An Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl 2 : Proof of a Radical Intermediate

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1 An Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl 2 : Proof of a Radical Intermediate Tongtong Wang, Michael Schrempp, Andreas Berndhäuser, Olav Schiemann, and Dirk Menche, * University of Bonn, Kekulé-Intitute of Organic Chemistry and Biochemistry, Gerhard- Domagk-Str. 1, D Bonn, Germany, EU University of Bonn, Institute of Physical and Theoretical Chemistry, Wegelerstr. 12, D Bonn, Germany, EU. dirk.menche@uni-bonn.de Contents: 1 General Remarks...S1 2 Substrates Synthesis...S2 3 Preparation of the Organozinc Reagents... S2 4 Experimental Details and Characterization Data...S3 5 NMR Spectra...S16 1. General Remarks All reactions were carried out under oxygen atmosphere unless otherwise noted. THF, Et 2 O, CH 2 Cl 2, DMF, acetone, methanol and toluene were dried using a 4 Å Molecular sieves. CuCl 2 was purchased from Acros company with 99 % purity. Diethylzinc (1 M in n-hexane) was purchased from Acros company. Zinc powder was purchased from Roth company with 98 % purity. All other commercially obtained chemicals were used as received without further purification. TLC was performed on silica gel plates visualized either with a UV lamp (254 nm) or using a staining solution (Cerium (IV) sulfate-phosphomolybdic acid in sulfuric acid) followed by heating. Purification was performed on silica gel (Merck-- Kieselgel 60, µnm). 1 H NMR spectra were recorded at 300 MHz, 400 MHz and 500 MHz. Proton chemical shifts are reported relative to residual solvent peak (CDCl 3 at 7.26 ppm, (CD 3 ) 2 CO at 2.05 ppm and CD 2 Cl 2 at 5.32 ppm). Data are reported as follows: chemical shift in ppm, S1

2 multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet) with respect to proton (deduced from DEPT experiments), and coupling constants J in Hertz. 13 C NMR spectra were recorded at 75 MHz, 100 MHz and 125 MHz. Carbon chemical shifts are reported relative to residual solvent peaks (CDCl 3 at 77.0 ppm, (CD 3 ) 2 CO at 29.9 ppm and CD 2 Cl 2 at 54.0 ppm). Mass spectra (MS) and high resolution-mass spectra (HR-MS) were recorded on the following mass spectrometers: Bruker ICR APEX-QE, Vacuum Generators ZAB-2F, Finnigan MAT TSQ 700, JEOL JMS-700, Bruker Daltonics microtof-q and a Thermo Finnigan MAT 95 XL. 2 Substrates Synthesis General Procedure for Synthesis of 2-Phenyl-tetrahydroisoquinoline Derivatives 1 A Schlenk-flask was evacuated and refilled with argon for three times. Copper (I) iodide (332 mg, 1.75 mmol, 83 mequiv) and potassium phosphate (7.42 g, 35.0 mmol, 1.7 equiv) were added into the flask. 2-Propanol (1.34 ml, 17.5 mmol, 0.83 equiv), ethylene glycol (1.95 ml, 35.0 mmol, 1.7 equiv), 1,2,3,4-tetrahydroisoquinoline (2.63 ml, 21.0 mmol, 1.0 equiv) and iodobenzene (1.96 ml, 17.5 mmol, 0.83 equiv) were added successively via syringe at rt. The resulting mixture was heated to C, stirred for 24 h at this temperature and then it was allowed to cool to rt. Ethyl acetate (200 ml) and brine (200 ml) were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate (2 200 ml) and the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel. 3 Preparation of Organozinc reagents One Pot-procedure for Preparation of Diorganozinc Reagents 2 1 F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett. 2002, 4, F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P. Knochel J. Org. Chem. 1996, 61 (23), S2

3 1-Octene (429 mg, 3.82 mmol, 1.0 equiv) was cooled to 0 C (ice bath) in a 50 ml Schlenkflask and Et 2 BH (0.6 M in Et 2 O) (6.37 ml, 3.82 mmol, 1.0 equiv) [prepared by mixing BH 3 Me 2 S (363 mg, 4.78 mmol), BEt 3 (1 M in hexane) (9.56 ml, 956 µmol) in Et 2 O (14 ml)] was added at 0 C. The reaction mixture was ready to use after 5 min and stable in refrigerator for several months. Et 2 BH was added via syringe and after stirring overnight at rt, the volatiles were removed under reduced pressure (0.1 mmhg, 0 C, 1h) affording the expected diethyl(octyl)borane. The borane derivative was cooled to 0 C, Et 2 Zn (1 M in n-hexane) (7.64 ml, 7.64 mmol, 2.0 equiv) was slowly added over 15 min and stirred for 3 h. Subsequently, the excess of Et 2 Zn and formed Et 3 B were removed under reduced pressure (0.1 mmhg, 0 C, 3 h). The resulting oil was diluted with THF (1.0 ml) and the dioctylzinc solution (1.9 M in THF) was stored in the refrigerator. General Procedure for Preparation of Alkylzinc Bromide Reagents 3 LiCl (304 mg, 7.17 mmol, 2.5 equiv) was added to a flask and heated to 450 C under reduced pressure (0.1 mmhg, 15 min) for three times. Zinc dust (approximately 5-mm 2 pieces, 562 mg, 8.60 mmol, 3.0 equiv) was added to a dried Schlenk-flask and heated to 450 C by heating gun under reduced pressure (0.1 mmhg, 15 min) for another three times. After the mixture was cooled to rt, dry THF (1.6 ml) was added. Subsequently, 1,2-dibromoethane (50.0 µl) and TMSCl (25.0 µl) were added into the flask. Soap-like bubbles was formed directly and indicated the activation of the zinc surface. The mixture was cooled to 0-5 C (ice bath) and a solution of allyl bromide (2.87 mmol, 1.0 equiv) in THF (400 µl) was added dropwise over 30 min. The mixture was stirred at 0 C for 3 h and the resulting alkylzinc bromide solution (1.4 M in THF) was stored in refrigerator. During the insertion of zinc (activated using 1,2-dibromoethane and TMSCl) into allyl bromides, the temperature for the insertion must be kept strictly between 0 to 5 C to avoid the formation of homo-coupling products. 4 Experimental Details and Characterization Data 3 A. Krasovskiy, P. Knochel, Synthesis, 2006 (5), S3

