Indole Functionalization via Photoredox Gold Catalysis

Transcription

1 Indole Functionalization via Photoredox Gold Catalysis Sherif J. Kaldas, Alexandre Cannillo, Terry McCallum, and Louis Barriault* Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Science, University of Ottawa 10 Marie Curie, Ottawa, ON, K1N 6N5 (Canada) Table of Contents 1. General Information General Procedures Characterization of Substrates and Products H NMR and 13 C NMR Spectra... 12

2 1. General Information All commercial reagents and solvents were used without further purification, unless otherwise noted. Reactions were monitored by analytical thin layer chromatography (TLC) on silica 60 F 254 (Merck) and viewed under UV light and stained with potassium permanganate. Column chromatography was carried out with silica gel µm (Merck). Photoredox reactions were performed using a 365nm LED (1.2 W) bought from (part number: LZ4-40U600). Gold catalyst [Au 2 (dppm) 2 ]Cl 2 was prepared according to the described procedure. 1 NMR spectra were recorded on AMX 300 MHz Bruker and AMX 400 MHz Bruker spectrometers. Chemical shifts are reported in ppm referenced to the solvent peak of CDCl 3, defined at 7.26 ppm ( 1 H NMR) and ppm ( 13 C NMR). IR spectra were recorded with a Bomem Michelson 100 FTIR spectrometer. Mass spectra were recorded on a Kratos Analytical Concept instrument (University of Ottawa, Mass Spectrum Centre). ######################################################## 1 Revol, G.; McCallum, T.; Morin, M.; Gagosz, F.; Barriault, L. Angew. Chem. Int. Ed. 2013, 52, # S2#

3 2. General Procedures General Procedure 1 (GP1). Preparation of N-alkylated indoles. To a stirred suspension of sodium hydride (1.2 eq., 60% in oil) in dry THF (0.2M) under argon atmosphere at room temperature was added dropwise a solution of indole (1.0 eq.) in dry THF (0.2M). The mixture was stirred for 30 minutes at room temperature and then added over 1 hour (syringe-pump) to a solution of dibromo-alkane (2.0 eq.) in dry THF (0.2M) under argon atmosphere. The resulting mixture was then stirred at room temperature until completion (about 12 hours, monitored by TLC). Saturated aqueous NH 4 Cl was then added, layers were separated and aqueous phase was extracted with Et 2 O (3x). Organic layers were combined, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica to afford the corresponding N-alkylated indole. General Procedure 2 (GP2). Preparation of N-benzylated indoles. To a stirred suspension of sodium hydride (1.2 eq., 60% in oil) in dry THF (0.2M) under argon atmosphere at room temperature was added dropwise a solution of indole (1.0 eq.) in dry THF (0.2M). The mixture was stirred for 30 minutes at room temperature. A solution of 2-bromo-benzyl bromide (1.0 eq.) in dry THF under argon atmosphere was then added dropwise to the reaction. The resulting mixture was then stirred at room temperature until completion (monitored by TLC). Saturated aqueous NH 4 Cl was then added, layers were separated and aqueous phase was extracted with Et 2 O (3x). Organic layers were combined, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica to afford the corresponding N-benzylated indole. # S3#

4 General Procedure 3 (GP3). Radical cyclization of indoles by photoredox catalysis. To a solution of N-alkylated indole (0.2 mmol, 1.0 eq.) in acetonitrile (1 ml, 0.2 M) was added sodium carbonate (0.4 mmol, 2.0 eq.) and [Au 2 (dppm) 2 ]Cl 2 ( mmol, 2.5 to 10 mol%). The resulting mixture was stirred and degassed by sparging with argon for 10 minutes then irradiated with a 365nm LED while stirring at room temperature for 12 hours. The mixture was then filtered over Celite, rinced with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica or filtration over a small silica plug to afford the corresponding polycyclic compound. 3. Characterization of Substrates and Products 1-(4-bromobutyl)-1H-indole (2a) was synthesized according to GP1. The product was isolated (70%, 4.52 g) after purification by filtration over a silica plug (Et 2 O/hexane 5:95). Spectral data were consistent with those reported in the literature. 2 1-(3-bromopropyl)-1H-indole (2b) was synthesized according to GP1. The product was isolated (45%, 915 mg) after purification by flash chromatography on silica (Et 2 O/hexane 5:95). Spectral data were consistent with those reported in the literature. 3 1-(4-bromopentyl)-1H-indole (2c) was synthesized according to GP1. The product was isolated (68%, 772 mg) after purification by flash chromatography on silica (Et 2 O/hexane 5:95). IR (neat, cm -1 ): 2922, 1463, 1314, 1238, 737. ######################################################## 2 Ye, Q.; Li, M.; Zhou, Y.; Pang, T.; Xu, L.; Cao, J.; Han, L.; Li, Y.; Wang, W.; Gao, J.; Li, J. Molecules 2013, 18, Yi, J.; Lu, X.; Sun, Y-Y.; Xiao, B.; Liu, L. Angew. Chem. Int. Ed. 2013, 52, # S4#

