Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists

Article abstract of DOI:10.1016/j.ejmech.2012.02.041

The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pK_i values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.

Full text of DOI:10.1016/j.ejmech.2012.02.041

Supplementary Material
Synthesis, modeling and functional activity of
substituted styrene-amides as small-molecule
CXCR7 agonists
Maikel Wijtmans,a,c David Maussang,a,c Francesco Sirci,a Danny J. Scholten,a Meritxell
a
a
a
a
Canals,a Azra Mujić-Delić, Milagros Chong, Kristell L. S. Chatalic, Hans Custers, Elwin
Janssen,b Chris de Graaf, a Martine J. Smit, a Iwan J. P. de Esch, a Rob Leurs a,*
aLeiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of
Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The
Netherlands.
bDepartment of Chemistry & Pharmaceutical Sciences, VU University Amsterdam, De
Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
cThese authors contributed equally.
S1

Table of contents
Figure S1.
Page S3
Synthesis.
Page S4-S25
Page S26-S30
Page S31
Exemplary spectra.
References.
S2

9
8.5
8
7.5
7
ACTIVES
INACTIVES
6.5
6
5.5
5
-5
-4
-3
-2
-1
0
1
2
3
LDA-R
Figure S1. Scatter plot of LDA-R vs. pKi showing the discrimination between actives and inactives for
CXCR7. Positive values of LDA-R score indicate a candidate that is predicted to be active. Negative
values are assigned by linear discriminant analysis when a candidate is predicted as inactive.
S3

Synthesis.
General notes and general procedures A-E
These can be found in the Experimental Section of the Main Text.
Aldol reaction
(E)-3-(2-Fluorophenyl)-2-methylacrylaldehyde (4b).
The general procedure A was followed, using 2-fluorobenzaldehyde (1.74 g, 14.0 mmol), 1-propanal
(0.85 g, 14.6 mmol) and KOH (0.08 g, 1.4 mmol). The crude product was purified by column
1
chromatography (9.5:0.5, n-hexane: EtOAc) to give a yellow oil (1.57 g, 68 %). H NMR (CDCl3, 250
MHz) δ 9.67 (s, 1H), 7.60-7.51 (m, 1H), 7.50-7.38 (m, 2H), 7.29-7.12 (m, 3H), 2.03 (s, 3H).
(E)-3-(3-Fluorophenyl)-2-methylacrylaldehyde (4c).
The general procedure A was followed, using 3-fluorobenzaldehyde (2.00 g, 16.1 mmol), 1-propanal
(0.98 g, 16.9 mmol) and KOH (0.09 g, 1.6 mmol). The crude product was purified by column
1
chromatography (9.5:0.5, n-hexane: EtOAc) to give a yellow oil (2.07 g, 78 %). H NMR (CDCl3, 250
MHz) δ δ 9.45 (s, 1H), 7.36-7.26 (m, 1H), 7.22-6.91 (m, 5H), 1.95 (s, 3H).
(E)-3-(4-Fluorophenyl)-2-methylacrylaldehyde (4d).
The general procedure A was followed, using 4-fluorobenzaldehyde (1.74 g, 14.0 mmol), 1-propanal
(0.85 g, 14.6 mmol) and KOH (0.08 g, 1.4 mmol). The crude product was purified by column
1
chromatography (9.5:0.5, n-hexane: EtOAc) to give a yellow oil (1.00 g, 44 %). H NMR (CDCl3, 250
MHz) δ 9.61 (s, 1H), 7.62-7.53 (m, 2H), 7.30-7.13 (m, 3H), 2.09 (s, 3H).
S4

(E)-3-(2,4-Difluorophenyl)-2-methylacrylaldehyde (4e).
The general procedure A was followed, using 2,4-difluorobenzaldehyde (1.99 g, 14.0 mmol), 1-
propanal (0.85 g, 14.6 mmol) and KOH (0.08 g, 1.4 mmol). The crude product was purified by
recrystallization from hot methanol to give yellow crystals (1.22 g, 48 %). 1H NMR (CDCl3, 400 MHz) δ
9.59 (s, 1H), 7.58-7.48 (m, 1H), 7.36 (s, 1H), 7.02-6.87 (m, 2H), 2.02 (s, 3H).
(E)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methylacrylaldehyde (4f).
The general procedure A was followed, using 3-fluoro-5-trifluoromethylbenzaldehyde (2.00 g, 10.4
mmol), 1-propanal (0.63 g, 10.8 mmol) and KOH (0.06 g, 1.1 mmol). The crude product was purified
1
by column chromatography (9.5:0.5, n-hexane: EtOAc) to give a yellow oil (1.57 g, 65 %). H NMR
(CDCl3, 400 MHz) δ 9.52 (s, 1H), 7.46 (s, 1H), 7.34-7.29 (m, 1H), 7.20-7.09 (m, 2H), 1.95 (s, 3H).
(E)-3-(2-Fluoro-4-methoxyphenyl)-2-methylacrylaldehyde (4g).
The general procedure A was followed, using 2-fluoro-4-methoxybenzaldehyde (0.71 g, 4.6 mmol),
1-propanal (0.28 g, 4.8 mmol) and KOH (0.02 g, 0.36 mmol). The crude product was purified by
1
column chromatography (9.5:0.5, n-hexane: EtOAc) to give a white solid (0.45 g, 50 %). H NMR
(CDCl3, 250 MHz) δ 9.46 (s, 1H), 7.43 (t, 1H, J=8.5 Hz), 7.26 (s, 1H), 6.71-6.57 (m, 2H), 3.73 (s, 3H),
1.92 (s, 3H).
Other aldehydes
(E)-Methyl 3-phenylbut-2-enoate (5).
Acetophenone (1.62 g, 13.51 mmol) was mixed with methyl (triphenylphosphoranylidene) acetate
(4.0 g, 11.96 mmol). The mixture was heated at 160°C overnight while stirring. After cooling, the
crude product was purified by column chromatography (9.5:0.5, n-hexane: EtOAc) to give a brown oil
1
(0.74 g, 35%). H NMR (CDCl3, 400 MHz) δ 7.45-7.39 (m, 2H), 7.33-7.22 (m, 3H), 6.12 (s, 1H), 3.69 (s,
3H), 2.55 (s, 3H).
S5

