Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2019.06.035

Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [³H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 (K_i = 193 nM) bearing a p-fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ₂ affinity (K_i = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ₁ and σ₂ receptors was rather low (K_i > 100 nM).

Full text of DOI:10.1016/j.bmc.2019.06.035

Accepted Manuscript
Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based
GluN2B receptor antagonists
Marina Wagner, Dirk Schepmann, Simon M. Ametamey, Bernhard Wünsch
PII:
S0968-0896(19)30782-5
https://doi.org/10.1016/j.bmc.2019.06.035
BMC 14972
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 May 2019
17 June 2019
19 June 2019
Please cite this article as: Wagner, M., Schepmann, D., Ametamey, S.M., Wünsch, B., Modification of the 4-
phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists, Bioorganic & Medicinal
Chemistry (2019), doi: https://doi.org/10.1016/j.bmc.2019.06.035
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1
Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based
GluN2B receptor antagonists
Marina Wagner,[a] Dirk Schepmann,[a] Simon M. Ametamey,[b] Bernhard Wünsch*[a,c]
[a]
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster,
Corrensstraße 48, D-48149 Münster, Germany Tel.: +49-251-8333311; Fax: +49-
251-8332144; Email: wuensch@uni-muenster.de
[b]
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical
Sciences, ETH Zurich, Zurich, Switzerland
[c]
Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany
Abstract
Excitotoxicity driven by overactivation of NMDA receptors represents a major
mechanism of acute and chronic neurological and neurodegenerative disorders.
Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA
receptor are able to interrupt this ongoing neurodamaging process. Starting from the
potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by
modification of the N-(4-phenylbutyl) side chain. With respect to developing novel
fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were
synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-
side chain were prepared by Sonogashira reaction and nucleophilic substitution. The
fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new
ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation

2
of a triple bond. The affinity towards the ifenprodil binding site was tested in an
established competition assay using [3H]ifenprodil as radioligand. Introduction of a
fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring
by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to
considerable reduction of GluN2B affinity. The phenol 15 (Ki = 193 nM) bearing a p-
fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B
ligand of this series of compounds. With exception of 15 showing moderate 2 affinity
(Ki = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding
site of the NMDA receptor, 1 and 2 receptors was rather low (Ki > 100 nM).
Keywords: glutamate receptors; NMDA receptor; GluN2B antagonists; ifenprodil
binding site; 3-benzazepines; arylbutynyl analogs; structure-affinity relationships;
selectivity
1. Introduction
The NMDA receptor belongs to the class of ionotropic glutamate receptors, which are
activated by the excitatory amino acid neurotransmitter (S)-glutamate. Its name is
derived from the synthetic prototypical agonist N-methyl-D-aspartate (NMDA). The
NMDA receptor is particularly involved in coincidence detection,1 i.e. two agonists, (S)-
glutamate and glycine, are required for opening of the ligand gated ion channel.
Moreover, the voltage-dependent Mg2+ block has to be removed by depolarization of
the surrounding membrane, before the agonists are able to open the ion channel. In
contrast to the other two ionotropic glutamate receptors (AMPA, kainate receptors),
the NMDA receptor shows a high permeability for Ca2+ ions, which activate various
intracellular pathways.2 The simultaneous detection of at least two different signals

3
together with the high Ca2+ permeability resulting in stabilization of synaptic
connections can be used to explain memory formation.3
On the other hand, overactivation of the NMDA receptor leading to massive influx of
Ca2+ ions results in necrosis and apoptosis of neurons.2,4 These excitotoxic effects are
involved in acute (e.g. cerebral ischemia, stroke, trauma) and chronic neurological and
neurodegenerative disorders (e.g. depression, Huntington’s, Parkinson’s, Alzheimer’s
disease) rendering the NMDA receptor a promising target for the development of novel
drugs.3,5-9
The heterotetrameric NMDA receptor is formed by four subunits. Seven different
subunits are known so far: One GluN1 subunit with eight splice variants (GluN1a-h),
four GluN2 subunits (GluN2A-D) and two GluN3 subunits (GluN3A-B). Each subunit
consists of four domains: the carboxy terminal domain (CTD) located intracellularly,
the membrane spanning transmembrane domain (TMD) controlling the ion flux, the
ligand binding domain (LBD) with the glycine and glutamate binding sites on the GluN1
and GluN2 subunit, respectively, and the amino terminal domain (ATD). Both the LBD
and the ATD are located extracellularly and can interact with extracellular signal
molecules.7,10,11
GluN2B subunit containing NMDA receptors are of particular interest, since the
GluN2B subunit is expressed only in some regions of the central nervous system,
including cortex, hippocampus and striatum. The concentration in other regions, e.g.
cerebellum is rather low. Moreover, interaction with an additional binding site located
at the GluN1/GluN2B subunit interface can modulate the opening state of the ion
channel pore. Positive and negative allosteric modulators addressing the ifenprodil

4
binding site affect only NMDA receptors containing the GluN2B subunit, which is
restricted to only some regions of the brain, leading to increased selectivity.10-12
Very recently, insights into the structure of the NMDA receptor have been gained. In
2011, a dimer of the ATDs of a GluN1 and a GluN2B subunit have been crystallized
together with some ligands, including ifenprodil (1) and Ro 25-6981 (2).13 (Figure 1)
Three years later the structure of the complete NMDA receptor containing two GluN1
and two GluN2B subunits together with glutamate, glycine and some antagonists was
reported.14,15 All structures show the binding site for ifenprodil and analogs at the
interface between GluN1 and GluN2B subunits. Cryo electron microscopy studies
showed the NMDA receptor in the active (channel open) and inactive (channel closed)
form.16,17 According to the structural analysis, an H-bond between the amide moiety of
glutamine 110 and the protonated amino moiety of ligands represents the key
interaction.
HO
CH3
OH
N
N
CH3
HO
HO
#
1
ifenprodil ( )
2
Ro 25-6981 ( )
O
HO
S
F
O
N
O
N
N
H
RO
3
besonprodil ( )
4a
4b
: R = H
: R = CH3
Figure 1. Lead compounds ifenprodil (1), Ro 25-6981 (2), besonprodil (3) and 3-
benzazepines 4 with high GluN2B affinity.
# only one enantiomer of racemic erythro-ifenprodil is shown.

5
In order to address selectively NMDA receptors with GluN2B subunit expressed in only
some regions of the central nervous system, we are interested in positive and negative
allosteric modulators interacting with the ifenprodil binding site. The prototypical ligand,
giving name to this binding site is ifenprodil (1)18,19 showing high GluN2B affinity but
moderate selectivity and low bioavailability.20 (Figure 1) Ro 25-6981 (2), and
besonprodil (3) represent negative allosteric modulators of GluN2B subunit containing
NMDA receptors. (Figure 1)
Recently, the 3-benzazepines 4a and 4b interacting with the ifenprodil binding site
were developed by rearrangement of ifenprodil (1).21,22 The promising GluN2B affinity,
selectivity and metabolic stability of 4a23 and 4b prompted us to further develop the 3-
benzazepine GluN2B compound class. Herein, we report on the variation of the 4-
phenylbutyl side chain at the 3-benzazepine N-atom. In particular, the flexible
tetramethylene spacer should be rigidified by introduction of a triple bond, the phenyl
ring should be replaced by heteroaryl moieties and the possibility of introducing an F-
atom in the 4-phenylbutyl substituent should be exploited. Finding an optimal position
for an F-atom would allow the development of a fluorinated PET tracer for imaging of
GluN2B subunit containing NMDA receptors.
2. Synthesis
The synthesis of 4-phenylbutynyl derivatives 11 with a fluoroethoxy substituent in
different positions started with fluoroethylation of para-, meta- and ortho-bromophenols
5a-c with (2-fluoroethyl) tosylate to provide the fluoroethyl ethers 6a-c.24-26
Sonogashira coupling27,28 of the phenyl bromides 6a-c with but-3-yn-1-ol (7) resulted
in the phenylbutynols 8a-c. Although phenylbutynols 8a-c are commercially available,
a clear procedure for their synthesis could not be found in the literature. After tosylation

6
of the primary alcohols 8a-c, nucleophilic substitution with the 3-benzazepine 1022
provided the phenylbutynyl substituted 3-benzazepines 11a-c in 68 – 95 % yields.
Finally, the ortho-substituted fluoroethoxy derivative 11c was hydrogenated to yield the
[o-(fluoroethoxy)phenyl]butyl derivative 12c.
OH
O
O
(a)
(b)
F
F
Br
Br
RO
8a c
- : R = H
9a c
- : R = Tos
5a c
-
6a c
-
(c)
HO
5 11
-
a
b
c
para
meta
ortho
(d)
NH
H3CO
F
10
HO
HO
O
O
F
(e)
N
N
H3CO
H3CO
11a c
-
12c
Scheme 1: Synthesis of fluoroethoxy derivatives 11 and 12. Reagents and reaction
conditions: (a) (2-fluoroethyl) tosylate, CH3CN, K2CO3, reflux, 16 h, 98 - 100 %. (b) but-
3-yn-1-ol (7), Pd(PPh3)4, CuI, NEt3, reflux, 16 h, 42 – 83 %. (c) TosCl, NEt3, DMAP,
CH2Cl2, rt, 16 h, 53 – 86 %. (d) CH3CN, K2CO3, reflux, 36 – 72 h, 68 – 95 %. (e) only
11c: H2, Pd/C, CH3OH, rt, 16 h, 97 %.
In order to obtain a phenol instead of methyl ethers 11 and 12, the 3-benzazepine 13
bearing a benzyloxy moiety in 7-position21 was used for the nucleophilic substitution of
tosylate 9a. Treatment of 14 with H2 and Pd/C led to hydrogenation of the triple bond
and hydrogenolytic removal of the benzyl group yielding the phenol 15 with a
phenylbutyl side chain.

