Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at the 3-benzazepine scaffold retaining GluN2B affinity

Article abstract of DOI:10.1016/j.bmc.2017.07.059

Since overactivation of NMDA receptors is associated with neurodegenerative disorders, the design and development of subunit-selective NMDA receptor antagonists are of great interest. In order to avoid the formation of quinone-like intermediates as starti

Full text of DOI:10.1016/j.bmc.2017.07.059

Accepted Manuscript
Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at
the 3–benzazepine scaffold retaining GluN2B affinity
Susann Rath, Dirk Schepmann, Bernhard Wünsch
PII:
S0968-0896(17)31209-9
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.07.059
BMC 13896
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 June 2017
14 July 2017
28 July 2017
Please cite this article as: Rath, S., Schepmann, D., Wünsch, B., Replacement of benzylic hydroxy group by vinyl
or hydroxymethyl moiety at the 3–benzazepine scaffold retaining GluN2B affinity, Bioorganic & Medicinal
Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.07.059
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Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at the
3-benzazepine scaffold retaining GluN2B affinity
Susann Rath,a Dirk Schepmann,a Bernhard Wünsch*a,b
a
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster,
Corrensstraße 48, D-48149 Münster, Germany
Tel.: +49-251-8333311; Fax: +49-251-8332144; E-mail: wuensch@uni-muenster.de
b
Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany
1

Abstract
Since overactivation of NMDA receptors is associated with neurodegenerative disorders, the
design and development of subunit-selective NMDA receptor antagonists are of great interest.
In order to avoid the formation of quinone-like intermediates as starting point for degradation
the benzylic OH group of the lead compounds 2 was replaced by an electron rich vinyl or
homologous hydroxymethyl moiety. The Bi(OTf)3 catalyzed intramolecular Friedel-Crafts
alkylation of 9a represents the key step in the synthesis of 1-vinyl substituted tetrahydro-3-
benzazepine 10. Ozonolysis of 10 and subsequent reduction led to the hydroxymethyl
derivative 14. The GluN2B affinities of the methyl ethers 2a, 3a and 4a and phenols 2b and
3b are very similar, respectively. It can be concluded that the ifenprodil binding site of
GluN2B subunit containing NMDA receptors well tolerates a vinyl or hydroxymethyl moiety
instead of the benzylic OH group. However, the selectivity has to improved, since the 1
affinity of the new ligands is higher than their GluN2B affinity.
Keywords
NMDA receptor; GluN2B ligands; 3-benzazepines; structure affinity relationships; selectivity
2

1. Introduction
The excitatory neurotransmitter (S)-glutamate mediates its effects via activation of
metabotropic and ionotropic glutamate receptors. The class of ionotropic glutamate receptors
is subdivided in 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA),
kainate (KA), and N-methyl-D-aspartate (NMDA) receptors.1,2 The NMDA receptor is highly
expressed in the central nervous system,3 but also in some tissues in the periphery, e.g. heart4
and pancreas.5 It is a heterotetrameric complex consisting of GluN1(a-h), GluN2(A-D), and
GluN3(A-B) subunits. A functional NMDA receptor contains at least one GluN1 and one
GluN2 subunit.6,7 For an activation of the NMDA receptor the simultaneous binding of
glycine at the GluN1 subunit and (S)-glutamate at the GluN2 subunit is required. Additionally,
depolarization of the membrane is necessary to remove Mg2+-ions blocking the channel
pore.2,8 The open channel is permeable for Na+- and K+-ions and especially, for Ca2+-ions,
which makes the NMDA receptor unique within the class of ionotropic (S)-glutamate
receptors.9 Ca2+-ions act as second messenger and activate several enzyme cascades in the
cell. Therefore, NMDA receptors are involved in a broad spectrum of physiological processes
like learning and memory.2 However, overactivation of the NMDA receptor is associated with
the so-called process of excitotoxicity.7 Whereas an acute and strong overactivation of the
NMDA receptor results after epileptic or ischemic events, a permanent slight overactivation is
associated with neurodegenerative disorders including Alzheimers’s and Parkinson’s
disease.7,10,11 Hence, the NMDA receptor represents an interesting target for the development
of innovative neuroprotective drugs.
Potent open-channel blockers interacting with the phencyclidine (PCP) binding site within the
channel pore and thus blocking all types of NMDA receptors are associated with severe side
effects such as increased heart rate, hallucinations and psychotomimetic effects.7 Therefore,
the development of subunit-selective NMDA receptor antagonists, interacting only with
3

NMDA receptors containing a particular subunit, is of great interest.6,11 Ifenprodil (1, Figure
1), which was initially developed as α1 adrenoreceptor antagonist,12 shows high affinity
towards NMDA receptors containing the GluN2B subunit.13 Site-directed mutagenesis
experiments led to the detection of a distinct binding pocket in the GluN2B subunit, which
was subsequently termed ifenprodil binding site.14
Figure 1: Development of 3-benzazepines as novel GluN2B selective NMDA receptor
antagonists starting from ifenprodil (1) as lead compound.
The low receptor selectivity and the fast metabolic degradation15 inhibited the clinical use of
ifenprodil. Recently, 3-benzazepines 2a and 2b containing the same structural elements as
ifenprodil (phenol (only 2b), benzylic alcohol, tertiary amine, phenylethanolamine) have been
reported.16 Both compounds show promising GluN2B affinity, high selectivity over a large set
of related targets and reduced metabolic degradation.16 However, due to the acetalic
arrangement of the aromatic methoxy or hydroxy moiety and the benzylic OH group, both
compounds 2a and 2b are able to form quinone-like intermediates.
4

In order to inhibit the formation of quinone-like compounds, a rearrangement of the
corresponding functional groups was envisaged. The substituent at the benzene ring should be
shifted by one position and the benzylic OH moiety should be replaced by the electronically
rich vinyl (compound 3) or homologous hydroxymethyl moiety (compound 4). (Figure 1)
Herein, we report on the synthesis and pharmacological evaluation of 3-benzazepines of type
3 and 4.
2. Results and Discussion
2.1. Synthesis
The synthesis of the envisaged 3-benzazepines 3 and 4 started with the substituted
4-phenylethylamines 7. Whereas the methoxy substituted derivative 7a was commercially
available, the benzyloxy analog 7b was prepared by benzylation of phenol 5 and subsequent
TFA cleavage of the Boc-protective group. At first the primary amino group was protected as
sulfonamide upon reaction of phenylethylamines 7 with p-TsCl. Sulfonamides 8 were
subsequently treated with 1,4-dibromobut-2-ene in the presence of K2CO3 to afford the allyl
bromides 9. Initial experiments inducing the intramolecular Friedel Crafts alkylation of 9a
17
with AlCl3 led to cleavage of the methyl ether. The use of the milder Lewis acid Bi(OTf)3
resulted in ring closure without cleavage of the methyl ether and the tetrahydro-3-benzazepine
10 with a vinyl moiety in benzylic position was isolated in 26 % yield.
5