5 1 H NMR (400MHz, CDCl 3 ) δ 7.67 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 4.17 (dd, J = 7.0 Hz, J = 2.0 Hz, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), 1.69 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 136.1, 128.8, 127.8, 121.7, 121.2, 119.5, 109.5, 101.5, 51.0, 45.8, 38.4, 28.7, HRMS (EI) calcd for C 13 H 16 BrN [M + ] , found (4-bromobutyl)-1H-indole-4-carbonitrile (2d) was synthesized according to GP1. The product was isolated (57%, 557 mg) after purification by flash chromatography on silica (EtOAc/hexane 2:8). IR (neat, cm -1 ): 2938, 2871, 2222, 1505, 1436, 1344, 1282, H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), (m, 2H), 6.75 (d, J = 3.0 Hz, 1H), 4.25 (t, J = 7.0 Hz, 2H), 3.42 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 135.8, 130.4, 130.0, 125.1, 121.4, 118.9, 114.2, 103.6, 100.7, 46.0, 32.9, 30.0, HRMS (EI) calcd for C 13 H 13 BrN 2 [M + ] , found (4-bromobutyl)-5-chloro-1H-indole (2e) was synthesized according to GP1. The product was isolated (66%, 1.25 g) after purification by flash chromatography on silica (Et 2 O/hexane 1:9). IR (neat, cm -1 ): 2937, 2871, 1464, 1319, 1244, 1220, 903, 755, H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), (m, 2H), 6.48 (d, J = 3.0 Hz, 1H), 4.12 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 136.5, 128.5, 127.8, 127.3, 122.1, 120.3, 109.5, 101.8, 45.9, 33.0, 30.1, HRMS (EI) calcd for C 12 H 13 BrClN [M + ] , found # S5#

6 1-(4-bromobutyl)-5-methoxy-1H-indole (2f) was synthesized according to GP1. The product was isolated (64%, 613 mg) after purification by flash chromatography on silica (AcOEt/hexane 1:9). IR (neat, cm -1 ): 2933, 2831, 1619, 1489, 1237, H NMR (400 MHz, CDCl 3 ) δ 7.23 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 3.0 Hz, 1H), 6.89 (dd, J = 9.0 Hz, J = 2.5 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 4.13 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.37 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 154.2, 131,4, 129.2, 128.3, 112.1, 110.2, 102.8, 101.0, 56.1, 45.9, 33.2, 30.2, HRMS (EI) calcd for C 13 H 16 BrNO [M + ] , found (4-bromobutyl)-1H-indole-3-carbaldehyde (2g) was synthesized according to GP1. The product was isolated (60%, 578 mg) after purification by flash chromatography on silica (Et 2 O/hexane 15:85). Spectral data were consistent with those reported in the literature. 4 # methyl 1-(4-bromobutyl)-1H-indole-3-carboxylate (2h) was synthesized according to GP1. The product was isolated (76%, 1.34 g) after purification by flash chromatography on silica (EtOAc/hexane 2:8). IR (neat, cm -1 ): 2947, 2881, 1698, 1534, 1214, 1155, 1092, H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.82 (s, 1H), (m, 1H), (m, 2H), 4.20 (t, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.39 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 165.7, 136.6, 134.2, 126.9, 123.1, 122.2, 122.1, 110.0, 107.5, 51.2, 46.4, 32.8, 29.9, ######################################################## 4 Ghavidast, A.; Mahmoodi, N. O.; Zanjanchi, M. A. J. Mol. Struct. 2013, 1048, # S6#