(E)-3-Phenylbut-2-en-1-ol (6).
LiAlH4 (0.27 g, 7.2 mmol) was added to dry diethylether (64 mL). Ester 5 (0.64 g, 3.63 mmol) was
mixed with dry diethylether (1.8 mL) and the resulting solution was added dropwise to the LAH
mixture at a temperature of -10°C. The mixture was stirred for 30 min at -10°C, after which TLC
showed full conversion. The mixture was quenched with water (100 mL) and a solution of cold aq.
H2SO4 (10%, 50 mL) was added. Extraction was performed with EtOAc (3x). The combined organic
layers were washed with water (2x), with a solution of aq. K2CO3 (10%, 3x) and with water (2x). The
organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The product was obtained
as a yellow oil (0.52 g, 97 %). It is noted that use of ether as solvent is important in this reaction, as
1
use of THF led to side products. H NMR (CDCl3, 250 MHz) δ 7.32-7.16 (m, 5H), 5.92-5.85 (m, 1H),
4.26 (d, 2H, J=6.25 Hz), 1.99 (s, 3H).
(E)-3-Phenylbut-2-enal (4i).
Alcohol 6 (0.43 g, 2.9 mmol) was dissolved in DCM (10 mL). An excess of MnO2 (1.3 g, 14.9 mmol) was
added. The mixture was stirred overnight at room temperature. TLC (eluent: EtOAc/Heptane=1/3)
showed partial conversion. An extra amount of MnO2 (0.41 g, 4.7 mmol) was added and stirring was
continued for another 24 hours at room temperature. The mixture was filtered over Celite and the
filtrate concentrated in vacuo. The crude product was purified by column chromatography
1
(EtOAc/heptane 1/3). This afforded the product (0.29 g, 68 %) as a yellow oil. H-NMR (CDCl3, 250
MHz) δ 10.19 (d, 1H, J= 7.8 Hz), 7.56-7.39 (m, 5H), 6.42 (d, 1H, J = 7.8 Hz), 2.57 (s, 3H). LR-MS [M+H]+
147.0.
S6

Reductive amination
(E)-2-Methyl-N-(3-morpholinopropyl)-3-phenylprop-2-en-1-amine (8a).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7a (0.57 g, 3.9 mmol), aldehyde 4a (0.56 g, 3.8
mmol), MgSO4 (5 g), DCM (20 mL) and a reaction time of 4 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1 hour. Purification with an SCX column (Si-SCX-2, 15 g) gave a yellowish
oil (0.47 g, 45 %). 1H-NMR (CDCl3, 250 MHz) δ 7.37-7.19 (m, 5H), 6.46 (s, 1H), 3.75-3.69 (m, 4H), 3.34
(s, 2H), 2.72 (t, 2H, J=6.75 Hz), 2.49-2.40 (m, 6H), 1.91 (s, 3H), 1.80-1.62 (m, 2H). LR-MS [M+H]+
C17H27N2O+, Calc. 275.2, found 275.0.
(E)-3-(2-Methyl-3-phenylallylamino)propan-1-ol (8b).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7b (0.30 g, 4.0 mmol), aldehyde 4a (0.53 g, 3.6
mmol), MgSO4 (5 g), DCM (20 mL) and a reaction time of 4 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 0.5 h. Purification was performed with an SCX column (Si-SCX-2, 15 g) to
give a yellowish oil (0.56 g, 76 %). 1H-NMR (CDCl3, 200 MHz) δ 7.33-7.14 (m, 5H), 6.38 (s, 1H), 3.77 (t,
2H), 3.28 (s, 2H), 2.84 (t, 2H), 1.88 (s, 3H), 1.78-1.64 (m, 2H). LR-MS [M+H]+ C13H20NO+, Calc. 206.2,
found 206.1.
(E)-2-Methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-3-phenylprop-2-en-1-amine (8c).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (2.0 g, 15.6 mmol), aldehyde 4a (2.32 g, 15.9
mmol), MgSO4 (20.7 g), DCM (83 mL) and a reaction time of 4 days. For the imine reduction, the
S7

following reagents and conditions were used: NaBH4 (0.58 g, 15.3 mmol), MeOH (41 mL), acetone (4
mL) and a reaction time of 1 hour. The crude product was purified by column chromatography
1
(74:13:13 EtOAc: Et3N: MeOH) to give a yellow oil (2.15 g, 53 %). H NMR (CDCl3, 250 MHz) δ 7.33-
7.17 (m, 5H), 6.42 (s, 1H), 3.30 (s, 2H), 3.09 – 2.98 (m, 1H), 2.74-2.55 (m, 2H), 2.32 (s, 3H), 2.15-2.00
+
(m, 2H), 1.94-1.80 (m, 2H), 1.85 (s, 3H), 1.80-1.59 (m, 2H), 1.55-1.41 (m, 2H). LR-MS [M+H]+ C17H27N2 ,
Calc. 259.2, found 259.0.
(E)-2-Methyl-N-(3-(2-methylpiperidin-1-yl)propyl)-3-phenylprop-2-en-1-amine (8d).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7d (0.60 g, 3.8 mmol), aldehyde 4a (0.53 g, 3.6
mmol), MgSO4 (5 g), DCM (20 mL) and a reaction time of 4 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 3 hour. Purification was performed with an SCX column (Si-SCX-2, 10g) to
give a yellowish oil (0.74 g, 72 %). 1H-NMR (CDCl3, 200 MHz) δ 7.31-7.12 (m, 5H), 6.40 (s, 1H), 3.25 (s,
2H), 2.90-2.65 (m, 4H), 2.40-2.02 (m, 4H), 1.85 (s, 3H), 1.70-1.15 (m, 8H), 1.02 (d, 3H). LR-MS [M+H]+
+
C19H31N2 , Calc. 287.2, found 287.1.
(E)-3-(2-Fluorophenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-1-amine (8e).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.78 g, 6.1 mmol), aldehyde 4b (1.0 g, 6.1
mmol), Na2SO4 (5.0 g), DCM (20 ml) and a reaction time of 24 hours. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.25 g, 6.6 mmol), MeOH (10 mL), acetone (1.0
mL) and a reaction time of 1 hour. The product was purified by column chromatography (eluent
1
EtOAc/MeOH/Et3N = 80/20/1) to give a light yellow oil (0.95 g, 56 %). H NMR (CDCl3, 250 MHz) δ
7.30-6.90 (m, 4H), 6.35 (s, 1H), 3.29 (s, 2H), 3.05 – 2.94 (m, 1H), 2.68-2.55 (m, 2H), 2.25 (s, 3H), 2.14-
1.98 (m, 2H), 1.94-1.79 (m, 2H), 1.75 (s, 3H), 1.79-1.62 (m, 2H), 1.55-1.41 (m, 2H). LR-MS [M+H]+
+
C17H26FN2 , Calc. 277.2, found 277.0.
S8

