Cobalt-Catalyzed Selective Synthesis of Isoquinolines Using Picolinamide as a Traceless Directing Group

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1 Supporting Information Cobalt-Catalyzed Selective Synthesis of Isoquinolines Using Picolinamide as a Traceless Directing Group Changsheng Kuai, Lianhui Wang, Bobin Li, Zhenhui Yang, Xiuling Cui* Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Xiamen Marine and Gene Drugs, Institute of Molecular Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, , China cuixl@hqu.edu.cn Table of Contents 1.General information...s-2 2.Preparation of substrates 1...S-2 3.General procedure for the synthesis of compounds 3...S-2 4.X-ray Crystallographic Data of 3aa and 3ap...S-3 5.Characterization data of compounds 3...S-12 6.NMR spectra of compounds 3...S-23 S 1

2 1. General information Unless otherwise stated, all commercial materials and solvents were used directly without further purification. Commercially available chemicals were obtained from Energy Chemical, TCI, Alfa Aesar, J&K. Melting points were obtained on a Beijing Science Instrument Dianguang Instrument Factory XT4B Melting Point apparatus and are uncorrected. 1 H and 13 C NMR spectra were measured on a 400 MHz Bruker spectrometer ( 1 H 400MHz, 13 C 100MHz), using CDCl 3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. High-resolution mass spectra (HRMS) were recorded using Agilent 6450 spectrometer. Column chromatography was performed on silica gel ( mesh ASTM) using the reported eluents. Thin-layer chromatography (TLC) was carried out on 4 15 cm plates with a layer thickness of 0.2 mm (silica gel 60 F254). 2. Preparation of substrates 1 R NH 2 + HO O N EDCI, HOBt, DIPEA DMF, rt, 24 h A solution of benzylamines (10 mmol), 2-picolinic acid (1.48 g, 12 mmol), EDCI (2.32 g, 12 mmol), HOBt (1.84 g, 12 mmol) and DIPEA (4.4 ml, 25 mmol) were dissolved in 15 ml of anhydrous DMF. The mixture was stirred at rt for 24 h. Water was then added and the mixture was extracted with EtOAc. The combined organic layers was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (n-hexane/etoac: 10:1) to give the desired product 1. R N H 1 O N 3. Representative procedure for the synthesis of compounds 3 O Ph Co(OAc) 2 4H 2 O (50 mol%) N N + H N PEG 400,140 o C,O 2 Ph Ph KPF 6 (50 mol%) Ph 1a 2a 3aa A mixture of 1a (0.25 mmol, 53.0 mg), 2a (0.3 mmol, 53.4mg), Co(OAc) 2 4H 2 O (0.125 mmol, 31.1 mg, 50 mol%),) KPF 6 ( mmol, 23.0 mg, 50 mol%) and PEG-400 (1.0 ml), 140 o C under O 2 (1 atm), in a 5 ml flask was heated at 140 o C for 20 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was diluted with H 2 O and extracted with t-buome (3 x 25 ml). The combined organic layers were dried over Na 2 SO 4. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel (n-hexane/etoac: 20:1) to yield 3aa (62.6 mg, 89%) as a white solid. Procedure for the synthesis of product 3a on a 1 mmol scale A mixture of 1a (1 mmol, mg), 2a (1.2 mmol, 213.6mg), Co(OAc) 2 4H 2 O (0.5 mmol, mg, 50 mol%), KPF 6 (0.5 mmol, 92.0 mg, 50 mol%) and PEG-400 (4.0 ml), 140 o C under O 2 (1 atm), in a 10 ml flask was heated at 140 o C for 20 hours. The reaction mixture was cooled to room temperature, diluted, washed with H 2 O and extracted with t-buome (3 x 25 ml). The combined organic layers were dried over Na 2 SO 4. After removal of the solvents in vacuo, the crude product was purified by column S 2

3 chromatography on silica gel (n-hexane/etoac: 20:1) to yield 3aa (194.1 mg, 69%) as a white solid. 4. X-ray Crystallographic Data of 3aa and 3ap X-ray Crystallographic Data of 3aa Figure S1. X-ray molecular structure of 3aa Table 1 Crystal data and structure refinement for exp_1025. Identification code Empirical formula C21H15N Formula weight Temperature/K 173.6(3) Crystal system monoclinic Space group P21/c a/å (7) b/å (7) c/å (11) α/ 90 β/ (7) γ/ 90 Volume/Å (19) Z 4 ρcalcg/cm μ/mm F(000) Crystal size/mm Radiation MoKα (λ = ) 2Θ range for data collection/ 6.05 to Index ranges -12 h 12, -12 k 13, -21 l 21 Reflections collected 9734 Independent reflections 3449 [Rint = , Rsigma = ] Data/restraints/parameters 3449/0/200 Goodness-of-fit on F Final R indexes [I>=2σ(I)] R1 = , wr2 = Final R indexes [all data] R1 = , wr2 = Largest diff. peak/hole / e Å /-0.22 S 3

4 Table 2 Fractional Atomic Coordinates ( 104) and Equivalent Isotropic Displacement Parameters (Å2 103) for exp_1025. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) C (15) (14) (8) 28.4(3) C (17) (15) (9) 34.7(4) C (17) (18) (9) 42.2(4) C (17) 5590(2) (10) 49.8(5) C (16) (18) (9) 40.0(4) C (14) (14) (8) 25.5(3) C (14) (14) (8) 24.5(3) C (13) (13) (8) 22.3(3) C (14) (14) (8) 23.3(3) C (15) (15) (8) 29.0(3) C (16) (16) (9) 34.4(4) C (17) 667.3(15) (9) 34.9(4) C (17) (15) (9) 33.8(4) C (16) (14) (9) 29.6(3) C (15) (16) (9) 33.0(4) C (16) (16) (9) 35.1(4) C (16) (16) (9) 34.4(4) C (15) (15) (8) 29.3(3) C (13) (14) (8) 23.4(3) C (14) (14) (8) 26.6(3) C (15) (15) (9) 31.1(3) N (13) (12) (7) 30.2(3) Table 3 Anisotropic Displacement Parameters (Å2 103) for exp_1025. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ]. Atom U11 U22 U33 U23 U13 U12 C1 29.3(7) 27.1(7) 27.9(7) 1.7(6) 4.0(5) 1.9(6) C2 42.8(9) 31.6(8) 31.5(7) -3.1(6) 12.2(6) -1.8(7) C3 44.7(9) 58.1(11) 22.8(7) -1.9(7) 4.7(6) -10.9(8) C4 31.5(8) 87.7(15) 27.2(7) 8.3(8) -0.4(6) 7.2(9) C5 30.3(8) 62.0(11) 28.2(7) 7.7(7) 7.5(6) 13.5(8) C6 26.3(7) 26.7(7) 23.5(6) 4.4(5) 5.2(5) -1.8(6) C7 21.9(6) 26.1(7) 25.0(6) 1.8(5) 4.2(5) 2.1(6) C8 19.6(6) 23.2(7) 23.4(6) 0.4(5) 3.0(5) 2.0(5) C9 27.2(7) 24.8(7) 18.6(6) 1.1(5) 6.5(5) -0.7(6) C (7) 32.0(8) 27.4(7) -2.3(6) 5.6(5) -0.6(6) C (8) 36.9(9) 30.7(7) -6.1(6) 7.0(6) -9.5(7) C (10) 26.0(8) 31.1(7) -5.5(6) 17.6(7) -7.7(7) C (9) 25.8(8) 36.3(8) 3.6(6) 13.6(6) 7.4(7) C (7) 27.3(8) 31.0(7) 0.7(6) 5.0(6) 0.9(6) C (8) 31.6(8) 31.1(7) -7.3(6) 5.1(6) -2.8(7) C (8) 45.3(10) 22.9(7) -5.6(6) 4.8(6) -4.6(7) S 4

