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Supporting Online Material
A Robustness Screen for the Rapid Assessment of Chemical Reactions
Authors: Karl D. Collins1 and Frank Glorius1*
Affiliations: 1Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany.
*Correspondence to: [email protected].
Table of Contents:
1. General experimental details S1 2. Preparation of substrates and products S2 3. Procedure for batch calibration of additives S10 4. Procedure for screening S10 5. Calibration for reaction yield S10 6. Simplified protocol for batch screening and analysis S11 7. NMR spectra S14
1. General experimental details
All reactions were carried out in oven dried reaction vessels with Teflon screw caps under argon, using
anhydrous solvents. NMR-spectra were recorded on a 300 or 400 MHz spectrometers with chemical
shifts (δ) being reported in ppm relative to residual chloroform (1H = 7.27 or 13C = 77.2) as an internal
standard. Coupling constants (J) are quoted in Hertz (Hz). High resolution mass spectra were obtained
using ESI. Infra-red spectra were recorded neat using FT/IR spectrometers. Reaction solvents were dried
using distillation over an appropriate drying agent or stored over molecular sieves from purchase: Et2O
(Na), toluene (CaH2), DMF (molecular sieves). All solvents used for purification were distilled. Column
chromatography was carried out using 40-63 mesh silica gel. Routine TLC analysis was carried out on
aluminum sheets coated with silica gel 60 F254, 0.2 mm thickness. Plates were viewed using a 254 mm
ultraviolet lamp or developed using p-anisaldehyde or KMnO4. All chemicals were used as purchased.
GC analysis methods are reported within were appropriate.
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2. Preparation of substrates and reaction products
4-(3-Methoxyphenyl)morpholine 3
To a solution of 1-bromo-3-methoxybenzene (0.500 mmol, 63 μL, 1 eq), PdCl2[P(o-tolyl)3]2, (0.010 mmol,
8 mg, 2 mol%), and sodium tert-butoxide (0.700 mmol, 67mg, 1.4 eq) in toluene (4.0 mL) was added
morpholine (0.600 mmol, 52 μL, 1 eq) and the reaction stirred for 3 h at 100 °C. Once cooled, the mixture
was diluted with MBTE (10 mL), washed with saturated aqueous NaCl (5 mL), dried (MgSO4) and
concentrated in vacuo. Purification by chromatography on silica gel, eluting with 20% EtOAc in pentane
gave 4-(3-methoxyphenyl)morpholine 3 (80 mg, 0.415 mmol, 89%) as a colourless oil. 1H NMR (300 MHz,
CDCl3) δ 7.20 (t, J = 8.4 Hz, 1H, ArH), 6.60 – 6.50 (m, 1H, ArH), 6.51 – 6.42 (m, 2H, 2 × ArH), 3.92 – 3.84
(m, 4H, 2 × OCH2), 3.81 (s, 3H, OCH3), 3.22 – 3.10 (m, 4H, 2 × NCH2).13C NMR (75 MHz, CDCl3) δ 160.6
(ArCq), 152.7 (ArCq), 129.9 (ArCH), 108.5 (ArCH), 104.7 (ArCH), 102.2 (ArCH), 66.9 (2 × OCH2 ), 55.2
(OCH3), 49.3 (2 × NCH2). Data is in accordance with the literature (23).
