supplementary material visible light promoted photoredox c
TRANSCRIPT
Supplementary Material
Visible Light Promoted Photoredox C(sp3)–H Bond Functionalization of Tetrahydroisoquinolines in Flow
Ana Filipović, Zdravko Džambaski, Dana Vasiljević Radović, Bojan P. Bondžić* University of Belgrade-Institute of Chemistry, Technology and Metallurgy Njegoševa 12, 11000 Belgrade, Republic of Serbia E-mail: [email protected]
General Remarks:
All reactions were monitored by thin-layer chromatography using Merck 60 F254 precoated
silica gel plates (0.25 mm thickness). Preparative thin layer chromatography was performed
using Merck 60 F254 silica gel purchased from Merck KGA. Column chromatography was
carried out on silica gel (12-26, ICN Biomedicals) using petrol ether/ethyl acetate as eluents.
1H-NMR and 13C-NMR spectra were measured on a Bruker Ultrashield Advance III
spectrometer (1H at 500 MHz, 13C at 125 MHz) and Varian 400 sprectrometer (1H at 400
MHz, 13C at 100 MHz) using CDCl3 as solvent with TMS as internal standard. Chemical
shifts (δ) are given in parts per million (ppm) and coupling constants are given in Hertz
(Hz).The proton spectra are reported as follows δ/ppm (multiplicity, coupling constant J/Hz,
number of protons). High-resolution mass spectral analyses (HRMS) were carried out using
Bruker ESI-TOF MS. IR spectra were measured on a PerkineElmer FT-IR 1725X
spectrophotometer using ATR technique. The peak intensities are defined as very strong (vs),
strong (s), middle (m) or weak (w).
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2021
For PDMS microreactor fabrication we used SYLGARD silicone elastomer kit 184 obtained by Dow Corning Corporation. This is a two-part liquid component kit consisting of base and curing agents. Microchannels are designed with 3-D printer Wanhao Duplicator i3 Mini using transparent ABS (1,75mm) as a filament (Fig.S1.a). SYLGARD Components are well mixed 10 minutes in weight mix ratio 10:1 (base: curing agent). During mixing, air bubbles are formed, which were degassed under a vacuum. One part of PDMS was transferred into a Petri dish and heated in the oven at 60 ºC for 20-30 min (Fig.S1.b). ABS printed filament was placed over baked PDMS. Then, the remaining amount of PDMS was poured out over ABS filament (1 mm layer thickness) and left for 48h at room temperature (Fig.S1.c). The PDMS with embedded ABS filament was then removed from a Petri dish and baked for about 10 minutes at 60 ºC (Fig.S1.d). To enable free entrance and exit from microreactor, one side of PDMS was cut (Fig.S1.e). The removal of ABS filament from PDMS was achieved by placing the whole system in acetone overnight. The formed microchannels were cleaned from ABS with a syringe and acetone. Finally, the obtained microreactor was left in the oven at 60 ºC for 24h to remove acetone completely. Reactors with internal volume of 500 µL are obtained. Microreactor in operation (Figure S2).
a)
b)
c)
d)
e)
Figure S1. PDMS microreactor fabrication
Figure S2. PDMS microreactor in operation. Air bubbles appearing in the microchanel due to the porosity of PDMS, change of colour is evident from light yellow to dark orange as
reaction progresses
For fabrication of FEP reactor the FEP tubing is wrapped in figure eights around glass tube so that a total of 100 cm (corresponding to 450 µL total volume) is used. The tubing is secured in place by 2 plastic joint clips. The coiled tubing is then placed approximately 2 cm from the LED stripes placed inside metal housing. An aluminum mirror is then placed above the coiled tubing to close the metal housing. At the bottom of the housing cooling fan is placed in order to maintain desired room temperature. The photoreactor tubing is connected to the syringe pump by means of a conical adapter (IDEX Health and Science, Part # P-797) which contains the appropriate female nut, ferrule and washer. Figure S3 depicts the assembled reactor.
Figure S3. Setup of FEP tube microreactor including cooling fan, led stripes, mirror top and metal housing
For fabrication of silicone/glass microreactor photolithography was used along with wet-etching of pyrex glass and anodic bonding technique. A close up photograph of the assembled photoreactor is shown in Figure S4.
Figure S4. Glass/silicon microreactor Vtotal= 25μl
Table S1. Optimization of the photoredox THIQ oxidation/Mannich addition in batch
N
O
Solvent
Ru cat. x mol%Organo catalyst 10 mol%+
N
OPh Ph
5 eq.1
NH
COOHN
NH
CH3
CH3
CH3
Ph
ON
NH
CH3
Ph
O
CH3
CH3CH3
L-Proline McMillan I gen. McMillan II gen.
*HCl
Entrya Solvent OrganoCatalyst (x mol%)
Photocatalyst (x mol%)
CFL Lamp
Time (h)
Yield (%)b Prec.c
1 CH3CN L-Proline (30mol%)
[Ru(bpy)3]Cl2 (1 mol%) 15 W 24 67 Y
2 CH3CN L-Proline (30mol%)
[Ru(bpy)3]Cl2 (1 mol%) 8W 24 71 Y
3 CH3CN L-Proline (10mol%)
[Ru(bpy)3]Cl2 (1 mol%) 8W 24 73 Y
4 CH3CN / [Ru(bpy)3]Cl2 (1 mol%) 8W 24 / N
5 MeOH L-Proline (10mol%)
[Ru(bpy)3]Cl2 (1 mol%) 8W 24 85 N
6 MeOH McMillan I gen.
(10mol%) [Ru(bpy)3]Cl2
(1 mol%) 8W 24 6 N
7 MeOH McMillan II gen. (10mol%)
[Ru(bpy)3]Cl2 (1 mol%) 8W 24 15 N
8 MeOH L-Proline (10mol%)
[Ru(bpz)3][PF6]2 (1 mol%) 8W 24 57 Y
9 MeOH L-Proline (10mol%)
Eosin Y (2 mol%) 8W 24 64 N
10d MeOH L-Proline (10mol%)
[Ru(bpy)3]Cl2 (1 mol%) 8W 86 N
a Reaction conditions : Tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru cat. (0.0025 mmol, 1 mol%) L-Proline (0.075 mmol, 0.3 equiv.) and acetone (10 equiv.) were added to solvent (2 mL) and irradiated with designated CFL lamp and stirred for designated period of time; b Isolated yield after column chromatography; c “Y”: Precipitation observed, “N”: no precipitation observed, all reactants are soluble in designated solvent; d1 equivalent of methyl viologen as terminal oxidant was added.
Table S2. Optimization of the photoredox THIQ oxidation/alkynilation reaction in flow and comparison to batch conditions
With 2h residence time for oxidation reaction at concentration of 0.25M and taking into account total internal volume of PDMS reactor of 0.5ml (flow rate 0.25 ml/h), total output is calculated to be 1.5 mmol of starting compound per day per reactor.
General procedure I, THIQ oxidation/Mannich reaction in flow Tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru(bpy)3Cl2*6H2O (0.0025 mmol, 1 mol%),
L-Proline (0.0025 mmol, 0.1 equiv.) and ketone (5-10 equiv.) were added to MeOH (1 mL)
and pumped through microfluidic device by means of syringe pump. System is irradiated with
CFL lamp, residence time depends on the substrate applied (2h or 6h depending on substrate).
Upon completion of reaction, excess of solvent was evaporated under reduced pressure on the
vacuum evaporator. Residue was submitted for 1H NMR analysis. Purification was performed
using SiO2 column chromatography with petrol ether/ethyl acetate as an eluents.
General procedure II, THIQ oxidation/Strecker reaction in flow Tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru(bpy)3Cl2*6H2O (0.0025 mmol, 1 mol%),
TMSCN (0.3 mmol, 1.2 equiv) were added to acetonitrile (1 mL) and pumped through
microfluidic device by means of syringe pump. System is irradiated with 8w CFL lamp,
residence time of 2h was applied. Upon completion of reaction, excess of solvent and reagents
was evaporated under reduced pressure on the vacuum evaporator. Residue was submitted for
NPh phenyl acetylene 5 equiv. CH
2Cl2
R
R
Ru cat.
