Palladium-Catalyzed Oxidative Cyclization of Tertiary Enamines for Synthesis of 1,3,4-Trisubstituted Pyrroles and 1,3-Disubstituted Indoles

Transcription

1 Supporting Information for Palladium-Catalyzed Oxidative Cyclization of Tertiary Enamines for Synthesis of 1,3,4-Trisubstituted Pyrroles and 1,3-Disubstituted Indoles Xiao-Li Lian, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan* Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi an , P. R. China CONTENTS 1. General information s2 2. General procedure for the preparation of tertiary enamines s2 3. The optimization of reaction conditions for Pd-catalyzed oxidative cyclization of enamines for synthesis of 1,3-disubstituted indoles S2-S3 4. Typical procedure for Pd-catalyzed cyclization of enamines S3 5. Characterization data of products S4 S10 6. Copies of 1 H and 13 C NMR spectra s11-s58 - S 1 -

2 1. General Information 1 H and 13 C NMR spectra were recorded on Varian instrument (400 MHz) and (100 MHz). The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. Coupling constants, J were reported in Hertz unit (Hz). Thin layer chromatography was carried out using silica gel GF254 and flash column chromatography was performed using silica gel mesh. Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. 2. General procedure for the preparation of N-substituted enamines N-substituted enamines were prepared according to following literatures: (1) Pen, Y.; Liu, H.; Tang, M.; Cai, L.; Pike, V. Chin. J. Chem. 2009, 27, (2) Byun, E.; Hong, B.; De Castro, K.; Lim, M.; Rhee, H. J. Org. Chem. 2007, 72, (3) X. Ji, H. Huang, W. Wu, X. Li, H. Jiang, J. Org. Chem. 2013, 78, The optimization of reaction conditions for Pd-catalyzed oxidative cyclization of enamines for synthesis of 1,3-disubstituted indoles. [a] Entry Catalyst Additive Solvent T ( o C) Yield[%] [b] 1 Pd(OAc) 2 - CH 3 CN Pd(OAc) 2 K 2 CO 3 CH 3 CN 100 NR 3 Pd(OAc) 2 PivOH CH 3 CN Pd(TFA) 2 PivOH CH 3 CN PdCl 2 PivOH CH 3 CN [c] PdCl 2 PivOH CH 3 CN S 2 -

3 7 [c] PdCl 2 TFA CH 3 CN [c] PdCl 2 TFA DMF [c] PdCl 2 TFA toluene [c] PdCl 2 TFA DCE [c] PdCl 2 TFA CH 3 CN [a] Reaction conditions: 3a (0.2 mmol), [Pd] (5 mol%), Cu(OAc) 2 (1.2 equiv), Additive (1.0 equiv) in CH 3 CN (2 ml) at 100 o C, in air. [b] Isolated yield. [c] The reaction was carried out with 2.0 equiv of Cu(OAc) Typical procedure for Pd-catalyzed cyclization of enamines Typical procedure for synthesis of 1,3,4-trisubstituted pyrroles: (E)-ethyl 3-(allyl(phenyl)amino)acrylate 1a (0.2 mmol), Pd(OAc) 2 (5 mol%), Cu(OAc) 2 (0.44 mmol), TFA (0.2 mmol) and CH 3 CN (2 ml) was stirred in a 10 ml round-bottom flask at 60 o C in air. After completion of the reaction (detected by TLC), the reaction mixture was cooled to room temperature, quenched with H 2 O (10 ml) and extracted with EtOAc (3 10 ml) or CH 2 Cl 2 (3 10 ml). Removal of the solvent in vacuo and purification of the residue by flash chromatography (SiO 2, pentane/etoac) provided pyrrole 2a (70%) as a pale yellow solid. Typical procedure for synthesis of 1,3-disubstituted indoles: (E)-butyl 3-(methyl(phenyl)amino)acrylate 3a (0.2 mmol), PdCl 2 (5 mol%), Cu(OAc) 2 (0.40 mmol), TFA (0.2 mmol) and CH 3 CN (2 ml) was stirred in a 10 ml round-bottom flask at 100 o C in air. After completion of the reaction (detected by TLC), the reaction mixture was cooled to room temperature, quenched with H 2 O (10 ml) and extracted with EtOAc (3 10 ml) or CH 2 Cl 2 (3 10 ml). Removal of the solvent in vacuo and purification of the residue by flash chromatography (SiO 2, pentane/etoac) provided indole 4a (68%) as a white solid. - S 3 -