1D-NOESY: Irradiation at Ha: diagnostic couplings observed with Hc (large), Hb (large), Hd (small);
Irradiation at Hc: diagnostic couplings observed with Ha (large), Hd (large); no coupling with Hb. Note:
this compound is the precursor for both 29 and 30.
(E)-3-(3-Fluorophenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-1-amine (8f).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.50 g, 3.9 mmol), aldehyde 4c (0.63 g, 3.8
mmol), MgSO4 (5.0 g), DCM (20 mL) and a reaction time of 5 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1 hour. The product was purified by column chromatography (85:10:5
1
EtOAc:MeOH: Et3N) to give a light yellow oil (0.235 g, 22 %). H-NMR (CDCl3, 250 MHz) δ 7.33-7.20
(m, 1H), 7.12-6.84 (m, 3H), 6.42 (s, 1H), 3.33 (s, 2H), 3.14-3.00 (m, 1H), 2.71-2.52 (m, 2H), 2.32 (s, 3H),
2.20-2.03 (m, 2H), 1.99-1.82 (m, 2H), 1.87 (s, 3H), 1.80-1.61 (m, 2H), 1.60-1.41 (m, 2H). LR-MS [M+H]+
+
C17H26FN2 , Calc. 277.2, observed 277.0.
(E)-3-(4-Fluorophenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-1-amine (8g).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.50 g, 3.9 mmol), aldehyde 4d (0.63 g, 3.8
mmol), MgSO4 (5.0 g), DCM (20 mL) and a reaction time of 5 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1 hour. The product was purified by column chromatography (85:10:5
EtOAc:MeOH:Et3N) to give a light yellow oil (0.639 g, 61 %). 1H-NMR (CDCl3, 250 MHz) δ 7.29-7.20 (m,
2H), 7.05 (t, 2H, J=7.5 Hz), 6.45 (s, 1H), 3.37 (s, 2H), 3.18-3.09 (m, 1H), 2.78-2.62 (m, 2H), 2.39 (s, 3H),
2.25-2.11 (m, 2H), 2.03-1.86 (m, 2H), 1.87 (s, 3H), 1.85-1.69 (m, 2H), 1.69-1.49 (m, 2H). LR-MS [M+H]+
+
C17H26FN2 , Calc. 277.2, observed 277.0.
S9

(E)-3-(2,4-Difluorophenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-1-amine (8h).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.50 g, 3.9 mmol), aldehyde 4e (0.70 g, 3.8
mmol), MgSO4 (5 g), DCM (20 mL mL) and a reaction time of 4 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1 hour. The crude product was purified by column chromatography
1
(85:10:5 EtOAc: MeOH: Et3N) to give a yellow oil (0.608 g, 54 %). H NMR (CDCl3, 400 MHz) δ 7.21-
7.15 (m, 1H), 6.82-6.73 (m, 2H), 6.30 (s, 1H), 3.31 (s, 2H), 3.09 – 2.98 (m, 1H), 2.74-2.55 (m, 2H), 2.32
(s, 3H), 2.15-1.99 (m, 2H), 1.93-1.78 (m, 2H), 1.75 (s, 3H), 1.78-1.59 (m, 2H), 1.53-1.41 (m, 2H). LR-MS
+
[M+H]+ C17H25N2F2 , Calc. 295.2, found 295.0.
(E)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-
1-amine (8i).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.50 g, 3.9 mmol), aldehyde 4f (0.89 g, 3.8
mmol), MgSO4 (4.96 g), DCM (20 mL) and a reaction time of 4 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (0.14 g, 3.7 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1 hour. The crude product was purified by column chromatography
(85:10:5 EtOAc: MeOH: Et3N) to give a yellow oil (0.064 g, 5 %). 1H NMR (CDCl3, 250 MHz) δ 7.22 (app
s, 1H), 7.09 (app s, 1H), 7.05 (app s, 1H), 6.38 (s, 1H), 3.25 (s, 2H), 3.01 – 2.92 (m, 1H), 2.71-2.50 (m,
2H), 2.22 (s, 3H), 2.15-1.92 (m, 2H), 1.91-1.75 (m, 2H), 1.82 (s, 3H), 1.72-1.55 (m, 2H), 1.55-1.34 (m,
+
2H). LR-MS [M+H]+ C18H25N2F4 , Calc. 345.2, found 345.1.
(E)-3-(2-Fluoro-4-methoxyphenyl)-2-methyl-N-(2-(1-methylpyrrolidin-2-yl)ethyl)prop-2-en-1-amine
(8j).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.20 g, 1.6 mmol), aldehyde 4g (0.30 g, 1.5
mmol), MgSO4 (2.0 g), DCM (8 mL) and a reaction time of 4 days. For the imine reduction, the
S10

following reagents and conditions were used: NaBH4 (0.06 g, 1.6 mmol), MeOH (4 mL), acetone (1
mL) and a reaction time of 1 hour. The crude product was purified by column chromatography
(85:10:5 EtOAc: MeOH: Et3N) to give a yellow oil (0.228 g, 49 %). 1H NMR (CDCl3, 250 MHz) δ 7.12 (t,
1H, J=8.5 Hz), 6.63-6.51 (m, 2H), 6.29 (s, 1H), 3.72 (s, 3H), 3.28 (s, 2H), 3.04 – 2.94 (m, 1H), 2.71-2.50
(m, 2H), 2.25 (s, 3H), 2.15-1.96 (m, 2H), 1.95-1.75 (m, 2H), 1.76 (s, 3H), 1.75-1.53 (m, 2H), 1.53-1.35
(m, 2H). LR-MS [M+H]+ C18H28N2FO+, Calc. 307.2, found 307.1
(E)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-3-phenylprop-2-en-1-amine (8k).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (0.71 g, 5.5 mmol), cinnamaldehyde 4h (1.46
g, 11.0 mmol), Na2SO4 (1.57 g), DCM (100 mL) and a reaction time of 1 day. For the imine reduction,
the following reagents and conditions were used: NaBH4 (0.42 g, 11.0 mmol), MeOH (100 mL),
acetone (40 mL) and a reaction time of 2 hour. The crude product was purified by column
1
chromatography (DCM/8% Et3N, MeOH gradient 0% to 8%) to give yellow oil (0.35 g, 26 %). H NMR
(250 MHz, CDCl3) δ 7.45 – 7.20 (m, 5H), 6.54 (d, J = 15.9 Hz, 1H), 6.31 (dt, J = 15.9 Hz, 6.2 Hz, 1H), 3.44
(d, J = 6.2 Hz, 2H), 3.15 – 3.04 (m, 1H), 2.80-2.63 (m, 2H), 2.33 (s, 3H), 2.20-2.05 (m, 2H), 2.02-1.85
(m, 2H), 1.85-1.60 (m, 2H), 1.60-1.44 (m, 2H). The trans-configuration of 8k was confirmed by the
+
large J-constant for coupling of the vinylic protons. LR-MS [M+H]+ C16H25N2 , Calc. 245.2, found
245.1.
(E)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-3-phenylbut-2-en-1-amine (8l).
This compound was prepared according to general procedure B. For the imine formation, the
following reagents and conditions were used: amine 7c (256 mg, 2.00 mmol), aldehyde 4i (289 mg,
1.98 mmol), Na2SO4 (10 g), DCM (20 mL) and a reaction time of 5 days. For the imine reduction, the
following reagents and conditions were used: NaBH4 (73 mg, 1.93 mmol), MeOH (10 mL), acetone (1
mL) and a reaction time of 1.5 hour. The crude product was purified by column chromatography
1
(EtOAc-MeOH (4:1)) to give an oil (357 mg, 70 %). H NMR (250 MHz, CDCl3) δ 7.34-7.08 (m, 5H), 5.80
(t, 1H, J=7.5 Hz), 3.35 (d, 2H, J= 7.5 Hz), 3.04 – 2.93 (m, 1H), 2.71-2.55 (m, 2H), 2.22 (s, 3H), 2.11-1.98
+
(m, 2H), 2.00 (s, 3H), 1.92-1.72 (m, 2H), 1.72-1.52 (m, 2H), 1.52-1.31 (m, 2H). LR-MS [M+H]+ C17H27N2 ,
Calc. 259.2, found 259.1.
S11