1-Bromo-3-(pent-4-enyloxy)benzene To a solution of 3-bromophenol (2.89 mmol, 500 mg, 1.25 eq) in DMF (5.5 mL) was added 5-
bromopentene (2.31 mmol, 273 μL, 1 eq), K2CO3 (8.67 mmol, 1.20 g, 3.75 eq) and KI (0.405 mmol, 67
mg, 0.175 eq) and the reaction stirred at 60 °C for 24 h. After cooling, the reaction mixture was diluted
with aqueous NaOH (2M, 20 mL), and Et2O (10 mL). The organic phase was separated and the aqueous
phase extracted with diethyl ether (3 × 10 mL), the combined organic phases were then washed with
aqueous NaOH (3 × 10 mL) and saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated in
vacuo. Purification by chromatography on silica gel, eluting with 5% EtOAc in pentane gave 1-bromo-3-
(pent-4-enyloxy)benzene 4 (523 mg, 2.15 mmol, 93%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ
7.19 – 6.98 (m, 3H, 3 × ArH), 6.89 – 6.78 (m, 1H, ArH), 5.86 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H, CH=CH2),
5.13 – 4.98 (m, 2H, CH=CH2), 3.96 (t, J = 6.4 Hz, 2H, OCH2), 2.25 (q, J = 7.3 Hz, 2H, CH2CH=CH2), 1.94
– 1.82 (m, 2H, OCH2CH2). 13C NMR (75 MHz, CDCl3) δ 159.8 (ArCq), 137.6 (CH=CH2), 130.5 (ArCH),
123.6 (ArCH), 122.8 (ArCq), 117.7 (ArCH), 115.3 (CH=CH2), 113.5 (ArCH), 67.3 (OCH2), 30.0
(CH2CH=CH2), 28.2 (OCH2CH2). Data is in accordance with the literature (24).
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5-(3-Bromophenoxy)pentan-2-one
To 1-bromo-3-(pent-4-enyloxy)benzene (0.830 mmol, 200 mg, 1 eq) in DMF (16 mL) and H2O (2.6 mL)
was added CuCl (1.00 mmol, 99 mg, 1.2 eq) and PdCl2 (0.156 mmol, 28 mg, 0.188 eq) and the reaction
stirred for 2 h under an oxygen atmosphere. The reaction was diluted with H2O (100 mL), then HCl (2 N)
until the solution became clear. The aqueous phase was extracted with EtOAc (3 × 50 mL), the combined
organic phases washed with H2O (5 × 50 mL), dried (MgSO4) and concentrated in vacuo. Purification by
chromatography on silica gel, eluting with 10% EtOAc in pentane gave 5-(3-bromophenoxy)pentan-2-one
(175 mg, 0.683 mmol, 82%) as colorless liquid. Rf = 0.25 (10% EtOAc in pentane); νmax (neat)/cm�1 2939,
2881, 2360, 2342, 1713, 1589, 1572, 1468, 1244, 1227, 992, 768, 681; 1H NMR (400 MHz, CDCl3) δ 7.20
– 6.96 (m, 3H, 3 × ArH), 6.81 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H, ArH), 3.96 (t, J = 6.1 Hz, 2H, OCH2), 2.65 (t, J
= 7.1 Hz, 2H, CH2C(O)), 2.18 (s, 3H, CH3), 2.05 (tt, J = 6.9, 5.9 Hz, 2H, OCH2CH2); 13C NMR 101 MHz,
CDCl3) δ 208.0 (C=O), 159.6 (ArCq), 130.5 (ArCH), 123.8 (ArCH), 122.8 (ArCq), 117.7 (ArCH), 113.3
(ArCH), 67.0 (OCH2), 39.7 (CH2C(O)), 30.0 (CH3), 23.1 (OCH2CH2); m/z (ESI) Found: (M + Na) 278.9991.
C14H12Br2NaO2 requires M, 278.9997.
1-Bromo-3-(pent-4-yn-1-yloxy)benzene
To a solution of 3-bromophenol (2.89 mmol, 500 mg, 1.25 eq) in DMF (5.5 mL) was added 5-chloropent-
1-yne (2.31 mmol, 246 μL, 1 eq), K2CO3 (8.67 mmol, 1.20 g, 3.75 eq) and KI (0.405 mmol, 67 mg, 0.175
eq) and the reaction stirred at 100 °C for 12 h. After cooling, the reaction mixture was diluted with
aqueous NaOH (2M, 20 mL). The organic phase was separated and the aqueous phase extracted with
diethyl ether (4 × 10 mL), the combined organic phases were then washed with aqueous NaOH (3 × 10
mL) and saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated in vacuo. Purification by
chromatography on silica gel, eluting with 1% EtOAc in pentane gave 1-bromo-3-(pent-4-yn-1-
yloxy)benzene (397 mg, 1.66 mmol, 72%) as colorless liquid. Rf = 0.50 (2% EtOAc in pentane); νmax
(neat)/cm�1 3299, 2957, 2941, 2878, 2360, 2340, 1589, 1572, 1466, 1283, 1243, 1228, 1045, 857, 766,
632; 1H NMR (300 MHz, CDCl3) δ 7.21 – 7.01 (m, 3H, 3 × ArH), 6.85 (ddd, J = 8.0, 2.4, 1.3 Hz, 1H, ArH),
4.06 (t, J = 6.1 Hz, 2H, OCH2), 2.42 (td, J = 7.0, 2.7 Hz, 2H, OCH2CH2), 2.13 – 1.87 (m, 3H, CH2CCH);
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13C NMR (75 MHz, CDCl3) δ 159.7 (ArCq), 130.5 (ArCH), 123.8 (ArCH), 122.8 (ArCq), 117.8 (ArCH),
113.5 (ArCH), 83.2 (CH2CCH), 69.0 (OCH2), 66.3 (CH2CCH), 28.0 (CH2), 15.1 (CH2); m/z (ESI) Found:
(M + Na) 260.9885. C11H11Br2NaO requires M, 260.9891.