Scheme 1: Synthesis of tosylated 3-benzazepines 10 and 11.
Reagents and reaction conditions: (a) BnBr, K2CO3, CH3CN, reflux, 17 h, 95 %. (b) TFA,
CH2Cl2, rt, 1 h, 99 %. (c) p-TsCl, NEt3, CH2Cl2, rt, 17 h, 98 % (8a), 92 % (8b). (d) 1,4-
dibromobut-2-ene (BrCH2CH=CHCH2Br), K2CO3, CH3CN, rt, 24 h, 71 % (9a), 65 % (9b). (e)
9a, Bi(OTf)3, molecular sieves (4 Å), CH2Cl2, rt, 21 h,26 % (10). (f) 9b, Bi(OTf)3, molecular
sieves (4 Å), CH2Cl2, rt, 21 h, 0.5 % (11A), 0.8 % (11B).
It is noteworthy that even in the presence of the mild Lewis acid Bi(OTf)3 the ring closure of
9b did not provide the desired (8-benzyloxy)-3-benzazepine, but led to the regioisomeric
phenols 11A and 11B which were isolated by flash chromatography in 0.5 and 0.8 % yield,
respectively. Analysis of the NMR spectra revealed that the benzyl moiety is connected
6

directly to the benzene ring in the products. Obviously, a shift of the benzyl moiety to the o-
position of the phenolic OH group had occurred in the presence of Bi(OTf)3.
The sulfonamide 10 represents the key intermediate to exploit the introduction of GluN2B
pharmacophoric structural elements. At first the sulfonamide was cleaved upon treatment of
10 with Mg in CH3OH under sonication to obtain the secondary amine 12 in 89 % yield.
(Scheme 2) Since compounds with a phenylbutyl side chain at the 3-benzazepine N-atom
showed high GluN2B affinity16,18 this moiety was introduced here as well. Reductive
alkylation of the secondary amine 12 with 4-phenylbutanal and NaBH(OAc)3 provided the
phenylbutyl derivative 3a in 22 % yield. Finally, cleavage of the methyl ether of 3a with BBr3
led to the phenol 3b, which was isolated in 51 % yield.
Scheme 2: Synthesis of tetrahydro-3-benzazepines 3a and 3b with a vinyl moiety in benzylic
position.
Reagents and reaction conditions: (a) Mg, CH3OH, ultrasonic bath, 8 h, 89 %. (b)
Ph(CH2)3CHO, NaBH(OAc)3, CH2Cl2, rt, 19 h, 22 %. (c) BBr3, CH2Cl2, -78 °C → rt, 21 h,
51 %.
7

According to the second strategy the vinyl group was transformed into a hydroxymethyl
moiety (Scheme 3). Ozonolysis of the vinyl derivative 10 followed by reductive work-up with
(CH3)2S provided the aldehyde 13, which was reduced with NaBH4 to give alcohol 14. Then,
the sulfonyl protective group of 14 was removed with Mg in CH3OH. The resulting secondary
amine 15 was reductively alkylated with 4-phenylbutanal and NaBH(OAc)3 to end up with the
phenylbutyl derivative 4a.
Scheme 3: Synthesis of tetrahydro-3-benzazepine 4a with a hydroxymethyl moiety in benzylic
position.
Reagents and reaction conditions: (a) O3, CH2Cl2, -78 °C, 20 min, then (CH3)2S, rt, 30 min.
(b) NaBH4, CH3OH, rt, 17 h, 51 % over two steps. (c) Mg0, CH3OH, ultrasonic bath, 12 h, 64
%. (d) Ph(CH2)3CHO, NaBH(OAc)3, CH2Cl2, rt, 17 h, 28 %.
2.2. Receptor Affinity
GluN2B affinity
The GluN2B affinity of the synthesized racemic 3-benzazepines 3 and 4 was investigated in
competitive radioligand binding assays.19 Tritium-labeled ifenprodil ([3H]1) was used as
radioligand, whilst selectivity for GluN2B subunit containing NMDA receptors was achieved
8

by using membrane preparations from a recombinant cell line stably expressing the GluN1a
splice variant and the GluN2B subunit.
Table 1: Receptor affinity of tetrahydro-3-benzazepines 3 and 4 with vinyl and
hydroxymethyl moiety and reference compounds.
Ki ± SEM [nM] (n = 3)
Compd.
R
GluN2B
706 ± 100
84 ± 18
472 ± 62
157 ± 6
606
PCP
22 %
33 %
3 %
0 %
10 %
-
1
2
CH3
H
182
554
57
2a
194
2b
CH3
H
122
>1 µM
118
883
-
3a
48
3b
CH3
80
4a
ifenprodil
dexoxadrol
haloperidol
di-o-tolylguanidine
10 ± 0.7
-
-
32 ± 7.4
-
-
-
-
6.3 ± 1.6
89 ± 29
78 ± 2.3
57 ± 18
-
-
For compounds with low affinity at a concentration of 1 µM only the inhibition of the radio-
ligand binding (in %) at 1 µM concentration is given in Table 1. – indicates not tested.
The affinity of 3-benzazepines 3 and 4 towards GluN2B containing NMDA receptors is
summarized in Table 1. Both methyl ethers 3a and 4a show GluN2B affinity in the high
9

nanomolar range with Ki values of 472 nM and 606 nM, respectively. The similar values for
3a and 4a indicate that both the vinyl and the hydroxymethyl moiety lead to similar
interactions with GluN2B receptors. Replacement of the methoxy moiety by a hydroxy moiety
resulted in 3-fold increased GluN2B affinity of the phenol 3b (Ki = 157 nM). This finding is
in good accordance with the data obtained for the lead compounds, since the phenol 2b
exhibits about 10-fold higher GluN2B affinity than the methyl ether 2a. Comparison of the
GluN2B affinity of the phenols 2b and 3b led to the conclusion that changed position of the
phenolic OH moiety and the replacement of the benzylic OH group by a vinyl moiety is well
tolerated by the GluN2B receptor although the affinity is slightly reduced. Moreover, for
compound 4a containing the hydroxymethyl side chain in benzylic position a similar GluN2B
affinity (Ki = 606 nM) as for the lead compound 2b (Ki = 706 nM) was obtained.
Receptor selectivity
In order to evaluate the selectivity of 3-benzazepines 3 and 4 towards related receptors, the
affinity to the PCP binding site of the NMDA receptor,20 and to σ1 and σ2 receptors21 was
determined in competitive receptor binding studies with radiolabeled ligands. The resulting
Ki values are summarized in Table 1.
The 3-benzazepines 3 and 4 show very low affinity towards the PCP binding site.
Consequently, high selectivity for the ifenprodil binding site over the PCP binding site results.
However, affinity of the 3-benzazepines 3 and 4 to σ1 receptors was even higher than their
affinity towards GluN2B receptors. Phenol 3b has the highest 1 affinity (Ki = 48 nM).
10

The 2 affinity of the 3-benzazepines 3b and 4a is almost the same as the their GluN2B
affinity. However, the methyl ether 3a with a vinyl moiety shows a considerable selectivity
for the GluN2B receptor over the 2 receptor.
3. Conclusion
Replacement of the benzylic OH moiety of the 3-benzazepines 2 by a vinyl or hydroxymethyl
moiety was envisaged in order to inhibit degradation via formation of quinoid-like
intermediates. The methyl ethers 3a and 4a reveal almost the same GluN2B affinity as the
methyl ether 2a indicating that the ifenprodil binding site well tolerates a vinyl or
hydroxymethyl group at the benzylic position without loss of GluN2B affinity. The similar
GluN2B affinities of the phenols 2b and 3b support this observation. In general, the OH
moiety at the benzene ring is preferred over the methoxy moiety, but its position seems not to
have a great impact on GluN2B affinity. Although the new 3-benzazepines 3 and 4 show
moderate to high GluN2B affinity, their selectivity over 1 and 2 receptors remains to be
improved.
4. Experimental Part
4.1. Chemistry, General
Unless otherwise noted, the moisture sensitive reactions were carried out under dry nitrogen.
Dry CH3CN was obtained from Acros and was used without further purification. CH2Cl2was
distilled over CaH2 and CH3OH was distilled from magnesium methanolate. Et3N was dried
with molecular sieves (3 Å). Thin layer chromatography (tlc): Silica gel 60, F254 plates
(Merck). Chromatography: Silica gel 60, 40-64 µm (Merck); parentheses include: diameter of
the column (d), length (l), fraction size (v), eluent, Rf value. Automatic flash chromatography:
Automatic flash column chromatography was performed with IsoleraTM Spektra One
11