5 C (8) 38.4(9) 24.8(7) 3.9(6) 6.1(6) -1.9(7) C (8) 25.9(7) 28.0(7) 1.6(6) 6.0(6) 0.0(6) C (6) 25.5(7) 23.2(6) -0.2(5) 4.0(5) 0.4(6) C (7) 26.6(7) 27.6(7) -1.5(5) 4.3(5) 1.2(6) C (8) 22.8(7) 32.2(7) -1.9(6) 6.4(6) -0.2(6) N1 35.6(7) 24.4(6) 30.5(6) 2.5(5) 6.6(5) 1.0(5) Table 4 Bond Lengths for exp_1025. Atom Atom Length/Å Atom Atom Length/Å C1 C (19) C10 C (2) C1 C (19) C11 C (2) C2 C (2) C12 C (2) C3 C (2) C13 C (2) C4 C (2) C15 C (2) C5 C (19) C15 C (18) C6 C (17) C16 C (2) C7 C (18) C17 C (19) C7 N (17) C18 C (19) C8 C (19) C19 C (2) C8 C (17) C20 C (19) C9 C (18) C21 N (17) C9 C (19) Table 5 Bond Angles for exp_1025. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C2 C1 C (13) C11 C10 C (14) C3 C2 C (14) C12 C11 C (14) C2 C3 C (14) C13 C12 C (14) C3 C4 C (14) C12 C13 C (14) C4 C5 C (15) C13 C14 C (14) C1 C6 C (12) C16 C15 C (14) C5 C6 C (12) C15 C16 C (13) C5 C6 C (12) C18 C17 C (14) C8 C7 C (12) C17 C18 C (14) N1 C7 C (11) C18 C19 C (13) N1 C7 C (12) C20 C19 C (12) C7 C8 C (11) C20 C19 C (12) C7 C8 C (12) C19 C20 C (12) C19 C8 C (11) C21 C20 C (13) C10 C9 C (12) C21 C20 C (12) C14 C9 C (12) N1 C21 C (13) C14 C9 C (13) C21 N1 C (12) Table 6 Torsion Angles for exp_1025. A B C D Angle/ A B C D Angle/ C1 C2 C3 C4 2.7(2) C9 C8 C19 C (19) C1 C6 C7 C (18) C9 C8 C19 C (11) C1 C6 C7 N (15) C9 C10 C11 C12-0.4(2) S 5

6 C2 C1 C6 C5-0.8(2) C10 C9 C14 C (19) C2 C1 C6 C (13) C10 C11 C12 C13 0.0(2) C2 C3 C4 C5-1.1(3) C11 C12 C13 C14 0.3(2) C3 C4 C5 C6-1.4(3) C12 C13 C14 C9-0.1(2) C4 C5 C6 C1 2.4(2) C14 C9 C10 C (19) C4 C5 C6 C (15) C15 C16 C17 C18-1.3(2) C5 C6 C7 C (16) C15 C20 C21 N (13) C5 C6 C7 N (18) C16 C15 C20 C19-0.1(2) C6 C1 C2 C3-1.7(2) C16 C15 C20 C (13) C6 C7 C8 C9-0.92(19) C16 C17 C18 C19 0.4(2) C6 C7 C8 C (11) C17 C18 C19 C (13) C6 C7 N1 C (12) C17 C18 C19 C20 0.6(2) C7 C8 C9 C (17) C18 C19 C20 C (19) C7 C8 C9 C (14) C18 C19 C20 C (12) C7 C8 C19 C (12) C19 C8 C9 C (14) C7 C8 C19 C (18) C19 C8 C9 C (16) C8 C7 N1 C21 0.4(2) C19 C20 C21 N1 0.9(2) C8 C9 C10 C (12) C20 C15 C16 C17 1.1(2) C8 C9 C14 C (12) C20 C21 N1 C7-0.9(2) C8 C19 C20 C (12) N1 C7 C8 C (12) C8 C19 C20 C (18) N1 C7 C8 C19 0.1(2) Table 7 Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for exp_1025. Atom x y z U(eq) H H H H H H H H H H H H H H H S 6

7 X-ray Crystallographic Data of 3ap Figure S1. X-ray molecular structure of 3ap Table 1 Crystal data and structure refinement for exp_1928. Identification code Empirical formula C16H13N Formula weight Temperature/K 293(2) Crystal system orthorhombic Space group Pna21 a/å (14) b/å (9) c/å (4) α/ 90 β/ 90 γ/ 90 Volume/Å (6) Z 8 ρcalcg/cm μ/mm F(000) Crystal size/mm Radiation MoKα (λ = ) 2Θ range for data collection/ to Index ranges -20 h 19, -11 k 10, -22 l 9 Reflections collected 7158 Independent reflections 3907 [Rint = , Rsigma = ] Data/restraints/parameters 3907/1/309 Goodness-of-fit on F Final R indexes [I>=2σ(I)] R1 = , wr2 = Final R indexes [all data] R1 = , wr2 = Largest diff. peak/hole / e Å /-0.26 Flack parameter -7.9(10) Table 2 Fractional Atomic Coordinates ( 104) and Equivalent Isotropic Displacement Parameters (Å2 103) for exp_1928. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) S 7

