Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2)

Article abstract of DOI:10.1016/j.bmc.2015.02.019

Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4′-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet-Spengler reaction of β-phenylethanols 5 with piperidone acetal 6. The substituted γ-hydroxybutanamides 11c-e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones 14c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided the γ-hydroxybutanamides 15c-e, which were converted into the bromides 11c-e by an Appel reaction using polymer-bound PPh₃. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand ¹²⁵I-CCL2 from the human CCR2. However, in the Ca²⁺-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC₅₀-values led to clear relationships between the structure and the inhibition of the Ca²⁺-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamide) represent the most potent CCR2 antagonists with IC₅₀-values of 89 and 17 nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure-activity-relationships detected in the Ca²⁺-flux assay were confirmed.

Full text of DOI:10.1016/j.bmc.2015.02.019

Accepted Manuscript
Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (che-
mokine CC receptor subtype 2)
Ann Kathrin Strunz, Annelien J.M. Zweemer, Christina Weiss, Dirk
Schepmann, Anna Junker, Laura Heitman, Michael Koch, Bernhard Wünsch
PII:
S0968-0896(15)00113-3
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.02.019
BMC 12082
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
13 November 2014
6 February 2015
10 February 2015
Please cite this article as: Strunz, A.K., Zweemer, A.J.M., Weiss, C., Schepmann, D., Junker, A., Heitman, L., Koch,
M., Wünsch, B., Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor
subtype 2), Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.02.019
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Synthesis and biological evaluation of spirocyclic antagonists of CCR2
(
chemokine CC receptor subtype 2)
[
a]
[b]
[c]
Ann Kathrin Strunz,
Annelien J.M. Zweemer,
Christina Weiss,
Dirk
[
a]
[a]
[b]
[c]
Schepmann,
Anna Junker,
Laura Heitman,
Michael Koch,
Bernhard
[
a,d]
Wünsch*
[
a]
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-
Universität Münster, Corrensstraße 48, 48149 Münster, Germany.
Tel.: +49-251-8333311; Fax: +49-251-8332144; E-mail: wuensch@uni-muenster.de
[
b]
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Division
of Medicinal Chemistry, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
[
c]
Bayer Pharma AG, Global Drug Discovery - Lead Discovery Wuppertal, Aprather
Weg 18a, Gebäude 456, D-42096 Wuppertal, Germany.
[
d]
Cells-in-Motion Cluster of Excellence ((EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany.
Abstract
Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in
chronic inflammatory processes such as atherosclerosis, multiple sclerosis and
rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-
dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamides) was prepared by
different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-
1
,4'-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic
piperidines 8 was an Oxa-Pictet-Spengler reaction of β-phenylethanols 5 with
piperidone acetal 6. The substituted γ-hydroxybutanamides 11c-e were prepared by
1

hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones
4c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided
the γ-hydroxybutanamides 15c-e, which were converted into the bromides 11c-e by
an Appel reaction using polymer-bound PPh . In radioligand binding assays the
spirocyclic butanamides 4 did not displace the iodinated radioligand I-CCL2 from
1
3
125
2+
the human CCR2. However, in the Ca -flux assay using human CCR2 strong
antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to
2+
clear relationships between the structure and the inhibition of the Ca -flux. 4g (4-
3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1’-yl)-N-[3,5-
bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) (N-[3,5-
(
and
4o
bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4’-
piperidin]-1’-yl)butanamide) represent the most potent CCR2 antagonists with IC50
-
values of 89 nM and 17 nM, respectively. Micromolar activities were found in the β-
arrestin recruitment assay with murine CCR2, but the structure-activity-relationships
2+
detected in the Ca -flux assay were confirmed.
Keywords
Chemokine CC receptor subtype 2 (CCR2) antagonists; Oxa-Pictet-Spengler
reaction; ethylene sulfate; Appel reaction; polymer-bound triphenylphospine;
2+
spirocyclic piperidines; receptor binding studies; Ca flux; β-arrestin recruitment;
structure-activity-relationships
2

1
. Introduction
The class of chemokines (= chemotactic cytokines) consists of several
chemoattractant proteins with 70 – 130 amino acids (8 - 14 kDa). Depending on the
position of four conserved cysteine residues forming disulfide bonds, chemokines are
divided into two major (CC and CXC chemokines) and two minor (C and CX
chemokines) groups. These chemokines interact with the corresponding CC, CXC, C,
and CX C receptors belonging to class A (rhodopsin class) of G protein-coupled
3
C
3
receptors. Chemokines and their receptors form a network, regulating the activation
1
and migration of immune cells in the organism. During the last years 26 chemokine
2
receptors and more than 45 endogenous ligands have been identified. Among those,
the chemokine CC receptor subtype 2 (CCR2), mainly expressed on monocytes, T
lymphocytes, dendritic cells and endothelial cells, is of high interest as a key target in
the therapy of chronic inflammatory diseases including atherosclerosis, asthma,
3
Morbus Crohn, rheumatoid arthritis, and multiple sclerosis.
In the therapy of atherosclerosis CCR2 has become a promising target because of
the interaction with its selective endogenous ligand monocyte chemotactic protein 1
(
MCP1). In addition to MCP1 CCR2 binds CCL7, CCL8, and CCL13 as agonists,
4
whereas CCL11 and CCL26 are antagonists at CCR2. MCP1, systematically termed
CCL2, plays an important role in the recruitment of monocytes from the blood into the
subendothelial tissue, which is known to be an early key step in the formation of
atherosclerotic plaques. Mechanic injury and toxins cause lesions of the arterial wall
and lead to migration of monocytes, mediated by several adhesion molecules and
chemokine receptors. In the arterial wall monocytes develop to macrophages, which
5-7
turn into foam cells by the uptake of blood lipids. Advanced plaques become
unstable and can suddenly rupture. Plaques release their content to the blood,
3

resulting in platelet aggregation and occlusion of the affected artery. On a long-term
basis stroke, myocardial infarction and thrombosis can occur as serious
complications.
Since the late 1990s, CCR2 antagonists with diverse structural elements have been
8
-10
reported.
,4‘-piperidines] (Figure 1). Whereas the butanamide 1 without a substituent at the
linear alkyl chain shows an IC50 value of 570 nM, the introduction of a p-fluorophenyl-
2) or cyclopropyl moiety (3) in α-position of the central butanamide increased the
In 2006 Butora et al. published a new series of promising spiro[indene-
1
(
CCR2 affinity considerably. In case of α-substituted butanamides 2 and 3 (S)-
configured enantiomers seem to show higher CCR2 affinity than their (R)-
11
enantiomers.
Figure 1. Spirocyclic CCR2 antagonists 1-3 serve as lead compounds.
Starting from the lead compounds 1-3 we developed a new series of CCR2
antagonists 4 based on the spiro[[2]benzopyran-1,4’-piperidine] system. The O-atom
within the ring system of 4 together with the substituent in 3-position should increase
the polarity of the rather lipophilic spiro[indene-piperidines] 1-3. Moreover the
4

synthetic strategy allows the introduction of various substituents in the 2-benzopyran
system. In particular the introduction of a phenolic hydroxy moiety in position 6 is
1
1
18
envisaged resulting in a precursor for the development of [ C]- and [ F]-labeled
tracers for positron emission tomography (PET). In addition to variations in the 2-
benzopyran system, p-fluorophenyl and cyclopropyl substituents should be
3
introduced into the α-position of the butanamide (R ) and fluoro and trifluoromethyl
4
groups (R ) were planned as substituents of the benzyl ring.
11-13
2
. Synthesis
For the synthesis of the designed spirocyclic butanamides 4 a building block system
was envisaged. At first the spirocyclic piperidines 8 and the γ-halobutanamides 11
were prepared and subsequently these building blocks were combined to generate
differently substituted CCR2 ligands 4.
The key step in the synthesis of the spirocyclic piperidines 8 was an Oxa-Pictet-
14
Spengler reaction. Since 1-acetylpiperidin-4-one did not react with β-phenylethanol
a, the dimethyl acetal 6 was employed. p-Toluenesulfonic acid in boiling acetonitrile
did not catalyze the reaction of phenylethanol 5a with dimethyl acetal 6, so that the
Lewis acid BF ·Et O was used. At room temperature the transformation stopped at
the intermediate mixed acetal. However microwave irradiation of the reaction mixture
5
3
2
15
and addition of Bi(OTf)
Scheme 1)
3
provided the spirocyclic piperidines 7a-d in 24-64 % yields.
(
For the connection of the spirocyclic building blocks with the γ-halobutanamide
building blocks 11 the secondary amines 8 were prepared by hydrolysis of the
5