(Biotage®). The cartridge size and the eluent are given in brackets. Fraction sizes were fixed
as 20 mL. Melting point: Melting point apparatus Mettler Toledo MP50 Melting point
system, uncorrected. MS: MicroOTOF-Q II (Bruker Daltronics); APCI, atmospheric pressure
chemical ionization. IR: FT-IR spectrophotometer MIRacle 10 (Shimadzu) equipped with
ATR technique. NMR spectra were recorded with Agilent 600-MR (600 MHz for 1H NMR
spectra, 151 MHz for 13C NMR spectra) or Agilent 400-MR (400MHz for 1H NMR spectra,
101 MHz for 13C NMR spectra); δ in ppm related to tetramethylsilane and measured referring
to CHCl3 (δ = 7.26 ppm for 1H NMR and δ = 77.16 ppm for 13C NMR) and DMSO-d6 (δ =
2.50 ppm for 1H NMR and δ = 39.52 ppm for 13C NMR); coupling constants are given with
0.5 Hz resolution; assignment of 13C and 1H NMR signals was supported by 2-D NMR
techniques where necessary. Purity (HPLC): Merck Hitachi Equipments; UV detectors: L-
7400; autosampler: L-7200; pump: L-7100; degasser: L-7614; column: LiChrospher® 60 RP-
select B (5µm); LiChroCART® 250-4 mm cartridge; flow rate: 1.0 mL/min; injection volume:
5.0µL; detection at λ = 210 nm; sol-vents: A: water with 0.05% (v/v) of trifluoroacetic acid;
B: acetonitrile with 0.05 % (v/v) of trifluoroacetic acid; gradient elution: (A%): 0-4 min: 90
%, 4-29 min: gradient from 90 % to 0 %, 29-31 min: 0 %, 31-31.5 min: gradient from 0 % to
90%, 31.5-40 min: 90 %. The purity of all compounds was determined by this method. Semi-
preparative HPLC: Merck Hitachi Equipments: pump: L-7150, autosampler: L-7200, UV
detector: L-7400, interface: D-7000, data transfer: D-line, data acquisition: HSM-Software;
column: Gemini C18 (10 µm) 250×21.2 mm (Phenomenex); solvent: CH3CN/H2O 6:4; flow
rate: 25.0 mL/min; injection volume: 400 µL; detection at λ = 210 nm.
4.2. Synthetic procedures
tert-Butyl N-[2-(4-benzyloxyphenyl)ethyl]carbamate (6) 22
N-Boc-tyramine (5) (500 mg, 2.11 mmol) was dissolved in CH3CN (15 mL) and treated with
K2CO3 (874 mg, 6.32 mmol, 3 eq.) and benzyl bromide (250 µL, 2.11 mmol, 1 eq.). The
12

suspension was heated to reflux under light exclusion for 17 h. After complete conversion, the
reaction mixture was diluted with H2O (50 mL) and the aqueous layer was extracted with
EtOAc (5×10 mL). The combined organic layers were washed with brine (30 mL), dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by automatic
flash column chromatography (Biotage® 50 g, cyclohexane/EtOAc 9:1 → 8:2). Colorless
solid, yield 660 mg (95 %, 2.01 mmol). C20H25NO3 (327.4 g/mol). 1H NMR (600 MHz,
DMSO-d6): δ [ppm] = 1.36 (s, 9H, C(CH3)3), 2.61 (t, J = 7.5 Hz, 2H, Ar-CH2CH2), 3.08 (q, J
= 6.9 Hz, 2H, Ar-CH2CH2), 5.06 (s, 2H, Ar-CH2O), 6.83 (t, J = 5.7 Hz, 1H, NH), 6.92 (d, J =
8.4 Hz, 2H, 3-H and 5-H phenyl), 7.09 (d, J = 8.5 Hz, 2H, 2-H and 6-H phenyl), 7.32 (t,
J = 7.4 Hz, 1H, 4-H benzyl), 7.38 (t, J = 7.5 Hz, 2H, 3-H and 5-H benzyl), 7.43 (d, J = 7.4 Hz,
2H, 2-H and 6-H benzyl). 13C NMR (151 MHz, DMSO-d6): δ [ppm] = 28.2 (3C, C(CH3)3),
34.6 (Ar-CH2CH2), 41.7 (Ar-CH2CH2), 69.1 (Ar-CH2O), 77.4 (C(CH3)3), 114.6 (2C, C-3 and
C-5 phenyl), 127.6 (2C, C-2 and C-6 benzyl), 127.7 (C-4 benzyl), 128.4 (2C, C-3 and C-5
benzyl), 129.5 (C-1 phenyl), 131.6 (2C, C-2 and C-6 phenyl), 137.2 (C-1 benzyl), 155.5
(N(CO)O), 156.7 (C-4 phenyl).
2-(4-Benzyloxyphenyl)ethan-1-amine trifluoroacetic acid (7b·CF3CO2H)23
Under N2, CF3CO2H (3 mL, 39.2 mmol, 10eq.) was added to a solution of carbamate 6
(1.26 g, 3.85 mmol) in CH2Cl2 (3 mL). The solution was stirred at rt for 1 h. The reaction was
stopped by addition of EtOH (40 mL) and the solvent was evaporated in vacuo. The addition
and removal of EtOH was repeated twice. Colorless solid, yield 1.30 g (99 %, 3.82 mmol).
C17H18F3NO3S (341.3 g/mol). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.80 (t, J = 7.8 Hz,
2H, Ar-CH2CH2), 3.00 (t, J = 7.7 Hz, 2H, Ar-CH2CH2), 5.08 (s, 2H, Ar-CH2O), 6.92 (d,
J = 8.5 Hz, 2H, 3-H and 5-H phenyl), 7.17 (d, J = 8.5 Hz, 2H, 2-H and 6-H phenyl), 7.29 -
7.35 (m, 1H, 4-H benzyl), 7.35 - 7.41 (m, 2H, 3-H and 5-H benzyl), 7.41 - 7.46 (m, 2H, 2-H
and 6-H benzyl), 7.95 (s, 3H, NH3). 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 32.2 (Ar-
13