Acid chloride synthesis
3,4,5-Trimethoxybenzoyl chloride (10a).
The general procedure C was followed, using acid 9a (2.00 g, 9.42 mmol) and SOCl2 (13.8 mL, 190.2
mmol). The product was a white solid (2.10 g, 97 %).[1]
2,4-Dimethoxybenzoyl chloride (10b).
Anhydrous DMF (8 µL, 0.1 mmol) was added to anhydrous DCM (7 mL). Acid 9b (1.00 g, 5.49 mmol)
was added and the mixture was cooled to 0°C. Oxalylchloride (1.0 mL, 11.7 mmol) was added
dropwise and the resulting solution was allowed to warm to r.t. (ca. 30 min.), after which it was
concentrated in vacuo and dried. The product was a white solid (1.06 g, 96 %) and was used without
purification. [2]
3,4-Dimethoxybenzoyl chloride (10c).
The general procedure C was followed, using acid 9c (1.00 g, 5.49 mmol) and SOCl2 (5.13 mL, 70.7
mmol). The product was a purple solid (1.07 g, 97 %).[3]
4-Methoxy-3-methylbenzoyl chloride (10d).
The general procedure C was followed, using acid 9d (0.10 g, 0.60 mmol) and SOCl2 (0.56 mL, 7.7
mmol). The product was a white-cream solid (0.10 g, 90 %).[4]
S12

2,3-Dihydrobenzo[b][1,4]dioxine-6-carbonyl chloride (10e).
The general procedure C was followed, using acid 9e (1.00 g, 5.55 mmol) and SOCl2 (5.19 mL, 71.5
mmol). The product was a brown solid (1.03 g, 93 %).[5]
Benzo[d][1,3]dioxole-5-carbonyl chloride (10f).
The general procedure C was followed, using acid 9f (1.55 g, 9.33 mmol) and SOCl2 (8.72 mL, 120.2
mmol). The product was a yellow solid (1.65 g, 96 %).[6]
S13

EDCI coupling
(E)-3,4,5-Trimethoxy-N-(2-methyl-3-phenylallyl)-N-(3-morpholinopropyl)-benzamide (11).
The general procedure D was followed, using THF (11 mL), EDCI.HCl (0.25 g, 1.3 mmol), Et3N (0.18
mL, 1.3 mmol), HOBt.H2O (0.13 g, 0.85 mmol), acid 9a (0.28 g, 1.3 mmol), amine 8a (0.23 g, 0.84
mmol) and a reaction time of 20 h. Purification was performed by sequential column
chromatography, first with eluent DCM:MeOH:Et3N 10:0.1:0.1, then with eluent DCM:MeOH 9.7:0.3.
This afforded the product as a yellow oil (0.287 g, 73 %). 1H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.38-
7.33 (m, 2H), 7.30-7.21 (m, 3H), 6.69 (s, 2H), 6.42 (s, 1H), 4.10 (s, 2H), 3.79 (s, 6H), 3.74 (s, 3H), 3.53-
3.48 (m, 4H), 3.42-3.37 (m, 2H), 2.33-2.27 (m, 6H), 1.79 (s, 3H), 1.79-1.72 (m, 2H). 13C-NMR (CDCl3,
62.5 MHz, 300 K) δ 171.5, 153.0, 138.6, 136.7, 133.6, 131.9, 128.5, 128.1, 126.6, 126.0, 103.6, 66.7,
+
60.5, 56.7, 56.0, 55.9, 53.4, 43.6, 23.9, 15.8. LC-purity: 99.3 %. HR-MS [M+H]+ C27H37N2O5 , Calc.
469.2697, found 469.2690.
(E)-N-(3-Hydroxypropyl)-3,4,5-trimethoxy-N-(2-methyl-3-phenylallyl)benzamide (12).
The general procedure D was followed, using THF (17 mL), EDCI.HCl (0.35 g, 1.83 mmol), Et3N (0.29
mL, 2.08 mmol), HOBt.H2O (0.20 g, 1.3 mmol), acid 9a (0.44 g, 2.07 mmol), amine 8b (0.28 g, 1.36
mmol) and a reaction time of 20 h. Purification was performed by column chromatography (gradient
DCM:MeOH 9.97:0.03 to DCM:MeOH 9.7:0.3). This gave the product as a yellowish oil (0.222 g, 41%).
1H-NMR (DMSO-d6, 400 MHz, 373 K) δ δ 7.36-7.33 (m, 2H), 7.28-7.21 (m, 3H), 6.69 (s, 2H), 6.40 (s,
1H), 4.12 -4.08 (m, 1H), 4.10 (s, 2H), 3.78 (s, 6H), 3.73 (s, 3H), 3.50-3.40 (m, 4H), 1.86-1.75 (m, 2H),
1.75 (s, 3H). 13C-NMR (CDCl3, 62.5 MHz, 300 K) δ 172.8, 153.0, 139.3, 136.8, 133.4, 131.0, 128.7,
128.1, 126.8, 126.1, 104.5, 60.8, 58.9, 56.4, 56.2, 41.7, 30.0, 16.0. LC-purity: 97.2 %. HR-MS [M+H]+
+
C23H30NO5 , Calc. 400.2118, found 400.2103.
S14

