Triple reuptake inhibitors: Design, synthesis and structure–activity relationship of benzylpiperidine–tetrazoles

Article abstract of DOI:10.1016/j.bmc.2017.07.046

Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine–tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.

Full text of DOI:10.1016/j.bmc.2017.07.046

Accepted Manuscript
Triple reuptake inhibitors: Design, synthesis and structure-activity relationship
of benzylpiperidine—tetrazoles
Suresh Paudel, Xiao Min, Srijan Acharya, Daulat Bikram Khadka, Goo Yoon,
Kyeong-Man Kim, Seung Hoon Cheon
PII:
S0968-0896(17)31195-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.07.046
BMC 13883
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 June 2017
23 July 2017
26 July 2017
Please cite this article as: Paudel, S., Min, X., Acharya, S., Khadka, D.B., Yoon, G., Kim, K-M., Cheon, S.H., Triple
reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine—tetrazoles,
Bioorganic & Medicinal Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.07.046
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Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of
benzylpiperidine—tetrazoles
Suresh Paudela,c,d, Xiao Mina,c, Srijan Acharyaa, Daulat Bikram Khadkaa, Goo Yoonb, Kyeong-
Man Kima,c,*, Seung Hoon Cheona,c,*
aCollege 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)
cThese authors contributed equally to this work.
dCurrent Address: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup,
Sejong 339-700, South Korea.
Abstract
Monoamine transporters are important targets in the treatment of various central nervous
disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action,
insomnia, and sexual dysfunction, have compelled the search for safer, more effective
compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors.
Based upon the docking study of compounds that we had reported previously, aromatic rings
(A1) were modified to generate a novel series of benzylpiperidine—tetrazoles. Thirty-one
compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin,
norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed
potent serotonin reuptake inhibition, validating our design approach.

Keywords:
Benzylpiperidine—tetrazoles,
Monoamine
neurotransmitters,
Serotonin,
norepinephrine and dopamine reuptake inhibitors, Docking
1. Introduction
Compounds that inhibit both neurotransmitter, serotonin (5-HT) and norepinephrine (NE)
reuptake, such as venlafaxine, duloxetine, milnacipran, reboxetine, nisoxetine, and atomoxetine,
have been clinically prescribed for the treatment of major depressive disorder, diabetic
neuropathy, stress urinary incontinence (SUI), attention deficit hyperactivity disorder (ADHD),
fibromyalgia, etc.1-10 Several limitations of traditional neurotransmitter reuptake inhibitors, like
delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer,
more effective compounds.11-15
Recently, more attention has been devoted to the synthesis and evaluation of triple
reuptake inhibitors (TRIs) that exhibit promising pharmacological activities.16-18 Several classes
of TRIs, including DOV21,947, SEP-225289, Lu-AA42202, NS-2359, and RG-7166, have been
studied extensively and are already in preclinical and early clinical stages of development (Fig.
1). TRIs represent the next generation of antidepressants with desirable therapeutic effects.19-24
Fig. 1. Several classes of TRIs in preclinical or early clinical stages of development

With an aim to develop safer, more potent and effective neurotransmitter reuptake
inhibitors, we have been studying several classes of compounds. These compounds, I-V,
essentially consist of a variable aromatic region (Ar1) linked to a piperazine/piperidine-aromatic
region (Ar2) by a linker (aliphatic chain with 2-4 carbons) (Fig. 2A and 2B).25-28 In addition,
they also contain a functional group (FG) such as tetrazole, oxygen, piperazine and amide which
acts as a sticky end to connect Ar1 with a linker. In our previous studies, the four fundamental
components of the neurotransmitter reuptake inhibitors were modified step-by-step to access
their pharmacological effects. This conventional method, however, is a time-consuming process.
Thus, rational drug design method for a time-economic and efficient approach has been applied
to generate neurotransmitter reuptake inhibitors. The 3-dimensional structure of human SERT
and antidepressant agents paroxetine (PDB ID: 5I6X) deposited in Protein Data Bank in 2016
was used for a rational drug design to find potent triple neurotransmitter reuptake inhibitors.29
Fig. 2. (A) Structural outline of neurotransmitter reuptake inhibitor. FG: functional group; X:
N/C. (B) Known neurotransmitter (5-HT and/or NE and/or DA) reuptake inhibitors. (C) Docking

