Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: Synthesis and structure optimization

Article abstract of DOI:10.3390/molecules13051081

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert- butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27 % inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identfied as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.

Full text of DOI:10.3390/molecules13051081

Molecules 2008, 13, 1081-1110; DOI: 10.3390/molecules13051081
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Identification of Terfenadine as an Inhibitor of Human
CD81-Receptor HCV-E2 Interaction: Synthesis and Structure
Optimization
Marcel Holzer 1, Sigrid Ziegler 1, Beatrice Albrecht 1, Bernd Kronenberger 1, Artur Kaul 2, Ralf
Bartenschlager 2, Lars Kattner 3, Christian D. Klein 1 and Rolf W. Hartmann 1,*
1
Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041
Saarbrücken, Germany
2
Department of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, D-69120
Heidelberg, Germany
3
Endotherm GmbH, Science-Park II, D-66123 Saarbrücken, Germany
* Author to whom correspondence should be addressed. E-mail: rwh@mx.uni-saarland.de
Received: 26 March 2008; in revised form: 2 May 2008 / Accepted: 7 May 2008 / Published: 7 May
2008
Abstract:
Terfenadine
(4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butyl-
phenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27
% inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biological
activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic
substitution. The prepared compounds were tested for their inhibitory potency by means of
a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity
relationships could be derived. Optimization was successful, leading to 3g, identfied as the
most potent compound (69 % inhibition). Experiments with viral particles revealed that
there might be additional HCV infection reducing mechanisms.
Keywords: Hepatitis C Virus, CD81-receptor, large extracellular loop, terfenadine
derivatives, microwave assisted syntheses.

Molecules 2008, 13
1082
Introduction
Despite the discovery of the Hepatitis C Virus (HCV) more than 15 years ago, chronic HCV
infection is still incurable in many patients, leading to cirrhosis, end-stage liver disease and
hepatocellular carcinoma [1]. According to the 2002 WHO report, in 2001 more than 280,000 deaths
worldwide were attributable to HCV infection [2]. The large extracellular loop (LEL) of the human
CD81 cell surface protein, a member of the tetraspanin family, was identified as a binding partner for
the Hepatitis C Virus envelope glycoprotein E2 (HCV-E2) [3]. Since inhibition of this interaction
prevents HCV from infecting hepatocytes, the HCV principal target cells [3], the aim of the present
work was to prepare compounds which restrain the CD81-LEL–HCV-E2 interaction by binding to the
LEL. Another approach to inhibit this interaction using compounds that bind to the E2 glycoprotein of
HCV was recently published by Van Compernolle et al. [3].
Results and Discussion
Biological Screening
The starting point of this work was a biological screening of natural products, current drugs and
our in-house substance library (approximately 350 compounds, including several structurally different
antihistamines) using a medium throughput assay developed in our group [4]. This assay is based on a
procedure developed by Pileri et al. [5], in which the compounds inhibit the binding of the
fluorescence-labeled CD81 antibody JS81 to HUH7.5 cells.
As an outcome of this screening an antihistamine,, terfenadine (Figure 1), was found to be a
moderate inhibitor of the CD81-LEL–HCV-E2 interaction (27 % at 50 µM), whereas all other
antihistamines showed no biological activity.
Figure 1. Terfenadine.
OH
OH
Ph
N
(CH2)3
Ph
Structure Modification
Based on these results, a series of terfenadine derivatives was prepared seeking to increase the
inhibitory activity and to derive structure-activity relationships. The following structural features were
modified: length of the alkyl “linker” between the piperidine and the phenyl moiety, alkyl substituent
on the phenyl ring, secondary hydroxy group and the azacyclonol moiety.

Molecules 2008, 13
1083
Syntheses
The first step of the preparation was a Friedel-Crafts (FC) acylation of the benzene derivative with
aluminium chloride as catalyst and the carboxylic acid chloride of the corresponding ω-bromo-
carboxylic acid, prepared using thionyl chloride (Scheme 1). The synthesized 1-aryl-ω-bromo ketones
are shown in Table 1.
Scheme 1. Reagents and conditions for the FC acylation and synthesized 1-aryl-ω-bromo
ketones.
O
(CH2)
n
O
Br
i
(CH2)
n
+
Br
OH
1a-1x
R
R
Reagents and conditions: (i) 1. SOCl2, rt, 30 min 2. dry CH2Cl2, AlCl3, 0 °C, 45 min (n = 3-5; R =
H; C1-C4).
Table 1. Synthesized 1-aryl-ω-bromo ketones 1a-1x (n = 3-5; R = H; C1-C4).
O
(CH2)
n
Br
1a-1x
R
R
n
5
5
5
5
5
5
5
5
compound
n
4
4
4
4
4
4
4
4
compound
n
3
3
3
3
3
3
3
3
compound
H
1a
1b
1c
1d
1e
1f
1i
1j
1q
1r
1s
Methyl
Ethyl
1k
1l
n-Propyl
iso-Propyl
n-Butyl
iso-Butyl
tert-Butyl
1t
1m
1n
1o
1p
1u
1v
1w
1x
1g
1h
In the second reaction step (Scheme 2) the precursors 1a-1x were coupled to azacyclonol
according to a described procedure [6]. The classical nucleophilic substitution was optimized for
microwave assisted synthesis. The desired compounds were obtained in satisfying yields in a very
short time (5-45 minutes). This led to compounds 2a-2x, shown in Table 2.

Molecules 2008, 13
1084
Scheme 2.
O
OH
Ph
(CH )
O
2
n
OH
Ph
Ph
N
(CH2)
n
Br
Ph
NH
i
+
1a-1x
2a-2x
R
azacyclonol
R
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, microwave:
150 Watt, 6.5 bar, 175 °C, 45 min (100 Watt, 140 °C, 3 h: 2g, 2h, 2t, 2u, 2v, 2w), n = 3-5; R =
H; C1-C4.
Table 2. Synthesized terfenadine derivatives 2a-2x and 3a-3w (n = 3-5; R = H; C1-C4).
OH
O
OH
OH
Ph
N
(CH )n
Ph
N
(CH )n
2
2
Ph
Ph
R
R
2a-2x
3a-3w
R
n
5
5
5
5
5
5
5
5
compound
n
4
4
4
4
4
4
4
4
compound
n
3
3
3
3
3
3
3
3
compound
n
5
5
5
5
5
5
5
5
compound
n
4
4
4
4
4
4
4
4
compound
n
3
3
3
3
3
3
3
3
compound
H
2a
2b
2c
2d
2e
2f
2i
2j
2q
2r
2s
3a
3b
3c
3d
3e
3f
3i
3j
3q
Methyl
Ethyl
3r
2k
2l
3k
3l
3s
n-Propyl
iso-Propyl
n-Butyl
iso-Butyl
tert-Butyl
2t
3t
2m
2n
2o
2p
2u
2v
2w
2x
3m
3n
3o
3p
3u
3v
2g
2h
3g
3h
3w
terfenadine
A sodium borohydride reduction (Scheme 3) of the ketone function followed. The prepared
alcohols 3a-3w, which were obtained as racemates, are also listed in Table 2.
Scheme 3.
OH
Ph
OH
Ph
OH
O
Ph
N
(CH2)
Ph
N
(CH2)
n
n
i
2a-2x
3a-3w
R
R
Reagents and conditions: (i) NaBH4, MeOH, 0 °C, 1 h (n = 3-5; R = H; C1-C4).
Since azacyclonol, the second component for the coupling reaction, was commercially available,
this synthetic procedure facilitated the preparation of a large variety of compounds in a minimum
amount of time. For further modification of the secondary hydroxy group the ester 5a, the amide 5b
and the alkane 8a were synthesized.

Molecules 2008, 13
1085
Activation of 6-bromo hexanoic acid with thionyl chloride followed by addition of commercially
available 4-tert-butyl phenol and 4-tert-butyl aniline, respectively, led to the ω-bromo substituted
precursors 4a and 4b (Scheme 4).
Scheme 4.
XH
Br
(CH2)5
X
i
Br
(CH2)5
OH
+
O
O
4a, 4b
Reagents and conditions: (i) 1. SOCl2, rt, 1 h 2. NEt3, dry CH2Cl2, 0 °C 30 min, rt 1 h (X = -O-:
4a, X = -NH-: 4b).
Next, these precursors were nucleophilically coupled to azacyclonol, leading to compounds 5a and
5b, respectively (Scheme 5).
Scheme 5.
O
O
OH
X
Ph
N (CH2)5
Br (CH2)5
X
OH
Ph
Ph
i
Ph
NH
+
4a, 4b
5a, 5b
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, 150 Watt, 140
°C, 1 h (X = -O-: 5a, X = -NH-: 5b).
For the synthesis of 8a compound 1h was reduced using sodium borohydride. The resulting
alcohol 6a was converted into the corresponding alkane 7a by means of a mixture of indium(III)
chloride and chlorodiphenylsilane (Scheme 6) and subsequently coupled to azacyclonol, leading to
compound 8a (Scheme 7).
Scheme 6.
OH
O
(CH )
2
5
(CH2)
5
(CH2)
Br
5
Br
Br
ii
i
6a
7a
1h
Reagents and conditions: (i) see Scheme 3; (ii) indium(III) chloride, chlorodiphenylsilane, dry
dichloromethane, 3 h, rt.

Molecules 2008, 13
1086
Scheme 7.
OH
Ph
(CH2)
Ph
N
(CH )
2 5
5
OH
Ph
Br
i
Ph
NH
+
8a
7a
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, 50 Watt, 100
°C, 5 min
The exchange of the azacyclonol component by smaller piperidine moieties started from the 1-aryl-
ω-bromo ketone 1o and was accomplished via microwave assisted nucleophilic substitution, followed
by reduction of the ketone (Scheme 8). The prepared compounds 9a-9d, as well as the corresponding
alcohols 10a-10d, obtained as racemates, are shown in Table 3.
Scheme 8.
O
OH
O
(CH2)
R
N
(CH )4
R
N
(CH )4
2
4
2
R
NH
Br
ii
9a-9d
10a-10d
i
1o
iBu
iBu
iBu
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, microwave
150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH4, MeOH, 0 °C, 1 h (R = -H, -CH3, -OH, benzyl).
Table 3. Synthesized terfenadine derivatives 9a-9d and 10a-10d.
O
OH
R
N
(CH )4
R
N
(CH )4
2
2
10a-10d
9a-9d
iBu
iBu
R
compound
R
compound
10a
H
9a
9b
9c
9d
H
Methyl
Methyl
Hydroxyl
Benzyl
10b
Hydroxyl
Benzyl
10c
10d
Furthermore, 1o was reacted with morpholine and piperidin-4-one resulting in compounds 11a,
12a and 13a (scheme 9). The morpholine derivative 12a was obtained as a racemate.

Molecules 2008, 13
1087
Scheme 9.
O
OH
O
N
(CH2)4
O
N
(CH2)4
O
ii
O
NH
11a
(CH2)
4
12a
i
Br
iBu
O
O
NH
O
1o
iBu
i
N
(CH2)4
iBu
13a
iBu
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, microwave
150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH4, MeOH, 0 °C, 1 h.
For the syntheses of the pyrrolidine compounds 15a and 16a, 1o was coupled with
diphenyl(pyrrolidin-3-yl)methanol (14a). The resulting ketone 15a was reduced with sodium
borohydride (Scheme 10), leading to the desired compound as a racemate.
Scheme 10.
O
(CH2)
4
OH
Ph
OH
Ph
Br
Ph
Ph
N
(CH2)4
O
N
(CH2)4
OH
ii
i
1o
iBu
+
OH
16a
15a
Ph
NH
Ph
iBu
iBu
14a
Reagents and conditions: (i) K2CO3, catalytic KI and 18-crown-6, dry acetonitrile, microwave
150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH4, MeOH, 0 °C, 1 h.
Biological evaluation
The synthesized terfenadine derivatives were tested for their inhibitory potency using the antibody
neutralization (AN) assay mentioned above (Tables 4-8) [4]. In this assay the potential inhibitors and
the fluorescence-labeled antibody JS81 compete for binding to the LEL on the CD81 receptor
molecule. The reduction of the interaction of JS81 with CD81 on HUH7.5 cells caused by the
compounds decreases fluorescence which is measured by FACS in comparison to untreated control
cells.
The % inhibition values of compounds 2a-2x (Table 4) and 3a-3w (Table 5) show that the alkyl
substituent R on the phenyl ring has a major influence on the activity. Another important feature is
obviously the length of the linker, whereas the activities of the ketones (Table 4) and the
corresponding alcohols (Table 5) do not differ significantly, at least in case of the n-propyl and n-butyl
compounds.

