Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors

Article abstract of DOI:10.1016/j.bmc.2017.02.051

Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC₅₀?=?158.7?nM for 5-HT, 99?nM for NE and 97.5?nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.

Full text of DOI:10.1016/j.bmc.2017.02.051

Accepted Manuscript
Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and pi-
peridines as triple reuptake inhibitors
Suresh Paudel, Srijan Acharya, Goo Yoon, Kyeong-Man Kim, Seung Hoon
Cheon
PII:
S0968-0896(17)30183-9
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.02.051
BMC 13581
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 January 2017
22 February 2017
24 February 2017
Please cite this article as: Paudel, S., Acharya, S., Yoon, G., Kim, K-M., Cheon, S.H., Design, synthesis and in vitro
activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors, Bioorganic & Medicinal
Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.02.051
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as
triple reuptake inhibitors.
Suresh Paudela, Srijan Acharyaa, Goo Yoonb, Kyeong-Man Kim*, Seung Hoon Cheon*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University,
Gwangju 61186, Republic of Korea
bCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University,
Jeonnam 58554, 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
Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are
essential for vital physiological processes, and their dysfunction can cause several central
nervous system diseases. Monoamine transporters currently appear to be the potential target in
the management of these disorders. In this study, homologation and bioisosterism techniques
have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These
derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the
structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-
1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter
reuptake in an in vitro test (IC50 = 158.7 nM for 5-HT, 99 nM for NE and 97.5 nM for DA).
These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine
scaffolds deserve further systematic optimization and pharmacological evaluation.
Keywords: Arylpiperazines, benzylpiperidines, tetrazole, monoamine transporters,
neurotransmitters, serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine
reuptake inhibitor, central nervous system disorders.

1. Introduction
Monoamine transporters are transmembrane transporter proteins, which belong to the
neurotransmitter/ sodium symporter (NSS) family, and they maintain the extracellular
concentration of monoamine neurotransmitters (Fig. 1). Monoamine neurotransmitters play a
significant role in physiological functions and their deficiency can cause several central nervous
system (CNS) diseases, such as depression, generalized anxiety disorder (GAD), social phobia,
Parkinson’s disease, attention deficit hyperactivity disorder (ADHD), restless legs syndrome
(RLS), etc.1-6 Thus, monoamine transporters are being used as the targets of various therapeutic
agents including selective serotonin (5-HT) reuptake inhibitor and dual serotonin and
norepinephrine (NE) reuptake inhibitors.6-7 Mostly, selective 5-HT and dual 5-HT and NE
inhibitors are the clinically prescribed drugs in the market.8-10
Figure 1. Chemical structure of three monoamine neurotransmitters
The disadvantages of selective 5-HT and dual 5-HT and NE reuptake inhibitors are delayed onset
of action and side effects such as insomnia and sexual dysfunction.11─21 One strategy to develop
safe and more effective therapeutic agents can be obtained through the incorporation of
dopamine (DA) components into a selective 5-HT reuptake inhibitor or dual 5-HT and NE
reuptake inhibitors.22-24 Recent clinical studies have revealed that the incorporation of dopamine
reuptake inhibitor (DARI) into selective serotonin reuptake inhibitor (SSRI) or serotonin and
norepinephrine reuptake inhibitor (SNRI) therapy resulted in a beneficial effect among depressed

patients, such as overcoming anhedonia and increased cognitive functions.25-29 Combination
therapy with dual reuptake inhibitor (DA and NE reuptake inhibitor, bupropion) or NE reuptake
inhibitors (e.g. methylphenidate) was able to enhance the activity of SSRI and SNRI like
duloxetine or mirtazapine.30-36 Therefore, triple reuptake inhibitors, which can inhibit reuptake of
5-HT, NE and DA by use of a single molecule, can be developed as a new class of therapeutic
agents that might have better efficacy and fewer side effects than traditional mono or dual
inhibitory drugs.37-40
We have already reported about new templates that inhibit monoamine reuptake.41-43. Inspired by
the initial success, the design of new triple reuptake inhibitors (TRIs), 1,4-disubstituted
piperazines and piperidines, originated from our series of dual 5-HT/NE inhibitors and dual
NE/DA inhibitors (Fig. 2).41-42 Substituted benzylpiperidine derivative (1) is a hybrid structure of
arylpiperazine-tetrazoles and 4-benzylpiperidine carboxamides. Following the pharmacological
strategy comprising homologation and bioisosterism, we further designed substituted piperazines
(2, 3) and 4-benzylpiperidines (4, 5).43-47 In addition, we now report about the replacement of
tetrazole with ether (6) and 4-benzylpiperidine with N-arylpiperazines (7) to explore their impact
on inhibition of neurotransmitter reuptake. Here, we report the synthesis, biological evaluation
and detailed structure-activity relationship (SAR) of a new series of 1,4-disubstituted piperazines
and piperidines.

Figure 2. Design of substituted 1,4-disubstituted piperazines and piperidines, 1–7.
2. Chemistry
The detailed synthesis procedure for substituted piperidines 1a−1c is described in Scheme 1.
Diphenyl acetonitrile (8) was refluxed with excess sodium azide and triethylamine hydrochloride
to obtain 5-benzhydryl-1H-tetrazole (9). The obtained tetrazole 9 was further reacted with 1-
bromo-2-chloroethane, or 1-bromo-3-chloropropane, or 1-bromo-4-chlorobutane to give various
haloalkyl-5-benzhydryl-1H-tetrazoles, 10a–10c. The substitution reaction of 10a–10c with 4-
benzylpiperidine gave piperidines 1a–1c.

N
N
N
N
N
N
Cl
N
N
NH
N
N
( )
N
N
( )
Br(CH2)nCl
n = 2, 3, 4
CN
.
n
n
NaN3, TEA HCl,
HN
C6H5CH3, 100 o
C
TEA, DMSO, 100 o
C
K2CO3, acetone
8
9
10a
10b
10c
, n = 2
, n = 3
, n = 4
1a
1b
1c
(n = 2)
(n = 3)
(n = 4)
Scheme 1. The synthesis of piperidines 1a−1c
Synthesis of substituted piperazines 2a−2i and 3a−3c is outlined in Scheme 2. Tert-butyl
piperazine-1-carboxylate (11) was refluxed with phenyl alkyl halide to get alkyl aryl tert-butyl
piperazine-1-carboxylate (12a–12b and 13) and it was hydrolyzed to obtain alkyl aryl
piperazines (14b–14c and 15). On the other hand, treatment of piperazine (16) with benzyl
bromide gave benzyl piperazine 14a. The substitution reaction of alkyl aryl piperazines, 14a–14c
and 15, with haloalkyl-5-benzhydryl-1H-tetrazoles, 10a–10c, gave substituted piperazines 2a–2i
and 3a–3c.
Scheme 2. The synthesis of substituted piperazines 2a–2i and 3a–3c.