4 5. Characterization data of products CO 2 Et N 2a 2a: Yield: 70% (32.1 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.55 (s, 1 H), δ = (m, 2 H), δ = (d, J = 7.6 Hz, 2 H), δ = (m, 1 H), δ = 6.72 (s, 1 H), δ = (m, 2 H), δ = 2.34 (s, 3 H), δ = 1.26 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.2, 139.7, 129.6, 126.3, 124.7, 122.9, 120.4, 118.9, 116.5, 59.4, 14.4, HRMS Calcd (ESI) m/z for C 14 H 15 NNaO 2 : [M+Na] , found: b: Yield: 62% (30.1 mg), pale yellow liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.53 (d, J = 2.4 Hz, 1 H), δ = (m, 4 H), δ = 6.72 (s, 1 H), δ = (m, 2 H), δ = 2.30 (s, 3 H), δ = 2.25 (s, 3 H), δ = 1.28 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.3, 137.5, 136.3, 130.1, 124.8, 122.8, 120.4, 119.0, 116.3, 59.4, 29.7, 20.9, 14.5, HRMS Calcd (ESI) m/z for C 15 H 17 NNaO 2 : [M+Na] , found: c: Yield: 62% (30.1 mg), pale yellow liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.54 (s, 1 H), δ = (m, 1 H), δ = (d, J = 11.6 Hz, 2 H), δ = (d, J = 7.2 Hz, 1 H), δ = 6.73 (s, 1 H), δ = (m, 2 H), δ = 2.31 (s, 3 H), 2.25 (s, 3 H), δ = 1.27 (t, J = 6.8 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.2, 139.7, 139.7, 129.4, 127.1, 124.7, 122.8, 121.1, 118.9, 117.5, 116.4, 59.4, 21.4, 14.5, HRMS Calcd (ESI) m/z for C 15 H 17 NNaO 2 : [M+Na] , found: CO 2 Et N 2d 2d: Yield: 52% (26.7 mg), yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.53 (d, J = 2.4 Hz, 1 H), δ = 7.08 (s, 2 H), δ = (m, 1 H), δ = 6.71 (s, 1 H), δ = (m, 2 H), δ = 2.25 (s, 3 - S 4 -

5 H), δ = 2.23 (s, 3 H), δ = 2.20 (s, 3 H), δ = 1.28 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.3, 138.0, 137.7, 134.9, 130.5, 124.8, 122.7, 121.8, 119.1, 117.8, 116.1, 59.4, 19.9, 19.2, 14.5, HRMS Calcd (ESI) m/z for C 16 H 19 NNaO 2 : [M+Na] , found: CO 2 Et N 2e 2e: Yield: 40% (19.4 mg), colourless liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.34 (d, J = 2.4 Hz, 1 H), (d, J = 3.6 Hz, 2H), ( m, 3H), δ = (m, 2 H), δ = 2.33 (s, 3 H), δ = 2.21 (s, 3 H), δ = 1.34 (t, J = 8.0 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.4, 139.6, 133.6, 131.1, 128.1, 127.7, 126.7, 126.4, 121.8, 121.6, 59.4, 17.8, 14.5, HRMS Calcd (ESI) m/z for C 15 H 17 NNaO 2 : [M+Na] , found: f: Yield: 55% (28.5 mg), pale yellow liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.47 (d, J = 2.0 Hz, 1 H), δ = 7.19 (d, J = 3.6 Hz, 2 H), δ = 6.86 (d, J = 8.8 Hz, 2 H), δ = 6.66 (s, 1 H), δ = (m, 2 H), δ = 3.75 (s, 3 H), δ = 2.25 (s, 3 H), δ = 1.27 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.3, 158.1, 133.4, 125.0, 122.1, 119.4, 116.0, 114.7, 59.4, 55.5, 29.7, 14.5, HRMS Calcd (ESI) m/z for C 15 H 17 NNaO 3 : [M+Na] , found: g: Yield: 60% (49.4 mg), yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.48 (d, J = 1.6 Hz, 1 H), δ = (m, 2 H), δ = (m, 2 H), δ = 6.67 (s, 1 H), δ = (m, 2 H), δ = 2.24 (s, 3 H), δ = 1.27 (t, J = 6.8 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.1, (d, J CF = 244.8Hz), 136.2, 125.0, 123.1, (d, J CF = 8.3 Hz), 119.2, 116.7, (d, J CF = 22.9 Hz), 59.5, 14.5, HRMS Calcd (ESI) m/z for C 14 H 14 FNNaO 2 : [M+Na] , found: CO 2 Et N 2h Cl - S 5 -