7
F
HO
O
NH
+
TosO
BnO
13
9a
(a)
F
HO
HO
F
(b)
O
N
O
N
BnO
HO
14
15
Scheme 2: Synthesis of fluoroethoxy substituted phenol 15. Reagents and reaction
conditions: (a) CH3CN, K2CO3, reflux, 72 h, 100 %. (b) H2, Pd/C, CH3OH, rt, 30 min,
69 %.
(a)
X Ar
16a-d
(b)
Ar
Ar
16-20
a
Ar
HO
TosO
HO
7
17a-d
18a d
-
16a c
- : X = I
b
c
d
HO
16d
:
X = Br
N
(c)
NH
HO
S
N
H3CO
10
S
HO
Ar
(d)
Ar
N
N
H3CO
H3CO
19a d
-
20b c
,
Scheme 3: Synthesis of various arylbutynyl and arylbutyl derivatives 19 and 20.
Reagents and reaction conditions: (a) Pd(PPh3)4, CuI, NEt3, reflux, 16 h, 62 – 100 %.
(b) TosCl, NEt3, DMAP, CH2Cl2, rt, 16 h, 42 – 85 %. (c) CH3CN, K2CO3, reflux, 72 h,
72 – 78 %. (d) only 19b, 19c: H2, Pd/C, CH3OH, rt, 16 h, 90 % (20b), 86 % (20c).
Next, various heteroaryl substituents should be introduced instead of the terminal
phenyl ring. For this purpose, the Sonogashira reaction of butynol 7 was performed

8
with various (het)aryl iodides 16a-c or bromide 16d. The resulting primary alcohols
17a-d28-30 were converted into the tosylates 18a-d,31,32 which were subsequently
reacted with 3-benzazepine 10 to afford the (hetero)arylbutynyl substituted 3-
benzazepines 19a-d. The pyridyl and thienyl derivatives 19b and 19c were reacted
with H2 and Pd/C to provide the pyridylbutyl and thienylbutyl substituted 3-
benzazepines 20b and 20c in 90 % and 86 % yield, respectively.
Since the triple bond is more rigid and considerably shorter than the single bond, the
complete butynyl spacer of 11, 14, and 19 is shorter than the more flexible saturated
butyl spacer of 12, 15, and 20. Therefore, the butynyl spacer of 19a was exemplarily
extended by one methylene moiety resulting in the homologous phenylpentynyl
derivative 24. Sonogashira reaction of iodobenzene (16a) was performed with pentynol
21 instead of butynol 7 to afford the phenylpentynol 2229 in 92 % yield. Activation of
primary alcohol 22 with tosyl chloride provided the tosylate 23,33 which was
transformed with 3-benzazepine 10 into phenylpentynyl derivative 24.
HO
(a)
Ph
16a
(b)
(c)
HO
HO
TosO
N
10
I
H3CO
Ph
Ph
Ph
21
22
23
24
Scheme 4: Synthesis of homologous phenylpentynyl derivative 24. Reagents and
reaction conditions: (a) Pd(PPh3)4, CuI, NEt3, reflux, 16 h, 92 %. (b) TosCl, NEt3,
DMAP, CH2Cl2, rt, 16 h, 39 %. (c) 10, CH3CN, K2CO3, reflux, 72 h, 100 %.
With the aim to exploit the terminal pyridyl moiety to introducing an F-atom for potential
PET tracers, fluoroethoxypyridines 2634 and 31 were prepared by alkylation of pyridin-

9
3-ols 25 and 30 with (2-fluoroethyl) tosylate. Sonogashira coupling of halopyridines 26
and 31 with butynol 7 led to the pyridylbutynols 27 and 32, which were reacted with
tosyl chloride to give the tosylates 28 and 33. Reaction of tosylates 28 and 33 with the
secondary amine 10 did not provide the desired substitution products, but
unexpectedly, elimination products 29 and 34 in more than 50 % yield. The formation
of the but-3-en-1-ynyl derivatives 29 and 34 might be explained by increased acidity of
the methylene protons adjacent to the triple bond due to the strong electron
withdrawing 3-pyridyl moiety.
OR2
R1O
Br
(b)
(d)
O
O
F
F
N
N
N
27
28
1
2
25
26
: R = H
: R = H
29
(a)
(c)
1
2
: R = CH2CH2F
: R = Tos
OR2
I
N
(b)
(d)
N
N
OR1
F
F
O
O
1
2
30
31
32
33
: R = H
: R = H
34
(a)
(c)
1
2
: R = CH2CH2F
: R = Tos
Scheme 5: Synthesis of pyridyl derivatives 29 and 34 with a but-3-en-1-ynyl
substituent. Reagents and reaction conditions: (a) 2-fluoroethyl tosylate, CH3CN,
K2CO3, reflux, 16 h, 73 % (26), 89 % (31). (b) but-3-yn-1-ol (7), Pd(PPh3)4, CuI, NEt3,
reflux, 16 h, 85 % (27), 71 % (32). (c) TosCl, NEt3, DMAP, CH2Cl2, rt, 16 h, 73 % (28),
62 % (33). (d) 10, CH3CN, K2CO3, reflux, 72 h, 50 % (29), 58 % (34).
Finally, it was planned to introduce an F-atom by a 1,3-dipolar cycloaddition (Click
reaction). For this purpose, 3-benzazepine 10 was alkylated with (hex-5-yn-1-yl)
tosylate (35)35 to form the tertiary amine 36 in 92 % yield. 1,3-Dipolar cycloaddition of

10
alkyne 36 with 1-azido-2-fluoroethane in the presence of Cu(I) generated in situ by
ascorbate reduction of CuSO4 regioselectively led to the fluoroethyltriazole 37. Due to
purification problems, the yield of triazole 37 did not exceed 11 %.
HO
(a)
+
NH
TosO
H3CO
35
10
HO
HO
F
F
N3
N
N
N
N
(b)
N
H3CO
H3CO
36
37
Scheme 6: Synthesis of fluoroethyltriazole 37 by 1,3-dipolar cycloaddition. Reagents
and reaction conditions: (a) CH3CN, K2CO3, reflux, 48 h, 92 %. (b) Na ascorbate,
CuSO4, DMF, rt, 16 h, 11 %.
3. Receptor affinity
GluN2B affinity
The affinity towards GluN2B subunit containing NMDA receptors was determined in
radioligand binding studies. Mouse fibroblast L(tk-) cells stably transfected with
dexamethasone-inducible expression vectors containing the genetic information for
the human GluN1a and human GluN2B subunits were used as receptor material.
Tritium labeled [3H]ifenprodil was employed as radioligand competing with the test
compounds for binding at the ifenprodil binding site.36,37 The GluN2B affinity of the test
compounds is summarized in Table 1

11
Table 1. Receptor affinity of 3-benzazepines with modified 4-phenylbutyl side chain.
p
m
F
O
o
HO
aryl
HO
X
X
N
N
RO
RO
19 20 24 37
11 12 14 15
,
,
,
,
,
,
Ki ± SEM [nM] (n = 3)a
compd.
R
X
position of
O(CH2)2F
-
aryl
GluN2B
84 ± 18
PCP
σ1
σ2
4a21
4b22
11a
11b
11c
12c
14
H
-
-
-
-
-
-
-
-
0 %
25 %
0 %
0 %
4 %
0 %
0 %
0 %
123
211
701
9 %
31 %
715
0 %
705
32 ± 13
96 ± 24
12 %
-CH2CH2-
-CH2CH2-
-CC-
-
CH3
CH3
CH3
CH3
CH3
Bn
706 ± 100
3 %
para
meta
ortho
ortho
para
para
-
-CC-
3 %
23 %
-CC-
4 %
22 %
-CH2CH2-
-CC-
19 %
0 %
593
12 %
-CH2CH2-
-CC-
15
H
193
79 ± 12
19a
19b
19c
19d
20b
20c
24
CH3
CH3
CH3
CH3
CH3
CH3
CH3
18 %
1 %
15 %
0 %
0 %
0 %
0 %
0 %
9 %
565
5 %
21 %
0 %
274
340
164
15 %
9 %
20 %
0 %
397
--
-CC-
N
-
-
-
-CC-
-CC-
13 %
0 %
S
N
S
-CH2CH2-
0 %
N
-CH2CH2-
-
-
20 %
460
562
S
-CH2CC-
878
3
4 N
N
37
CH3
-CH2CH2-
1-CH2CH2F
0 %
0 %
28 %
0 %
N
1
Ifenprodil
Eliprodil
10 ± 0.7
13 ± 2.0
-
-
125 ± 24 98 ± 34
-
-