(1mol%)CH3CN
Lightsourcetr = 2h
NPG
R
RN
PG
R
R
Ph
Copper source10 mol%
4a-d
at the outset or in theFLASK
Entry Reactor type Copper source Photosensitizer Retention time
(h) Light source Yield (%)
1 batch CuOTf·½C6H6 [Ru(bpy)3]Cl2 24h 8W 58
2 PDMS CuOTf·½C6H6 [Ru(bpy)3]Cl2 2h 8W 44 3 PDMS (MeCN)4CuPF6 [Ru(bpy)3]Cl2 2h 8W 40 4 PDMS (MeCN)4CuPF6 [Ru(bpz)3](PF6)2 2h 8W 31 5 PDMS CuOTf·½C6H6 [Ru(bpy)3]Cl2 2h White LED 22 6 PDMS CuOTf•½C6H6 [Ru(bpy)3]Cl2 2h 26W 20 7 PDMS+flask CuOTf·½C6H6 [Ru(bpy)3]Cl2 2h+18 h 8W 99
1H NMR analysis. Purification was performed using SiO2 column chromatography with
petrol ether/ethyl acetate as an eluents.
General procedure III, THIQ oxidation/alkynilation reaction in flow Tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru(bpy)3Cl2*6H2O (0.0025 mmol, 1 mol%),
were added to acetonitrile (1 mL) and pumped through microfluidic device by means of
syringe pump. System is irradiated with CFL lamp, residence time of 2h was applied.
Subsequently in recepient flask were added phenylacetylene (1.25 mmol, 5 equiv.), Cu
catalyst (0.025 mmol, 0.1 equiv) in CH2Cl2 and mixture was stirred at room temperature
overnight. Upon completion of reaction, excess of solvent was evaporated under reduced
pressure on the vacuum evaporator. Residue was submitted for 1H NMR analysis.
Purification was performed using SiO2 column chromatography with petrol ether/ethyl acetate
as an eluents.
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2a)
General procedure I was followed with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (52.3 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction
mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (58 mg, 88 %) as yellowish oil. Rf = 0.53 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.24 (t, 2H, ArH, J = 7.8 Hz), 7.12-7.15 (m, 4H, ArH), 6.93 (d, 2H, ArH, J = 8.5 Hz), 6.77 (t, 1H, J = 7.0 Hz), 5.39 (t, 1H, C(1)H, J = 6.2 Hz), 3.64 (dt, 1H, J = 5.5 Hz, 13.0 Hz), 3.52 (ddd, 1H, J = 4.4 Hz, 8.9 Hz, 12.5 Hz), 3.02-3.07 (m, 2H), 2.81 (dd, 2H, J = 7.2, 16.2 Hz), 2.06 (s, 3H, CH3); 13C NMR (CDCl3, 125.8 MHz): δ 207.2, 148.8, 138.3, 134.4, 129.3, 128.6, 126.83, 126.78, 126.3, 118.2, 114.8, 54.8, 50.2, 42.0, 31.1, 27.2. Spectroscopic data are in agreement with the published data.S1
1-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2b)
General procedure I was followed with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (52.3 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude
reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (62 mg, 89 %) as yellowish oil.
NN
OO
NN
EEtt
OO
Rf = 0.62 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.26 (t, 2H, ArH, J = 8.0 Hz), 7.13-7.18 (m, 4H, ArH), 6.95 (d, 2H, ArH, J = 8.5 Hz), 6.78 (t, 1H, ArH, J = 7.2 Hz), 5.43 (t, 1H, C(1)H, J = 6.2 Hz), 3.65 (dt, 1H, J = 5.2 Hz, 12.5 Hz), 3.54 (ddd, 1H, J = 4.5 Hz, 8.6 Hz, 12.9 Hz), 3.02-3.10 (m, 2H), 2.77-2.87 (m, 2H), 2.36 (dq, 1H, J = 7.3, 17.9 Hz), 2.26 (dq, 1H, J = 7.3, 17.9 Hz), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 209.9, 148.8, 138.3, 134.4, 129.3, 128.6, 126.8, 126.7, 126.2, 118.1, 114.6, 55.1, 48.9, 41.9, 37.2, 27.2, 7.5; Spectroscopic data are in agreement with the published data.S1
1-Phenyl-2-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)ethanone (2c) General procedure I was followed with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (52.3 mg, 0.25 mmol), acetophenone (300.4 mg, 0.292 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (68 mg, 83 %)
as yellowish oil. Rf = 0.61 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.87 (d, 2H, ArH, J = 7.5 Hz), 7.54 (t, 1H, ArH, J = 7.2 Hz), 7.42 (t, 2H, ArH, J = 7.8 Hz), 7.11-7.27 (m, 7H, ArH), 6.99 (d, 1H, ArH, J = 8.0 Hz), 6.77 (t, 1H, ArH, J = 7.2 Hz), 5.69 (dd, 1H, C(1)H, J = 5.5 Hz, 7.0 Hz), 3.63-3.71 (m, 2H) 3.60 (dd, 1H, J = 4.8 Hz, 16.8 Hz), 3.42 (dd, 1H, J = 7.2, 16.8 Hz), 3.10-3.16 (m, 1H), 2.95 (dt, 1H, J = 5.0 Hz, 16.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 198.6, 148.7, 138.5, 137.2, 134.5, 133.1, 129.3, 128.5, 128.1, 127.1, 126.8, 126.2, 117.9, 114.3, 55.0, 45.3, 42.1, 27.5; Spectroscopic data are in agreement with the published data.S2
1-(2-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2d) General procedure I was followed with 2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (69.3 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for
2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (67 mg, 95 %) as yellowish oil. Rf = 0.45 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.13-7.20 (m, 4H, ArH), 6.89-6.97 (m, 4H, ArH), 5.31 (t, 1H, C(1)H, J = 6.2 Hz), 3.59 (dt, 1H, J = 4.9, 12.5 Hz), 3.48-3.53 (m, 1H), 3.00-3.06 (m, 2H), 2.76-2.83 (m, 2H), 2.09 (s, 3H, CH3); 13C NMR (CDCl3, 125.8 MHz): δ 207.1, 156.4 (d, J = 237.6 Hz), 145.7, 138.0, 134.1, 128.8, 126.74, 126.72, 126.3, 117.1 (d, J = 7.6 Hz), 115.6 (d, J = 22.1 Hz), 55.5, 50.0, 42.6, 30.9, 26.7; Spectroscopic data are in agreement with the published data.S1
1-(2-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2e) General procedure I was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), ethyl
NN
OO FF
NN
OO
NN
EEtt
OO FF
methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (63 mg, 85%) as yellowish oil. Rf = 0.52 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.12-7.18 (m, 4H, ArH), 6.88-6.96 (m, 4H, ArH), 5.32 (t, 1H, C(1)H, J = 6.2 Hz), 3.58 (dt, 1H, J = 5.0 Hz, 13.0 Hz), 3.48-3.53 (m, 1H), 2.99-3.07 (m, 2H), 2.74-2.81 (m, 2H), 2.36 (dq, 1H, J = 7.2, 17.7 Hz), 2.28 (dq, 1H, J = 7.2, 17.7 Hz), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 209.8, 156.4 (d, J = 237.8 Hz), 145.7, 138.1, 134.2, 128.8, 126.8, 126.2, 116.9 (d, J = 7.2 Hz), 115.6 (d, J = 22.0 Hz), 55.8, 48.8, 42.5, 37.2, 26.8, 7.5; Spectroscopic data are in agreement with the published data.S3
2-(2-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-phenylethanone (2f) General procedure I was followed with 2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (69.3 mg, 0.25 mmol), acetophenone (300.4 mg, 0.292 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title
compound (72 mg, 84 %) as yellowish oil. Rf = 0.57 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.85 (d, 2H, ArH, J = 7.5 Hz), 7.53 (t, 1H, ArH, J = 7.5 Hz), 7.41 (t, 2H, ArH, J = 7.8 Hz), 7.21 (d, 1H, ArH, J = 7.5 Hz), 7.12-7.17 (m, 3H, ArH), 6.92 (d, 4H, ArH, J = 6.5 Hz), 5.57 (t, 1H, C(1)H, J = 6.2 Hz), 3.56-3.61 (m, 3H), 3.34 (dd, 1H, J = 6.5 Hz, 16.5 Hz), 3.06-3.12 (m, 1H), 2.87 (dt, 1H, J = 4.1 Hz, 16.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 198.6, 156.3 (d, J = 237.0 Hz), 145.6, 138.3, 137.2, 134.2, 133.1, 128.7, 128.5, 128.1, 127.0, 126.8, 126.3, 116.6 (d, J = 7.2 Hz), 115.6 (d, J = 22.1 Hz), 55.8, 45.1, 42.6, 27.1; Spectroscopic data are in agreement with the published data.S2 1-(2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2g)
General procedure I was followed with 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH/CH3CN=1/1 (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp,