6 2h: Yield: 67% (35.2 mg), yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.56 (s, 1 H), δ = 7.36 (d, J = 8.0 Hz, 2 H), δ = 7.27 (d, J = 8.0 Hz, 2 H), δ = 6.75 (s, 1 H), δ = (m, 2 H), δ = 2.29 (s, 3 H), δ = 1.32 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.0, 138.3, 131.9, 129.7, 124.6, 123.4, 121.6, 118.8, 117.0, 59.5, 14.5, HRMS Calcd (ESI) m/z for C 14 H 14 ClNNaO 2 : [M+Na] , found: i: Yield: 61% (32.1 mg), pale yellow liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.54 (s, 1 H), δ = (m, 2 H), δ = 7.18 (s, 2 H), δ = δ = 6.73 (s, 1 H), δ = (m, 2 H), δ = 2.24 (s, 3 H), δ = 1.28 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.0, 140.7, 135.3, 130.7, 126.4, 123.5, 120.6, 118.7, 118.4, 117.2, 59.6, 14.5, HRMS Calcd (ESI) m/z for C 14 H 14 ClNNaO 2 : [M+Na] , found: j: Yield: 56% (34.4 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.52 (s, 1 H), δ = 7.49 (d, J = 8.4 Hz, 2 H), δ = 7.17 (d, J = 8.8 Hz, 2 H), δ = 6.71 (s, 1 H), δ = (m, 2 H), δ = 2.24 (s, 3 H), δ = 1.28 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.0, 138.8, 132.7, 124.5, 123.4, 121.8, 119.6, 118.7, 117.1, 59.7, 14.5, HRMS Calcd (ESI) m/z for C 14 H 14 BrNNaO 2 : [M+Na] , found: k: Yield: 45% (25.1 mg), pale yellow solid 1 H NMR (CDCl 3, 400 MHz): δ = 7.82 (d, J = 8.8 Hz, 1 H), δ = (m, 2 H), δ = (m, 2 H), (m, 3 H), δ = 6.87 (s, 1 H), δ = (m, 2 H), δ = 2.29 (s, 3 H), δ = 1.30 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.2, 137.1, 133.6, 131.7, 129.8, 127.8, 126.0, 124.9, 123.2, 119.6, 119.1, 117.7, 116.8, 59.5, 14.5, HRMS Calcd (ESI) m/z for C 18 H 17 NNaO 2 : [M+Na] , found: S 6 -