For the synthesis of benzylpiperidine carboxamides 4a–4b and 5a–5b, substituted diphenylacetic
acids, 17a–17b, were refluxed overnight with excess thionyl chloride and the residue obtained on
evaporation of the solvent was further reacted with 2-chloroethylamine hydrochloride or 3-
bromopropylamine hydrobromide in the presence of triethylamine (TEA) to give amides 18a–
18b and 19a–19b as described in Scheme 3. The substitution reaction of 18a–18b and 19a–19b
with 4-benzylpiperidine gave carboxamide derivatives 4a–4b and 5a–5b.
Scheme 3. The synthesis of benzylpiperidine carboxamides 4a–4b and 5a–5b.
Furthermore, the synthesis of benzylpiperidine ether 6 and aryl piperazine ether 7a–7i is shown
in Scheme 4. 4,4′-Difluorobenzhydrol (20) was reacted with 2-chloroethanol to give 4,4'-((2
chloroethoxy) methylene) bis(fluorobenzene) (21). The reaction of 21 with 4-benzylpiperidines
and N-arylpiperazines 23a–23i (23h–23i were commercially available) gave compounds 6 and
7a–7i, respectively.

Scheme 4. The synthesis of substituted arylpiperazines and benzylpiperidine ether.
3. Results and discussion
3.1. Biological assay
A total of 29 compounds were synthesized based on the design. Analysis of neurotransmitters 5-
HT, NE and DA reuptake inhibition was performed by a neurotransmitter uptake assay. Human
embryonic kidney 293 (HEK-293) cells transfected with human serotonin transporter (hSERT),
human norepinephrine transporter (hNET) and human dopamine transporter (hDAT) were used
in this assay. The half maximal inhibitory concentration (IC50) of all the synthesized compounds
was determined and is presented in Table 1.
Table 1. Serotonin (5-HT), norepinephrine (NE) and dopamine reuptake inhibition (IC50) by 1,4-
disubstituted piperazines and piperidines.

Compd
1a
R
X
n
Y
R1
5-HT (µM)
NE (µM)
DA (µM)
H
2
C
7.7
1.71
0.31
”
”
”
”
3
4
C
C
”
”
>10
0.519
1.53
0.094
0.59
1b
1c
0.55
”
”
2
N
>10
4.218
2.289
2a
”
”
”
”
3
4
”
”
”
”
5.05
1.5
0.521
0.323
0.2923
0.317
2b
2c
”
”
2
”
4.83
2.83
0.6798
2d
”
”
”
”
3
4
”
”
”
”
1.121
8
0.3995
0.329
1.115
0.608
2e
2f
”
”
2
”
3.86
1.467
0.6921
2g
”
”
”
”
3
4
”
”
”
”
8
0.5689
0.099
1.636
2h
2i
0.1587
0.0975
”
”
2
”
>10
1.76
0.94
3a
”
”
”
”
3
4
”
”
”
”
7.5
1.327
0.318
2.231
3.64
3b
3c
6.29
”
CONH
2
C
>10
1.68
0.19
4a
Cl
H
Cl
F
”
2
3
3
2
”
”
”
”
”
”
”
”
>10
>10
7.67
1.67
8.03
2.21
2.02
5.862
0.63
1.07
1.35
6.816
4b
5a
5b
6
”
”
O
”
”
”
N
1.906
5.328
10
7a

”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
”
>10
4.96
6.91
5
1.26
1.313
1.59
3
5.6
7b
7c
7d
7e
7f
2.749
1.39
3
3.91
5.22
3.75
1.323
10
4.098
7g
”
”
”
”
”
”
”
”
0.579
1.414
0.6028
1.621
0.9895
1.704
7h
7i
-
-
-
VenlafaxineHCl
Bupropion
-
-
-
-
-
-
-
-
-
-
-
-
0.20
-
2.55
3.24
0.11
-
1.20
0.043
GBR12909
Our initial efforts focused on varying the linker size with benzylpiperidines to study their effect
on monoamine reuptake inhibition. To this end, a diverse range of linkers (n = 2, 3, 4) were

investigated. It was found that 5-HT reuptake inhibition improved as the size of the linker
increased, except for compounds with a three carbon linker (1b, n = 3). However, compounds
with a three carbon linker (1b) had greater NE and DA reuptake inhibitory activity than
compounds with a two carbon linker (1a) and a 4 carbon linker (1c). We next focused on the
effects of substitution of benzylpiperidines with benzylpiperazines. As expected, most
benzylpiperazines bearing a longer linker showed a greater monoamine reuptake inhibitory
activity than benzylpiperazines bearing a shorter linker. However, the derivatives with a three
carbon linker (2b, IC50 = 292 nM) showed potent DA reuptake inhibition.
To further elucidate the possible effects of piperazines on monoamine reuptake inhibition, we
increased the distance between the piperazine and phenyl rings from one carbon unit to two and
three carbon units and changed the nature of the carbon bond (2d−2i and 3a−3c). The biological
activity of piperazines (2d−2i) displayed a different pattern for 5-HT, NE and DA reuptake
inhibition. The compound 2e (n = 3, IC50 = 1.12 µM) possessed higher 5-HT reuptake inhibitory
activity than its analogues 2d (n = 2, IC50 = 4.83 µM) and 2f (n = 4, IC50 = 8.0 µM). However, 5-
HT reuptake inhibition was increased with an increase in the linker size when the distance
between the piperazine and phenyl rings was three carbon units (2g−2i). The NE activity of the
compounds (2d−2f) with a longer linker was stronger than that of the compounds with a shorter
linker when the distance between the piperazine and phenyl rings was two and three carbon units,
respectively. Similarly, the DA reuptake inhibitory activity of the derivatives (2f and 2i) with a
longer linker was greater than that of the derivatives bearing a distance of two and three carbon
units between the piperazine and phenyl rings. The activity was in the following order: 2d > 2e <
2f and 2g > 2h < 2i. The 5-HT and NE activity of the compounds, 3a−3c, was increased with an
increase in the linker size, whereas DA reuptake activity was the highest in compounds with a