for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (65 mg, 88 %) as yellowish oil. Rf = 0.65 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.17 – 7.03 (m, 4H), 6.89 (d, J = 9.1 Hz, 2H), 6.83-6.73 (m, 2H), 5.22 (t, J = 6.4 Hz, 1H), 3.73 (s, 3H), 3.58 – 3.49 (m, 1H), 3.49 – 3.36 (m, 1H), 3.07 – 2.88 (m, 2H), 2.81 – 2.64 (m, 2H), 2.04 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 207.3, 153.3, 143.6, 138.2, 134.3, 128.9, 126.8, 126.6, 126.1, 118.4, 114.6, 55.9, 55.6, 49.9, 42.9, 30.8, 26.7; Spectroscopic data are in agreement with the published data.S1
NN
OO FF
N
OOMe
1-(2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2h) General procedure I was followed with 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH/CH3CN=1/1 (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column
chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (61 mg, 79%) as yellowish oil. Rf = 0.62 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.18-7.08 (m, 4H), 6.91 (d, J = 9.1 Hz, 2H), 6.81 (d, J = 9.1 Hz, 2H), 5.27 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.60 – 3.51 (m, 1H), 3.51 – 3.39 (m, 1H), 3.07 – 2.92 (m, 2H), 2.74 (ddd, J = 15.8, 10.7, 5.2 Hz, 2H), 2.39 – 2.19 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 101 MHz): δ 210.0, 153.1, 143.6, 138.3, 134.3, 128.8, 126.8, 126.5, 126.1, 118.1, 114.6, 56.1, 55.6, 48.7, 42.6, 37.0, 26.8, 7.5. Spectroscopic data are in agreement with the published data.S4 2-(2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-phenylethanone (2i)
General procedure I was followed with 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.25 mmol), acetophenone (300.4 mg, 0.292 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH/CH3CN=1/1 (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column
chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (62.5 mg, 70 %) as yellowish solid. Rf = 0.66 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.82 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.21 – 7.05 (m, 4H), 6.92 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 9.1 Hz, 2H), 5.51 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.60-3.50 (m, 3H), 3.28 (dd, J = 16.3, 6.6 Hz, 1H), 3.13 – 3.01 (m, 1H), 2.82 (dt, J = 16.3, 4.1 Hz, 1H)č 13C NMR (CDCl3, 101 MHz): δ 198.7, 152.9, 143.6, 138.5, 137.3, 134.3, 132.9, 128.8, 128.4, 128.1, 127.0, 126.6, 126.1, 117.8, 114.6, 56.2, 55.6, 44.9, 42.7, 27.2. Spectroscopic data are in agreement with the published data.S5 1-(6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2j)
General procedure I was followed with 6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (67.3 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W
CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (77 mg, 95 %) as yellowish oil. Rf = 0.30 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.24 (t, 2H, ArH, J = 8.0 Hz), 6.93 (d, 2H, ArH, J = 8.0 Hz), 6.78 (t, 1H, ArH, J = 7.2 Hz), 6.69 (s, 1H, C(5)H or C(8)H), 6.61 (s, 1H, C(5)H or C(8)H), 5.30 (t, 1H, C(1)H, J = 6.2 Hz), 3.84 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.66 (dt, 1H, J = 5.0 Hz, 13.0 Hz), 3.49 (ddd, 1H, J = 4.5 Hz, 9.7 Hz, 12.8 Hz), 3.04 (dd, 1H, J = 5.5 Hz, 16.5 Hz), 2.97 (ddd, 1H, J = 5.8 Hz, 9.8 Hz, 15.8 Hz),
NN
OO
HH33CCOO
HH33CCOO
N
Et
OOMe
N
OOMe
2.82 (dd, 1H, J = 6.8 Hz, 12.2 Hz), 2.70 (dt, 1H, J = 4.2 Hz, 16.0 Hz), 2.08 (s, 3H, COCH3); 13C NMR (CDCl3, 125.8 MHz): δ 207.6, 148.9, 147.7, 147.3, 130.1, 129.2, 126.2, 118.4, 115.1, 111.3, 109.7, 55.9, 55.8, 54.5, 50.1, 41.9, 31.1, 26.5; Spectroscopic data are in agreement with the published data.S1
1-(6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2k) General procedure I was followed with 6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (67.3 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated
with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (75.5 mg, 89 %) as yellowish oil. Rf = 0.29 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.24 (t, 2H, ArH, J = 8.2 Hz), 6.95 (d, 2H, ArH, J = 8.5 Hz), 6.78 (t, 1H, ArH, J = 7.0 Hz), 6.66 (s, 1H, C(5)H or C(8)H), 6.61 (s, 1H, C(5)H or C(8)H), 5.32 (t, 1H, C(1)H, J = 6.5 Hz), 3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.66 (dt, 1H, J = 5.0 Hz, 13.0 Hz), 3.50 (ddd, 1H, J = 4.2 Hz, 9.2 Hz, 12.5 Hz), 3.02 (dd, 1H, J = 5.2 Hz, 15.8 Hz), 2.96-3.02 (m, 1H), 2.78 (dd, 1H, J = 7.0 Hz, 16.0 Hz), 2.72 (dt, 1H, J = 4.4 Hz, 16.0 Hz), 2.37 (dq, 1H, J = 7.4 Hz, 17.8 Hz), 2.28 (dq, 1H, J = 7.2 Hz, 17.8 Hz), 0.99 (t, 3H, COCH2CH3, J = 7.2 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 210.3, 148.9, 147.7, 147.3, 130.2, 129.3, 126.2, 118.2, 114.9, 111.3, 109.7, 55.9, 55.8, 54.9, 48.8, 41.8, 37.4, 26.6, 7.5; Spectroscopic data are in agreement with the published data.S4
2-(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-phenylethanone (2l) General procedure I was followed with 6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (67.3 mg, 0.25 mmol), acetophenone (300.4 mg, 0.292 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel
(petrolether/ethylacetate = 3/1) to give the title compound (71 mg, 73 %) as yellowish oil. Rf = 0.29 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.85 (d, 2H, ArH, J = 7.5 Hz), 7.52 (t, 1H, ArH, J = 7.5 Hz), 7.41 (t, 2H, ArH, J = 7.8 Hz), 7.24 (t, 2H, ArH, J = 7.5 Hz), 6.98 (d, 2H, ArH, J = 8.5 Hz), 6.76 (t, 1H, ArH, J = 7.2 Hz), 6.70 (s, 1H, C(5)H or C(8)H), 6.63 (s, 1H, C(5)H or C(8)H), 5.36 (dd, 1H, C(1)H, J = 5.0 Hz, 7.0 Hz), 3.84 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.68 (dt, 1H, J = 5.2 Hz, 12.5 Hz), 3.32-3.61 (m, 2H), 3.39 (dd, 1H, J = 7.5 Hz, 16.0 Hz), 3.03 (ddd, 1H, J = 5.8 Hz, 8.4 Hz, 15.6 Hz), 2.81 (dt, 1H, J = 4.4 Hz, 16.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 199.1, 148.9, 147.8, 147.3, 137.3, 133.1, 130.4, 129.3, 128.5, 128.1, 126.3, 118.1, 114.7, 111.3, 110.1, 55.9 (2C overlapped), 55.0, 45.1, 42.0, 27.0; Spectroscopic data are in agreement with the published data. S6
NN
EEtt
OO
HH33CCOO
HH33CCOO
NN
OO
HH33CCOO
HH33CCOO
1-(6,7-Dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2m) General procedure I was followed with 6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (70.8 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor
irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (70 mg, 83 %) as yellowish oil. Rf = 0.38 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.05 (d, 2H, ArH, J = 8.0 Hz), 6.86 (d, 2H, ArH, J = 8.0 Hz), 6.68 (s, 1H, C(5)H or C(8)H), 6.59 (s, 1H, C(5)H or C(8)H), 5.24 (t, 1H, C(1)H, J = 6.2 Hz), 3.842 (s, 3H, OCH3), 3.838 (s, 3H, OCH3), 3.64 (ddd, 1H, J = 4.0 Hz, 5.0 Hz, 12.9 Hz), 3.46 (ddd, 1H, J = 4.1 Hz, 10.1 Hz, 13.1 Hz), 3.02 (dd, 1H, J = 6.0 Hz, 16.0 Hz), 2.95 (ddd, 1H, J = 5.8 Hz, 10.2 Hz, 16.0 Hz), 2.79 (dd, 1H, J = 7.0 Hz, 16.0 Hz), 2.66 (brdt, 1H, J = 3.5 Hz, 16.0 Hz), 2.25 (s, 3H, ArCH3), 2.08 (s, 3H, COCH3); 13C NMR (CDCl3, 125.8 MHz): δ 207.7, 147.7, 147.3, 147.0, 130.1, 129.8, 128.1, 126.2, 116.0, 111.4, 109.7, 55.9, 55.8, 54.9, 49.9, 42.1, 31.0, 26.3, 20.3; Spectroscopic data are in agreement with the published data.S7
