Unless otherwise noted, chemicals were purchased from commercial suppliers and used without further purification. Flash column chromatography was performed on silica gel 60 from Merck (40–63 μm), whereas separations were carried out using a Büchi SepacoreTM MPLC system. For TLC, aluminum-coated silica gel was used and signals were visualized with UV light (254 nm). GC–MS runs were performed on a Thermo Finnigan Focus GC/DSQ II using a standard capillary column BGB 5 (30 m × 0.32 mm ID) and the following settings were used as standard: injection: 1 mm3 (hot needle-technique), split-injection (split-ratio: 1:8); flow: 2 cm3/min helium; injector block temperature: 250 °C; MS-transferline temperature: 280 °C. HR-MS was carried out by E. Rosenberg at the Vienna University of Technology, Institute for Chemical Technologies and Analytics. All samples were analyzed by LC–IT-TOF-MS in only positive ion detection mode upon recording of MS and MS/MS spectra. For the evaluation in the following, only positive ionization spectra were used (where the quasi-molecular ion is the one of [M+H]+), and further data or information were not taken into consideration. Melting points were determined using a Kofler-type Leica Galen III micro hot stage microscope. 1H NMR and 13C NMR spectra were recorded on a Bruker AC 200 (200 MHz) or on a Bruker Avance UltraShield 400 (400 MHz) spectrometer. Chemical shifts are reported as ppm downfield from TMS (tetramethylsilane) as internal standard with multiplicity, number of protons, allocation, and coupling constant(s) in Hertz.
General Procedure A
A mixture of 2 mg copper(I) chloride (0.02 mmol, 0.1 equiv.) and the corresponding 1,2,3,4-tetrahydroisoquinoline (0.4 mmol, 2.0 equiv.) in 1 cm3 MeCN was flushed with Ar for about 2 min and then 0.04 cm3
tert-butyl hydroperoxide (5.5 M in decane) was dropped into the mixture via syringe at room temperature, followed by the alkyne (0.2 mmol, 1.0 equiv.). The reaction temperature was raised to 50 °C and the mixture was stirred at this temperature for 2 days and then cooled to room temperature. The resulting suspension was diluted with diethyl ether or dichloromethane and filtered through a little amount of silica gel in a frit. The solvent was evaporated and the residue was purified by column chromatography or preparative TLC.
General Procedure B
To a mixture of 4 mg copper(I) chloride (0.04 mmol, 0.1 equiv.) and the corresponding 1,2,3,4-tetrahydroisoquinoline (0.4 mmol, 1.0 equiv.) in 1 cm3 water in a pressure vial, the alkyne (0.4 mmol, 1.0 equiv.) was added. The vial was quickly filled with air to a pressure of 4–5 bar. The reaction mixture was then stirred at 50 °C for 24 h. After cooling down to room temperature, the reaction mixture was extracted 3× with 2 cm3 EtOAc, the organic phases were combined, the solvent was evaporated, and the residue was purified by column chromatography or preparative TLC.
General Procedure C
To a mixture of 4 mg copper(I) chloride (0.04 mmol, 0.1 equiv.), 83.7 mg 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.4 mmol, 1.0 equiv.) in 1 cm3 of a 1:1 mixture of water and MeCN in a pressure vial, alkynoic acid (0.4 mmol, 1.0 equiv.) was added. The vial was quickly filled with air to a pressure of 4–5 bar. The reaction mixture was then stirred at 50 °C for 24 h. After cooling down to room temperature, the solvent was evaporated and the residue was purified by column chromatography or preparative TLC.
N-Phenyl-1,2,3,4-tetrahydroisoquinoline (1)
Copper(I) iodide (39.8 mg, 0.21 mmol, 0.1 equiv.) and 887.3 mg potassium phosphate (4.18 mmol, 2.09 equiv.) were weighed in a round flask which was evacuated and back filled with nitrogen three times. 2-Propanol (2 cm3), 0.23 cm3 ethylene glycol, 426.4 mg iodobenzene (0.23 cm3, 2.09 mmol, 1.05 equiv.) and 0.27 g 1,2,3,4-tetrahydroisoquinoline (0.26 cm3, 2.0 mmol, 1 equiv.) were added via micro syringe at room temperature. The reaction mixture was heated to 85–90 °C, stirred for 24 h and then allowed to cool to room temperature. Diethyl ether (5 cm3) and 5 cm3 water were then added to the reaction mixture. The organic layer was extracted by diethyl ether (2 × 20 cm3). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude mixture purified by column chromatography on silica gel (PE:EtOAc = 20:1) to give 83% (0.347 g, 1.66 mmol) of 1 as a beige solid. M.p.: 43–46 °C (lit. m.p.: 45–46 °C [27]); R
f = 0.69 (PE:EtOAc = 10:1).