7 CO 2 Me N CO 2 Me 2l 2l: Yield: 65% (32.5 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.34 (d, J = 7.6 Hz, 2 H), δ = 7.20 (d, J = 6.8 Hz, 2 H), δ = 6.58 (s, 1 H), δ = 3.78 (s, 3 H), δ = 3.63 (s, 3 H), δ =2.16 (s, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.4, 161.9, 139.3, 129.0, 128.1, 126.0, 125.2, 124.4, 120.9, 119.4, 52.2, 51.6, HRMS Calcd (ESI) m/z for C 15 H 15 NNaO 4 : [M+Na] , found: m: Yield: 62% (30.1 mg), yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.58 (s, 1 H), δ = (m, 4 H), δ = (d, J = 6.4 Hz, 2 H), δ = 6.76 (s, 1 H), δ = (m, 2 H), δ = (m, 3 H), δ = 1.28 (t, J = 6.8 Hz, 3 H), δ = (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ = 165.0, 139.9, 130.0, 129.6, 125.0, 120.5, 117.8, 116.0, 59.4, 19.6, 14.5, HRMS Calcd (ESI) m/z for C 15 H 17 NNaO 2 : [M+Na] , found: n: Yield: 55% (28.3 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.58 (s, 1 H), δ = (m, 4 H), δ = (d, J = 10.8 Hz, 1 H), δ = 6.77 (s, 1 H), δ = (m, 2 H), δ = (m, 1 H), δ = 1.28 (t, J = 6.8 Hz, 3 H), δ = 1.20 (d, J = 6.8 Hz, 6 H); 13 C NMR (CDCl 3, 100 MHz): δ = 164.9, 139.9, 135.4,129.6, 126.4,125.2, 120.6, 116.5, 115.4, 59.4, 25.5, 23.6, HRMS Calcd (ESI) m/z for C 16 H 19 NNaO 2 : [M+Na] , found: a: Yield: 68% (31.4 mg), white solid; 1 H NMR (CDCl 3, 400 MHz): δ = 8.17 (t, J = 4.8 Hz,1 H), 7.77 (s, 1H), (m, 3 H), 4.33 (t, J = 6.4 Hz, 2 H), 3.81 (s, 3 H), 1.78 (t, J = 6.8 Hz, 2 H), (m, 2 H), 0.99 (t, J = 7.2 Hz, 3H) ; 13 C NMR (CDCl 3, 100 MHz): δ =165.2, 137.1, 135.1, 126.5, 122.6, 121.7, 121.6, 109.7, 107.1, 63.5, 33.4, 31.0, 19.4, HRMS Calcd (ESI) m/z for - S 7 -

8 C 14 H 17 NNaO 2 : [M+Na] , found: CO 2 Me N 4b 4b: Yield: 55% (20.8 mg), white solid; 1 H NMR (CDCl 3, 400 MHz): δ = (m, 1 H), 7.78 (s, 1 H), (m, 3 H), 3.91 (s, 3 H), 3.82 (s, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =165.4, 137.1, 135.1, 126.5, 122.7, 121.8, 121.5, 109.7, 106.7, 50.9, HRMS Calcd (ESI) m/z for C 11 H 11 NNaO 2 : [M+Na] , found: CO 2 Et N 4c 4c: Yield: 55% (22.3 mg), white solid; 1 H NMR (CDCl 3, 400 MHz): δ = 8.18 (d, J = 6.8 Hz, 1 H), 7.77 (s, 1 H), (m, 3 H), 4.37(d, J = 6.8 Hz, 2 H), 3.80 (s, 3 H), (m, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =165.1, 137.1, 135.1, 126.5, 122.6, 121.7, 121.6, 109.7, 107.0, 59.6, 33.3, 29.7, HRMS Calcd (ESI) m/z for C 12 H 13 NNaO 2 : [M+Na] , found: d: Yield: 61% (28.2 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 8.15 (d, J = 6.0 Hz, 1 H), 7.70 (s, 1 H), (m, 3 H), 3.78 (s, 3 H), 1.63(s, 9 H); 13 C NMR (CDCl 3, 100 MHz): δ =164.6, 137.1, 135.0, 126.5, 122.5, 121.6, 109.6, 108.6, 79.7, 33.3, HRMS Calcd (ESI) m/z for C 14 H 17 NNaO 2 : [M+Na] , found: e: Yield: 50% (25.1 mg), white solid; 1 H NMR (CDCl 3, 400 MHz): δ = (m, 1 H), 7.93 (s, 1 H), (m, 5 H), 7.24 (d, J = 8.0 Hz, 2 H), 3.84 (s, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =164.6, 137.1, 135.0, 126.5, 122.5, 121.6, 109.6, 108.6, 79.7, 33.3, HRMS Calcd (ESI) m/z for C 16 H 13 NNaO 2 : [M+Na] , found: S 8 -