8 C0AA 4088(8) 452(11) 6176(7) 77(4) C1' 2551(6) 6131(12) 5369(6) 62(3) C2' 1928(6) 7296(14) 5213(8) 69(4) C3' 1679(6) 8304(12) 5750(8) 71(3) C4' 2044(7) 8178(11) 6452(7) 62(3) C5' 2621(7) 7057(11) 6599(7) 63(3) C6' 2900(5) 6016(9) 6087(6) 47(2) C7' 3562(5) 4767(9) 6248(5) 46(2) C8' 3466(6) 3172(11) 6121(6) 55(3) C9' 4115(6) 2154(11) 6316(7) 53(3) C10' 4850(6) 2740(12) 6653(7) 51(3) C11' 4875(6) 4376(11) 6787(6) 62(3) C13' 4741(8) -455(13) 6392(8) 84(4) C14' 5472(8) 205(12) 6728(7) 79(4) C15' 5539(7) 1740(14) 6859(6) 67(3) C16' 2609(6) 2495(10) 5789(9) 66(4) N1' 4267(5) 5360(8) 6600(5) 59(2) C1 4917(7) 3648(12) 4544(7) 67(3) C2 5494(7) 2501(11) 4702(8) 62(3) C3 5784(7) 1514(13) 4162(8) 75(3) C4 5449(7) 1658(13) 3441(8) 77(3) C5 4835(6) 2768(10) 3303(7) 53(3) C6 4572(5) 3863(10) 3855(6) 48(2) C7 3935(5) 5098(10) 3679(5) 50(2) C8 4040(5) 6662(11) 3862(6) 50(2) C9 3358(5) 7684(10) 3691(6) 43(2) C (6) 7210(12) 3320(7) 52(3) C (6) 5541(12) 3130(6) 63(3) C12' 3375(7) 9365(13) 3854(8) 80(4) C (9) 10339(13) 3677(9) 95(4) C (8) 9737(15) 3323(8) 83(4) C (7) 8142(16) 3132(6) 69(3) C (7) 7339(12) 4245(10) 86(5) N1 3232(5) 4569(9) 3305(5) 61(2) Table 3 Anisotropic Displacement Parameters (Å2 103) for exp_1928. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ]. Atom U11 U22 U33 U23 U13 U12 C0AA 107(8) 47(5) 79(10) -16(6) -7(8) 14(6) C1' 60(6) 71(6) 53(7) -4(6) 6(5) 13(5) C2' 42(6) 97(8) 67(9) -3(7)-13(6) 16(5) C3' 58(6) 59(6) 96(10) 15(7) 4(7) 10(5) C4' 85(7) 46(5) 55(7) -8(6) 0(6) 4(5) C5' 87(8) 44(5) 59(8) -1(6) 20(6) 3(5) C6' 48(5) 45(4) 48(6) 2(5) 1(5) -4(4) S 8

9 C7' 55(5) 41(4) 43(6) -2(4) 3(5) -9(4) C8' 57(5) 55(5) 54(7) -9(5) 1(5) -14(5) C9' 56(6) 48(5) 55(7) 12(5) 16(6) 10(5) C10' 35(5) 75(7) 42(7) -3(6) 7(5) 3(4) C11' 65(6) 62(6) 58(8) -8(6)-27(6) -1(5) C13' 101(9) 49(5) 103(11) 16(7) -10(8) 5(6) C14' 102(8) 56(6) 79(10) 12(7) 14(8) 27(6) C15' 73(7) 74(7) 56(7) 9(7) 3(6) 12(6) C16' 44(6) 60(6) 94(11) -6(6)-24(7) -1(4) N1' 63(4) 49(4) 65(6) 1(4) -15(5) -2(4) C1 67(6) 75(7) 60(8) -12(6) 9(6) 13(5) C2 64(7) 76(7) 46(7) 3(6) -3(6) 10(5) C3 68(7) 76(7) 81(9) 26(7) -2(7) 7(6) C4 89(8) 61(6) 80(10) -14(7) 10(8) 18(6) C5 47(5) 60(5) 52(7) -5(6)-18(5) 2(4) C6 46(5) 50(5) 48(6) 6(5) -1(5)-5(4) C7 53(5) 55(5) 42(6) -2(5)-6(5)-8(4) C8 36(4) 62(6) 52(6) 0(5) 0(5) 4(4) C9 30(4) 60(5) 39(6) 1(5) -3(4) 0(4) C10 51(6) 67(6) 38(6) 4(5) 1(5) 6(5) C11 49(5) 77(7) 63(8) -15(6) -7(5)-4(5) C12' 64(6) 73(7) 103(12) -3(8) 3(7) 0(6) C13 110(9) 56(6) 118(13) 21(8) -7(9) 27(7) C14 75(7) 89(8) 86(10) 15(8) 3(7) 26(6) C15 61(6) 96(8) 50(7) 13(7) -1(5) 6(6) C16 50(6) 72(7) 137(17) -20(8) -27(8) 1(5) N1 50(4) 64(5) 68(6) -6(5) -6(5)-2(4) Table 4 Bond Lengths for exp_1928. Atom Atom Length/Å Length/Å C0AA C9' 1.469(12) C1 C (14) C0AA C13' 1.333(14) C1 C (14) C1' C2' 1.412(14) C2 C (16) C1' C6' 1.411(14) C3 C (17) C2' C3' 1.351(17) C4 C (14) C3' C4' 1.395(16) C5 C (14) C4' C5' 1.335(14) C6 C (12) C5' C6' 1.352(14) C7 C (12) C6' C7' 1.507(12) C7 N (11) C7' C8' 1.383(11) C8 C (12) C7' N1' 1.364(10) C8 C (14) C8' C9' 1.375(13) C9 C (13) C8' C16' 1.569(13) C9 C12' 1.459(13) C9' C10' 1.388(14) C10 C (13) C10' C11' 1.412(12) C10 C (14) Atom Atom S 9