2-Phenyl-1-phenylethynyl-1,2,3,4-tetrahydroisoquinoline (2)
It was prepared according to the General Procedure A (86%, 53 mg, 0.17 mmol) and B (97%, 120 mg, 0.38 mmol). The product was isolated by column chromatography (PE:DCM = 10:3) as a light yellow oil. NMR data were in agreement with the literature [21].
N-Benzyl-1,2,3,4-tetrahydroisoquinoline (3)
To an argon-degassed solution of 2.66 g THIQ (2.53 cm3, 20 mmol, 1.0 equiv.) and 6.07 g TEA (8.4 cm3, 60 mmol, 3.0 equiv.) in 50 cm3 dry DCM, 5.13 g benzyl bromide (3.4 cm3, 30 mmol, 1.5 equiv.) was added at 0 °C. After 10 min, the reaction mixture was warmed to r.t. and stirred under argon for 5 h. The reaction mixture was quenched with aqueous saturated sodium carbonate solution, and extracted three times with EtOAc. The collected organic layers were washed twice with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was purified via column chromatography (PE:CHCl3 = 3:1) to give 82% (3.68 g, 16.5 mmol) of 3 as a pale yellow solid. M.p.: 35–37 °C (lit. m.p.: 35–36 °C [28]); TLC: R
f = 0.36 (PE:CHCl3 = 3:1).
N-(4-Methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (4)
To an argon-degassed solution of 1.33 g 1,2,3,4-tetrahydroisoquinoline (1.27 cm3, 10 mmol, 1.0 equiv.) and 3.04 g TEA (4.2 cm3, 30 mmol, 3.0 equiv.) in 15 cm3 dry DCM, 2.35 g 4-methoxybenzylchloride (2.03 cm3, 15 mmol, 1.5 equiv.) was added at 0 °C. After 10 min, the reaction mixture was warmed to r.t. and stirred under argon for 12 h. The reaction mixture was diluted with aqueous 2 M HCl and extracted three times with EtOAc. The collected organic layers were washed twice with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was triturated in hot EtOAc, cooled down to −20 °C, and the colorless precipitate collected by filtration to give 86% (2.50 g, 8.63 mmol) of 4 after drying as colorless solid. M.p.: 210–212 °C (lit. m.p.: 211 °C [29]); TLC: R
f = 0.55 (PE:EtOAc = 3:1).
N-Methyl-1,2,3,4-tetrahydroisoquinoline (5)
1,2,3,4-THIQ (1.332 g, 10 mmol) was added, under cooling, to 2.302 g formic acid (50 mmol) and 0.751 g formaldehyde (25 mmol). The reaction mixture was refluxed overnight, diluted with 2 M hydrochloric acid, and then extracted with EtOAc. This solution was neutralized with brine and dried with sodium sulfate. The EtOAc was vaporized and the crude mixture separated via column chromatography (PE:EtOAc = 20:1) to give 87% (1.28 g, 8.7 mmol) of 5 as a yellow oil. R
f = 0.70 (PE: EtOAc = 10:1); NMR data were in agreement with the literature [30].
N-(Pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (6)
1,2,3,4-Tetrahydroisoquinoline (666 mg, 0.63 cm3, 5.00 mmol, 1.0 equiv.) and 510 mg 2-fluoropyridine (0.45 cm3, 5.05 mmol, 1.05 equiv.) were placed in a screw-capped glass vial at r.t., heated to 120 °C, and stirred for 15 h. Completion of the reaction was monitored by TLC, the reaction mixture cooled to r.t., and directly subjected to flash column chromatography using gradient elution with PE:EtOAc (100:0–40:60) to afford the desired product 6 in 64% (670 mg, 3.19 mmol) as a pale yellow solid. M.p.: 39–42 °C; R
f = 0.65 (PE:EtOAC = 10:1); NMR data were in agreement with the literature [31].