acetamides 7 with NaOH. Whereas the secondary amines 8a-c were isolated in 82-
9 % yields, the hydroxy substituted derivative 8d was isolated in only 12 % yield.
9
The low yield of 8d was due to incomplete extraction of the zwitterionic aminophenol
from the water layer during work-up. Therefore the phenol 7d was protected with a
benzyl protective group (7e) before hydrolysis, which should be removed at the end
of the synthesis. Hydrolysis of the acetamide 7e with NaOH in dioxane led to a clean
conversion and the benzyl ether 8e was isolated in 34 % yield.
R2
R2
R2
OH
5,7,8 R1
R2
H CO
O
O
3
(a)
(c)
a
b
c
d
e
H
H
OCH3
H
CH3
H
H
H
+
H CO
3
R1
N
NH
N
Ac
Ac
R1
R1
OH
OBn
5
a-d
6
7
a-e
8a-e
(b)
7
d
7e
Scheme 1: Synthesis of the spirocyclic piperidines 8a-e.
Reagents and reaction conditions: (a) BF ·Et O, Bi(OTf)
irradiation 2 h, 150 °C, 400 W, 24-64 %. (b) Benzyl bromide, K
6 h, 60 %. (c) NaOH 2 M, reflux, 16 h, 8a-c 82-99 %; 8d 12 %; NaOH 2 M, dioxane,
reflux, 16 h, 8e 34 %.
3
2
3
, CH
3
CN, microwave
2
CO
3
, CH CN, reflux,
3
1
The γ-chlorobutanamides 11a and 11b without a further substituent in α-position of
the butanoyl chain were obtained by acylation of benzylamines 10a and 10b with γ-
16
chlorobutanoyl chloride (9). (Scheme 2)
The synthesis of the butanamides 11c and 11d with an α−(4-fluorophenyl)
substituent started with hydroxyethylation of ester 13c, which was obtained by
3 2 4
esterification of the acid 12c with CH OH/H SO . For this purpose ester 13c was
deprotonated with LiHMDS and the enolate was then trapped with ethylene sulfate.
6

After hydrolysis of the resulting monoester of sulfuric acid with NaOH, γ-lactone 14c
was isolated in 52 % yield. The cyclopropyl substituted γ-lactone 14e was prepared in
the same manner starting with cyclopropylacetic acid (12e). In order to achieve high
yields the volatility of the γ-lactone 14e during evaporation of solvents has to be taken
into account.
Scheme 2: Synthesis of γ-halobutanamides 11a-e.
Reagents and reaction conditions: (a) Na
2
CO
OH, reflux, 16 h, 45-75 %. (c) 1. LiHMDS, ethylene sulfate, THF, -15 °C,
h; 2. ethanolic NaOH, reflux, 16 h, 52-59 %. (d) 10a,b, AlCl , CH Cl , 0 °C ꢀ rt, 16
, rt, 48 h, 15e 7.1 %.
, rt, 1 h, 73 %. (f) CBr , polymer-bound
CN, 0 °C ꢀ rt, 48 h, 73-99 %.
3 3
, CH CN, rt, 16 h, 89-96 %. (b) conc.
H
2
2 4 3
SO , CH
3
2
2
h, 15c,d 23 %; 10a, 1,2,4-triazole, diazabicycloundecene, CDCl
e) Dess-Martin-Periodinane, CH Cl
triphenylphosphine, CH
3
(
2
2
4
3
The aminolysis of the γ-lactone 14c with benzylamines 10a,b turned out to be very
problematic, since the transformations were not complete. However after addition of
7

3
the Lewis acid AlCl the butanamides 15c and 15d were isolated in pure form. For
the aminolysis of the cyclopropyl substituted γ-lactone 14e with benzylamine 10a the
17
acyl transfer catalyst 1,2,4-triazole had to be added to obtain the butanamide 15e.
Unexpectedly all attempts to activate the alcohols 15c-e with methanesulfonyl
chloride or p-toluenesulfonyl chloride failed to give the corresponding sulfonates.
Therefore the alcohol 15c was oxidized with Dess-Martin-Periodinane. Instead of the
expected aldehyde the cyclic hemiaminal 16c was obtained in 73 % yield. The same
product has already been obtained by ozonolysis of the corresponding allyl
18
derivative. However, the hemiaminal did not react with the spirocyclic piperidines 8
under reductive amination conditions (NaBH(OAc) ) via opening of the hemiaminal.
Therefore activation of the alcohols 15c-e by conversion into the bromides 11c-e was
3
4 3
considered next. The Appel reaction of the alcohol 15c with CBr and PPh led to a
1
clean conversion. The H NMR spectrum of the non-purified bromide 11c indicated
complete and clean conversion. However all attempts to remove PPh
from the bromide 11c or from the alkylation product 4g failed. Therefore polymer-
bound PPh was used instead of soluble PPh in the Appel reaction. Simple filtration
3 3
and/or PPh O
3
3
provided the pure bromides 11c-e in 73-99 % yields.
In the final step the piperidines 8 were alkylated with the γ-halobutanamides 11 to
give a diverse set of spirocyclic butanamides 4. In order to optimize the conversion
various reaction conditions were applied for different combinations (Scheme 3). The
benzyl protective group of the benzyl ether 4m was removed hydrogenolytically to
afford the phenol 4n. According to our standard HPLC method the purity of the final
test compounds had to be higher than 95 %. To achieve this quality criterion different
8

purification methods including preparative HPLC had to be used. The extensive
purification procedures reduced the yields.
Scheme 3: Synthesis of final test compounds 4a-o.
Reagents and reaction conditions: (a) K
THF, 0 °C ꢀ 40 °C, 48 h, 4d,g-l 3-44 %; diisopropylethylamine, BuNI, DMF,
microwave irradiation, 1 h, 203 °C, 150 W, 4m,o 27-34 %. (b) H , Pd/C, 1 bar,
2 3
CO , THF, reflux, 16 h, 4a-c,e,f 3.5-43 %;
2
1
4
3
CH OH, 1 h, 48%. Definition of the residues R -R is given in Table 1.
3
. CCR2 affinity and antagonistic activity
The CCR2 affinity of the spirocyclic butanamides 4 was determined in radioligand
displacement assays with membranes of U2OS cells stably expressing the human
125
CCR2 (U2OS-CCR2) and the iodinated endogenous agonist
I-CCL2 as
19
radioligand. Moreover the antagonistic activity of the compounds 4 at the CCR2 was
2+
analyzed in two complementary functional assays. An intracellular Ca -flux assay
employing the Chem-1 cell line stably transfected with human CCR2B and
9

recombinant human CCL2 was performed. Inhibition of β−arrestin recruitment was
determined using the U2OS β-arrestin cell line transfected with murine CCR2. It
20
should be noted that human and murine CCR2 share 80 % sequence identity. This
2+
species difference accounts for different effects in the Ca -flux and β-arrestin
recruitment assay. The CCR2 affinities and the CCR2 antagonistic activities of the
spirocyclic compounds 4 are summarized in Table 1.
Table 1: CCR2 affinity and antagonistic activity of spirocyclic butanamides 4.
1
25
I-CCL2
IC50 human
IC50 murine
1
R
2
3
4
b
b
compd.
R
R
R
displacement CCR2 [µM]
a
CCR2 [µM]
2+
(Ca flux)
[%]
(β-arrestin)
4
4
4
4
4
4
4
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
F
10
-12
1
0.684
7.54
1.24
0.18
12.0
0.318
24
CH3
H
7.9
18
OCH3
H
H
4
>30
>30
>30
H
CH3
H
F
-10
-1
OCH3
F
g
H
H
H
4-F-C
6
H
4
4
4
CF
3
25
0
0.089
0.462
0.163
11.2
3.67
4.16
(
WMS-46-12)
4
h
i
CH3
H
4-F-C H
6
CF3
4
OCH
3
4-F-C
6
H
CF
3
nd
(
WMS-46-09)
4
4
4
j
H
H
H
4-F-C H
F
F
F
7
0.173
1.60
3.63
8.01
4.63
6
6
6
4
4
4
k
l
CH3
H
4-F-C H
9
OCH3
4-F-C H
-7
0.353
1
0

4
n
o
OH
H
H
H
4-F-C H
6
F
nd
nd
6.10
>30
3.3
23
4
4
c-C
3
H
5
CF
3
0.017
0.95 nM
(
WMS-46-14)
TAK779
K
i
= 2.0
c
±
0.7 nM
a
125
displacement of the radioligand
I-CCL2 from human CCR2 [%], measured at a
concentration of 1 µM of the test compound.
b
2+
The IC50-values in the functional Ca -flux assay (human CCR2) and the β-arrestin
2
recruitment assay (murine CCR2) are given in µM, respectively. In the Ca -flux
+
assay CCL2 was added in 5 nM concentration, in the β-arrestin recruitment assay the
CCL2 concentration was 3 nM.
c
For TAK779 the exact K-value was determined. In literature an IC50-value of 27 nM
i
21,22
is given for TAK779.
nd = not determined.
At a concentration of 1 µM the test compounds 4 could not significantly displace the
125
radioligand I-CCL2 (conc. 0.1 nM) from human CCR2.
2+
However, in the Ca -flux assay considerable effects of the spirocyclic butanamides 4
were detected, which allows the discussion of structure-activity relationships.
Concerning the substitution pattern of the 2-benzopyran system, the compounds 4a,
4
d, 4g, and 4j without a further substituent show the highest activity, respectively. A
methoxy moiety in position 6 leads to slight reduction of the activity (compare 4d/4f,
g/4i), whereas a methyl moiety in 3-position reduces the activity considerably
compare 4d/4e, 4g/4h).
4
(
1
1