1-(6,7-Dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2n)
General procedure I was followed with 6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (70.8 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped
through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (66 mg, 75 %) as yellowish oil. Rf = 0.52 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.05 (d, 2H, ArH, J = 8.2 Hz), 6.86 (d, 2H, ArH, J = 8.2 Hz), 6.65 (s, 1H, C(5)H or C(8)H), 6.29 (s, 1H, C(5)H or C(8)H), 5.26 (t, 1H, C(1)H, J = 6.2 Hz), 3.84 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.63 (dt, 1H, J = 4.8 Hz, 12.0 Hz), 3.46 (ddd, 1H, J = 4.2 Hz, 10.2 Hz, 12.5 Hz), 2.94-3.01 (m, 2H), 2.75 (dd, 1H, J = 7.0 Hz, 15.5 Hz), 2.67 (brdt, 1H, J = 3.5 Hz, 16.0 Hz), 2.36 (dq, 1H, J = 7.3 Hz, 17.9 Hz), 2.28 (dq, partially hidden by COCH2CH3 signal, 1H, J = 7.3 Hz, 17.9 Hz), 0.98 (t, 3H, COCH2CH3, J = 7.5 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 210.4, 147.7, 147.3, 147.0, 130.2, 129.8, 127.9, 126.2, 115.8, 111.3, 109.6, 55.9, 55.8, 55.3, 48.6, 41.9, 37.3, 26.5, 20.3, 7.5; Spectroscopic data are in agreement with the published data.S8
1-(6,7-Dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2o)
General procedure I was followed with 6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (70.8 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped
NN
OO
HH33CCOO
HH33CCOO
MMee
NN
EEtt
OO
HH33CCOO
HH33CCOO
CCHH33
N
O
H3CO
H3CO
CH3
through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (71 mg, 71 %) as yellowish oil. Rf = 0.53 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.2 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 6.61 (s, 1H), 5.50 (t, J = 4 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 3.69 – 3.60 (m, 1H), 3.58 – 3.46 (m, 2H), 3.35 (dd, J = 16.1, 7.2 Hz, 1H), 3.02 (ddd, J = 15.6, 9.6, 5.7 Hz, 1H), 2.76 (dt, J = 16.0, 4.3 Hz, 1H), 2.23 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 199.2, 147.7, 147.2, 146.9, 137.4, 133.0, 130.4, 129.8, 128.5, 128.1, 127.8, 126.2, 115.5, 111.3, 109.9, 55.8, 55.4, 44.8, 42.1, 26.9, 20.3; IR (ATR): ν = 2987 (m), 2834 (m), 1679 (s), 1612 (m), 1514 (vs), 1449 (m), 1273 (s), 1249 (s), 1116 (m), 1021 (m); HRMS: m/z (ESI/TOF) calc for C26H27NO3 (M+) 401.1991, found 401.1990; 1-(2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2p)
General procedure I was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), acetone (145.2 mg, 0.185 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor
irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (72 mg, 84 %) as yellowish oil. Rf = 0.36 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 6.86-6.94 (m, 4H, ArH), 6.66 (s, 1H, C(5)H or C(8)H), 6.59 (s, 1H, C(5)H or C(8)H), 5.18 (t, 1H, C(1)H, J = 6.2 Hz), 3.838 (s, 3H, OCH3), 3.831 (s, 3H, OCH3), 3.58 (ddd, 1H, J = 3.8 Hz, 5.2 Hz, 12.8 Hz), 3.46 (ddd, 1H, J = 4.2 Hz, 10.5 Hz, 16.0 Hz), 3.01 (dd, 1H, J = 6.2 Hz, 16.2 Hz), 2.92 (ddd, 1H, J = 5.8 Hz, 10.2 Hz, 16.0 Hz), 2.78 (dd, 1H, J = 6.5 Hz, 16.0 Hz), 2.64 (dt, 1H, J = 7.2 Hz, 16.0 Hz), 2.09 (s, 3H, COCH3); 13C NMR (CDCl3, 125.8 MHz): δ 207.5, 156.6 (d, J = 238.0 Hz), 147.8, 147.5, 145.9, 129.8, 126.0, 117.5 (d, J = 7.4 Hz), 115.6 (d, J = 22.4 Hz), 111.4, 109.6, 55.9, 55.8, 55.3, 50.0, 42.6, 31.0, 26.0; Spectroscopic data are in agreement with the published data.S8
1-(2-(4-Fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one (2r)
General procedure I was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), ethyl methyl ketone (180.3 mg, 0.224 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped
through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (77 mg, 86 %) as yellowish oil. Rf = 0.34 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 6.87-6.94 (m, 4H, ArH), 6.62 (s, 1H, C(5)H or C(8)H), 6.59 (s, 1H, C(5)H or C(8)H), 5.20 (t, 1H, C(1)H, J = 6.5 Hz), 3.84 (s, 3H, OCH3), 3.82 (s, 3H,
NN
OO
HH33CCOO
HH33CCOO
FF
NN
EEtt
OO
HH33CCOO
HH33CCOO
FF
OCH3), 3.57 (ddd, 1H, J = 3.9 Hz, 5.4 Hz, 12.9 Hz), 3.43-3.49 (m, 1H), 2.99 (dd, 1H, J = 6.5 Hz, 16.0 Hz), 2.88-2.98 (m, 1H), 2.74 (dd, 1H, J = 6.5 Hz, 15.5 Hz), 2.66 (dt, 1H, J = 3.8 Hz, 16.0 Hz), 2.26-2.40 (m, 2H, COCH2CH3), 0.99 (t, 3H, COCH2CH3, J = 7.2 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 210.2, 156.5 (d, J = 238.1 Hz), 147.8, 147.4, 145.8, 129.9, 126.0, 117.25 (d, J = 7.4 Hz), 115.6 (d, J = 22.0 Hz), 111.4, 109.5, 55.9, 55.8, 55.6, 48.7, 42.4, 37.3, 26.2, 7.5; Spectroscopic data are in agreement with the published data.S8 2-(2-(4-Fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-phenylethanone (2s)
General procedure I was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), acetophenone (300.4 mg, 0.292 ml, 2.5 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), and L-proline (2.9 mg, 0.025 mmol) in MeOH (2 mL). The reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel
(petrolether/ethylacetate = 3/1) to give the title compound (74 mg, 73 %) as yellowish oil. Rf = 0.34 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.85 (d, 2H, ArH, J = 7.5 Hz), 7.53 (d, 1H, ArH, J = 7.5 Hz), 7.41 (t, 2H, ArH, J = 7.5 Hz), 6.92 (d, 4H, ArH, J = 6.5 Hz), 6.67 (s, 1H, C(5)H or C(8)H), 6.62 (s, 1H, C(5)H or C(8)H), 5.44 (t, 1H, C(1)H, J = 6.0 Hz), 3.84 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.52-3.63 (m, 3H), 3.33 (dd, 1H, J = 6.8 Hz, 16.2 Hz), 3.00 (ddd, 1H, J = 6.1 Hz, 9.6 Hz, 15.9 Hz), 2.74 (brd, 1H, J = 16.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 199.0, 156.4 (d, J = 237.5 Hz), 147.8, 147.4, 145.8, 137.3, 133.2, 130.1, 128.6, 128.1, 126.1, 117.1 (d, J = 7.3 Hz), 115.6 (d, J = 22.1 Hz), 111.4, 109.9, 55.9 (3C overlapped), 44.9, 42.6.3, 26.6; Spectroscopic data are in agreement with the published data.S8
2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3a) General procedure II was followed with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (52.3 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol) and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor
irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (56 mg, 95 %) as colourless solid. Rf = 0.44 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 500 MHz): δ 7.36 (t, 2H, ArH, J = 8.0 Hz), 7.22-7.32 (m, 4H, ArH), 7.08 (d, 2H, ArH, J = 8.0 Hz), 7.02 (t, 1H, ArH, J = 7.2 Hz), 5.51 (s, 1H, C(1)H), 3.76 (dddd, 1H, J = 1.0 Hz, 3.0 Hz, 6.0 Hz, 12.5 Hz), 3.47 (ddd, 1H, J = 3.9 Hz, 10.9 Hz, 12.1 Hz), 3.14 (ddd, 1H, J = 5.9 Hz, 10.6 Hz, 16.4 Hz), 2.95 (dt, 1H, J = 3.4 Hz, 16.5 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 148.3, 134.5, 129.5 (2C overlapped), 129.3, 128.7, 127.0, 126.8, 121.8, 117.7, 117.5, 53.1, 44.1, 28.4; Spectroscopic data are in agreement with the published data.S9
NN
OO
HH33CCOO
HH33CCOO
FF
NN
CCNN