two carbon linker (3a, IC50 = 0.94 µM). The most potent compound among the benzylpiperazine-
tetrazoles was 2i, the compound with a longer linker and a longer distance between the
piperazine and phenyl rings (IC50 = 158.7 nM for 5-HT, 99 nM for NE and 97.5 nM for DA).
Furthermore, the replacement of tetrazole ring with carboxamide in derivatives 4a−4b and
5a−5b led to inhibition of 5-HT and NE reuptake inhibition. However, the DA reuptake activity
of benzylpiperidine carboxamides was comparable or strong irrespective of the length of the
linker (IC50 = 0.19−1.35 µM).
Finally, we made two substitutions, the carboxamide ring by the ether group (6) and
benzylpiperidines by N-arylpiperazine (7a−7i). Interestingly, there was improvement in 5-HT
and NE reuptake inhibitory activity. However, there was a slight reduction in DA reuptake
inhibition (IC50 = 0.98−10 µM). In general, the inhibitory activities of the unsubstituted
compound (7a), compounds with mono-halogen (7b−7d) and di-halogen substitution (7e−7g)
were less than the inhibitory activities of 2-pyridyl substituted compound 7h (IC50 = 0.57 µM for
5-HT, 0.60 µM for NE and 0.98 µM for DA) and 2-pyrimidyl substituted compound 7i (IC50 =
1.41 µM for 5-HT, 1.62 µM for NE and 1.704 µM for DA).

Figure 3: SAR of substituted 1,4-disubstituted piperazines and piperidines.
4. Conclusions
Three new series of piperazines and piperidines (carboxamide, tetrazole and ether) with chemical
scaffolds different from those of the reported triple reuptake agents were designed and
synthesized to explore their effects on inhibition of neurotransmitter reuptake. A
pharmacological strategy comprising bioisosterism and homologation was used in the design for
the search of safe, effective and selective therapeutic agents against monoamine
neurotransmitters. Among carboxamide, tetrazole and ether derivatives, tetrazole compound with
a longer linker and a longer distance between the piperazine and phenyl rings displayed the most
potent neurotransmitter reuptake inhibitory activity at submicromolar to nanomolar
concentrations (Fig. 3). The potent biological activities demonstrate that substituted 1,4-
disubstituted piperazines and piperidines can be established as a new class of CNS therapeutic
agents with a potential to target neurotransmitter activity.
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. Infrared (IR) spectra were
recorded on a JASCO-FT IR Spectrometer using KBr pellets. Varian Unity Plus 500, 400, 300
1 13
and 125 MHz spectrometers were used to obtain H and C 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. 5-Benzhydryl-1H-tetrazole (9)
A mixture of a diphenylacetonitile, 8 (1.74 g, 9 mmol), sodium azide (1.75 g, 27 mmol), and
triethylamine hydrochloride (3.71 g, 27 mmol) in toluene (80 mL) was heated to 100 °C for 24 h
with stirring. After cooling, the reaction mixture was extracted with water. Then, 36% HCl was
added dropwise to the aqueous layer. The precipitation occurred, which was filtered off and
1
washed with water to provide 9 (1.53 g, 72%). H NMR (500 MHz, CDCl3): δ 7.35–7.24 (m,
10H), 5.95 (s, 1H).
5.1.2. 5-Benzhydryl-1-(2-chloroethyl)-1H-tetrazole (10a)
Compound 9 (709 mg, 3 mmol) was dissolved in acetone (80 mL), potassium carbonate (K2CO3,
1.24 g, 9 mmol) was added and followed by dropwise addition of 1-bromo-2-chloroethane (0.37
mL, 4.5 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) = 4:1 to obtain 10a as clear liquid (429
1
mg, 48%). Retention factor Rf = 0.62 (n-hexane: EtOAc = 1:1). H NMR (300 MHz, CDCl3): δ