2+
Figure 2: Dose response curves of the most potent CCR2 antagonists in the Ca -flux
assay.
Introduction of the 4-fluorophenyl moiety into the butanamide chain increased the
antagonistic activity remarkably (compare 4a-f with 4g-l). A cyclopropyl ring in α-
position to the amide (compound 4o) led to a further increase in the CCR2
antagonistic activity. (Table 1, Figure 2)
Compounds with two CF
3
-groups at the benzyl moiety show generally higher
inhibition of Ca -flux than their analogs with one CF moiety and one fluorine atom
(compare 4g-4i with 4j-4l).
2+
3
(
2+
The phenol 4n does not inhibit the Ca -flux. However the corresponding methyl
ether 4l showed a promising IC50-value of 353 nM indicating that modification of the
phenolic OH group could result in potent CCR2 antagonists. In particular the
introduction of fluoroalkyl substituents with the aim to develop a fluoriniated PET
tracer is considered.
Finally the 4-fluorophenyl and the cyclopropyl derivatives 4g and 4o without further
3
substituents in the 2-benzopyran system and with two CF -moieties at the
1
2

benzylamine part represent the most potent ligands of this series of compounds with
IC50-values of 89 and 17 nM, respectively. Figure 2 shows full inhibitoty activity of 4g,
2
+
4
i and 4o in the Ca -flux assay.
In the β-arrestin recruitment assay using murine CCR2 IC50-values in the micromolar
range were found. The most potent antagonists in this assay are the 4-fluorophenyl
substituted derivatives 4h, 4i, 4j, and 4l and the cyclopropyl derivative 4o with IC50
-
values between 3 and 5 µM. Although the IC50-values in this assay are considerably
2
+
higher than in the Ca -flux assay, the tendency of increased antagonistic activity of
4
-fluorophenyl and, moreover, cyclopropyl derivatives is confirmed herein. With
exception of 4g, the IC50-values of bis(trifluoromethyl)benzylamides are lower than
the IC50-values of the corresponding 3-fluoro-5-(trifluoromethyl)benzyl analogs.
4
. Conclusion
A diverse set of spirocyclic butanamides 4 has been synthesized by combination of
various building blocks 8 and 11. Whereas the spirocyclic butanamides 4 cannot
125
2+
compete with the radioligand I-CCL2, the Ca -flux was inhibited depending on the
structure and concentration of the ligands. It is assumed that the spirocyclic
butanamides 4 are able to interact with the human CCR2 protein and inhibit the
2+
intracellular mobilization of Ca -ions. Interestingly, this class of compounds does not
disturb the interaction of the human CCR2 with its large endogenous ligand CCL2,
2+
but inhibits the Ca flux. The inhibition of the murine CCR2 coupled with β-arrestin
recruitment is much lower compared with inhibition of the human CCR2. It is
assumed that the different sequences of the receptor proteins are responsible for the
19
different effects of the ligands. In previous studies it has been shown that different
small molecule CCR2 inhibitors interact with different binding sites (orthosteric and
1
3

allosteric binding sites) resulting in different modes of inhibition. Therefore it is
2+
postulated that the CCR2 antagonists of type 4 block the Ca -flux via interaction with
an allosteric binding site, whilst not disturbing the interaction of the large endogenous
ligand CCL2. Altogether, the described compounds represent a novel class of
negative allosteric modulators of CCR2.
5
5
5
. Experimental
.1. Chemistry
.1.1. General
Unless otherwise noted, moisture sensitive reactions were conducted under dry
nitrogen. Acetonitrile and dimethylformamid were dried over molecular sieves. CH Cl
was distilled from CaH , methanol was distilled from magnesium methanolate and
tetrahydrofuran was distilled from sodium/benzophenone. Thin layer chromatography
tlc): Silica gel 60 F254 plates (Merck). Flash chromatography (fc): Silica gel 60, 40–
4 µm (Merck); parentheses include: diameter of the column, length, fraction size, R
2
2
2
(
6
f
value, eluent. Melting point: Melting point apparatus SMP3 (Stuart Scientific),
uncorrected. Microwave assisted reactions were carried out in a single mode cavity
CEM Discover LabMate Synthesiser with Discover-PC-Software (CEM Corporation)
or a multi mode system MARS (CEM Corporation). MS: microTOF-Q II (Bruker
Daltronics); APCI, atmospheric pressure chemical ionization. IR: FT-IR-480 plus
(
Jasco) or FT-IR Prestige 21 (Shimadzu) equipped with ATR technique. Nuclear
magnetic resonance (NMR) spectra were recorded on Agilent 600-MR (600 MHz for
1
1
13
1
H, 151 MHz for C), Agilent 400-MR spectrometer (400 MHz for H, 101 MHz for
3
C) or Varian AS 400 Mercury Plus NMR spectrometer; δ in ppm related to
1
(δ = 7.26 ppm ( H NMR) and δ =
tetramethylsilane and measured referring to CDCl
3
1
3
1
13
7
3
7.2 ppm ( C NMR)) and CD OD (δ = 3.31 ppm ( H NMR) and δ = 49.0 ppm ( C
1
4

NMR)); coupling constants are given with 0.5 Hz resolution. Analytical HPLC: Merck
Hitachi Equipment; UV detector: L-7400; autosampler: L-7200; pump: L-7100;
®
®
interface: D-7000; column: LiChrospher 60 RP-select B (5 µm); LiChroCART 250-4
mm cartridge; flow rate: 1.0 mL/min; injection volume: 5.0 µL; detection at λ = 210
nm; solvents: A: water with 0.05 % (v/v) trifluoroacetic acid; B: acetonitrile with 0.05
%
(v/v) trifluoroacetic acid: gradient elution: (A %): 0-4 min: 90%, 4-29 min: 90 → 0%,
2
9-31 min: 0%, 31-31.5 min: 0 → 90 %, 31.5-40 min: 90%. The purity of all
compounds was determined by this method. The purity of all test compounds is
higher than 95 %. Preparative HPLC: Merck Hitachi Equipment; UV detector: L-7400;
autosampler: L-7200; pump: L-7150; interface: D-7000; column: Phenomenex Gemini
C18 110 A 250-21.2 mm (5 µm; flow rate: 20.00 mL/min; injection volume: 200.0 µL;
3
detection at λ = 254 nm; solvent: acetonitrile:water 70:30 with 0.05 % (v/v) NH .
23
5
.1.2. 1-(4,4-Dimethoxypiperidin-1-yl)ethan-1-one (6)
1
-Acetylpiperidin-4-one (8.52 g, 60 mmol) was dissolved in CH OH (12 mL).
3
Trimethyl orthoformate (32.34 g, 0.3 mol) and p-toluenesulforic acid (521 mg, 3.0
mmol) were added quickly and the solution was stirred overnight at rt. The
transformation was terminated by addition of 10 % aqueous NaHCO
3
and the mixture
SO ),
was extracted with CH Cl (3x). The combined organic layers were dried (Na
2
2
2
4
filtered and concentrated under reduced pressure. The crude product was used in the
next reaction step without further purification. Pale yellow oil, yield 11.0 g (98 %).
C
9
H
17NO
3
(187.2 g/mol). MS (APCI): m/z = 188.1291 (calcd. 188.1281 for C
MH ]). H NMR (DMSO-d ): δ [ppm] = 1.57 (t, J = 5.8 Hz, 2H, N(CH CH ), 1.67 (t,
J = 5.8 Hz, 2H, N(CH CH ), 1.99 (s, 3H, NCOCH ), 3.10 (s, 6H, OCH ), 3.34 – 3.42
m, 4H, N(CH CH ). C NMR (DMSO-d ): δ [ppm] = 21.7 (1C, CH ), 32.3 (1C,
N(CH CH ), 33.1 (1C, N(CH CH ), 38.4 (1C, N(CH CH ), 43.3 (1C,
9 3
H18NO
+
1
[
6
2
2 2
)
2
2
)
2
3
3
13
(
2
2
)
2
6
3
2
2
)
2
2
2
)
2
2
2 2
)
1
5