1-Bromo-3-((3-(bromomethyl)benzyl)oxy)benzene
To a solution of NaH (60% dispersion in mineral oil) (5.06 mmol, 202 mg, 1.2 eq) in DMF (5.0 mL) at 0 °C
was added 3-bromophenol (4.22 mmol, 579 μL, 1.2 eq) and the mixture stirred for 20 min prior to the
addition of 1,3-bis(bromomethyl)benzene (4.22 mmol, 1.00 g, 1 eq). The reaction mixture was stirred for
2 h at 0 °C before quenching with aqueous saturated NH4Cl (10 mL). The aqueous phase was extracted
with Et2O (4 × 5 mL), the combined organic phases washed with H2O (3 × 5 mL), dried (MgSO4) and
concentrated in vacuo. Purification by chromatography on silica gel, eluting with 2% EtOAc in pentane
gave 1-bromo-3-((3-(bromomethyl)benzyl)oxy)benzene (323 mg, 0.971 mmol, 23%) as colorless oil. Rf =
0.27 (2% EtOAc in pentane); νmax (neat)/cm�1 3066, 2851, 2361, 1593, 1570, 1478, 1445, 1422 ,1379,
1307, 1237, 1205, 1160, 1091, 1065, 1038, 991, 871, 835, 768, 696, 677, 614, 561; 1H NMR (400 MHz,
CDCl3) δ 7.47 (s, 1H, ArH), 7.43 – 7.32 (m, 3H, 3 × ArH), 7.22 – 7.09 (m, 3H, 3 × ArH), 6.92 (ddd, J = 8.1,
2.4, 1.2 Hz, 1H, ArH), 5.04 (s, 2H, OCH2), 4.52 (s, 2H, CH2Br). 13C NMR (101 MHz, CDCl3) δ 159.4
(ArCq), 138.2 (ArCq), 137.1 (ArCq), 130.6 (ArCH), 129.1 (ArCH), 128.8 (ArCH), 128.0 (ArCH), 127.4
(ArCH), 124.2 (ArCH), 122.8 (ArCq), 118.1 (ArCH), 113.7 (ArCH), 69.8 (OCH2), 33.2 (CH2Br); m/z (ESI)
Found: (M + Na) 376.9153. C14H12Br2NaO requires M, 376.9153.