10 C10' C15' 1.417(14) C11 N (12) C11' N1' 1.306(11) C12' C (14) C13' C14' 1.406(15) C13 C (17) C14' C15' 1.330(14) C14 C (17) Table 5 Bond Angles for exp_1928. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C13' C0AA C9' 119.8(11) C2 C1 C (11) C6' C1' C2' 119.7(11) C1 C2 C (12) C3' C2' C1' 119.9(12) C2 C3 C (10) C2' C3' C4' 119.3(10) C5 C4 C (11) C5' C4' C3' 120.5(11) C4 C5 C (11) C4' C5' C6' 123.1(12) C1 C6 C (8) C1' C6' C7' 119.4(9) C1 C6 C (10) C5' C6' C1' 117.5(9) C5 C6 C (9) C5' C6' C7' 123.1(10) C8 C7 C (8) C8' C7' C6' 125.7(8) N1 C7 C (8) N1' C7' C6' 112.4(7) N1 C7 C (8) N1' C7' C8' 121.8(8) C7 C8 C (8) C7' C8' C16' 121.0(8) C7 C8 C (8) C9' C8' C7' 119.6(8) C9 C8 C (8) C9' C8' C16' 119.4(8) C8 C9 C12' 123.2(9) C8' C9' C0AA 123.6(10) C10 C9 C (8) C8' C9' C10' 119.5(9) C10 C9 C12' 113.4(8) C10' C9' C0AA 116.9(9) C9 C10 C (8) C9' C10' C11' 116.8(9) C15 C10 C (10) C9' C10' C15' 121.5(10) C15 C10 C (10) C11' C10' C15' 121.6(9) N1 C11 C (9) N1' C11' C10' 124.5(8) C13 C12' C (11) C0AA C13' C14' 120.8(11) C12' C13 C (11) C15' C14' C13' 122.1(10) C13 C14 C (10) C14' C15' C10' 118.8(11) C10 C15 C (10) C11' N1' C7' 117.8(8) C11 N1 C (8) Table 6 Torsion Angles for exp_1928. A B C D Angle/ A B C D Angle/ C0AA C9' C10' C11' (11) C1 C2 C3 C4-2.6(17) C0AA C9' C10' C15' -0.6(16) C1 C6 C7 C8 50.3(14) C0AA C13' C14' C15' 1(2) C1 C6 C7 N (10) C1' C2' C3' C4' 0.0(17) C2 C1 C6 C5 1.9(15) C1' C6' C7' C8' -54.3(13) C2 C1 C6 C (9) C1' C6' C7' N1' 130.8(9) C2 C3 C4 C5-0.8(17) C2' C1' C6' C5' -0.7(14) C3 C4 C5 C6 4.8(16) C2' C1' C6' C7' 179.8(9) C4 C5 C6 C1-5.4(14) C2' C3' C4' C5' -1.3(17) C4 C5 C6 C (9) C3' C4' C5' C6' 1.6(17) C5 C6 C7 C (10) C4' C5' C6' C1' -0.6(15) C5 C6 C7 N1 46.6(12) S 10

11 C4' C5' C6' C7' 178.9(9) C6 C1 C2 C3 2.0(17) C5' C6' C7' C8' 126.2(11) C6 C7 C8 C (10) C5' C6' C7' N1' -48.7(12) C6 C7 C8 C16 1.5(18) C6' C1' C2' C3' 0.9(16) C6 C7 N1 C (10) C6' C7' C8' C9' (10) C7 C8 C9 C10-3.4(16) C6' C7' C8' C16' -0.8(16) C7 C8 C9 C12' 179.7(10) C6' C7' N1' C11' 178.1(9) C8 C7 N1 C11-2.5(15) C7' C8' C9' C0AA (10) C8 C9 C10 C11 0.8(15) C7' C8' C9' C10' 1.4(16) C8 C9 C10 C (12) C8' C7' N1' C11' 3.0(14) C8 C9 C12' C (13) C8' C9' C10' C11' 1.2(15) C9 C10 C11 N1 1.1(16) C8' C9' C10' C15' (11) C9 C10 C15 C14 1.2(18) C9' C0AA C13' C14' -2(2) C9 C12' C13 C14 0(2) C9' C10' C11' N1' -1.8(17) C10 C9 C12' C13 2.1(18) C9' C10' C15' C14' -0.4(17) C10 C11 N1 C7-0.3(17) C10' C11' N1' C7' -0.3(16) C11 C10 C15 C (11) C11' C10' C15' C14' 178.9(11) C12' C9 C10 C (11) C13' C0AA C9' C8' (12) C12' C9 C10 C15-2.6(16) C13' C0AA C9' C10' 2.0(17) C12' C13 C14 C15-1(2) C13' C14' C15' C10' 0.1(18) C13 C14 C15 C10 1.0(19) C15' C10' C11' N1' 178.9(11) C15 C10 C11 N (11) C16' C8' C9' C0AA 5.3(18) C16 C8 C9 C (11) C16' C8' C9' C10' (11) C16 C8 C9 C12' 1.2(18) N1' C7' C8' C9' -3.5(15) N1 C7 C8 C9 4.2(15) N1' C7' C8' C16' 173.7(10) N1 C7 C8 C (11) Table 7 Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for exp_1928. Atom x y z U(eq) H0AA H1' H2' H3' H4' H5' H11' H13' H14' H15' H16A H16B H16C H H H H S 11

12 H H H12' H H H H16D H16E H16F Characterization data of compounds 3 3,4-diphenylisoquinoline (3aa) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3aa (62.5mg, 89%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (s, 1H), (m, 1H), 7.72 (dd, J = 5.2, 4.4 Hz, 1H), (m, 2H), (m, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.8, 150.7, 140.8, 137.3, 136.0, 131.3, 130.6, 130.5, 130.3, 128.3, 127.7, 127.6, 127.4, 127.4, 127.1, 126.9, HRMS (APCI) m/z calcd for C 21 H 16 N [M + H] + : ; Found: methyl-3,4-diphenylisoquinoline (3ba) The representative procedure was following using N-(4-methylbenzyl)picolinamide (1b) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3ba (64.2 mg, 87%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.1 Hz, 2H), (m, 5H), (m, 5H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.4, 150.7, 141.1, 140.9, 137.4, 136.2, 131.3, 130.3, 130.2, 129.2, 128.3, 127.7, 127.5, 127.3, 127.1, 125.9, 124.4, HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : ; Found: methoxy-3,4-diphenylisoquinoline (3ca) The representative procedure was following using N-(4-methoxybenzyl)picolinamide (1c) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3ca (69.2 mg, 89%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), (m, 5H), (m, 2H), (m, 3H), 6.91 (d, J = 1.9 Hz, 1H), 3.72 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 161.3, 151.0, 150.7, 140.8, 138.0, 137.5, 131.1, 130.3, , 129.5, 128.4, 127.6, 127.4, 127.1, 123.3, 119.7, 103.7, HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : ; Found: (tert-butyl)-3,4-diphenylisoquinoline (3da) The representative procedure was following using N-(4-(tert-butyl)benzyl)picolinamide (1d) (67.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3da (79.2 mg, 94%), S 12