12
Dexoxadrol
-
-
-
32 ± 7.4
-
-
Haloperidol
-
-
6.3 ± 1.6 78 ± 2.3
89 ± 29 57 ± 18
Di-o-tolylguanidine
a The Ki values of potent compounds were recorded three times (n = 3). For low-affinity
or very low-affinity compounds the competition curves were recorded only once (single
value) or the inhibition (in %) of the radioligand binding at a test compound
concentration of 1 µM is given.
Table 1 clearly shows that the introduction of a triple bond into the arylbutyl side chain
generally leads to very low GluN2B affinity. This might be due to the reduced
conformational flexibility of the linear triple bond or, alternatively, to the reduced
distance between the basic amine and the terminal aryl moiety. The moderate GluN2B
affinity (Ki = 460 nM) of the 3-benzazepine 24 with an enlarged phenylpentynyl side
chain points to the second argument of the shortened distance. The GluN2B affinity of
the 5-phenylpentynyl derivative 24 is comparable with the GluN2B affinity of the 4-
phenylbutyl derivative 4b.
Independent on a butyl or butynyl spacer heteroaryl rings (compounds 19 and 20) were
not tolerated by the ifenprodil binding site of the NMDA receptor. This is also valid for
the fluoroethyltriazolyl derivative 37. Since the corresponding thienyl and pyridyl
derivatives 20b and 20c are also inactive, the negligible GluN2B affinity of 37 was
attributed to the triazole heterocycle rather than the fluoroethyl side chain.
Since we had the development of a fluorinated PET tracer in mind, analogs with a 2-
fluoroethoxy moiety in various positions of the terminal phenyl ring were prepared. For
ligands 11a-c with a triple bond within the butyl spacer only negligible GluN2B affinity
was found. The highest GluN2B affinity was detected for the p-fluoroethoxy derivative

13
15 (Ki = 193 nM) with a butyl spacer and a phenolic OH moiety. However, this affinity
is more than two-fold lower than the GluN2B affinity of the corresponding unsubstituted
phenol 4a and, therefore, not appropriate for the development of a PET tracer to image
GluN2B subunit containing NMDA receptors.
Affinity towards related receptors
In order to analyze the effect of modified arylbutyl side chain on the interaction with
other receptors, the affinity towards the phencyclidine (PCP) binding site,38,39 1 and
2 receptors was determined.40-42
The PCP binding site is located within the channel pore of NMDA receptors. Since
ligands cannot differentiate between the PCP binding site of different GluN2 receptor
subtypes, interaction with the PCP binding site should be excluded. At a concentration
of 1 µM, the herein synthesized 3-benzazepines could not compete with the radioligand
[3H](+)-MK-80138,39 for binding at the PCP binding site. It was concluded that the
substituted 3-benzazepines do not interact with the PCP binding site (Table 1).
The prototypical GluN2B antagonist ifenprodil shows a moderate to high affinity
towards σ1 and σ2 receptors. Therefore, the 1 and 2 affinity of the 3-benzazepines
was also recorded in radioligand receptor binding studies.40-42 In general, the 1 affinity
of all test compounds is rather low. The highest 1 affinity was found for the pyridylbutyl
derivative 20b (Ki = 274 nM) and phenylpentynyl derivative 24 (Ki = 164 nM). However,
the Ki values of these compounds are still higher than 100 nM and, therefore, of low
interest (Table 1). A considerable 2 affinity was only found for the p-fluoroethoxy
derivative 15 exhibiting a Ki value of 79 nM. This compound represents the most active

14
GluN2B ligand as well, but, unfortunately, shows higher 2 affinity than GluN2B affinity
(Table 1).
3. Conclusion
The phenylbutyl substituent of the potent GluN2B antagonist 4a was modified with the
aim to uncover a fluorinated ligand with high GluN2B affinity, which could be developed
as a fluorinated PET tracer for imaging of NMDA receptors containing the GluN2B
subunit. Introduction of a 2-fluoroethoxy moiety in ortho-, meta- or para-position of the
terminal phenyl moiety (compounds 11-15) led to a considerably reduced affinity
towards the ifenprodil binding site. A heteroaryl moiety (compounds 19, 20, 37) instead
of the terminal phenyl ring was not tolerated by the GluN2B receptor. Also shortening
and rigidifying the butyl spacer by the introduction of a triple bond (compounds 11, 14,
19) resulted in very low GluN2B affinity. However, a moderate GluN2B affinity (Ki =
460 nM) was detected for the 3-benzazepine 24 with a longer phenylpentynyl
substituent at the N-atom.
4. Experimental Part
4.1. Chemistry, general methods
Flash chromatography (fc): Silica gel 60, 40–63 µm (VWR); parentheses include:
diameter of the column (d), length of the stationary phase (l), fraction size (V) and
eluent. MS: MicroTOFQII mass spectrometer (Bruker Daltonics, Bremen, Germany);
deviations of the found exact masses from the calculated exact masses were 5 mDa
or less; the data were analyzed with DataAnalysis® (Bruker Daltonics). NMR: NMR
spectra were recorded in deuterated solvents on Agilent DD2 400 MHz and 600 MHz
spectrometers (Agilent, Santa Clara CA, USA); chemical shifts (δ) are reported in parts
per million (ppm) against the reference compound tetramethylsilane (δ = 0 ppm).

15
Assignment of 1H and 13C NMR signals was supported by 2-D NMR techniques were
necessary.
4.2. HPLC method for the determination of the purity
The purity of all compounds was determined by the HPLC system described in the
Supporting Information.
4.3. Synthetic procedures
3-{4-[4-(2-Fluoroethoxy)phenyl]but-3-yn-1-yl}-7-methoxy-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (11a)
3-Benzazepine 10 (46.8 mg, 0.24 mmol, 1 eq) was dissolved in CH3CN (20 mL). After
addition of 9a (104 mg, 0.29 mmol, 1.2 eq) in CH3CN (2 mL) and K2CO3 (265 mg, 1.9
mmol, 8 eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and
the solvent was removed in vacuo. The residue was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 +
1 % N,N-dimethylethylamine). Yellow solid, mp 79 °C, yield 62.9 mg (0.16 mmol, 68
%). C23H26FNO3 (383.5). Rf = 0.26 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-
1
dimethylethylamine). HPLC: 99.5 %, tR = 18.77 min. H-NMR (600 MHz, CDCl3): δ
[ppm] = 2.56 – 2.75 (m, 5H, NCH2CH2CCPh, 2-H, 4-H and 5-H), 2.94 (t, J = 7.1 Hz,
2H, NCH2CH2CCPh), 3.08 – 3.16 (m, 1H, 4-H), 3.24 – 3.30 (m, 1H, 2-H), 3.30 – 3.38
(m, 1H, 5-H), 3.78 (s, 3H, OCH3), 4.19 (dt, J = 27.7/4.1 Hz, 2H, OCH2CH2F), 4.64 (d,
J = 6.7 Hz, 1H, 1-H), 4.74 (dt, J = 47.6/4.5 Hz, 2H, OCH2CH2F), 6.61 – 6.71 (m, 2H,
6-H and 8-H), 6.81 – 6.85 (m, 2H, 3-Harom. and 5-Harom.), 7.12 (d, J = 8.1 Hz, 1H, 9-H),
7.32 – 7.37 (m, 2H, 2-Harom. and 6-Harom.). A signal for the OH proton is not seen in the
spectrum. 13C-NMR (151 MHz, CDCl3): δ [ppm] = 18.2 (1C, NCH2CH2CCPh), 37.0 (1C,
C-5), 55.4 (1C, OCH3), 55.9 (1C, C-4), 58.6 (1C, NCH2CH2CCPh), 60.6 (1C, C-2), 67.2