1-(3-((3-Bromophenoxy)methyl)benzyl)-1H-pyrrole
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To a solution of 18-crown-6 (0.105 mmol, 28 mg, 0.125 eq) and potassium tert-butoxide (1,05 mmol, 118
mg, 1.25 eq) in Et2O (1.5 mL) was added pyrrole (1.05 mmol, 73 μL, 1.25 eq) and the reaction mixture
stirred for 15 min. The mixture was cooled to 0 °C and 1-bromo-3-((3-(bromomethyl)benzyl)oxy)benzene
(0.843 mmol, 300 mg, 1 eq) added dropwise as a solution in Et2O (0.5 mL), and the resultant mixture
stirred for 2 h at room temperature. The reaction was quenched with water (5 mL) and the aqueous phase
extracted with Et2O (3 × 3 mL), the combined organic phases then washed with saturated aqueous
sodium chloride (7.5 mL), dried (MgSO4) and concentrated in vacuo. Purification by chromatography on
silica gel, eluting with 2% EtOAc in pentane gave 1-(3-((3-bromophenoxy)methyl)benzyl)-1H-pyrrole (198
mg, 0.575 mmol, 68%) as a colorless oil. Rf = 0.23 (2% EtOAc in pentane); νmax (neat)/cm�1 2832, 2520,
1593, 1570, 1478, 1384, 1283, 1234, 1156, 1088, 1066, 1013, 873, 845, 773, 728, 700, 684, 621; 1H
NMR (400 MHz, CDCl3) δ 7.43 – 7.32 (m, 2H, 2 × ArH), 7.21 – 7.04 (m, 5H, 5 × ArH), 6.90 (ddd, J = 7.8,
2.5, 1.3 Hz, 1H, ArH), 6.72 (t, J = 2.1 Hz, 2H, 2 × NCH=CH), 6.23 (t, J = 2.1 Hz, 2H, 2 × NCH=CH), 6.23
(d, J = 2.1 Hz, 1H, NCH=CH), 5.11 (s, 2H, NCH2), 5.02 (s, 2H, OCH2); 13C NMR (101 MHz, CDCl3) δ
159.4 (ArCq), 138.7 (ArCq), 136.9 (ArCq), 130.6 (ArCH), 129.1 (ArCH), 126.8 (ArCH), 126.7 (ArCH), 126.0
(ArCH), 124.1 (ArCH), 122.8 (ArCq), 121.1 (2 × NCH=CH), 118.1 (ArCH), 113.8 (ArCH), 108.6 (2 ×
NCH=CH), 69.9 (OCH2), 53.1 (NCH2). m/z (ESI) Found: (M + Na) 364.0307. C18H16BrNNaO requires M,
364.0313.
Methyl 4-((3-((3-bromophenoxy)methyl)benzyl)oxy)benzoate
To a solution of 1-bromo-3-((3-(bromomethyl)benzyl)oxy)benzene (0.420 mmol, 150 mg, 1 eq) and methyl
4-hydroxybenzoate (0.460 mmol, 70 mg, 1.1 eq) in acetone (0.5 mL) was added K2CO3 (0.693 mmol, 96
mg, 1.65 eq) and the reaction heated at 60 °C for 10h. After cooling, the solvent was evaporated and the
precipitate dissolved in H2O (1 mL). The aqueous phase extracted with EtOAc (3 × 0.75 mL), the
combined organic phases dried (MgSO4) and concentrated in vacuo. Purification on silica gel using an
automated MPLC system, eluting with pentane/EtOAc (0 – 40% EtOAc) gave methyl 4-((3-((3-
bromophenoxy)methyl)benzyl)oxy)benzoate (147 mg, 0.344 mmol, 82%) as a colorless viscous oil. Rf =
0.54 (20% EtOAc in pentane); νmax (neat)/cm�1 2949, 2874, 2360, 2343, 1712, 1604, 1588, 1509, 1475,
1434, 1279, 124, 1223, 1167, 1104, 1009, 846, 767, 695; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.9
Hz, 2H, 2 × ArH), 7.57 – 7.34 (m, 4H, 4 × ArH), 7.21 – 7.06 (m, 3H, 3 × ArH), 7.05 – 6.96 (m, 2H, 2 ×
ArH), 6.91 (ddd, J = 8.1, 2.5, 1.3 Hz, 1H, ArH), 5.15 (s, 2H, OCH2), 5.07 (s, 2H, OCH2), 3.90 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 166.8 (C=O), 162.4 (ArCq), 159.4 (ArCq), 137.0 (ArCq), 136.8 (ArCq), 131.6
(ArCH), 130.6 (ArCH), 129.0 (ArCH), 127.3 (ArCH), 127.2 (ArCH), 126.4 (ArCH), 124.2 (ArCH), 122.9
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(ArCq), 122.8 (ArCq), 118.2 (ArCH), 114.5 (ArCH), 113.8 (ArCH), 69.9 (OCH2), 69.9 (OCH2), 51.9 (OCH3);
m/z (ESI) Found: (M + H) 427.0539. C22H20Br2O4 requires M, 427.0545.