13 colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 8.6, 1.7 Hz, 1H), 7.67 (s, 1H), (m, 5H), (m, 2H), 7.23 (d, J = 7.5 Hz, 3H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 153.7, 151.1, 150.7, 141.0, 137.4, 136.0, 131.3, 130.8, 130.3, 128.3, 127.6, 127.3, 127.2, 127.0, 125.9, 125.8, 120.6, 35.5, HRMS (APCI) m/z calcd for C 25 H 24 N [M + H] + : ; Found: fluoro-3,4-diphenylisoquinoline (3ea) The representative procedure was following using N-(4-fluorobenzyl)picolinamide (1e) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3ea (61.2 mg, 82%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.09 (dd, J = 8.9, 5.7 Hz, 1H), 7.40 (d, J = 6.5 Hz, 5H), (m, 2H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.9, 162.4, 151.4, 151.3, 140.5, (d, J = 10.0 Hz), 136.8, 131.1, (d, J = 9.8 Hz), (d, J = 5.6 Hz), 130.3, 128.6, 127.7, (d, J = 29.3 Hz), 124.6, (d, J = 25.9 Hz), (d, J = 22.6 Hz). 19 F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : ; Found: chloro-3,4-diphenylisoquinoline (3fa) N The representative procedure was following using Cl Ph N-(4-chlorobenzyl)picolinamide (1f) (61.5mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3fa (61.4 mg, 78%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), (m, 1H), 7.57 (dd, J = 8.7, 1.9 Hz, 1H), (m, 5H), 7.25 (ddd, J = 6.8, 5.1, 2.3 Hz, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.4, 140.4, 137.0, 136.9, 136.5, 131.1, 130.2, 129.9, 129.3, 128.6, 128.0, 127.7, 127.7, 127.4, 125.6, HRMS (APCI) m/z calcd for C 21 H 15 ClN [M + H] + : ; Found: bromo-3,4-diphenylisoquinoline (3ga) N The representative procedure was following using Br Ph N-(4-bromobenzyl)picolinamide (1g) (72.5mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ga (64.5 mg, 72%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.36 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H), 7.39 (dt, J = 6.7, 3.9 Hz, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.5, 140.4, 137.1, 136.5, 131.1, 130.6, 130.2, 129.7, 129.2, 128.6, 127.9, 127.7, 127.4, HRMS (APCI) m/z calcd for C 21 H 15 BrN [M + H] + : ; Found: ,4-diphenyl-6-(trifluoromethoxy)isoquinoline (3ha) The representative procedure was following using N-(4-(trifluoromethoxy)benzyl)picolinamide (1h) (74.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3Ha (57.5 mg, 63%), white solid, mp 71-73ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (s, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.40 (td, J = 6.5, 1.8 Hz, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.3, 150.4, 140.3, 137.0, 136.4, 131.0, 130.6, 130.2, 130.1, 128.6, 127.8, 127.8, S 13

14 127.4, 125.5, 120.8, F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 22 H 15 F 3 NO [M + H] + : ; Found: ,4-diphenyl-6-(trifluoromethyl)isoquinoline (3ia) N The representative procedure was following using F 3 C Ph N-(4-(trifluoromethyl)benzyl)picolinamide (1i) (70.0mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ia (36.7 mg, 42%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.49 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), (m, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.1, 151.6, 140.2, 136.1, 135.3, (d, J = 32.3 Hz), 131.3, 131.1, 130.3, 128.7, (d, J = 94.5 Hz), 128.0, 127.8, 127.5, (d, J = Hz), (d, J = 4.6 Hz), (d, J = 3.0 Hz). 19 F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 22 H 15 F 3 N [M + H] + : ; Found: ,4-diphenylisoquinolin-6-ol (3ja) The representative procedure was following using N-(4-hydroxybenzyl)picolinamide (1j) (57.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 6:1) yielded compound 3ja (39.8 mg, 54%), yellow solid, mp ºC. 1 H NMR (400 MHz, DMSO) δ (s, 1H), 9.22 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), (m, 3H), 7.30 (d, J = 3.5 Hz, 2H), (m, 6H), 6.77 (s, 1H). 13 C NMR (100 MHz, DMSO) δ 160.0, 151.2, 150.3, 141.4, 137.9, 137.9, 131.3, 130.5, 130.4, 129.1, 128.9, 127.8, 127.7, 127.3, 122.6, 120.2, HRMS (APCI) m/z calcd for C 21 H 16 NO [M + H] + : ; Found: methyl-3,4-diphenylisoquinoline (3ka) The representative procedure was following using N-(2-methylbenzyl)picolinamide (1k) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ka (55.0 mg, 75%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), (m, 2H), (m, 6H), (m, 5H), 2.90 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 150.3, 148.5, 140.7, 137.5, 136.3, 135.4, 131.3, 131.0, 130.4, 130.3, 128.3, 127.8, 127.7, 127.3, 127.1, 126.3, 124.0, HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : ; Found: methoxy-3,4-diphenylisoquinoline (3la) The representative procedure was following using N-(2-methoxybenzyl)picolinamide (1l) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3la (63.7 mg, 82%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.80 (d, J = 0.5 Hz, 1H), (m, 1H), (m, 5H), (m, 6H), 6.91 (d, J = 7.7 Hz, 1H), 4.09 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 156.6, 151.2, 146.8, 140.9, 137.6, 137.2, 131.3, 130.9, 130.3, 130.1, 128.2, 127.6, 127.3, 127.1, 119.5, 117.6, 104.8, HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : ; Found: fluoro-3,4-diphenylisoquinoline (3ma) S 14