4 A dried Schlenk-flask equipped with a stirring bar was evacuated and filled up with pure oxygen by a balloon (1 atm). Subsequently, dried acetonitrile (4.8 ml) was added. A mixture of CuCl 2 (6.40 mg, 48.0 µmol, 0.1 equiv) and 2-phenyl-tetrahydroisoquinoline (3 or 5) (480 µmol, 1.0 equiv) were added to the solvent. The reaction was stirred at rt (at 60 C for selected substrates) for 1h. Then Et 2 Zn (1 M in n-hexane) (1.44 ml, 1.44 mmol, 3.0 equiv), diorganozinc solution (1.9 M in THF) (1.0 ml, 1.91 mmol, 4.0 equiv) or alkylzinc bromide solution (1.4 M in THF) (1.36 ml, 1.91 mmol, 4.0 equiv) was added at rt and the resulting mixture was stirred at rt for another 3 h. In final, the mixture was extracted with ethyl acetate, filtered through a short layer of silica gel and eluted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel to give the desired product. 1-Ethyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (6a) Yield (104 mg, 92%), purification by flash chromatography (n-hexane/dichloromethane = 10:1), R f = 0.55 (n-hexane/ethyl acetate = 10:1). 1 H NMR (CDCl 3, 400 MHz) δ = 1.01 (t, J=7.4 Hz, 3 H), 1.76 (dp, J=15, 7.3 Hz, 1 H), 2.00 (dp, J=15, 7.4 Hz, 1 H), 2.88 (dt, J=16, 5.7 Hz, 1 H), 3.03 (ddd, J=16, 7.8, 5.4 Hz, 1 H), (m, 2 H), 4.57 (t, J=7.0 Hz, 1 H), 6.73 (t, J=7.2 Hz, 1 H), 6.89 (d, J=8.2 Hz, 2 H), (m, 4 H), (m, 2 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 149.9, 139.0, 135.2, (2 C), 128.6, 127.5, 126.6, 125.9, 117.0, (2 C), 60.8, 42.1, 29.7, 27.4, 11.5 ppm. EI + -HRMS C 17 H 19 N + [M + ]: calcd , found: Ethyl-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (6b) S4

5 Yield (96.0 mg, 86%), purification by flash chromatography (hexane/ethyl acetate/et 3 N= 40: 1: 0.2 %), R f = 0.47 (cyclohexane/ethyl acetate = 10:1). 1 H NMR (d 6 -Acetone, 400 MHz) δ = 0.97 (t, J=7.4 Hz, 3 H), (m, 1 H), 1.90 (dp, J=14, 7.5 Hz, 1 H), 2.74 (dt, J=16, 4.8 Hz, 1 H), 2.93 (ddd, J=16, 8.7, 6.2 Hz, 1 H), (m, 2 H), 3.70 (s, 3 H), 4.50 (dd, J=7.8, 5.9 Hz, 1 H), 6.79 (d, J=9.1 Hz, 2 H), 6.91 (d, J=9.1 Hz, 2 H), (m, 3 H), (m, 1 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 153.5, 145.7, 140.1, 135.9, 129.5, 128.2, 127.0, 126.5, (2 C), (2 C), 61.7, 55.7, 43.4, 30.1, 27.2, 11.6 ppm. EI + -HRMS C 18 H 21 NO + [M + ]: calcd , found: Ethyl-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (6c) Yield (84.4 mg, 86%), purification by flash chromatography (n-hexane/ethyl acetate/et 3 N = 40:1:0.2 %), R f = 0.70 (cyclohexane/ethyl acetate = 10:1). 1 H NMR (d 6 -Acetone, 400 MHz) δ = 0.98 (t, J=7.4 Hz, 3 H), 1.76 (dqd, J=14, 7.4, 7.1 Hz, 1 H), 1.93 (dqd, J=14, 7.4, 7.1 Hz, 1 H), 2.18 (s, 3 H), 2.78 (dt, J=16, 5.0 Hz, 1 H), 2.98 (dt, J=16, 7.0 Hz, 1 H), 3.59 (dd, J=7.0, 5.2 Hz, 2 H), 4.60 (t, J=7.1 Hz, 1 H), 6.83 (d, J=8.6 Hz, 2 H), 6.99 (d, J=8.5 Hz, 2 H), (m, 3 H), (m, 1 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 148.9, 140.0, 135.9, (2 C), 129.4, 128.3, 127.1, 126.8, 126.5, (2 C), 61.2, 42.5, 30.2, 27.3, 20.3, 11.6 ppm. EI + -HRMS C 18 H 21 NO + [M + ]: calcd , found: (4-Chlorophenyl)-1-ethyl-1,2,3,4-tetrahydroisoquinoline (6d) S5