(E)-3,4,5-Trimethoxy-N-(2-methyl-3-phenylallyl)-N-(3-(2-methylpiperidin-1-yl)propyl)benzamide
(13).
The general procedure D was followed, using THF (16 mL), EDCI.HCl (0.37 g, 1.93 mmol), Et3N (0.27
mL, 1.93 mmol), HOBt.H2O (0.19 g, 1.24 mmol), acid 9a (0.41 g, 1.93 mmol), amine 8d (0.37 g, 1.29
mmol) and a reaction time of 36 hour. Purification was performed by column chromatography
(eluent DCM:MeOH 9:1). This afforded the product as a yellowish oil (0.144 g, 23 %). 1H-NMR (DMSO-
d6, 400 MHz, 373 K) δ 7.37-7.33 (m, 2H), 7.28-7.21 (m, 3H), 6.68 (s, 2H), 6.42 (s, 1H), 4.10 (s, 2H),
3.79 (s, 6H), 3.74 (s, 3H), 3.42-3.26 (m, 2H), 2.72-2.66 (m, 1H), 2.62-2.50 (m, 1H), 2.34-2.25 (m, 1H),
2.25-2.17 (m, 1H), 2.12-2.02 (m, 1H), 1.79 (s, 3H), 1.79-1.69 (m, 2H), 1.61-1.12 (m, 6H), 0.95 (d, 3H,
J=6.4 Hz). 13C-NMR (CDCl3, 50 MHz, 300 K) δ 171.5, 153.0, 138.7, 136.8, 133.6, 131.6, 128.6, 128.1,
126.6, 126.1, 104.0, 60.7, 56.5, 56.0, 51.7, 51.0, 46.3, 43.6, 34.2, 29.5, 25.9, 23.9, 18.7, 15.8. IR (neat)
+
1624 cm-1. LC-purity: 98.8 %. HR-MS [M+H]+ C29H41N2O4 , Calc. 481.3061, found 481.3046.
S15

Acid chloride coupling
(E)-3,4,5-Trimethoxy-N-(2-methyl-3-phenylallyl)-N-(2-1-methylpyrrolidin-2-yl)ethyl)benzamide
(14).
This compound was prepared following the general procedure E, using amine 8c (50 mg, 0.19 mmol),
acid chloride 10a (48 mg, 0.21 mmol), Et3N (0.030 mL, 0.22 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (56 mg, 65%). H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.37-7.33
(m, 2H), 7.30-7.21 (m, 3H), 6.68 (s, 2H), 6.43 (s, 1H), 4.10 (s, 2H), 3.79 (s, 6H), 3.73 (s, 3H), 3.38-3.33
(m, 2H), 2.95-2.87 (m, 1H, overlaps with H2O signal), 2.18 (s, 3H), 2.12-2.02 (m, 2H), 1.92-1.73 (m,
2H), 1.78 (s, 3H), 1.62-1.55 (m, 3H), 1.49-1.35 (m, 1H). 13C-NMR (CDCl3, 50 MHz, 300 K) δ 171.6,
153.2, 138.9, 137.0, 132.2, 131.8, 128.8, 128.3, 126.8, 104.2, 103.9, 64.4 (br), 60.9, 57.1, 56.2, 45.3,
+
44.8, 40.4, 30.8, 30.4, 21.8, 15.7. LC-purity: 98.9 %. HR-MS [M+H]+ C27H37N2O4 , Calc. 453.2748,
found 453.2741.
(E)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-N-(3-phenylbut-2-enyl)benzamide (15).
This compound was prepared following the general procedure E, using amine 8l (67 mg, 0.26 mmol),
acid chloride 10a (111 mg, 0.48 mmol), Et3N (0.07 mL, 0.50 mmol), DCM (1.0 mL + 1.0 mL) and a
reaction time of 2 days. The product was purified using sequential column chromatography (1st
column: EtOAc/MeOH/TEA = 4/1/0.1; 2nd column: DCM/EtOAc/TEA = 1/1/0.05) to give an oil (24 mg,
20 %). 1H-NMR (400 MHz, DMSO-d6, 373 K) δ 7.43-7.40 (m, 2H), 7.36-7.27 (m, 3H), 6.68 (s, 2H), 5.82
(t, 1H, J=6.4 Hz), 4.16 (d, 2H, J=6.4 Hz), 3.79 (s, 6H), 3.73 (s, 3H), 3.41-3.33 (m, 2H), 2.26 (s, 3H), 2.28-
2.15 (m, 2H), 1.97 (s, 3H), 1.97-1.79 (m, 2H), 1.69-1.59 (m, 3H), 1.43-1.32 (m, 1H), an 1H signal
+
overlaps with H2O peak according to 2D-NOESY. LC-purity: 93.1 %. HR-MS [M+H]+ C27H37N2O4 , Calc.
453.2748, found 453.2707.
The trans-configuration of 15 was confirmed by high-temperature NOESY NMR:
-
-
Coupling Ha and Hb
Absence coupling Ha and Hd
S16

(E)-N-Cinnamyl-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-yl)ethyl)benzamide (16).
This compound was prepared following the general procedure E, using amine 8k (0.150 g, 0.61
mmol), acid chloride 10a (0.170 g, 0.74 mmol), Et3N (0.075 g, 0.74 mmol), DCM (7.5 mL + 7.5 mL) and
a reaction time of 20 hours. The product was purified using column chromatography (EtOAc/5% Et3N,
MeOH gradient 0% to 10%) to give a yellow oil (0.197 g, 73 %). 1H NMR (400 MHz, DMSO-d6, 375 K) δ
7.43 (d, J = 7.3, 2H), 7.35-7.30 (m, 2H), 7.27-7.23 (m, 1H), 6.70 (s, 2H), 6.55 (d, J = 15.9, 1H), 6.28 (dt, J
= 15.9 Hz, 5.6 Hz, 1H), 4.12 (d, J = 5.6 Hz, 2H), 3.80 (s, 6H), 3.74 (s, 3H), 3.40-3.33 (m, 2H), 2.95-2.87
(m, 1H, overlaps with H2O signal), 2.19 (s, 3H), 2.15-2.05 (m, 2H), 1.95-1.75 (m, 2H), 1.65-1.54 (m,
3H), 1.41-1.25 (m, 1H). 13C NMR (100 MHz, DMSO-d6, 375 K) δ 170.6, 153.5, 137.1, 132.8, 132.5,
129.0, 128.0, 126.7, 126.4, 121.0, 105.7, 64.3, 60.6, 57.0, 56.7, 45.1, 40.1, 31.5, 30.3, 22.3, one signal
+
overlaps with another one or with DMSO signal. LC-purity: 99.0 %. HR-MS [M+H]+ C26H35N2O4 , Calc.
439.2591, found 439.2552.
N
O
Hd
Hb
O
O
N
O
Ha Hc Hd
The trans-configuration for 16 was confirmed by:
1) The large J-constant for coupling of Hb and Hc
2) High-temperature NOESY NMR, revealing:
-
-
Coupling of both Hb and Hc with Hd and with Ha
Absence of a coupling of Ha with Hd
(E)-2,4-Dimethoxy-N-(2-methyl-3-phenylallyl)-N-(2-1-methylpyrrolidin-2-yl)ethyl)benzamide (17).
This compound was prepared following the general procedure E, using amine 8c (50 mg, 0.19 mmol),
acid chloride 10b (69 mg, 0.34 mmol), Et3N (0.050 mL, 0.36 mmol), DCM (5 mL + 5 mL) and a reaction
time of 3 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (34 mg, 42 %). The H-NMR spectrum is complex and shows
rotamers in a ca. 1:3 ratio. Some signals below 5.0 ppm are broad and cannot be clearly interpreted.
1H-NMR (CDCl3, 250 MHz, 300 K) Major rotamer δ 7.35-7.15 (m, 6H), 6.52-6.43 (m, 3 overlapping H),
S17