15 The representative procedure was following using N-(2-fluorobenzyl)picolinamide (1m) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3ma (38.1 mg, 51%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.70 (s, 1H), (m, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 6.4, 3.2 Hz, 5H), 7.26 (ddd, J = 8.2, 7.2, 2.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.6, 158.0, 151.6, (d, J = 5.8 Hz), 140.4, (d, J = 3.2 Hz), 136.9, 131.1, (d, J = 8.7 Hz), 130.3, 128.4, 127.7, 127.6, 127.4, (d, J = 4.3 Hz), (d, J = 15.4 Hz), (d, J = 19.0 Hz). 19 F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : ; Found: chloro-3,4-diphenylisoquinoline(3na) The representative procedure was following using N-(2-chlorobenzyl)picolinamide (1n) (61.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3na (46.5mg, 59%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.85 (s, 1H), (m, 2H), 7.50 (dd, J = 8.5, 7.4 Hz, 1H), (m, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 148.7, 140.4, 137.5, 136.9, 132.6, 131.2, 130.4, 130.3, 128.5, 127.8, 127.6, 127.4, 127.2, 125.0, HRMS (APCI) m/z calcd for C 21 H 15 ClN [M + H] + : ; Found: bromo-3,4-diphenylisoquinoline (3oa) The representative procedure was following using N-(2-bromobenzyl)picolinamide (1o) (72.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3oa (59.7 mg, 66%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.79 (d, J = 0.6 Hz, 1H), 7.85 (dd, J = 7.4, 0.7 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), (m, 1H), (m, 5H), (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 151.2, 140.3, 137.7, 136.8, 131.2, 130.9, 130.7, 130.3, 128.4, 127.7, 127.6, 127.4, 125.7, 125.5, HRMS (APCI) m/z calcd for C 21 H 15 BrN [M + H] + : ; Found: methyl-3,4-diphenylisoquinoline (3pa) The representative procedure was following using N-(3-methylbenzyl)picolinamide (1p) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3pa (47.1 mg, 73%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7, 1.5 Hz, 1H), (m, 5H), (m, 5H), 2.59 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.2, 149.9, 140.8, 137.4, 136.9, 134.2, 132.8, 131.2, 130.5, 130.3, 128.3, 127.6, 127.3, 127.0, 126.4, 125.5, HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : ; Found: methoxy-3,4-diphenylisoquinoline (3qa) The representative procedure was following using N-(3-methoxybenzyl)picolinamide (1q) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3qa (46.8 mg, 60%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (t, S 15

16 J = 7.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.19 (ddd, J = 12.8, 6.1, 3.5 Hz, 8H), 6.99 (d, J = 7.6 Hz, 1H), 3.46 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.4, 152.3, 151.4, 141.4, 140.8, 130.4, 130.2, 129.4, 129.2, 127.5, 127.4, 127.3, 126.6, 126.6, 126.0, 120.2, 110.3, HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : ; Found: methoxy-3,4-diphenylisoquinoline (3qa ) The representative procedure was following using N-(3-methoxybenzyl)picolinamide (1q) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3q a (18.2 mg, 19%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.30 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 6.9 Hz, 5H), 7.33 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 6.5, 4.4 Hz, 3H), 7.23 (s, 1H), 7.21 (s, 1H), 4.01 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.2, 150.3, 149.0, 140.8, 137.4, 131.5, 131.2, 130.7, 130.2, 128.7, 128.3, 127.6, 127.4, 127.3, 126.9, 123.5, 104.6, HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : ; Found: fluoro-3,4-diphenylisoquinoline (3ra) The representative procedure was following using N-(3-fluorobenzyl)picolinamide (1r) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ra (25.4 mg, 34%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 7.70 (ddd, J = 11.0, 8.9, 3.8 Hz, 2H), 7.39 (dd, J = 6.7, 5.5 Hz, 6H), 7.25 (ddd, J = 10.7, 5.0, 2.8 Hz, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = 5.4 Hz), (d, J = 2.9 Hz), 140.4, 136.9, 133.1, 131.1, 130.7, 130.2, (d, J = 8.4 Hz), 128.4, (d, J = 8.6 Hz), 127.7, 127.6, 127.2, (d, J = 25.0 Hz), (d, J = 20.5 Hz). 19 F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : ; Found: fluoro-3,4-diphenylisoquinoline (3ra ) The representative procedure was following using N-(3-fluorobenzyl)picolinamide (1r) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3r a (27.7 mg, 37%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.59 (td, J = 7.9, 4.3 Hz, 1H), (m, 6H), 7.27 (d, J = 5.6 Hz, 2H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), 152.7, d, J = 2.3 Hz), 140.5, (d, J = 3.5 Hz), 130.5, 130.4, 130.2, (d, J = 2.6 Hz), 127.6, 127.4, 127.3, 127.1, 127.0, (d, J = 10.3 Hz), (d, J = 4.7 Hz), (d, J = 22.1 Hz). 19 F NMR (376 MHz, CDCl3) δ (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : ; Found: ,4-diphenylbenzo[g]isoquinoline (3sa) The representative procedure was following using N-(naphthalen-2-ylmethyl)picolinamide (1s) (65.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3sa (43.2 mg, 52%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), (m, 1H), (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 8.2, 6.6 Hz, 5H), (m, 5H). 13 C NMR (100 MHz, S 16

17 CDCl 3 ) δ 152.8, 145.8, 140.7, 137.4, 135.6, 131.7, 131.7, 131.6, 131.4, 130.2, 129.3, 128.8, 128.4, 128.1, 127.7, 127.6, 127.5, 127.3, 123.6, 123.5, HRMS (APCI) m/z calcd for C 25 H 18 N [M + H] + : ; Found: methyl-3,4-diphenylisoquinoline (3ta) The representative procedure was following using N-(1-phenylethyl)picolinamide (1t) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3ta (50.0 mg, 68%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.71 (dt, J = 6.9, 3.2 Hz, 1H), (m, 2H), (m, 5H), (m, 5H), 3.13 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.8, 149.5, 141.1, 137.6, 136.0, 131.5, 130.3, 130.0, 129.2, 128.3, 127.7, 127.2, 127.0, 126.6, 126.3, 126.2, 125.6, HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : ; Found: ,3,4-triphenylisoquinoline (3ua) The representative procedure was following using N-benzhydrylpicolinamide (1u) (72.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3ua (68.7 mg, 77%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 8.3 Hz, 1H), (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), (m, 5H), 7.45 (ddd, J = 21.0, 11.3, 4.7 Hz, 5H), (m, 2H), (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.9, 149.7, 140.9, 139.8, 137.6, 137.0, 131.4, 130.5, 130.3, 130.0, 129.8, 128.6, 128.4, 127.6, 127.6, 127.3, 127.0, 126.6, 126.0, HRMS (APCI) m/z calcd for C 27 H 20 N [M + H] + : ; Found: ,4-di-p-tolylisoquinoline (3ab) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-di-p-tolylethyne (2b) (61.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ab (58.0 mg, 75%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.38 (s, 1H), (m, 1H), (m, 1H), (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 20.1, 8.0 Hz, 4H), 7.06 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.33 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 150.5, 137.9, 136.9, 136.7, 136.2, 134.3, 131.1, 130.4, 130.2, 129.1, 128.4, 127.6, 127.3, 126.7, 125.7, 21.4, HRMS (APCI) m/z calcd for C 23 H 20 N [M + H] + : ; Found: ,4-bis(4-methoxyphenyl)isoquinoline (3ac) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-methoxyphenyl)ethyne (2c) (71.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 10:1) yielded compound 3ac (61.7 mg, 72%), yellow solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.36 (s, 1H), 8.04 (dd, J = 7.0, 2.0 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), (m, 2H), (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.8, 158.6, 151.5, 150.3, 136.4, 133.3, 132.3, 131.6, 130.4, 129.8, 129.6, 127.6, 127.2, 126.6, 125.6, 113.9, 113.2, 55.3, HRMS (APCI) m/z calcd for C 23 H 20 NO 2 [M + H] + : ; Found: S 17