16
(d, J = 20.4 Hz, 1C, OCH2CH2F), 72.5 (1C, C-1), 81.7 (1C, NCH2CH2CCPh), 81.9 (d,
J = 171.0 Hz, 1C, OCH2CH2F), 86.5 (1C, NCH2CH2CCPh), 110.4 (1C C-8), 114.7 (2C,
C-3arom. and C-5arom.), 116.5 (1C, C-1arom.), 116.8 (1C, C-6), 130.0 (1C, C-9), 133.1 (2C,
C-2arom. and C-6arom.), 135.4 (1C, C-9a), 141.1 (1C, C-5a), 158.1 (1C, C-4arom.), 159.1
(1C, C-7). IR: [cm-1] = 2913 (C-Haliph.), 2824 (O-CH3), 1605, 1582, 1508 (C=Carom.),
푣
1443 (CH2 deform.), 1281, 1250 (C-O), 1111 (C-OH), 1042 (C-O). Exact Mass (APCI):
m/z = 384.1982 (calcd. 384.1969 for C23H27FNO3 [MH]+).
3-{4-[3-(2-Fluoroethoxy)phenyl]but-3-yn-1-yl}-7-methoxy-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (11b)
3-Benzazepine 10 (43.7 mg, 0.24 mmol, 1 eq) was dissolved in CH3CN (20 mL). After
addition of 9b (98.2 mg, 0.27 mmol, 1.2 eq) in CH3CN (2 mL) and K2CO3 (254 mg, 1.84
mmol, 8 eq), the suspension was heated to reflux for 36 h. K2CO3 was filtered off and
the solvent was removed in vacuo. The residue was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 +
1 % N,N-dimethylethylamine). Yellow oil, yield 76.8 mg (0.20 mmol, 83 %).
C23H26FNO3 (383.5), Rf = 0.20 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-
1
dimethylethylamine). HPLC: 99.2 %, tR = 18.56 min. H NMR (400 MHz, CDCl3): δ
[ppm] = 2.60 – 2.81 (m, 5H, NCH2CH2CCPh, 2-H, 4-H and 5-H), 2.98 (t, J = 7.1 Hz,
2H, NCH2CH2CCPh), 3.13 (dd, J = 12.4/6.1 Hz, 1H, 4-H), 3.24 – 3.40 (m, 2H, 2-H and
5-H), 3.78 (s, 3H, OCH3), 4.19 (dt, J = 27.7/4.1 Hz, 2H, OCH2CH2F), 4.63 – 4.83 (m,
3H, OCH2CH2F and 1-H), 6.62 – 6.70 (m, 2H, 6-H and 8-H), 6.87 (dd, J = 8.4/2.6 Hz,
1H, 4-Harom.), 6.94 – 6.98 (m, 1H, 2-Harom.), 7.02 (d, J = 7.6 Hz, 1H, 6-Harom.), 7.13 (d, J
= 8.0 Hz, 1H, 9-H), 7.19 (t, J = 8.0 Hz, 1H, 5-Harom.). A signal for the OH proton is not
seen in the spectrum. 13C NMR (101 MHz, CDCl3): δ [ppm] = 18.1 (1C,
NCH2CH2CCPh), 36.7 (1C, C-5), 55.4 (1C, OCH3), 55.9 (1C, C-4), 58.4 (1C,

17
NCH2CH2CCPh), 60.6 (1C, C-2), 67.3 (1C, OCH2CH2F), 72.3 (1C, C-1), 81.94 (1C,
NCH2CH2CCPh), 81.96 (d, J = 170.8 Hz, 1C, OCH2CH2F), 87.8 (1C, NCH2CH2CCPh),
110.5 (1C, C-8), 115.3 (1C, C-4arom.), 116.8 (1C, C-6), 117.3 (1C, C-2arom.), 124.7 (1C,
C-1arom.), 124.8 (1C, C-6arom.), 129.6 (1C, C-5arom.), 129.9 (1C, C-9), 135.3 (1C, C-9a),
140.9 (1C, C-5a), 158.3 (1C, C-3arom.), 159.1 (1C, C-7). IR: [cm-1] = 3399 (O-H), 2947,
푣
2913 (C-Haliph.), 2831 (OCH3-H), 1605, 1578, 1489 (C=Carom.), 1427 (CH2 deform.),
1292, 1261 (C-O), 1188 (C-OH), 1045 (C-O). Exact Mass (APCI): m/z = 384.1978
(calcd. 384.1969 for C23H27FNO3 [MH]+).
3-{4-[2-(2-Fluoroethoxy)phenyl]but-3-yn-1-yl}-7-methoxy-2,3,4,5-tetrahydro-1H-
3-benzazepin-1-ol (11c)
3-Benzazepine 10 (61.1 mg, 0.32 mmol, 1 eq) was dissolved in CH3CN (20 mL). After
addition of 9c (137 mg, 0.38 mmol, 1.2 eq) in CH3CN (2 mL) and K2CO3 (354 mg, 2.56
mmol, 8 eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and
the solvent was removed in vacuo. The residue was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 +
1 % N,N-dimethylethylamine). Yellow oil, yield 117 mg (0.30 mmol, 95 %). C23H26FNO3
(383.5). Rf = 0.30 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-dimethylethylamine).
HPLC: 98.5 %, tR = 18.45 min. 1H-NMR (600 MHz, CDCl3): δ [ppm] = 2.61 – 2.82 (m,
5H, NCH2CH2CCPh, 2-H, 4-H and 5-H), 3.01 (t, J = 7.2 Hz, 2H, NCH2CH2CCPh), 3.12
– 3.20 (m, 1H, 4-H), 3.27 – 3.39 (m, 2H, 2-H and 5-H), 3.78 (s, 3H, OCH3), 4.27 (dt, J
= 27.3/4.2 Hz, 2H, OCH2CH2F), 4.63 – 4.70 (m, 1H, 1-H), 4.76 (dt, J = 47.4/4.2 Hz, 2H,
OCH2CH2F), 6.62 – 6.70 (m, 2H, 6-H and 8-H), 6.86 (d, J = 8.3 Hz, 1H, 3-Harom.), 6.92
(t, J = 7.5 Hz, 1H, 5-Harom.), 7.13 (d, J = 8.1 Hz, 1H, 9-H), 7.21 – 7.25 (m, 1H, 4-Harom.),
7.38 (dd, J = 7.6/1.7 Hz, 1H, 6-Harom.). A signal for the OH proton is not seen in the
spectrum. 13C-NMR (151 MHz, CDCl3): δ [ppm] = 18.3 (1C, NCH2CH2CCPh), 36.7 (1C,

18
C-5), 55.4 (1C, OCH3), 55.8 (1C, C-4), 58.6 (1C, NCH2CH2CCPh), 60.5 (1C, C-2), 68.3
(d, J = 21.0 Hz, 1C, OCH2CH2F), 72.4 (1C, C-1), 78.0 (1C, NCH2CH2CCPh), 82.1 (d,
J = 171.0 Hz, 1C, OCH2CH2F), 92.2 (1C, NCH2CH2CCPh), 110.5 (1C, C-8), 112.9 (1C,
C-3arom.), 113.8 (1C, C-1arom.), 116.7 (1C, C-6), 121.5 (1C, C-5arom.), 129.2 (1C, C-
4arom.), 129.9 (1C, C-9), 133.8 (1C, C-6arom.), 135.3 (1C, C-9a), 141.1 (1C, C-5a),
159.06, 159.11 (2C, C-2arom. and C-7). IR: [cm-1] = 3395 (O-H), 2947, 2913 (C-Haliph.),
푣
2832 (OCH3-H), 1609, 1578, 1493 (C=Carom.), 1443 (CH2 deform.), 1258 (C-O), 1115
(C-OH), 1045 (C-O). Exact Mass (APCI): m/z = 384.1965 (calcd. 384.1969 for
C23H27FNO3 [MH]+).
3-{4-[2-(2-Fluoroethoxy)phenyl]butyl}-7-methoxy-2,3,4,5-tetrahydro-1H-3-
benzazepin-1-ol (12c)
11c (65.2 mg, 0.17 mmol, 1 eq) was dissolved in abs. CH3OH (5 mL) and the solution
was added to a suspension of Pd/C (13.0 mg, 10 %) in CH3OH (10 mL). After the
mixture had been stirred for 16 h under H2 atmosphere (1 bar) at room temperature,
the catalyst was removed by filtration over Celite® and the solvent was evaporated in
vacuo. Yellow oil, yield 64.1 mg (0.17 mmol, 97 %). C23H30FNO3 (387.5). Rf = 0.24
(cyclohexane:ethyl acetate = 1:1 + 1 % N,N-dimethylethylamine). HPLC: 97.1 %, tR =
18.91 min. 1H NMR (400 MHz, CDCl3): δ [ppm] = 1.55 – 1.70 (m, 4H,
NCH2CH2CH2CH2Ph), 2.45 (t, J = 11.9 Hz, 1H, 4-H), 2.55 (d, J = 12.1 Hz, 1H, 2-H),
2.60 – 2.71 (m, 5H, NCH2CH2CH2CH2Ph and 5-H), 2.97 – 3.06 (m, 1H, 4-H), 3.13 –
3.21 (m, 1H, 2-H), 3.27 (ddd, J = 14.8/11.8/2.5 Hz, 1H, 5-H), 3.77 (s, 3H, OCH3), 4.22
(dt, J = 28.1/4.1 Hz, 2H, OCH2CH2F), 4.61 (d, J = 6.7 Hz, 1H, 1-H), 4.76 (dt, J =
47.5/4.1 Hz, 2H, OCH2CH2F), 6.61 – 6.70 (m, 2H, 6-H and 8-H), 6.82 (d, J = 8.0 Hz,
1H, 3-Harom.), 6.92 (t, J = 7.4 Hz, 1H, 5-Harom.), 7.11 (d, J = 8.1 Hz, 1H, 9-H), 7.13 –
7.19 (m, 2H, 4-Harom. and 6-Harom.). A signal for the OH proton is not seen in the