N-Boc-1,2,3,4-tetrahydroisoquinoline (7)
To an argon-degassed solution of 2.66 g 1,2,3,4-tetrahydroisoquinoline (2.53 cm3, 20.0 mmol, 1.0 equiv.) and 6.07 g TEA (8.37 cm3, 60.0 mmol, 3.0 equiv.) in 45 cm3 dry DCM, a solution of 4.80 g Boc2O (5.05 cm3, 22.0 mmol, 1.1 equiv.) in 5 cm3 DCM was added dropwise. The reaction was stirred under argon atmosphere at r.t. for 15 h. Then, the solvent was evaporated in vacuo, and the residue directly subjected to flash column chromatography using gradient elution with PE:Et2O (100:0–40:60) to afford the desired product 7 in 99% (4.60 g, 19.7 mmol) as a colorless solid. M.p.: 27–35 °C; TLC: R
f = 0.79 (PE:Et2O = 5:1); NMR data were in agreement with the literature [32].
N-Acetyl-1,2,3,4-tetrahydroisoquinoline (8)
A 50 cm3 flask was loaded with 1.51 g 1,2,3,4-tetrahydroisoquinoline (1.44 cm3, 11.3 mmol, 1.0 equiv.) and 1.19 g acetic acid anhydride (1.10 cm3, 11.3 mmol, 1.0 equiv.). The mixture was heated to 100 °C for 3 h. After 1 h another equivalent of acetic acid anhydride was added to the reaction. The reaction mixture was cooled to r.t. and diluted with 200 cm3 DCM. The organic layer was washed twice with 2 M aqueous NaOH to get rid of excess acetic acid, washed twice with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was subjected to flash column chromatography using gradient elution with PE:EtOAc (100:0–50:50) to afford the desired product 8 in 75% (1.49 g, 8.50 mmol) as pale yellow crystals. M.p.: 44–46 °C (lit. m.p.: 45–46 °C [33]); R
f = 0.29 (PE:EtOAc = 10:1).
N-Pivaloyl-1,2,3,4-tetrahydroisoquinoline (9)
To an argon-degassed solution of 2.66 g 1,2,3,4-tetrahydroisoquinoline (2.53 cm3, 20.0 mmol, 1.0 equiv.) and 6.07 g TEA (8.37 cm3, 60.0 mmol, 3.0 equiv.) in 50 cm3 dry DCM, 3.61 g pivaloyl chloride (3.68 cm3, 30.0 mmol, 1.5 equiv.) was added slowly at 0 °C. Then, the reaction mixture was warmed to r.t. and stirred at r.t. under argon for 2 h. The reaction mixture was cooled to 0 °C, diluted with aqueous 2 N HCl, and extracted three times with Et2O. The collected organic layers were washed twice with 2 N NaOH, and once with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was subjected to flash column chromatography using gradient elution with PE:Et2O (100:0–40:60) to afford the desired product 9 in 86% (3.75 g, 17.3 mmol) as a pale yellow solid. M.p.: 63–65 °C (lit. m.p.: 67–69 °C [34]); R
f = 0.47 (PE:EtOAc = 5:1).
N-Benzoyl-1,2,3,4-tetrahydroisoquinoline (10)
Benzoyl chloride (4.22 g, 30.0 mmol, 1.5 equiv.), was added slowly to a solution of 2.66 g THIQ (2.53 cm3, 20.0 mmol, 1.0 equiv.) and 6.07 g TEA (8.37 cm3, 60.0 mmol, 3.0 equiv.) in 50 cm3 dry DCM at 0 °C. The reaction mixture was warmed to r.t. after completion of the addition and stirred at r.t. under argon for 15 h. Then, the reaction mixture was cooled to 0 °C, diluted with aqueous 2 N HCl, and extracted three times with Et2O. The collected organic layers were washed twice with 2 N NaOH, and once with brine, dried over sodium sulfate, filtered, and evaporated. The crude product was subjected to flash column chromatography using gradient elution with PE:Et2O (100:0–40:60) to afford the desired product 10 in 98% (4.67 g, 19.7 mmol) as a pale yellow solid. M.p.: 125–127 °C (lit. m.p.: 127–129 °C [34]); R
f = 0.24 (PE:EtOAc = 5:1).