18 3,4-bis(4-fluorophenyl)isoquinoline (3ad) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-fluorophenyl)ethyne (2d) (64.2mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ad (58.1 mg, 73%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.09 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 3H), 7.35 (dd, J = 8.6, 5.6 Hz, 2H), 7.23 (dd, J = 8.4, 5.5 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.95 (t, J = 8.7 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = 14.3 Hz), (d, J = 14.1 Hz), (s), 149.8, (d, J = 3.3 Hz), 135.9, (d, J = 3.5 Hz), (d, J = 8.0 Hz), (d, J = 8.1 Hz), 130.9, 129.6, 127.7, 127.4, 127.1, 125.3, (d, J = 21.4 Hz), (d, J = 21.5 Hz). 19 F NMR (376 MHz, CDCl3) δ (s), (s). HRMS (APCI) m/z calcd for C 21 H 14 F 2 N [M + H] + : ; Found: ,4-bis(4-chlorophenyl)isoquinoline (3ae) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-chlorophenyl)ethyne (2e) (73.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ae (68.6 mg, 79%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.09 (dd, J = 5.1, 2.3 Hz, 1H), (m, 3H), 7.40 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 13.4, 8.4 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.2, 149.4, 138.9, 135.7, 135.4, 133.7, 133.4, 132.5, 131.6, 131.0, 129.5, 128.9, 128.1, 127.8, 127.4, 127.3, HRMS (APCI) m/z calcd for C 21 H 14 Cl 2 N [M + H] + : ; Found: ,4-bis(4-(trifluoromethyl)phenyl)isoquinoline (3af) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-(trifluoromethyl)phenyl)ethyne (2f) (94.3mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3af (72.4 mg, 70%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 (s, 1H), 8.13 (dd, J = 6.3, 3.0 Hz, 1H), 7.71 (dd, J = 8.7, 3.2 Hz, 4H), (m, 1H), (m, 4H), 7.43 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.6, 149.1, 143.9, 140.7, 135.4, 131.6, 131.3, 130.6, (d, J = 32.7 Hz), 129.8, (d, J = 32.4 Hz), 127.9, 127.7, 127.6, (m), (d, J = 7.3 Hz), 125.2, (m), (m). 19 F NMR (376 MHz, CDCl3) δ (s), (s). HRMS (APCI) m/z calcd for C 23 H 14 F 6 N [M + H] + : ; Found: diethyl 4,4'-(isoquinoline-3,4-diyl)dibenzoate (3ag) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-(ethylperoxy)phenyl)ethyne (2g) (89.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 10:1) yielded compound 3ag (54.8 mg, 55%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), (m, 3H), 7.92 (d, J = 8.4 Hz, 2H), (m, 3H), 7.46 (s, 2H), 7.36 (d, J = 8.3 Hz, 2H), 4.40 (dq, J = 25.5, 7.1 Hz, 4H), 1.42 (dt, J = 17.4, 7.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.5, 166.3, 152.4, 149.5, 144.8, 141.8, 135.4, 131.3, 131.1, 130.3, 130.3, 129.8, 129.7, 129.2, 129.1, 127.8, 127.5, S 18

19 127.5, 125.3, 61.2, 61.0, 14.4, HRMS (APCI) m/z calcd for C 27 H 23 NO 4 [M + H] + : ; Found: ,4-di-m-tolylisoquinoline (3ah) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-di-m-tolylethyne (2h) (61.8 mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ah (55.2 mg, 72%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.06 (dd, J = 6.0, 3.2 Hz, 1H), (m, 1H), 7.63 (dq, J = 5.8, 2.0 Hz, 2H), 7.36 (s, 1H), (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), (m, 2H), 7.07 (ddd, J = 19.8, 11.2, 4.7 Hz, 4H), 2.36 (s, 3H), 2.30 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.6, 150.6, 140.7, 137.8, 137.2, 137.2, 136.1, 131.8, 131.0, 130.7, 130.4, 128.3, 128.2, 128.0, 127.8, 127.5, 127.4, 127.3, 126.8, 125.8, 21.5, HRMS (APCI) m/z calcd for C 23 H 20 N [M + H] + : ; Found: ,4-bis(3-methoxyphenyl)isoquinoline (3ai) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-methoxyphenyl)ethyne (2i) (71.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ai (66.7 mg, 78%), yellow solid, mp 97-98ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.07 (dd, J = 6.2, 3.0 Hz, 1H), (m, 1H), (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), 3.74 (s, 3H), 3.66 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.6, 158.9, 151.8, 150.3, 142.0, 138.7, 135.9, 130.6, 130.5, 129.4, 128.7, 127.6, 127.4, 127.0, 125.7, 123.7, 122.8, 116.7, 114.9, 113.9, 113.2, 55.3, HRMS (APCI) m/z calcd for C 23 H 20 NO 2 [M + H] + : ; Found: ,4-bis(3-fluorophenyl)isoquinoline (3aj) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-fluorophenyl)ethyne (2j) (64.2mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3aj (60.7 mg, 77%), colorless solid, mp 87-89ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (s, 1H), (m, 1H), (m, 3H), (m, 1H), (m, 1H), (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.01 (dd, J = 9.3, 1.9 Hz, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = 38.6 Hz), (d, J = 36.5 Hz), (s), (d, J = 2.4 Hz), (d, J = 7.8 Hz), (d, J = 7.8 Hz), 135.6, 131.0, (d, J = 8.5 Hz), (d, J = 1.8 Hz), (d, J = 8.3 Hz), 127.7, 127.5, 127.4, (d, J = 2.9 Hz), (d, J = 2.9 Hz), 125.3, (d, J = 21.5 Hz), (d, J = 22.6 Hz), (d, J = 20.9 Hz), (d, J = 21.1 Hz). 19 F NMR (376 MHz, CDCl3) δ (s), (s). HRMS (APCI) m/z calcd for C 21 H 14 F 2 N [M + H] + : ; Found: ,4-bis(3-chlorophenyl)isoquinoline (3ak) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-chlorophenyl)ethyne (2k) (73.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ak (67.6 mg, S 19