~
-1
N(CH
2
CH
2 2 3 3 2
) ), 47.6 (2C, OCH ), 98.5 (1C, C(OCH ) ), 168.5 (1C, C=O). IR: υ [cm ] =
2
943 (C-H), 1639 (C=O), 1107, 1045 (C-O).
5
.1.3. 1-(3,4-Dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)ethan-1-one (7a)
-Phenylethanol 5a (2.48 g, 20.3 mmol) was dissolved in CH CN (40 mL) under
2
3
nitrogen flow and the solution was given into 8 microwave vials, 5 mL each. A
solution of piperidone acetal 6 (4.49 g, 24.0 mmol) in CH CN (3.2 mL) was prepared.
.4 mL of this solution were added to each mixture and the mixtures were stirred at rt
for 30 min. BF ·Et O (1.8 mL) was added to each vial dropwise under ice cooling and
the mixtures were stirred at rt overnight. After addition of Bi(OTf) (16 mg, 0.02 mmol)
3
0
3
2
3
to each vial, the reaction mixtures were heated under microwave irradiation for 120
min at 150 °C and 400 W, respectively. The transformation was terminated by
addition of 10 % aqueous NaHCO
and the aqueous layer was extracted with CH
were dried (Na SO ), filtered and the solvent was removed under reduced pressure.
3
to the combined mixtures. Layers were separated
2
Cl (3x). Combined organic layers
2
2
4
The crude product was coated on silica gel and then purified by flash column
chromatography (Ø 8 cm, length 12 cm, cyclohexane:EtOAc 1:4 ꢀ EtOAc, fraction
f 2 2
size 65 mL, R = 0.19 (CH Cl :MetOH 96:4)). The isolated product was recrystallized
from diisopropyl ether. Colorless solid, mp 152 °C, yield 1.53 g (31 %). Purity (HPLC):
1
9
6.4 %, t
dd, J = 11.0 / 4.6 Hz, 2H, N(CH
.15 (s, 3H, NCOCH ), 2.82 (t, J = 5.5 Hz, 2H, PhCH
Hz, 1H, N(CH CH ), 3.51 (td, J = 13.1 / 3.2 Hz, 1H, N(CH
H, N(CH CH ), 3.93 (t, J = 5.5 Hz, 2H, PhCH CH ), 4.41 – 4.48 (m, 1H,
N(CH CH ), 7.08 – 7.19 (m, 4H, Harom). C NMR (CD OD): δ [ppm] = 19.8 (1C,
COCH ), 29.1 (1C, PhCH CH ), 35.9 (1C, N(CH CH ), 36.6 (1C, N(CH CH ), 37.5
R
= 16.95 min. C15
H
19NO
2
(245.3 g/mol). H NMR (CD
3
OD): δ [ppm] = 1.88
CH ),
), 3.01 (td, J = 12.0 / 4.9
CH ), 3.76 – 3.82 (m,
(
2
CH
2
)
2
), 1.99 (td, J = 13.3 / 4.7 Hz, 2H, N(CH
2
2 2
)
2
3
2
CH
2
2
2
)
2
2
2 2
)
1
2
2
)
2
2
2
13
2
2
)
2
3
3
2
2
2
2
)
2
2
2 2
)
1
6

(
1C, N(CH
2
CH
24.9 (1C, C-8arom), 125.96 and 126.04 (2C, C-5arom, C-6arom), 128.5 (1C, C-7arom),
33.5 (1C, C-4aarom), 140.8 (1C, C-8aarom), 170.1 (1C, C=O). MS (APCI): m/z =
2 2 2 2 2 2 2
) ), 42.4 (1C, N(CH CH ) ), 58.8 (1C, PhCH CH ), 72.9 (1C, ArCO),
1
1
2
+
~
-1
2
46.1487 (calcd. 246.1489 for C15H20NO [MH ]). IR: υ [cm ] = 1643 (C=O), 1088
(
C-O), 760, 694 (C-Harom).
5
.1.4. 1-(3-Methyl-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)ethanone
(
7b)
-Phenylpropan-2-ol 5b (2.80 g, 20.4 mmol) was dissolved in CH
nitrogen flow and the solution was given into 8 microwave vials, 5 mL each. Acetal 6
4.62 g, 24.7 mmol) was dissolved in CH CN (3.2 mL). 0.4 mL of this solution were
added to each mixture and the mixtures were stirred at rt for 30 min. BF ·Et O (1.8
1
3
CN (40 mL) under
(
3
3
2
mL) was added dropwise to each vial under ice cooling and the mixture was stirred at
rt overnight. The reaction mixtures were heated under microwave irradiation for 120
min at 150 °C and 400 W, respectively. The transformation was terminated by
addition of 10 % aqueous NaHCO
separated and the aqueous layer was extracted with CH
organic layers were dried (Na SO ), filtered and the solvent was removed under
3
to the combined mixtures. The layers were
2
Cl (3x). The combined
2
2
4
reduced pressure. The crude product was coated on silica gel and then purified by
flash column chromatography (Ø 8 cm, length 17 cm, cyclohexane: EtOAc 20:80 ꢀ
EtOAc, fraction size 65 mL, R
f
2
= 0.18 (CH Cl
2
: CH
3
OH 96:4)). Colorless solid, mp 128
= 18.43 min. C16 (259.3
OD): δ [ppm] = 1.35 (d, J = 6.1 Hz, 3x 0.5 H, CH ), 1.35 (d, J =
), 1.61 – 1.76 (m, 1H, N(CH CH ), 1.83 (td, J = 13.8 / 4.6 Hz,
), 2.03 (td, J = 13.3 / 4.9 Hz, 1H, N(CH CH ), 2.08 – 2.15 (m, 1H,
), 2.16 (s, 3H, NCOCH ), 2.67 – 2.70 (m, 2H, PhCH CH), 3.01 (td, J =
°
C, yield 4.42 g (64 %). Purity (HPLC): 98.6 %, t
R
H21NO
2
1
g/mol). H NMR (CD
3
3
6
1
.1 Hz, 3x 0.5 H, CH
H, N(CH CH
CH
3
2
2 2
)
2
2
)
2
2
2 2
)
N(CH
2
2
)
2
3
2
1
7

1
3.1 / 2.9 Hz, 0.5 H, N(CH
.52 (td, J = 13.2 / 2.8 Hz, 0.5 H, N(CH
CH ), 3.75 – 3.84 (m, 1H, N(CH CH
4.49 (m, 1H, N(CH CH ), 7.05 – 7.21 (m, 4H, CHarom). C NMR (CD
19.83 (0.5 C, COCH ), 19.85 (0.5 C, COCH ), 20.62 (0.5 C, CH ), 20.63 (0.5 C,
), 29.3 (1C, CH CHO), 34.0 and 34.6 (1C, N(CH CH ), 37.4 and 37.6 (1C,
N(CH CH ), 38.4 and 39.1 (1C, N(CH CH ), 42.3 and 42.4 (1C, N(CH CH ),
4.3 and 64.4 (1C, CH CHO), 73.60 and 73.62 (1C, ArCO), 124.65 and 124.66 (1C,
C-8arom), 125.92 and 125.93 (2C, C-5arom, C-6arom), 128.36 and 128.37 (1C, C-7arom),
2
CH
2
)
2
), 3.10 (td, J = 13.1 / 2.9 Hz, 0.5 H, N(CH
CH ), 3.62 (td, J = 13.1 / 2.8 Hz, 0.5 H,
), 3.89 – 3.99 (m, 1H, PhCH CH), 4.40
OD): δ [ppm]
2 2 2
CH ) ),
3
2
2 2
)
N(CH
2
2
)
2
2
2
)
2
2
13
–
=
2
2
)
2
3
3
3
3
CH
3
2
2
2 2
)
2
2
)
2
2
2
)
2
2
2 2
)
6
2
1
33.7 (1C, C-4aarom), 140.56 and 140.57 (1C, C-8aarom), 170.09 and 170.13 (1C,
+
~
-
2
C=O). MS (APCI): m/z = 260.1634 (calcd. 260.1645 for C16H22NO [MH ]). IR: υ [cm
1
]
= 1628 (C=O), 1064 (C-O), 756, 702 (C-Harom).
5
.1.5. 1-(6-Methoxy-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin-1'-yl])ethan-1-
one (7c)
-(3-Methoxyphenyl)ethanol 5a (3.16 g, 20.8 mmol) was dissolved in CH
mL) under nitrogen flow and the solution was given into 8 microwave vials, 5 mL
each. A solution of piperidone acetal 6 (4.57 g, 24.4 mmol) in CH CN (3.2 mL) was
prepared. 0.4 mL of this solution were added to each mixture and the mixtures were
stirred at rt for 30 min. BF ·Et O (1.8 mL) was added to each vial dropwise under ice
cooling and the mixtures were stirred at rt overnight. After addition of Bi(OTf) (16 mg,
.02 mmol) to each vial, reaction mixtures were heated under microwave irradiation
for 120 min at 150 °C and 400 W, respectively. The transformation was terminated by
addition of 10 % aqueous NaHCO to the combined mixtures. The layers were
separated and the aqueous layer was extracted with CH Cl (3x). The combined
organic layers were dried (Na SO ), filtered and the solvent was removed under
2
3
CN (40
3
3
2
3
0
3
2
2
2
4
1
8