Molecules 2008, 13
1088
Table 4. Inhibition of protein interaction in AN assay by compounds 2a-2x
(concentration: 50 µM, standard deviation ≤ 6 %).
O
OH
Ph
N
(CH )n
2
Ph
R
2a-2x
n = 5
n = 4
n = 3
inhibition
inhibition
inhibition
R
compound
compound
compound
(%)
10
12
42
59
63
56
46
49
(%)
4
(%)
7
H
2a
2b
2c
2d
2e
2f
2i
2j
2q
2r
2s
Methyl
8
7
Ethyl
2k
2l
24
64
29
57
60
53
1
n-Propyl
iso-Propyl
n-Butyl
iso-Butyl
tert-Butyl
2t
57
41
56
44
37
2m
2n
2o
2p
2u
2v
2w
2x
2g
2h
Table 5. Inhibition of protein interaction in AN assay by compounds 3a-3w
(concentration: 50 µM, standard deviation ≤ 6 %).
OH
OH
Ph
N
(CH )n
2
Ph
R
3a-3w
n = 5
n = 4
n = 3
inhibition
inhibition
inhibition
R
compound
compound
compound
(%)
4
(%)
1
(%)
5
H
3a
3b
3c
3d
3e
3f
3i
3j
3q
Methyl
8
5
3r
4
Ethyl
13
32
9
3k
3l
4
3s
4
n-Propyl
iso-Propyl
n-Butyl
iso-Butyl
tert-Butyl
53
4
3t
23
11
64
42
27
3m
3n
3o
3p
3u
3v
49
69
58
49
67
44
3g
3h
3w
terfenadine
Increasing the size of R from hydrogen to bulkier alkyl substituents increases inhibition. A
maximum inhibition, not depending on the linker length, could be reached by the use of n-propyl for
the ketones and iso-butyl for the alcohols, with the exception of compounds 2d and 3w, which are less
active than the analogous 2e and 3v. Generally, compounds with n = 3 show a lower inhibition than
those with n = 4 or 5, with the exception of 3v, which is more active than 3f and 3n. Furthermore,
reduction of the ketones 2a-2x to the corresponding alcohols 3a-3w and terfenadine led to a decreased

Molecules 2008, 13
1089
activity for compounds with small substituents at the phenyl ring, whereas a reduction of bulky
substituted compounds led to derivatives with comparable inhibition. The reduction of the ketones
with R = iso-propyl to the corresponding alcohols led to a nearly complete loss of biological activity.
The most active compound in this series of terfenadine derivatives is 3g (69 % inhibition). Therefore,
the hexanol linker combined with an iso-butyl group at the phenyl ring is the most favorable
substitution pattern in this class of compounds.
Replacement of the azacyclonol moiety by smaller piperidine residues (9a-9c, 10a-10c and 11a-
13a) led to a loss of inhibitory activity compared to the reference compounds 2o and 3o (Table 6).
Substitution of the piperidine group by a 4-benzyl group (9d and 10d) increased the inhibition to a
moderate level. Again bulky substituents are essential for activity at this part of the molecule.
Table 6. Inhibition of protein interaction in AN assay by compounds 9a-13a compared to
compounds 2o and 3o (concentration: 50 µM, standard deviation ≤ 6 %).
O
OH
R
(CH2)4
R
(CH2)4
iBu
iBu
inhibition
(%)
inhibition
(%)
R
compound
compound
azacyclonol
2o
9a
9b
60
7
3o
67
5
N
10a
10b
N
5
7
HO
Ph
N
N
9c
9d
7
29
8
10c
10d
12a
6
31
4
O
N
11a
13a
O
N
5
Reduction of the secondary hydroxy group of 3h to the corresponding alkane 8a led to a strong
decrease of inhibition (Table 7). Exchange of the ketone of 2h by an ester function (compound 5a) did
not influence the inhibitory activity, whereas an amide group (compound 5b) increased the inhibition.
These SAR results indicate that the functional group X might act as an H-bond acceptor interacting
with the CD81 protein.

Molecules 2008, 13
1090
Table 7. Inhibition of protein interaction in AN assay by compounds 5a-5b, 8a compared to
compounds 2h and 3h (R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %).
OH
Ph
N
(CH2)5
X
Ph
tBu
inhibition
(%)
inhibition
(%)
X
compound
X
compound
OH
3h
2h
58
49
8a
5a
5b
9
O
O
48
57
O
O
NH
Exchange of the piperidine of the azacyclonol moiety of 2o and 3o by pyrrolidine (compounds 15a
and 16a) did not lead to a significant change of the inhibitory activity (Table 8). Obviously due to the
flexibility of the chain, appropriate conformations can be found for both heterocycles.
Table 8. Inhibition of protein interaction in AN assay by compounds 15a, 16a compared to
compounds 2p and 3p (R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %).
OH
OH
X
Ph
N
(CH2)4
X
Ph
N
(CH )4
2
Ph
Ph
iBu
iBu
inhibition
inhibition
X
compound
compound
(%)
60
(%)
64
O
2o
3o
15a
16a
OH
67
62
Selected compounds with high, moderate and low inhibition in the AN assay were tested for their
inhibition in an infectivity assay developed by Pietschmann and coworkers [7] (Table 9), in which
HUH7.5 cells were incubated with HCV particles of the LUC-Jc1 genome (genotype 2a) [8] and
potential inhibitors. After 48 hours, the cells were lysed and luciferase activity (a marker of infection
and viral replication) was measured. The infectivity assay was performed at the highest non-cytotoxic
concentrations of the compounds (0.5 µM: 2e, 2s, 3f, 3g, 3i, 8a and 5 µM: 3q, 10d).
Compounds with high biological activity in the neutralization assay showed good inhibition in the
infectivity assay as well. This clearly indicates that inhibition of the protein-protein interaction leads to
a reduction of infectivity. On the other hand there are compounds which reduced infectivity without
having been active in the AN assay. One plausible reason for this phenomenon could be an interaction
of these compounds with an additional target which is involved in viral infection.

Molecules 2008, 13
Table 9. Inhibition of infectivity of viral particles by selected compounds.
1091
Antibody neutralization assay
Infectivity assay with viral
Compound
(inhibition (%), 50 µM)
particles (inhibition (%), 0.5 µM)
2e
2s
63
1
43
19
40
32
27
33a
27
45a
3f
49
69
1
3g
3i
3q
8a
10d
5
9
31
Concentration: 0.5 µM, a 5 µM, standard deviation ≤ 14 % compared to AN assay
data.
Conclusions
After having identified terfenadine as an active compound inhibiting the CD81-LEL–HCV-E2
interaction by 27 %, the compound was structurally modified with the aim of increasing the activity.
The results obtained clearly demonstrate that a bulky substituent at the phenyl moiety as well as an
additional bulky substituent at the other part of the molecule (like azacyclonol) are necessary for
activity as well as the secondary OH-group. Another H-bond acceptor like ketone, ester or amide can
replace the latter. Importantly, the activity of the parent compound can be increased by elongation of
the alkyl chain resulting in 3g with an inhibition of 69 %. A further experiment with viral particles and
HUH7.5 cells showed that there are possibly further mechanisms by which the test compounds unfold
their anti-viral activity. These mechanisms remain to be elucidated.
Experimental
General
Solvents and reagents were used as received from commercial distributors without further
purification. Anhydrous reactions were conducted under a nitrogen atmosphere. Proton and carbon
NMR spectra (in CDCl3, unless otherwise noted) were recorded on a Bruker AM 500 instrument The
proton NMR spectra were recorded at 500 MHz, the carbon NMR spectra at 125 MHz. Chemical shifts
δ are reported in ppm units. Molecular mass was determined by liquid chromatography – tandem mass
spectrometry (LC-MS/MS) using a TSQ Quantum from Thermo Finnigan equipped with an electro
spray interface and connected to a Surveyor HPLC (Thermo Finnigan). Positive and negative ion mass
spectra were recorded (mass range m/z 150–1500) in normal scan mode. Melting points were
determined using a Stuart Scientific SMP3 melting point apparatus. IR measurements were performed
on a Bruker Vector 33 at a frequency range from 4000–250 cm-1. Wave numbers υ are reported in cm-
1. Microwave assisted syntheses was performed using a CEM DISCOVER microwave oven or a MLS

Molecules 2008, 13
1092
MultiSYNTH microwave oven respectively. Preparative HPLC was carried out using an Agilent
Technologies, 1200 Series Isocratic, with an Agilent Prep-C18 (5 µm; 30x100mm) preparative column
using 70:30 methanol/water as eluent. Flash chromatography was performed using Merck silica gel
35/40–63/70.
Antibody neutralization assay.
For the antibody neutralization assay HUH7.5 cells were used, derived from a human hepatoma
cell line which was preselected via FACS for cells displaying high amounts of CD81 on their cell
surface. Cells were grown under standard conditions (Dulbecco’s Modified Eagle’s Medium with 10
% FCS, 1% penicillin/streptavidin, pH 7.4, at 37°C with 5% CO2). 1·105 cells were incubated with 100
µL (50µM) of the potential inhibitor. The inhibitor solution contained 1 % DMSO, a concentration
tolerated by the used HUH7.5 cells and without influence on MFI (mean fluorescence intensity) values
(data not shown). Incubation was performed in 96 transwell plates for 10 minutes at room temperature.
Subsequently 4 µL of the fluorescence-labeled anti human CD81 antibody JS81 (Pharmingen) and 21
µL of phosphate buffered saline buffer (PBS) were added and kept at room temperature for 10
minutes. The final concentration of JS81 in the assay was 1.6·10-3 µg/µL. After addition of 125 µL of
PBS the cell suspension was incubated in the dark for 5 hours followed by FACS (Becton Dickison –
FACS Calibur; software: Cell Quest Pro) analysis. Ten thousand vital cells out of a predetermined area
were analyzed for their MFI.
Infectivity assay.
In vitro synthesis of the LUC-Jc1 RNA genome in which the luciferase reporter gene was inserted
into the genome of the Jc1 HCV variant and electroporation of Huh-7 cells was performed as described
previously [9, 10]. We collected culture medium containing viral particles 48 h after transfection.
HUH7.5 target cells were seeded 24 h before infection at a density of 6·105 cells/well in a 24 well
plate. Cells were infected with 200 µL inoculum containing the potential inhibitors at 5 µM or 0.5 µM
for 4 h. Concentrations were chosen according to the highest non-cytotoxic concentration of the given
compound. Cells were washed, complete medium was added and cells were cultured for 48 h.
Afterwards cells were lysed for luciferase assay as previously described [7].
Chemistry
General procedure for the Friedel-Crafts-acylation
The carboxylic acid was stirred with thionyl chloride (10 mL) at room temperature for 1h. After
removing the excess of thionyl chloride under reduced pressure, dry dichloromethane (15 mL) and the
benzene derivative (1 equivalent, referring to the carboxylic acid) were added. The solution was
cooled to 0 °C and AlCl3 (1.2 equivalents) were added. After stirring at that temperature for 45 min,
the mixture was hydrolyzed, the layers separated and the water phase was extracted with

Molecules 2008, 13
1093
dichloromethane two times. The combined organic layers were dried and the solvent removed. Flash
chromatography using 1/15 ethyl acetate/n-hexane as eluent led to the desired compounds.
General procedure for the nucleophilic substitution
Azacyclonol (1 equivalent), ketone (1 equivalent), potassium carbonate (5 equivalents), a catalytic
amount of potassium iodide and 18-crown-6 were stirred in dry acetonitrile (4 mL) in the microwave
(CEM Discover) at 150 Watt, 6.5 bar, 175 °C for 45 min or (MultiSYNTH) at 100 Watt, 140 °C, 3 h
(2g, 2h, 2t, 2u, 2v, 2w) or at 50 Watt, 100 °C, 5 min (8a). The microwave assisted reactions were
performed in a continuous air stream cooled closed vessel. Reaction temperature was monitored via an
IR sensor in both microwave ovens and an additional fiber optic component in case of the
MultiSYNTH. After filtering off the remaining precipitate the solvent was removed. The impurities
could not be removed completely by flash chromatography (6/1 ethyl acetate/n-hexane + 3 % NEt3), so
preparative HPLC (isocratic 70/30 MeOH/H2O) was performed and the pure product isolated.
General procedure for the reduction of the ketones
Sodium borohydride (5 equivalents) and ketone (1 equivalent) were added to 2 mL methanol at 0
°C. After stirring for 30 min a spatula tip of sodium borohydride was added to the mixture which was
stirred for another 30 min at 0 °C. The mixture was hydrolyzed using 2 mL NH4Cl-solution. After
removing the solvents under reduced pressure, the remaining solid was washed two times with
methanol and ethyl acetate (2 mL each). The combined organic layers were freed from solvent and the
raw product was purified by preparative HPLC (isocratic MeOH/H2O: 70/30) to give the racemates in
satisfying yields.
General procedure for the ester and amide coupling
The carboxylic acid (1 equivalent) was stirred with an excess of thionyl chloride for 1 hour at room
temperature. The resulting clear solution was freed from remaining thionyl chloride under reduced
pressure. The acid chloride was dissolved in dry dichloromethane and added dropwise at 0 °C to a
solution of the corresponding alcohol or amine (1.2 equivalents) and an equimolar amount of
triethylamine in dry dichloromethane. After stirring for 30 minutes at 0 °C the mixture was warmed to
room temperature and stirred for 1 hour. The precipitated solid was filtered off. The solvent was
removed and the raw product purified by column flash chromatography using an ethyl acetate/n-
hexane mixture.
1
6-Bromo-1-phenylhexan-1-one (1a). Yield: 26 %; H-NMR: 7.88–7.85 (2 H, m), 7.49–7.45 (1 H, m),
7.39–7.35 (2 H, m), 3.35–3.32 (2 H, m), 2.92–2.88 (2 H, m), 1.86–1.79 (2 H, m), 1.72–1.64 (2 H, m),
1.48–1.40 (2 H, m) [Lit. [11] 400 MHz, CDCl3: 7.94 (2 H, m), 7.55 (1 H, m), 7.45 (2 H, m), 3.41 (2 H,
13
t, J = 6.80), 2.98 (2 H, t, J = 7.00), 1.90 (2 H, m), 1.76 (2 H, m), 1.53 (2 H, m)]; C-NMR: 199.96,
136.95, 133.02, 128.61, 128.02, 38.29, 33.69, 32.66, 27.89, 23.33.