6 Yield (78.1 mg, 70%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 50:1:0.2 %), R f = 0.63 (n-hexane/ethyl acetate = 10:1) 1 H NMR (CDCl 3, 400 MHz) δ = 1.00 (t, J=7.4 Hz, 3 H), 1.75 (dp, J=15, 7.3 Hz, 1 H), 1.97 (dp, J=15, 7.4 Hz, 1 H), 2.89 (dt, J=16, 5.7 Hz, 1 H), 3.01 (ddd, J=16, 7.7, 5.3 Hz, 1 H), 3.53 (dt, J=12, 5.8 Hz, 1 H), 3.61 (ddd, J=13, 7.8, 5.1 Hz, 1 H), 4.50 (t, J=7.0 Hz, 1 H), 6.79 (d, J=9.0 Hz, 2 H), (m, 6 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 148.4, 138.6, 134.9, (2 C), 128.6, 127.5, 126.7, 126.0, (2 C), 61.0, 42.4, 29.6, 27.3, 11.5 ppm. EI + -HRMS C 17 H 18 ClNH + [M+H + ]: calcd , found: Ethyl-2-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (6e) N OMe Chemical Formula: C 18 H 21 NO Exact Mass: Molecular Weight: Yield (78.0 mg, 70%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 15:1:0.2 %), R f = 0.73 (cyclohexane/ethyl acetate = 10:1) 1 H NMR (d 6 -Acetone, 400 MHz) δ = 0.92 (t, J=7.3 Hz, 3 H), (m, 2 H), 2.63 (dt, J=16, 4.2 Hz, 1 H), (m, 1 H), (m, 2 H), 3.85 (s, 3 H), 4.43 (dd, J=8.2, 4.8 Hz, 1 H), 6.76 (ddd, J=7.9, 6.0, 2.6 Hz, 1 H), 6.83 (dd, J=7.4, 1.4 Hz, 1 H), (m, 2 H), (m, 4 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 154.3, 142.0, 140.7, 135.9, 129.7, 127.9, 126.7, 126.5, 123.3, 122.4, 121.6, 113.3, 61.5, 56.0, 43.5, 39.9, 27.6, 11.7 ppm. EI + -HRMS C 18 H 21 NNaO + [M+Na + ]: calcd , found: Octyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (7a) S6

7 Yield (130 mg, 85%), Purification by flash chromatography (n-hexane/chloroform/et 3 N = 8:1:0.2 %), R f = 0.58 (hexanes/dichloromethane = 1:1). 1 H NMR (CDCl 3, 400 MHz) δ = 0.87 (t, J=6.6 Hz, 3 H), (m, 11 H), (m, 1 H), (m, 1 H), (m, 1 H), 2.86 (dt, J=16, 5.4 Hz, 1 H), 3.03 (ddd, J=16, 7.8, 5.8 Hz, 1 H), (m, 2 H), 4.65 (t, J=7.0 Hz, 1 H), 6.73 (t, J=7.3 Hz, 1 H), 6.89 (d, J=8.1 Hz, 2 H), (m, 4 H), (m, 2 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 149.8, 139.3, 135.1, (2 C), 128.6, 127.4, 126.5, 125.9, 117.0, (2 C), 59.4, 42.0, 36.9, 32.0, 29.9, 29.7, 29.4, 27.2, 27.0, 22.8, 14.3 ppm. EI + -HRMS C 17 H 18 BrN + [M + ]: calcd , found: (6-Iodohexyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (7b) Yield (160 mg, 80%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 10:1:0.2 %), R f = 0.63 (n-hexane/dichloromethane = 1:1) 1 H NMR (d 6 -Acetone, 400 MHz) δ = (m, 8 H), (m, 3 H), (m, 1 H), (m, 1 H), 3.01 (dt, J=16, 7.2 Hz, 1 H), 3.25 (t, J=7.0 Hz, 1 H), 3.64 (t, J=6.1 Hz, 1 H), 4.77 (dd, J=7.4, 5.1 Hz, 1 H), 6.65 (t, J=7.2 Hz, 1 H), 6.93 (d, J=8.3 Hz, 2 H), (m, 6 H) ppm. 13 C NMR (d 6 - Acetone, 100 MHz) δ = 150.8, 140.1, 135.8, (2 C), 129.4, 128.2, 127.2, 126.5, 117.7, (2 C), 59.5, 42.1, 37.3, 34.3, 31.1, 29.1, 27.3 (2 C), 7.9 ppm. ESI + -HRMS C 21 H 26 INH + [M+H + ]: calcd , found: Methyl 6-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)hexanoate (7c) S7