reduced pressure. The crude product was coated on silica gel and then purified by
flash column chromatography (Ø 8 cm, length 15 cm, cyclohexane:EtOAc 20:80,
fraction size 65 mL, R
recrystallized from iPr
HPLC): 93.7 %, t
ppm] = 1.82 – 1.99 (m, 4H, N(CH
H, PhCH CH ), 2.99 (td, J = 12.4 / 4.6 Hz, 1H, N(CH
Hz, 1H, N(CH CH ), 3.76 (s, 3H, OCH ), 3.92 (t, J = 5.5 Hz, 2H, PhCH
.19 (m, 1H, N(CH CH ), 4.41 - 4.47 (m, 1H, N(CH CH ), 6.66 (d, J = 2.7 Hz, 1H,
-Harom), 6.75 (dd, J = 8.6 / 2.8 Hz, 1H, 7-Harom), 7.05 (d, J = 8.7 Hz, 1H, 8-Harom). C
OD): δ [ppm] = 19.8 (1C, COCH ), 29.4 (1C, CH CH O), 36.0 (1C,
), 37.5 (1C, N(CH CH ), 42.4 (1C,
), 58.7 (1C, CH CH O), 72.7 (1C, ArCO), 112.3 (1C, C-
f 2 2 3
= 0.20 (CH Cl :CH OH 96:4)). The isolated product was
2
O. Colorless solid, mp 110 °C, yield 1.56 g (27 %). Purity
1
(
R
= 17.74 min. C16
H
21NO
3
(275.3 g/mol). H NMR (CD
3
OD): δ
), 2.79 (t, J = 5.5 Hz,
), 3.51 (td, J = 12.7 / 3.4
CH ), 4.14 –
[
2 2
CH )
2
), 2.15 (s, 3H, NCOCH
CH
3
2
2
2
2
2 2
)
2
2
)
2
3
2
2
4
5
2
2
)
2
2
2 2
)
13
NMR (CD
3
3
2
2
N(CH
2
CH
2
)
2
), 36.8 (1C, N(CH
), 54.2 (1C, OCH
2
CH
2
)
2
2
2 2
)
N(CH
2
CH
2
)
2
3
2
2
7
8
2
arom), 112.8 (1C, C-5arom), 126.1 (1C, C-8arom), 133.0 (1C, C-4aarom), 134.9 (1C, C-
aarom), 158.0 (1C, C-6arom), 170.1 (1C, C=O). MS (APCI): m/z = 276.1610 (calcd.
+
~
-1
3 3
76.1594 for C16H22NO [MH ]). IR: υ [cm ] = 1640 (C=O), 1501 (OCH ), 1085 (C-
O), 822, 683 (C-Harom).
5
1
2
.1.6. 1-(6-Hydroxy-3,4-dihydrospiro[[2]benzopyran-1,4’-piperidin]]-1’-yl))ethan-
-one (7d)
3
-(3-Hydroxyphenyl)ethanol 5d (2.23 g, 16.2 mmol) was dissolved in CH CN (40 mL)
under nitrogen flow and the solution was given into 8 microwave vials, 5 mL each. A
solution of piperidone acetal 6 (3.70 g, 19.8 mmol) in CH CN (3.2 mL) was prepared.
.4 mL of this solution were added to each mixture and the mixtures were stirred at rt
for 30 min. BF ·Et O (1.8 mL) was added to each vial dropwise under ice cooling and
the mixture was stirred at rt overnight. After addition of Bi(OTf) (16 mg, 0.02 mmol) to
3
0
3
2
3
1
9

each vial, the reaction mixtures were heated under microwave irradiation for 120 min
at 150 °C and 400 W, respectively. Then 10 % aqueous NaHCO was added to the
combined mixtures. The layers were separated and the aqueous layer was extracted
with CH Cl (3x). The combined organic layers were dried (Na SO ), filtered and the
3
2
2
2
4
solvent was removed under reduced pressure. The crude product was coated on
silica gel and then purified by flash column chromatography (Ø 8 cm, length 10 cm,
cyclohexane:EtOAc 20:80 ꢀ EtOAc:CH
3 f
OH 80:20, fraction size 65 ml, R = 0.1
(
CH Cl :CH OH 96:4)). The isolated product was recrystallized from diisopropyl
2
2
3
R
ether. Colorless solid, mp 239 °C, yield 1.01 g (24 %). Purity (HPLC): 92.6 %, t =
1
1
4
4.57 min. C15
H
19NO
3
(261.3 g/mol). H NMR (CD
3
OD): δ [ppm] = 1.76 – 2.02 (m,
), 2.73 (t, J = 5.5 Hz, 2H, PhCH CH ), 2.98
), 3.50 (td, J = 12.9 / 3.7 Hz, 1H, N(CH CH ),
), 3.89 (t, J = 5.3 Hz, 2H, PhCH CH ), 4.38 – 4.46
), 6.49 – 6.53 (m, 1H, 5-Harom), 6.62 (dd, J = 8.5 / 2.5 Hz, 1H, 7-
arom), 6.94 (d, J = 8.5 Hz, 1H, 8-Harom), a signal for the OH proton is not seen in the
H, N(CH CH
2
2
)
2
), 2.14 (s, 3H, NCOCH
CH
3
2
2
(
td, J = 12.4 / 4.1 Hz, 1H, N(CH
.73 – 3.80 (m, 1H, N(CH CH
m, 1H, N(CH CH
2
2
)
2
2
2 2
)
3
2
2
)
2
2
2
(
2
2 2
)
H
1
3
spectrum. C NMR (CD
6.1 (1C, N(CH CH ), 36.8 (1C, N(CH
N(CH CH ), 58.7 (1C, PhCH CH ), 72.7 (1C, ArCO), 113.4 (1C, C-7arom), 114.3 (1C,
3
OD): δ [ppm] = 19.8 (1C, NCOCH
3
), 29.3 (1C, PhCH
2 2
CH ),
3
2
2
)
2
2
CH ), 37.6 (1C, N(CH
2
)
2
2
CH ), 42.4 (1C,
2 2
)
2
2
)
2
2
2
C-5arom), 126.0 (1C, C-8arom), 131.8 (1C, C-4aarom), 134.8 (1C, C-8aarom), 155.3 (1C,
C-6arom), 170.1 (1C, C=O). MS (APCI): m/z = 262.1433 (calcd. 262.1438 for
~
+
-1
υ
15 3
C H20NO [MH ]). IR: [cm ] = 2978 (C-H), 1585 (C=O), 1450 (O-H), 1088 (C-O).
2
0

5
1
7
.1.7. 1-[6-(Benzyloxy)-3,4-dihydrospiro[[2]benzopyran-1,4’-piperidin]-
’yl]ethan-1-one (7e)
d (499 mg, 1.9 mmol) and benzyl bromide (479 mg, 2.8 mmol) were dissolved in
CH
to reflux overnight. Cooled to rt, K
under reduced pressure. The residue was recrystallized from diisopropyl ether, R
.92, (CH Cl :CH OH:NH 95:4.5:0.5). Colorless solid, mp 183 °C, yield 443 mg (60
). Purity (HPLC): 96.3 %, t
CDCl ): δ [ppm] = 1.77 – 1.94 (m, 4H, N(CH
J = 5.1 Hz, 2H, PhCH CH ), 2.96 (td, J = 12.9 / 3.1 Hz, 1H, N(CH
12.8 / 3.3 Hz, 1H, N(CH CH ), 3.62 – 3.70 (m, 1H, N(CH CH
Hz, 2H, PhCH CH ), 4.50 – 4.60 (m, 1H, N(CH CH ), 5.03 (s, 1H, PhCH
s, 1H, PhCH O), 6.71 (d, J = 1.8 Hz, 1H, 5-Harom), 6.84 (td, J = 8.6 / 2.7 Hz, 1H, 7-
arom), 6.97 (d, J = 8.7 Hz, 1H, 8-Harom), 7.32 – 7.44 (m, 5H, H’arom). C NMR
CDCl ): δ [ppm] = 21.9 (1C, NCOCH ), 29.8 (1C, PhCH CH ), 36.3 (1C,
), 37.8 (1C, N(CH CH ), 42.6 (1C,
), 70.0 (1C, PhCH O), 72.9 (1C, ArCO), 113.4
3
CN (50 mL). After addition of K
2
CO
3
(1.08 g, 7.8 mmol) the solution was heated
2
CO
3
was filtered off and CH CN was removed
3
f
=
0
2
2
3
3
1
%
R
= 22.50 min. C22
CH ), 2.14 (s, 3H, NCOCH
CH ), 3.51 (td, J
), 3.91 (t, J = 5.4
O), 5.05
H
25NO
3
(351.4 g/mol). H NMR
(
3
2
2
)
2
3
), 2.81 (q,
2
2
2
2 2
)
=
2
2
)
2
2
2 2
)
2
2
2
2
)
2
2
(
2
13
H
(
3
3
2
2
N(CH
N(CH
2
CH
2
)
2
), 37.5 (1C, N(CH
2
CH
2
)
2
2
2 2
)
2
CH
2
)
2
), 59.0 (1C, PhCH CH
2
2
2
(
1C, C-7arom), 114.4 (1C, C-5arom), 126.4 (1C, C-8arom), 127.4 and 128.6 (4C, C-2’arom
,
C-3’arom, C-5’arom, C-6’arom), 133.5 (1C, C-4aarom), 135.1 (1C, C-8aarom), 128.0 and
1
3
36.9 (2C, C-1’arom, C-4’arom), 157.1 (1C, C-6arom), 168.9 (1C, C=O). MS (APCI): m/z =
+
~
-1
52.1918 (calcd. 352.1907 for C22H26NO
3
[MH ]). IR: υ [cm ] = 2928 (C-H), 1632
(
C=O), 1119 (C-O), 764, 694 (C-Harom).
5
.1.8. 3,4-Dihydrospiro[[2]benzopyran-1,4'-piperidine] (8a)
A solution of 7a (619 mg, 2.5 mmol) in 2 M NaOH (40 mL) was heated to reflux
overnight. The reaction mixture was cooled to rt and extracted with CH Cl (3x). The
2
2
2
1

