Design, synthesis, and biological evaluation of arylpiperazine-benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities

Article abstract of DOI:10.1016/j.bmc.2016.03.044

The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine-benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC₅₀ = 0.38 μM for NE and 1.18 μM for 5-HT). The biological activity data demonstrate that arylpiperazine-benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.

Full text of DOI:10.1016/j.bmc.2016.03.044

Accepted Manuscript
Design, synthesis, and biological evaluation of arylpiperazine–benzylpiperi-
dines with dual serotonin and norepinephrine reuptake inhibitory activities
Suresh Paudel, Srijan Acharya, Kyeong-Man Kim, Seung Hoon Cheon
PII:
S0968-0896(16)30201-2
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.03.044
BMC 12893
Reference:
Bioorganic & Medicinal Chemistry
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Received Date:
Revised Date:
Accepted Date:
7 March 2016
25 March 2016
26 March 2016
Please cite this article as: Paudel, S., Acharya, S., Kim, K-M., Cheon, S.H., Design, synthesis, and biological
evaluation of arylpiperazine–benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory
activities, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.2016.03.044
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Design, synthesis, and biological evaluation of arylpiperazine–
benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory
activities
Suresh Paudela, Srijan Acharyaa, Kyeong-Man Kim*, Seung Hoon Cheon*
College of Pharmacy and Research Institute of Drug Development, Chonnam National
University, Gwangju 500-757, Republic of Korea
Corresponding authors. Tel.: +82625302929; fax: +82625302911; e-mail: shcheon@jnu.ac.kr
(S. H. Cheon); tel.: +82625302936; fax: +82625302949; e-mail: kmkim@jnu.ac.kr (K.-M. Kim)
aThese authors contributed equally to this work.

Abstract
The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE)
reuptake inhibitors necessitate the development of safer and more effective therapeutic agents.
Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine–
benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed,
synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority
of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities
were even greater than those of the standard drug, venlafaxine hydrochloride were. The
derivatives with a three-carbon linker showed better activities than the derivatives with a two-
carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake
inhibition of the neurotransmitters (IC50 = 0.38 µM for NE and 1.18 µM for 5-HT). The
biological activity data demonstrate that arylpiperazine–benzylpiperidines have the potential to
be developed as a new class of therapeutic agents to treat neuropsychiatric and
neurodegenerative disorders.
Keywords: Arylpiperazine–benzylpiperidine, dual serotonin and norepinephrine reuptake
inhibitor, neuropsychiatric disorder, neurodegenerative disorder

1. Introduction
Serotonin and norepinephrine transporters regulate synaptic cleft concentrations of the
corresponding neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine
(NE), via a reuptake mechanism.1–5 5-HT and NE are involved in the control of human behaviors
such as mood, sleep, pain, appetite, aggression, and sexual activity.6,7 Reduction in the synaptic
levels of 5-HT and NE is associated with various neuropsychiatric and neurodegenerative
disorders, such as attention deficit hyperactivity disorder, anxiety, and depression.8–15 One of the
attractive approaches to the treatment of these disorders is inhibition of reuptake of the
neurotransmitters to increase their concentrations in the synaptic cleft.16–21
Dual 5-HT and NE reuptake inhibitors such as duloxetine, venlafaxine, and milnacipran (Fig. 1)
have been used for the treatment of disorders, including depression, anxiety, and painful
peripheral neuropathy.22–27 However, these drugs have several limitations and cause side effects.
Suicidal risk is high in patients prescribed duloxetine and venlafaxine. Duloxetine can cause
hepatotoxicity and severe cutaneous hypersensitivity reactions. Treatment with venlafaxine can
exacerbate or trigger migraines, and the patients may develop potentially life-threatening
serotonin syndrome. Moreover, all of these dual reuptake inhibitors may cause cardiac disorders
such as arterial hypertension, tachycardia, and arrhythmias.28–32
Figure 1. Some of the marketed dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine
(NE) reuptake inhibitors.
A common strategy to avoid drug-related side effects is to design molecules with a different
chemical scaffold. With this fact in mind, we successfully developed 4-benzylpiperidine

carboxamides as dual reuptake inhibitors.33 Inspired by the initial success of the 4-
benzylpiperidine carboxamides and the quest to identify safe and effective dual reuptake
inhibitors, we designed a series of arylpiperazine–benzylpiperidines (Fig. 2). An arylpiperazine–
benzylpiperidine derivative is a hybrid structure of 4-benzylpiperidine carboxamide and
trazodone. Trazodone, a 5-HT reuptake inhibitor, was considered for the design of new dual
reuptake inhibitors since it has structural similarity with 4-benzylpiperidine carboxamides (Ar1–
linker–Ar2) and exhibits a reduced onset of action with no side effects commonly displayed by
conventional selective 5-HT reuptake inhibitors.34–41 The details of the synthetic pathways
employed, biological evaluation, and structure–activity relationship of these compounds are
discussed in the following sections.
Figure 2. Design of arylpiperazine–benzylpiperidines 1 and 2.

2. Chemistry
The detailed synthetic procedures for obtaining arylpiperazine–benzylpiperidines are shown in
Scheme 1. Various aromatic amines, 3a–3h, were reacted with bis(2-chloroethyl)amine
hydrochloride to obtain 4-phenylpiperazine hydrochloride salts 4a–4h (4i–4l were commercially
available). Substitution reactions between 4-phenylpiperazines 4a–4l and 1-bromo-2-
chloroethane or 1-bromo-3-chloropropane gave various haloalkyl-4-phenylpiperazines, 5a–5l (n
= 2) and 6a–6l (n = 3). Finally, arylpiperazine–benzylpiperidines 1a–1l and 2a–2l were obtained
by substitution reactions of 5a–5l and 6a–6l with 4-benzylpiperidine, respectively.
Scheme 1. Synthesis of arylpiperazine–benzylpiperidines 1 and 2. Reagents and conditions: (i)
diethylene glycol monomethyl ether, 150 °C; (ii) K2CO3, acetone, room temperature (r.t.); (iii)
dimethyl sulfoxide (DMSO), triethylamine (TEA), 100 °C.

3. Results and discussion
3.1. Biological assay
Inhibition of 5-HT and NE reuptake was assessed using a neurotransmitter uptake assay. Human
embryonic kidney 293 (HEK-293) cells stably transfected with human serotonin transporter
(hSERT) and human norepinephrine transporter (hNET) were used in this assay. The 5-HT and
NE reuptake-inhibiting activities of the arylpiperazine–benzylpiperidines are presented in Table
1.
Table 1. Relative serotonin (5-HT) and norepinephrine (NE) reuptake inhibition by
arylpiperazine–benzylpiperidines 1a–1l (n = 2) and 2a–2l (n = 3).
Compound
R
X
C
C
C
C
C
C
C
C
C
C
N
N
Y
C
C
C
C
C
C
C
C
C
C
C
N
5-HTa NEb
Compd
2a
R
X
C
C
C
C
C
C
C
C
C
C
N
N
Y
C
C
C
C
C
C
C
C
C
C
C
N
5-HTa NEb
-H
0.89
0.93
0.27
0.41
0.41
0.56
1.01
0.85
0.69
0.64
0.31
0.33
1.0
-H
0.58
2.83
2.40
0.69
0.27
0.44
0.87
1.06
0.76
0.79
0.32
0.08
1.51
1.37
1.36
1.41
1.40
1.46
1.60
1.45
1.34
1.63
1.23
1.01
1a
1b
1c
1d
1e
1f
2,6-Me2
2-OMe
3-Cl
1.26
0.20c
1.29
1.16
1.18
1.31
1.29
1.26
0.41c
0.08c
-0.05c
2,6-Me2
2-OMe
3-Cl
2b
2c
2d
2e
4-F
4-F
4-Cl
4-Cl
2f
4-Br
4-Br
1g
1h
1i
2g
2,4-(Cl)2
4-CF3
2,3-(Cl)2
-H
2,4-(Cl)2
4-CF3
2,3-(Cl)2
-H
2h
2i
1j
2j
1k
1l
2k
2l
-H
-H
a5-HT reuptake inhibition by the test compounds at 1 µM relative to that by venlafaxine·HCl.
bNE reuptake inhibition by the test compounds at 10 µM relative to that by venlafaxine HCl.
cNE reuptake inhibition by the test compounds at 1 µM relative to that by GBR-12909.