20 78%), colorless solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (s, 1H), (m, 1H), 7.69 (dd, J = 8.0, 6.1 Hz, 3H), 7.51 (s, 1H), (m, 3H), (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.3, 149.2, 142.1, 138.7, 135.6, 134.4, 133.9, 131.1, 131.0, 130.4, 129.9, 129.6, 129.4, 128.9, 128.4, 127.9, 127.8, 127.6, 127.5, 127.5, HRMS (APCI) m/z calcd for C 21 H 14 Cl 2 N [M + H] + : ; Found: ,4-dipropylisoquinoline (3al) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and oct-4-yne (2l) (33.1mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3al (46.5 mg, 87%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), (m, 2H), (m, 2H), 1.84 (dd, J = 15.4, 7.6 Hz, 2H), (m, 2H), 1.12 (t, J = 7.3 Hz, 3H), 1.07 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.9, 150.1, 135.4, 130.0, 128.2, 128.1, 127.2, 125.6, 123.0, 37.3, 29.9, 24.1, 23.7, HRMS (APCI) m/z calcd for C 15 H 20 N [M + H] + : ; Found: ,4-diethylisoquinoline(3am) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and hex-3-yne (2m) (24.6mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3am (42.1 mg, 91%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 3.09 (dt, J = 7.9, 6.7 Hz, 2H), (m, 2H), 1.39 (td, J = 7.5, 1.4 Hz, 3H), 1.32 (td, J = 7.5, 1.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 153.6, 150.1, 135.2, 130.2, 129.2, 128.3, 127.3, 125.7, 122.8, 28.2, 20.8, 15.0, HRMS (APCI) m/z calcd for C 13 H1 5 N [M + H] + : ; Found: phenylisoquinoline (3an) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and ethynylbenzene (2n) (30.6mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3an (38.7 mg, 76%), white solid, mp 97-98ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.16 (d, J = 7.4 Hz, 2H), 8.09 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.5, 151.3, 139.6, 136.7, 130.6, 128.8, 128.6, 127.8, 127.6, 127.1, 127.0, 126.9, HRMS (APCI) m/z calcd for C 15 H 12 N [M + H] + : ; Found: (pyridin-3-yl)isoquinoline (3ao) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 3-ethynylpyridine (2o) (30.9mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 5:1) yielded compound 3ao (30.1 mg, 58%), white solid, mp 77-79ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 9.34 (d, J = 1.6 Hz, 1H), (m, 1H), (m, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 11.2, 3.9 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.9, 149.5, 148.5, 148.3, 136.5, 135.2, 134.4, 130.9, 128.0, 127.7, 127.0, 123.7, HRMS (APCI) m/z calcd for C 14 H 11 N 2 [M + H] + : ; Found: S 20

21 3-(thiophen-2-yl)isoquinoline (3ap) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 2-ethynylthiophene (2p) (32.4mg, 0.3mmol). After S 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ap (25.2 mg, 48%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.25 (s, 1H), 8.01 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.71 (dd, J = 12.5, 5.6 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.5, 146.6, 145.1, 136.5, 130.8, 128.2, 127.8, 127.8, 126.9, 126.9, 126.7, 123.9, HRMS (APCI) m/z calcd for C 13 H 10 NS [M + H] + : ; Found: methyl-3-phenylisoquinoline(3aq) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and prop-1-yn-1-ylbenzene (2q) (34.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3aq (50 mg, 91%), white solid, mp 80-82ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.3 Hz, 1H), 7.64 (dd, J = 14.7, 7.4 Hz, 3H), 7.52 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 2.69 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 150.1, 141.2, 136.3, 130.5, 129.9, 128.2, 127.6, 127.3, 126.7, 124.2, 123.6, HRMS (APCI) m/z calcd for C 16 H 14 N [M + H] + : ; Found: ethyl-3-phenylisoquinoline (3ar) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and but-1-yn-1-ylbenzene (2r) (39.0mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ar (50.5 mg, 87%), white solid, mp ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), (m, 1H), 7.64 (dd, J = 11.1, 3.9 Hz, 1H), (m, 2H), 7.51 (t, J = 7.3 Hz, 2H), 7.45 (dd, J = 8.4, 6.0 Hz, 1H), 3.09 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.9, 150.2, 141.6, 135.2, 130.4, 130.3, 129.2, 128.4, 128.2, 127.9, 127.6, 126.6, 123.6, 21.8, HRMS (APCI) m/z calcd for C 17 H 16 N [M + H] + : ; Found: butyl-3-phenylisoquinoline (3as) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and hex-1-yn-1-ylbenzene (2s) (47.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3as (51.5 mg, 79%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), (m, 1H), 7.63 (t, J = 7.5 Hz, 1H), (m, 2H), 7.51 (dd, J = 11.1, 4.1 Hz, 2H), 7.43 (dd, J = 10.3, 4.0 Hz, 1H), (m, 2H), (m, 2H), 1.39 (dt, J = 14.7, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.1, 150.1, 141.6, 135.4, 130.3, 129.3, 129.2, 128.3, 128.1, 127.8, 127.5, 126.6, 123.7, 33.4, 28.4, 23.0, HRMS (APCI) m/z calcd for C 19 H 20 N [M + H] + : ; Found: (4-nitrophenyl)-3-(p-tolyl)isoquinoline (3at) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1-methyl-4-((4-nitrophenyl)ethynyl)benzene (2t) (71.1mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3at (30.9 mg, NO 2 S 21