CH2CH2), 40.2 (Ar-CH2CH2), 69.2 (Ar-CH2O), 114.9 (2C, C-3 and C-5 phenyl), 127.6 (2C,
C-2 and C-6 benzyl), 127.8 (C-4 benzyl), 128.4 (2C, C-3 and C-5 benzyl), 129.4 (C-1 phenyl),
129.7 (2C, C-2 and C-6 phenyl), 137.1 (C-1 benzyl), 157.2 (C-4 phenyl). Signals for the C-
atoms of trifluoroacetic acid are not observed in the spectrum.
N-[2-(4-Methoxyphenyl)ethyl]-4-methylbenzenesulfonamide (8a)24
In a flame-dried Schlenk flask, 2-(4-methoxyphenyl)ethylamine (7a) (3 mL, 20.4 mL) was
dissolved in CH2Cl2 (45 mL) under N2. Afterwards NEt3 (5.7 mL, 40.9 mmol, 2 eq.) and p-
TsCl (4.68 g, 24.5 mmol, 1.2 eq.) were added. Under light exclusion, the reaction mixture was
stirred at rt for 20 h. The mixture was acidified with 4 M HCl and diluted with H2O (40 mL).
The layers were separated and the aqueous layer was extracted with CH2Cl2 (6×15 mL). The
combined organic layers were washed with brine (60 mL), dried (Na2SO4) and the solvent was
evaporated in vacuo. The product was purified in two batches by automatic flash column
chromatography (2×Biotage® 340 g, cyclohexane/EtOAc 8:2). Colorless solid, yield 6.02 g
(97 %, 19.7 mmol). C16H19NO3S (305.4 g/mol). 1H NMR (400 MHz, DMSO-d6): δ [ppm] =
2.37 (s, 3H, Ar-CH3 tosyl), 2.59 (t, J = 7.5 Hz, 2H, Ar-CH2CH2), 2.88 (t, J = 7.6 Hz, 2H, Ar-
CH2CH2), 3.70 (s, 3H, Ar-OCH3), 6.81 (d, J = 8.6 Hz, 2H, 3-H and 5-H phenyl), 7.04 (d, J =
8.6 Hz, 2H, 2-H and 6-H phenyl), 7.37 (d, J = 8.3 Hz, 2H, 3-H and 5-H tosyl), 7.57 (s, 1H,
NH), 7.65 (d, J = 8.3 Hz, 2H, 2-H and 6-H tosyl). 13C NMR (101 MHz, DMSO-d6): δ [ppm] =
20.9 (Ar-CH3 tosyl), 34.3 (Ar-CH2CH2), 44.4 (Ar-CH2CH2), 55.0 (Ar-OCH3), 113.7 (2C, C-3
and C-5 phenyl), 126.5 (2C, C-2 and C-6 tosyl), 129.6 (4C, C-2 and C-6 phenyl, C-3 and C-5
tosyl), 130.5 (C-1 phenyl), 137.5 (C-1 tosyl), 142.5 (C-4 tosyl), 157.7 (C-4 phenyl).
N-[2-(4-Benzyloxyphenyl)ethyl]-4-methylbenzenesulfonamide (8b)
A suspension of the ammonium salt 7b·CF3CO2H (1.30 g, 3.80 mmol), Na2CO3 (806 mg,
7.60 mmol, 2 eq.) in CHCl3 (12 mL) and H2O (3.5 mL) was stirred for 10 min at rt followed
14

by addition of p-TsCl (761 mg, 3.99 mmol, 1.05 eq.) in CHCl3 (6 mL). The mixture was
stirred for additional 3 h before adding dropwise a solution of Na2CO3 (604 mg, 5.70 mmol,
1.5 eq.) in H2O (4.5 mL). After 13 h, the mixture was acidified with 1 M HCl at 0 °C and
diluted with H2O (40 mL). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (5×10 mL). The combined organic layers were washed with brine (20 mL) and
dried (Na2SO4). The solvent was evaporated in vacuo and the resulting residue was purified
by automatic flash column chromatography (Biotage® 340 g, cyclohexane/EtOAc 7:3, Rf =
0.31). Colorless solid, mp 107 °C, yield 1.34 g (92 %, 3.51 mmol). C22H23NO3S
(381.5 g/mol). Exact Mass (APCI): m/z = 382.1457 (calcd. 382.1471 for C23H24NO3S
[M+H]+). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.37 (s, 3H, Ar-CH3 tosyl), 2.60 (t, J =
7.4 Hz, 2H, Ar-CH2CH2), 2.89 (q, J = 6.9 Hz, 2H, Ar-CH2CH2), 5.05 (s, 2H, Ar-CH2O), 6.89
(d, J = 8.5 Hz, 2H, 3-H and 5-H phenyl), 7.05 (d, J = 8.5 Hz, 2H, 2-H and 6-H phenyl), 7.30 -
7.33 (m, 1H, 4-H benzyl), 7.34 - 7.45 (m, 6H, 2-H, 3-H, 5-H and 6-H benzyl, 3-H and 5-H
tosyl), 7.58 (t, J = 5.9 Hz, 1H, NH), 7.66 (dd, J = 8.3 Hz, 2H, 2-H and 6-H tosyl). 13C NMR
(101 MHz, DMSO-d6): δ [ppm] = 20.9 (Ar-CH3 tosyl), 34.3 (Ar-CH2CH2), 44.3
(Ar-CH2CH2), 69.1 (Ar-CH2O), 114.6 (2C, C-3 and C-5 phenyl), 126.5 (2C, C-2 and C-6
tosyl), 127.6 (2C, C-2 and C-6 benzyl), 127.7 (C-4 benzyl), 128.4 (2C, C-3 and C-5 benzyl),
129.6 (2C, C-3 and C-5 tosyl), 129.6 (2C, C-2 and C-6 phenyl), 130.8 (C-1 phenyl), 137.2 C-1
benzyl), 137.5 (C-1 tosyl), 142.5 (C-4 tosyl), 156.8 (C-4 phenyl). FTIR: [cm-1] = 3264
(SO2N-H), 1612 (C=Carom.), 1512 (C=Carom.), 1315 (SO2-N), 1234 (C-O-C), 1153 (SO2-N).
Purity (HPLC): 98.8 %, tR = 24.00 min.
N-(trans-4-Bromobut-2-en-1-yl)-N-[2-(4-methoxyphenyl)ethyl]-4-methyl-benzenesulfon-
amide (9a)17
15

A solution of sulfonamide 8a (6.02 g, 19.7 mmol) in CH3CN (300 mL) was treated with
K2CO3 (13.6 g, 98.5 mmol, 5 eq.) and 1,4-dibromobut-2-ene (8.43 g, 39.4 mmol, 2 eq.). After
stirring at rt under light exculsion for 24 h, the suspension was diluted with H2O (150 mL).
The aqueous layer was extracted with EtOAc (5×40 mL). The combined organic layers were
washed with brine (120 mL) and dried (Na2SO4). The solvent was evaporated in vacuo. The
crude product was splitted into three parts which were purified by automatic flash column
chromatography (3×Biotage® 340 g, cyclohexane/EtOAc 9:1 → 8:2). Colorless solid, yield
6.16 g (71 %, 14.1 mmol). C20H24BrNO3S (438.4 g/mol). 1H NMR (400 MHz, DMSO-d6): δ
[ppm] = 2.39 (s, 3H, Ar-CH3 tosyl), 2.63 - 2.72 (m, 2H, Ar-CH2CH2), 3.14 - 3.23 (m, 2H, Ar-
CH2CH2), 3.71 (s, 3H, Ar-OCH3), 3.79 (d, J = 6.4 Hz, 2H, NCH2CH=CH), 4.09 (d, J = 7.5
Hz, 2H, CH2Br), 5.62 - 5.69 (m, 1H, NCH2CH=CH), 5.85 - 5.98 (m, 1H, NCH2CH=CH), 6.83
(d, J = 8.5 Hz, 2H, 3-H and 5-H phenyl), 7.05 (d, J = 8.5 Hz, 2H, 2-H and 6-H phenyl), 7.39
(d, J = 8.2 Hz, 2H, 3-H and 5-H tosyl), 7.67 (d, J = 8.2 Hz, 2H, 2-H and 6-H tosyl).
N-(trans-4-Bromobut-2-en-1-yl)-N-[2-(4-benzyloxyphenyl)ethyl]-4-methyl-benzene-
sulfonamide (9b)
Sulfonamide 8b (1.32 g, 3.46 mmol) was dissolved in CH3CN (70 mL) and K2CO3 (2.39 g,
17.3 mmol, 2 eq.) and 1,4-dibromobut-2-ene (1.48 g, 17.3 mmol, 5 eq.) were added. Under
light exclusion, the suspension was stirred at rt for 23 h. H2O (80 mL) was added and the
aqueous layer was extracted with EtOAc (5×15 mL). The combined organic layers were
washed with brine (60 mL), dried (Na2SO4) and the solvent was evaporated in vacuo. The
crude product was purified by automatic flash column chromatography (Biotage® 340 g,
cyclohexane/EtOAc 8:2, Rf = 0.45 (cyclohexane/EtOAc 7:3)). Colorless oil, yield 1.17 g
(65 %, 2.27 mmol). C26H28BrNO3S (514.5 g/mol). Exact Mass (APCI): m/z = 514.1046
(calcd. 514.1046 for C26H2979BrNO3S [M+H]+). 1H NMR (400 MHz, DMSO-d6): δ [ppm] =
2.38 (s, 3H, Ar-CH3 tosyl), 2.67 (t, J = 7.9 Hz, 2H, Ar-CH2CH2), 3.18 (t, J = 7.9 Hz, 2H, Ar-
16