The 5-HT reuptake-inhibiting activities of the arylpiperazine–benzylpiperidine derivatives,
measured relative to that of venlafaxine·HCl, were 0.08–2.83. Consistent with our previous
results,33 most of the arylpiperazine–benzylpiperidines with three carbon units in the linker
displayed better 5-HT reuptake inhibition than the derivatives with two carbon units.
Interestingly, the activity of 2-Me compound 1c increased significantly (9-fold) when the length
of the linker was extended from two to three carbons. However, compounds 1a, 1f, and 1l with
shorter linkers were more effective than their longer-linker analogs 2a, 2f, and 2l. The 5-HT
reuptake inhibitory activities of the derivatives with mono-halogen substitution were in the
following order: 3-Cl (1d) = 4-F (1e) < 4-Cl (1f) < 4-Br (1g) for the compounds with two-
carbon-unit linkers and 4-Br (2g) > 3-Cl (2d) > 4-Cl (2f) > 4-F (2e) for the compounds with
three-carbon-unit linkers. The derivatives with 2,4-(Cl)2 substitutions (1h and 2h) had greater
activities than the derivatives with 2,3-(Cl)2 substitutions (1j and 2j), irrespective of the linker
size. Moreover, the longer-linker derivatives with two halogen substitutions showed better
activities than the derivatives having a mono-halogen substitution (except 4-Br-substituted
compound 2g). Overall, derivative 1l with a 2-pyrimidyl ring exhibited the lowest relative
inhibition (RI) of 5-HT reuptake (RI = 0.08), while 2,6-Me2 substituted analog 2b showed the
highest relative inhibitory activity (RI = 2.83).
The relative inhibition of NE reuptake by all the synthesized compounds was equal to or greater
than that shown by the standard drugs, venlafaxine·HCl and GBR-12909, except the compounds
with heteroaromatic rings, 2-pyridyl (1k), 2-pyrimidyl (1l), 2-OMe (1c), and 2,3-(Cl)2 (1j). The
inhibitory activities of the derivatives correlated with the length of the linker. All three-carbon
linker compounds were more active than the two-carbon linker ones, which is in agreement with
our previous results.33 The activity increased significantly, 10-fold for 2-pyrimidyl (1l) and 4-
fold for 2-Me (1c) and 2,3-(Cl)2 (1j) compounds, when the linker size was increased from two to
three carbon units. The lowest reuptake inhibitory activities (RI = −0.05–0.08) were observed for
the derivatives with the heteroaromatic ring (1k and 1l), whereas moderate activities (RI = 0.20–
0.41) were shown by the derivatives with 2-OMe (1c) and 2,3-(Cl)2 (1j) substitutions.
Furthermore, the remaining compounds displayed equal or more potent activities (RI = 1–1.63)
than the standard drug, venlafaxine hydrochloride.

Derivatives 1g, 1h, 2a–2d, and 2f–2j, with the relative reuptake inhibitory activities for 5-HT ≥
0.44 and for NE ≥ 1.29, were selected for the determination of IC50. The IC50 values of the
compounds for 5-HT and NE reuptake inhibition are presented in Table 2.
Table 2. Serotonin (5-HT) and norepinephrine (NE) reuptake inhibition (IC50) by
arylpiperazine–benzylpiperidines.
Compound
R
n
2
2
3
3
3
3
3
3
3
3
3
-
5-HT (µM)
4.92
NE (µM)
2.10
2.50
0.60
1.07
0.89
0.38
0.53
0.61
0.76
1.17
0.56
2.55
4-Br
1g
2,4-(Cl)2
-H
4.32
1h
1.36
2a
2,6-Me2
2-OMe
3-Cl
2.00
2b
1.76
2c
1.18
2d
4-Cl
2.03
2f
4-Br
2.25
2g
2,4-(Cl)2
4-CF3
2,3-(Cl)2
-
1.46
2h
2.61
2i
2j
2.51
VenlafaxineHCl
0.20
The levels of inhibition of the 5-HT reuptake shown by compounds 2g and 2h confirmed that
arylpiperazine–benzylpiperidines having three carbon units in the linker were better inhibitors
than those with two carbon units (Fig. 3). Unsubstituted phenyl derivative 2a was more potent
than the 2-OMe-, 2,6-Me2-, and 4-CF3-substituted phenyl compounds (2c, 2b, and 2i,
respectively). The inhibitory activities of the compounds with mono-halogen substitution were in
the following order: 3-Cl > 4-Cl > 4-Br. However, compound 2h with 2,4-(Cl)2 was more potent
than the 2,3-(Cl)2 derivative (2j).

The NE reuptake-inhibiting activities of all the arylpiperazine-benzylpiperidines were greater
than that of the standard drug, venlafaxine hydrochloride. The data obtained for derivatives 2g
and 2h confirmed that derivatives with three carbon units were more active than those with a
two-carbon-unit linker were.
Figure 3. Structure–activity relationship (SAR) of arylpiperazine–benzylpiperidines.
4. Conclusions
A series of arylpiperazine–benzylpiperidines with chemical scaffolds different from those of
marketed drugs were designed and synthesized to explore their effects on inhibition of
neurotransmitter reuptake. These derivatives differed in the length of the linker and in the
substituents on the aromatic ring. As expected, the compounds that contained a longer linker
were more active than those with a shorter linker. The majority of the compounds displayed
better NE than 5-HT reuptake inhibitory activities (IC50 = 0.38–2.50 µM for NE and 1.18–4.92
µM for 5-HT). We believe that the synthetic pathway, structure–activity relationship, and
biological results obtained for the arylpiperazine–benzylpiperidines will provide a framework for
further design and development of safe and effective therapeutic agents against neuropsychiatric
and neurodegenerative disorders.
5. Experimental Section

5.1. Chemistry
A Thomas Hoover melting point apparatus was used for the determination of the melting point
(mp) by the capillary method, and the values were uncorrected. Varian Unity Plus 300 MHz and
1
Bruker BioSpin GmbH spectrometers were used to obtain H and 13C NMR data, which are
reported in ppm downfield from the peak of the internal standard, tetramethylsilane. The data are
reported as chemical shift, number of protons, and multiplicity (s: singlet, d: doublet, t: triplet, q:
quartet, quin: quintet, m: multiplet, dd: doublet of doublets). Merck silica gel 60 (70–230 mesh)
was used for column chromatography. Plates coated with silica gel 60 F254 (Merck) were used
for thin-layer chromatography. Reagents were purchased from Sigma–Aldrich and Alfa Aesar
and used without further purification.
5.1.1. 1-Phenylpiperazine hydrochloride (4a)
A mixture of compound 3a (279.4 mg, 3 mmol), bis(2-chloroethyl)amine hydrochloride (535.5
mg, 3 mmol), and diethylene glycol monomethyl ether (0.75 mL) was heated at 150 °C for about
12 h. The reaction mixture was cooled to room temperature and dissolved in methanol (4 mL),
followed by the addition of diethyl ether (150 mL). The precipitate formed was recovered by
filtration and washed with diethyl ether to provide 4a as an HCl salt (530 mg, 89%). The HCl
salt was used for the next reaction without further purification.
5.1.2. 1-(2,6-Dimethylphenyl)piperazine hydrochloride (4b)
The procedure described for the preparation of 4a was used with compound 3b (363.5 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol), and diethylene glycol
monomethyl ether (0.75 mL) to obtain 4b as an HCl salt (540 mg, 79%). The HCl salt was used
for the next reaction without further purification.
5.1.3. 1-(2-Methoxyphenyl)piperazine hydrochloride (4c)
The procedure described for the preparation of 4a was used with compound 3c (369.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol

monomethyl ether (0.75 mL) to obtain 4c as an HCl salt (510 mg, 74%). The HCl salt was used
for next reaction without further purification.
5.1.4. 1-(3-Chlorophenyl)piperazine hydrochloride (4d)
The procedure described for the preparation of 4a was used with compound 3d (321.5 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol
monomethyl ether (0.75 mL) to obtain 4d as an HCl salt (490 mg, 70%). The HCl salt was used
for next reaction without further purification.
5.1.5. 1-(4-Fluorophenyl)piperazine hydrochloride (4e)
The procedure described for the preparation of 4a was used with compound 3e (333.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol
monomethyl ether (0.75 mL) to obtain 4e as an HCl salt (550 mg, 85%). The HCl salt was used
for next reaction without further purification.
5.1.6. 1-(4-Chlorophenyl)piperazine hydrochloride (4f)
The procedure described for the preparation of 4a was used with compound 3f (321.4 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol
monomethyl ether (0.75 mL) to obtain 4f as an HCl salt (630 mg, 90%). The HCl salt was used
for next reaction without purification.
5.1.7. 1-(4-Bromophenyl)piperazine hydrochloride (4g)
The procedure described for the preparation of 4a was used with compound 3g (516.1 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol
monomethyl ether (0.75 mL) to obtain 4g as an HCl salt (540 mg, 65%). The HCl salt was used
for next reaction without purification.
5.1.8. 1-(2,4-Dichlorophenyl)piperazine hydrochloride (4h)
The procedure described for the preparation of 4a was used with compound 3h (486.1 mg, 3
mmol), bis(2-chloroethyl)amine hydrochloride (535.5 mg, 3 mmol) and diethylene glycol

monomethyl ether (0.75 mL) to obtain 4h as an HCl salt (640 mg, 80%). The HCl salt was used
for next reaction without purification.
5.1.9. 1-(2-Chloroethyl)-4-phenylpiperazine (5a)
Compound 4a (200 mg, 1.0 mmol) was dissolved in acetone (10 mL), potassium carbonate
(K2CO3, 276 mg, 2.0 mmol) was added and followed by dropwise addition of 1-bromo-2-
chloroethane (0.17 mL, 2.01 mmol) The reaction mixture was stirred at room temperature (r.t.)
The reaction mixture was filtered after the completion of reaction and was concentrated. The
obtained product was purified by column chromatography with n-hexane: ethyl acetate (EtOAc)
= 6:1 to obtain 5a (133 mg, 58%) as clear liquid. Retention factor Rf = 0.66 (n-hexane: EtOAc =
2:1). 1H NMR (300 MHz, CDCl3): δ 7.29–7.23 (m, 2H), 6.94–6.83 (m, 3H), 3.65–3.60 (m, 2H),
3.21 (t, J = 5.1 Hz, 4H), 2.81–2.77 (m, 2H), 2.68 (t, J = 5.1 Hz, 4H).
5.1.10 1-(2-Chloroethyl)-4-(2,6-dimethylphenyl)piperazine (5b)
The procedure described for the preparation of 5a was used with compound 4b (220 mg, 0.97
mmol), potassium carbonate (K2CO3, 268 mg, 1.94 mmol) and 1-bromo-2-chloroethane (0.16
mL, 1.94 mmol) to obtain 5b (120 mg, 49%) as clear liquid. Rf = 0.73 (n-hexane: EtOAc = 2:1).
1H NMR (300 MHz, CDCl3): δ 7.00–6.91 (m, 3H), 3.66–3.61 (m, 2H), 3.12 (t, J = 4.8 Hz, 4H),
2.82–2.77 (m, 4H), 2.61 (t, J = 4.8 Hz, 4H), 2.31 (s, 6H).
5.1.11 1-(2-Chloroethyl)-4-(2-methoxyphenyl)piperazine (5c)
The procedure described for the preparation of 5a was used with compound 4c (230 mg, 1
mmol), potassium carbonate (K2CO3, 276 mg, 2.00 mmol) and 1-bromo-2-chloroethane (0.16
mL, 2.0 mmol) to obtain 5C (130 mg, 51%) as clear liquid. Rf = 0.43 (n-hexane: EtOAc = 2:1).
1H NMR (300 MHz, CDCl3): δ 7.08–6.84 (m, 4H), 3.86 (s, -OCH3), 3.65–3.61 (m, 2H), 3.10–
3.09 (m, 4H), 2.83–2.78 (m, 2H), 2.74–2.71 (m, 4H).
5.1.12 1-(2-Chloroethyl)-4-(3-chlorophenyl)piperazine (5d)
The procedure described for the preparation of 5a was used with compound 4d (230 mg, 0.98
mmol), potassium carbonate (K2CO3, 271 mg, 1.96 mmol) and 1-bromo-2-chloroethane (0.16
mL, 1.96 mmol.) to obtain 5d (140 mg, 55%) as light yellow liquid. Rf = 0.66 (n-hexane: EtOAc

= 1:1). 1H NMR (300 MHz, CDCl3): δ 7.15 (t, J = 8.1 Hz, 1H), 6.86–6.74 (m, 3H), 3.63–3.58 (m,
2H), 3.21–3.17 (m, 4H), 2.77–2.74 (m, 2H), 2.64 (t, J = 5.1 Hz, 4H).
5.1.13 1-(2-Chloroethyl)-4-(4-fluorophenyl)piperazine (5e)
The procedure described for the preparation of 5a was used with compound 4e (220, 1 mmol)
potassium carbonate (K2CO3, 276 mg, 2.0 mmol) and 1-bromo-2-chloroethane (0.16 mL, 2.0
mmol) to obtain 5e (110 mg, 45%) as solid. Rf = 0.69 (n-hexane: EtOAc = 1:1). Mp ; 346–
1
348 °C. H NMR (300 MHz, CDCl3): δ 6.99–6.81 (m, 4H), 3.65–3.60 (m, 2H), 3.14–3.11 (m,
4H), 2.82–2.77 (m, 2H), 2.70–2.67 (m, 4H).
5.1.14 1-(2-Chloroethyl)-4-(4-chlorophenyl)piperazine (5f)
The procedure described for the preparation of 5a was used with compound 4f (222 mg, 0.95
mmol), potassium carbonate (K2CO3, 262 mg, 1.9 mmol) and 1-bromo-2-chloroethane (0.16 mL,
1
1.9 mmol) to obtain 5f (123 mg, 50%) as clear liquid. Rf = 0.60 (n-hexane: EtOAc = 2:1). H
NMR (300 MHz, CDCl3): δ 7.22–7.17 (m, 2H), 6.86–6.80 (m, 2H), 3.62–3.60 (t, J = 6.9 Hz, 2H),
3.19–3.16 (m, 4H), 2.79 (t, J = 6.9 Hz, 2H), 2.67 (t, J = 5.1 Hz, 4H).
5.1.15 1-(4-Bromophenyl)-4-(2-chloroethyl)piperazine (5g)
The procedure described for the preparation of 5a was used with compound 4g (280 mg, 1.16
mmol), potassium carbonate (K2CO3, 320 mg, 2.32 mmol) and 1-bromo-2-chloroethane (0.19
mL, 2.32 mmol) to obtain 5g (186 mg, 53%) as brown solid. Rf = 0.70 (n-hexane: EtOAc = 2:1).
1
Mp; 348–350 °C. H NMR (300 MHz, CDCl3): δ 7.30–7.23 (m, 2H, overlapped with CDCl3),
6.95–6.84 (m, 3H), 3.65–3.60 (m, 2H), 3.21 (t, J = 5.1 Hz, 4H), 2.82–2.77 (m, 2H), 2.69 (t, J =
5.1 Hz, 4H).
5.1.16 1-(2-Chloroethyl)-4-(2,4-dichlorophenyl)piperazine (5h)
The procedure described for the preparation of 5a was used with compound 4h (270 mg, 1 mmol)
potassium carbonate (K2CO3, 276 mg, 2.0 mmol) and 1-bromo-2-chloroethane (0.16 mL, 2.0
mmol) to obtain 5h (180 mg, 61%) as clear liquid. Rf = 0.54 (n-hexane: EtOAc = 2:1). 1H NMR
(300 MHz, CDCl3): δ 7.36 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz 1H), 6.95 (d, J = 8.7 Hz,
1H), 3.62 (t, J = 6.9 Hz, 2H), 3.07–3.04 (m, 4H), 2.81 (t, J = 6.9 Hz, 2H), 2.72–2.69 (m, 4H).