7 HRMS (EI) calcd for C 14 H 16 BrNO 2 [M + ] , found (4-bromobutyl)-1H-indole-3-carbonitrile (2i) was synthesized according to GP1. The product was isolated (66%, 653 mg) after purification by flash chromatography on silica (EtOAc/hexane 2:8). IR (neat, cm -1 ): 2942, 2868, 2215, 1531, 1468, 1395, 1253, H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 4.21 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 135.4, 134.6, 128.1, 124.1, 122.4, 120.2, 116.0, 110.6, 86.1, 46.6, 32.7, 29.8, HRMS (EI) calcd for C 13 H 13 BrN 2 [M + ] , found (4-bromobutyl)-3-methyl-1H-indole (2j) was synthesized according to GP1. The product was isolated (72%, 730 mg) after purification by flash chromatography on silica (Et 2 O/hexane 5:95). IR (neat, cm -1 ): 2918, 2869, 1468, 1363, 1252, H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.87 (s, 1H), 4.11 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 136.4, 129.0, 125.4, 121.7, 119.3, 118.8, 110.7, 109.2, 45.4, 33.3, 30.2, 29.2, 9.8. HRMS (EI) calcd for C 13 H 16 BrN [M + ] , found # S7#

8 1-(4-bromobutyl)-3-phenyl-1H-indole (2k) was synthesized according to GP1. The product was isolated (78%, 1.32 g) after purification by flash chromatography on silica (Et 2 O/hexane 15:85). Spectral data were consistent with those reported in the literature. 5 1-(2-bromobenzyl)-1H-indole (2l) was synthesized according to GP2. The product was isolated (73 %, 3.56 g) after purification by flash chromatography on silica (Et 2 O/hexane 2:8). Spectral data were consistent with those reported in the literature. 6 1-(2-bromo-5-methoxybenzyl)-1H-indole (2m) was synthesized according to GP2. The product was isolated (77 %, 2.07 g) after purification by flash chromatography on silica (Et 2 O/hexane 2:8). Spectral data were consistent with those reported in the literature. 7 6,7,8,9-tetrahydropyrido[1,2-a]indole (3a) was synthesized according to GP3. The product was isolated (quant., 34 mg) after purification by filtration over a small silica plug (DCM). Spectral data were consistent with those reported in the literature. 8 ######################################################## 5 Mésangeau, C.; Amata, E.; Alsharif, W.; Seminerio, M. J.; Robson, M. J.; Matsumoto, R. R.; Poupaert, J. H.; McCurdy, C. R. Eur. J. Med. Chem. 2011, 46, Laha, J. K.; Dayal, N.; Singh, S.; Bhimpuria, R. Eur. J. Org. Chem. 2014, # 7 Lim, Y. H.; Ong, Q.; Duong, H. A.; Nguyen, T. M.; Johannes, C. W. Org. Lett. 2012, 14, # 8 Ishikura, M.; Ida, W.; Yanada, K. Tetrahedron. 2006, 62, # # S8#

9 2,3-dihydro-1H-pyrrolo[1,2-a]indole (3b) was synthesized according to GP3. The product was isolated (88%, 28 mg) after purification by flash chromatography on silica (Et 2 O/hexane 1:9). Spectral data were consistent with those reported in the literature. 9 9-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (3c) was synthesized according to GP3. The product was isolated (98%, 36 mg) after purification by filtration over a small silica plug (DCM). Spectral data were consistent with those reported in the literature. 10 6,7,8,9-tetrahydropyrido[1,2-a]indole-1-carbonitrile (3d) was synthesized according to GP3. The product was isolated (90%, 35 mg) after purification by filtration over a small silica plug (Et 2 O). IR (neat, cm -1 ): 2944, 2872, 2217, 1537, 1439, 1366, 1321, 1283, H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz 1H), 6.41 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 140.8, 136.2, 130.1, 125.1, 119.8, 119.4, 113.3, 101.6, 97.2, 42.7, 24.4, 23.3, HRMS (EI) calcd for C 13 H 12 N 2 [M + ] , found chloro-6,7,8,9-tetrahydropyrido[1,2-a]indole (3e) was synthesized according to GP3. The product was isolated (95%, 39 mg) after purification by by filtration over a small silica plug (DCM). IR (neat, cm -1 ): 2942, 2868, 1462, 1412, 1319, 1162, 1061, 918, 805. ######################################################## 9 Ishikura, M.; Ida, W.; Yanada, K. Tetrahedron. 2006, 62, # 10 Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron. 1998, 54, # # S9#