combined organic layers were dried (Na
concentrated under reduced pressure. The product was used in the next reaction
step without further purification, R = 0.22 (CH Cl :MetOH 70:30 + 1%
2 4
SO ), filtered and the filtrate was
f
2
2
ethyldimethylamine). Colorless solid, mp 95 °C, yield 418 mg (82 %). Purity (HPLC):
1
9
7.0 %, t
R
= 12.03 min. C13
H
17NO (203.3 g/mol). H NMR (CD
3
OD): δ [ppm] = 1.84
CH ),
CH
), 3.91 (t, J = 5.5 Hz, 2H, PhCH CH
(
dd, J = 15.7 / 1.8 Hz, 2H, N(CH
2
CH
CH ), 2.86 (dd, J = 11.9 / 4.1 Hz, 2H, N(CH
.04 (td, J = 12.5 / 3.1 Hz, 2H, N(CH CH
2
)
2
), 1.93 (td, J = 12.6 / 4.6 Hz, 2H, N(CH
2
2 2
)
2
3
7
.80 (t, J = 5.6 Hz, 2H, PhCH
2
2
2
2
)
2
),
2
2
)
2
2
2
),
13
.07 – 7.20 (m, 4H, Harom), a signal for the NH proton is not seen in the spectrum. C
OD): δ [ppm] = 29.1 (1C, PhCH CH ), 35.4 (2C, N(CH CH ), 40.8 (2C,
), 58.7 (1C, PhCH CH ), 72.5 (1C, ArCO), 124.8 (1C, C-8arom), 126.0 and
26.1 (2C, C-5arom, C-6arom), 128.5 (1C, C-7arom), 133.4 (1C, C-4aarom), 141.1 (1C, C-
NMR (CD
N(CH CH
3
2
2
2
2 2
)
2
2
)
2
2
2
1
+
~
-
8
aarom). MS (APCI): m/z = 204.1422 (calcd. 204.1383 for C13H18NO [MH ]). IR: υ [cm
1
]
= 1085 (C-O), 760, 690 (C-Harom).
5
.1.9. 3-Methyl-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine] (8b)
A solution of 7b (503 mg, 1.9 mmol) in 2 M NaOH (33 mL) was heated to reflux
overnight. The reaction mixture was cooled to rt and extracted with CH Cl (3x). The
combined organic layers were dried (Na SO ), filtered and the filtrate was
concentrated under reduced pressure. The crude product was used in the next
reaction step without further purification, R = 0.11 (CH Cl :CH OH 70:30 + 1%
2
2
2
4
f
2
2
3
ethyldimethylamine). Colorless solid, mp 99 °C, yield 421 mg (99 %). Purity (HPLC):
1
9
7.6 %, t
d, J = 6.1 Hz, 3H, CH
4.1 / 4.1 Hz, 1H, N(CH
td, J = 13.3 / 4.7 Hz, 1H, N(CH
R
= 14.49 min. C14
H
19NO (217.3 g/mol). H NMR (CD
3
OD): δ (ppm) = 1.32
CH ), 1.74 (td, J =
), 2.02 (dd, J = 14.7 / 2.0 Hz, 1H, N(CH CH ), 2.09
CH ), 2.58 – 2.68 (m, 2H, PhCH CH), 2.80 – 2.88
(
3
), 1.58 (dd, J = 13.8 / 2.5 Hz, 1H, N(CH
CH
2
2 2
)
1
2
2
)
2
2
2 2
)
(
2
2
)
2
2
2
2

(
m,2H, N(CH
.9 Hz, 1H, N(CH
CHarom), a signal for the NH proton is not seen in the spectrum. C NMR (CD
ppm] = 20.7 (1C, CH ), 30.2 (1C, CH CHO), 34.3 (1C, N(CH CH ), 35.5 (0.5C,
), 36.7 (0.5C, N(CH CH ), 38.8 (1C, N(CH CH ), 41.0 (0.5C,
), 41.2 (0.5C, N(CH CH ), 64.0 (1C, CH CHO), 73.7 (1C, ArCO), 124.8
2
CH
2
)
2
), 3.02 (td, J = 12.6 / 2.8 Hz, 1H, N(CH
2 2 2
CH ) ), 3.12 (td, J = 12.6 /
2
2
CH ), 3.84 – 3.92 (m, 1H, PhCH CH), 7.02 – 7.22 (m, 4H,
2
)
2
2
1
3
3
OD): δ
[
3
2
2
2 2
)
N(CH
N(CH
2
CH
2
)
2
2
2
2
)
2
2
2 2
)
2
CH
2
)
2
2
)
2
2
(
1C, C-8arom), 125.85 and 125.88 (2C, C-5arom, C-6arom), 128.3 (1C, C-7arom), 133.6
1C, C-4aarom), 141.6 (1C, C-8aarom). MS (APCI): 218.1535 (calcd. 218.1539 for
(
+
~
-1
C
14
H20NO [MH ]). IR: υ [cm ] = 2924 (C-H), 1643 (C=O), 1064 (C-O), 760 (C-Harom).
5
.1.10. 6-Methoxy-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine] (8c)
A solution of 7c (233 mg, 0.85 mmol) in 2 M NaOH (10 mL) was heated to reflux
overnight. The reaction mixture was cooled to rt and extracted with CH Cl (3x). The
combined organic layers were dried (Na SO ), filtered and the filtrate was
concentrated under reduced pressure. The crude product was used in the next
reaction step without further purification, R = 0.11 (CH Cl :CH OH 70:30 + 1%
2
2
2
4
f
2
2
3
ethyldimethylamine). Colorless solid, mp 136 °C, yield 193 mg (98 %). C14H19NO
2
1
(
233.3 g/mol). H NMR (CD
3
OD): δ [ppm] = 1.86 (dd, J = 15.5 / 2.0 Hz, 2H,
CH , 2.78 (t, J = 5.5 Hz, 2H,
), 3.09 (td, J = 12.4 / 3.2 Hz, 2H,
), 3.89 (t, J = 5.5 Hz, 2H, PhCH CH ), 6.66 (d, J =
.7 Hz, 1H, 5-Harom), 6.77 (dd, J = 8.7 / 2.7 Hz, 1H, 7-Harom), 7.09 (d, J = 8.7 Hz, 1H,
N(CH
PhCH
N(CH
2
CH
), 2.94 (dd, J = 12.2 / 3.4 Hz, 2H, N(CH
CH ), 3.76 (s, 3H, OCH
2
)
2
), 1.95 (td, J = 13.9 / 4.4 Hz, 2H, N(CH
2
2 2
)
2
2 2 2
CH )
2
2
)
2
3
2
2
2
8
13
-Harom), a signal for the NH proton is not seen in the spectrum. C NMR (CD
CH O), 35.2 (1C, N(CH CH ), 38.2 (1C, N(CH CH
), 54.2 (1C, OCH ), 58.7 (1C, CH CH O), 72.0 (1C, ArCO), 112.4
1C, C-7arom), 112.8 (1C, C-5arom), 125.9 (1C, C-8arom), 134.8 (1C, C-8aarom), 158.0
3
OD): δ
[
ppm] = 29.4 (1C, PhCH
2C, N(CH CH
2
2
2
2
)
2
2
2 2
) ), 40.7
(
(
2
2
)
2
3
2
2
2
3

(
1C, C-6arom), a signal for the C-atom of C-4 is not seen in the spectrum. MS (APCI):
+
~
-1
2 3
m/z = 234.1529 (calcd. 234.1489 for C14H20NO [MH ]). IR: υ [cm ] = 1501 (OCH ),
1
085 (C-O), 810, 606 (C-Harom).
5
.1.11. 3,4-Dihydrospiro[[2]benzopyran-1,4’-piperidin]-6-ol (8d)
A solution of 7d (391 mg, 1.5 mmol) in 2 M NaOH (25 mL) was heated to reflux
overnight. The reaction mixture was cooled to rt. The pH value was adjusted to pH 8-
1
0 and the aqueous layer was extracted with EtOAc (3x). The combined organic
layers were dried (Na SO
2
4
), filtered and the filtrate was concentrated under reduced
1
pressure. Colorless oil, yield 40 mg (12 %). C13
CD OD): δ [ppm] = 1.77 - 1.96 (m, 4H, N(CH CH
PhCH CH ), 2.88 (dd, J = 11.2 / 3.4 Hz, 2H, N(CH CH
H, N(CH CH ), 3.86 (t, J = 5.5 Hz, 2H, PhCH CH
arom), 6.58 – 6.68 (m, 1H, 7-Harom), 6.98 (d, J = 8.5 Hz, 1H, 8-Harom), a signal for the
H
17NO
2
(219.3 g/mol). H NMR
(
3
2
2
)
2
), 2.71 (t, J = 5.5 Hz, 2H,
), 3.05 (td, J = 11.9 / 2.7 Hz,
2
), 6.50 (d, J = 1.9 Hz, 1H, 5-
2
2
2
2 2
)
2
2
2
)
2
2
H
NH proton is not seen in the spectrum.
5
7
.1.12. 6-(Benzyloxy)-3,4-dihydrospiro[[2]benzopyran-1,4’-piperidin] (8e)
e (495 mg, 1.4 mmol) was suspended in dioxane (24 mL). 2 M NaOH (52 mL) was
added and the mixture was heated to reflux overnight. The reaction mixture was then
cooled to rt and extracted with CH
Na SO
crude product was dissolved in CH
2
Cl
2
(3x). The combined organic layers were dried
(
2
4
), filtered and the filtrate was concentrated under reduced pressure. The
2 2 2
Cl and a saturated solution of HCl in Et O was
added. Resulting crystals were filtered, washed and dissolved in water. The pH value
was adjusted to pH 10 with 2 M NaOH and the aqueous layer was extracted with
CH
Cl
2 2
(3x). Combined organic layers were dried (Na
2
SO
4
), filtered and the filtrate
was concentrated in vacuo, R
f
= 0.20 (CH Cl : CH OH:NH
2
2
3
3
95:4.5:0.5). Colorless
2
4