CH2CH2), 3.78 (d, J = 6.4 Hz, 2H, NCH2CH=CH), 4.08 (d, J = 7.5 Hz, 2H, CH2Br), 5.06 (s,
2H, Ar-CH2O), 5.61 - 5.68 (m, 1H, NCH2CH=CH), 5.85 - 5.96 (m, 1H, NCH2CH=CH), 6.91
(d, J = 8.6 Hz, 2H, 3-H and 5-H phenyl), 7.08 (d, J = 8.6 Hz, 2H, 2-H and 6-H phenyl), 7.29 -
7.35 (m, 1H, 4-H benzyl), 7.35 - 7.46 (m, 6H, 2-H and 6-H benzyl, 3-H and 5-H benzyl, 3-H
and 5-H tosyl), 7.68 (d, J = 8.3 Hz, 2H, 2-H and 6-H tosyl). 13C NMR (101 MHz, DMSO-d6):
δ [ppm] = 21.0 (Ar-CH3 tosyl), 33.0 (CH2Br), 33.6 (Ar-CH2CH2), 48.7 (NCH2CH=CH), 49.1
(Ar-CH2CH2), 69.1 (Ar-CH2O), 114.7 (2C, C-3 and C-5 phenyl), 126.9 (2C, C-2 and C-6
tosyl), 127.6 (2C, C-2 and C-6 benzyl), 127.7 (C-4 benzyl), 128.4 (2C, C-3 and C-5 benzyl),
129.7 (2C, C-2 and C-6 phenyl), 129.8 (2C, C-3 and C-5 tosyl), 130.3 (2C, NCH2CH=CH),
130.5 (C-1 phenyl), 136.3 (C-1 benzyl), 137.2 (C-1 tosyl), 143.1 (C-4 tosyl), 156.9 (C-4
phenyl). FTIR: [cm-1] = 1609 (C=Carom.), 1508 (C=Carom.), 1335 (SO2-N), 1238 (C-O-C),
1153 (SO2-N), 1092 (C-O-C). Purity (HPLC): 97.7 %, tR = 26.75 min.
8-Methoxy-3-(4-methylphenylsulfonyl)-1-vinyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(10)17
Molecular sieves (4 Å) were placed in a Schlenk flask and vacuum was applied for 20 min.
Under N2, allyl bromide 9a (2.00 g, 4.56 mmol) was dissolved in dry CH2Cl2 (90 mL) and
Bi(OTf)3 (1.50 g, 2.28 mmol, 0.5 eq.) was added. The suspension was stirred at rt for 18 h.
Molecular sieves were filtered off over Celite and the Celite pad was washed with EtOAc.
The solvent was evaporated in vacuo and the crude product was adsorbed on silica gel and
purified by automatic flash column chromatography (Biotage® 340 g, cyclohexane/EtOAc
8:2). Colorless oil, yield 405 mg (25 %, 1.13 mmol). C20H23NO3S (357.5 g/mol). 1H NMR
(400 MHz, DMSO-d6): δ [ppm] = 2.36 (s, 3H, Ar-CH3 tosyl), 2.58 - 2.69 (m, 1H, 4-H), 2.73 -
2.79 (m, 1H, 5-H), 2.84 - 3.00 (m, 2H, 2-H, 5-H), 3.55 - 3.59 (m, 1H, 4-H), 3.69 (s, 3H, Ar-
OCH3), 3.70 - 3.78 (m, 2H, 1-H, 2-H), 4.84 (dt, J = 17.3/1.7 Hz, 1H, HC=CH2), 5.13 (dt, J =
17

10.4/1.7 Hz, 1H, HC=CH2), 6.10 (ddd, J = 17.2/10.4/5.5 Hz, 1H, HC=CH2), 6.66 - 6.70 (m,
2H, 7-H, 9-H), 7.01 (d, J = 8.0 Hz, 1H, 6-H), 7.38 (d, J = 8.4 Hz, 2H, 3-H and 5-H tosyl), 7.61
(d, J = 8.4 Hz, 2H, 2-H and 6-H tosyl). 13C NMR (101 MHz, DMSO-d6): δ [ppm] = 20.9 (Ar-
CH3), 34.1 (C-5), 48.5 (C-4), 49.1 (C-1), 51.4 (C-2), 54.9 (Ar-OCH3), 111.2 (C-7), 115.7 (C-
9), 116.0 (HC=CH2), 126.8 (2C, C-2 and C-6 tosyl), 129.8 (2C, C-3 and C-5 tosyl), 131.1 (C-
5a), 131.2 (C-6), 134.7 (C-1 tosyl), 138.0 (HC=CH2), 142.2 (C-9a), 143.2 (C-4 tosyl), 157.8
(C-8).
6-Benzyl-3-(4-methylphenylsulfonyl)-5-vinyl-2,3,4,5-tetrahydro-1H-3-benzaze-pin-7-ol
(11A) and
8-benzyl-3-(4-methylphenylsulfonyl)-5-vinyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol
(11B)
A Schlenk flask equipped with molecular sieves (4 Å) was evacuated for 10 min. Under N2, a
solution of sulfonamide 12 (1.03 g, 2.01 mmol) in dry CH2Cl2 (45 mL) was treated with
Bi(OTf)3 (658 mg, 1.00 mmol, 0.5 eq.). The reaction mixture was stirred at rt for 21 h. The
suspension was filtered over Celite and the Celite pad washed with EtOAc. The solvent was
evaporated in vacuo and the crude product was adsorbed on silica gel which was purified by
automatic flash column chromatography (Biotage® 340 g, cyclohexane/EtOAc 8:2 → 7:3).
The products were additionally purified by semi-preparative HPLC (CH3CN/H2O 6:4).
11A Colorless oil, yield 4.6 mg (0.5 %, 10.6 µmol). Rf = 0.34 (cyclohexane/EtOAc 7:3).
tR = 19.94 min (semi-prep. HPLC). C26H27NO3S (433.6 g/mol). 1H NMR (600 MHz, DMSO-
d6): δ [ppm] = 2.28 (t, J = 11.8 Hz, 1H, 2-H), 2.36 (s, 3H, Ar-CH3 tosyl), 2.34 - 2.36 (m, 1H,
4-H), 2.65 (dd, J = 15.1/5.9 Hz, 1H, 1-H), 2.97 (ddd, J = 14.8/11.5/2.3 Hz, 1H, 1-H), 3.80 (d,
J = 15.5 Hz, 1H, Ar-CH2-Ar), 3.79 - 3.82 (m, 1H, 2-H), 3.89 (ddd, J = 13.2/6.5/1.9 Hz, 1H, 4-
H), 4.02 - 4.05 (m, 1H, 5-H), 4.07 (d, J = 15.4 Hz, 1H, Ar-CH2-Ar), 4.55 (dt, J = 17.3/2.0 Hz,
1H, CH=CH2), 4.96 (dt, J = 10.3/2.0 Hz, 1H, CH=CH2), 5.95 (ddd, J = 17.4/10.4/4.5 Hz, 1H,
18