7.31–7.20 (m, 11H, overlapped with CHCl3), 5.95 (s, 1H), 4.90–4.85 (m, 2H), 3.99 (t, J = 6.3 Hz,
2H).
5.1.3. 5-Benzhydryl-1-(3-chloropropyl)-1H-tetrazole (10b)
The procedure described for the preparation of 10a was used with compound 9 (708 mg, 3
mmol), K2CO3 (1.24 g, 9 mmol), 1-bromo-3-chloropropane (0.44 mL, 4.5 mmol) and acetone
(80 mL) to obtain 10b as clear liquid (779 mg, 83%). Retention factor Rf = 0.29 (n-hexane:
1
EtOAc = 4:1). H NMR (300 MHz, CDCl3): δ 7.31–7.16 (m, 10H), 5.80 (s, 1H), 4.70–4.65 (m,
2H), 3.50–3.46 (m, 2H), 2.40–2.31 (m, 2H).
5.1.4. 5-Benzhydryl-1-(4-chlorobutyl)-1H-tetrazole (10c)
The procedure described for the preparation of 10a was used with compound 9 (958 mg, 4.05
mmol), K2CO3 (1.68 g, 12.15 mmol), 1-bromo-4-chloropropane (0.69 mL, 6.075 mmol) and
acetone (80 mL) to obtain 10c as clear liquid (1.05 g, 80%). Retention factor Rf = 0.57 (n-hexane:
EtOAc = 1:1). 1H NMR (500 MHz, CDCl3): δ 7.39–7.25 (m, 10H), 5.86 (s, 1H), 4.63 (t, J = 7 Hz,
2H), 3.57–3.54 (m, 2H), 2.21–2.16 (m, 2H), 1.83–1.77 (m, 2H).
5.1.5. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)ethyl)-4-benzylpiperidine (1a)
The mixture of compound 10a (140 mg, 0.47 mmol), 4-benzylpiperidine (0.1 mL, 0.56 mmol),
o
TEA (0.19 mL, 1.41 mmol) and DMSO (1.5 mL) was 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 (72 mg, 36%) as light brown liquid. Rf = 0.60 (n-hexane: EtOAc = 1:1). 1H NMR (300
MHz, CDCl3): δ 7.32–7.13 (m, 14H, overlapped with CHCl3), 7.11–7.08 (m, 2H), 5.80 (s, 1H),
4.66–4.61 (m, 2H), 2.92–2.87 (m, 2H), 2.79 (d, J = 11.4 Hz, 2H), 2.47 (d, J = 6.9 Hz, 2H), 2.0–
13
1.92 (m, 2H), 1.57–1.38 (m, 3H), 1.25–1.12 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.7,
140.9, 140.6, 129.2, 128.8, 128.6, 128.3, 127.0, 125.9, 56.8, 53.7, 50.7, 48.6, 43.2, 37.7, 32.1.
5.1.6. 1-(3-(5-Benzhydryl-1H-tetrazol-1-yl)propyl)-4-benzylpiperidine (1b)
The procedure described for the preparation of 1a was used with compound 10b (300 mg, 0.95
mmol), 4-benzylpiperidine (0.20 mL, 1.14 mmol), TEA (0.39 mL, 2.85 mmol) and DMSO (1.5
mL) to obtain 1b (340 mg, 79%) as light brown liquid. Rf = 0.66 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (300 MHz, CDCl3): δ 7.33–7.10 (m, 17H, overlapped with CHCl3), 5.79 (s,
1H), 4.63–4.58 (m, 2H), 2.79 (d, J = 11.7 Hz, 2H), 2.49 (d, J = 6.9 Hz, 2H), 2.32–2.27 (m, 2H),
13
2.17–2.08 (m, 2H), 1.85–1.76 (m, 2H), 1.60–1.40 (m, 3H), 1.30–1.16 (m, 2H); C NMR (125
MHz, CDCl3): δ 167.8, 140.7, 140.4, 129.1, 128.7, 128.6, 128.2, 127.0, 125.9, 55.1, 53.7, 51.3,
48.6, 42.9, 37.7, 31.6, 26.3.
5.1.7. 1-(4-(5-Benzhydryl-1H-tetrazol-1-yl)butyl)-4-benzylpiperidine (1c)
The procedure described for the preparation of 1a was used with compound 10c (300 mg, 0.91
mmol), 4-benzylpiperidine (0.20 mL, 1.09 mmol), TEA (0.38 mL, 2.73 mmol) and DMSO (2 mL)

to obtain 1c (296 mg, 70%) as light brown liquid. Rf = 0.62 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.37–7.16 (m, 15H), 5.83 (s, 1H), 4.63–4.60 (m, 2H),
2.83 (d, J = 6.9 Hz, 2H), 2.55 (d, J = 4.5 Hz, 2H), 2.34–2.31 (m, 2H), 2.07–2.01 (m, 2H), 1.85–
13
1.80 (m, 2H), 1.63 (d, J = 7.8 Hz, 2H), 1.55–1.49 (m, 3H), 1.39–1.25 (m, 2H); C NMR (125
MHz, CDCl3): δ 167.8, 140.8, 140.5, 129.1, 128.7, 128.6, 128.2, 127.0, 125.9, 57.7, 53.7, 52.9,
48.6, 43.0, 37.7, 31.7, 27.3, 23.4.
5.1.8. tert-Butyl 4-phenethylpiperazine-1-carboxylate (12a)
The acetonitrile solution containing tert-butyl piperazine-1-carboxylate, 11 (1.83 g, 9.82 mmol),
K2CO3 (1.35 g, 9.82 mmol), NaI (catalyst) and (2-chloroethyl)benzene (0.43 ml, 3.27 mmol)
was refluxed. After the completion, reaction mixture was cooled, filtered and concentrated. The
obtained product was purified by column chromatography on silica gel with Hexane: EtOAc (4:1)
to obtain 12a (435 mg, 50%) as white solid. Rf = 0.57 (n-hexane: EtOAc = 1:1). Mp = 59–61 °C.
1H NMR (500 MHz, CDCl3): δ 7.30–7.18 (m, 5H), 3.47–3.45 (m, 4H), 2.82–2.79 (m, 2H), 2.62–
2.59 (m, 2H), 2.46 (s, 4H), 1.47 (s, 9H).
5.1.9. tert-Butyl 4-(3-phenylpropyl)piperazine-1-carboxylate (12b)
The procedure described for the preparation of 12a was used with compound tert-butyl
piperazine-1-carboxylate (1.83 mg, 9.82 mmol), K2CO3 (1.35 g, 9.82 mmol mg, mmol , NaI
(catalyst) and (3-chloropropyl)benzene (0.48 mL, 3.27 mmol) to obtain 12b (410 mg, 45%) as
clear liquid. Rf = 0.56 (n-hexane: EtOAc = 1:1). 1H NMR (500 MHz, CDCl3): δ 7.28–7.17 (m,
5H), 3.44–3.42 (m, 4H), 2.65–2.62 (m, 2H), 2.36 (t, J = 9 Hz, 6H), 1.84–1.78 (m, 2H), 1.45 (s,
9H).

5.1.10. 1-Benzylpiperazine (14a)
Benzyl bromide (684 mg, 4 mmol) was added dropwise at 0°C to a solution of piperazine, 16
(862 mg, 10 mmol) in dry CH2Cl2 (80 mL). The reaction mixture was stirred at the same
temperature for 4 h, rinsed with NaHCO3 (2 x 100 mL of a saturated aqueous solution), dried
over Mg2SO4 and concentrated under vacuum. The crude product was dissolved in 50 mL of
absolute EtOH and the white solid formed (1,4-dibenzylpiperazine) was filtered off. The solvent
was evaporated under vacuum. The obtained product was purified by column chromatography on
silica gel with CH3OH: CH2Cl2 (4:1) to obtain 14a (560 mg, 46%) as colorless oil. Rf = 0.25
1
(CH3OH: CH2Cl2 = 1:1). H NMR (500 MHz, CDCl3): δ 7.33–7.22 (m, 6H, overlapped with
CHCl3), 3.50 (s, 2H), 2.90–2.89 (m, 4H), 2.42 (s, 4H).
5.1.11. 1-Phenylethylpiperazine (14b)
To a solution of compound 12a (420 mg, 1.44 mmol) in CH2Cl2 (34 mL) was added slowly
trifluoroacetic acid (2.20 mL, 28.8 mmol) at 0 °C (ice bath). The solution was stirred at this
temperature for 15 min and then at ambient temperature for a day. Removal of the solvent by
evaporation gave pale yellow oil, to which NaOH (aq) was added slowly until the pH of the
solution became about 7. The aqueous solution was extracted with CH2Cl2 (30 mL x 3). The
organic layer was dried over MgSO4, filtered and concentrated. The obtained product was
purified by column chromatography with Hexane: EtOAc (4:1) to obtain 13b (260 mg, 95%) as
white solid which was used for next reaction without purification.