5.1.17 1-(2-Chloroethyl)-4-(4-(trifluoromethyl)phenyl)piperazine (5i)
The procedure described for the preparation of 5a was used with compound 4i (230 mg, 1 mmol),
potassium carbonate (K2CO3, 276 mg, 2.0 mmol) and 1-bromo-2-chloroethane (0.16 mL, 2
mmol) to obtain 5i (150 mg, 51%) as solid. Rf = 0.75 (n-hexane: EtOAc = 1:1). Mp; 73–75 °C.
1H NMR (300 MHz, CDCl3): δ 7.47 (dd, J = 9.3, 0.6 Hz, 2H), 6.91 (d, J = 8.4 Hz 2H), 3.62 (t, J
= 6.9 Hz, 2H), 3.29 (t, J = 5.1 Hz, 4H), 2.81–2.77 (m, 2H), 2.69–2.66 (m, 4H).
5.1.18 1-(2-Chloroethyl)-4-(2,3-dichlorophenyl)piperazine (5j)
The procedure described for the preparation of 5a was used with compound 4j (200 mg, 0.74
mmol), potassium carbonate (K2CO3, 204 mg, 1.48 mmol) and 1-bromo-2-chloroethane (0.12
mL, 1.48 mmol) to obtain 5j (120 mg, 55%) as clear liquid. Rf = 0.70 (n-hexane: EtOAc = 2:1).
1H NMR (300 MHz, CDCl3): δ 7.19–7.11 (m, 2H), 6.97–6.93 (m, 1H), 3.65–3.61 (m, 2H), 3.09–
3.06 (m, 4H), 2.82 (t, J = 6.9 Hz, 2H), 2.73–2.70 (m, 4H).
5.1.19 1-(2-Chloroethyl)-4-(pyridin-2-yl)piperazine (5k)
The procedure described for the preparation of 5a was used with compound 4k (200 mg, 1.22
mmol), potassium carbonate (K2CO3, 337 mg, 2.44 mmol) and 1-bromo-2-chloroethane (0.2 mL,
1
2.44 mmol) to obtain 5k (151 mg, 55%) as clear liquid. Rf = 0.48 (n-hexane: EtOAc = 2:1). H
NMR (300 MHz, CDCl3): δ 8.20–8.17 (m, 1H), 7.50–7.49 (m, 1H), 6.65–6.60 (m, 2H), 3.65–
3.61 (m, 2H), 3.58–3.54 (m, 4H), 2.81–2.76 (m, 2H), 2.63 (t, J = 5.1 Hz, 4H).
5.1.20 2-(4-(2-Chloroethyl)piperazin-1-yl)pyrimidine (5l)
The procedure described for the preparation of 5a was used with compound 4l (200 mg, 1.21
mmol), potassium carbonate (K2CO3, 334 mg, 2.42 mmol) and 1-bromo-2-chloroethane (0.2 mL,
1
2.42 mmol) to obtain 5l (140 mg, 51%) as clear liquid. Rf = 0.45 (n-hexane: EtOAc = 2:1). H
NMR (300 MHz, CDCl3): δ 8.30 (d, J = 4.8 Hz, 2H), 6.48 (m, 1H), 3.84 (d, J = 5.1 Hz, 4H), 3.63
(t, J = 6.9 Hz, 2H), 2.80–2.75 (m, 4H), 2.58 (t, J = 5.1 Hz, 4H).
5.1.21. 1-(3-Chloropropyl)-4-phenylpiperazine (6a)

Compound 4a (200 mg, 1.0 mmol) was dissolved in acetone (10 mL), potassium carbonate
(K2CO3, 276 mg, 2.00 mmol) was added and followed by dropwise addition of 1-bromo-3-
chloropropane (0.19 mL, 2.0 mmol). The reaction mixture was stirred at r.t. The reaction mixture
was filtered after the completion of reaction and was concentrated. The obtained product was
purified by column chromatography with n-hexane: ethyl acetate (EtOAc) = 3:1 to obtain 6a
1
(150 mg, 62%) as clear liquid. Rf = 0.75 (n-hexane: EtOAc = 1:1). H NMR (300 MHz, CDCl3):
δ 7.28–7.21 (m, 2H), 6.92– 6.81(m, 3H), 3.62–3.57 (m, 2H), 3.17 (t, J = 5.1 Hz, 4H), 2.60–2.49
(m, 6H), 1.96 (quin, J = 6.75 Hz, 2H).
5.1.22 1-(3-Chloropropyl)-4-(2,6-dimethylphenyl)piperazine (6b)
The procedure described for the preparation of 6a was used with compound 4b (222 mg, 0.98
mmol), potassium carbonate (K2CO3, 271 mg, 1.96 mmol) and 1-bromo-3-chloropropane (0.19
mL, 1.96 mmol) to obtain 6b (130 mg, 50%) as clear liquid. Rf = 0.75 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 7.06–6.97 (m, 3H), 3.71–3.66 (m, 2H), 3.19–3.16 (m, 4H), 2.63–
2.59 (m, 6H), 2.39 (s, 6H), 2.06 (quin, J = 6.9 Hz, 2H).
5.1.23 1-(3-Chloropropyl)-4-(2-methoxyphenyl)piperazine (6c)
The procedure described for the preparation of 6a was used with compound 4b (238 mg, 1.04
mmol), potassium carbonate (K2CO3, 287 mg, 2.08 mmol) and 1-bromo-3-chloropropane (0.20
mL, 2.08 mmol) to obtain 6c (140 mg, 50%) as clear liquid. Rf = 0.68 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 7.02–6.84 (m, 4H), 3.86 (s, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.09 (s,
4H), 2.67–2.65 (m, 4H), 2.58–2.53 (m, 2H), 1.99 (quin, J = 6.9 Hz, 2H).
5.1.24 1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine (6d)
The procedure described for the preparation of 6a was used with compound 4d (230 mg, 0.98
mmol), potassium carbonate (K2CO3, 271 mg, 1.96 mmol) and 1-bromo-3-chloropropane (0.19
mL, 1.96 mmol) to obtain 6d (155 mg, 58%) as clear liquid. Rf = 0.54 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 7.15 (t, J = 8.1 Hz, 1H), 6.87–6.75 (m, 3H), 3.64–3.61 (m, 2H),
3.20–3.17 (m, 4H), 2.60–2.51 (m, 6H), 2.04–1.93 (m, 2H).
5.1.25 1-(3-Chloropropyl)-4-(4-fluorophenyl)piperazine (6e)