R
solid, mp 136 °C, yield 150.1 mg (34 %). Purity (HPLC): 95.6 %, t = 17.86 min.
1
C
20
H
23NO
2
(309.4 g/mol). H NMR (CDCl
3
): δ [ppm] = 1.89 (d, broad, J = 12.5 Hz, 2H,
CH ), 2.80 (t, J = 5.5 Hz, 2H,
CH ), 3.13 (td, J = 12.1 / 2.8 Hz,
CH ), 5.03 (s, 2H, PhCH O), 6.71 (d,
J = 2.1 Hz, 1H, 5-Harom), 6.85 (dd, J = 8.3 / 3.0 Hz, 1H, 7-Harom), 7.11 (d, J = 8.7 Hz,
N(CH
PhCH
H, N(CH
2
CH
2
)
2
), 1.98 (td, J = 13.6 / 4.6 Hz, 2H, N(CH
), 2.89 (d, broad, J = 11.1 Hz, 2H, N(CH
CH ), 3.89 (t, J = 5.2 Hz, 2H, PhCH
2
2 2
)
2
CH
2
2
2 2
)
2
2
2
)
2
2
2
2
1
H, 8-Harom), 7.30 – 7.46 (m, 5H, H’arom), a signal for the NH proton is not seen in the
1
3
spectrum.
C NMR (CDCl
), 42.3 (2C, N(CH
3.5 (1C, ArCO), 113.4 (1C, C-7arom), 114.4 (1C, C-5arom),126.8 (1C, C-8arom), 127.6
and 128.1 (4C, C-2’arom, C-3’arom, C-5’arom, C-6’arom), 135.07 and 135.12 (2C, C-4aarom
C-8aarom), 128.7 and 137.2 (2C, C-1’arom, C-4’arom), 157.0 (1C, C-6arom). MS (APCI):
3
): δ [ppm] = 30.1 (1C, PhCH
2
CH
2
), 37.8 (2C,
N(CH
CH
2 2
)
2
2
CH ), 58.8 (1C, PhCH CH ), 70.1 (1C, PhCH
2
)
2
2
2
2
O),
7
,
+
~
-1
m/z = 310.1801 (calcd. 310.1802 for C20H24NO
2
[MH ]). IR: υ [cm ] = 2936 (C-H),
1
088 (C-O), 737, 698 (C-Harom).
5
.1.13. N-[3,5-Bis(trifluoromethyl)benzyl]-4-chlorobutanamide (11a)
,5-Bis(trifluoromethyl)benzylamine 10a (172 mg, 0.7 mmol) and Na CO
CN (5 ml) and 4-chlorobutanoyl chloride 9 (107 mg, 0.8
mmol) was added dropwise. The solution was stirred overnight at rt. The pH value
was adjusted to pH 7 with saturated aqueous NaHCO to stop the transformation and
the mixture was extracted with EtOAc (3x). The organic layers were combined, dried
Na SO ), filtered and concentrated under reduced pressure. The product was used
in the next reaction step without further purification, R = 0.58 (cyclohexane:EtOAc
0:60). Colorless solid, mp 79 °C, yield 236 mg (96 %). Purity (HPLC): 95.6 %, t
3
2
3
(78 mg, 0.7
mmol) were dissolved in CH
3
3
(
2
4
f
4
2
6
R
=
1
NO (347.7 g/mol). H NMR (CDCl
0.59 min. C13
H
12ClF
6
3
): δ [ppm] = 2.16 (quint, J =
.5 Hz, 2H, ClCH
2
CH
CH ), 2.46 (t, J = 7.1Hz, 2H, ClCH
2 2
2
CH CH ), 3.61 (t, J = 6.1
2
2
2
5

Hz, 2H, ClCH
.72 (s, 2H, 2-Harom, 6-Harom), 7.78 (s, 1H, 4-Harom). C NMR (CDCl
1C, ClCH CH CH ), 32.9 (1C, ClCH CH CH ), 42.7 (1C, PhCH
CH ), 121.5 (hept, J = 3.9 Hz, 1C, C-4arom), 123.1 (q, J = 271.2 Hz, 2C,
2
CH
2
CH
2
), 4.56 (d, J = 6.0 Hz, 2H, PhCH
2
NH), 6.00 (s, broad, 1H, NH),
): δ [ppm] = 27.8
NH), 44.3 (1C,
13
7
3
(
2
2
2
2
2
2
2
ClCH
2
CH
2
2
CF
3
), 127.6 (2C, C-2arom, C-6arom), 132.0 (q, J = 33.5 Hz, 2C, C-3arom, C-5arom), 141.0
(
1C, C-1arom), 171.9 (1C, C=O). MS (APCI): m/z = 348.0594 (calcd. 348.0584 for
+
~
-1
C
13 6
H13ClF NO [MH ]). IR: υ [cm ] = 1644 (C=O), 1276 (C-F), 705, 681 (C-Harom).
5
.1.14. 4-Chloro-N-[3-fluoro-5-(trifluoromethyl)benzyl]butanamide (11b)
-Fluoro-5-(trifluoromethyl)benzylamine 10b (968 mg, 5.0 mmol) and Na
CN (33 mL) and 4-chlorobutanoyl chloride 9
707 mg, 5.0 mmol) was added dropwise. The solution was stirred overnight at rt. The
pH value was adjusted to pH 7 with saturated aqueous NaHCO to stop the
transformation and the mixture was extracted with EtOAc (3x). The organic layers
were combined, dried (Na SO ), filtered and the solvent was evaporated in vacuum.
A further purification of the crude product was not necessary, R = 0.58
cyclohexane:EtOAc 40:60). Colorless solid, mp 60 °C, yield 1334 mg (89 %). Purity
3
2 3
CO (551
mg, 5.2 mmol) were dissolved in CH
3
(
3
2
4
f
(
(
1
HPLC): 90.8 %, t
ppm] = 2.15 (quint, J = 6.6 Hz, 2H, ClCH
ClCH CH CH ), 3.61 (t, J = 6.1 Hz, 2H, ClCH CH
PhCH
-Harom). C NMR (CDCl
ClCH CH CH ), 42.7 (d, J = 1.5, 1C, PhCH
dq, J = 24.5 / 3.9 Hz, 1C, C-4arom), 118.0 (d, J = 22.0 Hz, 1C, C-2arom), 119.9 (quint, J
3.6 Hz, 1C, C-6arom), 132. 8 (qd, J = 33.3 / 8.1 Hz, 1C, C-5arom), 142.3 (d, J = 7.7
Hz, 1C, C-1arom), 162.6 (d, J = 249.2 Hz, 1C, C-3arom), 171.8 (1C, C=O), the signal for
R
= 19.40 min. C12
H
12ClF
4
NO (297.7 g/mol). H NMR (CDCl
3
): δ
), 2.45 (t, 7.1 Hz, 2H,
), 4.48 (d, J = 6.2 Hz, 2H,
[
2
CH
2
CH
2
2
2
2
2
2
CH
2
2
NH), 6.04 (s, broad, 1H, NH), 7.16 - 7.25 (m, 2H, 2-Harom, 4-Harom), 7.31 (s, 1H,
13
6
3
): δ [ppm] = 27.9 (1C, ClCH
2
CH
2
CH
2
), 33.0 (1C,
2
2
2
2
NH), 44.4 (1C, ClCH
2
CH
2
CH ), 111.9
2
(
=
2
6