4-((3-((3-Bromophenoxy)methyl)benzyl)oxy)benzonitrile
To a solution of 1-bromo-3-((3-(bromomethyl)benzyl)oxy)benzene (0.420 mmol, 150 mg, 1 eq) and methyl
4-hydroxybenzonitrile (0.460 mmol, 55 mg, 1.1 eq) in acetonitrile (3.7 mL) was added K2CO3 (1.09 mmol,
151 mg, 2.6 eq) and KI (0.046 mmol, 8 mg, 0.11 eq) and the reaction heated at 80 °C for 18h. After
cooling H2O (5 mL) was added to the reaction mixture. The aqueous phase extracted with EtOAc (3 × 3
mL), the combined organic phases dried (MgSO4) and concentrated in vacuo. Purification on silica gel
using an automated MPLC system, eluting with pentane/EtOAc (0 – 30% EtOAc) gave 4-((3-((3-
bromophenoxy)methyl)benzyl)oxy)benzonitrile (147 mg, 0.372 mmol, 89%) as a white solid. Rf = 0.24
(10% EtOAc in pentane); νmax (neat)/cm�1 3072, 2882, 2217, 1603, 1587, 1574, 1506, 1474, 1466, 1377,
1284, 1246, 1227, 1009, 839, 769, 698, 549; 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.55 (m, 2H, 2 × ArH),
7.53 – 7.34 (m, 4H, 4 × ArH), 7.23 – 7.08 (m, 3H, 3 × ArH), 7.07 – 6.98 (m, 2H, 2 × ArH), 6.90 (ddd, J =
8.1, 2.4, 1.4 Hz, 1H, ArH), 5.14 (s, 2H, OCH2), 5.07 (s, 2H, OCH2); 13C NMR (101 MHz, CDCl3) δ 161.8
(ArCq), 159.3 (ArCq), 137.1 (ArCq), 136.2 (ArCq), 134.0 (ArCH), 130.6 (ArCH), 129.1 (ArCH), 127.4
(ArCH), 127.1 (ArCH), 126.3 (ArCH), 124.2 (ArCH), 122.8 (ArCq), 119.1 (ArCq), 118.1 (ArCH), 115.5
(ArCH), 113.7 (ArCH), 104.3 (CN), 70.0 (OCH2), 69.8 (OCH2); m/z (ESI) Found: (M + Na) 416.0252.
C21H16BrNNaO2 requires M, 416.0262.
4-(3-(Pent-4-en-1-yloxy)phenyl)morpholine 4
To a solution of 1-bromo-3-(pent-4-enyloxy)benzene 4 (0.415 mmol, 100 mg, 1 eq), PdCl2[P(o-tolyl)3]2,
(8.30 μmol, 7 mg, 2 mol%), and sodium tert-butoxide (0.581 mmol, 56 mg, 1.4 eq) in toluene (3.3 mL) was
added morpholine (0.498 mmol, 39 μL, 1.2 eq) and the reaction stirred for 3 h at 100 °C. Once cooled,
the mixture was diluted with Et2O (5 mL), washed with saturated aqueous NaCl (3 mL), dried (MgSO4)
and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 5% EtOAc in
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pentane gave 4-(3-(pent-4-en-1-yloxy)phenyl)morpholine 4 (74 mg, 0.311 mmol, 75%) as a colourless oil.
Rf = 0.18 (5% EtOAc in pentane); νmax (neat)/cm�1 2956, 2854, 1598, 1494, 1449, 1225, 1190 , 1121,
1049, 994, 913, 835, 756, 687; 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 8.1 Hz, 1H, ArH), 6.54 (dd, J =
8.0, 2.1 Hz, 1H, ArH), 6.50 – 6.22 (m, 2H, ArH), 5.87 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H, CH=CH2), 5.27 –
4.83 (m, 2H, CH=CH2), 3.97 (t, J = 6.4 Hz, 1H, ArOCH2), 3.86 (t, J = 4.9 Hz, 4H, 2 × OCH2CH2N), 3.16 (t,
J = 4.9 Hz, 4H, 2 × OCH2CH2N), 2.36 – 2.16 (m, 2H, CH2CH2CH=CH2), 1.97 – 1.82 (m, 2H,
CH2CH=CH2); 13C NMR (101 MHz, CDCl3) δ 160.1 (ArCq), 152.6 (ArCq), 137.8 (CH=CH2), 129.8
(CH=CH2), 115.1 (ArCH), 108.3 (ArCH), 105.3 (ArCH), 102.8 (ArCH), 67.0 (ArOCH2), 66.9 (2 ×
OCH2CH2N), 49.3 (2 × OCH2CH2N), 30.1 (CH2CH2CH=CH2), 28.5 (CH2CH=CH2). m/z (ESI) Found: (M +
H) 248.1646. C15H22NO2 requires M, 248.1651.