Molecules 2008, 13
1094
6-Bromo-1-(4-methylphenyl)hexan-1-one (1b). Yield: 50 %; 1H-NMR: 7.76 (2 H, d, J = 8.06), 7.16 (2
H, d, J = 7.98), 3.34–3.31 (2 H, t, J = 6.78), 2.88–2.84 (2 H, t, J = 7.44), 2.31 (3 H, s), 1.85–1.78 (2 H,
m), 1.70–1.62 (2 H, m), 1.47–1.39 (2 H, m) [Lit. [12] CDCl3: 7.85 (2 H, d, J = 7.30), 7.25 (2 H, d, J =
8.60), 3.42 (2 H, d, J = 8.60), 2.96 (2 H, t, J = 7.30), 2,41 (3 H, s), 1.97–1.86 (2 H, m), 1.82–1.74 (2 H,
m), 1.58–1.47 (2 H, m)]; 13C-NMR: 199.61, 143.72, 134.47, 129.26, 128.13, 38.14, 33.67, 32.65,
27.89, 23.41, 21.62.
1
6-Bromo-1-(4-ethylphenyl)hexan-1-one (1c). Yield: 75 %; H-NMR: 7.89 (2 H, d, J = 8.34), 7.29 (2
H, d, J = 8.49), 3.43 (2 H, t, J = 6.79), 2.99–2.96 (2 H, m), 2.74–2.68 (2 H, m), 1.95–1.88 (2 H, m),
1.81–1.73 (2 H, m), 1.57–1.50 (2 H, m), 1.26 (3 H, t, J = 7.60) [Lit. [12] CDCl3: 7.88 (1 H, d, J =
8.60), 7.28 (1 H, d, J = 8.60), 3.43 (2 H, t, J = 7.00), 2.97 (2 H, t, J = 7.30), 2.71 (2 H, q, J = 7.20),
2.04–1.48 (6 H, m), 1.26 (3 H, t, J = 7.60)]; 13C-NMR: 199.65, 148.91, 133.65, 127.22, 127.06, 37.16,
32.67, 31.64, 27.91, 26.89, 22.41, 14.22.
1
6-Bromo-1-(4-n-propylphenyl)hexan-1-one (1d). Yield: 74 %; H-NMR: 7.84 (2 H, d, J = 8.32), 7.23
(2 H, d, J = 8.35), 3.40 (2 H, t, J = 6.78), 2.94 (2 H, t, J = 7.24), 2.63–2.60 (2 H, m), 1.92–1.86 (2 H,
13
m), 1.77–1.71 (2 H, m), 1.67–1.60 (2 H, m), 1.53–1.47 (2 H, m), 0.92 (3 H, t, J = 7.34); C-NMR:
199.69, 148.45, 134.75, 128.71, 128.17, 38.20, 38.04, 33.69, 32.70, 27.95, 24.26, 23.46, 13.81.
6-Bromo-1-(4-iso-propylphenyl)hexan-1-one (1e). Yield: 65 %; 1H-NMR: 7.89 (2 H, d, J = 8.40), 7.30
(2 H, d, J = 8.14), 3.42 (2 H, t, J = 6.79), 2.99–2.93 (3 H, m), 1.94–1.88 (2 H, m), 1.79–1.73 (2 H, m),
1.56–1.49 (2 H, m), 1.26 (6 H, d, J = 6.93); 13C-NMR: 199.66, 154.50, 134.88, 128.31, 126.70, 38.21,
34.27, 33.69, 32.70, 27.96, 23.72. 23.47.
6-Bromo-1-(4-n-butylphenyl)hexan-1-one (1f). Yield: 44 %; 1H-NMR: 7.98 (2 H, d, J = 8.25), 7.37 (2
H, d, J = 8.03), 3.53 (2 H, t, J = 6.77), 3.09–3.06 (2 H, m), 2.79–2.76 (2 H, m), 2.05–2.00 (2 H, m),
1.91–1.85 (2 H, m), 1.76–1.70 (2 H, m), 1.67–1.61 (2 H, m), 1.51–1.43 (2 H, m), 1.04 (3 H, t, J =
7.32); 13C-NMR: 199.66, 148.69, 134.71, 128.66, 128.19, 38.20, 35.71, 33.68, 33.29, 32.70, 27.95,
23.46, 22.36, 13.95.
1
6-Bromo-1-(4-iso-butylphenyl)hexan-1-one (1g). Yield: 68 %; H-NMR: 7.89 (2 H, d, J = 8.28), 7.23
(2 H, d, J = 8.28), 3.43 (2 H, t, J = 6.79), 2.97 (2 H, t, J = 7.35), 2.21 (2 H, d, J = 7.21). 1.95–1.88 (3
13
H, m), 1.81–1.75 (2 H, m), 1.57–1.51 (2 H, m), 0.92 (6 H, t, J = 6.62); C-NMR: 199.64, 147.44,
134.79, 129.31, 128.01, 45.38, 38.17, 33.61, 32.68, 30.11, 27.93, 23.43, 22.35.
6-Bromo-1-(4-tert-butylphenyl)hexan-1-one (1h). Yield: 60 %; 1H-NMR: 7.89 (2 H, d, J = 8.50), 7.47
(2 H, d, J = 8.52), 3.41 (2 H, t, J = 6.79), 2.96 (2 H, t, J = 7.35), 1.94–1.88 (2 H, m), 1.79–1.73 (2 H,
m), 1.56–1.50 (2 H, m), 1.34 (9 H, s); 13C-NMR: 199.60, 156.68, 134.44, 128.00, 125.53, 38.18, 35.10,
33.62, 32.68, 31.12, 27.94, 23.46.
1
5-Bromo-1-phenylpentan-1-one (1i). Yield: 11 %; H-NMR: 7.96–7.94 (2 H, m), 7.58–7.54 (1 H, m),
7.48–7.45 (2 H, m), 3.38 (2 H, t, J = 6.62), 3.03–3.00 (2 H, m), 1.99–1.87 (4 H, m) [Lit. [13] CDCl3:

Molecules 2008, 13
1095
13
7.90–7.10 (5 H, m), 3.40 (2 H, t), 2.99 (2 H, t), 1.91 (4 H, m)]; C-NMR: 199.53, 136.80, 133.05,
128.59, 127.97, 37.38, 33.29, 32.16, 22.72.
5-Bromo-1-(4-methylphenyl)pentan-1-one (1j). Yield: 57 %; 1H-NMR: 7.83 (2 H, d, J = 8.20), 7.23 (2
H, d, J = 7.88), 3.43–3.41 (2 H, m), 2.97–2.94 (2 H, m), 2.38 (3 H, s), 1.94–1.84 (4 H, m); 13C-NMR:
199.16, 143.83, 134.38, 129.29, 128.13, 37.29, 33.41, 32.25, 22.86, 21.63.
1
5-Bromo-1-(4-ethylphenyl)pentan-1-one (1k). Yield: 68 %; H-NMR: 7.78 (2 H, d, J = 8.03), 7.17 (2
H, d, J = 8.03), 3.34–3.31 (2 H, m), 2.88–2.85 (2 H, m), 2.62–2.57 (2 H, m), 1.84–1.76 (4 H, m), 1.15
(3 H, t, J = 7.53); 13C-NMR: 199.19, 150.02, 134.66, 128.29, 128.15, 37.35, 33.39, 32.32, 28.98,
22.93, 15.25.
1
5-Bromo-1-(4-n-propylphenyl)pentan-1-one (1l). Yield: 55 %; H-NMR: 7.87 (2 H, d, J = 8.33), 7.26
(2 H, d, J = 8.45), 3.46–3.43 (2 H, m), 3.00–2.97 (2 H, m), 2.66–2.62 (2 H, m), 1.99–1.85 (4 H, m),
1.71–1.61 (2 H, m), 0.94 (3 H, t, J = 7.33); 13C-NMR: 199.26, 148.54, 134.63, 128.72, 128.15, 38.02,
37.32, 33.38, 32.27, 24.23, 22.88, 13.77.
1
5-Bromo-1-(4-iso-propylphenyl)pentan-1-one (1m). Yield: 33 %; H-NMR: 7.88 (2 H, d, J = 8.20),
7.30 (2 H, d, J = 8.20), 3.45 (2 H, t, J = 6.62), 2.99–2.93 (3 H, m), 1.98–1.85 (4 H, m), 1.26 (6 H, d, J
= 6.94); 13C-NMR: 199.21, 154.57, 134.74, 128.28, 126.70, 37.31, 34.23, 33.38, 32.25, 23.67, 22.87.
5-Bromo-1-(4-n-butylphenyl)pentan-1-one (1n). Yield: 37 %; 1H-NMR: 7.78 (2 H, d, J = 8.33), 7.16 (2
H, d, J = 8.43), 3.36–3.33 (2 H, m), 2.90–2.87 (2 H, m), 2.59–2.55 (2 H, m), 1.89–1.75 (4 H, m), 1.56–
1.48 (2 H, m), 1.31–1.22 (2 H, m), 0.84 (3 H, t, J = 7.37); 13C-NMR: 199.18, 148.77, 134.60, 128.67,
128.18, 37.31, 35.69, 33.38, 33.26, 32.29, 22.89, 22.35, 13.93.
5-Bromo-1-(4-iso-butylphenyl)pentan-1-one (1o). Yield: 51 %; 1H-NMR: 7.87 (2 H, d, J = 8.21), 7.23
(2 H, d, J = 8.14), 3.46–3.43 (2 H, m), 3.00–2.97 (2 H, m), 2.53 (2 H, d, J = 7.22), 1.97–1.86 (5 H, m),
0.90 (6 H, d, J = 6.65); 13C-NMR: 199.29, 147.61, 134.66, 129.37, 128.03, 45.41, 37.34, 33.42, 32.30,
30.15, 22.89, 22.38.
5-Bromo-1-(4-tert-butylphenyl)pentan-1-one (1p). Yield: 58 %; 1H-NMR: 7.81 (2 H, d, J = 8.66), 7.39
13
(2 H, d, J = 8.67), 3.37–3.34 (2 H, m), 2.91–2.88 (2 H, m), 1.90–1.77 (4 H, m), 1.25 (9 H, s); C-
NMR: 199.22, 156.81, 134.31, 128.02, 125.58, 37.32, 35.12, 33.38, 32.27, 31.11, 22.89.
1
4-Bromo-1-phenylbutan-1-one (1q). Yield: 38 %; H-NMR: 7.85–7.83 (2 H, m), 7.45–7.41 (1 H, m),
7.34–7.31 (2 H, m), 3.41 (2 H, t, J = 6.38), 3.03 (2 H, t, J = 6.93), 2.19–2.14 (2 H, m) [Lit. [12] CDCl3:
8.00–7.96 (2 H, m), 7.60–7.50 (1 H, m), 7.48–7.44 (2 H, m), 3.55 (2 H, t, J = 6.60), 3.19 (2 H, t, J =
6.60), 2.36–2.27 (2 H, m)]; 13C-NMR: 198.36, 136.43, 132.93, 128.37, 127.72, 36.30, 33.43, 26.64.

Molecules 2008, 13
1096
1
4-Bromo-1-(4-methylphenyl)butan-1-one (1r). Yield: 52 %; H-NMR: 7.85 (2 H, d, J = 8.21), 7.23 (2
H, d, J = 7.92), 3.51 (2 H, t, J = 6.43), 3.11 (2 H, t, J = 6.98), 2.38 (3 H, s), 2.29–2.24 (2 H, m); 13C-
NMR: 198.14, 143.80, 134.09, 129.13, 127.93, 36.23, 33.54, 26.82, 21.48.
4-Bromo-1-(4-ethylphenyl)butan-1-one (1s). Yield: 56 %; 1H-NMR: 7.90 (2 H, d, J = 8.24), 7.28 (2 H,
d, J = 8.21), 3.54 (2 H, t, J = 6.44), 3.15 (2 H, t, J = 6.98), 2.73–2.68 (2 H, m), 2.32–2.27 (2 H, m),
1.26 (3 H, t, J = 7.68); 13C-NMR: 198.32, 150.15, 134.51, 128.25, 128.14, 36.47, 33.74, 28.97, 27.04,
15.25.
4-Bromo-1-(4-n-propylphenyl)butan-1-one (1t). Yield: 56 %; 1H-NMR: 7.91 (2 H, d, J = 8.26), 7.28 (2
H, d, J = 8.31), 3.55 (2 H, t, J = 6.39), 3.16 (2 H, t, J = 6.95), 2.67–2.64 (2 H, m), 2.33–2.28 (2 H, m),
1.71–1.64 (2 H, m), 0.96 (3 H, t, J = 7.40); 13C-NMR: 198.22, 148.50, 134.37, 128.58, 127.99, 37.87,
36.30, 33.57, 26.86, 24.08, 13.63.
4-Bromo-1-(4-iso-propylphenyl)butan-1-one (1u). Yield: 70 %; 1H-NMR: 7.93 (2 H, d, J = 8.34), 7.33
(2 H, d, J = 8.26), 3.55 (2 H, t, J = 6.38), 3.17 (2 H, t, J = 6.93), 3.01–2.95 (1 H, m), 2.34–2.29 (2 H,
13
m), 1.28 (6 H, d, J = 6.93); C-NMR: 198.39, 154.74, 134.68, 128.29, 126.73, 36.46, 34.27, 33.68,
27.03, 23.68.
4-Bromo-1-(4-n-butylphenyl)butan-1-one (1v). Yield: 38 %; 1H-NMR: 7.80 (2 H, d, J = 8.30), 7.17 (2
H, d, J = 8.36), 3.45 (2 H, t, J = 6.40), 3.05 (2 H, t, J = 6.94), 2.58–2.55 (2 H, m), 2.22–2.17 (2 H, m),
13
1.55–1.49 (2 H, m), 1.30–1.22 (2 H, m), 0.84 (3 H, t, J = 7.38); C-NMR: 198.34, 148.90, 134.52,
128.68, 128.16, 36.46, 35.69, 33.67, 33.23, 27.04, 22.33, 13.92.
1
4-Bromo-1-(4-iso-butylphenyl)butan-1-one (1w). Yield: 51 %; H-NMR: 7.88 (2 H, d, J = 8.25), 7.22
(2 H, d, J = 8.21), 3.53 (2 H, t, J = 6.39), 3.14 (2 H, t, J = 6.94), 2.52 (2 H, d, J = 7.20), 2.31–2.26 (2
H, m), 1.93–1.85 (1 H, m), 0.90 (6 H, d, J = 6.63); 13C-NMR: 198.32, 147.60, 134.45, 129.25, 127.90,
45.28, 36.35, 33.56, 29.99, 26.92, 22.23.
1
4-Bromo-1-(4-tert-butylphenyl)butan-1-one (1x). Yield: 47 %; H-NMR: 7.92 (2 H, d, J = 8.66), 7.49
(2 H, d, J = 8.66), 3.56–3.54 (2 H, m), 3.16 (2 H, t, J = 6.93), 2.34–2.28 (2 H, m), 1.35 (9 H, s); 13C-
NMR: 198.46, 156.98, 134.21, 127.99, 125.58, 36.44, 35.12, 33.66, 31.08, 27.00.
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylhexan-1-one (2a). Yield: 22 %; mp 130 °C; IR
2942, 2363, 1680, 1596, 1448, 1318, 1180; 1H-NMR: 8.45 (1 H, s), 7.96–7.94 (2 H, m), 7.59–7.45 (7
H, m), 7.31–7.27 (4 H, m), 7.20–7.17 (2 H, m), 3.46 (2 H, d, J = 10.83), 3.00–2.97 (2 H, m), 2.85–2.83
(2 H, m), 2.62–2.59 (3 H, m), 2.17–2.14 (2 H, m), 1.79–1.76 (4 H, m), 1.61 (2 H, d, J = 13.78), 1.44–
1.41 (2 H, m); 13C-NMR: 199.92, 167.85, 145.55, 136.88, 133.09, 128.63, 128.32, 128.01, 126.69,
125.58, 78.85, 52.58, 42.61, 37.98, 26.57, 23.93, 23.43; LC/MS-MS 442.11 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)hexan-1-one (2b). Yield: 26 %; mp:
169 °C; IR: 2934, 2364, 1684, 1604, 1447, 1383, 1344, 1320, 1179; 1H-NMR: 8.44 (1 H, s), 7.81 (2 H,