3
the C-atom of the CF group is not seen in the spectrum. MS (APCI): m/z = 298.0642
+
~
-1
(
4
calcd. 298.0616 for C12H13ClF NO [MH ]). IR: υ [cm ] = 1639 (C=O), 1231 (C-F),
1
169 (C-Farom), 876, 698 (C-Harom).
5
.1.15.N-[3,5-Bis(trifluoromethyl)benzyl]-4-bromo-2-(4-fluorophenyl)butanamide
(
11c)
5c (503 mg, 1.19 mmol) and CBr
25 mL) and cooled to 0 °C. Then triphenylphosphine (1.85 g, polymer-bound, 1.6
1
4 3
(593 mg, 1.78 mmol) were dissolved in CH CN
(
mmol/g) was added, during 30 min at 0 °C. The mixture was stirred at rt for 2 d. The
®
mixture was filtered over Celite and water was added to the eluent. The aqueous
layer was extracted with Et
with water, dried (Na SO ), filtered and the solvent was removed under reduced
pressure. The crude product was used in the next reaction step without further
2
O (3x) and the combined organic layers were washed
2
4
purification, R
HPLC): 62.5 %, t
ppm] = 2.26 (dtd, J = 14.8 / 7.5/ 4.7 Hz, 1H, BrCH
.7 Hz, 1H, BrCH CH CH), 3.26 (ddd, J = 10.2 / 7.9 / 4.6 Hz, 1H, BrCH
ddd, J = 10.2 / 7.2 / 4.7 Hz, 1H, BrCH CH CH), 3.79 (t, J = 7.4 Hz, 1H,
BrCH CH CH), 4.44 (dd, J = 15.8 / 5.8 Hz, 1H, PhCH NH), 4.62 (dd, J = 15.8 / 6.6
Hz, 1H, PhCH NH), 5.95 (s, broad, 1H, NH), 7.06 (t, J = 8.6 Hz, 2H, 3-Harom, 5-Harom),
.31 (dd, J = 8.7 / 5.2 Hz, 2H, 2-Harom, 6-Harom), 7.56 (s, 2H, 2’-Harom, 6’-Harom), 7.75
f
= 0.90 (CH
2 2
Cl :EtOAc 40:60). Brown oil, yield 419.7 mg (73 %). Purity
1
(
R
= 24.44 min. C19
H
15BrF
7
NO (486.2 g/mol). H NMR (CDCl
3
): δ
[
2
CH
2
CH), 2.66 (dtd, J = 14.9 / 7.5 /
CH CH), 3.46
4
2
2
2
2
(
2
2
2
2
2
2
7
1
3
(
s, 1H, 4’-Harom). C NMR (CDCl
BrCH CH CH), 42.6 (1C, PhCH NH), 49.8 (1C, BrCH
C, C-3arom, C-5arom), 121.4 (hept, J = 3.7 Hz, 1C, C-4’arom), 123.1 (q, J = 274.2 Hz,
C, CF ), 127.2 (q, J = 3.8 Hz, 2C, C-2’arom, C-6’arom), 129.5 (d, J = 8.1 Hz, 2C, C-
arom, C-6arom), 131.9 (q, J = 33.3 Hz, 2C, C-3’arom, C-5’arom), 133.9 (d, J = 3.4 Hz, 1C,
3
): δ [ppm] = 31.8 (1C, BrCH
2 2
CH CH), 35.6 (1C,
2
2
2
2
CH CH), 116.2 (d, J = 21.7 Hz,
2
2
2
2
3
2
7

C-1arom), 140.9 (1C, C-1’arom), 162.4 (d, J = 247.6 Hz, 1C, C-4arom), 172.5 (1C, C=O).
+
-1
MS (APCI): m/z = 486.0295 (calcd. 486.0298 for C19
H
16BrF
7
NO [MH ]). IR: v [cm ] =
1
670 (C=O), 1277 (C-F), 1169 (C-Farom), 721, 660 (C-Harom).
5
.1.16.4-Bromo-2-(4-fluorophenyl)-N-[3-fluoro-5-
(
trifluoromethyl)benzyl]butanamide (11d)
5d (796 mg, 2.13 mmol) and CBr (761 mg, 2.29 mmol) were dissolved in CH
40 mL) and cooled to 0 °C. Then triphenylphosphine (3.33 g, polymer-bound, 1.6
1
4
3
CN
(
mmol/g) was added during 30 min at 0 °C. The mixture was stirred at rt overnight.
®
The mixture was filtered over Celite and water was added. The aqueous layer was
extracted with Et
Na SO ), filtered and the solvent was removed under reduced pressure. The crude
product was used in the next reaction step without further purification, R = 0.60
CH Cl :EtOAc 40:60). Brown oil, yield 920 mg (99 %). Purity (HPLC): 47.25 %, t
3.51 min. C18
2.2 / 7.4 / 4.8 Hz, 1H, BrCH
CH CH), 3.25 (ddd, J = 10.3 / 8.0 / 4.7 Hz, 1H, BrCH
0.3 / 7.1 / 4.8 Hz, 1H, BrCH CH CH), 3.76 (t, J = 7.4 Hz, 1H, BrCH
dd, J = 15.7 / 5.9 Hz, 1H, PhCH NH), 4.51 (dd, J = 15.6 / 6.3 Hz, 1H, PhCH
.86 (s, broad, 1H, NH), 7.03 (d, J = 6.4 Hz, 1H, 2’-Harom), 7.06 (t, J = 8.5 Hz, 2H, 3-
2
O (3x), the combined organic layers were washed with water, dried
(
2
4
f
(
2
2
R
=
1
2
1
H15BrF
5
NO (436.2 g/mol). H NMR (CDCl
CH CH), 2.66 (dtd, J = 12.3 / 7.4 / 4.7 Hz, 1H,
CH CH), 3.46 (ddd, J =
CH CH), 4.41
NH),
3
): δ [ppm] = 2.26 (dtd, J =
2
2
BrCH
2
2
2
2
1
2
2
2
2
(
2
2
5
H
arom, 5-Harom), 7.16 (s, 1H, 6’-Harom), 7.20 (d, J = 8.3 Hz, 1H, 4’-Harom), 7.32 (dd, J =
1
3
8
.7 / 5.3 Hz, 2H, 2-Harom, 6-Harom). C NMR (CDCl
3
): δ [ppm] = 31.8 (1C,
CH), 42.7 (1C, PhCH NH), 49.9 (1C,
CH), 111.9 (dq, J = 24.4 / 3.8 Hz, 1C, C-4’arom), 116.2 (d, J = 21.7 Hz, 2C,
BrCH
BrCH
2
CH
2
2
CH), 35.6 (1C, BrCH
2
CH
2
2
2
CH
C-3arom, C-5arom), 117.7 (d, J = 20.6 Hz, 1C, C-2’arom), 119.5 (quint, J = 3.7 Hz, 1C, C-
arom), 129.5 (d, J = 8.0 Hz, 2C, C-2arom, C-6arom), 133.9 (d, J = 3.4 Hz, 1C, C-1arom),
6
’
2
8

1
2
42.1 (d, J = 7.6 Hz, 1C, C-1’arom), 162.4 (d, J = 247.6 Hz, 1C, C-3’arom), 162.6 (d, J =
49.9 Hz, 1C, C-4arom), 172.4 (1C, C=O), signals for the C-atom of the CF group and
3
for C-5’ are not seen in the spectrum. MS (APCI): m/z = 436.0301 (calcd. 436.0330
+
-1
5
for C18H16BrF NO [MH ]). IR: v [cm ] = 1651 (C=O), 1227 (C-F), 1169 (C-Farom), 664
(
C-Br).
5
.1.17.N-[3,5-Bis(trifluoromethyl)benzyl]-4-bromo-2-cyclopropylbutanamide
(
11e)
4 3
5e (60 mg, 0.16 mmol) and CBr (100 mg, 0.30 mmol) were dissolved in CH CN (4
1
mL) and cooled to 0 °C. Then triphenylphosphine (266 mg, polymer-bound, 1.6
mmol/g) was added during 30 min at 0 °C. The mixture war stirred at rt overnight. The
®
mixture was filtered over Celite and water was added to the eluent. The aqueous
layer was extracted with CH
water, dried (Na SO ), filtered and the solvent was removed under reduced pressure.
The crude product was used in the next reaction step without further purification, R
2 2
Cl (3x), the combined organic layers were washed with
2
4
f
=
0
5
–
.40 (CH
4 %, t = 23.32 min. C16
0.33 (m, 2H, CH2cycloprop), 0.59 – 0.71 (m, 2H, CH2cycloprop), 0.95 – 1.05 (m, 1H,
2 2 3 3
Cl : CH OH:NH 95:4.5:0.5). Brown oil, yield 33 mg (47 %). Purity (HPLC):
1
R
6 3
H16BrF NO (432.2 g/mol). H NMR (CDCl ): δ [ppm] = 0.25
CHcycloprop), 1.74 (td, J = 9.2 / 5.4 Hz, 1H, BrCH
BrCH CH CH), 2.42 (ddt, J = 14.3 / 8.8 / 5.3 Hz, 1H, BrCH
0.2 / 9.2 / 4.9 Hz, 1H, BrCH CH CH), 3.56 – 3.66 m, 1H, BrCH
15.8 / 6.1 Hz, 1H, PhCH NH), 4.70 (dd, J = 15.8 / 6.2 Hz, 1H, PhCH
2
CH
2
CH), 2.08 – 2.16 (m, 1H,
CH CH), 3.43 (ddd, J =
CH CH), 4.53 (dd, J
NH), 6.19 (s,
2
2
2
2
1
=
2
2
2
2
2
2
13
broad, 1H, NH), 7.75 (s, 2H, 2-Harom, 6-Harom), 7.79 (s, 1H, 4-Harom). C NMR
CDCl ): δ [ppm] = 3.9 (1C, CH2cycloprop), 4.5 (1C, CH2cycloprop), 13.7 (1C, CHcycloprop),
2.2 (1C, BrCH
BrCH CH CH), 121.4 (hept, J = 3.9 Hz, 1C, C-4arom), 123.2 (q, J = 272.2 Hz, 2C,
(
3
3
2 2 2 2 2
CH CH), 35.0 (1C, BrCH CH CH), 42.5 (1C, PhCH NH), 50.0 (1C,
2
2
2
9