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SUPPLEMENTARY INFORMATIONDOI: 10.1038/NCHEM.1669

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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.

© 2013 Macmillan Publishers Limited. All rights reserved.



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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),


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),


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.




S10

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




S11

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




S12

Group A Chromatogram

Group B Chromatogram




S13

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.




S14

7. NMR spectra

4-(3-Methoxyphenyl)morpholine 3. 1H NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).




S15

1-Bromo-3-(pent-4-en-1-yloxy)benzene. 1H NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).




S16

5-(3-Bromophenoxy)pentan-2-one. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).




S17

1-Bromo-3-(pent-4-yn-1-yloxy)benzene. NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).




S18

1-Bromo-3-((3-(bromomethyl)benzyl)oxy)benzene. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).




S19

1-(3-((3-Bromophenoxy)methyl)benzyl)-1H-pyrrole. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).




S20

Methyl 4-((3-((3-bromophenoxy)methyl)benzyl)oxy)benzoate. 1H NMR (400 MHz, CDCl3), 13C NMR (101

MHz, CDCl3).




S21

4-((3-((3-Bromophenoxy)methyl)benzyl)oxy)benzonitrile. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz,

CDCl3).




S22

4-(3-(Pent-4-en-1-yloxy)phenyl)morpholine 4. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).




S23

4-(3-((3-((1H-Pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine 5. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).




S24

Methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate 7. 1H NMR (400 MHz, CDCl3), 13C NMR

(101 MHz, CDCl3).




S25

4-((3-((3-Morpholinophenoxy)methyl)benzyl)oxy)benzonitrile 8. 1H NMR (400 MHz, CDCl3), 13C NMR (101 MHz, CDCl3).


supplementary information - media.nature.com · nature chemistry | 2 doi: 10.1038/nchem.1669...

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