CH=CH2), 6.66 (d, J = 8.2 Hz, 1H, 8-H), 6.82 (d, J = 8.2 Hz, 1H, 9-H), 7.05 (d, J = 7.3 Hz,
2H, 2-H and 6-H benzyl), 7.10 (t, J = 7.2 Hz, 1H, 4-H benzyl), 7.18 (t, J = 7.5 Hz, 2H, 3-H
and 5-H benzyl), 7.37 (d, J = 8.3 Hz, 2H, 3-H and 5-H tosyl), 7.55 (d, J = 8.3 Hz, 2H, 2-H and
6-H tosyl), 9.34 (s, 1H, Ar-OH). 13C NMR (151 MHz, DMSO-d6): δ [ppm] = 21.0 (Ar-CH3
tosyl), 30.8 (Ar-CH2-Ar), 34.6 (C-1), 43.4 (C-5), 48.7 (C-2), 51.0 (C-4), 113.1 (C-8), 115.5
(CH=CH2), 125.5 (C-4 benzyl), 125.8 (C-6), 126.9 (2C, C-2 and C-6 tosyl), 128.0 (2C, C-2
and C-6 benzyl), 128.1 (2C, C-3 and C-5 benzyl), 129.4 (C-9), 129.8 (2C, C-3 and C-5 tosyl),
130.4 (C-9a), 134.4 (C-1 tosyl), 137.4 (CH=CH2), 140.5 (C-5a), 141.1 (C-1 benzyl), 143.2 (C-
4 tosyl), 154.1 (C-7).
11B Colorless oil, yield 7.1 mg (0.8 %, 16.4 µmol). Rf = 0.34 (cyclohexane/EtOAc 7:3),
tR = 24.69 min (HPLC method 3). C26H27NO3S (433.6 g/mol). 1H NMR (600 MHz, DMSO-
d6): δ[ppm] = 2.36 (s, 3H, Ar-CH3 tosyl), 2.66 (m, 2H, 1-H, 2-H), 2.86 (m, 2H, 1-H, 4-H),
3.45 - 3.49 (m, 1H, 2-H), 3.55 - 3.58 (m, 1H, 5-H), 3.64 (dd, J = 13.3/6.9 Hz, 1H, 4-H), 3.74
(d, J = 14.6 Hz, 1H, Ar-CH2-Ar), 3.78 (d, J = 14.5 Hz, 1H, Ar-CH2-Ar), 4.85 (dt, J = 17.2/1.8
Hz, 1H, CH=CH2), 5.11 (dt, J = 10.4/1.7 Hz, 1H CH=CH2), 6.05 (ddd, J = 17.2/10.4/6.0 Hz,
1H, CH=CH2), 6.55 (s, 1H, 6-H), 6.75 (s, 1H, 9-H), 7.10 - 7.14 (m, 1H, 4-H benzyl), 7.15 -
7.18 (m, 2H, 2-H and 6-H benzyl), 7.20 - 7.25 (m, 2H, 3-H and 5-H benzyl), 7.37 (d, J = 8.2
Hz, 2H, 3-H and 5-H tosyl), 7.59 (d, J = 8.3 Hz, 2H, 2-H and 6-H tosyl), 9.22 (s, 1H, Ar-OH).
13C NMR (151 MHz, DMSO-d6): δ[ppm] = 21.0 (Ar-CH3 tosyl), 34.3 (C-1), 34.7 (Ar-CH2-
Ar), 48.7 (C-2), 48.8 (C-5), 51.7 (C-4), 115.8 (CH=CH2), 116.4 (C-6), 125.1 (C-8), 125.6 (C-
4 benzyl), 126.8 (2C, C-2 and C-6 tosyl), 128.2 (2C, C-3 and C-5 benzyl), 128.6 (2C, C-2 and
C-6 benzyl), 129.5 (C-9a), 129.8 (2C, C-3 and C-5 tosyl), 132.1 (C-9), 134.8 (C-1 tosyl),
138.3 (CH=CH2), 139.7 (C-5a), 141.2 (C-1 benzyl), 143.2 (C-4 tosyl), 153.2 (C-7).
8-Methoxy-1-vinyl-2,3,4,5-tetrahydro-1H-3-benzazepine (12)
19

Under N2, Mg0 turnings (483 mg, 19.9 mmol, 15 eq.) was added to a solution of sulfonamide
10 (473 mg, 1.32 mmol) in abs. CH3OH (30 mL). The suspension was sonicated in an
ultrasonic bath for 7.5 h and strirred afterwards at rt for 17 h. At 0 °C, AcOH and then NH3
solution were added (pH 9). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (6×10 mL). The combined organic layers were washed with brine (50 mL) and
dried (Na2SO4). After removal of the solvent in vacuo, the product was used without further
purifications. (Rf = 0.37 (CH2Cl2/CH3OH 95:5 + drops of NH3)). Yellow oil, yield 231 mg
(86 %, 1.14 mmol). C13H17NO (203.3 g/mol). Exact Mass (APCI): m/z = 204.1391 (calcd.
204.1383 for C13H18NO [M+H]+). 1H NMR (600 MHz, CDCl3): δ [ppm] = 2.75 (dd, J =
15.5/6.6 Hz, 1H, 5-H), 2.80 - 2.84 (m, 1H, 4-H), 2.96 - 3.01 (m, 1H, 5-H), 3.03 - 3.12 (m, 2H,
2-H, 4-H), 3.17 (dd, J = 13.4/6.1 Hz, 1H, 2-H), 3.53 - 3.59 (m, 1H, 1-H), 3.78 (s, 3H, Ar-
OCH3), 4.89 - 4.93 (m, 1H, HC=CH2), 5.19 - 5.22 (m, 1H, HC=CH2), 6.11 (m, 1H, HC=CH2),
6.66 (dd, J = 8.2/2.8 Hz, 1H, 7-H), 6.70 (d, J = 2.8 Hz, 1H, 9-H), 7.01 (d, J = 8.2 Hz, 1H, 6-
H). A signal for the NH proton is not observed in the spectum. 13C NMR (151 MHz, CDCl3):
δ [ppm] = 39.0 (C-5), 48.9 (C-4), 53.0 (C-1), 53.1 (C-2), 55.3 (Ar-OCH3), 110.8 (C-7), 115.8
(C-9), 116.5 (HC=CH2), 131.2 (C-6), 133.8 (C-5a), 138.7 (HC=CH2), 144.0 (C-9a), 158.1 (C-
8). Purity (HPLC): 76.2 %, tR = 13.20 min.
8-Methoxy-3-(4-phenylbutyl)-1-vinyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3a)
Under N2, a solution of amine 12 (132 mg, 0.648 mmol) and 4-phenylbutanal (110 mg,
0.745 mmol, 1.1 eq.) in dry CH2Cl2 (5 mL) was treated with NaBH(OAc)3 (275 mg,
1.30 mmol, 2 eq.) and the mixture was stirred at rt for 19 h. The reaction mixture was diluted
with H2O (15 mL) and the aqueous layer was extracted with CH2Cl2 (6×5 mL). The combined
organic layers were washed with brine (15 mL), dried (Na2SO4) and the solvent was
evaporated in vacuo. The crude product was purified by automatic flash column
chromatography (Biotage® 25 g, cyclohexane/EtOAc 8:2 → 7:3, Rf = 0.36
20