9 4f: Yield:60% (29.4 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 8.03 (d, J = 8.0 Hz, 1 H), 7.70 (s, 1 H), 7.11 (d, J =9.2 Hz, 2 H), 4.32 (t, J = 6.4 Hz, 2 H), 3.77 (s, 3 H), 2.50 (s, 3 H), 1.77 (t, J = 7.2 Hz,2 H), (m, 2 H), 0.99 (t, J = 7.6 Hz, 3 H) ; 13 C NMR (CDCl 3, 100 MHz): δ =165.3, 137.5, 134.6, 132.6, 124.3, 123.5, 121.2, 109.7, 107.0, 63.4, 33.2, 31.0, 21.8, 19.4, HRMS Calcd (ESI) m/z for C 15 H 19 NNaO 2 : [M+Na] , found: g: Yield: 52% (27.0 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.92 (s, 1 H), 7.65 (s, 1 H), 7.09 (s, 1 H), 4.32 (t, J = 6.8 Hz, 2 H), 3.75 (s, 3 H), 2.39 (s, 6 H), 1.77 (t, J = 7.2 Hz, 2 H), (m, 2 H), 0.99 (t, J = 7.2 Hz, 3H) ; 13 C NMR (CDCl 3, 100 MHz): δ =165.3, 136.0, 134.3, 131.8, 130.6, 124.8, 121.6, 110.0, 106.4, 63.3, 33.3, 31.0, 20.6, 20.2, 19.4, HRMS Calcd (ESI) m/z for C 16 H 21 NNaO 2 : [M+Na] , found: h: Yield: 65% (31.9 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = (m, 1 H), 7.85 (s, 1 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 1.78 (t, J = 7.6 Hz, 2 H), 1.50 (t, J = 7.6 Hz, 5 H), 0.99 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =165.3, 136.2, 133.4, 126.7, 121.7, 121.7, 109.8, 107.2, 63.5, 41.5, 31.0, 19.4, 15.1, HRMS Calcd (ESI) m/z for C 15 H 19 NNaO 2 : [M+Na] , found: i: Yield: 51% (26.2 mg), pale yellow solid; 1 H NMR (CDCl 3, 400 MHz): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.79 (s, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), (m, 1 H), (m, 2 H), 4.19 (s, 2 H), 3.00 (s, 2 H), 2.25 (s, 2 H), (m, 2 H), 1.51 (d, J = 7.2 Hz, 2 H), 0.99 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =165.6, 134.4, 132.3, 124.4, 122.2, 122.2, 119.8, 119.0, 107.3, - S 9 -

10 63.5, 44.7, 31.0, 24.3, 22.7, 19.4, HRMS Calcd (ESI) m/z for C 16 H 19 NNaO 2 : [M+Na] , found: j: Yield: 15% (8.0 mg), pale yellow liquid; 1 H NMR (CDCl 3, 400 MHz): δ = 8.26 (d, J = 7.2 Hz, 1 H), 8.04 (s, 1 H), (m, 5 H), (m, 3 H), (m, 2 H), 1.44 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 100 MHz): δ =165.1, 138.5, 136.6, 134.1, 129.8, 127.8, 126.9, 124.8, 123.4, 122.4, 121.9, 111.0, 109.4, 59.9, HRMS Calcd (ESI) m/z for C 17 H 15 NNaO 2 : [M+Na] , found: S 10 -

11 6. Copies of 1 H and 13 C NMR Spectra CO 2 Et N 2a - S 11 -

12 CO 2 Et N 2a - S 12 -

13 - S 13 -

14 - S 14 -

15 - S 15 -

16 - S 16 -

17 CO 2 Et N 2d - S 17 -

18 CO 2 Et N 2d - S 18 -

19 CO 2 Et N 2e - S 19 -

20 CO 2 Et N 2e - S 20 -

21 - S 21 -

22 - S 22 -

23 - S 23 -

24 - S 24 -

25 CO 2 Et N 2h Cl - S 25 -

26 CO 2 Et N 2h Cl - S 26 -

27 - S 27 -

28 - S 28 -

29 - S 29 -

30 - S 30 -

31 - S 31 -

32 - S 32 -

33 CO 2 Me N CO 2 Me 2l - S 33 -

34 CO 2 Me N CO 2 Me 2l - S 34 -

35 - S 35 -

36 - S 36 -

37 - S 37 -

38 - S 38 -

39 - S 39 -

40 - S 40 -

41 CO 2 Me N 4b - S 41 -

42 CO 2 Me N 4b - S 42 -

43 CO 2 Et N 4c - S 43 -

44 CO 2 Et N 4c - S 44 -

45 - S 45 -

46 - S 46 -

47 - S 47 -

48 - S 48 -

49 - S 49 -

50 - S 50 -

51 - S 51 -

52 - S 52 -

53 - S 53 -

54 - S 54 -

55 - S 55 -

56 - S 56 -

57 - S 57 -

58 - S 58 -