N-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (12)
Copper(I) iodide (39.8 mg, 0.21 mmol, 0.1 equiv.), 887.3 mg potassium phosphate (4.18 mmol, 2.09 equiv.), and 489.1 mg 4-iodoanisole (2.09 mmol, 1.05 equiv.) were put into a round flask which was evacuated and back filled with nitrogen three times. 2-Propanol (2 cm3), 0.23 cm3 ethylene glycol, and 0.27 g 1,2,3,4-tetrahydroisoquinoline (0.26 cm3, 2.0 mmol, 1.0 equiv.) were added via Hamilton syringe at room temperature. The reaction mixture was heated to 85–90 °C, stirred for 24 h, and then allowed to cool to room temperature. Diethyl ether (5 cm3) and 5 cm3 water were then added to the reaction mixture. The organic layer was extracted by diethyl ether (2 × 20 cm3). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the product purified by column chromatography on silica gel (PE:EtOAc = 20:1) to give 79% (0.38 g, 1.58 mmol) of 12 as a colorless solid. M.p.: 89–91 °C; TLC: R
f = 0.56 (PE:EtOAc = 5:1); NMR data were in agreement with the literature [35].
1-(Hept-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (13a, C22H25N)
It was prepared according to the General Procedure A (67%, 41 mg, 0.13 mmol), B (93%, 116 mg, 0.36 mmol), and C (98%, 118 mg, 0.40 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.57 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 0.78–1.02 (m, 3H, H5″), 1.22–1.56 (m, 6H, H2″-H4″), 1.99 (t, 2H, H1″), 2.86–3.27 (m, 2H, H4), 3.51–3.87 (m, 2H, H3), 5.45 (s, 1H, H1), 6.90 (m, 1H, H4′), 7.02–7.48 (m, 8H, H5–H8, H2′, H3′) ppm; 13C NMR (50 MHz, APT, CDCl3): δ = 13.9 (q, C5″), 17.9 (t, C1″), 21.6 (t, C4″), 27.9 (t, C2″), 28.2 (t, C4), 30.2 (t, C3″), 42.0 (t, C3), 50.5 (d, C1), 79.9 (s, C alkyne), 84.5 (s, C alkyne), 116.1 (d, C2′), 118.9 (d, C4′), 125.9 (d, C7), 126.9 (d, C6), 127.4 (d, C5), 128.6 (d, C8), 128.9 (d, C3′), 133.8 (s, C8a), 135.9 (s, C4a), 149.2 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 304.2060, found 304.2064.
1-(Oct-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (13b, C23H27N)
It was prepared according to General Procedure A (49%, 31 mg, 0.1 mmol) and B (91%, 116 mg, 0.36 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.62 (PE:EtOAc = 20:1); NMR data were in agreement with the literature [21].
1-(Octa-1,7-diyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (13c, C23H23N)
It was prepared according to General Procedure A (93%, 58 mg, 0.19 mmol) and B (88%, 110 mg, 0.34 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.47 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 1.45–1.68 (m, 4H, H2″, H3″), 1.99 (s, 1H, H6″), 2.09-2.31 (m, 4H, H1″, H4″), 2.99–3.27 (m, 2H, H4), 3.55–3.83 (m, 2H, H3), 5.50 (s, 1H, H1), 6.88–7.46 (m, 9H, H5-H8, H2′, H3′) ppm; 13C NMR (50 MHz, CDCl3): δ = 18.2 (t, C4″), 18.6 (t, C1″), 27.6 (t, C3″), 27.8 (t, C2″), 29.1 (t, C4), 43.4 (t, C3), 52.2 (d, C1), 68.7 (d, C6″), 79.9 (s, C alkyne), 84.9 (s, C alkyne, C5″), 117.0 (d, C2′), 119.9 (d, C4′), 126.5 (d, C7), 127.3 (d, C6), 127.6 (d, C5), 129.2 (d, C8), 129.4 (d, C3′), 134.4 (s, C4a), 136.3 (s, C8a), 150.0 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 314.1903, found 314.1900.
1-(Cyclopropylethynyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (13d, C20H19N)
It was prepared according to General Procedure A (42%, 23 mg, 0.08 mmol) and B (78%, 86 mg, 0.32 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.55 (PE:EtOAc = 20:1); NMR data were in agreement with the literature [36].