2-(4-Fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3b) General procedure II was followed with 2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (69.3 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol), and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through
microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (56 mg, 89 %) as colourless solid. Rf = 0.38 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.21-7.31 (m, 4H, ArH), 7.02-7.08 (m, 4H, ArH), 5.38 (s, 1H, C(1)H), 3.61 (dddd, 1H, J = 1.0 Hz, 2.2 Hz, 6.2 Hz, 12.3 Hz), 3.44 (dt, 1H, J = 4.0 Hz, 11.8 Hz), 3.14 (ddd, 1H, J = 6.0 Hz, 10.8 Hz, 16.5 Hz), 2.93 (dt, 1H, J = 3.0 Hz, 16.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 158.6 (d, J = 242.2 Hz), 145.1, 134.2, 129.42, 129.36, 128.8, 127.0, 126.8, 120.4 (d, J = 7.9 Hz), 117.4, 116.2 (d, J = 22.4 Hz), 54.7, 44.7, 28.5; Spectroscopic data are in agreement with the published data.S10
2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3c) General procedure II was followed with 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol), and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with
8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (55 mg, 84 %) as colourless solid. Rf = 0.45 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.32 – 7.17 (m, 4H), 7.08 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 5.35 (s, 1H), 3.79 (s, 3H), 3.57 (dd, J = 12.2, 6.1 Hz, 1H), 3.43 (td, J = 11.7, 4.0 Hz, 1H), 3.15 (ddd, J = 17.1, 11.1, 6.3 Hz, 1H), 2.96 – 2.87 (m, 1H); 13C NMR (CDCl3, 125.8 MHz): δ 155.7, 142.6, 134.3, 129.7, 129.4, 128.6, 127.0, 126.7, 120.9, 117.6, 114.8, 55.5, 55.5, 44.9, 28.7; Spectroscopic data are in agreement with the published data.S11
2-(4-Fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3d) General procedure II was followed with 6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (67.3 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol), and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through
microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (73.5 mg, 100 %) as colourless solid. Rf = 0.45 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 400 MHz): δ = 7.39-7.34 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.07-7.02 (m, 1H), 6.70 (s, 1H), 6.67 (s, 1H), 5.46 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.82-3.77 (m, 1H), 3.48 (ddd, J = 3.5, 11, 12 Hz, 1H), 3.11 (ddd, J = 6.0, 11, 16 Hz, 1H), 2.88 (ddd, J = 3, 3.8, 16.4 Hz, 1H), ; 13C NMR (CDCl3, 101 MHz): δ = 149.4, 148.3, 148.0, 129.4, 126.7, 122.1, 121.0, 117.9, 117.7, 111.5, 109.2, 56.2, 55.9, 53.3, 44.3, 28.2; Spectroscopic data are in agreement with the published data.S12
NN
CCNN FF
N
CN
H3CO
H3CO
N
CNOMe
2-(4-Fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3e) General procedure II was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol), and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The
reaction was pumped through microflow reactor irradiated with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (71 mg, 91 %) as colourless solid. Rf = 0.44 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.05-7.06 (m, 4H, ArH), 6.72 (s, 1H, C(5)H or C(8)H), 6.68 (s, 1H, C(5)H or C(8)H), 5.33 (s, 1H, C(1)H), 3.882 (s, 3H, OCH3), 3.876 (s, 3H, OCH3), 3.61 (brdd, 1H, J = 5.5 Hz, 12.5 Hz), 3.41 (dt, 1H, J = 4.0 Hz, 11.8 Hz), 3.08 (ddd, 1H, J = 5.8 Hz, 10.8 Hz, 16.2 Hz), 2.83 (dt, 1H, J = 2.5 Hz, 15.0 Hz); 13C NMR (CDCl3, 125.8 MHz): δ 158.6 (d, J = 242.2 Hz), 149.4, 148.1, 145.1 (d, J = 2.1 Hz), 126.5, 120.9, 120.5 (d, J = 8.1 Hz), 117.6, 116.1 (d, J = 22.4 Hz), 111.5, 109.3, 56.0, 55.9, 54.5, 44.8, 28.1. Spectroscopic data are in agreement with the published data.S8
6,7-Dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (3f)
General procedure II was followed with 6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (70.8 mg, 0.25 mmol), trimethylsilyl cyanide (29.8 mg, 0.038 ml, 0.3 mmol), and Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated
with 8W CFL lamp, for 2 h. Crude reaction mixture was purified by column chromatography on silica gel (petrolether/ethylacetate = 3/1) to give the title compound (65.5 mg, 85 %) as colourless solid. Rf = 0.53 (Petrol Ether/EtOAc : 3/1); 1H NMR (CDCl3, 500 MHz): δ 7.16 (d, 2H, ArH, J = 8.5 Hz), 6.99 (d, 2H, ArH, J = 8.5 Hz), 6.73 (s, 1H, C(5)H or C(8)H), 6.67 (s, 1H, C(5)H or C(8)H), 5.38 (s, 1H, C(1)H), 3.88 (s, 6H, 2OCH3), 3.69 (brdd, 1H, J = 5.5 Hz, 12.5 Hz), 3.40 (td, 1H, J = 3.8 Hz, 10.9 Hz), 3.07 (ddd, 1H, J = 5.8 Hz, 11.0 Hz, 16.2 Hz), 2.82 (brdt, 1H, J = 2.2 Hz, 15.5 Hz), 2.31 (s, 3H, ArCH3); 13C NMR (CDCl3, 125.8 MHz): δ 149.3, 148.0, 146.3, 131.8, 130.0, 126.8, 121.2, 118.4, 117.8, 111.5, 109.3, 56.0, 55.9, 53.9, 44.4, 28.1, 20.5; Spectroscopic data are in agreement with the published data.S8
2-phenyl-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline (4a)
General procedure III was followed with 2-phenyl-1,2,3,4-tetrahydroisoquinoline (52.3 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp, for 2 h. Recipient flask contained CuOTf·½C6H6 (12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml CH2Cl2. The mixture was stirred overnight,
evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (76.5 mg, 99 %) as yellowish oil. Rf = 0.85 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.31–7.21 (m, 5 H), 7.17–7.09 (m, 6 H), 7.04 (dd, J = 8.4, 1 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1 H), 5.59 (s, 1 H), 3.66-
NN
CCNN
HH33CCOO
HH33CCOO
FF
NN
CCNN
HH33CCOO
HH33CCOO
MMee
N
Ph
3.58 (m, 2H), 3.08 (ddd, J = 16.0, 10.0, 6.0 Hz, 1 H), 2.90 (dt, J = 16.0, 4.0 Hz, 1 H); 13C NMR (CDCl3, 101 MHz): δ 149.4, 135.2, 134.2, 131.6, 128.9, 128.7, 127.9, 127.8, 127.3, 127.1, 126.1, 122.8, 119.5, 116.6, 88.6, 84.7, 52.3, 43.5, 29.0; Spectroscopic data are in agreement with the published data.S13 2-(4-fluorophenyl-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline (4b)
General procedure III was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp, for 2 h. Recipient flask contained CuOTf·½C6H6 (12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml
CH2Cl2. The mixture was stirred overnight, evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (72mg, 88 %) as yellowish oil. Rf = 0.80 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.42-7.35 (m, 1H), 7.33-7.22 (m, 8H), 7.12-7.05 (m, 2H), 7.05-6.98 (m, 2H), 5.55 (s, 1H), 3.65-3.60 (m, 2H), 3.22-3.14 (m, 1H), 2.96 (dt, J = 3.6, 16.3 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 157.6 (d, J = 240 Hz), 146.5, 135.1, 134.2, 131.8 (2C), 129.0, 128.1 (3C), 127.6, 127.4, 126.3, 123.0, 119.5 (d, J = 8 Hz, 2C), 115.6 (d, J = 22 Hz, 2C), 88.2, 85.5, 53.7, 44.1, 29.0; Spectroscopic data are in agreement with the published data.S14
2-(4-methoxyphenyl)-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline (4c)
General procedure III was followed with 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp, for 2 h. Recipient flask contained CuOTf·½C6H6 (12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml CH2Cl2.