4.9-4.4 (br, 2H?), 3.81 (s, 3H), 3.79 (s, 3H), 3.20-3.00 (m, 2H), 2.15 (s, 3H), 2.20-1.30 (br m, 12 H). LC-
+
purity: 97.2 %. HR-MS [M+H]+ C26H35N2O3 , Calc. 423.2642, found 423.2628.
(E)-3,4-Dimethoxy-N-(2-methyl-3-phenylallyl)-N-(2-1-methylpyrrolidin-2-yl)ethyl)benzamide (18).
This compound was prepared following the general procedure E, using amine 8c (50 mg, 0.19 mmol),
acid chloride 10c (69 mg, 0.34 mmol), Et3N (0.050 mL, 0.36 mmol), DCM (5 mL + 5 mL) and a reaction
time of 3 hours. The crude product was purified by column chromatography (8.0:1.5:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (48 mg, 60 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.37-7.20 (m, 5H), 7.04-6.98 (m, 2H), 6.84 (d, 1H, J=8.75 Hz), 6.44 (s, 1H),
4.40-3.95 (br, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.75-3.25 (br m, 2H), 3.09-2.95 (br m, 1H), 2.40-1.40 (br
+
m, 14 H). LC-purity: 98.8 %. HR-MS [M+H]+ C26H35N2O3 , Calc. 423.2642, found 423.2626.
(E)-4-Methoxy-3-methyl-N-(2-methyl-3-phenylallyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)benzamide
(19).
This compound was prepared following the general procedure E, using amine 8c (50 mg, 0.19 mmol),
acid chloride 10d (70 mg, 0.38 mmol), Et3N (0.052 mL, 0.37 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (4.5:5:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (20 mg, 26 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 400 MHz, 300 K) δ 7.36-7.32 (m, 2H), 7.28-7.21 (m, 5H), 6.80 (d, 1H, J=8.4 Hz), 6.43 (s, 1H),
4.50-3.95 (br, 2H), 3.84 (s, 3H), 3.75-3.25 (br m, 2H), 3.10-2.95 (br m, 1H), 2.22 (s, 3H), 2.45-1.30 (br
+
m, 14 H). LC-purity: 99.0 %. HR-MS [M+H]+ C26H35N2O2 , Calc. 407.2693, found 407.2695.
S18

(E)-N-(2-Methyl-3phenylallyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2,3-
dihydrobenzo[b][1,4]dioxine-6-carboxamide (20).
This compound was prepared following the general procedure E, using amine 8c (194 mg, 0.75
mmol), acid chloride 10e (270 mg, 1.36 mmol), Et3N (0.20 mL, 1.43 mmol), DCM (5 mL + 5 mL) and a
reaction time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (192 mg, 61 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.31-7.11 (m, 5H), 6.95-6.77 (m, 3H), 6.37 (s, 1H), 4.30-3.85 (br, 2H), 4.19
(br s, 4H), 3.72-3.20 (br m, 2H), 3.05-2.90 (br m, 1H), 2.40-1.40 (br m, 14 H). LC-purity: 98.1 %. HR-
+
MS [M+H]+ C26H33N2O3 , Calc. 421.2486, found 421.2467.
(E)-N-(3-(2,4-Difluorophenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (21).
This compound was prepared following the general procedure E, using amine 8h (55 mg, 0.19 mmol),
acid chloride 10a (79 mg, 0.34 mmol), Et3N (0.050 mL, 0.36 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (72 mg, 78 %). H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.40-7.30
(m, 1H), 7.15-7.00 (m, 2H), 6.69 (s, 2H), 6.33 (s, 1H), 4.11 (s, 2H), 3.79 (s, 6H), 3.73 (s, 3H), 3.38-3.30
(m, 2H), 2.95-2.87 (m, 1H, overlaps with H2O signal), 2.19 (s, 3H), 2.12-1.98 (m, 2H), 1.94-1.73 (m,
2H), 1.70 (s, 3H), 1.65-1.55 (m, 3H), 1.40-1.28 (m, 1H). LC-purity: 98.3 %. HR-MS [M+H]+
+
C27H35F2N2O4 , Calc. 489.2559, found 489.2561.
(E)-N-(3-(2,4-Difluorophenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (22).
This compound was prepared following the general procedure E, using amine 8h (0.50 g, 1.7 mmol),
acid chloride 10c (0.60 g, 2.99 mmol), Et3N (0.47 mL, 3.37 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
S19

1
EtOAc:Hex:TEA) to give an orange oil (0.50 g, 64 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.11-7.00 (m, 1H), 6.92-6.85 (m, 2H), 6.75-6.63 (m, 3H), 6.22 (s, 1H), 4.30-
3.70 (br, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 3.65-3.12 (br m, 2H), 2.92-2.80 (br m, 1H),2.20-1.30 (br m, 14
+
H). LC-purity: 95.7 %. HR-MS [M+H]+ C26H33F2N2O3 , Calc. 459.2454, found 459.2451.
(E)-N-(3-(4-Fluorophenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (23).
This compound was prepared following the general procedure E, using amine 8g (0.349 g, 1.26
mmol), acid chloride 10a (0.51 g, 2.21 mmol), Et3N (0.35 mL, 2.51 mmol), DCM (5 mL + 5 mL) and a
reaction time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
EtOAc:Hex:Et3N) to give a yellow oil (0.420 g, 71 %). 1H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.32-7.26
(m, 2H), 7.17-7.11 (m, 2H), 6.69 (s, 2H), 6.41 (s, 1H), 4.10 (s, 2H), 3.79 (s, 6H), 3.73 (s, 3H), 3.39-3.29
(m, 2H), 2.95-2.87 (m, 1H, overlaps with H2O signal), 2.19 (s, 3H), 2.15-2.00 (m, 2H), 1.94-1.73 (m,
+
2H), 1.76 (s, 3H), 1.64-1.54 (m, 3H), 1.41-1.28 (m, 1H). LC-purity: 96.4 %. HR-MS [M+H]+ C27H36FN2O4 ,
Calc. 471.2654, found 471.2634.
(E)-N-(3-(4-Fluorophenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (24).
This compound was prepared following the general procedure E, using amine 8g (0.168 g, 0.61
mmol), acid chloride 10c (0.219 g, 1.09 mmol), Et3N (0.17 mL, 1.22 mmol), DCM (5 mL + 5 mL) and a
reaction time of 4 hours. The product was purified using column chromatography (8.5:1:0.5
1
EtOAc:Hex:TEA) to give a yellow oil (0.111 g, 41 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(DMSO-d6, 250 MHz, 300 K) δ 7.38-7.29 (m, 2H), 7.26-7.13 (t, 2H), 7.03-6.94 (m, 3H), 6.42 (br s, 1H),
4.30-3.90 (br, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.50-3.10 (br, 2H, overlaps with H2O peak), 2.95-2.81 (br
+
m, 1H), 2.30-1.40 (br m, 14 H). LC-purity: 97.3 %. HR-MS [M+H]+ C26H34FN2O3 , Calc. 441.2548, found
441.2546.
S20