5.1.12. 1-(3-Phenylpropyl)piperazine (14c)
The procedure described for the preparation of 14b was used with compound 12b (400 mg, 1.34
mmol) and trifluoroacetic acid (2.05 mL, 26.8 mmol) to obtain 14c (250 mg, 91%) as white solid
which was used for next reaction without purification.
5.1.13. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)ethyl)-4-benzylpiperazine (2a)
The mixture of haloalkyl-5-benzhydryl-1H-tetrazole, 10a (300 mg, 1 mmol), alkylpiperazine,
13a (264, 1.5 mmol), K2CO3 (276 mg, 2 mmol), NaI (catalyst) and CH3CN (15 mL) was
refluxed. After the completion, reaction mixture was cooled, 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 2a (131 mg, 30%) as light brown liquid. Rf = 0.56 (n-hexane:
EtOAc: MeOH = 2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.35–7.24 (m, 15H), 5.84 (s, 1H),
13
4.72–4.69 (m, 2H), 3.49 (s, 2H), 3.04–2.97 (m, 2H), 2.53–2.42 (m, 8H); C NMR (125 MHz,
CDCl3): δ 167.7, 140.9, 138.0, 129.2, 128.8, 128.6, 128.2, 127.1, 127.0, 63.0, 56.4, 52.9, 52.8,
50.5, 48.6.
5.1.14. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)propyl)-4-benzylpiperazine (2b)
The procedure described for the preparation of 2a was used with compound 10b (300 mg, 0.96
mmol), 13a (253 mg, 1.44 mmol), K2CO3 (265 mg, 1.92 mmol) and CH3CN (15 mL) to obtain
2b (261 mg, 60%) as light brown liquid. Rf = 0.59 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H
NMR (500 MHz, CDCl3): δ 7.43–7.25 (m, 15H), 5.90 (s, 1H), 4.65 (t, J = 7 Hz, 2H), 3.54 (s, 2H),

13
2.48–2.39 (m, 10H), 2.20–2.15 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.7, 140.8, 138.3,
129.2, 128.8, 128.7, 128.3, 127.11, 127.1, 63.1, 54.9, 53.1, 51.4, 48.7, 26.7.
5.1.15. 1-(4-(5-Benzhydryl-1H-tetrazol-1-yl)butyl)-4-benzylpiperazine (2c)
The procedure described for the preparation of 2a was used with compound 10c (400 mg, 1.22
mmol), 13a (322 mg, 1.83 mmol), K2CO3 (337 mg, 2.44 mmol), NaI (catalyst) and CH3CN (15
mL) to obtain 2c (296 mg, 52%) as light brown liquid. Rf = 0.56 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.38–7.23 (m, 15H), 5.86 (s, 1H), 4.61 (t, J = 7 Hz,
13
2H), 3.54 (s, 2H), 2.48–2.00 (m, 10H), 2.07–2.02 (m, 2H), 1.52–1.49 (m, 2H); C NMR (125
MHz, CDCl3): δ 167.8, 140.9, 138.2, 129.2, 128.7, 128.6, 128.2, 127.1, 127.0, 63.1, 57.6, 53.2,
53.1, 53.0, 48.7, 27.4, 23.6.
5.1.16. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)ethyl)-4-phenethylpiperazine (2d)
The procedure described for the preparation of 1a was used with compound 10a (300 mg, 3.
mmol), 13b (285 mg, 1.5 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) to obtain 2d (95
mg, 21%) as white solid. Rf = 0.32 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). Mp = 95–99 °C. 1H
NMR (500 MHz, CDCl3): δ 7.35–7.22 (m, 17H, overlapped with CHCl3), 5.85 (s, 1H), 4.72 (t, J
13
= 6.5 Hz, 2H), 3.0 (t, J = 6.5 Hz, 2H), 2.83–2.79 (m, 2H), 2.61–2.50 (m, 10H); C NMR (125
MHz, CDCl3): δ 167.7, 140.9, 140.2, 129.1, 128.8, 128.7, 128.68, 128.6, 128.58, 128.4, 128.0,
127.2, 127.0, 126.1, 60.5, 56.4, 53.0, 52.9, 50.5, 48.6, 33.7.
5.1.17. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)propyl)-4-phenethylpiperazine (2e)

The procedure described for the preparation of 1a was used with compound 10b (300 mg, 0.96
mmol), 13b (274 mg, 1.44 mmol), TEA (0.41 mL, 2.88 mmol) and DMSO (2 mL) to obtain 2e
(360 mg, 80%) as light brown liquid. Rf = 0.63 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR
(400 MHz, CDCl3): δ 7.34–7.15 (m, 16H, overlapped with CHCl3), 5.80 (s, 1H), 4.65–4.62 (m,
2H), 2.80–2.76 (m, 2H), 2.58–2.35 (m, 12H), 2.18–2.11 (m, 2H); 13C NMR (125 MHz, CDCl3):
δ 167.7, 140.8, 140.2, 128.7, 128.71, 128.6, 128.4, 127.0, 126.0, 60.4, 54.9, 53.0, 51.4, 48.7, 33.6,
26.6.
5.1.18. 1-(4-(5-Benzhydryl-1H-tetrazol-1-yl)butyl)-4-phenylethylpiperazine (2f)
The procedure described for the preparation of 1a was used with compound 10c (330 mg, 1
mmol), 13b (285 mg, 1.2 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) to obtain 2f (202
mg, 42%) as light brown liquid. Rf = 0.36 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR (500
MHz, CDCl3): δ 7.36–7.20 (m, 16H, overlapped with CHCl3), 5.83 (s, 1H), 4.64–4.61 (m, 2H),
13
2.84–2.80 (m, 2H), 2.63–2.36 (m,12H), 2.08–2.02 (m, 2H), 1.56–1.50 (m, 2H); C NMR (125
MHz, CDCl3): δ 167.8, 140.8, 140.3, 128.7, 128.6, 128.4, 127.0, 126.1, 60.6, 57.6, 53.2, 53.16,
53.0, 48.6, 33.7, 27.4, 23.6.
5.1.19. 1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)ethyl)-4-(3-phenylpropylpiperazine (2g)
The procedure described for the preparation of 1a was used with compound 10a (300 mg, 1
mmol), 13c (306 mg, 1.5 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) to obtain 2g (116
mg, 25%) as light brown liquid. Rf = 0.32 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR (500
MHz, CDCl3): δ 7.35–7.19 (m, 17H, overlapped with CHCl3), 5.85 (s, 1H), 4.71 (t, J = 6.5 Hz,