(cyclohexane/EtOAc 7:3)). Orange oil, yield 47.7 mg (22 %, 0.142 mmol). C23H29NO
(335.5 g/mol). Exact Mass (APCI): m/z = 336.2322 (calcd. 336.2322 for C23H30NO [M+H]+).
1H NMR (400 MHz, CDCl3): δ [ppm] = 1.52 - 1.59 (m, 2H, NCH2CH2), 1.60 - 1.69 (m, 2H,
CH2CH2Ph), 2.44 - 2.58 (m, 2H, NCH2CH2), 2.58 - 2.68 (m, 4H, 4-H, 5-H), 2.68 - 2.99 (m,
4H, 2-H, CH2CH2Ph), 3.57 - 3.68 (m, 1H, 1-H), 3.78 (s, 3H, Ar-OCH3), 4.95 (d, J = 17.1 Hz,
1H, HC=CH2), 5.15 (d, J = 10.4 Hz, 1H, HC=CH2), 6.16 (ddd, J = 17.2/10.4/6.8 Hz, 1H,
HC=CH2), 6.66 (dd, J = 8.2/2.7 Hz, 1H, 7-H), 6.71 (d, J = 2.7 Hz, 1H, 9-H), 7.00 (d, J = 8.2
Hz, 1H, 6-H), 7.15 - 7.21 (m, 3H, 2-H, 4-H and 6-H phenyl), 7.25 - 7.31 (m, 2H, 3-H and 5-H
phenyl). 13C NMR (101 MHz, CDCl3): δ [ppm] = 26.6 (NCH2CH2), 29.5 (CH2CH2Ph), 35.5
(CH2CH2Ph), 36.0 (C-5), 49.7 (C-1), 55.4 (Ar-OCH3), 56.1 (C-4), 59.5 (NCH2CH2), 60.1
(C-2), 110.7 (C-7), 114.9 (C-9), 115.4 (HC=CH2), 125.8 (C-4 phenyl), 128.4 (2C, C-3 and C-
5 phenyl), 128.5 (2C, C-2 and C-6 phenyl), 130.6 (HC=CH2), 133.6 (C-6), 133.7 (C-5a),
142.7 (C-1 phenyl), 144.6 (C-9a), 158.1 (C-8). FTIR: [cm-1] = 1605 (C=Carom.), 1497
(C=Carom.), 1261 (C-O-C), 1042 (C-O-C). Purity (HPLC): 92.7 %, tR = 20.75 min.
3-(4-Phenylbutyl)-5-vinyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (3b)
Under N2 at -78 °C, a 1 M solution of BBr3 in CH2Cl2 (0.17 mL, 0.166 mmol, 1.17 eq.) was
added to a solution of methyl ether 3a (47.7 mg, 0.142 mmol) in dry CH2Cl2 (1 mL). After
stirring at rt for 21 h, H2O (10 mL) was added and the mixture was stirred at rt for 1 h. The
aqueous layer was saturated with NaCl and extracted with CH2Cl2 (5×4 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was
purified by column chromatography (ø 2 cm, l = 6 cm, EtOAc/CH3OH 9:1 + 0.5 % NEt3,
V = 4 mL, Rf = 0.41 (cyclohexane/EtOAc 4:6 + 1 % NEt3)). Pale brown resin, yield 23.1 mg
(51 %, 71.9 µmol). C22H27NO (321.5 g/mol). Exact Mass (APCI): m/z = 322.2166 (calcd.
322.2165 for C22H28NO [M+H]+). 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.41 - 1.47 (m,
2H, NCH2CH2), 1.54 - 1.60 (m, 2H, CH2CH2Ph), 2.31 - 2.41 (m, 3H, NCH2CH2, 2-H), 2.44 -
21

2.50 (m, 1H, 4-H), 2.54 - 2.63 (m, 3H, 2-H, 1-H), 2.63 - 2.84 (m, 3H, CH2CH2Ph, 4-H), 3.44 -
3.52 (m, 1H, 5-H), 4.85 (dt, J = 17.3/1.8 Hz, 1H, HC=CH2), 5.04 (dt, J = 10.4/1.7 Hz, 1H,
HC=CH2), 6.13 (ddd, J = 17.2/10.3/6.7 Hz, 1H, HC=CH2), 6.47 (dd, J = 8.0/2.5 Hz, 1H, 8-H),
6.51 (d, J = 2.5 Hz, 1H, 6-H), 6.85 (d, J = 8.0 Hz, 1H, 9-H), 7.13 - 7.20 (m, 3H, 2-H, 4-H and
6-H phenyl), 7.25 - 7.29 (m, 2H, 3-H and 5-H phenyl), 9.07 (s, 1H, Ar-OH). 13C NMR (101
MHz, DMSO-d6): δ [ppm] = 26.1 (NCH2CH2), 28.8 (CH2CH2Ph), 34.8 (CH2CH2Ph), 35.0 (C-
1), 49.4 (C-5), 55.8 (C-2), 58.4 (NCH2CH2), 59.8 (C-4), 112.4 (C-8), 114.3 (HC=CH2), 115.6
(C-6), 125.6 (C-4 phenyl), 128.2 (2C, C-2 and C-6 phenyl), 128.2 (2C, C-3 and C-5 phenyl),
130.4 (C-9), 131.3 (C-9a), 140.2 (HC=CH2), 142.3 (C-1 phenyl), 143.9 (C-5a), 155.4 (C-7).
FTIR: [cm-1] = 3291 (br., O-H), 1605 (C=Carom.), 1497 (C=Carom.), 918 (C=C). Purity
(HPLC): 91.7 %, tR = 18.34 min.
[8-Methoxy-3-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]me-
thanol (14)
Alkene 10 (440 mg, 1.23 mmol) was dissolved in dry CH2Cl2 (25 mL) and a small amount of
Sudan Red III was added. The reddish solution was cooled to -78 °C, purged by O2 for 10 min
and then treated with ozone until bleaching of the solution was observed. After purging by O2
for 30 min, (CH3)2S (0.9 mL, 12.3 mmol, 10 eq.) was added and the reaction mixture was
allowed to warm up to rt and stirred for 30 min. To remove DMSO, the organic layer was
washed with H2O (3×25 mL) and dried (Na2SO4). The solvent was evaporated in vacuo and
the crude product was purified by filtration over silica gel (Biotage® 100 g,
cyclohexane/EtOAc 7:3, Rf = 0.20). Under N2, a solution of aldehyde 13 in abs. CH3OH
(13 mL) was treated with NaBH4 (187 mg, 4.93 mmol, 6 eq.) at 0 °C. After stirring for 17 h at
rt, H2O (30 mL) was added and the aqueous layer was extracted with EtOAc (5×8 mL). The
combined organic layers were washed with brine (25 mL), dried (Na2SO4) and the solvent was
evaporated in vacuo. The crude product was purified by automatic flash column
22