(E)-N-(3-(3-Fluorophenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (25).
This compound was prepared following the general procedure E, using amine 8f (0.40 g, 1.45 mmol),
acid chloride 10a (1.12 g, 4.86 mmol), Et3N (0.74 mL, 5.3 mmol), DCM (5 mL + 5 mL) and a reaction
time of 18 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (0.40 g, 59 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 400 MHz, 300 K) δ 7.19-7.14 (app q, 1H), 6.90 (d, 1H, J=7.6 Hz), 6.84-6.76 (m, 2H), 6.61-6.50
(br, 2H), 6.29 (s, 1H), 4.30-3.80 (br, 2H), 3.72 (s, 6H), 3.70 (br s, 3H), 3.60-2.80 (br m, 3 H), 2.30-1.40
+
(br m, 14 H). LC-purity: 96.6 %. HR-MS [M+H]+ C27H36FN2O4 , Calc. 471.2654, found 471.2633.
(E)-N-(3-(3-Fluorophenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (26).
This compound was prepared following the general procedure E, using amine 8f (0.235 g, 0.85
mmol), acid chloride 10c (0.307 g, 1.53 mmol), Et3N (0.24 mL, 1.7 mmol), DCM (5 mL + 5 mL) and a
reaction time of 4 hours. The product was purified using column chromatography (8.5:1:0.5
EtOAc:Hex:TEA) to give a yellow oil (0.187 g, 50 %). 1H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.42-7.36
(m, 1H), 7.09 (d, 1H, J=7.6 Hz), 7.03-6.96 (m, 5H), 6.40 (s, 1H), 4.10 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H),
3.35 (t, 2H, J=7.6 Hz), 2.95-2.85 (m, 1H), 2.18 (s, 3H), 2.13-2.02 (m, 2H), 1.92-1.75 (m, 2H), 1.77 (s,
+
3H), 1.64-1.51 (m, 3H), 1.39-1.24 (m, 1H). LC-purity: 95.3 %. HR-MS [M+H]+ C26H34FN2O3 , Calc.
441.2548, found 441.2536.
(E)-N-(3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-
methylpyrrolidin-2-yl)ethyl)benzamide (27).
This compound was prepared following the general procedure E, using amine 8i (0.30 g, 0.87 mmol),
acid chloride 10a (0.36 g, 1.57 mmol), Et3N (0.25 mL, 1.79 mmol), DCM (5 mL + 5 mL) and a reaction
S21

time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (0.31 g, 66 %). H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.43-7.39
(m, 3H), 6.70 (s, 2H), 6.51 (s, 1H), 4.12 (s, 2H), 3.80 (s, 6H), 3.75 (s, 3H), 3.35 (t, 2H, J=7.6 Hz), 2.95-
2.87 (m, 1H), 2.17 (s, 3H), 2.11-2.02 (m, 2H), 1.92-1.75 (m, 2H), 1.82 (s, 3H), 1.62-1.54 (m, 3H), 1.48-
1.36 (m, 1H). 13C-NMR (DMSO-d6, 100 MHz, 373 K) δ 170.9, 163.7, 161.3, 153.5, 141.7 (d, J=8 Hz),
138.8, 132.7, 124.3, 121.8, 119.5 (d, J=21 Hz), 110.9 (m), 105.7, 64.0, 60.6, 57.0, 56.9, 44.5, 40,4,
31.5, 30.4, 22.3, 16.1, one signal overlaps with another one or with DMSO signal. The signals for the
quaternary C-F and CF3 carbons were not visible under these conditions. LC-purity: 97 %. HR-MS
[M+H]+ C28H35F4N2O4 , Calc. 539.2527, found 539.2504. A trace of DCM remains as solvate and could
+
not be removed after prolonged drying (ca. 15 mole %).
(E)-N-(3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-
methylpyrrolidin-2-yl)ethyl)benzamide (28).
This compound was prepared following the general procedure E, using amine 8i (0.30 g, 0.87 mmol),
acid chloride 10c (0.31 g, 1.55 mmol), Et3N (0.25 mL, 1.79 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:TEA) to give a yellow oil (0.34 g, 77 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.20 (s, 1H), 7.12-7.02 (m, 2H), 6.95-6.87 (m, 2H), 6.77 (d, 1H, J=8 Hz), 6.33
(s, 1H), 4.30-3.90 (br, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.65-3.20 (br m, 2H), 2.98-2.85 (br m, 1H), 2.30-
+
1.40 (br m, 14 H). LC-purity: 96.8 %. HR-MS [M+H]+ C27H33F4N2O3 , Calc. 509.2422, found 509.2423.
(E)-N-(3-(2-Fluorophenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (29, VUF11207)
This compound was prepared following the general procedure E, using amine 8e (50 mg, 0.18 mmol),
acid chloride 10a (75 mg, 0.33 mmol), Et3N (0.050 mL, 0.36 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a colorless oil (63 mg, 74 %). H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.33-
7.25 (m, 2H), 7.21-7.12 (m, 2H), 6.69 (s, 2H), 6.41 (s, 1H), 4.13 (s, 2H), 3.81 (s, 6H), 3.74 (s, 3H), 3.35
(t, 2H, J=8.0 Hz), 2.93-2.87 (m, 1H), 2.18 (s, 3H), 2.11-1.99 (m, 2H), 1.92-1.75 (m, 2H), 1.72 (s, 3H),
1.63-1.55 (m, 3H), 1.40-1.28 (m, 1H). 13C-NMR (DMSO-d6, 100 MHz, 373 K) δ 170.9, 160.0 (d, J=245
S22

