41, 22.61, 22.53, 14.14, HRMS (EI-TOF) calcd for C 31 H 36 N 2 O (M+): , found: S10

11 2,3-bis(4-(tert-butyl)phenyl)-N,N-dimethyl-1H-indole-1-carboxamide (5d) 5d was obtained according to the general procedure as a yellow solid (28.9 mg, 64%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), (m, 9H), 7.11 (t, J = 7.5 Hz, 1H), 2.89 (s, 3H), 2.42 (s, 3H), 1.26 (d, J = 11.0 Hz, 18H). 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 38.02, 36.56, 34.78, 34.65, 31.54, HRMS (EI-TOF) calcd for C 31 H 36 N 2 O (M+): , found: ,3-bis(4-fluorophenyl)-N,N-dimethyl-1H-indole-1-carboxamide (5e) 5e was obtained according to the general procedure as a yellow solid (23.6 mg, 63%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), (m, 7H), 7.04 (q, J = 8.6 Hz, 4H), 3.01 (s, 3H), 2.60 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = Hz), , , , , (d, J = 7.8 Hz), (d, J = 8.1 Hz), (d, J = 3.3 Hz), , (d, J = 3.4 Hz), , , , , (d, J = 21.6 Hz), (d, J = 21.2 Hz), , 38.11, HRMS (EI-TOF) calcd for C 23 H 18 F 2 N 2 O (M+): , found: ,3-bis(4-bromophenyl)-N,N-dimethyl-1H-indole-1-carboxamide (5f) 5f was obtained according to the general procedure as a yellow solid (23.8 mg, 48%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (d, J = 7.9 Hz, 1H), (m, 5H), 7.34 (t, J = 7.6 Hz, 1H), (m, 5H), 3.02 (s, 3H), 2.61 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , S11

12 122.22, , , , , 38.05, HRMS (EI-TOF) calcd for C 23 H 18 Br 2 N 2 O (M+): , found: N,N-dimethyl-2,3-di(thiophen-2-yl)-1H-indole-1-carboxamide (5g) 5g was obtained according to the general procedure as a yellow solid (23.0 mg, 65%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 7.9 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 3H), 3.02 (brs, 3H), 2.67 (brs, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 38.22, HRMS (EI-TOF) calcd for C 19 H 16 N 2 OS 2 (M+): , found: N,N,3-trimethyl-2-phenyl-1H-indole-1-carboxamide (5h) [8] 5h was obtained according to the general procedure as a yellow solid (22.4 mg, 81%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 5H), (m, 1H), (m, 1H), (m, 1H), 2.78 (brs, 6H), 2.37 (s, 3H). S12

13 2.3 General Procedure for Mechanistic Experiments a) Reaction Conditions: N-arylurea 1ab (0.15 mmol, 1.5 equiv) or 1ab-[d 5 ] (0.15 mmol, 0.15 equiv), alkyne 2a (0.10 mmol, 1.0 equiv), [CoCp * (CO)I 2 ] (0.01 mmol, 10 mol %), AgSbF 6 (0.02 mmol, 20 mol %), NaH 2 PO 4 (0.20 mmol, 2.0 equiv) Ag 2 CO 3 (0.20 mmol, 1.2 equiv) and 1,2-dichloroethane (1 ml) were added in two separated Schlenk tubes. The reaction mixture was stirred for 45 min at 130 under O 2, then immediately quenched with EtOAc at the same time. Then two reaction mixtures were combined and the volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: pentane/ethyl acetate = 10:1) to afford 3ab and 3ab-[d 4 ]. The ratio of 3ab and 3ab-[d 4 ] was determined by 1 HNMR to be 1.6 : f1 (ppm) S13

14 b) Reaction Conditions: N-arylurea 1ab (0.075 mmol, 0.75 equiv), 1ab-[d 5 ] (0.075 mmol, 0.75 equiv), alkyne 2a (0.10 mmol, 1.0 equiv), [CoCp * (CO)I 2 ] (0.01 mmol, 10 mol %), AgSbF 6 (0.02 mmol, 20 mol %), NaH 2 PO 4 (0.20 mmol, 2.0 equiv) Ag 2 CO 3 (0.20 mmol, 1.2 equiv) and 1,2-dichloroethane (1 ml) were charged into a pressure tube. The reaction mixture was stirred for 45 min at 130 under O 2, then immediately quenched with EtOAc at the same time and then removed under reduced pressure. The crude product was purified by column chromatography on silica gel to (eluent: pentane/ethyl acetate = 10:1) afford 3ab and 3ab-[d 4 ]. The ratio of 3ab and 3ab-[d 4 ] was determined by 1 HNMR to be 3.3 : 1. S14

15 c) Reaction Conditions: N-arylurea 1ab-[d 5 ] (0.15 mmol, 1.5 equiv), [CoCp * (CO)I 2 ] (0.01 mmol, 10 mol %), AgSbF 6 (0.02 mmol, 20 mol %), NaH 2 PO 4 (0.20 mmol, 2.0 equiv) Ag 2 CO 3 (0.20 mmol, 1.2 equiv) and 1,2-dichloroethane (1 ml) were charged into a pressure tube. The reaction mixture was stirred for 24 h at 130 under O 2 followed by cooling. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using EA/PE=1/2 to afford the product. 1 H NMR snalysis of the recovered starting material revealed no H/D exchange. S15

16 2. References (1) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M. Adv. Synth. Catal. 2014, 356, (b) Frith, S. A.; Spencer, J. Inorganic Syntheses. 1990, 28, 273. (c) Li, W.; Weng, L.; G. Jin, Inorg. Chem. Commun. 2004, 7, (2) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M.; Llyod-Jones, R.G.; BookerMilburn, K. I. J. Am. Chem. Soc. 2008, 130, (3) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, (4) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, (5) Kathiravana, S.; Nicholls, I. A. Chem. Commun. 2014, 50, (6) Leogane, O.; Lebel, H. Angew. Chem. Int. Ed. 2008, 47, 350. (7) Al-Talib, M.; Jochims, J. C.; Wang, Q.; Hamed, A.; Ismail, A. E.-H. Synthesis 1992, 9, 8. (8) Wang, H.; Grohmann, C.; Nimphius, C.; Glorius, F. J. Am. Chem. Soc. 2012, 134, S16

17 3. Spectra 3aa ( 1 H NMR) 3ab ( 1 H NMR) 3ba ( 1 H NMR) S17

18 3ca ( 1 H NMR) S18

19 3da ( 1 H NMR) 3ea ( 1 H NMR) S19

20 3fa ( 1 H NMR) 3ga ( 1 H NMR) S20

21 3ha ( 1 H NMR) 3ia ( 1 H NMR) S21

22 3ja ( 1 H NMR) 4aa ( 1 H NMR) S22

23 5a ( 1 H NMR and 13 C NMR) S23

24 5b ( 1 H NMR and 13 C NMR) S24

25 5c ( 1 H NMR and 13 C NMR) n Bu Me 2 N N O n Bu n Bu Me 2 N N O n Bu S25

26 5d ( 1 H NMR and 13 C NMR) S26

27 5e ( 1 H NMR and 13 C NMR) S27

28 5f ( 1 H NMR and 13 C NMR) S28

29 5g ( 1 H NMR and 13 C NMR) S29

30 5h ( 1 H NMR) Me N Me 2 N O Ph S30