8 Yield (121 mg, 75%), Purification by flash chromatography (n-hexane/ethyl acetate/ Et 3 N = 40:1:0.2 %), R f = 0.14 (n-hexane/dichloromethane = 1:1) 1 H NMR (d 6 -Acetone, 400 MHz) δ = (m, 6 H), (m, 1 H), (m, 1 H), 2.27 (t, J=7.4 Hz, 2 H), (m, 1H), 3.01 (dt, J=16, 7.2 Hz, 1 H), 3.59 (s, 3 H), (m, 2 H), 4.76 (t, J=7.8, 6.4 Hz, 1 H), 6.64 (tt, J=7.1, 1.0 Hz, 1 H), 6.93 (dt, J=7.9, 1.1 Hz, 2 H), (m, 6 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 174.1, 150.8, 140.1, 135.8, (2 C), 129.4, 128.2, 127.2, 126.5, 117.8, (2 C), 59.5, 51.4, 42.1, 37.2, 34.3, 29.8, 27.3, 27.2, 25.6 ppm. ESI + -HRMS C 22 H 27 NO 2 H + [M+H + ]: calcd , found: (2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)hexanenitrile (7d) Yield (109 mg, 75%), purification by flash chromatography (n-hexane/ethyl acetate/ Et 3 N = 12.5:1:0.2 %), R f = 0.45 (n-hexane/dichloromethane = 1:1), 1 H NMR (CD 2 Cl 2, 400 MHz) δ = (m, 4 H), (m, 2 H), (m, 1 H), (m, 1 H), 2.21 (t, J=7.1 Hz, 2 H), 2.73 (dt, J=16, 5.2 Hz, 1 H), 2.91 (dt, J=16, 7.1 Hz, 1 H), 3.51 (dd, J=7.1, 5.2 Hz, 2 H), 4.56 (t, J=7.1 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 6 H) ppm. 13 C NMR (CD 2 Cl 2, 100 MHz) δ = 150.4, 139.5, 135.6, (2 C), 129.1, 127.8, 127.0, 126.3, 120.4, 117.6, (2 C), 59.5, 42.2, 37.0, 29.3, 27.3, 26.6, 26.0, 17.6 ppm. ESI + - HRMS C 21 H 24 N 2 Na + [M+ Na + ]: calcd , found: (Cyclohexylmethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (7e) S8

9 Yield (87.6 mg, 60%), purification by flash chromatography (n-hexane/dichloromethane = 10:1), R f = 0.55 (n-hexane/dichloromethane = 1:1), 1 H NMR (d 6 -Acetone, 400 MHz) δ = (m, 2 H), (m, 3 H), (m, 1 H), (m, 3 H), 1.80 (br d, J=13 Hz, 1 H), (m, 2 H), 1.90 (ddd, J=14, 8.3, 5.5 Hz, 1 H), 2.77 (dt, J=16, 4.7 Hz, 1 H), 2.98 (ddd, J=16, 9.1, 6.0 Hz, 1 H), 3.63 (dt, J=13, 4.8 Hz, 1 H), 3.70 (dt, J=13, 5.6 Hz, 1 H), 4.88 (dd, J=8.2, 6.4 Hz, 1 H), 6.65 (tt, J=7.2, 1.0 Hz, 1 H), 6.94 (d, J=7.9 Hz, 2 H), (m, 6 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 151.0, 140.5, 135.8, (2 C), 129.6, 128.2, 127.2, 126.6, 118.1, (2 C), 56.8, 45.2, 42.0, 35.5, 34.5, 34.2, 27.4, 27.2, 27.0, 26.8 ppm. ESI + -HRMS C 22 H 27 NH + [M+H + ]: calcd , found: Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (7f) Yield (83.5 mg, 60%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 8:1:0.2 %), R f = 0.74 (n-hexane/dichloromethane = 1:1). 1 H NMR (d 6 -Acetone, 400 MHz) δ = (m, 5 H), (m, 5 H), 1.98 (d, J=11 Hz, 1 H), 3.02 (t, J=6.6 Hz, 2 H), 3.50 (dt, J=13, 7.0 Hz, 1 H), 3.75 (dt, J=13, 6.3 Hz, 1 H), 4.52 (d, J=8.6 Hz, 1 H), 6.60 (t, J= 7.3 Hz, 1 H), 6.91 (d, J=8.5 Hz, 2H), (m, 6 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 151.2, 138.9, 136.3, (2 C), 129.3, 129.2, 127.5, 126.0, 117.2, (2 C), 64.2, 44.7, 43.4, 31.7, 31.5, 27.6, 27.3, 27.2, 27.1 ppm. ESI + -HRMS C 21 H 25 NH + [M+H + ]: calcd , found: Allyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8a) S9