Hz), 153.5, 139.9, 137.6, 132.7, 130.9, 129.2, 125.1 (d, J=15 Hz), 124.5, 119.3, 115.7 (d, J=22 Hz),
106.6, 64.1, 60.6, 56.9, 56.8, 44.2, 40.4, 31.4, 30.3, 22.3, 16.2, one signal overlaps with another one
or with DMSO signal. LC-purity: 98.7 %. HR-MS [M+H]+ C27H36FN2O4 , Calc. 471.2654, found 471.2643.
+
When prepared at larger scale, a trace of EtOAc solvate remained and could not be removed by
prolonged drying (13 mole %).
2D-NOESY (DMSO-d6, 400 MHz, 373 K): Diagnostic couplings for E-configuration: Ha x Hc, Ha x Hb;
absent: Hc x Hb.
(E)-N-(3-(2-Fluorophenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (30, VUF11403)
This compound was prepared following the general procedure E, using amine 8e (0.244 g; 0.88
mmol), acid chloride 10c (0.319 g, 1.59 mmol), Et3N (0.25 mL, 1.79 mmol), DCM (5 mL + 5 mL) and a
reaction time of 4 hours. The product was purified using column chromatography (8.5:1:0.5
EtOAc:Hex:TEA) to give a yellow oil (0.123 g, 32 %). 1H-NMR (DMSO-d6, 400 MHz, 373 K) δ 7.34-7.28
(m, 2H), 7.22-7.14 (m, 2H), 7.02-6.95 (m, 3H), 6.40 (s, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.37
(t, 2H, J=8.0 Hz), 2.95-2.86 (m, 1H), 2.18 (s, 3H), 2.10-2.00 (m, 2H), 1.92-1.75 (m, 2H), 1.70 (s, 3H),
1.62-1.52 (m, 3H), 1.42-1.35 (m, 1H). 13C-NMR (DMSO-d6, 100 MHz, 373 K) δ 171.2, 160.0 (d, J=243
Hz), 150.7, 149.5, 137.7, 131.0, 130.2, 129.2, 125.1 (d, J=15 Hz), 124.5, 120.1, 119.2, 115.7 (d, J=22
Hz), 113.0, 112.2, 64.0, 56.9, 56.6, 56.6, 44.2, 40.4, 31.5, 30.4, 22.4, 16.2, one signal overlaps with
another one or with DMSO signal. LC-purity: 98.3 %. HR-MS [M+H]+ C26H34FN2O3+, Calc. 441.2548,
found 441.2551. When prepared at larger scale, a trace of EtOAc solvate remained and could not be
removed by prolonged drying (18 mole %).
S23

(E)-N-(3-(2-Fluoro-4-methoxyphenyl)-2-methylallyl)-3,4,5-trimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (31).
This compound was prepared following the general procedure E, using amine 8j (0.17 g, 0.56 mmol),
acid chloride 10a (0.20 g, 0.87 mmol), Et3N (0.14 mL, 1.00 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:Et3N) to give a yellow oil (0.23 g, 82 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.19-7.03 (br m, 1H), 6.69-6.52 (m, 4H), 6.33 (s, 1H), 4.40-3.80 (br, 2H),
3.81-3.71 (m, 12H), 3.70-3.10 (br m, 2H), 3.05-2.88 (br m, 1H), 2.30-1.40 (br m, 14 H). LC-purity: 93.7
%. HR-MS [M+H]+ C28H38FN2O5 , Calc. 501.2759, found 501.2750.
+
(E)-N-(3-(2-Fluoro-4-methoxyphenyl)-2-methylallyl)-3,4-dimethoxy-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzamide (32)
This compound was prepared following the general procedure E, using amine 8j (16 mg, 0.05 mmol),
acid chloride 10c (40 mg, 0.20 mmol), Et3N (0.020 mL, 0.14 mmol), DCM (5 mL + 5 mL) and a reaction
time of 4 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:TEA) to give a yellow oil (5 mg, 21 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.19-7.07 (br m, 1H), 7.06-6.95 (m, 2H), 6.85 (d, 1H, J=7.8 Hz), 6.70-6.55
(m, 2H), 6.36 (s, 1H), 4.40-3.90 (br, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.70-3.15 (br m, 2H),
+
3.10-2.94 (br m, 1H), 2.40-1.40 (br m, 14 H). LC-purity: 92.0 %. HR-MS [M+H]+ C27H36FN2O4 , Calc.
471.2654, found 471.2643.
(E)-N-(3-(2,4-Difluorophenyl)-2-methylallyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-2,3-
dihydrobenzo[b][1,4]dioxine-6-carboxamide (33).
This compound was prepared following the general procedure E, using amine 8h (0.41 g, 1.39 mmol),
acid chloride 10e (0.49 g, 2.47 mmol), Et3N (0.38 mL, 2.72 mmol), DCM (5 mL + 5 mL) and a reaction
S24

time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:TEA) to give a yellow oil (0.47 g, 74 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.21-7.05 (m, 1H), 6.95-6.68 (m, 5H), 6.27 (s, 1H), 4.40-3.80 (br, 2H), 4.20
(br s, 4H), 3.75-3.20 (br m, 2H), 3.05-2.88 (br m, 1H), 2.40-1.40 (br m, 14 H). LC-purity: 96.5 %. HR-
MS [M+H]+ C26H31F2N2O3 , Calc. 457.2297, found 457.2305.
+
(E)-N-(3-(2,4-Difluorophenyl)-2-methylallyl)-N-(2-(1-methylpyrrolidin-2-
yl)ethyl)benzo[d][1,3]dioxole-5-carboxamide (34)
This compound was prepared following the general procedure E, using amine 8h (0.61 g, 2.07 mmol),
acid chloride 10f (0.69 g, 3.73 mmol), Et3N (0.57 mL, 4.09 mmol), DCM (5 mL + 5 mL) and a reaction
time of 2 hours. The crude product was purified by column chromatography (8.5:1:0.5
1
EtOAc:Hex:TEA) to give a yellow oil (0.78 g, 85 %). The H-NMR spectrum is complex and indicates
rotamers. Many signals below 5.0 ppm are broad and cannot always be clearly interpreted. 1H-NMR
(CDCl3, 250 MHz, 300 K) δ 7.06-6.95 (m, 1H), 6.78-6.70 (m, 2H), 6.69-6.56 (m, 3H), 6.14 (s, 1H), 5.76
(s, 2H), 4.20-3.70 (br, 2H), 3.60-2.90 (br m, 2H), 2.85-2.72 (br m, 1H), 2.20-1.30 (br m, 14 H). LC-
purity: 96.4 %. HR-MS [M+H]+ C25H29F2N2O3+, Calc. 443.2141, found 443.2139.
S25

Exemplary spectra
Figure S2. 1H-NMR spectrum of compound 29 in DMSO-d6 at 300 K. This particular NMR sample had
a trace of DCM left (at 5.74 ppm).
S26

Figure S3. 1H-NMR spectrum of compound 29 in DMSO-d6 at 373 K. This particular NMR sample had
a trace of DCM left (at 5.66 ppm).
S27

Figure S4. 13C-APT-NMR spectrum of compound 29 in DMSO-d6 at 373 K. This particular NMR sample
had a trace of DCM left (at 55.1 ppm).
S28

Figure S5. Blow-up of 2D-NOESY spectrum of compound 29 in DMSO-d6 at 373 K. This particular
NMR sample had a trace of DCM left (at 5.66 ppm). Clearly visible is the Ha x Hb coupling (blue,
indicative for trans-configuration) and the absence of Hc x Hb couping (green, if present this would
be indicative of cis-configuration).
S29

Figure S6. LC-MS chromatogram of compound 29 (detection at 230 nm).
S30