The procedure described for the preparation of 6a was used with compound 4e (220 mg, 1
mmol), potassium carbonate (K2CO3, 276 mg, 2 mmol) and 1-bromo-3-chloropropane (0.19 mL,
1
2 mmol) to obtain 6e as (126 mg, 49%) as clear liquid. Rf = 0.63 (n-hexane: EtOAc = 1:1). H
NMR (300 MHz, CDCl3): δ 6.99–6.83 (m, 4H), 3.62 (t, J = 6.6 Hz, 2H), 3.13–3.10 (m, 4H),
2.62–2.52 (m, 6H), 1.98 (quin, J = 6.7 Hz, 2H).
5.1.26 1-(4-Chlorophenyl)-4-(3-chloropropyl)piperazine (6f)
The procedure described for the preparation of 6a was used with compound 4f (230 mg, 0.98
mmol), potassium carbonate (K2CO3, 271 mg, 1.96 mmol) and 1-bromo-3-chloropropane (0.19
mL, 1.96 mmol) to obtain 6f (155 mg, 58%) as clear liquid. Rf = 0.71 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 7.22–7.16 (m, 2H), 6.85–6.80 (m, 2H), 3.61 (t, J = 6.6 Hz, 2H),
3.16–3.13 (m, 4H), 2.61–2.51 (m, 6H), 1.97 (quin, J = 6.7 Hz, 2H).
5.1.27 1-(4-Bromophenyl)-4-(3-chloropropyl)piperazine (6g)
The procedure described for the preparation of 6a was used with compound 4g (216 mg, 0.78
mmol), potassium carbonate (K2CO3, 215 mg, 1.56 mmol) and 1-bromo-3-chloropropane (0.15
mL, 1.56 mmol) to obtain 6g (112 mg, 45%) as clear liquid. Rf = 0.68 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 7.29–7.21 (m, 2H, overlapped with CDCl3), 6.94–6.82 (m, 3H),
3.62 (t, J = 6.6 Hz, 2H), 3.20 (t, J = 5.1 Hz, 4H), 2.63–2.53 (m, 6H), 1.99 (quin, J = 6.8 Hz, 2H).
5.1.28 1-(3-Chloropropyl)-4-(2,4-dichlorophenyl)piperazines (6h)
The procedure described for the preparation of 6a was used with compound 4h (270 mg, 1
mmol), potassium carbonate (K2CO3, 276 mg, 2 mmol) and 1-bromo-3-chloropropane (0.19 mL,
2 mmol) to obtain 6h as clear liquid (185 mg, 60%) as clear liquid. Rf = 0.59 (n-hexane: EtOAc
= 1:1). 1H NMR (300 MHz, CDCl3): δ 7.35 (d, J = 2.4 Hz, 1H), 7.20–7.16 (m, 1H), 6.95 (d, J =
8.7 Hz, 1H), 3.64–3.60 (m, 2H), 3.03 (s, 4H), 2.63–2.54 (m, 6H), 1.98 (quin, J = 6.8 Hz, 2H).
5.1.29 1-(3-Chloropropyl)-4-(4-(trifluoromethyl)phenyl)piperazine (6i)
The procedure described for the preparation of 6a was used with compound 4i (230 mg, 1 mmol),
potassium carbonate (K2CO3, 276 mg, 2 mmol) and 1-bromo-3-chloropropane (0.19 mL, 2 mmol)
1
to obtain 6i (165 mg, 54%) as clear liquid. Rf = 0.65 (n-hexane: EtOAc = 1:1). H NMR (300

MHz, CDCl3): δ 7.47 (dd, J = 9, 0.6 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 3.62 (t, J = 6.6 Hz, 2H),
3.27 (t, J = 5.1 Hz, 4H), 2.60–2.51 (m, 6H), 1.98 (quin, J = 6.75 Hz, 2H).
5.1.30 1-(3-Chloropropyl)-4-(2,3-dichlorophenyl)piperazine (6j)
The procedure described for the preparation of 6a was used with compound 4j (270 mg, 1 mmol),
potassium carbonate (K2CO3, 276 mg, 2.0 mmol) and 1-bromo-3-chloropropane (0.19 mL, 2.0
1
mmol) to obtain 6j (149 mg, 48%) as clear liquid. Rf = 0.60 (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 7.17–7.10 (m, 2H), 6.98–6.93 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.06 (s,
4H), 2.64–2.55 (m, 6H), 1.99 (quin, J = 6.8 Hz, 2H).
5.1.31 1-(3-Chloropropyl)-4-(pyridin-2-yl)piperazine (6k)
The procedure described for the preparation of 6a was used with compound 4k (200 mg, 1.22
mmol), potassium carbonate (K2CO3, 337 mg, 2.44 mmol) and 1-bromo-3-chloropropane (0.24
mL, 2.44 mmol) to obtain 6k (146 mg, 50%) as clear liquid. Rf = 0.60 (n-hexane: EtOAc = 1:1).
1H NMR (300 MHz, CDCl3): δ 8.20–8.17 (m, 1H), 7.50–7.44 (m, 1H), 6.65–6.59 (m, 2H), 3.65–
3.60 (m, 2H), 3.54 (t, J = 5.1 Hz, 4H), 2.57–2.51 (m, 6H), 1.99 (quin, J = 6.8 Hz, 2H).
5.1.32 2-(4-(3-Chloropropyl)piperazin-1-yl)pyrimidine (6l)
The procedure described for the preparation of 6a was used with compound 4l (231 mg, 1.40
mmol), potassium carbonate (K2CO3, 387 mg, 2.8 mmol) and 1-bromo-3-chloropropane (0.27
mL, 2.8 mmol) to obtain 6l (176 mg, 52%) as clear liquid. Rf = 0.74 (n-hexane: EtOAc = 1:1). 1H
NMR (300 MHz, CDCl3): δ 8.30 (d, J = 4.8 Hz, 2H), 6.47 (t, J = 4.8 Hz, 1H), 3 .84–3.80 (m, 4H),
3.65–3.61 (m, 2H), 2.54–2.48 (m, 6H), 2.04–1.94 (m, 2H).
5.1.33 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-phenylpiperazine (1a)
A mixture of compound 5a (130 mg, 0.57 mmol), 4-benzylpiperidine (0.12 mL, 0.68 mmol),
triethylamine (TEA) (0.24 mL, 1.71 mmol) and dimethyl sulfoxide (DMSO) (1.5 mL) was
o
stirred at 100 C. After the reaction was completed, the water was added to the reaction mixture
and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and
concentrated. The obtained product was purified by column chromatography on silica gel with n-
hexane: EtOAc: MeOH (10:1.5:0.5) to obtain 1a (93 mg, 45%) as light brown liquid. Rf = 0.45

1
(n-hexane: EtOAc: MeOH = 2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.28–7.17 (m, ≈ 8H,
overlapped with CHCl3 peaks) 6.92–6.81 (m, 3H), 3.18 (t, J = 5.1 Hz, 4H), 2.91 (d, J = 11.7 Hz,
13
2H), 2.64–2.61 (m, 4H), 1.97–1.88 (m, 2H), 1.65–1.45 (m, 3H), 1.37–1.24 (m, 2H); C NMR
(100 MHz, CDCl3): δ 151.5, 140.6, 129.1, 129.0, 128.1, 125.7, 119.6, 115.9, 56.2, 56.1, 54.4,
53.6, 49.0, 43.2, 37.8, 32.1.
5.1.34 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(2,6-dimethylphenyl)piperazine (1b)
The procedure described for the preparation of 1a was used with compound 5b (115 mg, 0.45
mmol), 4-benzylpiperidine (0.10 mL, 0.54 mmol), TEA (0.19 mL, 1.35 mmol) and DMSO (1.5
mL) to obtain 1b (70 mg, 40%) as light brown liquid. Rf = 0.75 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.28–7.12 (m, ≈ 6H, overlapped with CHCl3 peaks),
6.98–6.89 (m, 3H), 3.11–3.08 (m, 4H), 2.93 (d, J = 11.4 Hz, 2H), 2.58–2.51 (m, 10H), 2.31 (s,
6H), 1.94 (dd, J = 11.7, 2.1 Hz, 2H), 1.65–1.45 (m, 3H), 1.38–1.26 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 148.3, 140.7, 137.0, 129.1, 128.9, 128.1, 125.8, 125.0, 56.6, 55.0, 54.5, 49.6, 43.2,
37.9, 32.2, 19.7.
5.1.35 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(2-methoxyphenyl)piperazine (1c)
The procedure described for the preparation of 1a was used with compound 5c (130 mg, 0.51
mmol), 4-benzylpiperidine (0.11 mL, 0.61 mmol), TEA (0.21 mL, 1.53 mmol) and DMSO (1.5
mL) to obtain 1c (80 mg, 40%) as light brown liquid. Rf = 0.33 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 6H, overlapped with CHCl3 peaks),
7.01–6.83 (m, 4H), 3.85 (s, 3H), 3.08 (s, 4H), 2.93 (d, J = 11.7 Hz, 2H), 2.68–2.51 (m, 10H),
13
1.98–1.90 (m, 2H), 1.65–1.45 (m, 3H), 1.38–1.28 (m, 2H); C NMR (100 MHz, CDCl3): δ
160.8, 152.1, 140.8, 139.4, 139.1, 129.0, 128.99, 128.4, 128.38, 128.3, 123.1, 120.9, 118.1, 111.2,
55.3, 53.5, 53.3, 50.2, 43.9, 42.0, 40.9, 36.4, 36.2, 29.4, 28.4.
5.1.36 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(3-chlorophenyl)piperazine (1d)
The procedure described for the preparation of 1a was used with compound 5d (130 mg, 0.5
mmol), 4-benzylpiperidine (0.1 mL, 0.6 mmol), TEA (0.20 mL, 1.5 mmol) and DMSO (1.5 mL)
to obtain 1d (98 mg, 49%) as light brown liquid. Rf = 0.32 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.28–7.09 (m, ≈ 7H, overlapped with CHCl3 peaks),