Molecules 2008, 13
1097
d, J = 8.14), 7.47 (4 H, d, J = 7.70), 7.28–7.21 (6 H, m), 7.16–7.13 (2 H, m), 3.38 (2 H, d, J = 11.19),
2.92 (2 H, t, J = 7.09), 2.78–2.75 (2 H, m), 2.60–2.49 (3 H, m), 2.38 (3 H, s), 2.14–2.06 (2 H, m),
13
1.75–1.69 (4 H, m), 1.56 (2 H, d, J = 13.83), 1.41–1.34 (2 H, m); C-NMR: 199.64, 168.13, 145.62,
143.90, 134.42, 129.32, 128.32, 128.17, 126.69, 125.62, 78.90, 52.72, 42.70, 37.92, 26.68, 24.11,
23.60, 21.67; LC/MS-MS: 456.13 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)hexan-1-one (2c). Yield: 36 %; mp:
174 °C; IR: 2939, 1685, 1605, 1447, 1383, 1345, 1320, 1286, 1148; 1H-NMR: 8.48 (1 H, s), 7.86 (2 H,
d, J = 8.33), 7.51–7.49 (4 H, m), 7.30–7.26 (6 H, m), 7.19–7.16 (2 H, m), 3.38 (2 H, d, J = 11.17), 2.94
(2 H, t, J = 7.10), 2.77–2.68 (4 H, m), 2.63–2.45 (3 H, m), 2.15–2.05 (2 H, m), 1.78–1.69 (4 H, m),
1.58 (2 H, d, J = 13.44), 1.43–1.36 (2 H, m), 1.25 (3 H, t, J = 7.60); 13C-NMR: 199.65, 150.05, 145.62,
134.62, 128.31, 128.26, 128.12, 126.67, 125.59, 78.92, 42.73, 37.94, 28.95, 26.72, 24.23, 23.62, 15.23;
LC/MS-MS: 470.18 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)hexan-1-one (2d). Yield: 43 %;
mp: 172 °C; IR: 2940, 2395, 1686, 1605, 1447, 1384, 1345, 1318, 1286, 1177; 1H-NMR: 8.27 (1 H, s),
7.64 (2 H, d, J = 8.33), 7.30–7.28 (4 H, m), 7.09–7.03 (6 H, m), 6.96 (2 H, t, J = 7.34), 3.17 (2 H, d, J
= 11.10), 2.73 (2 H, t, J = 7.11), 2.56–2.53 (2 H, m), 2.44–2.23 (5 H, m), 1.95–1.85 (2 H, m), 1.57–
1.35 (8 H, m), 1.22–1.16 (2 H, m), 0.73 (3 H, t, J = 7.37); 13C-NMR: 199.64, 167.99, 148.52, 145.58,
128.69, 128.28, 128.12, 126.65, 125.55, 119.97, 52.75, 43.18, 42.71, 38.00, 37.91, 26.70, 24.21, 23.58,
13.75; LC/MS-MS: 484.24 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)hexan-1-one (2e). Yield: 43 %;
1
mp: 154 °C; IR: 2936, 2360, 1686, 1606, 1446, 1382, 1345, 1317, 1286, 1181; H-NMR (d4-MeOH):
8.53 (1 H, s), 7.91 (2 H, d, J = 8.35), 7.53–7.51 (4 H, m), 7.36 (2 H, d, J = 8.25), 7.31–7.28 (4 H, m),
7.19–7.16 (2 H, m), 3.51 (2 H, d, J = 12.19), 3.05–2.92 (7 H, m), 2.86–2.80 (1 H, m), 1.83–1.69 (8 H,
m), 1.46–1.40 (2 H, m), 1.26 (6 H, d, J = 6.93); 13C-NMR (d4-MeOH): 202.03, 156.18, 147.20, 136.14,
129.54, 129.47, 129.25, 129.19, 127.87, 127.80, 127.67, 127.13, 79.87, 53.91, 42.96, 38.90, 35.51,
27.33, 25.50, 25.16, 24.80, 24.09; LC/MS-MS: 484.24 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)hexan-1-one (2f). Yield: 41 %; mp:
142 °C; IR: 2947, 2337, 1684, 1606, 1446, 1383, 1345, 1316, 1285, 1177; 1H-NMR (d4-MeOH): 8.53
(1 H, s), 7.90 (2 H, d, J = 8.27), 7.53–7.51 (4 H, m), 7.32–7.28 (6 H, m), 7.18 (2 H, t, J = 7.32), 3.52 (2
H, d, J = 12.35), 3.05–2.93 (6 H, m), 2.85–2.81 (1 H, m), 2.69–2.66 (2 H, m), 1.84–1.70 (8 H, m),
1.65–1.59 (2 H, m), 1.46–1.33 (4 H, m), 0.94 (3 H, t, J = 7.34); 13C-NMR (d4-MeOH): 204.60, 152.84,
149.71, 138.49, 132.38, 132.32, 131.92, 131.87, 131.70, 130.18, 129.63, 82.37, 56.42, 45.46, 39.13,
37.09, 29.81, 28.02, 27.66, 27.28, 25.88, 16.78; LC/MS-MS: 498.24 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)hexan-1-one (2g). Yield: 43 %;
mp: 201 °C; IR: 2940, 2357, 1684, 1605, 1446, 1385, 1345, 1286, 1177; 1H-NMR (d4-MeOH): 8.54 (1
H, s), 7.91 (2 H, d, J = 8.29), 7.54–7.52 (4 H, m), 7.32–7.29 (6 H, m), 7.20–7.17 (2 H, m), 3.52 (2 H,
d, J = 12.22), 3.06–2.94 (6 H, m), 2.86–2.81 (1 H, m), 2.56 (2 H, d, J = 7.22), 1.96–1.72 (10 H, m),

Molecules 2008, 13
1098
13
1.48–1.42 (2 H, m), 0.92 (6 H, d, J = 6.63); C-NMR (d4-MeOH): 200.20, 149.13, 147.16, 136.06,
130.54, 129.18, 127.68, 127.12, 79.88, 53.96, 46.29, 42.97, 31.35, 27.27, 25.55, 25.52, 25.18, 24.71,
22.67; LC/MS-MS: 498.23 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)hexan-1-one (2h). Yield 56 %; mp
67 °C; IR 2962, 2359, 1677, 1603, 1447, 1271, 1191; 1H-NMR (d4-MeOH) 8.48 (1 H, s), 7.92 (2 H, d,
J = 8.49), 7.54–7.51 (6 H, m), 7.31–7.28 (4 H, m), 7.18 (2 H, t, J = 7.30), 3.53 (2 H, d, J = 12.10),
13
3.07–2.96 (6 H, m), 2.86–2.81 (1 H, m), 1.84–1.74 (8 H, m), 1.47–1.41 (2 H, m), 1.34 (9 H, s); C-
NMR (d4-MeOH) 202.08, 158.30, 147.16, 135.67, 129.19, 127.65, 127.11, 126.73, 112.07, 79.86,
53.87, 42.89, 38.89, 36.00, 31.49, 27.26, 25.07, 24.80, 24.77; LC/MS-MS 498.23 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylpentan-1-one (2i). Yield: 25 %; mp: 143 °C;
1
IR: 3059, 2954, 2361, 1682, 1595, 1446, 1388, 1341, 1206; H-NMR: 8.31 (1 H, s), 7.81–7.79 (2 H,
m), 7.45–7.42 (1 H, m), 7.38–7.37 (4 H, m), 7.35–7.32 (2 H, m), 7.17–7.14 (4 H, m), 7.06–7.03 (2 H,
m), 3.33 (2 H, d, J = 11.67), 2.92–2.90 (2 H, m), 2.76–2.73 (2 H, m), 2.51–2.43 (3 H, m), 2.05–1.96 (2
H, m), 1.70–1.61 (4 H, m), 1.47 (2 H, d, J = 14.19); 13C-NMR: 199.46, 145.57, 136.68, 133.22,
128.66, 128.30, 127.98, 126.67, 125.58, 78.84, 52.64, 42.63, 37.60, 23.76, 21.24; LC/MS-MS: 428.10
(M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)pentan-1-one (2j). Yield: 40 %; mp:
1
165 °C; IR: 2953, 2358, 1679, 1592, 1445, 1387, 1343, 1318, 1180; H-NMR (CDCl3 + d4-MeOH):
8.44 (1 H, s), 7.76 (2 H, d, J = 8.28), 7.43 (4 H, d, J = 7.28), 7.23–7.17 (6 H, m), 7.11–7.07 (2 H, m),
3.42 (2 H, d, J = 12.05), 2.97–2.85 (4 H, m), 2.58–2.52 (3 H, m), 2.33 (3 H, s), 2.03–1.90 (2 H, m),
1.72–1.67 (4 H, m), 1.52 (2 H, d, J = 14.56); 13C-NMR (CDCl3 + d4-MeOH): 199.21, 168.45, 145.32,
143.90, 133.78, 129.02, 127.93, 127.79, 126.25, 125.16, 78.01, 52.32, 42.18, 37.02, 23.13, 23.11,
23.06, 21.26, 20.79, 20.74; LC/MS-MS: 442.20 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)pentan-1-one (2k). Yield: 30 %; mp:
1
167 °C; IR 2953, 2362, 1678, 1605, 1446, 1388, 1342, 1318, 1178; H-NMR (CDCl3 + d4-MeOH):
8.38 (1 H, s), 7.78 (2 H, d, J = 8.34), 7.42 (4 H, d, J = 9.52), 7.23–7.19 (6 H, m), 7.11–7.08 (2 H, m),
3.36 (2 H, d, J = 11.60), 2.94–2.91 (2 H, m), 2.79–2.75 (2 H, m), 2.63 (2 H, q, J = 7.60), 2.56–2.40 (3
H, m), 2.03 (2 H, d, J = 12.51), 1.72–1.69 (4 H, m), 1.52 (2 H, d, J = 13.92), 1.18 (3 H, t, J = 7.62);
13C-NMR (CDCl3 + d4-MeOH): 199.16, 168.05, 150.19, 145.59, 134.44, 128.29, 128.21, 128.14,
126.65, 125.58, 78.86, 52.66, 42.67, 37.52, 30.92, 28.92, 23.87, 23.53, 21.38, 15.17; LC/MS-MS:
465.20 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)pentan-1-one (2l). Yield: 37 %;
mp: 166 °C; IR: 3059, 2954, 2357, 1679, 1605, 1446, 1384, 1341, 1315, 1179 1H-NMR: 8.37 (1 H, s),
7.77 (2 H, d, J = 8.24), 7.42 (4 H, d, J = 7.91), 7.22–7.16 (6 H, m), 7.10–7.07 (2 H, m), 3.34 (2 H, d, J
= 11.46), 2.93–2.90 (2 H, m), 2.75–2.73 (2 H, m), 2.57–2.42 (5 H, m), 2.06–1.97 (2 H, m), 1.68–1.48
13
(8 H, m), 0.86 (3 H, t, J = 7.31); C-NMR: 199.19, 168.15, 148.67, 145.67, 134.46, 128.74, 128.26,