10 Yield (107 mg, 90%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 8:1:0.2 %), R f = 0.40 (n-hexanes/dichloromethane = 1:1) 1 H NMR (CDCl 3, 300MHz) δ = 2.51 (dtt, J=14, 7.3, 0.9 Hz, 1 H), 2.76 (dtt, J=14, 6.8, 1.3, 1 H), 2.90 (dt, J=16, 5.6 Hz, 1 H), 3.06 (ddd, J=16, 7.9, 5.7 Hz, 1 H), (m, 2 H), 4.77 (t, J=6.9 Hz, 1 H), 5.07 (ddt, J=10, 2.0, 0.8 Hz, 1 H), 5.09 (ddt, J=17, 2.0, 1.4 Hz, 1 H), 5.88 (ddt, J=17, 10., 7.2 Hz, 1 H), 6.76 (tt, J=7.3, 1.0 Hz, 1 H), 6.92 (d, J=8.0 Hz, 2 H), (m, 4 H), (m, 2 H) ppm. 13 C NMR (CDCl 3, 75 MHz) δ = 149.4, 138.1, 135.7, 135.0, (2 C), 128.5, 127.3, 126.5, 125.7, 117.2, 117.0, (2 C), 59.3, 41.9, 40.9, 27.4 ppm. EI + -HRMS C 18 H 19 N + [M + ]: calcd , found: (2-Methylallyl)-2-Phenyl-1,2,3,4-tetrahydroisoquinoline (8b) Yield (94.0 mg, 75%), purification by flash chromatography (n-hexane/chloroform/ Et 3 N = 8:1:0.2 %), R f = 0.75 (n-hexane/dichloromethane = 1:1) 1 H NMR (CD 2 Cl 2, 400 MHz) δ =1.80 (t, J=1.1 Hz, 3 H), 2.42 (ddd, J=14, 7.1, 1.0 Hz, 1 H), 2.70 (ddd, J=14, 7.7, 0.9 Hz, 1 H), 2.83 (dt, J=16, 5.0 Hz, 1 H), 3.01 (dt, J=16, 7.4 Hz, 1 H), 3.64 (dd, J=7.4, 5.0 Hz, 2 H), 4.67 (td, J=2.1, 1.1 Hz, 1 H), 4.80 (dq, J=2.5, 1.4 Hz, 1 H), 4.87 (t, J=7.2 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 6 H) ppm. 13 C NMR (CD 2 Cl 2, 100 MHz) δ = 150.2, 143.7, 139.1, 135.5, (2 C), 129.1, 128.0, 127.0, 126.1, 117.8, (2 C), 113.7, 58.5, 45.1, 42.1, 27.3, 23.1 ppm. ESI + -HRMS C 19 H 21 NH + [M+H + ]: calcd , found: Phenyl-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline (8c) S10

11 Yield (105 mg, 80%), purification by flash chromatography (n-hexane/chloroform = 5:1), R f = 0.63 (n-hexane/dichloromethane = 1:1) 1 H NMR (CDCl 3, 400 MHz) δ = 2.06 (t, J=2.7 Hz, 1 H), 2.62 (ddd, J =17, 7.8, 2.6 Hz, 1 H), 2.86 (ddd, J =17, 5.2, 2.7 Hz, 1 H), 2.95 (dt, J =16, 5.9 Hz, 1 H), 3.07 (ddd, J =16, 7.5, 5.4 Hz, 1 H), 3.57 (dt, J = 12, 5.8 Hz, 1 H), 3.66 (ddd, J =1, 7.7, 5.0 Hz, 1 H), 4.93 (dd, J =7.7, 5.4 Hz, 1 H), 6.81 (t, J=7.3 Hz, 1 H), 6.97 (d, J =8.2 Hz, 2 H) (m, 3 H), (m, 3 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 148.8, 136.8, 134.8, (2 C), 128.4, 127.6, 127.1, 125.9, 118.0, (2 C), 81.9, 70.9, 58.7, 42.3, 27.8, 26.0 ppm. ESI + -HRMS C 18 H 17 NH + [M+H + ]: calcd , found: (But-2-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8d) Yield (75.0 mg, 60%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 12:1:0.2 %), R f = 0.68 (n-hexane/dichloromethane = 1:1) 1 H NMR (d 6 -Acetone, 300 MHz) δ = 1.71 (t, J=2.6 Hz, 3 H), 2.52 (ddq, J=17, 7.5, 2.5 Hz, 1 H), 2.70 (ddq, J=17, 5.5, 2.6 Hz, 1 H), (m, 2 H), 3.55 (dt, J=13, 5.9 Hz, 1 H), 3.67 (ddd, J=13, 7.7, 5.1 Hz, 1 H), 4.88 (t, J=6.4 Hz, 1 H), 6.70 (tt, J=7.2, 0.8 Hz, 1 H), 6.97 (d, J=8.0 Hz, 2 H), (m, 5 H), (m, 1H) ppm. 13 C NMR (d 6 -Acetone, 75 MHz) δ = 150.3, 138.5, 136.0, (2 C), 129.2, 128.6, 127.7, 126.6, 118.2, (2 C), 78.6, 77.6, 59.6, 42.6, 28.4, 26.7, 3.4 ppm. ESI + -HRMS C 19 H 19 NH + [M+H + ]: calcd , found: Phenyl-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline (8e) S11