6.85–6.72 (m, 3H), 3.17–3.13 (m, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.60–2.50 (m, 10H), 1.95–1.87
13
(m, 2H), 1.63–1.44 (m, 3H), 1.36–1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 160.6, 152.2,
140.5, 134.8, 129.0, 128.3, 128.1, 125.8, 119.0,115.5, 113.7, 56.1, 56.0, 54.4, 53.4, 48.5, 43.1,
37.7, 32.0.
5.1.37 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(4-fluorophenyl)piperazine (1e)
The procedure described for the preparation of 1a was used with compound 5e (110 mg, 0.43
mmol), 4-benzylpiperidine (0.09 mL, 0.51 mmol), TEA (0.18 mL, 1.2 mmol) and DMSO (1.5
mL) to obtain 1e (80 mg, 47%) as light brown liquid. Rf = 0.22 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 6H, overlapped with CHCl3 peaks)
6.97–6.83 (m, 4H), 3.12–3.09 (m, 4H), 2.92 (d, J = 11.7 Hz, 2H), 2.63–2.46 (m, 10H), 1.97–1.89
13
(m, 2H), 1.65–1.45 (m, 3H), 1.37–1.28 (m, 2H); C NMR (100 MHz, CDCl3): δ 158.3, 155.9,
148.0, 147.9, 140.6, 129.1, 128.1, 125.8, 117.8, 117.7, 115.6, 115.3, 56.2, 56.1, 54.4, 53.7, 50.1,
43.2, 37.8, 32.1.
5.1.38 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(4-chlorophenyl)piperazine (1f)
The procedure described for the preparation of 1a was used with compound 5f (120 mg, 0.46
mmol), 4-benzylpiperidine (0.1 mL, 0.55 mmol), TEA (0.19 mL, 1.38 mmol) and DMSO (1.5
1
mL) to obtain 1f (70 mg, 38%) as light brown liquid. Rf = 0.51 (n-hexane: EtOAc = 1:1). H
NMR (300 MHz, CDCl3): δ 7.29–7.11 (m, ≈ 8H, overlapped with CHCl3 peaks) 6.83–6.78 (m,
2H), 3.15–3.11 (m, 4H), 2.91 (d, J = 11.7 Hz, 2H), 2.63–2.47 (m, 10H), 1.97–1.88 (m, 2H),
13
1.64–1.44 (m, 3H), 1.37–1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 149.8, 140.5, 129.0,
128.8, 128.0, 125.7, 124.3, 117.0, 56.11, 56.0, 54.3, 53.4, 49.0, 43.1, 37.7, 32.0.
5.1.39 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(4-bromophenyl)piperazine (1g)
The procedure described for the preparation of 1a was used with compound 5g (150 mg, 0.49
mmol), 4-benzylpiperidine (0.1 mL, 0.59 mmol), TEA (0.20 mL, 1.48 mmol) and DMSO (2 mL)
to obtain 1g (76 mg, 35%) as light brown liquid. Rf = 0.45 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.34–7.11 (m, ≈ 8H, overlapped with CHCl3 peaks)
6.93–6.73 (m, 2H), 3.20–3.12 (m, 4H), 2.91 (d, J = 11.7 Hz, 2H), 2.65–2.47 (m, 10H), 1.93 (dd,
13
J = 11.7, 2.1 Hz, 2H), 1.65–1.45 (m, 3H), 1.37–1.28 (m, 2H); C NMR (100 MHz, CDCl3): δ

151.3, 150.3, 140.6, 131.8, 129.0, 128.1, 125.8, 119.6, 117.5, 116.0, 111.7, 56.2, 56.0, 54.4, 53.6,
53.4, 49.0, 48.9, 43.2, 37.8, 32.1.
5.1.40 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(2,4-dichlorophenyl)piperazine (1h)
The procedure described for the preparation of 1a was used with compound 5h (120 mg, 0.40
mmol), 4-benzylpiperidine (0.09 mL, 0.48 mmol), TEA (0.20 mL, 1.44 mmol) and DMSO (1.5
mL) to obtain 1h (95 mg, 55%) as light brown liquid. Rf = 0.31 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.35–7.12 (m, ≈ 8H, overlapped with CHCl3 peaks)
6.93 (d, J = 11.7 Hz , 1H), 3.04–3.01 (m, 4H), 2.92 (d, J = 11.7 Hz, 2H), 2.65–2.48 (m, 10H),
13
1.93 (dd, J = 11.7, 2.1 Hz, 2H), 1.65–1.45 (m, 3H), 1.37–1.28 (m, 2H); C NMR (100 MHz,
CDCl3): δ 148.0, 140.6, 130.2, 129.3, 129.0, 128.3, 128.1, 128.0, 127.5, 125.7, 121.0, 56.2, 56.0,
53.7, 51.1, 43.1, 37.8, 32.1.
5.1.41 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(4-(trifluoromethyl)phenyl)piperazine (1i)
The procedure described for the preparation of 1a was used with compound 5i (140 mg, 0.48
mmol), 4-benzylpiperidine (0.1 mL, 0.57 mmol), TEA (0.20 mL, 1.44 mmol) and DMSO (1.5
mL) to obtain 1i (99 mg, 48%) as light brown liquid. Rf = 0.61 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3) ): δ 7.46 (d, J = 8.7 Hz, 2H), 7.29–7.12 (m, ≈ 6H,
overlapped with CHCl3 peaks), 6.90 (d, J = 8.7 Hz , 2H), 3.28–3.25 (m, 4H), 2.92 (d, J = 11.7 Hz,
2H), 2.64–2.51 (m, 10H), 1.93 (dd, J = 11.7, 2.1 Hz, 2H), 1.65–1.48 (m, 3H), 1.37–1.29 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 152.2, 139.5, 128.1, 127.1, 125.4, 125.34, 125.3,125.27,124.8,
113.4, 55.1, 54.9, 53.4, 52.3, 46.9, 42.1, 36.7, 31.0.
5.1.42 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(2,3-dichlorophenyl)piperazine (1j)
The procedure described for the preparation of 1a was used with compound 5j (120 mg, 0.40
mmol), 4-benzylpiperidine (0.09 mL, 0.48 mmol), TEA (0.17 mL, 1.2 mmol) and DMSO (1 mL)
to obtain 1j (75 mg, 44%) as light brown liquid. Rf = 0.47 (n-hexane: EtOAc: MeOH = 2.5:1.5:1).
1H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 8H, overlapped with CHCl3 peaks), 6.95–6.92
(m, 1H), 3.05 (s, 4H), 2.92 (d, J = 11.4 Hz, 2H), 2.67–2.49 (m, 10H), 1.93 (dd, J = 11.7, 2.1 Hz,
2H), 1.65–1.45 (m, 3H), 1.38–1.29 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 151.2, 140.6, 134.0,
129.1, 128.2, 127.4, 125.8, 124.5, 118.6, 56.2, 56.0, 54.4, 53.7, 51.3, 43.2, 37.8, 32.0.