2H), 2.98 (t, J = 6.5 Hz, 2H), 2.66–2.34 (m, 12H), 1.86–1.79 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 167.7, 142.1, 140.9, 140.2, 137.6, 129.1, 128.8, 128.72, 128.7, 128.6, 128.57, 128.4,
128.3, 128, 127.2, 127.1, 127, 125.8, 57.9, 56.5, 53.0, 52.9, 50.5, 48.6., 33.7, 28.6.
5.1.20. 1-(3-(5-Benzhydryl-1H-tetrazol-1-yl)propyl)-4-(3-phenylpropylpiperazine (2h)
The procedure described for the preparation of 1a was used with compound 10b (300 mg, 0.95
mmol), 13c (291 mg, 1.42 mmol), TEA (0.39 mL, 2.85 mmol) and DMSO (2 mL) to obtain 2h
(375 mg, 82%) as light brown liquid. Rf = 0.63 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR
(400 MHz, CDCl3): δ 7.33–7.11 (m, 16H, overlapped with CHCl3), 5.79 (s, 1H), 4.58–4.55 (m,
13
2H), 2.60 (t, J = 7.6 Hz, 2H), 2.38–2.29 (m, 2H), 2.13–2.06 (m, 2H), 1.81–1.74 (m, 2H); C
NMR (125 MHz, CDCl3): δ 167.7, 142.2, 140.9, 128.8, 128.6, 128.5, 128.4, 127.0, 125.8, 58.0,
54.9, 53.2, 51.4, 48.7, 33.8, 28.7, 26.6.
5.1.21. 1-(4-(5-Benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i)
The procedure described for the preparation of 1a was used with compound 10c (330 mg, 1
mmol), 13c (306 mg, 1.2 mmol), TEA (0.41 mL, 3 mmol) and DMSO (2 mL) to obtain 2i (190
mg, 38%) as light brown liquid. Rf = 0.36 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR (500
MHz, CDCl3): δ 7.35–7.18 (m, 16H, overlapped with CHCl3), 5.82 (s, 1H), 4.62 (t, J = 4.2 Hz,
13
2H), 2.66–2.34 (m, 14H), 2.07–2.01(m, 2H), 1.86–1.80 (m, 2H), 1.54–1.48 (m, 2H); C NMR
(125 MHz, CDCl3): δ 167.8, 142.1, 140.8, 128.7, 128.6, 128.4, 128.3, 127.0, 125.8, 58.0, 57.6,
53.2, 53, 48.6, 33.7, 28.7, 27.4, 23.6.

5.1.22. tert-Butyl 4-cinnamylpiperazine-1-carboxylate (13)
The procedure described for the preparation of 12a was used with compound tert-butyl
piperazine-1-carboxylate, 11 (1.86 mg, 10 mmol), K2CO3 (1.38 g, 10 mmol), NaI (catalyst) and
cinnamyl bromide (788 mg, 4 mmol) to obtain tert-butyl 4-cinnamylpiperazine-1-carboxylate, 13
(850 mg, 70%) as clear liquid. Rf = 0.56 (n-hexane: EtOAc = 1:1). 1H NMR (500 MHz, CDCl3):
δ 7.38–7.30 (m, 4H), 7.25–7.22 (m, 1H), 6.53 (d, J = 6 Hz, 1H), 6.29–6.23 (m, 1H), 3.46 (t, J = 5
Hz, 4H), 3.18–3.16 (m, 2H), 2.46–2.45 (m, 4H), 1.46 (s, 9H).
5.1.23. 1-Cinnamylpiperazine (15)
The procedure described for the preparation of 14b was used with compound 13 (840 mg, 2.77
mmol) and trifluoroacetic acid (4.23 mL, 55.4 mmol) to obtain 15 (520 mg, 93%) as white solid
which was used for next reaction without purification.
5.1.24. (E)-1-(2-(5-Benzhydryl-1H-tetrazol-1-yl)ethyl)-4-(3-phenylprop-1-en-1-
yl)piperazine (3a)
The procedure described for the preparation of 2a was used with compound 10a (500 mg, 1.67
mmol), 16 (506 mg, 2.50 mmol), K2CO3 (461 mg, 3.34 mmol), NaI (catalyst) and CH3CN (30
mL) to obtain 3a (350 mg, 45%) as light brown liquid. Rf = 0.44 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.42–7.23 (m, 15H), 6.55 (d, J = 15.5 Hz, 1H), 6.33–
6.27 (m, 1H), 5.87 (s, 1H), 4.70 (t, J = 6.5 Hz, 2H), 3.16 (dd, J = 7, 1 Hz, 2H), 3.07–2.98 (m,