19
spectrum. 13C NMR (101 MHz, CDCl3): δ [ppm] = 26.8 (1C, NCH2CH2CH2CH2Ph), 27.7
(1C, NCH2CH2CH2CH2Ph), 30.2 (1C, NCH2CH2CH2CH2Ph), 36.7 (1C, C-5), 55.3 (1C,
OCH3), 56.1 (1C, C-4), 59.7 (1C, NCH2CH2CH2CH2Ph), 60.9 (1C, C-2), 67.5 (d, J =
20.5 Hz, 1C, OCH2CH2F), 72.3 (1C, C-1), 82.2 (d, J = 170.8 Hz, 1C, OCH2CH2F), 110.4
(1C, C-8), 111.6 (1C, C-3arom.), 116.7 (1C, C-6), 121.2 (1C, C-5arom.), 127.1 (1C, C-
4arom.), 129.8 (1C, C-9), 130.3 (1C, C-6arom.), 131.4 (1C, C-1arom.), 135.6 (1C, C-9a),
141.2 (1C, C-5a), 156.4 (1C, C-2arom.), 159.0 (1C, C-7). IR: [cm-1] = 3379 (O-H), 2928,
푣
2859 (C-Haliph.), 2832 (OCH3-H), 1605, 1582, 1493 (C=Carom.), 1451 (CH2 deform.),
1242 (C-O), 1115 (C-OH), 1045 (C-O). Exact Mass (APCI): m/z = 388.2316 (calcd.
388.2282 for C23H31FO3 [MH]+).
7-(Benzyloxy)-3-{4-[4-(2-fluoroethoxy)phenyl]but-3-yn-1-yl}-2,3,4,5-tetrahydro-
1H-3-benzazepin-1-ol (14)
§-Benzazepine 13 (269 mg, 1.00 mmol, 1 eq) was dissolved in CH3CN (40 mL). After
addition of 9a (435 mg, 1.20 mmol, 1.2 eq) in CH3CN (2 mL) and K2CO3 (1.1 g, 8.0
mmol, 8 eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and
the solvent was evaporated in vacuo. The residue was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 2:1 +
1 % N,N-dimethylethylamine  cyclohexane:ethyl acetate = 1:1 + 1 % N,N-
dimethylethylamine). Yellow oil, yield 460 mg (1.00 mmol, 100 %). C29H30FNO3
(459.6). Rf = 0.34 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-dimethylethylamine).
HPLC: 95.8 %, tR = 20.62 min. 1H NMR (400 MHz, CDCl3) : δ [ppm] = 2.52 – 2.75 (m,
5H, NCH2CH2CCPh, 2-H, 4-H and 5-H), 2.93 (t, J = 7.0 Hz, 2H, NCH2CH2CCPh), 3.06
– 3.16 (m, 1H, 4-H), 3.21 – 3.38 (m, 2H, 2-H and 5-H), 4.19 (dt, J = 27.7/4.0 Hz, 2H,
OCH2CH2F), 4.63 (d, J = 6.6 Hz, 1H, 1-H), 4.74 (dt, J = 47.3/4.1 Hz, 2H, OCH2CH2F),
5.04 (s, 2H, O-CH2-Ph), 6.71 – 6.76 (m, 2H, 6-H and 8-H), 6.81 – 6.86 (m, 2H, 3-Harom.

20
and 5-Harom.), 7.09 – 7.13 (m, 1H, 9-H), 7.29 – 7.44 (m, 7H, 2-Harom., 6-Harom. and
benzyl). A signal for the OH proton is not seen in the spectrum. 13C NMR (101 MHz,
CDCl3): δ [ppm] = 18.3 (1C, NCH2CH2CCPh), 37.1 (1C, C-5), 55.9 (1C, C-4), 58.6 (1C,
NCH2CH2CCPh), 60.6 (1C, C-2), 67.2 (d, J = 20.5 Hz, 1C, OCH2CH2F), 70.1 (1C, O-
CH2-Ph), 72.6 (1C, C-1), 81.7 (1C, NCH2CH2CCPh), 81.9 (d, J = 170.9 Hz, 1C,
OCH2CH2F), 86.6 (1C, NCH2CH2CCPh), 111.4 (1C C-8), 114.7 (2C, C-3arom. and C-
5arom.), 116.5 (1C, C-1arom.), 117.7 (1C, C-6), 127.6, 128.0, 128.7 (5C, C-2benzyl, C-
3benzyl, C-4benzyl, C-5benzyl and C-6benzyl), 130.0 (1C, C-9), 133.1 (2C, C-2arom. and C-
6arom.), 135.8 (1C, C-9a), 137.2 (1C, C-1benzyl), 141.2 (1C, C-5a), 158.1 (1C, C-4arom.),
158.3 (1C, C-7). IR: [cm-1] = 3402 (O-H), 2913, 2824 (C-Haliph.), 1605, 1578, 1504
푣
(C=Carom.), 1454 (CH2 deform.), 1246 (C-O), 1165 (C-OH), 1053, 1026 (C-O). Exact
Mass (APCI): m/z = 460.2296 (calcd. 460.2282 for C29H31FNO3 [MH]+).
3-{4-[4-(2-Fluoroethoxy)phenyl]butyl}-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-
diol (15)
Alkyne 14 (103 mg, 0.22 mmol, 1 eq) was dissolved in abs. CH3OH (5 mL) and the
solution was added to a suspension of Pd/C (20.6 mg, 10 %) in CH3OH (20 mL). After
the mixture had been stirred for 16 h under H2 atmosphere (1 bar) at room temperature,
the catalyst was removed by filtration over Celite® and the solvent was removed in
vacuo. Brown solid, mp 52 °C, yield 56.5 mg (0.15 mmol, 69 %). C22H28FNO3 (373.5).
Rf = 0.56 (CH2Cl2:CH3OH = 9:1 + 2 % NH3). HPLC: 95.9 %, tR = 16.32 min. 1H NMR
(400 MHz, CDCl3): δ [ppm] = 1.43 – 1.68 (m, 4H, NCH2CH2CH2CH2Ph), 2.35 (t, J =
12.0 Hz, 1H, 4-H), 2.47 (d, J = 11.9 Hz, 1H, 2-H), 2.50 – 2.62 (m, 5H,
NCH2CH2CH2CH2Ph and 5-H), 2.87 – 3.00 (m, 1H, 4-H), 3.06 – 3.22 (m, 2H, 2-H and
5-H), 4.18 (dt, J = 27.9/4.1 Hz, 2H, OCH2CH2F), 4.52 (d, J = 7.0 Hz, 1H, 1-H), 4.73 (dt,
J = 47.4/4.1 Hz, 2H, OCH2CH2F), 6.51 (s, 2H, 6-H and 8-H), 6.82 – 6.88 (m, 2H, 3-

21
Harom. and 5-Harom.), 6.96 (d, J = 7.9 Hz, 1H, 9-H), 7.06 – 7.13 (m, 2H, 2-Harom. and 6-
Harom.). Signals for the OH protons are not seen in the spectrum. 13C NMR (101 MHz,
CDCl3): δ [ppm] = 26.7 (1C, NCH2CH2CH2CH2Ph), 29.5 (1C, NCH2CH2CH2CH2Ph),
35.0 (1C, NCH2CH2CH2CH2Ph), 36.9 (1C, C-5), 56.2 (1C, C-4), 59.8 (1C,
NCH2CH2CH2CH2Ph), 60.9 (1C, C-2), 67.4 (d, J = 20.5 Hz, 1C, OCH2CH2F), 72.6 (1C,
C-1), 82.2 (d, J = 170.4 Hz ,1C, OCH2CH2F), 112.7 (1C C-8), 114.7 (2C, C-3arom. and
C-5arom.), 117.9 (1C, C-6), 129.5 (2C, C-2arom. and C-6arom.), 130.1 (1C, C-9), 134.8 (1C,
C-9a), 135.2 (1C, C-1arom.), 141.5 (1C, C-5a), 156.1 (1C, C-7), 156.7 (1C, C-4arom.). IR:
[cm-1] = 3275 (O-H), 2928, 2859, 2824 (C-Haliph.), 1609, 1585, 1508 (C=Carom.), 1450
푣
(CH2 deform.), 1242 (C-O), 1161 (C-OH), 1049 (C-O). Exact Mass (ESI): m/z =
374.2137 (calcd. 374.2126 for C22H29FNO3 [MH]+).
7-Methoxy-3-(4-phenylbut-3-yn-1-yl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol
(19a)
3-Benzazepine 10 (243 mg, 1.26 mmol, 1 eq) was dissolved in CH3CN (40 mL). After
addition of tosylate 18a (378 mg, 1.26 mmol, 1 eq) and K2CO3 (1.39 g, 10.1 mmol, 8
eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and the solvent
was evaporated in vacuo. The residue was purified by flash column chromatography
(d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 + 1 % N,N-
dimethylethylamine). Yellow oil, yield 318 mg (0.99 mmol, 78 %). C21H23NO2 (321.4).
Rf = 0.49 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-dimethylethylamine). HPLC: 99.2
1
%, tR = 17.75 min. H NMR (400 MHz, CDCl3): δ [ppm] = 2.54 – 2.73 (m, 5H,
NCH2CH2CCPh, 2-H, 4-H and 5-H), 2.90 – 2.97 (m, 2H, NCH2CH2CCPh), 3.11 (ddt, J
= 12.4/6.1/2.2 Hz, 1H, 4-H), 3.22 – 3.39 (m, 2H, 2-H and 5-H), 3.77 (s, 3H, OCH3),
4.61 (d, J = 6.6 Hz, 1H, 1-H), 6.62 – 6.69 (m, 2H, 6-H and 8-H), 7.08 – 7.13 (m, 1H, 9-
H), 7.24 – 7.43 (m, 5H, phenyl). A signal for the OH proton is not seen in the spectrum.