4-(3-((3-((1H-Pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine 5
To a solution of 1-(3-((3-bromophenoxy)methyl)benzyl)-1H-pyrrole (0.415 mmol, 100 mg, 1 eq),
PdCl2[P(o-tolyl)3]2, (8.30 μmol, 7 mg, 2 mol%), and sodium tert-butoxide (0.581 mmol, 56 mg, 1.4 eq) in
toluene (3.3 mL) was added morpholine (0.498 mmol, 39 μL, 1.2 eq) and the reaction stirred for 3 h at
100 °C. Once cooled, the mixture was diluted with Et2O (5 mL), washed with saturated aqueous NaCl (3
mL), dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica gel, eluting with
20% EtOAc in pentane gave 4-(3-((3-((1H-pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine 5 (117 mg,
0.336 mmol, 81%) as a as a yellow oil. Rf = 0.28 (20% EtOAc in pentane); νmax (neat)/cm�1 2959, 2855,
2829, 1602, 1574, 1493, 1447, 1269, 1191, 1121, 1024, 728, 690, 622; 1H NMR (400 MHz, CDCl3) δ 7.27
– 6.85 (m, 4H, 4 × ArH), 6.62 (t, J = 2.1 Hz, 2H, 2 × NCH=CH ), 6.52 – 6.34 (m, 4H, 4 × ArH), 6.12 (t, J =
2.1 Hz, 2H, 2 × NCH=CH), 5.00 (s, 2H, ArOCH2), 4.92 (s, 2H, ArCH2N), 3.77 (d, J = 4.9 Hz, 4H, 2 ×
OCH2CH2N), 3.07 (t, J = 4.9 Hz, 4H, 2 × OCH2CH2N); 13C NMR (101 MHz, CDCl3) δ 159.7 (ArCq), 152.6
(ArCq), 138.5 (ArCq), 137.6 (ArCq), 129.8 (ArCH), 129.0 (ArCH), 126.8 (ArCH), 126.6 (ArCH), 126.1
(ArCH), 121.1 (2 × NCH=CH), 108.8 (ArCH), 108.5 (2 × NCH=CH), 105.4 (ArCH), 103.0 (ArCH), 69.7
(OCH2), 66.8 (2 × OCH2CH2N), 53.1 (NCH2), 49.2 (2 × OCH2CH2N); m/z (ESI) Found: (M + Na) 371.1730.
C22H24N2NaO2 requires M, 371.1735.