2H), 2.56–2.48 (m, 8H); 13C NMR (125 MHz, CDCl3): δ 167.7, 140.9, 136.9, 133.2, 128.8, 128.6,
128.6, 127.6, 127.0, 126.5, 126.4, 61.0, 56.4, 53.1, 52.9, 50.5, 48.6.
5.1.25. (E)-1-(3-(5-Benzhydryl-1H-tetrazol-1-yl)propyl)-4-(3-phenylprop-1-en-1-
yl)piperazine (3b)
The procedure described for the preparation of 2a was used with compound 10b (550 mg, 1.75
mmol), 16 (531 mg, 2.60 mmol), K2CO3 (624 mg, 4.52 mmol), NaI (catalyst) and CH3CN (30
mL) to obtain 3b (352 mg, 42%) as light brown liquid. Rf = 0.38 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.42–7.30 (m, 15H), 6.56 (d, J = 15.5 Hz, 1H), 6.37–
6.27 (m, 1H), 5.85 (s, 1H), 4.66 (t, J = 7 Hz, 2H), 3.16 (dd, J = 7, 1Hz, 2H), 2.48–2.39 (m, 10H),
13
2.20–2.15 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.7, 140.9, 136.9, 133.1, 128.7, 128.6,
127.5, 127.0, 126.6, 126.3, 61.0, 54.9, 53.1, 51.4, 48.7, 26.6.
5.1.26. (E)-1-(4-(5-Benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylprop-1-en-1-
yl)piperazine (3c)
The procedure described for the preparation of 2a was used with compound 10c (500 mg, 1.53
mmol), 16 (464 mg, 2.30 mmol), K2CO3 (423 mg, 3.06 mmol), NaI (catalyst) and CH3CN (30
mL) to obtain 3c (264 mg, 35%) as light brown liquid. Rf = 0.29 (n-hexane: EtOAc: MeOH =
2.5:1.5:1). 1H NMR (500 MHz, CDCl3): δ 7.39–7.20 (m, 15H), 6.55 (d, J = 16 Hz, 1H), 6.30–
6.24 (m, 1H), 5.80 (s, 1H), 4.61 (t, J = 7 Hz, 2H), 3.18–3.16 (m, 2H), 2.48–2.36 (m, 10H), 2.06–
13
2.00 (m, 2H), 1.54–1.48 (m, 2H); C NMR (125 MHz, CDCl3): δ 167.8, 140.7, 136.8, 133.4,
128.7, 128.6, 127.6, 127.0, 126.3, 126.0, 60.9, 57.4, 52.9, 52.89, 48.6, 27.3, 23.5.

5.1.27. N-(2-Chloroethyl)-2,2-diphenylacetamide (18a).
Compound 17a (530 mg, 2.49 mmol) was refluxed in excess of thionyl chloride (10 mL) in
presence of benzene for overnight. Excess of thionyl chloride and benzene was evaporated and
the residue was dissolved in CH2Cl2, 2-chloroethylamine hydrochloride (432mg, 3.73 mmol) was
added followed by triethylamine (TEA; 1 mL, 7.47 mmol). The reaction mixture was stirred at
room temperature. After the reaction was completed, the reaction mixture was diluted with
CH2Cl2 and sequentially washed with water, 1N HCl and saturated NaHCO3. The organic layer
was dried over MgSO4, filtered and concentrated. The obtained product was purified by column
chromatography with n-hexane: Ethyl acetate (EtOAc) = 4:1 to obtain 18a (386 mg, 60%) as
1
light yellow liquid. Rf = 0.82 (n-hexane: EtOAc = 1:1). H NMR (300 MHz, CDCl3): δ 7.43–
7.33 (m, 11H), 3.73–3.65 (m, 4H).
5.1.28. N-(2-Chloroethyl)-2,2-bis(4-chlorophenyl)acetamide (18b).
The procedure described for the preparation of 18a was used with compound 17b (300 mg, 1.06
mmol), thionyl chloride (5 mL), 2-chloroethylamine hydrochloride (184 mg, 1.59 mmol and
TEA (0.44 mL), 3.18 mmol) to obtain 18b (138 mg, 40%) as white solid. Rf = 0.85 (n-hexane:
EtOAc = 1:1). Mp = 129 °C. 1H NMR (300 MHz, CDCl3): δ 7.48–7.42 (m, 1H), 7.37–7.30 (m, ≈
9H, Ar-H, overlapped with CHCl3 peak), 3.73–3.64 (m, 4H).
5.1.29. N-(3-Bromopropyl)-2,2-diphenylacetamide (19a).

The procedure described for the preparation of 18a was used with compound 17a (600 mg, 2.82
mmol), thionyl chloride (10 mL) in presence of benzene (10 mL), 3-bromopropylamine
hydrobromide (926mg, 4.23mmol and TEA (1.17 mL), 8.46 mmol) to obtain 19a (563 mg, 63%)
as light brown liquid. Rf = 0.82 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): δ 7.43–
7.32 (m, ≈ 11H, Ar-H, overlapped with CHCl3), 7.16 (s, 1H), 3.51 (q, J = 6.4 Hz, 2H), 3.38 (t, J
= 6.4 Hz, 2H), 2.17–2.10 (m, 2H).
5.1.30. N-(3-Bromopropyl)-2,2-bis(4-chlorophenyl)acetamide (19b).
The procedure described for the preparation of 18a was used with compound 17b (300mg, 1.06
mmol), thionyl chloride (5 mL), 3-bromopropylamine hydrobromide (348 mg, 1.59 mmol and
TEA (0.44 mL, 3.18 mmol) to obtain 19b (175 mg, 43%) as white solid Rf = 0.83 (n-hexane:
EtOAc = 1:1). Mp = 109 °C. IR (cm-1): 3448 (NH). 1H NMR (300 MHz, CDCl3): δ 7.36–7.25 (m,
≈ 11H, overlapped with CHCl3 peak), 3.56–3.43 (m, 2H), 3.37 (t, J = 6.45, 2H), 2.11 (q, J = 6.5,
2H).
5.1.31. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-diphenylacetamide (4a).
The procedure described for the preparation of 1a was used with compound 18a (150 mg, 0.54
mmol), 4-benzylpiperidine (0.19 mL, 1.08 mmol), TEA (0.30 mL, 2.16 mmol) and DMSO (2 mL)
1
to obtain 4a (111 mg, 50%) as light brown liquid. Rf = 0.31 (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 7.45–7.42 (m, 1H, Ar-H), 7.29–7.20 (m, 12H, Ar-H overlapped with
CHCl3), 7.10–7.08 (m, 3H), 6.51 (s, 1H), 3.30–3.23 (m, 2H), 2.62 (d, J = 11.1 Hz, 2H), 2.46 (d, J