22
13C NMR (101 MHz, CDCl3): δ [ppm] = 18.3 (1C, NCH2CH2CCPh), 37.2 (1C, C-5), 55.4
(1C, OCH3), 56.0 (1C, C-4), 58.6 (1C, NCH2CH2CCPh), 60.6 (1C, C-2), 72.7 (1C, C-
1), 82.1 (1C, NCH2CH2CCPh), 88.0 (1C, NCH2CH2CCPh), 110.4 (1C, C-8), 116.8 (1C,
C-6), 123.7 (1C, C-1phenyl), 127.9 (1C, C-4phenyl), 128.4 (2C, C-3phenyl and C-5phenyl),
130.1 (1C, C-9), 131.7 (2C, C-2phenyl and C-6phenyl), 135.5 (1C, C-9a), 141.2 (1C, C-
5a), 159.1 (1C, C-7). IR: [cm-1] = 3399 (O-H), 2936, 2909 (CHaliph.), 2832 (OCH3-H),
푣
1609, 1582, 1493 (C=Carom.), 1462, 1439 (CH2 deform.), 1250 (C-O), 1157 (C-OH),
1042 (C-O). Exact Mass (APCI): m/z = 322.1815 (calcd. 322.1802 for C21H24NO2
[MH]+).
7-Methoxy-3-[4-(pyridin-3-yl)but-3-yn-1-yl]-2,3,4,5-tetrahydro-1H-3-benzazepin-
1-ol (19b)
3-Benzazepine 10 (100 mg, 0.52 mmol, 1 eq) was dissolved in CH3CN (20 mL). After
addition of tosylate 18b (156 mg, 0.52 mmol, 1 eq) and K2CO3 (575 mg, 4.16 mmol, 8
eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and the solvent
was removed in vacuo. The crude product was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 +
1 % N,N-dimethylethylamine  ethyl acetate + 1 % N,N-dimethylethylamine). Orange
oil, yield 98.7 mg (0.31 mmol, 59 %). C20H22N2O2 (322.4). Rf = 0.42 (ethyl acetate + 1
% N,N-dimethylethylamine). HPLC: 97.7 %, tR = 10.83 min. 1H NMR (600 MHz, CDCl3):
δ [ppm] = 2.62 (t, J = 12.0 Hz, 1H, 4-H), 2.65 – 2.75 (m, 4H, NCH2CH2CCPy, 2-H and
5-H), 2.96 (t, J = 7.1 Hz, 2H, NCH2CH2CCPy), 3.08 – 3.14 (m, 1H, 4-H), 3.23 – 3.29
(m, 1H, 2-H), 3.29 – 3.36 (m, 1H, 5-H), 3.77 (s, 3H, OCH3), 4.64 (d, J = 6.6 Hz, 1H, 1-
H), 6.62 – 6.69 (m, 2H, 6-H and 8-H), 7.12 (d, J = 8.1 Hz, 1H, 9-H), 7.21 (dd, J = 7.9/4.9
Hz, 1H, 5-Hpyridine), 7.68 (dt, J = 8.0/1.9 Hz, 1H, 4-Hpyridine), 8.48 (dd, J = 4.8/1.7 Hz, 1H,
6-Hpyridine), 8.62 (d, J = 2.3 Hz, 1H, 2-Hpyridine). A signal for the OH proton is not seen in

23
the spectrum. 13C NMR (151 MHz, CDCl3): δ [ppm] = 18.3 (1C, NCH2CH2CCPy), 37.0
(1C, C-5), 55.4 (1C, OCH3), 55.9 (1C, C-4), 58.3 (1C, NCH2CH2CCPy), 60.6 (1C, C-
2), 72.5 (1C, C-1), 78.9 (1C, NCH2CH2CCPy), 91.6 (1C, NCH2CH2CCPy), 110.5 (1C,
C-8), 116.8 (1C, C-6), 120.8 (1C, C-3pyridine), 123.1 (1C, C-5pyridine), 130.0 (1C, C-9),
135.3 (1C, C-9a), 138.7 (1C, C-4pyridine), 141.0 (1C, C-5a), 148.3 (1C, C-6pyridine), 152.4
(1C, C-2pyridine), 159.1 (1C, C-7). IR: [cm-1] = 3352 (O-H), 2928, (CHaliph.), 2832 (O-
푣
CH ), 2222 (C C), 1609, 1582, 1501 (C=Carom.), 1462, 1408 (CH2 deform.), 1254 (C-
≡
3
O), 1157 (C-OH), 1042 (C-O). Exact Mass (APCI): m/z = 323.1747 (calcd. 323.1754
for C20H23N2O2 [MH]+).
7-Methoxy-3-[4-(thiophen-2-yl)but-3-yn-1-yl]-2,3,4,5-tetrahydro-1H-3-
benzazepin-1-ol (19c)
3-Benzazepine 10 (100 mg, 0.52 mmol, 1 eq) was dissolved under N2 atmosphere in
CH3CN (20 mL). After addition of tosylate 18c (159 mg, 0.52 mmol, 1 eq) and K2CO3
(575 mg, 4.16 mmol, 8 eq), the suspension was heated to reflux for 72 h. K2CO3 was
filtered off and the solvent was removed in vacuo. The crude product was purified by
flash column chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl
acetate = 2:1 + 1 % N,N-dimethylethylamine). Yellow oil, yield 85.6 mg (0.26 mmol, 50
%). C19H21NO2S (327.4). Rf = 0.43 (cyclohexane:ethyl acetate = 2:1 + 1 % N,N-
1
dimethylethylamine). HPLC: 96.1 %, tR = 17.55 min. H NMR (400 MHz, CDCl3): δ
[ppm] = 2.59 (t, J = 12.0 Hz, 1H, 4-H), 2.63 – 2.74 (m, 4H, NCH2CH2CCAr, 2-H and 5-
H), 2.94 (t, J = 7.1 Hz, 2H, NCH2CH2CCAr), 3.06 – 3.14 (m, 1H, 4-H), 3.21 – 3.28 (m,
1H, 2-H), 3.28 – 3.37 (m, 1H, 5-H), 3.78 (s, 3H, ZCH3), 4.62 (d, J = 6.5 Hz, 1H, 1-H),
6.62 – 6.70 (m, 2H, 6-H and 8-H), 6.90 – 6.96 (m, 1H, 4-Harom.), 7.09 – 7.15 (m, 2H,
9-H and 3-Harom.), 7.17 (d, J = 5.2 Hz, 1H, 5-Harom.). A signal for the OH proton is not
seen in the spectrum. 13C NMR (101 MHz, CDCl3): δ [ppm] = 18.5 (1C,

24
NCH2CH2CCAr), 37.1 (1C, C-5), 55.4 (1C, OCH3), 55.9 (1C, C-4), 58.4 (1C,
NCH2CH2CCAr), 60.6 (1C, C-2), 72.6 (1C, C-1), 75.3 (1C, NCH2CH2CCAr), 92.0 (1C,
NCH2CH2CCAr), 110.4 (1C, C-8), 116.8 (1C, C-6), 123.8 (1C, C-2arom.), 126.4 (1C, C-
5arom.), 127.0 (1C, C-4arom.), 130.0 (1C, C-9), 131.5 (1C, C-3arom.), 135.5 (1C, C-9a),
141.2 (1C, C-5a), 159.1 (1C, C-7). IR: [cm-1] = 3399 (O-H), 3102, 3075 (=C-H), 2997,
푣
2909 (CHaliph.), 2832 (O-CH3), 1609, 1582, 1501 (C=Carom.), 1462, 1427 (CH2 deform.),
1250 (C-O), 1157 (C-OH), 1042 (C-O). Exact Mass (APCI): m/z = 328.1366 (calcd.
328.1366 for C19H22NO2S [MH]+).
7-Methoxy-3-[4-(thiazol-2-yl)but-3-yn-1-yl]-2,3,4,5-tetrahydro-1H-3-benzazepin-1-
ol (19d)
3-Benzazepine 10 (50 mg, 0.26 mmol, 1 eq) was dissolved in CH3CN (15 mL). After
addition of tosylate 18d (95.9 mg, 0.31 mmol, 1.2 eq) and K2CO3 (286 mg, 2.07 mmol,
8 eq), the suspension was heated to reflux for 72 h. K2CO3 was filtered off and the
solvent was evaporated under reduced pressure. The residue was purified twice by
flash column chromatography (1. d = 2 cm, h = 15 cm, V = 10 mL, ethyl acetate + 1 %
N,N-dimethylethylamine, 2. d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate
= 1:1 + 1 % N,N-dimethylethylamine). Orange oil, yield 20.9 mg (0.06 mmol, 23 %).
C18H20N2O2S (328.4). Rf = 0.25 (ethyl acetate + 1 % N,N-dimethylethylamine). HPLC:
1
98.7 %, tR = 14.15 min. H NMR (600 MHz, CDCl3):δ [ppm] = 2.63 – 2.86 (m, 5H,
NCH2CH2CCAr, 2-H, 4-H and 5-H), 3.00 – 3.08 (m, 2H, NCH2CH2CCAr), 3.09 – 3.16
(m, 1H, 4-H), 3.24 – 3.29 (m, 1H, 2-H), 3.30 – 3.37 (m, 1H, 5-H), 3.78 (s, 3H, OCH3),
4.66 – 4.75 (m, 1H, 1-H), 6.62 – 6.70 (m, 2H, 6-H and 8-H), 7.14 (d, J = 8.2 Hz, 1H, 9-
H), 7.29 (d, J = 3.3 Hz, 1H, 5-Harom.), 7.77 (d, J = 3.3 Hz, 1H, 4-Harom.). 13C NMR (151
MHz, CDCl3): δ [ppm] = 18.1 (1C, NCH2CH2CCAr), 36.5 (1C, C-5), 55.4 (1C, OCH3),
55.8 (1C, C-4), 57.8 (1C, NCH2CH2CCAr), 60.5 (1C, C-2), 72.2 (1C, C-1), 75.6 (1C,