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Methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate 7 To a solution of methyl 4-((3-((3-bromophenoxy)methyl)benzyl)oxy)benzoate (0.270 mmol, 115 mg, 1 eq),
PdCl2[P(o-tolyl)3]2, (5.40 μmol, 5 mg, 2 mol%), and sodium tert-butoxide (0.378 mmol, 36 mg, 1.4 eq) in
toluene (2.2 mL) was added morpholine (0.32 mmol, 28 μL, 1.2 eq) and the reaction stirred for 3 h at 100
°C. Once cooled, the mixture was diluted with Et2O (4 mL), washed with saturated aqueous NaCl (2 mL),
dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 30%
EtOAc in pentane gave methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate 7 (28 mg, 0.065
mmol, 24%) as a yellow oil. Rf = 0.11 (20% EtOAc in pentane); νmax (neat)/cm�1 2953, 2856, 2361, 2343,
1713,1604, 1509, 1435, 1248, 1168, 1113, 751; 1H NMR (400 MHz, CDCl3) δ 8.08 – 7.90 (m, 2H, 2 ×
ArH), 7.52 (d, J = 1.9 Hz, 1H, ArH), 7.47 – 7.33 (m, 3H, 3 × ArH), 7.23 – 7.17 (m, 1H, ArH), 7.06 – 6.88
(m, 2H, 2 × ArH), 6.57 (m, 3H, 3 × ArH), 5.14 (s, 2H, OCH2), 5.08 (s, 2H, OCH2), 3.90 (br. s, 7H, CH3, 2 ×
OCH2CH2N), 3.30 – 3.05 (m, 4H, 2 × OCH2CH2N); 13C NMR (101 MHz, CDCl3) δ 166.8 (C=O), 162.4
(ArCq), 159.8 (ArCq), 136.7 (ArCq), 131.6 (ArCH), 130.0 ((ArCq), 129.0 (ArCH), 127.3 (ArCH), 127.1
(ArCH), 126.5 (ArCH), 122.9 (ArCq), 114.5 (ArCH), 69.9 (ArOCH2), 69.8 (ArOCH2), 66.7 (br. OCH2CH2N),
51.9 (CH3). m/z (ESI) Found: (M + H) 434.1962. C26H28NO5 requires M, 434.1967.
4-((3-((3-Morpholinophenoxy)methyl)benzyl)oxy)benzonitrile 8 To a solution of 4-((3-((3-Bromophenoxy)methyl)benzyl)oxy)benzonitrile (0.254 mmol, 100 mg, 1 eq),
PdCl2[P(o-tolyl)3]2, (5.08 μmol, 4 mg, 2 mol%), and sodium tert-butoxide (0.360 mmol, 34 mg, 1.4 eq) in
toluene (2.1 mL) was added morpholine (0.305 mmol, 27 μL, 1.2 eq) and the reaction stirred for 3 h at
100 °C. Once cooled, the mixture was diluted with Et2O (4 mL), washed with saturated aqueous NaCl (2
mL), dried (MgSO4) and concentrated in vacuo. Purification on silica gel using an automated MPLC
system, eluting with pentane/EtOAc (10 – 60% EtOAc) gave 4-((3-((3-
morpholinophenoxy)methyl)benzyl)oxy)benzonitrile 8 (43 mg, 0.065 mmol, 42%) as a yellow oil. Rf = 0.15
(20% EtOAc in pentane); νmax (neat)/cm�1 2960, 2921, 2856, 2360, 2343, 2224, 1603, 1507, 1251,
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1171,1121, 833, 751; 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.56 (m, 2H, 2 × ArH), 7.51 (s, 1H, ArH), 7.47
– 7.41 (m, 3H, 3 × ArH), 7.41 – 7.36 (m, 1H, ArH), 7.24 – 7.18 (m, 1H, ArH), 7.06 – 6.99 (m, 2H, 2 × ArH),
6.67 – 6.46 (m, 2H, 2 × ArH), 5.14 (s, 2H, OCH2), 5.08 (s, 2H, OCH2), 3.7 (br. s, 4H, 2 × OCH2CH2N),
3.17 (br. s, 4H, 2 × OCH2CH2N); 13C NMR (101 MHz, CDCl3) δ 161.9 (ArCq), 159.7 (ArCq), 136.1(ArCq),
134.0, 130.0 (ArCq), 129.0 (ArCH), 127.5 (ArCH), 127.0 (ArCH), 126.5 (ArCH), 119.1(ArCq), 115.6
(ArCH), 104.3 (CN), 70.1 (ArOCH2), 69.7 (ArOCH2), 66.7 (br. OCH2CH2N). m/z (ESI) Found: (M + H)
401.1857. C25H25N2O3 requires M, 401.1865.
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3. Procedure for gas chromatography batch calibration
Additives were individually analyzed by gas chromatography to determine retention times. Calibration
solutions with up to ten compounds (0.125 mmol of each compound in 20 mL of toluene) were
subsequently prepared, ensuring compounds with similar retention times were separated. Standard gas
chromatography calibration using mesitylene as a standard was undertaken, and calibration lines
produced for each additive. See section 6 for sample chromatograms.