Molecules 2008, 13
1099
128.12, 126.62, 125.61, 78.84, 52.62, 42.70, 38.00, 37.54, 24.19, 23.89, 23.57, 21.40, 13.75; LC/MS-
MS: 470.22 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)pentan-1-one (2m). Yield: 33 %;
mp: 166 °C; IR: 2963, 2360, 1679, 1596, 1447, 1389, 1342, 1317, 1188; 1H-NMR: 8.37 (1 H, s), 7.80
(2 H, d, J = 8.20), 7.42 (4 H, d, J = 8.20), 7.23–7.19 (6 H, m), 7.11–7.08 (2 H, m), 3.34 (2 H, d, J =
11.98), 2.93–2.85 (3 H, m), 2.78–2.75 (2 H, m), 2.54–2.44 (3 H, m), 2.06–1.99 (2 H, m), 1.69–1.68 (4
13
H, m), 1.51 (2 H, d, J = 13.87), 1.18 (6 H, d, J = 6.94); C-NMR: 199.17, 168.13, 154.75, 145.63,
134.58, 128.29, 128.26, 126.73, 125.59, 126.64, 78.85, 42.68, 37.53, 34.24, 23.86, 23.65, 21.38;
LC/MS-MS: 470.30 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-n-butylphenyl)pentan-1-one (2n). Yield: 28 %;
mp: 157 °C; IR: 2955, 2365, 1679, 1604, 1447, 1387, 1341, 1314, 1248, 1183; 1H-NMR: 8.37 (1 H, s),
7.77 (2 H, d, J = 8.24), 7.42 (4 H, d, J = 7.41), 7.22–7.17 (6 H, m), 7.11–7.07 (2 H, m), 3.37 (2 H, d, J
= 11.56), 2.94–2.91 (2 H, m), 2.79–2.76 (2 H, m), 2.60–2.45 (5 H, m), 2.09–2.00 (2 H, m), 1.71–1.65
13
(4 H, m), 1.57–1.49 (4 H, m), 1.32–1.24 (2 H, m), 0.85 (3 H, t, J = 7.29); C-NMR: 199.17, 168.09,
148.96, 145.62, 134.41, 128.70, 128.30, 128.14, 126.65, 125.59, 78.85, 52.64, 42.66, 37.52, 35.69,
33.23, 23.84, 23.51, 22.32, 21.37, 13.91; LC/MS-MS: 484.34 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-one (2o). Yield: 29 %;
mp: 173 °C; IR: 2953, 2365, 1679, 1605, 1447, 1387, 1341, 1318, 1234, 1187; 1H-NMR: 8.47 (1 H, s),
7.87–7.85 (2 H, m), 7.52–7.50 (4 H, m), 7.30–7.19 (8 H, m), 3.45–3.43 (2 H, m), 3.03–3.01 (2 H, m),
2.85–2.84 (2 H, m), 2.64–2.53 (5 H, m), 2.16–2.11 (2 H, m), 1.94–1.89 (1 H, m), 1.78 (4 H, m), 1.60
13
(2 H, d, J = 13.64), 0.93–0.91 (6 H, m); C-NMR: 199.19, 167.96, 147.75, 145.56, 134.51, 129.38,
128.32, 127.99, 126.69, 125.58, 78.90, 52.69, 45.39, 42.71, 37.53, 30.10, 23.91, 23.57, 22.34, 21.41;
LC/MS-MS: 484.34 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-tert-butylphenyl)pentan-1-one (2p). Yield: 26 %;
mp: 171 °C; IR: 2964, 2365, 1684, 1588, 1446, 1380, 1342, 1322, 1230, 1188; 1H-NMR: 8.38 (1 H, s),
7.81–7.79 (2 H, m), 7.43–7.39 (6 H, m), 7.23–7.20 (4 H, m), 7.12–7.09 (2 H, m), 3.37–3.35 (2 H, d, J
= 10.49), 2.94–2.92 (2 H, m), 2.77–2.76 (2 H, m), 2.55–2.45 (3 H, m), 2.08–2.01 (1 H, m), 1.70 (4 H,
m), 1.52 (2 H, d, J = 14.12), 1.26 (9 H, s); 13C-NMR: 199.16, 167.91, 156.99, 145.55, 134.16, 128.32,
127.97, 126.70, 125.60, 125.58, 78.90, 52.73, 52.69, 42.70, 37.54, 35.13, 31.09, 23.89, 23.58, 23.55,
21.42; LC/MS-MS: 484.31 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylbutan-1-one (2q). Yield: 18 %; mp: 175 °C;
IR: 2358, 1681, 1596, 1489, 1447, 1365, 1345, 1065; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 8.00–7.99 (2
H, m), 7.61 (1 H, t, J = 7.41), 7.54–7.49 (6 H, m), 7.32–7.28 (4 H, m), 7.18 (2 H, t, J = 7.36), 3.57 (2
H, d, J = 12.26), 3.20–3.17 (2 H, m), 3.12–3.09 (2 H, m), 3.01–2.96 (2 H, m), 2.88–2.82 (1 H, m),
2.13–2.07 (2 H, m), 1.86–1.72 (4 H, m) [Lit. [14] 200 MHz, CDCl3: 7.90–7.05 (15 H, m), 2.89 (4 H,
13
m), 2.31 (3 H, m), 1.98–1.77 (4 H, m), 1.52–1.20 (4 H, m)]; C-NMR (d4-MeOH): 198.98, 145.82,

Molecules 2008, 13
1100
136.52, 133.16, 128.42, 127.79, 127.71, 126.26, 125.71, 78.49, 55.98, 52.63, 47.64, 41.59, 34.77,
24.17, 18.35; LC/MS-MS: 414.18 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)butan-1-one (2r). Yield: 13 %; mp:
191 °C; IR: 2358, 1681, 1596, 1489, 1447, 1365, 1345, 1065; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 7.89
(2 H, d, J = 8.24), 7.54–7.52 (4 H, m), 7.32–7.28 (6 H, m), 7.18 (2 H, t, J = 7.35), 3.56 (2 H, d, J =
12.32), 3.16–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.88–2.82 (1 H, m), 2.40 (3 H, s), 2.10–2.06 (2 H, m),
13
1.86–1.71 (4 H, m); C-NMR (d4-MeOH): 200.22, 147.24, 145.74, 133.45, 130.44, 129.30, 129.21,
127.67, 127.12, 79.90, 54.03, 43.00, 25.57, 21.66, 19.76, 19.70; LC/MS-MS: 428.32 (M+H+) [Lit.
[15] 428 (M+H+)].
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)butan-1-one (2s). Yield: 20 %; mp:
204 °C; IR: 2968, 2358, 1687, 1606, 1446, 1388, 1346, 1183; 1H-NMR (d4-MeOH): 8.52 (1 H, s), 7.92
(2 H, d, J = 8.33), 7.54–7.52 (4 H, m), 7.35–7.28 (6 H, m), 7.19–7.16 (2 H, m), 3.56 (2 H, d, J =
12.34), 3.17–3.08 (4 H, m), 3.01–2.95 (2 H, m), 2.87–2.81 (1 H, m), 2.74–2.69 (2 H, m), 2.12–2.06 (2
H, m), 1.85–1.72 (4 H, m), 1.25 (3 H, t, J = 7.62); 13C-NMR (d4-MeOH): 200.19, 151.95, 147.19,
135.67, 129.40, 129.28, 129.18, 127.67, 127.12, 79.91, 54.09, 43.02, 36.08, 29.89, 25.62, 19.87, 15.70;
LC/MS-MS: 442.32 (M+H+) [Lit. [15] 442 (M+H+)].
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)butan-1-one (2t). Yield: 10 %; mp:
182 °C; IR: 3182, 2359, 1684, 1602, 1446, 1388, 1347; 1H-NMR (d4-MeOH): 8.54 (1 H, s), 7.92 (2 H,
d, J = 8.31), 7.55–7.53 (4 H, m), 7.34–7.29 (6 H, m), 7.20–7.17 (2 H, t, J = 7.35), 3.56 (2 H, d, J =
12.20), 3.18–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.87–2.82 (1 H, m), 2.69–2.66 (2 H, m), 2.11–2.07 (2
H, m), 1.83–1.64 (6 H, m), 0.95 (3 H, t, J = 7.38); 13C-NMR (d4-MeOH): 200.21, 150.33, 147.21,
135.71, 129.91, 129.31, 129.18, 127.66, 127.12, 79.91, 57.50, 54,08, 43.04, 38.96, 36.10, 25.62, 25.37,
19.89, 19.83, 14.02; LC/MS-MS: 456.24 (M+H+) [Lit. [15] 456 (M+H+)].
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)butan-1-one (2u). Yield: 32 %;
mp: 189 °C; IR: 2960, 2366, 1691, 1596, 1446, 1345, 1189, 1062; 1H-NMR (d4-MeOH): 8.52 (1 H, s),
7.92 (2 H, d, J = 8.38), 7.54–7.52 (4 H, m), 7.37 (2 H, d, J = 8.26), 7.30 (4 H, t, J = 7.76), 7.19–7.16 (2
H, m), 3.56 (2 H, d, J = 12.30), 3.17–3.08 (4 H, m), 3.00–2.95 (3 H, m), 2.87–2.81 (1 H, m), 2.11–2.06
13
(2 H, m), 1.85–1.72 (4 H, m), 1.27 (6 H, t, J = 6.92); C-NMR (d4-MeOH): 200.24, 156.44, 147.21,
135.82, 129.45, 129.19, 127.86, 127.67, 127.12, 79.90, 57.43, 54,06, 43.02, 36.10, 35.53, 25.59, 24.04,
19.80; LC/MS-MS: 456.38 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)butan-1-one (2v). Yield: 6 %; mp:
161 °C; IR: 2963, 1687, 1607, 1448, 1362, 1182, 1139; 1H-NMR (d4-MeOH): 8.54 (1 H, s), 7.91 (2 H,
d, J = 8.30), 7.54–7.52 (4 H, m), 7.33–7.28 (6 H, m), 7.18 (2 H, t, J = 7.33), 7.19–7.16 (2 H, m), 3.55
(2 H, d, J = 12.29), 3.16–3.06 (4 H, m), 2.98–2.93 (2 H, m), 2.87–2.81 (1 H, m), 2.70–2.67 (2 H, m),
2.12–2.06 (2 H, m), 1.85–1.71 (4 H, m), 1.65–1.59 (2 H, m), 1.40–1.32 (2 H, m), 0.94 (3 H, t, J =
7.40); 13C-NMR (d4-MeOH): 200.23, 150.56, 147.23, 135.67, 129.85, 129.32, 129.18, 127.65, 127.12,

Molecules 2008, 13
1101
79.92, 57.50, 54,08, 43.07, 36.61, 36.11, 34.52, 25.62, 23.33, 19.91, 14.22; LC/MS-MS: 470.17
(M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)butan-1-one (2w). Yield: 20 %;
mp: 155 °C; IR: 2956, 1689, 1605, 1448, 1385, 1316, 1193; 1H-NMR (d4-MeOH): 8.55 (1 H, s), 7.93
(2 H, d, J = 8.28), 7.55–7.53 (4 H, m), 7.33–7.29 (6 H, m), 7.19 (2 H, t, J = 7.33), 3.56 (2 H, d, J =
12.35), 3.18–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.88–2.83 (1 H, m), 2.56 (2 H, d, J = 7.23), 2.13–2.07
13
(2 H, m), 1.96–1.73 (5 H, m), 0.92 (6 H, d, J = 6.63); C-NMR (d4-MeOH): 195.87, 149.37, 147.20,
135.75, 130.54, 129.18, 127.66, 127.12, 79.92, 54.11, 46.30, 43.05, 36.10, 31.35, 25.66, 22.66, 19.90,
19.85; LC/MS-MS: 470.17 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)butan-1-one (2x). Yield: 27 %;
mp: 175 °C; IR: 2961, 2330, 1691, 1590, 1447, 1383, 1346, 1192; 1H-NMR (d4-MeOH): 8.39 (1 H, s),
7.93 (2 H, d, J = 8.58), 7.55–7.53 (6 H, m), 7.31–7.28 (4 H, m), 7.19–7.16 (2 H, m), 3.59 (2 H, d, J =
12.22), 3.18–3.12 (4 H, m), 3.04–3.00 (2 H, m), 2.89–2.84 (1 H, m), 2.13–2.07 (2 H, m), 1.89–1.80 (2
H, m), 1.74–1.71 (2 H, m), 1.34 (9 H, s); 13C-NMR (d4-MeOH): 200.12, 168.28, 158.52, 147.21,
135.34, 129.21, 127.67, 127.10, 126.75, 79.87, 53.88, 42.88, 36.08, 36.02, 31.49, 25.40, 19.66;
LC/MS-MS: 470.03 (M+H+) [Lit. 470 (M+H+)] [15].
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylhexan-1-ol (3a). Yield: 83 %; mp: 80 °C; IR:
1
2941, 2503, 1492, 1448, 1345, 1066; H-NMR (d4-MeOH): 7.52 (4 H, d, J = 7.80), 7.32–7.28 (8 H,
m), 7.24–7.21 (1 H, m), 7.19–7.16 (2 H, m), 4.61–4.59 (1 H, m), 3.52 (2 H, d, J = 12.23), 3.03–2.96 (4
13
H, m), 2.88–2.82 (1 H, m), 1.82–1.66 (8 H, m), 1.49–1.29 (4 H, m); C-NMR (d4-MeOH): 146.97,
146.31, 129.16, 129.05, 128.12, 127.53, 126.95, 126.91, 79.65, 74.79, 58.06, 53.90, 42.67, 39.71,
27.44, 26.21, 25.61, 24.93; LC/MS-MS: 444.21 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)hexan-1-ol (3b). Yield: 62 %; mp: 71
°C; IR: 2941, 2361, 1593, 1491, 1447, 1335, 1066; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 7.51 (4 H, d, J
= 7.39), 7.31–7.28 (4 H, m), 7.21–7.16 (4 H, m), 7.12 (2 H, d, J = 7.92), 4.55 (1 H, t, J = 6.62), 3.48 (2
H, d, J = 12.38), 2.98–2.89 (4 H, m), 2.84–2.78 (1 H, m), 2.30 (3 H, s), 1.81–1.63 (8 H, m), 1.47–1.27
(4 H, m); 13C-NMR (d4-MeOH): 170.17, 147.20, 143.39, 137.98, 129.91, 129.20, 127.68, 127.12,
127.07, 79.88, 74.85, 53.92, 42.99, 39.82, 27.68, 26.42, 25.56, 25.53, 25.24, 21.17; LC/MS-MS:
458.21 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)hexan-1-ol (3c). Yield: 82 %; mp: 75
°C; IR: 2936, 2364, 1595, 1447, 1359, 1066; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 7.53–7.51 (4 H, m),
7.31–7.27 (4 H, m), 7.22 (2 H, d, J = 8.04), 7.19–7.14 (4 H, m), 4.56 (1 H, t, J = 6.62), 3.48 (2 H, d, J
= 12.67), 2.99–2.90 (4 H, m), 2.85–2.79 (1 H, m), 2.63–2.59 (2 H, q, J = 7.61), 1.83–1.63 (8 H, m),
13
1.47–1.27 (4 H, m), 1.21 (3 H, t, J = 7.59); C-NMR (d4-MeOH): 147.21, 144.55, 143.66, 129.20,
128.76, 127.67, 127.15, 127.11, 79.87, 74.87, 53.87, 42.95, 39.82, 29.57, 27.67, 26.43, 25.50, 25.18,
16.32; LC/MS-MS: 472.21 (M+H+).