The mixture was stirred overnight, evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (69mg, 82 %) as yellowish oil. Rf = 0.70 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.38-7.35 (m, 1H), 7.31-7.27 (m, 2H), 7.26 – 7.17 (m, 6H), 7.15 – 7.08 (m, 2H), 6.94 – 6.87 (m, 2H), 5.52 (s, 1H), 3.79 (s, 3H), 3.70 – 3.60 (m, 1H), 3.56 (ddd, J = 8.9, 6.1, 1.9 Hz, 1H), 3.15 (ddd, J = 16.7, 10.7, 6.2 Hz, 1H), 2.98 – 2.89 (m, 1H); 13C NMR (CDCl3, 101 MHz): δ 154.2, 144.1, 135.4, 134.0, 131.7, 129.0, 128.0, 127.9, 127.5, 127.1, 126.1, 123.1, 120.2, 114.4, 88.5, 85.5, 55.6, 54.4, 44.2, 29.0; Spectroscopic data are in agreement with the published data.S13
6,7-dimethoxy-2-phenyl-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline (4d)
General procedure III was followed with 6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (67.3 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp,
N
H3CO
H3CO
Ph
N
F
Ph
N
OMe
Ph
for 2 h. Recipient flask contained CuOTf·½C6H6 (12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml CH2Cl2. The mixture was stirred overnight, evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (78.5 mg, 85 %) as yellowish oil. Rf = 0.15 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.39–7.33 (m, 4 H), 7.28–7.26 (m, 2 H), 7.17 (d, J = 8 Hz, 2 H), 6.96 (t, J = 7.0 Hz, 1 H), 6.93 (s, 1 H), 6.72 (s, 1 H), 5.63 (s, 1 H), 3.98 (s, 3 H), 3.92 (s, 3 H), 3.88–3.79 (m, 1 H), 3.68 (m, 1 H), 3.10 (ddd, J = 6.0, 10.9, 16.0 Hz, 1 H), 2.92 (dt, J = 3, 16 Hz, 1 H); 13C NMR (CDCl3, 101 MHz): δ 149.8, 148.4, 147.6, 131.9, 129.4, 128.4, 128.1, 127.3, 126.6, 123.2, 119.8, 116.9, 111.4, 110.3, 88.9, 84.9, 56.2, 55.9, 52.3, 43.5, 28.6; Spectroscopic data are in agreement with the published data.S15
2-(4-fluorophenyl)-6,7-dimethoxy-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinoline (4e) General procedure III was followed with 2-(4-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (71.8 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp, for 2 h. Recipient flask contained CuOTf·½C6H6 (12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml CH2Cl2. The
mixture was stirred overnight, evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (78.5 mg, 80 %) as yellowish oil. Rf = 0.24 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.31 – 7.17 (m, 5H), 7.11 – 7.05 (m, 2H), 7.05 – 6.98 (m, 2H), 6.84 (s, 1H), 6.66 (s, 1H), 5.46 (s, 1H), 3.90 (s, 1H), 3.88 (s, 1H),3.62 – 3.56 (m, 2H), 3.11 – 3.02 (m, 1H), 2.84 (dt, J = 15.9, 3.2 Hz, 1H). 13C NMR (CDCl3, 101 MHz): δ 158.7, 156.8, 148.6, 147.9, 146.7, 131.9, 128.4, 127.2, 126.3, 123.1, 119.8, 119.7, 115.8, 115.6, 111.6, 110.4, 88.5, 85.5, 56.3, 56.1, 53.7, 44.3, 28.7; IR (ATR): ν = 2933 (w), 2833 (w),1611 (w), 1509 (vs), 1463 (m), 1247 (s), 1118 (s), 1027 (w),816 (w); HRMS (ESI) m/z calculated for C25H22FNO2
+ ([M+]) 387.1635, found 387.1631. 6,7-dimethoxy-1-(phenylethynyl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (4f)
General procedure III was followed with 6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (70.8 mg, 0.25 mmol), Ru(bpy)3Cl2 (1.9 mg, 0.0025 mmol), in CH3CN (1 mL). The reaction was pumped through microflow reactor irradiated with 11W CFL lamp, for 2 h. Recipient flask contained CuOTf·½C6H6
(12.6 mg, 0.025 mmol) and phenylacetylene (137 μl, 1.25 mmol) in 1 ml CH2Cl2. The mixture was stirred overnight, evaporated and purified by column chromatography on silica gel (petrolether/ethylacetate = 7/1) to give the title compound (86 mg, 90%) as yellowish oil. Rf = 0.29 (Petrol Ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.33-7.26 (m, 2H), 7.25-7.18 (m, 3H), 7.15-7.08 (m, 2H), 7.06-7.01 (m, 2H), 6.84 (s, 1H), 6.65 (s, 1H), 5.51 (s, 1H), 3.88 (d, J = 11 Hz, 6H), 3.73 – 3.56 (m, 2H), 3.06 (ddd, J = 16.6, 10.5, 6.4 Hz, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 148.2, 147.6, 147.5, 131.7, 129.6, 129.4, 128.0, 127.9, 127.3, 126.3, 123.1, 117.6, 111.4, 110.2, 88.7, 84.9, 56.1, 55.9, 52.7, 43.7, 28.4, 20.45; IR (ATR): ν = 3000 (m), 2917 (m), 2832 (m), 1612 (m), 1516 (vs),
N
H3CO
H3CO
Me
Ph
NN
PPhh
FF
MMeeOO
MMeeOO
1463 (s), 1407 (s), 1260 (s), 1248 (s), 1213 (s), 1117 (s); HRMS (ESI) m/z calculated for C26H25NO2
+ ([M+]) 383.1885, found 383.1878. REFERENCES S1 M. Rueping, C. Vila, R. M. Koenigs, K. Poscharny, D. C. Fabry, Chem. Commun. 2011, 47, 2360-2362. S2 G. Zhao, C. Yang, L. Guo, H. Sun, C. Chen, W. Xia, Chem. Commun. 2012, 48, 2337-2339. S3K. Alagiri, P. Devadig, K. R. Prabhu, Chem. Eur. J. 2012, 18, 5160-5164. S4 A. Sud, D. Sureshkumar, M. Klussmann, Chem. Commun. 2009, 3169-3171. S5Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan, C.-C. Guo, Chem. Comm. 2009, 8, 953-955. S6 J.-B. Yu, G. Peng, Z.-J. Jiang, Z.-K. Hong, W.-K. Su, Eur. J. Org. Chem. 2016, 5340-5344. S7 T. Zhang, W. Liang, Y. Huang, X. Li, Y. Liu, B. Yang, C. He, X. Zhou, J. Zhang, Chem. Commun. 2017, 53, 12536-12539. S8 Z. Džambaski, B. P. Bondžić, Org. Biomol. Chem., 2019, 17, 6420. S9 S.-I. Murahashi, T. Nakae, H. Terai, N. Komiya, J. Am. Chem. Soc., 2008, 130, 11005-11012. S10 M. Rueping, J. Zoller, D. C. Fabry, K. Poscharny, R. M. Koenigs, T. E. Weirich, J. Mayer, Chem. Eur. J., 2012, 18, 3478-3481. S11 S. Dhanasekaran, A. Suneja, V. Bisai, V. K. Singh, Org. Lett. 2016, 18, 634-637 S12 K. Alagiri, K. R. Prabhu, Org. Biomol. Chem 2012, 10, 835-842 S13 Z. Li, C.-J. Li, Org. Lett., 2004, 6, 4997. S14 X. Marset, J. M. Pérez, D. J. Ramón, Green Chem., 2016, 18, 826-833. S15 D. B. Freeman, L Furst, A. G. Condie, C. R. J. Stephenson, Org. Lett. 2012, 14, 94.