chromatography (Biotage® 50 g, cyclohexane/EtOAc 7:3 → 6:4, Rf = 0.23 (cyclohexane/
EtOAc 6:4)). Colorless oil, yield 225 mg (51 %, 0.622 mmol). C19H23NO4S (361.5 g/mol).
Exact Mass (APCI): m/z = 362.1428 (calcd. 362.1421 for C19H24NO4S [M+H]+). 1H NMR
(400 MHz, DMSO-d6): δ [ppm] = 2.36 (s, 3H, Ar-CH3 tosyl), 2.74 - 2.80 (m, 1H, 5-H), 2.91 -
3.01 (m, 5H, 1-H, 2-H, 4-H, 5-H), 3.40 - 3.44 (m, 1H, 2-H), 3.68 (s, 3H, Ar-OCH3) 3.67 -
3.70 (m, 2H, CH2OH), 4.73 (t, J = 4.4 Hz, 1H, CH2OH), 6.62 - 6.66 (m, 2H, 7-H, 9-H), 6.98
(d, J = 8.1 Hz, 1H, 6-H), 7.37 (d, J = 8.0 Hz, 2H, 3-H and 5-H tosyl), 7.59 (d, J = 7.9 Hz, 2H,
2-H and 6-H tosyl). 13C NMR (151 MHz, DMSO-d6): δ [ppm] = 20.9 (Ar-CH3 tosyl), 33.8 (C-
5), 47.6 (C-1), 48.6 (C-4), 48.9 (C-2), 54.9 (Ar-OCH3), 61.8 (CH2OH), 110.9 (C-7), 115.0 (C-
9), 126.9 (2C, C-2 and C-6 tosyl), 129.7 (2C, C-3 and C-5 tosyl), 130.7 (C-6), 131.1 (C-5a),
134.6 (C-1 tosyl), 142.0 (C-9a), 143.1 (C-4 tosyl), 157.8 (C-8). FTIR: [cm-1] = 3522 (O-H),
1609 (C=Carom.), 1504 (C=Carom.), 1327 (SO2-N), 1153 (SO2-N). Purity (HPLC): 96.9 %,
tR = 21.27 min.
(8-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl)methanol (15)
Under N2, sulfonamide 14 (157 mg, 0.710 mmol) was dissolved in abs. CH3OH (20 mL) and
Mg0 turnings (605 mg, 24.9 mmol, 35 eq.) were added in 4 portions. The suspension was
treated with ultrasound for 12 h and stirred at rt for further 12 h. At 0 °C, the reaction mixture
was acidified with AcOH, afterwards NH3 was added (pH 10) and the mixture was diluted
with H2O (30 mL). The aqueous layer was extracted with CH2Cl2 (6×6 mL). The combined
organic layers were washed with brine (30 mL) and dried (Na2SO4). The crude product was
purified by flash column chromatography (ø 2 cm, l = 15 cm, CH2Cl2/CH3OH 95:5 → 90:10 +
2 % NH3, V = 4 mL, Rf = 0.18 (CH2Cl2/CH3OH 95:5 + 1 % NEt3)). Yellow resin, yield
93.9 mg (64 %, 0.453 mmol). C12H17NO2 (207.3 g/mol). Exact Mass (APCI): m/z = 208.1333
(calcd. 208.1332 for C12H18NO2 [M+H]+). 1H NMR (600 MHz, DMSO-d6): δ [ppm] = 2.93 -
3.03 (m, 2H, 4-H, 5-H), 3.18 - 3.28 (m, 3H, 1-H, 2-H, 5-H), 3.38 - 3.43 (m, 1H, 4-H), 3.57 -
23

3.62 (m, 1H, 2-H), 3.78 (m, 3H, Ar-OCH3), 3.94 (dd, J = 11.6/5.8 Hz, 1H, CH2OH), 4.08 (dd,
J = 11.7/10.0 Hz, 1H, CH2OH), 5.05 (s, 2H, NH, CH2OH), 6.68 - 6.72 (m, 2H, 7-H, 9-H),
7.03 (d, J = 9.0 Hz, 1H, 6-H). 13C NMR (151 MHz, DMSO-d6): δ [ppm] = 34.3 (C-5), 47.5
(C-1), 47.5 (C-4), 47.9 (C-2), 55.4 (Ar-OCH3), 62.0 (CH2OH), 111.9 (C-7), 116.0 (C-9),
131.2 (C-5a), 131.9 (C-6), 141.1 (C-9a), 158.8 (C-8). FTIR: [cm-1] = 3256 (br., O-H/N-H),
1609 (C=Carom.), 1501 (C=Carom.), 1261 (C-O-C), 1038 (C-O-C). Purity (HPLC): 94.3 %,
tR = 10.38 min.
[8-Methoxy-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]methanol (4a)
Under N2, NaBH(OAc)3 (61.4 mg, 0.289 mmol, 1.5 eq.) was added to a solution of amine 15
(40.0 mg, 0.193 mmol) and 4-phenylbutanal (30.1 mg, 0.203 mmol, 1.05 eq.) in dry CH2Cl2
(4 mL). The reaction mixture was stirred at rt for 17 h. After addition of H2O (20 mL), the
layers were separated and the aqueous layer was extracted with CH2Cl2 (5×5 mL). The
combined organic layers were washed with brine (15 mL), dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by column chromatography (ø 2 cm, l = 10 cm,
CH2Cl2/CH3OH 95:5 + 1 % NEt3, V = 4 mL, Rf = 0.31). Colorless oil, yield 27.2 mg (39 %,
80.1 µmol). C22H29NO2 (339.5 g/mol). Exact Mass (APCI): m/z = 340.2255 (calcd. 340.2271
for C22H30NO2S [M+H]+). 1H NMR (400 MHz, CDCl3): δ [ppm] = 2.25 - 2.28 (m, 4H,
NCH2CH2CH2CH2Ph), 3.10 - 3.14 (m, 1H, 4-H), 3.20 - 3.29 (m, 4H, NCH2CH2CH2CH2Ph),
3.32 - 3.46 (m, 2H, 2-H, 5-H), 3.62 -3.69 (m, 2H, 1-H, 4-H), 3.80 - 3.92 (m, 2H, 2-H, 5-H),
4.37 (s, 3H, Ar-OCH3), 4.58 - 4.62 (m, 2H, CH2OH), 7.25 - 7.30 (m, 2H, 7-H, 9-H), 7.61 (d,
J = 8.0 Hz, 1H, 6-H), 7.76 - 7.80 (m, 3H, 2-H, 4-H and 6-H phenyl), 7.84 - 7.89 (m, 2H, 3-H
and 5-H phenyl). A signal for the OH proton is not observed in the spectrum. 13C NMR (101
MHz, CDCl3): δ [ppm] = 25.8 (NCH2CH2), 29.2 (CH2CH2Ph), 35.2 (C-5), 35.7 (CH2CH2Ph),
48.0 (C-1), 55.4 (Ar-OCH3), 56.2 (C-4), 57.7 (C-2), 60.0 (NCH2CH2), 64.9 (CH2OH), 111.5
(C-7), 115.8 (C-9), 126.0 (C-4 phenyl), 128.5 (4C, C-2, C-3, C-5 and C-6 phenyl), 131.5 (C-
24

6), 132.4 (C-5a), 142.1 (C-1 phenyl), 142.6 (C-9a), 158.4 (C-8). FTIR [cm-1] = 3318 (br.,
O-H), 1608 (C=Carom.), 1497 (C=Carom.), 1250 (C-O-C), 1038 (C-O-C). Purity (HPLC):
98.0 %, tR = 17.98 min.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (DFG), which is
gratefully acknowledged.
Supporting Information Available
Supporting Information contains purity data of all compounds, experimental details of
receptor binding studies, as well as 1H and 13C NMR spectra.
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Graphical Abstracts
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