5.1.43 1-(2-(4-Benzylpiperidin-1-yl)ethyl)-4-(pyridin-2-yl)piperazine (1k)
The procedure described for the preparation of 1a was used with compound 5k (150 mg, 0.66
mmol), 4-benzylpiperidine (0.14 mL, 0.8 mmol), TEA (0.27 mL, 1.98 mmol) and DMSO (2 mL)
to obtain 1k (96 mg, 40%) as light brown liquid. Rf = 0.35 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 8.17 (dd, J = 4.8, 1.5 Hz, 2H), 7.49–7.43 (m, 1H),
7.29–7.12 (m, ≈ 6H, overlapped with CHCl3 peaks), 6.64–6.58 (m, 2H), 3.53 (t, J = 5.1 Hz, 4H),
2.92 (d, J = 11.7 Hz, 2H), 2.60–2.51 (m, 10H), 1.98–1.89 (m, 2H), 1.65–1.45 (m, 3H), 1.37–1.28
13
(m, 2H); C NMR (100 MHz, CDCl3): δ 159.2, 147.8, 138.3, 137.6, 129.1, 129., 128.6, 128.5,
126.6, 126.3, 113.7, 107.3, 57.8, 53.1, 52.9, 51.1, 45.1, 34.0, 25.7.
5.1.44 2-(4-(2-(4-Benzylpiperidin-1-yl)ethyl)piperazin-1-yl)pyrimidine (1l)
The procedure described for the preparation of 1a was used with compound 5l (140 mg, 0.61
mmol), 4-benzylpiperidine (0.13 mL, 0.73 mmol), TEA (0.25 mL, 1.83 mmol) and DMSO (2 mL)
to obtain 1l (90 mg, 40%) as light brown liquid. Rf = 0.32 (n-hexane: EtOAc: MeOH = 2.5:1.5:1).
1H NMR (300 MHz, CDCl3): δ 8.29 (d, J = 4.8, 2H), 7.29–7.12 (m, ≈ 6H, overlapped with
CHCl3 peaks), 6.46 (t, J = 4.8, 1H), 3.81 ((t, J = 5.1 Hz, 4H), 2.91 (d, J = 11.7 Hz, 2H), 2.54–
2.51 (m, 10H), 1.97–1.88 (m, 2H), 1.65–1.46 (m, 3H), 1.36–1.28 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 161.6, 157.7, 140.6, 129.1, 128.1, 125.7, 109.8, 56.3, 56.2, 54.5, 53.5, 43.6, 43.2, 37.8,
32.1.
5.1.45 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-phenylpiperazine (2a)
The procedure described for the preparation of 1a was used with compound 6a (140 mg, 0.58
mmol), 4-benzylpiperidine (0.12 mL, 0.70 mmol) and TEA (0.24 mL, 1.74 mmol) in DMSO (1.5
mL) to obtain 2a (121 mg, 55%) as light brown liquid. Rf = 0.50 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 8H, overlapped with CHCl3 peaks),
6.93–6.81 (m, 3H), 3.19 (t, J = 5.1 Hz, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.61–2.51 (m, 6H), 2.39–
13
2.31 (m, 4H), 1.89–1.45 (m, 7H), 1.37–1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 155.4,
150.0, 149.8, 140.6, 129.1, 129.06, 129.0, 128.2, 125.8, 117.9, 117.1, 57.0, 56.7, 55.5, 54.0, 53.1,
49.4, 49.1, 43.2, 37.8, 32.2, 32.0.
5.1.46 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(2,6-dimethylphenyl)piperazine (2b)

The procedure described for the preparation of 1a was used with compound 6b (130 mg, 0.48
mmol), 4-benzylpiperidine (0.1 mL, 0.57 mmol), TEA (0.20 mL, 1.44 mmol) and DMSO (1.5
mL) to obtain 2b (98 mg, 59%) as light brown liquid. Rf = 0.66 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 6H, overlapped with CHCl3 peaks),
6.99–6.90 (m, 3H), 3.12–3.09 (m, 4H), 2.91 (d, J = 11.7 Hz, 2H), 2.54–2.51 (m, 6H), 2.42–2.30
(m, 10H), 1.89–1.47 (m, 7H), 1.37–1.29 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 147.2, 139.6,
135.8, 128.0, 127.8, 127.1, 124.7, 123.9, 56.2, 56.0, 53.5, 52.9, 48.5, 42.1, 36.9, 31.0, 23.3, 18.6.
5.1.47 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(2-methoxyphenyl)piperazine (2c)
The procedure described for the preparation of 1a was used with compound 6c (135 mg, 0.50
mmol), 4-benzylpiperidine (0.1 mL, 0.6 mmol), TEA (0.20 mL, 1.5 mmol) and DMSO (1.5 mL)
to obtain 2c (90 mg, 44%) as light brown liquid. Rf = 0.45 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.28–7.18 (m, ≈ 6H, overlapped with CHCl3 peaks),
7.01–6.82 (m, 4H), 3.84 (s, 3H), 3.09 (s, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.64–2.51 (m, 10H),
13
1.89–1.81 (m, 2H), 1.77–1.70 (m, 2H), 1.65–1.45 (m, 3H), 1.36–1.27 (m, 2H); C NMR (100
MHz, CDCl3): δ 152.1, 141.2, 140.5, 129.0, 128.0, 122.7, 120.9, 118.0, 111.0, 56.9, 56.8, 53.8,
53.4, 50.5, 43.1, 37.8, 32.0, 24.4.
5.1.48 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(3-chlorophenyl)piperazine (2d)
The procedure described for the preparation of 1a was used with compound 6d (150 mg, 0.55
mmol), 4-benzylpiperidine (0.12 mL, 0.66 mmol), TEA (0.23 mL, 1.65 mmol) and DMSO (2 mL)
to obtain 2d (95 mg, 42%) as light brown liquid. Rf = 0.31 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 7H, overlapped with CHCl3 peaks),
6.93–6.81 (m, 3H), 3.18 (t, J = 5.1 Hz, 4H), 2.90 (d, J = 11.7 Hz, 2H, 2.58–2.51 (m, 6H), 2.41–
13
2.31 (m, 4H), 1.89–1.46 (m, 7H), 1.37–1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 151.30,
139.7, 133.9, 128.9, 128.1, 127.1, 124.7, 118.1, 114.6, 112.7, 56.0, 55.7, 52.9, 52.0, 47.6, 42.2,
36.9, 31.0, 28.7, 23.5.
5.1.49 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(4-fluorophenyl)piperazine (2e)
The procedure described for the preparation of 1a was used with compound 6e (120 mg, 0.49
mmol), 4-benzylpiperidine (0.1 mL, 0.59 mmol), TEA (0.20 mL, 1.47 mmol) and DMSO (1.5