2a
2b
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-5000
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
55000
60000
65000
70000
75000
80000AF-1
2.95
2.02
2.05
1.04
1.04
1.00
0.97
2.03
4.01
2.10
2.02
2.75
2.75
2.76
2.78
2.79
2.79
2.97
2.98
2.99
3.00
3.01
3.02
3.45
3.46
3.47
3.48
3.49
3.50
3.51
3.57
3.59
3.60
3.61
5.34
5.35
5.37
6.71
6.73
6.74
6.88
6.90
7.07
7.08
7.09
7.09
7.11
7.11
7.12
7.12
7.18
7.19
7.19
7.20
7.21
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-10000
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
1E+05
1E+05AF2
3.02
2.02
2.06
2.12
1.05
1.06
1.00
1.00
2.08
4.11
2.22
0.98
0.99
1.01
2.25
2.27
2.29
2.34
2.35
2.78
2.80
2.81
3.02
3.03
3.05
3.07
3.55
3.55
3.56
3.57
3.63
3.64
3.65
3.67
5.42
5.43
5.44
6.76
6.78
6.79
6.95
6.96
7.13
7.15
7.15
7.17
7.24
7.26
7.27
2c
2d
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000AF3
1.03
1.10
1.03
3.17
1.00
1.05
2.26
3.48
3.59
2.26
1.13
1.97
2.94
2.95
2.96
2.97
2.98
3.11
3.12
3.13
3.14
3.15
3.16
3.17
3.40
3.41
3.43
3.45
3.58
3.59
3.61
3.62
3.64
3.64
3.65
3.66
3.67
3.68
3.69
3.70
5.68
5.69
5.70
5.71
6.78
6.99
7.01
7.13
7.14
7.14
7.15
7.18
7.18
7.25
7.26
7.28
7.41
7.43
7.44
7.53
7.54
7.87
7.88
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
24000
26000AF4
2.78
1.85
1.98
1.99
1.00
3.90
4.05
2.04
2.72
2.74
2.75
2.76
2.77
2.78
2.97
2.98
3.00
3.01
3.46
3.46
3.47
3.48
3.53
3.54
5.25
5.26
5.27
6.84
6.85
6.86
6.87
6.88
6.88
6.90
6.92
7.08
7.09
7.10
7.12
7.13
7.14
7.14
2e
2f
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
24000
26000
28000
30000
32000
34000
36000AF5
3.04
2.03
2.07
2.09
2.15
1.00
4.17
4.20
0.97
0.99
1.00
2.25
2.27
2.28
2.29
2.30
2.31
2.32
2.33
2.34
2.36
2.36
2.38
2.73
2.75
2.76
2.78
3.00
3.02
3.03
3.47
3.48
3.49
3.50
3.51
3.52
3.52
3.56
3.57
3.58
3.58
3.59
5.30
5.32
5.33
6.88
6.90
6.91
6.92
6.93
6.95
7.12
7.13
7.14
7.15
7.15
7.16
7.17
7.17
7.26
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
24000
26000
28000
30000
32000
34000
36000AF6
1.01
1.09
1.05
3.15
1.00
4.43
4.46
2.11
1.11
1.99
2.87
2.90
2.90
3.08
3.09
3.11
3.13
3.34
3.35
3.37
3.39
3.58
3.59
3.60
3.61
3.61
3.62
3.63
5.58
5.59
5.60
6.93
6.94
7.14
7.15
7.16
7.17
7.18
7.18
7.19
7.19
7.22
7.24
7.28
7.42
7.43
7.45
7.54
7.55
7.57
7.87
7.88
2g
2h
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
26001791_PROTON_01
2.60
1.97
2.06
1.09
1.01
2.82
1.00
1.81
1.78
3.65
2.04
2.69
2.72
2.73
2.74
2.76
2.77
2.95
2.97
2.98
2.99
3.01
3.40
3.41
3.43
3.44
3.45
3.46
3.47
3.51
3.52
3.52
3.53
3.54
3.55
3.57
3.73
5.21
5.22
5.24
6.78
6.80
6.81
6.88
6.90
7.08
7.09
7.10
7.13
7.15
7.24
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
20001789_PROTON_01
2.63
1.95
1.98
1.95
2.06
2.71
1.00
1.85
1.89
3.52
0.95
0.97
0.99
2.23
2.25
2.26
2.28
2.30
2.30
2.32
2.34
2.35
2.37
2.71
2.73
2.75
2.96
2.97
3.00
3.01
3.42
3.43
3.45
3.46
3.47
3.48
3.49
3.53
3.54
3.54
3.55
3.56
3.57
3.58
3.74
5.25
5.27
5.28
6.80
6.82
6.90
6.92
7.09
7.11
7.11
7.13
7.13
7.15
7.16
7.25
2i
2j
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
19001827_PROTON_01
1.06
1.10
1.05
2.85
2.84
1.00
1.90
1.90
4.05
1.85
1.00
1.85
2.79
2.80
2.81
2.83
2.84
2.85
3.02
3.04
3.06
3.08
3.10
3.26
3.27
3.30
3.31
3.52
3.52
3.53
3.54
3.55
3.56
3.57
3.57
3.71
5.50
5.51
5.53
6.77
6.79
6.90
6.93
7.10
7.11
7.12
7.14
7.17
7.19
7.36
7.38
7.40
7.48
7.50
7.51
7.81
7.82
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-5000
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
55000
60000
65000
70000AF7
3.02
0.99
1.04
2.08
1.01
1.05
6.12
1.00
1.00
1.02
1.02
2.16
2.15
2.09
2.69
2.73
2.80
2.82
2.84
2.85
2.98
3.03
3.04
3.06
3.07
3.47
3.48
3.49
3.50
3.51
3.52
3.53
3.65
3.66
3.67
3.67
3.68
3.69
3.84
3.85
3.90
5.30
5.31
5.33
6.62
6.70
6.79
6.80
6.94
6.95
7.23
7.25
7.26
2k
2l
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
24000
26000
28000BB-226
3.00
2.09
1.00
1.03
2.10
1.00
1.05
6.30
1.02
0.97
1.01
1.03
2.07
2.21
0.97
60.
990
1.00
52.
259
2.27
32.
280
2.28
82.
294
2.30
92.
323
2.33
22.
347
2.36
12.
367
2.37
62.
382
2.39
7
2.75
52.
769
2.78
72.
801
2.98
93.
000
3.01
0
3.47
63.
485
3.49
53.
502
3.51
03.
520
3.52
93.
639
3.64
93.
659
3.66
43.
675
3.68
43.
830
3.85
0
5.31
15.
324
5.33
7
6.61
46.
660
6.76
16.
775
6.78
96.
939
6.95
67.
229
7.24
57.
262
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900AF9
1.17
1.09
1.29
2.37
1.41
3.01
3.04
1.00
1.11
1.15
0.98
2.04
2.97
2.02
0.95
1.92
2.79
2.80
2.83
3.01
3.02
3.03
3.04
3.05
3.06
3.37
3.39
3.41
3.42
3.52
3.53
3.55
3.56
3.57
3.59
3.60
3.61
3.61
3.66
3.67
3.68
3.70
3.71
3.74
3.85
5.55
5.56
5.57
6.63
6.71
6.75
6.76
6.78
6.98
7.00
7.23
7.24
7.26
7.40
7.41
7.43
7.85
7.85
2m
2n
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-2000
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000
20000
21000
22000
23000
24000AF-15
2.95
3.09
0.99
1.02
2.05
0.99
0.99
6.20
1.00
0.95
1.05
2.02
2.03
2.09
2.25
2.65
2.68
2.77
2.79
2.81
2.82
2.96
3.00
3.01
3.03
3.46
3.47
3.48
3.63
3.64
3.65
3.84
3.85
5.23
5.24
5.26
6.60
6.69
6.85
6.87
7.04
7.06
7.26
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000AF-72P
3.09
3.46
1.99
1.10
1.02
2.05
1.06
1.10
6.24
1.00
2.13
2.03
2.08
0.97
0.98
1.00
2.25
2.26
2.28
2.28
2.30
2.31
2.33
2.34
2.35
2.73
2.74
2.76
2.77
2.97
2.98
3.00
3.46
3.46
3.47
3.48
3.61
3.62
3.63
3.64
3.65
3.83
3.85
5.25
5.26
5.27
6.60
6.65
6.86
6.87
7.04
7.06
7.26
2o
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600AF-73G_PROTON_01
2.55
1.00
1.06
0.98
1.89
1.05
2.59
2.93
0.92
0.94
0.91
1.81
1.87
1.82
1.02
1.75
2.23
2.74
2.77
2.78
2.79
2.98
2.99
3.00
3.02
3.04
3.32
3.34
3.36
3.38
3.49
3.50
3.51
3.53
3.54
3.56
3.57
3.62
3.63
3.65
3.65
3.66
3.68
3.73
3.83
5.48
5.50
5.51
6.61
6.69
6.89
6.91
7.03
7.05
7.26
7.38
7.40
7.42
7.52
7.83
7.85
102030405060708090100110120130140150160170180190200f1 (ppm)
-5
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70AF-73G_CARBON_01
20.2
9
26.8
9
42.1
144
.81
55.4
355
.84
76.6
877
.00
77.3
2
109.