1-(5-Chloropent-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (13e, C20H20ClN)
It was prepared according to General Procedure A (77%, 46 mg, 0.15 mmol) and B (95%, 118 mg, 0.38 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.45 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 1.83 (qui, 3
J = 6.5 Hz, 2H, H2″), 2.31 (dt, 3
J = 6.7 Hz, 4
J = 2.1 Hz, 2H, H3″), 2.87–3.23 (m, 2H, H4), 3.38–3.79 (m, 4H, H3, H2″) 5.46 (s, 1H, H1), 6.9 (dt, 3
J = 7.2 Hz, 4
J = 1.0 Hz, 1H, H4′), 7.08 (dd, 3
J = 8.7 Hz, 4
J = 1.0 Hz, 2H, H2′), 7.16-7.40 (m, 6H, H5–H8, H3′) ppm; 13C NMR (50 MHz, CDCl3): δ = 16.4 (t, C3″), 29.1 (t, C4), 31.5 (t, C2″), 43.2 (t, C1″), 43.7 (t, C3), 52.2 (d, C1), 80.5 (s, CA1), 83.2 (s, CA2), 116.9 (d, C2′), 119.8 (d, C4′), 126.4 (d, C7), 127.3 (d, C6), 127.5 (d, C5), 129.1 (d, C8), 129.3 (d, C3′), 134.3 (s, C8a), 135.9 (s, C4a), 149.9 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 310.1357, found 310.1347.
2-Phenyl-1-(thiophen-3-ylethynyl)-1,2,3,4-tetrahydroisoquinoline (13f, C21H17NS)
It was prepared according to General Procedure A (57%, 36 mg, 0.11 mmol) and B (71%, 90 mg, 0.28 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.49 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 2.92–3.28 (m, 2H, H4), 3.55–3.87 (m, 2H, H3), 5.66 (s, 1H, H1), 6.84–7.48 (m, 12H, H5-H8, H2′-H4′, H2″, H3″, H4″) ppm; 13C NMR (50 MHz, CDCl3): δ = 29.2 (t, C4), 43.7 (t, C3), 52.5 (d, C1), 80.11 (s, C alkyne), 88.42 (s, C alkyne), 116.9 (d, C2′), 119.9 (d, C4′), 122.3 (d, C2″), 125.3 (s, C1″), 126.6 (d, C7), 127.5 (d, C6), 127.7 (d, C5), 128.9 (d, C3″), 129.2 (d, C8), 129.4 (d, C3′), 130.3 (d, C4″), 134.7 (s, C4a), 135.6 (s, C8a), 149.8 (d, C4′) ppm; HR-MS: m/z calculated [M+H]+ 316.1154, found 316.1143.
1-(2-Phenylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14a)
It was prepared according to General Procedure A (42%, 29 mg, 0.08 mmol). The product was isolated by column chromatography (PE/DCM) as a light yellow oil. R
f = 0.30 (PE:EtOAc = 20:1); NMR data were in agreement with the literature [21].
1-(Hept-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14b, C23H27NO)
It was prepared according to General Procedure A (75%, 50 mg, 0.15 mmol). The product was isolated by preparative TLC (CHCl3) as an orange oil. R
f = 0.31 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 0.83 (t, 3
J = 6.4 Hz, 3
J = 6.4 Hz, 3H, H5″), 1.11–1.45 (m, CH2, 6H, H2″–H4″), 2.07(dt, 3
J = 6.8 Hz, 3
J = 6.9 Hz, 4
J = 1.9 Hz, 2H, H1″), 2.87 (td, 3
J = 16.3 Hz, 4
J = 3.5 Hz, 4
J = 3.5 Hz, 1H, H4), 3.09 (ddd, 3
J = 16.5 Hz, 4
J = 9.7 Hz, 4
J = 6.8 Hz, 1H, H4), 3.45–3.58 (m, 2H, H3), 3.77 (s, 3H, OCH3), 5.28 (s, 1H, H1), 6.86 (d, 3
J = 9.1 Hz, 2H, H3′), 7.04 (d, 3
J = 9.1 Hz, 2H, H2′), 7.10–7.30 (m, 4H, H5–H8) ppm; 13C NMR (50 MHz, APT, CDCl3): δ = 14.0 (q, C5″), 18.7 (t, C1″), 22.2 (t, C2″), 28.4 (t, C4″), 29.0 (t, C4), 30.9 (t, C3″), 44.0 (t, C3), 53.8 (q, OCH3), 55.5 (d, C1), 78.9 (s, C alkyne), 86.0 (s, C alkyne), 114.3 (d, C2′), 120.0 (d, C3′), 126.0 (d, C7), 126.9 (d, C6), 127.4 (d, C5), 129.0 (d, C8), 133.8 (s, C4a), 136.3 (s, C8a), 144.3 (s, C1′), 154.0 (s, C4′) ppm; HR-MS: m/z calculated [M+H]+ 334.2165, found 334.2162.