4. Procedure for screening
To a solution of 1-bromo-3-methoxybenzene (1.38 mmol, 173 μl, 1 eq), PdCl2[P(o-tolyl)3]2, (0.028 mmol,
22 mg, 2 mol%), and sodium tert-butoxide (1.93 mmol, 185 mg, 1.4 eq) in toluene (11.0 mL) was added
morpholine (1.65 mmol, 142 μL, 1.2 eq). The reaction mixture was distributed into ten reaction vessels (1
mL, 0.125 mmol of 1-bromo-3-methoxybenzene per reaction), each containing one additive (0.125 mmol).
The reactions were stirred for 3 h at 100 °C, before cooling and subsequent analysis by GC. For GC
sample preparation, the sample was filtered through silica with the exception of reactions containing
dodecylamine, 1-methylimidazole, and 2-methyl pyridine-N-oxide which were filtered through celite.
5. Calibration for reaction yield
The calibration line for determination of the yield using gas chromatography analysis is given. Calibration
was undertaken using mesitylene as the standard.
Column: HP-5 quartz column
Method: Initial temperature 50 °C, hold 3 min, increment 40 °C/min, final temperature 280 °C, hold 3 min.
Detection: Flame ionization detection.
Retention time: 4-(3-Methoxyphenyl)morpholine 3 = 8.195 min
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6. Simplified protocol for batch screening and analysis Compounds were selected on the basis of diversity and retention time.
Compounds can be substituted or excluded as appropriate.
GC analysis is utilized for demonstration of batch calibration, though alternative methods may be
employed.
The standard can be substituted as appropriate.
Scale of reactions can be modified as appropriate.
1) Two calibration solutions containing 10 additives (0.125 mmol of each additive) and standard (0.125
mmol, mesitylene) in toluene (20 mL) are prepared, and analyzed.
Example GC method, compounds, retention times and chromatograms are provided:
Column: HP-5 quartz column
Method: Initial temperature 50 °C, hold 3 min, increment 40 °C/min, final temperature 280 °C, hold 3 min.
Detection: Flame ionization detection.
Retention time of standard: Mesitylene = 5.55 min
y = 142.68x + 0.359R² = 0.9999
0
20
40
60
80
100
120
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Yiel
d %
Ratio of product to standard
Calibration chart for product 3 yield
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Group A Chromatogram
Group B Chromatogram
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The relative integrals of the additive to the standard can be used for a semi-quantitative determination of
the amount of additive present in a reaction mixture.
2) The standard reaction is performed and the product isolated. Calibration of the product (0.125 mmol)
against the standard (0.125 mmol) is undertaken.
3) For Group A, the standard reaction is prepared on scale (10 × 0.125 mmol) and distributed to reaction
vessels (× 10) containing one additive (0.125 mmol). After the given reaction time, the standard is
introduced to each reaction (0.125 mmol), and analysis by the selected method undertaken. This
procedure is repeated for Group 2.
4) The yield of the reaction and the amount of additive remaining as determined by comparison with the
calibration should be reported in a simple table.
Note: In the preparation of samples for analysis, reactions containing dodecylamine and 1-
methylimidazole should be filtered if required, through celite rather than silica to avoid removing the
additive.
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7. NMR spectra
4-(3-Methoxyphenyl)morpholine 3. 1H NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).
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1-Bromo-3-(pent-4-en-1-yloxy)benzene. 1H NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).
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5-(3-Bromophenoxy)pentan-2-one. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).
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1-Bromo-3-(pent-4-yn-1-yloxy)benzene. NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).
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1-Bromo-3-((3-(bromomethyl)benzyl)oxy)benzene. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).
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1-(3-((3-Bromophenoxy)methyl)benzyl)-1H-pyrrole. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).
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Methyl 4-((3-((3-bromophenoxy)methyl)benzyl)oxy)benzoate. 1H NMR (400 MHz, CDCl3), 13C NMR (101
MHz, CDCl3).
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4-((3-((3-Bromophenoxy)methyl)benzyl)oxy)benzonitrile. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz,
CDCl3).
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4-(3-(Pent-4-en-1-yloxy)phenyl)morpholine 4. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).
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4-(3-((3-((1H-Pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine 5. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).
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Methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate 7. 1H NMR (400 MHz, CDCl3), 13C NMR
(101 MHz, CDCl3).
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