Molecules 2008, 13
1102
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)hexan-1-ol (3d). Yield: 71 %; mp:
1
73 °C; IR: 2933, 2364, 1596, 1448, 1334, 1179, 1064; H-NMR (d4-MeOH): 8.54 (1 H, s), 7.52–7.51
(4 H, m), 7.31–7.27 (4 H, m), 7.22 (2 H, d, J = 8.05), 7.19–7.12 (4 H, m), 4.56 (1 H, t, J = 6.55), 3.45
(2 H, d, J = 12.32), 2.95–2.78 (5 H, m), 2.57–2.54 (2 H, m), 1.80–1.58 (10 H, m), 1.46–1.28 (4 H, m),
0.92 (3 H, t, J = 7.38); 13C-NMR (d4-MeOH): 145.80, 142.28, 141.43, 127.98, 127.76, 126.23, 125.69,
125.63, 120.00, 79.47, 73.45, 56.54, 52.53, 41.65, 38.39, 37.32, 26.28, 25.03, 24.41, 24.17, 23.88,
12.68; LC/MS-MS: 486.27 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)hexan-1-ol (3e). Yield: 75 %;
mp: 62 °C; IR: 2961, 2364, 1597, 1448, 1333, 1180, 1064; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 7.51 (4
H, d, J = 8.15), 7.31–7.28 (4 H, m), 7.23 (2 H, d, J = 8.12), 7.19–7.16 (4 H, m), 4.58–4.55 (1 H, m),
3.47 (2 H, d, J = 11.87), 2.98–2.79 (6 H, m), 1.80–1.63 (7 H, m), 1.47–1.24 (4 H, m), 1.23 (6 H, d, J =
13
6.93); C-NMR (d4-MeOH): 149.17, 147.19, 143.81, 129.20, 127.68, 127.29, 127.12, 79.88, 74.86,
53.91, 42.98, 39.81, 35.14, 27.68, 26.45, 25.54, 25.23, 24.54; LC/MS-MS: 486.34 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)hexan-1-ol (3f). Yield: 55 %; mp: 64
1
°C; IR 2930, 2356, 1595, 1448, 1341, 1068; H-NMR (d4-MeOH): 8.54 (1 H, s), 7.51 (4 H, d, J =
7.37), 7.31–7.27 (4 H, m), 7.22 (2 H, d, J = 8.04), 7.19–7.12 (4 H, m), 4.56 (1 H, m), 3.44 (2 H, d, J =
12.00), 2.93–2.76 (5 H, m), 2.58 (2 H, t, J = 7.72), 1.79–1.54 (10 H, m), 1.46–1.29 (6 H, m), 0.93 (3 H,
t, J = 7.40); 13C-NMR (d4-MeOH): 147.24, 143.66, 143.08, 129.35, 129.19, 127.67, 127.14, 79.91,
74.90, 54.01, 43.14, 39.81, 36.33, 35.07, 27.74, 26.47, 25.67, 25.38, 23.36, 14.32; LC/MS-MS: 500.45
(M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)hexan-1-ol (3g). Yield: 76 %; mp:
1
70 °C; IR: 2953, 1596, 1447, 1339, 1168, 1065; H-NMR (d4-MeOH): 8.55 (1 H, s), 7.53–7,52 (4 H,
m), 7.32–7.29 (4 H, m), 7.25–7.17 (4 H, m), 7.11 (2 H, d, J = 8.05), 4.59–4.57 (1 H, m), 3.48 (2 H, d, J
= 12.41), 2.98–2.79 (5 H, m), 2.47–2.45 (2 H, d, J = 7.18), 1.87–1.64 (9 H, m), 1.49–1.29 (4 H, m),
0.90 (6 H, d, J = 6.62); 13C-NMR (d4-MeOH): 147.17, 143.76, 141.87, 130.05, 129.18, 127.67, 127.11,
126.93, 79.89, 74.88, 53.94, 46.13, 43.01, 39.76, 31.50, 27.66, 26.43, 25.25, 22.71, 19.23; LC/MS-MS:
500.19 (M+H+).
6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)hexan-1-ol (3h). Yield: 69 %; mp:
1
73 °C; IR: 2957, 2365, 1597, 1447, 1341, 1171, 1066; H-NMR (d4-MeOH): 8.52 (1 H, s), 7.53–7.52
(4 H, m), 7.37 (2 H, d, J = 8.41), 7.32–7.25 (6 H, m), 7.20–7.17 (2 H, m), 4.59–4.57 (1 H, m), 3.50 (2
H, d, J = 12.34), 3.02–2.94 (4 H, m), 2.86–2.80 (1 H, m), 1.83–1.65 (8 H, m), 1.49–1.32 (4 H, m), 1.31
(9 H, s); 13C-NMR (d4-MeOH): 169.85, 151.33, 147.13, 143.35, 129.20, 127.69, 127.10, 126.84,
126.16, 79.88, 74.76, 53.87, 49.04, 42.90, 39.74, 35.32, 31.85, 27.63, 26.41, 25.14; LC/MS-MS:
500.33 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylpentan-1-ol (3i). Yield: 75 %; mp: 182 °C; IR:
1
2778, 2361, 1629, 1448, 1356, 1064; H-NMR (d4-MeOH): 8.55 (2 H, s), 7.52–7.50 (4 H, m), 7.34–
7.27 (8 H, m), 7.24–7.20 (1 H, m), 7.18–7.15 (2 H, m), 4.61 (1 H, t, J = 5.78), 3.45 (2 H, d, J = 12.37),
13
2.95–2.76 (5 H, m), 1.84–1.65 (8 H, m), 1.51–1.29 (3 H, m); C-NMR (d4-MeOH): 147.20, 146.29,

Molecules 2008, 13
1103
129.34, 129.15, 128.32, 127.63, 127.11, 127.02, 79.89, 74.71, 53.93, 43.11, 39.53, 25.56, 25.28, 24.13;
LC/MS-MS: 430.14 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)pentan-1-ol (3j). Yield: 71 %; mp:
84 °C; IR: 3340, 2951, 2361, 1595, 1491, 1447, 1330, 1173; 1H-NMR: 8.41 (1 H, s), 7.49 (4 H, d, J =
7.53), 7.29–7.25 (4 H, m), 7.20–7.09 (6 H, m), 4.61–4.60 (1 H, m), 3.41–3.38 (2 H, m), 2.82–2.80 (2
H, m), 2.58–2.55 (3 H, m), 2.31 (3 H, s), 2.15–2.08 (2 H, m), 1.82–1.67 (4 H, m), 1.54 (2 H, d, J =
13.11), 1.44–1.35 (2 H, m); 13C-NMR: 168.26, 145.65, 141.87, 136.90, 129.04, 128.29, 126.62,
125.78, 125.59, 78.74, 73.28, 52.47, 42.43, 38.27, 23.64, 23.05, 21.12; LC/MS-MS: 444.38 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)pentan-1-ol (3k). Yield: 80 %; mp: 70
1
°C; IR: 2933, 1595, 1447, 1341, 1065; H-NMR (d4-MeOH): 8.46 (1 H, s), 7.49 (4 H, d, J = 8.27),
7.28–7.25 (4 H, m), 7.21 (2 H, d, J = 8.01), 7.16–7.12 (4 H, m), 4.56 (1 H, t, J = 6.90), 3.46 (2 H, d, J
= 12.17), 2.99–2.90 (4 H, m), 2.82–2.78 (1 H, m), 2.58 (1 H, q, J = 7.58), 1.79–1.65 (8 H, m), 1.45–
13
1.27 (2 H, m), 1.17 (3 H, t, J = 7.59); C-NMR (d4-MeOH): 145.74, 143.24, 142.06, 127.79, 127.40,
126.28, 125.69, 120.02, 78.43, 73.19, 52.47, 41.45, 37.99, 36.34, 28.15, 23.67, 22.65, 14.91; LC/MS-
MS: 458.16 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)pentan-1-ol (3l). Yield: 64 %; mp:
1
83 °C; IR: 2933, 2362, 1594, 1447, 1342, 1242, 1066; H-NMR (d4-MeOH): 8.50 (1 H, s), 7.50–7.48
(4 H, m), 7.28–7.25 (4 H, m), 7.21–7.20 (2 H, m), 7.15–7.10 (4 H, m), 4.56–4.55 (1 H, m), 3.44 (2 H,
d, J = 12.59), 2.94–2.87 (4 H, m), 2.81–2.76 (1 H, m), 2.54–2.52 (1 H, m), 1.75–1.58 (10 H, m), 1.44–
1.27 (2 H, m), 0.91–0.88 (3 H, m); 13C-NMR (d4-MeOH): 147.02, 143.36, 142.79, 138.87, 129.47,
129.29, 129.03, 127.51, 127.38, 126.94, 126.86, 79.69, 74.46, 53.69, 42.78, 39.24, 38.57, 25.68, 25.32,
24.98, 23.93, 13.94; LC/MS-MS: 472.23 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)pentan-1-ol (3m). Yield: 68 %;
1
mp: 82 °C; IR: 3337, 2956, 2298, 1597, 1447, 1385, 1179; H-NMR: 8.40 (1 H, s), 7.49 (2 H, d, J =
7.54), 7.30–7.23 (6 H, m), 7.19–7.17 (4 H, m), 4.66–4.63 (1 H, m), 3.47–3.45 (2 H, m), 2.90–2.86 (3
H, m), 2.63–2.59 (3 H, m), 2.21–2.17 (2 H, m), 1.82–1.68 (4 H, m), 1.59 (2 H, d, J = 13.79). 1.51–1.41
13
(2 H, m), 1.23 (6 H, d, J = 6.92); C-NMR: 167.61, 148.08, 145.45, 142.05, 128.34, 126.71, 126.45,
125.82, 125.56, 78.82, 73.46, 42.43, 38.05, 33.79, 24.02, 23.55, 23.05; LC/MS-MS: 472.38 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-n-butylphenyl)pentan-1-ol (3n). Yield: 71 %; IR:
1
2930, 2362, 1592, 1448, 1343, 1066; H-NMR (d4-MeOH): 8.34 (1 H, s), 7.51 (4 H, d, J = 8.30),
7.31–7.27 (4 H, m), 7.23 (2 H, d, J = 8.04), 7.19–7.12 (4 H, m), 4.58 (1 H, t, J = 6.20), 3.49 (2 H, d, J
= 12.36), 3.02–2.79 (5 H, m), 2.58 (2 H, t, J = 7.72), 1.83–1.66 (8 H, m), 1.60–1.48 (2 H, m), 1.31–
13
1.29 (4 H, m), 0.92 (3 H, t, J = 7.32); C-NMR (d4-MeOH): 166.41, 145.71, 142.05, 141.77, 127.99,
127.80, 126.29, 125.69, 125.63, 78.43, 73.21, 52.43, 41.42, 37.96, 34.89, 33.65, 23.67, 22.64, 21.94,
12.89; LC/MS-MS: 486.20 (M+H+).

Molecules 2008, 13
1104
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-ol (3o). Yield: 68 %;
mp: 75 °C; IR: 2952, 2504, 1593, 1447, 1345, 1186, 1067; 1H-NMR (d4-MeOH): 8.36 (1 H, s), 7.53–
7.50 (4 H, m), 7.31–7.27 (4 H, m), 7.24 (2 H, d, J = 8.02), 7.19–7.16 (2 H, m), 7.11 (2 H, d, J = 8.11),
4.59 (1 H, t, J = 5.99), 3.49 (2 H, d, J = 12.54), 3.03–2.80 (5 H, m), 2.44 (2 H, d, J = 7.18), 1.86–1.67
13
(9 H, m), 1.50–1.29 (2 H, m), 0.88 (6 H, d, J = 6.63); C-NMR (d4-MeOH): 147.12, 143.58, 141.96,
130.10, 129.20, 127.69, 127.10, 126.90, 79.84, 74.61, 53.88, 46.11, 42.82, 39.34, 31.51, 25.07, 24.06,
22.70; LC/MS-MS: 486.27 (M+H+).
5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-tert-butylphenyl)pentan-1-ol (3p). Yield: 58 %;
mp: 88 °C; IR: 2950, 2359, 1597, 1447, 1345, 1033; 1H-NMR (d4-MeOH): 8.46 (1 H, s), 7.52–7.50 (4
H, m), 7.36 (2 H, d, J = 8.43), 7.31–7.25 (6 H, m), 7.19–7.16 (2 H, m), 4.60 (1 H, t, J = 6.84), 3.49 (2
H, d, J = 12.54), 3.02–2.94 (4 H, m), 2.86–2.80 (1 H, m), 1.84–1.67 (8 H, m), 1.49–1.32 (2 H, m), 1.29
(9 H, s); 13C-NMR (d4-MeOH): 153.94, 149.62, 145.67, 131.73, 130.23, 130.19, 129.60, 129.36,
129.33, 128.74, 82.38, 77.04, 56.43, 45.35, 41.83, 37.85, 34.37, 27.61, 26.54; LC/MS-MS: 486.27
(M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylbutan-1-ol (3q). Yield: 76 %; mp: 94 °C; IR:
2778, 2361, 2339, 1595, 1448, 1356, 1064; 1H-NMR (d4-MeOH): 8.53 (1 H, s), 7.51 (4 H, d, J = 7.56),
7.36–7.23 (9 H, m), 7.17 (2 H, d, J = 7.29), 4.68–4.66 (1 H, m), 3.45–3.44 (2 H, m), 3.02–2.99 (2 H,
m), 2.92–2.78 (3 H, m), 1.84–1.67 (8 H, m) [Lit. [14] 200 MHz, CDCl3: 7.67–7.11 (15 H, m), 4.60 (1
H, m), 3.43 (1 H, d, J = 7.00), 3.12 (1 H, d, J = 11.00), 2.94 (1 H, d, J = 11.00), 2.51–2.34 (5 H, m),
2.15–1.74 (4 H, m), 1.62–1.44 (4 H, m)]; 13C-NMR (d4-MeOH): 147.21, 145.98, 129.43, 129.17,
128.46, 127.65, 127.09, 126.91, 79.89, 74.27, 54.03, 53.91, 43.05, 37.21, 25.57, 22.08, 21.89; LC/MS-
MS: 416.21 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)butan-1-ol (3r). Yield: 45 %; mp: 97
1
°C; IR: 2355, 1595, 1447, 1356, 1063; H-NMR (d4-MeOH): 8.54 (1 H, s), 7.52 (4 H, d, J = 7.90),
7.32–7.29 (4 H, m), 7.24 (2 H, d, J = 8.00), 7.20–7.14 (4 H, m), 4.65–4.63 (1 H, m), 3.48–3.45 (2 H,
m), 3.04–3.00 (2 H, m), 2.94–2.79 (3 H, m), 2.31 (3 H, s), 1.83–1.68 (8 H, m); 13C-NMR (d4-MeOH):
170.06, 147.18, 142.87, 138.23, 130.02, 129.18, 127.66, 127.09, 126.89, 79.89, 74.14, 54.03, 53.91,
43.02, 37.13, 25.60, 22.08, 21.89, 21.12; LC/MS-MS: 430.14 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)butan-1-ol (3s). Yield: 41 %; mp: 99
1
°C; IR: 2959, 1596, 1490, 1447, 1344, 1066; H-NMR (d4-MeOH): 8.55 (1 H, s), 7.52 (4 H, d, J =
7.83), 7.31–7.25 (6 H, m), 7.19–7.17 (4 H, m), 4.65–4.63 (1 H, m), 3.41–3.36 (2 H, m), 2.95–2.91 (2
H, m), 2.79–2.76 (3 H, m), 2.65–2.60 (2 H, m), 1.82–1.66 (8 H, m), 1.21 (3 H, t, J = 7.61); 13C-NMR
(d4-MeOH): 170.26, 147.31, 144.78, 143.23, 143.21, 129.17, 128.88, 127.63, 127.13, 127.01, 79.97,
74.28, 74.17, 58.31, 54.21, 54.08, 43.36, 37.38, 29.56, 25.82, 22.39, 22.19, 16.29; LC/MS-MS: 444.28
(M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)butan-1-ol (3t). Yield: 76 %; mp:
104 °C; IR: 2933, 2363, 1593, 1491, 1447, 1342, 1065; 1H-NMR (d4-MeOH): 8.56 (1 H, s), 7.52 (4 H,