mL) to obtain 2e (86 mg, 46%) as light brown liquid. Rf = 0.21 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (300 MHz, CDCl3): δ 7.29–7.11 (m, 5H), 6.97–6.82 (m, 4H), 3.12–3.08 (m,
4H), 2.90 (d, J = 11.7 Hz, 2H), 2.60–2.51 (m, 6H), 2.41–2.30 (m, 4H), 1.89–1.41 (m, 7H), 1.37–
13
1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 158.28, 155.9, 148.0, 147.9, 140.5, 129.1, 128.2,
125.8, 117.7, 117.6, 115.6, 115.3, 56.9, 56.6, 53.9, 53.2, 50.1, 43.0, 37.8, 31.8, 24.2.
5.1.50 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(4-chlorophenyl)piperazine (2f)
The procedure described for the preparation of 1a was used with compound 6f (150 mg, 0.54
mmol), 4-benzylpiperidine (0.11 mL, 0.65 mmol), TEA (0.22 mL, 1.62 mmol) and DMSO (2 mL)
to obtain 2f (100 mg, 45%) as light brown liquid. Rf = 0.53 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.11 (m, ≈ 8H, overlapped with CHCl3 peaks),
6.84–6.80 (m, 4H), 3.16–3.06 (m, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.59–2.28 (m, 10H), 1.89–1.28
(m, 9H).
5.1.51 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(4-bromophenyl)piperazine (2g)
The procedure described for the preparation of 1a was used with compound 6g (100 mg, 0.31
mmol), 4-benzylpiperidine (0.07 mL, 0.37 mmol), TEA (0.13 mL, 0.93 mmol) and DMSO (1 mL)
to obtain 2g (61 mg, 43%) as light brown liquid. Rf = 0.45 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.29–7.22 (m, ≈ 4H, overlapped with CHCl3 peaks),
7.20–7.12 (m, 3H), 6.94–6.82 (m, 3H), 3.21–3.18 (m, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.61–2.52
(m, 6H), 2.42–2.31 (m, 4H), 1.89–1.47 (m, 7H), 1.37–1.27 (m, 2H);.13C NMR (100 MHz,
CDCl3): δ 151.3, 140.7, 129.1, 129.08, 128.1, 125.8, 119.6, 116.0, 57.0, 56.8, 54.0, 53.2, 49.1,
43.2, 37.9, 32.1, 24.5.
5.1.52 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(2,4-dichlorophenyl)piperazine (2h)
The procedure described for the preparation of 1a was used with compound 6h (140 mg, 0.45
mmol), 4-benzylpiperidine (0.1 mL, 0.54 mmol), TEA (0.19 mL, 1.35 mmol) and DMSO (1.5
mL) to obtain 2h (121 mg, 60%) as light brown liquid. Rf = 0.30 (n-hexane: EtOAc: MeOH =
1
2.5:1.5:1). H NMR (300 MHz, CDCl3): δ 7.35–7.14 (m, ≈ 8H overlapped with CHCl3 peaks),
6.95 (d, J = 8.7 Hz, 1H), 3.03 (s, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.61–2.30 (m, 10H), 1.89–1.46

13
(m, 7H), 1.36–1.28 (m, 2H); C NMR (100 MHz, CDCl3): δ 148.0, 140.6, 130.1, 129.3, 129.0,
128.0, 127.9, 127.5, 125.7, 121.0, 57.0, 56.7, 53.9, 53.2, 53.1, 43.2, 37.9, 32.1, 24.5.
5.1.53 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(4-(trifluoromethyl)phenyl)piperazine (2i)
The procedure described for the preparation of 1a was used with compound 6i (150 mg, 0.49
mmol), 4-benzylpiperidine (0.10 mL, 0.59 mmol), TEA (0.20 mL, 1.47 mmol) and DMSO (2 mL)
to obtain 2i (111 mg, 51%) as white solid. Rf = 0.62 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp;
1
78–80 °C. H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H), 7.29–7.12 (m, ≈ 6H,
overlapped with CHCl3 peaks), 6.90 (d, J = 8.7 Hz, 2H), 3.29–3.25 (m, 4H), 2.90 (d, J = 11.7 Hz,
2H), 2.59–2.52 (m, 6H), 2.42–2.31 (m, 4H), 1.90–1.81 (m, 2H), 1.77–1.45 (m, 5H), 1.37–1.28
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 152.2, 139.6, 128.1, 127.1, 124.7, 122.4, 113.3, 55.96,
55.7, 53.0, 51.9, 46.8, 42.2, 36.9, 31.1, 23.6.
5.1.54 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(2,3-dichlorophenyl)piperazine (2j)
The procedure described for the preparation of 1a was used with compound 6j (140 mg, 0.45
mmol), 4-benzylpiperidine (0.1 mL, 0.54 mmol), TEA (0.18 mL, 1.35 mmol) and DMSO (1.5
mL) to obtain 2j (80 mg, 40%) as light brown liquid. Rf = 0.47 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (300 MHz, CDCl3): δ 7.29–7.12 (m, ≈ 8H, overlapped with CHCl3 peaks),
6.96–6.93 (m, 1H), 3.06 (s, 4H), 2.91 (d, J = 11.7 Hz, 2H, ), 2.62–2.51 (m, 6H), 2.44–2.31 (m,
4H), 1.89–1.82 (m, 2H), 1.75–1.44 (m, 5H), 1.37–1.28 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
151.3, 140.7, 133.9, 129.1, 127.45, 127.40, 125.7, 124.5, 118.5, 57.0, 56.7, 53.3, 51.3, 43.2, 37.9,
32.1, 24.5.
5.1.55 1-(3-(4-Benzylpiperidin-1-yl)propyl)-4-(pyridin-2-yl)piperazine (2k)
The procedure described for the preparation of 1a was used with compound 6k (140 mg, 0.58
mmol), 4-benzylpiperidine (0.13 mL, 0.69 mmol), TEA (0.24 mL, 1.74 mmol) and DMSO (1.5
mL) to obtain 2k (140 mg, 64%) as light brown liquid. Rf = 0.41 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (300 MHz, CDCl3): δ 8.19–8.16 (m, 1H), 7.48–7.42 (m, 1H), 7.29–7.12 (m,
≈ 6H, overlapped with CHCl3 peaks), 6.64–6.58 (m, 2H), 3.53 (t, J = 5.1 Hz, 4H), 2.90 (d, J =
11.7 Hz, 2H), 2.54–2.51 (m, 6H), 2.41–2.31 (m, 4H), 1.85(dd, J =11.7, 2.1 Hz, 2H), 1.77–1.70

13
(m, 2H), 1.67–1.44 (m, 3H), 1.38–1.27 (m, 2H); C NMR (100 MHz, CDCl3): δ 159.4, 147.9,
140.6, 137.3, 129.1, 128.1, 125.7, 113.1, 106.9, 56.9, 56.8, 53.9, 53.0, 45.1, 43.2, 37.9, 32.1, 24.5.
5.1.56 2-(4-(3-(4-Benzylpiperidin-1-yl)propyl)piperazin-1-yl)pyrimidine (2l)
The procedure described for the preparation of 1a was used with compound 6l (170 mg, 0.70
mmol), 4-benzylpiperidine (0.15 mL, 0.84 125), TEA (0.29 mL, 2.1 mmol) and DMSO (2 mL)
to obtain 2l (160 mg, 60%) as light brown liquid. Rf = 0.41 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (300 MHz, CDCl3): δ 8.28 (d, J = 4.5Hz, 2H), 7.29–7.12 (m, 5H), 6.48–6.43
(m, 1H, ), 3.82 (t, J = 5.1 Hz, 4H), 2.90 (d, J = 11.7 Hz, 2H), 2.53–2.27 (m, 10H), 1.89–1.44 (m,
7H), 1.36–1.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.6, 157.7, 140.6, 129.1, 128.1, 125.8,
109.8, 57.0, 56.9, 54.0, 53.1, 43.6, 43.2, 37.9, 32.1, 24.5.
6. Neurotransmitter uptake assay
The assay was performed following the method described in the literature.33 HEK-293 cells were
cultured in a medium with fetal bovine serum and transfected with hSERT and hNET.
Radiolabeled [3H]-5-HT (PerkinElmer, Waltham, MA, USA) and [3H]-NE (PerkinElmer) were
used at a concentration of 20 nM in the assay. Radioactivity was measured using a Wallac 1450
MicroBeta® TriLux liquid scintillation counter (PerkinElmer). Venlafaxine hydrochloride and
GBR-12909 were used as standard neurotransmitter reuptake inhibitors.
Acknowledgments
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (grant No.
2012R1A1A2006613) and KM Kim was funded by KRF- 2014R1A2A2A01002547. The authors
would like to thank the Korea basic science institute Gwangju center for performing the 1H NMR
and 13C NMR.
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Graphical Abstract
Design, synthesis and biological evaluation of
arylpiperazine–benzylpiperidines with dual
serotonin and norepinephrine reuptake
inhibitory actvities
Suresh Paudel, Srijan Acharya, Kyeong-Man Kim and Seung Hoon Cheon*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju
500-757, Republic of Korea