12 Yield (99.0 mg, 65%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 8:1:0.2 %), R f = 0.73 (n-hexanes/dichloromethane = 1:1) 1 H NMR (CDCl 3, 300 MHz) δ = 0.10 (s, 9 H), 2.57 (dd, J=17, 7.9 Hz, 1 H), 2.84 (dd, J=17, 5.3 Hz, 1 H), 2.91 (dt, J=16, 6.1 Hz, 1 H), 3.03 (ddd, J=16, 7.2, 5.3 Hz, 1 H), 3.50 (ddd, J=12, 6.4, 5.6 Hz, 1 H), 3.61 (ddd, J=12, 7.4, 5.1 Hz, 1 H), 4.87 (dd, J=7.9, 5.4 Hz, 1 H), 6.75 (t, J=7.3 Hz, 1 H), 6.93 (d, J=8.2 Hz, 2 H), (m, 6 H) ppm. 13 C NMR (CDCl 3, 75 MHz) δ = 148.8, 136.8, 134.8, (2 C), 128.2, 127.9, 127.0, 125.7, 117.8, (2 C), 104.6, 87.6, 58.9, 42.3, 27.9, 27.2, (3 C) ppm. ESI + -HRMS C 21 H 25 NSiH + [M+H + ]: calcd , found: Benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8f) Yield (114 mg, 80%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 5:1:0.2 %), R f = 0.63 (n-hexanes/dichloromethane 1:1), 1 H NMR (CDCl 3, 400 MHz) δ = 2.77 (dt, J=16, 5.7 Hz, 1 H), 3.00 (dt, J=13, 5.5 Hz, 1 H), 3.02 (dd, J=13, 7.5 Hz, 1 H), 3.28 (dd, J=13, 5.8 Hz, 1 H), 3.57 (dt, J=12, 5.6 Hz, 1 H), 3.67 (ddd, J=12, 7.7, 5.0 Hz, 1 H), 4.92 (t, J=6.6 Hz, 1 H), (m, 2 H), 6.86 (d, J=8.3 Hz, 2 H), (m, 3 H), (m, 7 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 149.3, 138.9, 137.6, 135.1, (2 C), (2 C), 128.2, (2 C), 127.6, 126.6, 126.2, 125.5, 117.2, (2 C), 61.5, 42.4, 42.1, 27.5 ppm. ESI + -HRMS C 22 H 21 NH + [M+H + ]: calcd , found: (4-Methylbenzyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8g) S12

13 Yield (115 mg, 77%), purification by flash chromatography (n-hexane/chloroform/et 3 N = 10:1:0.2 %), R f = 0.55 (n-hexane/dichloromethane 1:1), 1 H NMR (CDCl 3, 400 MHz) δ = 2.34 (s, 3 H), 2.79 (dt, J=16, 5.6 Hz, 1 H), 3.02 (ddd, J=15.7, 7.5, 5.6 Hz, 1 H), 3.00 (dd, J=13, 7.5 Hz, 1 H), 3.26 (dd, J=13.4, 5.5 Hz, 1 H), 3.47 (dt, J=12, 5.8 Hz, 1 H), 3.68 (ddd, J=12.4, 7.5, 5.1 Hz, 1 H), 4.91 (t, J=6.5 Hz, 1 H), (m, 2 H), (m, 4 H), (m, 3 H) (m, 2 H) (m, 2 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = 149.3, 137.7, (2 C), 135.0, (2 C), (2 C), (2 C), 128.2, 127.7, 126.5, 125.5, 117.1, (2 C), 61.5, 42.1, 42.0, 27.5, 21.1 ppm. ESI + -HRMS C 23 H 23 NH + [M+H + ]: calcd , found: (4-Methoxybenzyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8h) Yield (110 mg, 70%), purification by flash chromatography (n-hexane/dichloromethane/et 3 N = 8:1:0.2 %), R f = 0.32 (n-hexane/dichloromethane 1:1) 1 H NMR (d 6 -Acetone, 400 MHz) δ = 2.75 (dt, J=16, 5.6 Hz, 1 H), 2.99 (ddd, J=16, 8.5, 5.6 Hz, 1 H), 3.02 (dd, J=14, 6.5 Hz, 1 H), 3.18 (dd, J=14, 6.9 Hz, 1 H), 3.61 (dt, J=13, 5.5 Hz, 1 H), 3.70 (ddd, J=13, 8.6, 5.0 Hz, 1 H), 3.73 (s, 3 H), 4.97 (t, J=6.7 Hz, 1 H), 6.63 (t, J=7.3 Hz, 1 H), 6.78 (d, J=8.7 Hz, 2 H), 6.87 (d, J=8.1 Hz, 2 H), 6.97 (d, J=7.4 Hz, 1 H), 7.03 (d, J=8.7 Hz, 2 H), (m, 2 H), (m, 3 H) ppm. 13 C NMR (d 6 -Acetone, 100 MHz) δ = 159.3, 150.6, 139.0, 136.2, 132.0, (2 C), (2 C), 129.3, 128.6, 127.4, 126.4, 117.9, (2 C), (2 C), 62.1, 55.5, 42.4, 42.0, 27.7 ppm. ESI + -HRMS C 23 H 23 NOH + [M+H + ]: calcd , found: S13