= 6.9 Hz, 2H), 2.29 (t, J = 6.15, 2H), 1.78 (t, J = 10.8 Hz, 2H), 1.51–1.38 (m, 3H), 1.10–0.95 (m,
2H); 13C NMR (125 MHz, CDCl3): δ 171.8, 140.5, 139.7, 129.1, 129.0, 128.7, 128.4, 128.2,
127.9, 127.6, 127.1, 125.9, 59.2, 56.2, 53.4, 43.2, 37.7, 36.4, 32.0.
5.1.32. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-bis(4-chlorophenyl)acetamide (4b).
The procedure described for the preparation of 1a was used with compound 18b (180 mg, 0.52
mmol), 4-benzylpiperidine (0.18 mL, 1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO (2 mL)
1
to obtain 4b (82 mg, 33%) as white solid. Rf = 0.35 (n-hexane: EtOAc = 1:1). Mp = 107 °C. H
NMR (300 MHz, CDCl3): δ 7.29–7.24 (m, 6H), 7.18–7.12 (m, 7H), 6.50 (s, 1H), 4.83 (s, 1H),
3.28 (q, J = 5.5 Hz, 2H), 2.64 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 6.9 Hz, 2H), 2.33 (t, J = 5.8 Hz,
2H), 1.81 (t, J = 10.8 Hz, 2H), 1.55–1.37 (m, 3H), 1.04–0.95 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 171.0, 160.8, 140.6, 137.9, 133.3, 130.3, 129.1, 128.9, 128.2, 125.9, 57.1, 56.1, 53.4,
43.2, 37.8, 36.4, 32.2.
5.1.33. N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-diphenylacetamide (5a).
The procedure described for the preparation of 1a was used with compound 19a (350 mg, 1.05
mmol), 4-benzylpiperidine (0.37 mL, 2.1 mmol), TEA (0.58 mL, 4.2 mmol) and DMSO (3 mL)
to obtain 5a (237 mg, 53%) as white solid. Rf = 0.40 (n-hexane: EtOAc = 1:1). Mp = 115 °C. 1H
NMR (300 MHz, CDCl3): δ 7.54–7.01 (m, ≈ 17H, overlapped with CHCl3), 4.79 (s, 1H), 3.29 (q,
J = 5.7 Hz, 2H), 2.75 (d, J = 10.8 Hz, 2H), 2.49 (d, J = 6.6 Hz, 2H), 2.29 (t, J = 6.3 Hz, 2H), 1.74
13
(t, J = 11.1, Hz),1.59–1.43 (m, 5H), 1.14–1.03 (m, 2H); C NMR (125 MHz, CDCl3): δ 171.8,

140.9, 139.6, 128.9, 128.7, 128.4, 128.0, 126.9, 125.7, 59.0, 57.2, 53.7, 42.9, 39.4, 37.6, 31.9,
25.1.
5.1.34. N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-bis(4-chlorophenyl) acetamide (5b).
The procedure described for the preparation of 1a was used with compound 19b (200 mg, 0.49
mmol), 4-benzylpiperidine (0.17 mL, 0.98 mmol), TEA (0.27 mL, 2.96 mmol) and DMSO (2 mL)
1
to obtain 5b (84 mg, 35%) as light brown liquid. Rf = 0.30, (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 7.64 (t, J = 4.0 Hz, 1H, -CONH), 7.36–7.25 (m, ≈ 7H, Ar-H, overlapped
with CHCl3), 7.20–7.16 (m, 2H), 3.35 (q, J = 5.7Hz, 2H), 2.80 (d, J = 11.7 Hz, 2H), 2.51 (d, J =
6.9 Hz, 2H), 2.36 (t, J = 6.1, 2H), 1.83–1.75 (m, 2H), 1.66–1.45 (m, 5H), 1.11–1.02 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 170.7, 140.2, 137.9, 133.2, 130.0, 129.1, 128.8, 128.2, 125.9, 57.70,
57.66, 53.8, 43.0, 40.0, 37.7, 32.0, 24.6.
5.1.35. 4,4'-((2-Chloroethoxy)methylene)bis(fluorobenzene) (21)
To a solution of 4,4′-difluorobenzhydrol, 20 (220 mg, 1 mmol) in toulene (5 mL) was added 2-
chloroethanol (0.1 mL, 1.5 mmol) followed by phosphoric acid (0.20 mL, 3.85 mmol). The
reaction mixture was stirred at room temperature. After the reaction was completed, the reaction
mixture was diluted with brine (4 mL) and extracted with ethyl acetate. The organic layer was
dried over MgSO4, filtered and concentrated. The obtained product was purified by column
chromatography with n-hexane: Ethyl acetate (EtOAc) = 30:1 to obtain 21 (186 mg, 66%) as

colorless liquid. Rf = 0.85 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): δ 7.38–7.23
(m, 4H), 7.05–6.97 (m, 4H), 5.38 (s, 1H), 3.72–3.63 (m, 4H).
5.1.36. 4-Benzyl-1-(2-(bis(4-fluorophenyl)methoxy)ethyl)piperidine (6)
The procedure described for the preparation of 2a was used with compound 21 (100 mg, 0.35
mmol), 4-benzylpiperidine (0.12 mL, 0.7 mmol), K2CO3 (96 mg, 0.7 mmol), NaI (catalyst) in
CH3CN (15 mL) to obtain 6 (103 mg, 70%) as liquid. Rf = 0.83 (n-hexane: EtOAc = 2:1). 1H
NMR (500 MHz, CDCl3): δ 7.33–7.29 (m, 3H), 7.24–7.17 (m, 4H), 7.06–7.01 (m, 6H), 5.37 (s,
1H), 3.60 (t, J = 3.6 Hz, 2H), 2.94 (d, J = 7.2 Hz, 2H), 2.69–2.67 (m, 2H), 2.57 (d, J = 4.2 Hz,
2H), 2.05–1.99 (m, 2H), 1.68–1.52 (m, 3H), 1.38–1.30 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
163.161.2, 140.7, 138.0, 137.96, 129.2, 128.7, 128.6, 128.2, 125.8, 115.4, 115.2, 82.4, 67.2, 58.2,
54.4, 43.27, 37.80, 32.3.
5.1.37. 1-Phenylpiperazine hydrochloride (23a)
The mixture of compound 22a (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 (r.t.) and was dissolved in
methanol (4 mL) followed by addition of diethyl ether (150 mL). The precipitation occurred
which was filtered off and washed with diethyl ether to provide 23a as HCl salt (530 mg, 89%).
The HCl salt was used for next reaction without further purification.