Molecules 2008, 13
1105
d, J = 7.74), 7.31–7.25 (6 H, m), 7.19–7.15 (4 H, m), 4.64–4.63 (1 H, m), 3.38–3.32 (2 H, m), 2.90–
2.86 (2 H, m), 2.78–2.70 (3 H, m), 2.59–2.56 (2 H, m), 1.78–1.60 (8 H, m), 0.93 (3 H, t, J = 7.35); 13C-
NMR (d4-MeOH): 147.35, 143.27, 143.03, 129.49, 129.12, 127.57, 127.11, 126.91, 79.98, 74.20,
58.38, 54.26, 54.12, 43.51, 38.71, 25.90, 25.79, 22.31, 14.06; LC/MS-MS: 460.23 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)butan-1-ol (3u). Yield: 69 %;
mp: 173 °C; IR: 2959, 2363, 1606, 1446, 1327, 1176, 1071; 1H-NMR (d4-MeOH): 8.52 (1 H, s), 7.51
(4 H, d, J = 7.62), 7.31–7.26 (6 H, m), 7.21–7.16 (4 H, m), 4.65–4.63 (1 H, m), 3.47–3.45 (2 H, m),
13
3.04–3.01 (2 H, m), 2.94–2.78 (4 H, m), 1.83–1.68 (8 H, m), 1.22 (6 H, t, J = 6.93); C-NMR (d4-
MeOH): 149.42, 147.18, 143.27, 129.18, 127.67, 127.41, 127.08, 126.97, 79.86, 74.13, 53.97, 53.87,
49.01, 42.97, 37.06, 35.10, 25.52, 24.46, 22.01; LC/MS-MS: 458.13 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)butan-1-ol (3v). Yield: 65 %; mp:
175 °C; IR: 2932, 2366, 1596, 1448, 1342, 1065; 1H-NMR (d4-MeOH): 8.54 (1 H, s), 7.51 (4 H, d, J =
7.48), 7.30–7.24 (6 H, m), 7.18–7.14 (4 H, m), 4.64–4.62 (1 H, m), 3.41–3.35 (2 H, m), 2.93–2.90 (2
H, m), 2.80–2.74 (3 H, m), 2.60–2.57 (2 H, m), 1.81–1.65 (8 H, m), 1.60–1.54 (2 H, m), 1.37–1.32 (2
H, m), 0.92 (3 H, t, J = 7.40); 13C-NMR (d4-MeOH): 147.27, 143.29, 143.18, 129.45, 129.14, 127.61,
127.10, 126.92, 85.09, 79.96, 74.27, 54.08, 43.34, 37.33, 36.27, 35.01, 31.79, 25.81, 23.31, 22.37,
19.23, 14.27; LC/MS-MS: 472.20 (M+H+).
4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)butan-1-ol (3w). Yield: 68 %; mp:
177 °C; IR: 2950, 2361, 1595, 1447, 1328, 1171, 1067; 1H-NMR (d4-MeOH): 8.54 (1 H, s), 7.52–7,50
(4 H, d, J = 7.42), 7.30–7.24 (6 H, m), 7.18–7.15 (2 H, m), 7.13–7.11 (2 H, m), 4.65–4.62 (1 H, m),
3.42–3.38 (2 H, m), 2.96–2.93 (2 H, m), 2.83–2.74 (3 H, m), 2.45 (2 H, d, J = 7.18), 1.86–1.66 (9 H,
13
m), 0.88 (6 H, d, J = 6.63); C-NMR (d4-MeOH): 147.29, 143.32, 142.10, 130.18, 129.17, 127.64,
127.12, 126.81, 79.95, 74.27, 58.25, 54.15, 46.12, 43.29, 37.29, 31.52, 25.76, 22.71, 22.32; LC/MS-
MS: 472.34 (M+H+).
4-tert-Butylphenyl-6-bromohexanoate (4a). Yield: 61 %; 1H-NMR: 7.41–7.40 (2 H, d, J = 8.59), 7.03–
7.02 (2 H, d, J = 8.77), 3.47–3.44 (2 H, t, J = 6.72), 2.61–2.58 (2 H, t, J = 7.38), 1.98–1.92 (2 H, m),
1.84–1.78 (2 H, m), 1.63–1.59 (2 H, m), 1.34 (9 H, s); 13C-NMR: 172.06, 148.59, 148.36, 126.31,
120.84, 77.33, 77.06, 76.82, 34.49, 34.17, 33.43, 32.41, 31.44, 27.64, 24.12.
N-(4-tert-Butylphenyl)-6-bromohexanamide (4b). Yield: 71 %; 1H-NMR: 7.43–7.41 (2 H, d, J = 8.59),
7.34–7.32 (2 H, d, J = 8.58), 3.43–3.40 (2 H, t, J = 6.70), 2.38–2.25 (2 H, t, J = 7.38), 1.93–1.87 (2 H,
m), 1.79–1.73 (2 H, m), 1.56–1.50 (2 H, m), 1.30 (9 H, s); 13C-NMR: 170.95, 147.37, 135.09, 125.80,
119.72, 38.74, 37.37, 33.53, 32.43, 31.34, 27.72, 24.70.
4-tert-Butylphenyl-6-(4’-(hydroxydiphenylmethyl)pi-peridin-1-yl)hexanoate (5a). Yield: 52 %; IR:
3398, 2962, 2359, 1749, 1591, 1509, 1448, 1347, 1207, 1172, 1147, 1108, 1017, 951, 839, 749, 702;
1H-NMR: 8.46 (1 H, s), 7.54–7.53 (4 H, m), 7.41–7.39 (2 H, m), 7.30–7.29 (4 H, m), 7.18–7.17 (2 H,
m), 6.99–6.98 (2 H, m), 3.50 (2 H, s), 3.04–2.82 (5 H, m), 2.60–2.59 (2 H, m), 1.83–1.70 (8 H, m),
1.47 (2 H, s), 1.30 (9 H, s); 13C-NMR: 173.82, 169.06, 169.02, 149.95, 147.27, 129.25, 127.76, 127.36,

Molecules 2008, 13
1106
127.12, 122.12, 79.88, 53.77, 42.93, 35.38, 34.68, 31.94, 27.74, 27.14, 25.35, 24.85, 24.41, 24.03,
23.82; LC/MS-MS: 514.25 (M+H+).
N-(4-tert-Butylphenyl)-6-(4-(hydroxydiphenylmethyl)piperidin-1-yl)hexanamide (5b). Yield: 36 %; IR:
1
3286, 2959, 1662, 1598, 1537, 1448, 1346, 1111, 1031, 953, 839, 749, 702; H-NMR: 8.44 (1 H, s),
7.53–7.52 (4 H, d, J = 7.36), 7.46–7.44 (2 H, d, J = 8.70), 7.34–7.28 (6 H, m), 7.19–7.16 (2 H, t, J =
7.35), 3.63 (1 H, s), 3.53–3.51 (2 H, m), 3.07–2.99 (4 H, m), 2.87–2.81 (1 H, m), 2.41–2.38 (2 H, t, J =
7.16), 1.78–1.71 (8 H, m), 1.46–1.43 (2 H, m), 1.30 (9 H, s); 13C-NMR: 174.07, 148.32, 147.13,
129.20, 127.69, 127.11, 126.58, 121.09, 42.88, 42.85, 37.31, 35.25, 31.82, 27.22, 27.18, 26.06, 26.02,
24.90; LC/MS-MS: 513.27 (M+H+).
5-Bromo-1-(4-tert-butylphenyl)hexan-1-ol (6a). Yield: 74 %; 1H-NMR (d4-MeOH): 7.26–7.24 (2 H, d,
J = 7.85), 7.13–7.12 (2 H, d, J = 7.81), 4.47–4.44 (1 H, t, J = 6.80), 3.27–3.24 (2 H, t, J = 6.72), 2.43–
2.39 (1 H, m), 1.74–1.56 (4 H, m), 1.34–1.33 (4 H, m), 1.22 (9 H, s); 13C-NMR: 150.11, 141.63,
125.41, 125.08, 73.89, 38.49, 34.31, 33.64, 32.54, 31.26, 27.90, 24.86.
1-(5-Bromohexyl)-4-tert-butylbenzene (7a).
To a mixture of indium(III) chloride (33 mg) and 6a (920 mg) in dry dichloromethane
chlorodiphenylsilane (1.2 mL) was added dropwise. After stirring at room temperature for 3 hours the
solution was hydrolyzed with a little amount of water. Diethyl ether was added, the organic layer
separated and the water phase extracted with diethyl ether two times. The combined organic layers
were dried, the solvent removed under reduced pressure and the raw product was purified by column
1
chromatography (ethyl acetate/n-hexane: 1/12, followed by pure hexane). Yield: 23 %; H-NMR (d4-
MeOH): 7.26–7.24 (2 H, d, J = 8.27), 7.06–7.05 (2 H, d, J = 8.26), 3.34–3.31 (2 H, t, J = 6.83), 2.55–
2.52 (2 H, t, J = 7.88), 1.82–1.78 (2 H, m), 1.59–1.55 (2 H, m), 1.43–1.38 (2 H, m), 1.34–1.30 (2 H,
m), 1.27 (9 H, s); 13C-NMR: 148.33, 139.38, 127.97, 125.08, 35.23, 34.28, 33.78, 32.73, 31.41, 31.18,
28.45, 28.02.
(1-(6-(4-tert-Butylphenyl)hexyl)piperidin-4-yl)diphenylmethanol (8a). Yield: 40 %; IR: 2933, 2363,
1662, 1596, 1491, 1447, 1343, 1172, 1067, 955, 832, 749, 702; 1H-NMR: 7.46–7.45 (4 H, d, J = 8.49),
7.26–7.22 (6 H, t, J = 8.45), 7.14–7.11 (2 H, t, J = 7.31), 7.05–7.03 (2 H, d, J = 8.26), 3.43–3.41 (2 H,
d, J = 11.05), 2.81–2.77 (2 H, m), 2.58–2.55 (2 H, m), 2.52–2.49 (2 H, t, J = 7.85), 2.15–2.13 (2 H, m),
1.68–1.67 (2 H, m), 1.58–1.55 (4 H, m), 1.31–1.29 (4 H, m), 1.27 (9 H, s); 13C-NMR: 148.45, 145.48,
139.22, 128.27, 127.96, 126.65, 125.54, 125.12, 78.78, 52.52, 52.5, 52.46, 52.45, 45.38, 42.50, 35.13,
34.30, 31.39, 31.09, 28.72, 26.79, 23.76, 23.31, 23.27; LC/MS-MS: 485.00 (M+H+).
1-(4-iso-Butylphenyl)-5-(piperidin-1-yl)pentan-1-one (9a). Yield: 78 %; mp: 143 °C; IR: 2955, 2869,
1739, 1676, 1604, 1453, 1368, 1273, 1184, 1022; 1H-NMR: 7.93–7.91 (2 H, d, J = 8.31), 7.30–7.28 (2
H, d, J = 8.25), 3.13–3.07 (4 H, m), 2.56–2.55 (2 H, d, J = 7.23), 1.95–1.68 (12 H, m), 1.35–1.32 (1 H,
m), 0.92–0.91 (6 H, d, J = 6.63); 13C-NMR: 201.45, 149.18, 136.01, 130.53, 129.21, 64.32, 64.29,