14 1-(4-Fluorobenzyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (8i) Yield (109 mg, 72%), purification by flash chromatography (n-hexane/dichloromethane/et 3 N = 10:1:0.2 %), R f = 0.60 (n-hexane/dichloromethane 1:1), 1 H NMR (CDCl 3, 400 MHz) δ = 2.74 (br d, J=16 Hz, 1 H), 3.00 (ddd, J=13, 5.9, 5.1 Hz, 1 H), 3.02 (ddd, J=13, 6.8, 5.9 Hz, 1 H), 3.24 (dd, J=13, 3.8 Hz, 1 H), 3.56 (dt, J=12, 6.0 Hz, 1 H), 3.65 (ddd, J=12, 7.5, 5.1 Hz, 1 H), 4.89 (t, J=6.5 Hz, 1 H), (m, 2 H), (m, 6 H), (m, 3 H), (m, 2 H) ppm. 13 C NMR (CDCl 3, 100 MHz) δ = (d, J=244 Hz), 149.2, 137.3, 135.1, (d, J=3.4 Hz), (d, J=7.8 Hz, 2 C), (2 C), 128.3, 127.5, 126.7, 125.6, 117.4, (d, J=21.0 Hz, 2 C), (2 C), 61.4, 42.2, 41.5, 27.4 ppm. ESI + -HRMS C 22 H 20 FNH + [M+H + ]: calcd , found: Phenyl-1-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinoline (8j) N F 3 C O ChemicalFormula:C 23 H 20 F 3 NO Exact Mass: Molecular Weight: Yield (147 mg, 80%), purification by flash chromatography (n-hexane/dichloromethane/et 3 N = 10:1:0.2 %), R f = 0.43 (n-hexane/dichloromethane 1:1), 1 H NMR (CDCl 3, 300 MHz) δ = 2.72 (dt, J=16, 5.7 Hz, 1 H), 3.00 (ddd, J=16, 7.7, 5.5 Hz, 1 H), 3.15 (dd, J=14, 7.0 Hz, 1 H), 3.26 (dd, J=13, 6.4 Hz, 1 H), 3.55 (dd, J=13, 6.0 Hz, 1 H), 3.65 (ddd, J=13, 7.7, 5.1 Hz, 1 H), 4.91 (t, J=6.5 Hz, 1 H), (m, 4 H), (m, 5 H), (m, 4 H) ppm. 13 C NMR (CDCl 3, 75 MHz) δ = 149.2, (q, J=1.8 Hz), 137.6, 137.2, 135.1, (2 C), (2 C), 128.4, 127.5, 126.8, 125.7, (q, J=0.9 Hz, 2 C), (q, J=257 Hz), 117.6, S14

15 113.9 (2 C), 61.4, 42.2, 41.7, 27.3 ppm. ESI + -HRMS C 23 H 20 F 3 NOH + [M+H + ]: calcd , found: Phenyl-1-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinoline (8k) Yield (132 mg, 75%), purification by flash chromatography (n-hexane/dichloromethane/et 3 N = 10:1:0.2 %), R f = 0.68 (n-hexanes/dichloromethane 1:1). 1 H NMR (CD 2 Cl 2, 400 MHz) δ = 2.73 (dt, J=16, 5.4 Hz, 1 H), 3.00 (ddd, J=16, 8.2, 5.5 Hz, 1 H), 3.11 (dd, J=14, 6.7 Hz, 1 H), 3.31 (dd, J=13, 6.7 Hz, 1 H), 3.58 (dt, J=12, 5.7 Hz, 1 H), 3.66 (ddd, J=13, 8.2, 4.9 Hz, 1 H), 4.95 (t, J=6.7 Hz, 1 H), (m, 1 H), (m, 3 H), (m, 1 H), (m, 6 H), 7.50 (d, J=8.0 Hz, 2 H) ppm. 13 C NMR (CD 2 Cl 2, 100 MHz) δ = 149.9, (q, J=1.3 Hz), 137.8, 135.8, (2 C), (2 C), 129.1, 128.0, 127.3, 126.1, (q, J=3.8 Hz, 2 C), 118.1, (2 C), 71.6, 61.6, 42.7, 42.5, 27.6 ppm. ESI + - HRMS C 23 H 20 F 3 NH + [M+H + ]: calcd , found: ((2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)benzonitrile (8l) Yield (132 mg, 85%), purification by flash chromatography (n-hexane/ethyl acetate/et 3 N = 20:1:0.2 %), R f = 0.38 (n-hexane/dichloromethane 1:1). 1 H NMR (d 6 -Acetone, 300 MHz) δ = 2.75 (dt, J=16, 5.0 Hz, 1 H), 3.00 (ddd, J=16, 8.9, 5.7 Hz, 1 H), 3.20 (dd, J=13, 6.1 Hz, 1 H), 3.34 (dd, J=13, 7.8 Hz, 1 H), (m, 2 H), 5.10 (t, J=6.6 Hz, 1 H), 6.64 (tt, J=7.3, 1.0 Hz, 1 H), (m, 2 H), (m, 6 H), (m, 2 H), (m, 2 H) ppm. 13 C NMR (d 6 -Acetone, 75 MHz) δ = 150.3, 146.1, 138.4, 136.0, (2 C), S15