25
NCH2CH2CCAr), 93.5 (1C, NCH2CH2CCAr), 110.6 (1C, C-8), 116.7 (1C, C-6), 120.3
(1C, C-5arom.), 129.8 (1C, C-9), 135.1 (1C, C-9a), 140.7 (1C, C-5a), 143.3 (1C, C-4arom.),
149.0 (1C, C-2arom.), 159.2 (1C, C-7). IR: [cm-1] = 3383, 3109, 3078 (=C-H), 2997,
푣
2936 (C-Haliph.), 2832 (OCH -H), 2230 (C C), 1609, 1582, 1497, 1481 (C=Carom.),
≡
3
1462, 1435 (CH2 deform.), 1254 (C-O), 1130 (C-OH), 1042 (C-O). Exact Mass (ESI):
m/z = 329.1331 (calcd. 329.1318 for C18H21N2O2S [MH]+).
7-Methoxy-3-[4-(pyridin-3-yl)butyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol (20b)
19b (69.2 mg, 0.21 mmol, 1 eq) was dissolved in abs. CH3OH (5 mL) and the solution
was added to a suspension of Pd/C (13.8 mg, 10 %) in CH3OH (15 mL). After the
mixture had been stirred for 16 h under H2 atmosphere (1 bar) at room temperature,
the catalyst was removed by filtration over Celite®. Evaporation of the solvent in vacuo
and purification by flash column chromatography (d = 2 cm, h = 15 cm, V = 10 mL,
ethyl acetate + 1 % N,N-dimethylethylamine) yielded 20b. Yellow oil, yield 62.0 mg
(0.19 mmol, 90 %). C20H26N2O2 (326.4). Rf = 0.23 (ethyl acetate + 1 % N,N-
dimethylethylamine). HPLC: 95.7 %, tR = 8.17 min. 1H NMR (600 MHz, CDCl3): δ [ppm]
= 1.53 – 1.70 (m, 4H, NCH2CH2CH2CH2Py), 2.45 (t, J = 11.9 Hz, 1H, 4-H), 2.55 (d, J
= 12.1 Hz, 1H, 2-H), 2.59 – 2.71 (m, 5H, NCH2CH2CH2CH2Py and 5-H), 2.95 – 3.01
(m, 1H, 4-H), 3.11 – 3.17 (m, 1H, 2-H), 3.22 – 3.29 (m, 1H, 5-H), 3.77 (s, 3H, OCH3),
4.61 (d, J = 6.8 Hz, 1H, 1-H), 6.62 – 6.68 (m, 2H, 6-H and 8-H), 7.11 (d, J = 8.1 Hz,
1H, 9-H), 7.21 (dd, J = 7.8/4.8 Hz, 1H, 5-Hpyridine), 7.49 (dt, J = 7.9/1.9 Hz, 1H, 4-
Hpyridine), 8.42 – 8.46 (m, 2H, 2-Hpyridine and 6-Hpyridine). A signal for the OH proton is not
seen in the spectrum. 13C NMR (151 MHz, CDCl3) δ [ppm] = 26.6 (1C,
NCH2CH2CH2CH2Py),
28.9
(1C,
NCH2CH2CH2CH2Py),
33.0
(1C,
NCH2CH2CH2CH2Py), 36.8 (1C, C-5), 55.3 (1C, OCH3), 56.2 (1C, C-4), 59.5 (1C,
NCH2CH2CH2CH2Py), 60.9 (1C, C-2), 72.3 (1C, C-1), 110.4 (1C, C-8), 116.7 (1C, C-

26
6), 123.5 (1C, C-5pyridine), 129.7 (1C, C-9), 135.5 (1C, C-9a), 135.9 (1C, C-4pyridine),
137.5 (1C, C-3pyridine), 141.1 (1C, C-5a), 147.5 (1C, C-6pyridine), 150.0 (1C, C-2pyridine),
159.1 (1C, C-7). IR: [cm-1] = 3283 (O-H), 3052, 3028 (=C-H), 2994, 2936, 2859
푣
(CHaliph.), 2836 (OCH3-H), 1609, 1578, 1497 (C=Carom.), 1462, 1423 (CH2 deform.),
1250 (C-O), 1107 (C-OH), 1042 (C-O). Exact Mass (ESI): m/z = 327.2065 (calcd.
327.2067 for C20H27N2O2 [MH]+).
7-Methoxy-3-[4-(thiophen-2-yl)butyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol
(20c)
19c (54.1 mg, 0.17 mmol, 1 eq) was dissolved in abs. CH3OH (5 mL) and the solution
was added to a suspension of Pd/C (10.8 mg, 10 %) in CH3OH (15 mL). After the
mixture had been stirred for 16 h under H2 atmosphere (1 bar) at room temperature,
the catalyst was removed by filtration over Celite®. The solvent was removed under
reduced pressure. Brown solid, mp 79 °C, yield 48.5 mg (0.15 mmol, 86 %).
C19H25NO2S (331.5). Rf = 0.29 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-
1
dimethylethylamine). HPLC: 95.2 %, tR = 17.30 min. H NMR (400 MHz, CDCl3): δ
[ppm] = 1.54 – 1.77 (m, 4H, NCH2CH2CH2CH2Ar), 2.40 (t, J = 12.2 Hz, 1H, 4-H), 2.51
(d, J = 12.0 Hz, 1H, 2-H), 2.57 – 2.70 (m, 3H, NCH2CH2CH2CH2Ar and 5-H), 2.87 (t, J
= 7.4 Hz, 2H, NCH2CH2CH2CH2Ar), 2.96 – 3.04 (m, 1H, 4-H), 3.16 (ddd, J =
12.2/6.8/2.0 Hz, 1H, 2-H), 3.26 (ddd, J = 15.0/12.0/2.5 Hz, 1H, 5-H), 3.78 (s, 3H,
OCH3), 4.57 (d, J = 6.7 Hz, 1H, 1-H), 6.62 – 6.68 (m, 2H, 6-H and 8-H), 6.79 (dd, J =
3.3/1.3 Hz, 1H, 3-Harom.), 6.92 (dd, J = 5.1/3.4 Hz, 1H, 4-Harom.), 7.08 – 7.14 (m, 2H, 5-
Harom. and 9-H). A signal for the OH proton is not seen in the spectrum. 13C NMR (101
MHz, CDCl3):
δ
[ppm]
=
26.7 (1C, NCH2CH2CH2CH2Ar), 29.6 (1C,
NCH2CH2CH2CH2Ar), 29.9 (1C, NCH2CH2CH2CH2Ar), 37.2 (1C, C-5), 55.3 (1C,
OCH3), 56.3 (1C, C-4), 59.6 (1C, NCH2CH2CH2CH2Ar), 61.0 (1C, C-2), 72.6 (1C, C-1),