9711
1.28
115.
55
126.
1912
7.77
128.
0712
8.49
129.
7813
0.38
133.
0413
7.36
146.
8614
7.20
147.
69
199.
24
2p
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5
f1 (ppm)
-5000
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
55000AF-71P
2.95
0.99
1.01
1.05
1.02
1.00
1.03
6.09
1.00
2.00
3.96
2.09
2.63
2.66
2.76
2.78
2.80
2.81
2.93
2.99
3.00
3.02
3.03
3.46
3.47
3.57
3.57
3.58
3.83
3.84
5.16
5.18
5.19
6.59
6.66
6.88
6.89
6.89
6.91
6.92
7.26
2r
2s
0.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
AF-69_P_PROTON_01
2.81
2.17
1.15
1.06
2.06
1.10
1.09
5.69
1.00
2.00
3.95
0.95
0.97
0.99
2.03
2.29
2.31
2.32
2.34
2.66
2.70
2.71
2.74
2.75
2.94
2.96
2.98
3.44
3.45
3.47
3.54
3.55
3.81
3.83
5.17
5.18
5.20
6.58
6.61
6.86
6.87
6.88
6.89
6.91
7.24
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700AF-70_P_PROTON_01
1.04
1.08
1.04
2.80
2.66
2.75
1.00
1.92
3.55
1.84
0.96
1.80
2.70
2.74
2.99
3.28
3.30
3.32
3.34
3.50
3.51
3.52
3.54
3.55
3.56
3.57
3.57
3.58
3.73
3.83
5.41
5.43
5.44
6.60
6.66
6.90
6.91
7.24
7.38
7.40
7.42
7.50
7.52
7.83
7.85
3a
3b
1.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-2000
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
22000
24000
26000
28000
30000
32000
34000
36000AF-3a
1.07
1.07
1.06
1.06
1.01
1.00
2.05
1.19
3.02
2.04
2.96
2.97
2.98
3.00
3.00
3.01
3.14
3.16
3.16
3.18
3.19
3.20
3.21
3.51
3.51
3.51
3.78
3.78
3.78
3.79
3.79
3.79
3.80
3.80
3.81
3.81
3.81
3.82
5.54
7.05
7.07
7.11
7.13
7.25
7.27
7.30
7.31
7.31
7.32
7.32
7.33
7.34
7.34
7.38
7.40
7.41
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-5000
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
55000AF-3b
1.11
1.06
1.11
1.09
1.00
4.23
4.44
2.94
2.95
2.96
2.98
2.98
2.99
3.14
3.15
3.16
3.18
3.44
3.45
3.47
3.47
3.49
3.50
3.62
3.62
3.63
3.63
3.64
3.64
3.65
3.65
3.65
3.66
3.66
3.66
5.41
7.08
7.08
7.09
7.24
7.26
7.26
7.28
7.29
7.31
7.32
7.32
7.33
7.34
3c
3d
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
0
500
1000
1500
2000
2500
1725_PROTON_01
1.11
1.16
1.12
1.15
3.10
1.00
2.06
2.07
4.23
2.90
2.90
2.93
2.94
2.94
3.12
3.14
3.15
3.42
3.43
3.55
3.56
3.79
5.35
6.90
6.92
7.06
7.09
7.20
7.22
7.24
7.25
7.26
7.27
7.28
7.29
7.30
2.22.42.62.83.03.23.43.63.84.04.24.44.64.85.05.25.45.65.86.06.26.46.66.87.07.27.47.6f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000AF-85P_PROTON_011.
09
1.14
1.13
1.10
6.08
1.00
2.07
1.02
1.97
1.99
2.82
2.83
2.85
2.86
3.03
3.05
3.06
3.07
3.40
3.41
3.43
3.44
3.46
3.74
3.75
3.77
3.78
3.87
4.10
4.11
5.43
6.67
6.74
6.98
7.00
7.02
7.06
7.08
7.25
7.33
7.34
7.37
3e
3f
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000AF-86P_PROTON_01
1.15
1.36
1.24
1.20
6.25
1.00
2.16
4.01
-0.0
0
2.82
2.86
3.05
3.06
3.07
3.09
3.41
3.42
3.44
3.45
3.60
3.61
3.89
5.33
6.68
6.72
7.06
7.08
7.26
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
AF-87P_PROTON_01
2.80
1.05
1.15
1.09
1.11
5.75
1.00
2.02
2.01
1.96
2.80
2.84
3.04
3.05
3.07
3.39
3.40
3.42
3.66
3.67
3.69
3.70
3.87
5.37
6.66
6.72
6.98
7.00
7.14
7.16
7.25
4a
4b
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700AF-96P_PROTON_01
1.12
1.13
2.14
1.01
1.00
1.96
5.99
5.08
2.92
2.93
2.94
2.96
2.97
2.98
3.07
3.09
3.10
3.11
3.13
3.14
3.15
3.62
3.63
3.64
3.65
3.65
3.66
3.67
3.68
3.70
3.71
3.72
3.72
3.73
3.74
3.75
5.63
6.86
6.87
6.89
7.12
7.18
7.19
7.20
7.28
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
0
100
200
300
400
500
600
700
800
900
10001540_PROTON_01
1.18
1.14
2.06
1.00
1.86
1.88
7.37
0.99
0.00
2.93
2.93
2.94
2.97
2.97
2.98
3.10
3.12
3.13
3.14
3.16
3.17
3.18
3.59
3.60
3.62
3.63
3.64
5.54
6.99
7.02
7.04
7.07
7.08
7.09
7.11
7.19
7.20
7.21
7.22
7.23
7.24
7.25
7.26
7.27
7.28
7.34
7.35
7.36
4c
4d
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
1726_PROTON_01
1.08
1.11
1.08
1.10
2.95
1.00
1.95
2.02
5.75
1.89
1.11
2.91
2.91
2.92
2.95
2.96
2.96
3.11
3.13
3.14
3.15
3.17
3.18
3.19
3.54
3.55
3.56
3.56
3.57
3.58
3.58
3.61
3.62
3.64
3.65
3.67
3.68
3.79
5.52
6.89
6.89
6.91
6.91
7.11
7.12
7.13
7.13
7.19
7.20
7.21
7.21
7.22
7.22
7.23
7.23
7.24
7.28
7.28
7.29
7.30
7.35
7.36
7.36
7.37
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
21001532_PROTON_01
1.12
1.22
1.17
1.13
5.93
1.00
1.05
2.04
2.14
3.22
4.13
-0.0
0
2.82
2.83
2.83
2.86
2.87
2.87
3.02
3.04
3.05
3.06
3.08
3.09
3.11
3.61
3.62
3.64
3.65
3.66
3.67
3.73
3.74
3.74
3.75
3.76
3.77
3.77
3.87
3.90
5.56
6.66
6.85
6.88
6.90
7.22
7.23
7.29
7.31
4e
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
0
5000
10000
15000
20000
25000
30000
35000
40000
AF-134d
1.00
1.00
1.93
2.98
3.06
0.98
1.00
1.00
1.96
2.02
3.04
1.96
0102030405060708090100110120130140150160170f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
2400AF-134d28
.75
44.3
0
53.7
056
.15
56.3
1
77.0
177
.26
77.5
2
85.4
588
.46
110.
3611
1.64
115.
6511
5.82
119.
7211
9.78
123.
1212
6.27
127.
1712
8.36
131.
93
146.
6914
7.91
148.
60
156.
7715
8.67
4f
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
1000
1100bbaf-121_PROTON_01
3.19
1.20
1.25
2.39
6.19
1.00
1.14
1.04
2.21
2.18
3.37
2.06
2.29
2.80
2.84
3.02
3.04
3.05
3.06
3.08
3.09
3.10
3.61
3.62
3.65
3.67
3.87
3.87
3.89
3.90
5.51
6.65
6.84
7.02
7.04
7.11
7.13
7.21
7.22
7.28
7.29
0102030405060708090100110120130140150f1 (ppm)
-5
0
5
10
15
20
25
30
35
40
45
50
55bbaf-121_CARBON_01
20.4
9
28.4
4
43.6
8
52.6
755
.89
56.0
6
76.6
877
.00
77.3
2
84.9
3
88.7
0
110.
1611
1.42
117.
59
123.
0812
6.28
127.
2612
7.93
128.
0312
9.38
129.
5813
1.69
147.
5014
7.59
148.
25