10 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (d, J = 8.5 Hz, 1H), (m, 1H), 7.05 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 6.17 (s, 1H), 3.99 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 138.2, 136.9, 126.9, 126.2, 120.5, 120.3, 108.9, 97.9, 42.6, 24.4, 23.5, HRMS (EI) calcd for C 13 H 12 N 2 [M + ] , found methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indole (3f) was synthesized according to GP3. The product was isolated (quant., 40 mg) after purification by filtration over a small silica plug (Et 2 O). IR (neat, cm -1 ): 2928, 2859, 1615, 1578, 1484, 1205, H NMR (400 MHz, CDCl 3 ) δ 7.16 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.80 (dd, J = 8.5 Hz, J = 2.5 Hz, 1H), 6.13 (s, 1H), 4.01 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 2.96 (t, J = 6.5 Hz, 2H), (m, 2H), (m, 2H). 13 C NMR (400 MHz, CDCl 3 ) δ 154.4, 138.0, 131.8, 128.8, 110.1, 109.3, 102.1, 97.4, 56.2, 42.6, 24.5, 23.6, HRMS (EI) calcd for C 13 H 15 NO [M + ] , found ,7,8,9-tetrahydropyrido[1,2-a]indole-10-carbaldehyde (3g) was synthesized according to GP3. The product was isolated (95%, 38 mg) after purification by filtration over a small silica plug (Et 2 O). Spectral data were consistent with those reported in the literature. 11 methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carboxylate (3h) was synthesized according to GP3. The product was isolated (92%, 42 mg) after purification by filtration ######################################################## 11 Artis, D. R.; Cho, I-S.; Jaime-Figueroa, S.; Muchowski, J. M. J. Org. Chem. 1994, 59, # # S10#

11 over a small silica plug (Et 2 O). Spectral data were consistent with those reported in the literature. 11 # 6,7,8,9-tetrahydropyrido[1,2-a]indole-10-carbonitrile (3i) was synthesized according to GP3. The product was isolated (95%, 37 mg) after purification by filtration over a small silica plug (Et 2 O). Spectral data were consistent with those reported in the literature methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (3j) was synthesized according to GP3. The product was isolated (86%, 32 mg) after purification by flash chromatography on silica (DCM/hexane 15:85). Spectral data were consistent with those reported in the literature phenyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (3k) was synthesized according to GP3. The product was isolated (99%, 49 mg) after purification by filtration over a small silica plug (DCM). Spectral data were consistent with those reported in the literature. 13 # ######################################################## 12 Ishikura, M.; Ida, W.; Yanada, K. Tetrahedron. 2006, 62, # 13 Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem. Int. Ed. 2008, 47, # S11#

12 6H-isoindolo[2,1-a]indole (3l)/1-benzyl-1H-indole (10l) was synthesized according to GP3. The products were isolated (96%, 40 mg) as 3:1 mixture after purification by filtration over a small silica plug (DCM). Spectral data were consistent with those reported in the literature methoxy-6H-isoindolo[2,1-a]indole (3m)/1-(3-methoxybenzyl)-1H-indole (10m) was synthesized according to GP3. The products were isolated (96%, 45 mg) as 1:1 mixture after purification by filtration over a small silica plug (Et 2 O). Spectral data were consistent with those reported in the literature. 15 # # # # # # # # # # # # # # # ######################################################## 14 a) Shen, Z.; Ni, Z.; Mo, S.; Wang, J.; Zhu, Y. Chem. Eur. J. 2012, 18, ; b) Kim, J.; Kim, H.; Chang, S. Org. Lett. 2012, 14, Molander, G. A.; Ryu, D.; Hosseini-Sarvari, M.; Devulapally, R.; Seapy, D. G. J. Org. Chem. 2013, 78, # # S12#

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64