Molecules 2008, 13
1107
58.04, 54.22, 52.98, 46.31, 38.41, 31.35, 24.60, 24.27, 22.82, 22.69, 22.15, 16.65, 16.60; LC/MS-MS:
302.93 (M+H+).
1-(4-iso-Butylphenyl)-5-(4-methylpiperidin-1-yl)pentan-1-one (9b). Yield: 21 %; IR: 2956, 2361,
1
1679, 1605, 1457, 1414, 1369, 1336, 1182, 977, 855, 759; H-NMR: 7.88–7.86 (2 H, d, J = 8.24),
7.26–7.24 (2 H, d, J = 8.19), 3.52–3.51 (2 H, m), 3.06–3.03 (2 H, t, J = 6.84), 2.99–2.96 (2 H, m),
2.64–2.54 (4 H, m), 1.93–1.75 (9 H, m), 1.63–1.62 (1 H, m), 1.04–1.02 (3 H, d, J = 6.37), 0.93–0.92 (6
13
H, d, J = 6.62); C-NMR: 199.10, 147.76, 134.45, 129.31, 127.96, 45.36, 37.37, 30.07, 23.41, 22.31,
21.19; LC/MS-MS: 315.94 (M+H+).
1-(4-iso-Butylphenyl)-5-(4-hydroxypiperidin-1-yl)-pentan-1-one (9c). Yield: 68 %; IR: 3345, 2954,
1
2495, 1735, 1679, 1605, 1465, 1414, 1372, 1239, 1181, 1042, 978, 852, 763; H-NMR: 7.90–7.88 (2
H, d, J = 8.27), 7.26–7.25 (2 H, d, J = 8.20), 3.93 (1 H, s), 3.38 (2 H, s), 3.19–3.05 (5 H, m), 2.52–2.51
13
(2 H, d, J = 7.21), 2.06–2.03 (2 H, m), 1.89–1.73 (8 H, m), 0.88–0.87 (6 H, d, J = 6.63); C-NMR:
201.44, 149.14, 136.02, 130.54, 129.23, 71.13, 57.71, 46.32, 38.47, 31.83, 31.35, 24.77, 22.72, 22.13,
20.94; LC/MS-MS: 318.11 (M+H+).
5-(4-Benzylpiperidin-1-yl)-1-(4-iso-butylphenyl) pentan-1-one (9d). Yield: 34 %; mp: 143 °C; IR:
3454, 2931, 1682, 1605, 1455, 1241, 1112; 1H-NMR: 7.86–7.84 (2 H, d, J = 8.26), 7.27–7.10 (7 H, m),
7.95–7.92 (2 H, m), 2.86 (2 H, d, J = 11.65), 2.51–2.50 (4 H, d, J = 7.21), 2.33–2.30 (2 H, m), 1.90–
1.80 (3 H, m), 1.80–1.69 (2 H, m), 1.61–1.46 (5 H, m), 1.32–1.20 (2 H, m), 0.89–0.88 (6 H, d, J =
6.62); 13C-NMR: 199.89, 147.24, 140.66, 134.76, 129.18, 129.03, 128.05, 127.98, 125.66, 77.01,
70.54, 58.67, 53.90, 45.30, 43.18, 38.25, 37.91, 32.15, 30.02, 26.69, 22.52, 22.27; LC/MS-MS: 392.07
(M+H+).
1-(4-iso-Butylphenyl)-5-(piperidin-1-yl)pentan-1-ol (10a). Yield: 94 %; mp: 64 °C; IR: 3386, 2952,
1587, 1446, 1347, 1018; 1H-NMR (d4-MeOH): 8.55 (1 H, s), 7.25–7.24 (2 H, d, J = 8.01), 7.12–7.10 (2
H, d, J = 8.36), 4.60–4.58 (1 H, m), 3.31–2.98 (3 H, m), 2.85–2.82 (2 H, m), 2.46–2.45 (2 H, d, J =
13
7.18), 1.87–1.61 (10 H, m), 1.48–1.28 (3 H, m), 0.90–0.88 (2 H, d, J = 6.62); C-NMR (d4-MeOH):
170.38, 143.64, 141.89, 130.07, 126.92, 74.61, 58.69, 54.46, 46.13, 31.50, 25.46, 25.43, 24.26, 24.15,
23.40, 22.70; LC/MS-MS: 306.92 (M+H+).
1-(4-iso-Butylphenyl)-5-(4-methylpiperidin-1-yl)pentan-1-ol (10b). Yield: 57 %; IR: 3349, 2953, 2667,
1717, 1594, 1458, 1177, 1051, 948, 848; 1H-NMR (d4-MeOH): 7.23–7.21 (2 H, d, J = 8.01), 7.11–7.09
(2 H, d, J = 7.82), 3.54–3.53 (2 H, m), 2.92–2.90 (2 H, m), 2.56–2.54 (2 H, m), 2.45–2.44 (2 H, d, J =
7.15), 1.87–1.70 (10 H, m), 1.50–1.39 (3 H, m), 1.02–1.01 (3 H, d, J = 6.47), 0.89–0.88 (6 H, d, J =
6.61); 13C-NMR: 141.75, 141.05, 129.21, 125.55, 73.65, 57.35, 52.99, 45.08, 37.98, 30.19, 23.04,
22.36, 20.97; LC/MS-MS: 318.04 (M+H+).
1-(4-iso-Butylphenyl)-5-(4-hydroxypiperidin-1-yl)-pentan-1-ol (10c). Yield: 47 %; IR: 3357, 2950,
1
2868, 2670, 1466, 1383, 1040, 973, 849, 802, 609; H-NMR: 7.28–7.27 (2 H, d, J = 8.01), 7.14–7.13
(2 H, d, J = 8.01), 4.64–4.62 (1 H, t, J = 7.19), 4.10–3.56 (2 H, m), 3.37 (1 H, s), 3.25 (1 H, s), 3.09–

Molecules 2008, 13
1108
3.06 (2 H, t, J = 8.17), 2.48–2.47 (2 H, d, J = 7.17), 2.12–1.77 (10 H, m), 1.52–1.38 (2 H, m), 0.91–
13
0.90 (6 H, d, J = 6.62); C-NMR: 143.61, 141.94, 130.10, 126.93, 74.62, 52.21, 46.13, 39.39, 31.51,
30.98, 24.07, 22.72; LC/MS-MS: 319.93 (M+H+).
5-(4-Benzylpiperidin-1-yl)-1-(4-iso-butylphenyl) pentan-1-ol (10d). Yield: 45 %; mp: 64 °C; IR: 2929,
1
2361, 1454, 1275; H-NMR (d4-MeOH): 7.30–7.17 (7 H, m), 7.12–7.10 (2 H, d, J = 7.99), 7.19–7.12
(4 H, m), 4.61–4.59 (1 H, m), 3.50–3.49 (2 H, m), 3.03–2.87 (4 H, m), 2.62–2.61 (2 H, d, J = 7.17),
13
2.62–2.61 (2 H, m), 1.89–1.71 (8 H, m), 1.52–1.47 (4 H, m), 0.89–0.88 (2 H, d, J = 6.05); C-NMR
(d4-MeOH): 143.59, 141.95, 140.50, 130.19, 130.10, 129.50, 127.40, 126.91, 74.61, 46.12, 39.36,
31.51, 25.10, 24.07, 22.71; LC/MS-MS: 394.24 (M+H+).
1-(4-iso-Butylphenyl)-5-morpholinopentan-1-one (11a). Yield: 63 %; IR: 2867, 1681, 1606, 1466,
1353, 1251, 1182, 1114, 988, 949, 861, 734; 1H-NMR: 7.85–7.83 (2 H, d, J = 8.21), 7.22–7.20 (2 H, d,
J = 8.14), 3.88–3.86 (4 H, t, J = 4.76), 3.00–2.98 (2 H, t, J = 6.22), 2.90 (4 H, s), 2.79–2.76 (2 H, t, J =
7.28), 2.52–2.50 (2 H, d, J = 7.19), 1.89–1.87 (1 H, m), 1.76–1.75 (4 H, m), 0.89–0.88 (6 H, d, J =
6.62); 13C-NMR: 199.68, 147.25, 134.66, 129.14, 127.88, 70.57, 66.73, 58.56, 53.58, 45.24, 38.06,
29.96, 25.97, 22.02, 22.14; LC/MS-MS: 304.12 (M+H+).
1-(4-iso-Butylphenyl)-5-morpholinopentan-1-ol (12a). Yield: 26 %; IR: 3422, 2952, 2868, 2465, 1722,
1599, 1514, 1466, 1366, 1264, 1105, 977, 849, 803, 620 1H-NMR: 7.26–7.24 (2 H, d, J = 8.00), 7.13–
7.11 (2 H, d, J = 8.03), 4.62–4.60 (1 H, m), 3.89 (4 H, s), 3.20 (4 H, s), 3.06–3.03 (2 H, t, J = 8.31),
2.47–2.45 (2 H, d, J = 7.18), 1.84–1.74 (5 H, m), 1.49–1.35 (2 H, m), 0.90–0.88 (6 H, d, J = 6.63) 13C-
NMR: 143.62, 141.94, 130.10, 126.92, 74.63, 71.51, 65.28, 58.56, 53.25, 46.13, 45.60, 39.43, 31.51,
24.81, 24.00, 22.71 LC/MS-MS: 306.08 (M+H+).
1-(5-(4-iso-Butylphenyl)-5-oxopentyl)piperidin-4-one (13a). Yield: 3 %; IR: 2955, 2869, 2808, 1716,
1678, 1606, 1570, 1466, 1307, 1275, 1183, 954, 846, 796; 1H-NMR: 7.93–7.90 (2 H, m), 7.30–7.28 (2
H, m), 2.79–2.76 (2 H, t, J = 6.16), 2.56–2.42 (9 H, m), 1.93–1.90 (1 H, m), 1.78–1.60 (7 H, m), 0.92–
13
0.91 (6 H, d, J = 6.63); C-NMR: 199.42, 129.34, 127.99, 70.48, 56.68, 52.04, 45.41, 39.37, 37.67,
30.04, 22.27, 21.65; LC/MS-MS: 316.15 (M+H+).
5-(3-(Hydroxydiphenylmethyl)pyrrolidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-one (15a). Yield: 36 %;
IR: 2957, 1679, 1605, 1448, 1367, 1182, 984, 751, 700; 1H-NMR: 7.79–7.77 (2 H, d, J = 8.15), 7.43–
7.40 (4 H, t, J = 8.27), 7.27–7.22 (4 H, m), 7.18–7.14 (4 H, m), 3.75–3.72 (1 H, m), 3.07–2.92 (8 H,
m), 2.49–2.47 (2 H, d, J = 7.19), 2.16–1.99 (2 H, m), 1.86–1.84 (1 H, m), 1.72–1.69 (4 H, m), 0.87–
13
0.85 (6 H, d, J = 6.62); C-NMR: 199.11, 147.86, 145.41, 134.32, 129.37, 128.65, 128.46, 127.97,
127.91, 127.04, 125.51, 125.45, 78.48, 55.24, 54.54, 45.61, 45.36, 37.28, 30.07, 25.56, 25.13, 22.30,
20.89; LC/MS-MS: 470.10 (M+H+).
5-(3-(Hydroxydiphenylmethyl)pyrrolidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-ol (16a). Yield: 48 %;
IR: 3351, 2954, 2373, 1597, 1448, 1338, 1176, 1107, 1067, 1034, 850, 750, 703; 1H-NMR: 7.45–7.42
(4 H, t, J = 7.67), 7.29–7.24 (4 H, m), 7.19–7.16 (4 H, m), 7.08–7.06 (2 H, d, J = 7.97), 4.62–4.59 (1
H, m), 3.77–3.74 (1 H, m), 2.91–2.88 (6 H, m), 2.43–2.42 (2 H, d, J = 7.14), 2.19–2.15 (2 H, m), 1.83–

Molecules 2008, 13
1109
1.79 (1 H, m), 1.76–1.64 (4 H, m), 1.46–1.35 (2 H, m), 0.87–0.86 (6 H, d, J = 6.61); 13C-NMR:
145.66, 141.83, 141.02, 129.20, 128.63, 128.47, 127.19, 127.07, 125.58, 125.52, 125.49, 78.49, 73.66,
61.84, 54.56, 54.38, 45.09, 37.95, 30.20, 25.63, 25.32, 22.91, 22.37; LC/MS-MS: 472.20 (M+H+).
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG) for the grants given to Marcel Holzer and
Sigrid Ziegler (KFO129) and the Fonds der Chemischen Industrie for financial support. Furthermore
we thank Susanne Reinhardt for the syntheses of compounds 9a, 9d, 10a and 10d.
References and Notes
1. Chisari, F. V. Unscrambling hepatitis C virus-host interactions. Nature 2005, 436, 930-932.
2. WHO Annex Table 2: deaths by cause, sex and mortality stratum in WHO regions, estimates for
2001. www.who.int/entity/whr/2002/en/whr2002_annex2002.pdf (accessed 01.2008). World
Health Report 2002.
3. VanCompernolle, S. E.; Wiznycia, A. V.; Rush, J. R.; Dhanasekaran, M.; Baures, P. W.; Todd, S.
C. Small molecule inhibition of hepatitis C virus E2 binding to CD81. Virology 2003, 314, 371-
380.
4. Ziegler, S.; Kronenberger, B.; Zeuzem, S.; Hartmann, R. W.; Klein, C. D. in preparation.
5. Pileri, P.; Uematsu, Y.; Campagnoli, S.; Galli, G.; Falugi, F.; Petracca, R.; Weiner, A. J.;
Houghton, M.; Rosa, D.; Grandi, G.; Abrignani, S. Binding of hepatitis C virus to CD81. Science
1998, 282, 938-941.
6. Carr, A.; Clyde, R. Piperidinderivate. D.E. Patent 25.06.770, 1975.
7. Pietschmann, T.; Kaul, A.; Koutsoudakis, G.; Shavinskaya, A.; Kallis, S.; Steinmann, E.; Abid,
K.; Negro, F.; Dreux, M.; Cosset, F. L.; Bartenschlager, R. Construction and characterization of
infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc. Natl. Acad. Sci.
USA 2006, 103, 7408-7413.
8. Koutsoudakis, G.; Kaul, A.; Steinmann, E.; Kallis, S.; Lohmann, V.; Pietschmann, T.;
Bartenschlager, R. Characterization of the early steps of hepatitis C virus infection by using
luciferase reporter viruses. J. Virol. 2006, 80, 5308-5320.
9. Lohmann, V.; Korner, F.; Koch, J.; Herian, U.; Theilmann, L.; Bartenschlager, R. Replication of
subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999, 285, 110-113.
10. Kato, T.; Date, T.; Miyamoto, M.; Furusaka, A.; Tokushige, K.; Mizokami, M.; Wakita, T.
Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology
2003, 125, 1808-1817.
11. Zhang, W. C.; Li, C. J. A direct retro-barbier fragmentation. J. Org. Chem. 2000, 65, 5831-5833.
12. Kawakita, T.; Kuroita, T.; Murozono, T.; Hakira, H.; Haga, H.; Ito, K.; Sonda, S.; Kawahara, S.;
Asona, K. Benzoic acid compounds and use thereof as medicaments. U.S. Patent 5,864,039, 1999.
13. Wagner, P. J.; Lindstrom, M. J.; Sedon, J. H.; Ward, D. R. Photochemistry of & Halo Ketones:
Anchimeric Assistance in Triplet-State g-Hydrogen Abstraction and b-Elimination of Halogen
Atoms from the Resulting Diradicals. J. Am. Chem. Soc. 1981, 103, 3842-3849.

Molecules 2008, 13
1110
14. Zhang, M. Q.; ter Laak, A. M.; Timmerman, H. Structure-activity relationships within a series of
analogues of the histamine H1-antagonist terfenadine. Eur. J. Med. Chem. 1993, 28, 165-173.
15. Lafite, P.; Andre, F.; Zeldin, D. C.; Dansette, P. M.; Mansuy, D. Unusual regioselectivity and
active site topology of human cytochrome P450 2J2. Biochemistry 2007, 46, 10237-10247.
Sample Availability: Contact the authors.
© 2008 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).