1-(Oct-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14c)
It was prepared according to General Procedure A (61%, 42 mg, 0.12 mmol). The product was isolated by preparative TLC (CHCl3) as a light yellow oil. R
f = 0.35 (PE:EtOAc = 20:1); NMR data were in agreement with the literature [21].
1-(Octa-1,7-diyn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14d, C24H25NO)
Prepared according to General Procedure A (25%, 17 mg, 0.05 mmol). The product was isolated by preparative TLC (CHCl3) as a light yellow oil. R
f = 0.30 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 1.48–1.57 (m, 4H, Alkyl-CH2), 1.99–2.02 (m, 1H, alkyne-CH), 2.13–2.29 (m, 4H, alkyl-CH2), 2.88–3.30 (m, 2H, TIQ-CH2), 3.52–3.65 (m, 2H, TIQ-CH2), 3.88 (s, 3H, OCH3), 5.38 (s, 1H, TIQ-CH), 6.91–7.40 (m, 8H, Ar–CH) ppm; 13C NMR (50 MHz, CDCl3): δ = 18.2 (t, C4″), 18.6 (t, C1″), 27.6 (t, C3″), 27.9 (t, C2″), 29.3 (t, C4), 44.3 (t, C3), 54.1 (q, OCH3), 55.9 (d, C1), 56.3 (OCH3), 68.7 (C1), 79.7 (s, CA1), 84.6 (d, C6″), 85.5 (s, CA2), 94.8 (s, C5″), 114.6 (d, C2′), 118.4, 120.3 (d, C3′), 126.3 (d, C7), 127.2 (d, C6), 127.7 (d, C5), 129.3 (d, C8), 132.6, 134.1 (s, C4a), 136.4 (s, C8a), 144.6 (s, C1′), 154.3 (s, C4′) ppm; HR-MS: m/z calculated [M+H]+ 344.2009, found 344.2006.
1-(Cyclopropylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14e, C21H21NO)
It was prepared according to General Procedure A (93%, 56 mg, 0.19 mmol). The product was isolated by preparative TLC (CHCl3) as a yellow oil. R
f = 0.31 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 0.49–0.76 (m, 4H, H2″), 1.09–1.26 (m, 1H, C1″), 2.84–3.23 (m, 2H, H4), 3.45–3.68 (m, 2H, H3), 3.83 (s, 3H, OCH3), 5.33 (s, 1H, H1), 6.91 (d, 3
J = 9.1 Hz, 2H, H3′), 7.08 (d, 3
J = 9.1 Hz, 2H, H2′), 7.14–7.35 (m, 4H, H5–H8) ppm; 13C NMR (50 MHz, CDCl3): δ = 0.0 (d, C1″), 8.6 (t, C2″), 29.2 (t, C4), 44.3 (t, C3), 54.0 (q, OCH3), 55.9 (d, C1), 74.3 (s, C alkyne), 89.3 (s, C alkyne), 114.5 (d, C2′), 120.3 (d, C3′), 126.3 (d, C7), 127.2 (d, C6), 127.7 (d, C5), 129.3 (d, C8), 134.1 (s, C4a), 136.4 (s, C8a), 144.5 (s, C1′), 154.3 (s, C4′) ppm; HR-MS: m/z calculated [M+H]+ 304.1696, found 304.1694.
1-(5-Chloropent-1-yn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (14f, C20H20ClN)
It was prepared according to General Procedure A (52%, 32 mg, 0.10 mmol). The product was isolated by preparative TLC (CHCl3) as a light yellow oil. R
f = 0.28 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 1.72–1.88 (m, 2H, H2″), 2.21–2.35 (m, 2H, H3″), 2.81–3.23 (m, 2H, H4), 3.34–3.59 (m, 4H, H3, H1″), 3.80 (s, 3H, OCH3), 5.32 (s, 1H, H1), 6.89 (d, 3
J = 9.1 Hz, 2H, H3′), 7.05 (d, 3
J = 9.1 Hz, 2H, H2′), 7.12–7.34 (m, 4H, H5–H8) ppm; 13C NMR (50 MHz, CDCl3): δ = 16.5 (t, C3″), 29.3 (t, C4), 31.7 (t, C2″), 43.8 (t, C1″), 44.3 (t, C3), 54.3 (q, OCH3), 55.9 (d, C1), 77.8 (s, C alkyne), 80.4 (s, C alkyne), 114.7 (d, C2′), 120.4 (d, C3′), 126.4 (d, C7), 127.3 (d, C6), 127.7 (d, C5), 129.3 (d, C8), 134.1 (s, C4a), 136.0 (s, C8a), 154.6 (s, C4′) ppm; HR-MS: m/z calculated [M+H]+ 340.1463, found 340.1456.