16 (2 C), (2 C), 129.5, 128.4, 127.6, 126.5, 119.5, 118.3, (2 C), 110.7, 61.4, 42.8, 42.1, 27.3 ppm. ESI + -HRMS C 23 H 20 N 2 Na + [M+Na + ]: calcd , found: Ethyl-1,2,3,4-tetrahydroisoquinoline (11) 1-Ethyl-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (6b) (24.9 mg, 93.1 µmol, 1.0 equiv) was dissolved in acetonitrile (930 µl) and cooled to 0 C. CAN (153 mg, 279 µmol, 3.0 equiv) was dissolved in water (280 µl) and added dropwise to the acetonitrile solution. After 2 h additional CAN (153 mg, 279 µmol, 3.0 equiv) was dissolved in water (280 µl) and added dropwise to the acetonitrile solution. The reaction mixture was stirred for 1 h and then the solvent was evaporated in vacuo. The remaining solid was diluted with water (40 ml) and washed with diethyl ether (2 40 ml). The ph of the aqueous layer was adjusted to 9 with 1 M NaOH and extracted with dichlormethane (3 40 ml). The combined organic phases were washed once with sat aq NaCl (40 ml) and dried over MgSO 4. Evaporation of the solvent and purification by flash chromatography (cyclohexane/ethyl acetate/ i PrNH 2 = 1: 1: 3%) gave 1-ethyl-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (11) (8.4 mg, 52.1 µmol, 56%) as pale yellow oil. R f = 0.38 (cyclohexane/ethyl acetate/ i PrNH 2 = 1:1:3%). 1 H NMR (CDCl 3, 500 MHz) δ = 1.05 (t, J=7.4 Hz, 3 H), 1.83 (ddd, J=14, 8.2, 7.2 Hz, 1 H), 1.97 (dtd, J=15, 7.4, 4.1 Hz, 1 H), 2.48 (br s, 1 H), 2.81 (dt, J=17, 5.3 Hz, 1 H), 2.92 (ddd, J=17, 8.0, 5.2 Hz, 1 H), 3.05 (ddd, J=13, 8.1, 4.9 Hz, 1 H), 3.32 (dt, J=12, 5.4 Hz, 1 H), 4.01 (dd, J=8.3, 4.1 Hz, 1 H), (m, 4 H). 13 C NMR (CDCl 3, 125 MHz) δ = 138.2, 134.8, 129.4, 126.3, 126.3, 126.1, 57.1, 41.0, 29.4, 28.8, ESI + -HRMS C 11 H 15 NH [M+H + ]: calcd , found: NMR Spectra S16

17 N S17

18 N S18

19 N 6b OMe S19

20 N 6b OMe S20

21 N 6c S21

22 N 6c OMe S22

23 N 6d Cl S23

24 N 6d Cl S24

25 N OMe 6e S25

26 N OMe 6e S26

27 S27

28 S28

29 N 7a S29

30 N 7a S30

31 N 7b I S31

32 N I 7b S32

33 N OMe 7c O S33

34 N OMe 7c O S34

35 7d S35

36 N 7d N S36

37 w653hnmr.esp N 7e Chemical Shift (ppm) S37

38 w653cnmr.esp e N Chemical Shift (ppm) S38

39 w619hnmr.esp N f Chemical Shift (ppm) S39

40 w619cnmr.esp N 7f Chemical Shift (ppm) S40

41 w609hnmr.esp N 8a Chemical Shift (ppm) S41

42 w609cnmr.esp N 8a Chemical Shift (ppm) S42

43 8b S43

44 8b S44

45 w628.hnmr.esp N 8c Chemical Shift (ppm) S45

46 w628cnmr.esp N 8c Chemical Shift (ppm) S46

47 tw634hnmr.esp N 8d Chemical Shift (ppm) S47

48 w634cnmr.esp d N Chemical Shift (ppm) S48

49 W633hnmr.esp TMS 0.10 N TMS 8e Chemical Shift (ppm) S49

50 x3b017.14_011001r N TMS 8e Chemical Shift (ppm) S50

51 w590ahnmr.esp N 8f Chemical Shift (ppm) S51

52 w590a. cnmr f N Chemical Shift (ppm) S52

53 w638hnmr.esp N 8g Chemical Shift (ppm) S53

54 w638cnmr.esp N 8g Chemical Shift (ppm) S54

55 w639hnmr.esp N O 8h Chemical Shift (ppm) S55

56 tw639cnmr.esp O N 8h Chemical Shift (ppm) S56

57 w640hnmr.esp N F 8i Chemical Shift (ppm) S57

58 w640cnmr.esp N F 8i Chemical Shift (ppm) S58

59 w646hnmr.esp N F 3 C O 8j Chemical Shift (ppm) S59

60 w646cnmr.esp N F 3 C O 8j Chemical Shift (ppm) S60

61 8k S61

62 8k S62

63 S63

64 8l S64