27
110.3 (1C, C-8), 116.8 (1C, C-6), 123.1 (1C, C-5arom.), 124.3 (1C, C-3arom.), 126.9 (1C,
C-4arom.), 129.9 (1C, C-9), 135.7 (1C, C-9a), 141.4 (1C, C-5a), 145.3 (1C, C-2arom.),
159.0 (1C, C-7). IR: [cm-1] = 3102, 3071, 3001 (=C-H), 2940 (CHaliph.), 2820 (OCH3-
푣
H), 1609, 1585, 1497 (C=Carom.), 1466, 1431 (CH2 deform.), 1254 (C-O), 1099 (C-OH),
1038 (C-O). Exact Mass (ESI): m/z = 332.1692 (calcd. 332.1679 for C19H26NO2S,
[MH]+).
7-Methoxy-3-(5-phenylpent-4-yn-1-yl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol
(24)
3-Benzazepine 10 (40 mg, 0.21 mmol, 1 eq) was dissolved in CH3CN (20 mL). After
addition of tosylate 23 (79.2 mg, 0.25 mmol, 1.2 eq) and K2CO3 (232 mg, 1.68 mmol,
8 eq) the suspension was heated to reflux for 72 h. K2CO3 was filtered off and the
solvent was removed in vacuo. The crude product was purified by flash column
chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate = 1:1 +
1 % N,N-dimethylethylamine). Yellow oil, yield 71.5 mg (0.21 mmol, 100 %), C22H25NO2
(335.4). Rf = 0.27 (cyclohexane:ethyl acetate = 1:1 + 1 % N,N-dimethylethylamine).
HPLC: 95.7 %, tR = 18.47 min. 1H NMR (600 MHz, CDCl3): δ [ppm] = 1.90 – 1.97 (m,
2H, NCH2CH2CH2CCPh), 2.51 (t, J = 6.9 Hz, 2H, NCH2CH2CH2CCPh), 2.60 – 2.71 (m,
1H, 4-H), 2.76 – 2.85 (m, 2H, 2-H and 5-H), 2.90 (t, J = 7.5 Hz, 2H,
NCH2CH2CH2CCPh), 3.10 – 3.16 (m, 1H, 4-H), 3.25 – 3.31 (m, 1H, 2-H), 3.31 – 3.39
(m, 1H, 5-H), 3.78 (s, 3H, OCH3), 4.78 (d, J = 7.2 Hz, 1H, 1-H), 6.62 – 6.71 (m, 2H, 6-
H and 8-H), 7.17 (d, J = 8.3 Hz, 1H, 9-H), 7.27 – 7.42 (m, 5H, phenyl). A signal for the
13
OH proton is not seen in the spectrum. C NMR (151 MHz, CDCl3): δ [ppm] = 17.4
(1C, NCH2CH2CH2CCPh), 25.5 (1C, NCH2CH2CH2CCPh), 35.7 (1C, C-5), 55.4 (1C,
OCH3), 56.0 (1C, C-4), 58.8 (1C, NCH2CH2CH2CCPh), 60.8 (1C, C-2), 71.6 (1C, C-1),
81.6 (1C, NCH2CH2CH2CCPh), 88.9 (1C, NCH2CH2CH2CCPh), 110.7 (1C, C-8), 116.6

28
(1C, C-6), 123.7 (1C, C-1phenyl), 127.9 (1C, C-4phenyl), 128.4 (2C, C-3phenyl and C-5phenyl),
129.6 (1C, C-9), 131.7 (2C, C-2phenyl and C-6phenyl), 134.9 (1C, C-9a), 140.5 (1C, C-
5a), 159.2 (1C, C-7). IR: [cm-1] = 3395 (O-H), 2940, 2909 (CHaliph.), 2832 (OCH3-H),
v
1609, 1582, 1489 (C=Carom.), 1462, 1439 (CH2 deform.), 1250 (C-O), 1157 (C-OH),
1042 (C-O). Exact Mass (APCI): m/z = 336.1968 (calcd. 336.1958 for C22H26NO2
[MH]+).
3-(Hex-5-yn-1-yl)-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol (36)
Benzazepine 10 (100 mg, 0.52 mmol, 1 eq) was dissolved under N2 in CH3CN(20 mL).
K2CO3 (575 mg, 4.16 mmol, 8 eq) and 3535 (157 mg, 0.62 mmol, 1.2 eq) dissolved in
CH3CN (1 mL) were added and the mixture was heated to reflux for 48 h. K2CO3 was
filtered off and the solvent was evaporated in vacuo. The residue was purified by flash
column chromatography (d = 2 cm, h = 15 cm, V = 10 mL, cyclohexane:ethyl acetate
= 1:1 + 1 % N,N-dimethylethylamine). Colorless solid, mp 55 °C, yield 131 mg (0.48
mmol, 92 %). C17H23NO2 (273.4). Rf = 0.21 (cyclohexane:ethyl acetate = 1:1 + 1 %
N,N-dimethylethylamine). HPLC: 99.9 %, tR = 14.07 min. 1H NMR (600 MHz, CDCl3):
δ [ppm] = 1.58 (quint, J = 7.3 Hz, 2H, NCH2CH2CH2CH2CCH), 1.61 – 1.73 (m, J =
17.2/13.1/7.1 Hz, 2H, NCH2CH2CH2CH2CCH), 1.96 (t, J = 2.7 Hz, 1H,
NCH2CH2CH2CH2CCH), 2.24 (td, J = 6.9/2.7 Hz, 2H, NCH2CH2CH2CH2CCH), 2.48 (t,
J = 12.0 Hz, 1H, 4-H), 2.59 (d, J = 12.1 Hz, 1H, 2-H), 2.64 (t, J = 7.4 Hz, 2H,
NCH2CH2CH2CH2CCH), 2.71 (dd, J = 15.3/6.4 Hz, 1H, 5-H), 3.01 – 3.07 (m, 1H, 4-H),
3.16 – 3.22 (m, 1H, 2-H), 3.25 – 3.32 (m, 1H, 5-H), 3.77 (s, 3H, OCH3), 4.64 (d, J = 6.8
Hz, 1H, 1-H), 6.62 – 6.68 (m, 2H, 6-H and 8-H), 7.12 (d, J = 8.1 Hz, 1H, 9-H). A signal
for the OH proton is not seen in the spectrum. 13C NMR (151 MHz, CDCl3): δ [ppm] =
18.4 (1C, NCH2CH2CH2CH2CCH), 26.0 (1C, NCH2CH2CH2CH2CCH), 26.2 (1C,
NCH2CH2CH2CH2CCH), 36.7 (1C, C-5), 55.4 (1C, OCH3), 56.1 (1C, C-4), 59.3 (1C,

29
NCH2CH2CH2CH2CCH), 60.9 (1C, C-2), 68.8 (1C, NCH2CH2CH2CH2CCH), 72.3 (1C,
C-1), 84.2 (1C, NCH2CH2CH2CH2CCH), 110.4 (1C, C-8), 116.7 (1C, C-6), 129.8 (1C,
C-9), 135.5 (1C, C-9a), 141.1 (1C, C-5a), 159.1 (1C, C-7). IR: [cm-1] = 3298 (O-H),
푣
3140 (=C-H), 2940 (CHaliph.), 1659, 1609, 1582, 1501 (C=Carom.), 1458, 1435 (CH2
deform.), 1254 (C-O), 1157 (C-OH), 1038 (C-O). Exact Mass (APCI): m/z = 274.1804
(calcd. 274.1802 for C17H24NO2 [MH]+).
3-{4-[1-(2-Fluoroethyl)-1H-1,2,3-triazol-4-yl]butyl}-7-methoxy-2,3,4,5-tetrahydro-
1H-3-benzazepin-1-ol (37)
(2-Fluoroethyl) tosylate (32.9 mg, 0.15 mmol, 1 eq) was dissolved in DMF (5 mL). After
addition of NaN3 (14.6 mg, 0.23 mmol, 1.5 eq), the mixture was stirred for 24 h at room
temperature. The alkyne 36 (29.1 mg, 0.15 mmol, 1 eq) dissolved in DMF (2 mL),
sodium ascorbate (5.9 mg, 0.03 mmol, 0.2 eq) and CuSO4 (2.4 mg, 0.02 mmol, 0.1 eq)
were added and the mixture was stirred for 16 h at room temperature. After addition of
H2O (30 mL) and EtOAc (30 mL) the layers were separated and the organic layer was
washed with H2O (2 x 25 mL). The combined aqueous layers were extracted with
EtOAc (3 x 20 mL) and the combined organic layers were dried over Na2SO4. After
removal of the solvent in vacuo, the crude product was purified by flash column
chromatography (d = 1 cm, h = 15 cm, V = 5 mL, ethyl acetate + 1 % N,N-
dimethylethylamine). Green oil, yield 5.8 mg (0.02 mmol, 11 %). C19H27FN4O2 (362.4).
Rf = 0.63 (CH2Cl2:CH3OH = 9:1 + 2 % NH3). HPLC: 86.9 %, tR = 13.03 min. 1H NMR
(400 MHz, CDCl3): δ [ppm] = 1.63 – 1.81 (m, 4H, NCH2CH2CH2CH2Ar), 2.65 (d, J =
12.0 Hz, 1H, 4-H), 2.71 – 2.84 (m, 6H, NCH2CH2CH2CH2Ar, 2-H and 5-H), 3.04 – 3.12
(m, 1H, 4-H), 3.24 (dd, J = 12.3/7.0 Hz, 1H, 2-H), 3.28 – 3.37 (m, 1H, 5-H), 3.78 (s, 3H,
OCH3), 4.64 (dt, J = 27.0/4.4 Hz, 2H, OCH2CH2F), 4.77 (d, J = 6.9 Hz, 1H, 1-H), 4.71
– 4.87 (m, 2H, OCH2CH2F), 6.61 – 6.73 (m, 2H, 6-H and 8-H), 7.17 (d, J = 8.2 Hz, 1H,