1-(Hept-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline (15b, C23H27N)
It was prepared according to General Procedure A (30%, 19 mg, 0.06 mmol). The product was isolated by preparative TLC (CHCl3) as a light yellow oil. R
f = 0.65 (PE:CHCl3 = 3:2); 1H NMR (200 MHz, CDCl3): δ = 0.92 (t, 3H, H5″), 1.29–1.62 (m, 6H, H2″–H4″), 2.17–2.30 (m, 2H, H1″), 2.70–3.08 (m, 4H, H4, H3), 3.86 (dt, 3
J = 17 Hz, 4
J = 7.8 Hz, 2H, Ph-CH2), 4.56 (s, 1H, H1), 7.05–7.50 (m, 9H, H5–H8, H2′–H4′) ppm; 13C NMR (50 MHz, CDCl3): δ = 14.2 (q, C5″), 18.9 (t, C1″), 22.3 (t, C4″), 28.8 (t, C2″), 29.1 (t, C4), 31.2 (t, C3″), 45.7 (t, C3), 54.2 (t, Ph-CH2), 59.6 (d, C1), 78.0 (s, C alkyne), 87.3 (s, C alkyne), 125.8 (d, C7), 126.8 (d, C4′), 127.2 (d, C6), 127.8 (d, C5), 128.4 (d, C3′), 129.0 (d, C8), 129.4 (d, C2′), 133.9 (s, C4a), 136.4 (s, C8a), 138.6 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 318.2216, found 318.2206.
1-(Oct-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline (15c)
It was prepared according to General Procedure A (40%, 27 mg, 0.08 mmol). The product was isolated by preparative TLC (CHCl3) as a yellow oil. R
f = 0.62 (PE:CHCl3 = 3:2); NMR data were in agreement with the literature [37].
1-(Cyclopropylethynyl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline (15e, C21H21N)
It was prepared according to General Procedure A (53%, 30 mg, 0.11 mmol). The product was isolated by preparative TLC (CHCl3) as a light orange oil. R
f = 0.45 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 0.60–0.88 (m, 4H, H2″), 1.19–1.31 (m, 1H, H1″), 2.62–3.09 (m, 4H, H4, H3), 3.68–3.96 (m, 2H, Ph-CH2), 4.54 (s, 1H, H1), 7.01–7.56 (m, 9H, H5–H8, H2′–H4′) ppm; 13C NMR (50 MHz, CDCl3): δ = 0.0 (d, C1″), 8.8 (t, C2″), 29.3 (t, C4), 45.9 (t, C3), 54.4 (t, Ph-CH2), 59.7 (d, C1), 73.4 (s, C alkyne), 90.6 (s, C alkyne), 126.0 (d, C7), 127.0 (d, C4′), 127.40 (d, C6), 128.0 (d, C5), 128.6 (d, C3′), 129.2 (d, C8), 129.6 (d, C2′), 134.2 (s, C4a), 136.4 (s, C8a), 138.8 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 288.1747, found 288.1738.
1-(5-Chloropent-1-yn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline (15f, C21H22ClN)
It was prepared according to General Procedure A (48%, 31 mg, 0.10 mmol). The product was isolated by preparative TLC (CHCl3) as a light yellow oil. R
f = 0.4 (PE:EtOAc = 20:1); 1H NMR (200 MHz, CDCl3): δ = 1.98 (qui, 3
J = 6.6 Hz, 2H, H2″), 2.46 (dt, 3
J = 6.8 Hz, 4
J = 2.0 Hz, 2H, H3″), 2.68–2.86 (m, 2H, H4), 2.88–3.01 (m, 2H, H3), 3.67 (t, 3
J = 6.4 Hz, 2H, H1″), 3.80 (d, 3
J = 13.2 Hz, 1H, Ph-CH2), 3.90 (d, 3
J = 13.2 Hz, 1H, Ph-CH2), 4.57 (s, 1H, H1), 7.05–7.49 (m, 9H, H5–H8, H2′–H4′) ppm; 13C NMR (50 MHz, CDCl3): δ = 16.5 (t, C3″), 31.8 (t, C2″), 43.9 (t, C1″), 45.8 (t, C3), 54.2 (t, Ph-CH2), 59.7 (d, C1), 79.3 (s, C alkyne), 85.2 (s, C alkyne), 125.9 (d, C7), 127.0 (d, C4′), 127.3 (d, C6), 127.8 (d, C5), 128.5 (d, C3′), 129.2 (d, C8), 129.4 (d, C2′), 134.1 (s, C4a), 136.2 (s, C8a), 138.5 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 324.1514, found 324.1504.
1-Ethynyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (17, C17H15N)
It was prepared according to General Procedure C (80%, 75 mg, 0.32 mmol). The product was purified via preparative TLC (PE:CHCl3 = 3:1) as a colorless oil. R
f = 0.70 (CHCl3); 1H NMR (200 MHz, CDCl3): δ = 2.33 (d, 1H, HA2), 3.00 (m, 2H, H4), 3.59 (m, 2H, H3), 5.48 (s, 1H, H1), 6.91 (t, 3
J = 7.2 Hz, 1H, H4′), 7.03–7.42 (m, 8H, H5-H8, H2′, H3′) ppm; 13C NMR (50 MHz, CDCl3): δ = 29.13 (t, C4), 43.42 (t, C3), 51.85 (d, C1), 73.07 (d, C alkyne), 83.18 (s, C alkyne), 116.87 (d, C2′), 120.13 (d, C4′), 126.66 (d, C7), 127.56 (d, C6), 127.73 (d, C5), 129.31 (d, C8), 129.51 (d, C3′), 134.59 (s, C4a), 135.16 (s, C8a), 149.61 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 234.1277, found 234.1271.
1-(Propyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (18, C18H17N)
It was prepared according to General Procedure C (32%, 32 mg, 0.13 mmol). The product was purified via preparative TLC (PE:CHCl3 = 3:1) as a light yellow oil. R
f = 0.18 (PE:CHCl3 = 4:1); 1H NMR (200 MHz, DMSO-d
6
): δ = 1.77 (s, 3H, H1″), 2.90–3.22 (m, 2H, H4), 3.52–3.75 (m, 2H, H3), 5.42 (s, 1H, H1), 6.79–7.50 (m, 9H, H5–H8, H2′–H4′) ppm; 13C NMR (50 MHz, DMSO-d
6
): δ = 2.8 (q, C1″), 27.6 (t, C4), 41.6 (t, C3), 49.7 (d, C1), 78.4 (s, C alkyne), 79.7 (s, Calkyne), 115.3 (d, C2′), 118.2 (d, C4′), 125.5 (d, C7), 126.5 (d, C6), 126.9 (d, C5), 128.2 (d, C8), 128.5 (d, C3′), 133.4 (s, C4a), 135.4 (s, C8a), 148.5 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 248.1434, found 248.1422.
1-(Butyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (19, C19H19N)
It was prepared according to General Procedure C (47%, 49 mg, 0.19 mmol). The product was purified via preparative TLC (PE:CHCl3 = 3:1) as an orange oil. R
f = 0.22 (PE:CHCl3 = 4:1); 1H NMR (200 MHz, CDCl3): δ = 1.10 (t, 3
J = 7.5 Hz, 3H, H2″), 2.91 (dq, 3
J = 7.4 Hz, 4
J = 1.8 Hz, 2H, H1″), 2.92–3.28 (m, 2H, H4), 3.60–3.86 (m, 2H, H3), 5.48 (s, 1H, H1), 6.94 (t, 3
J = 7.2 Hz, 1H, H4′), 7.09–7.44 (m, 8H) ppm; 13C NMR (50 MHz, CDCl3): δ = 12.81 (q, C2″), 14.29 (t, C1″), 29.13 (t, C4), 43.52 (t, C3), 51.94 (d, C1), 78.71 (s, C alkyne), 86.86 (s, C alkyne), 116.76 (d, C2′), 119.57 (d, C4′), 126.46 (d, C7), 127.29 (d, C6), 127.60 (d, C5), 129.15 (d, C8), 129.36 (d, C3′), 134.52 (s, C4a), 136.54 (s, C8a), 149.88 (s, C1′) ppm; HR-MS: m/z calculated [M+H]+ 262.1590, found 262.1584.
1-(Pentyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (20)
It was prepared according to General Procedure C (95%, 105 mg, 0.38 mmol). The product was purified via preparative TLC (PE:CHCl3 = 3:1) as an orange oil. R
f = 0.25 (PE:CHCl3 = 4:1); NMR data were in agreement with the literature [38].