model of hSERT-I showing H-bond interaction between tetrazole and amino acids. (D) Newer
benzylpiperidine—tetrazoles 1 (n = 2) and 2 (n = 3).
The tetrazoles (e.g. I, III),25-26 ether (e.g. II),25 piperazine (e.g. IV)27 and amide (e.g. V)28
which were previously examined for inhibition of 5-HT reuptake were subjected to docking
study. The Surflex Dock program available in Sybyl-X 2.1.1 (winnt_os5x) was used to dock the
compounds into the pocket formed after removal of the ligand from the structure of hSERT-
paroxetine. Among the compounds subjected to the docking study, tetrazoles achieved highest
docking score and reasonable hypothetical binding mode (Table S1 and Fig. 2C). The tetrazole
moiety had H-bond interaction with amino acids Tyr175 and Thr497 surrounding the ligand
binding pocket (LBP). Thus, preserving the tetrazole moiety and varying the aromatic rings
(Ar1) to investigate their interaction with amino acids in the vicinity and effect on ultimate
pharmacological activities, benzylpiperidine-tetrazoles (1 and 2) were designed, synthesized and
evaluated as triple reuptake inhibitors (TRIs).
2. Chemistry
Scheme 1 represents the detailed procedures for synthesizing benzylpiperidine—tetrazole
compounds. Various aromatic nitriles 3a–3q were refluxed with excess sodium azide and
triethylamine hydrochloride to obtain tetrazoles 4a–4q. These tetrazoles were further reacted
with 1-bromo-2-chloroethane or 1-bromo-3-chloropropane to yield various chloroalkyl-5-
phenyltetrazoles, 5a–5q (n = 2) and 6a–6q (n = 3). The substitution reactions of 5a–5q and 6a–
6q with 4-benzylpiperidine gave benzylpiperidine—tetrazoles 1a–1q (n = 2) and 2a–2q (n = 3).
Despite the successful synthesis of many benzylpiperidine—tetrazoles, we failed to synthesize 1f,
1i, and 1o compounds, most likely because of steric hindrance.

Scheme 1. Reagents and conditions: (i) Sodium azide (NaN3), triethylamine hydrochloride
(TEA·HCl), and toluene at 100 °C; (ii) K2CO3 and acetone at room temperature (r.t.); (iii)
dimethyl sulfoxide (DMSO) and triethylamine (TEA) at 100 °C.
3. Results and discussion
3.1. Monoamine reuptake inhibition

Monoamine reuptake inhibitory activities were assessed by a neurotransmitter uptake
assay using human embryonic kidney 293 (HEK-293) cell lines transfected with human
serotonin transporter (hSERT), human norepinephrine transporter (hNET), or human dopamine
transporter (hDAT). Reuptake inhibitory activities of the synthesized compounds at a single
concentration (10 µM) are presented in Figure 3.
A
B
Figure 3: Monoamine reuptake inhibitory activity of benzylpiperidine—tetrazoles, 1 (n = 2) in
(A) and 2 (n = 3) in (B) in HEK-293 cells

As expected, the majority of benzylpiperidine—tetrazole compounds with three-carbon
units in the linker showed better reuptake inhibitory activties for 5-HT, NE and DA. than did
compounds with two-carbon units. The introduction of various substitutions at the meta- or para-
position of the phenyl ring also produced favorable reuptake inhibition. In general, dihalogen
substitituted derivatives produced potent neurotransmitter reuptake inhibitory activities than
monohalogen substituted compounds. Based upon the primary screening, compounds 1c, 1d, 1q,
2a-2e, 2h-2o, and 2q, which inhibited reuptake of 5-HT, NE and DA by >55% at 10 µM were
selected for the IC50 value determination (Table 1).
Table 1: IC50 (µM) value for monoamine reuptake inhibition of benzylpiperidine—tetrazoles
S.N.
1c
n
2
2
2
3
3
3
3
3
3
3
3
3
R
5-HT
4.05
1.24
>10
0.88
8.81
0.54
5.25
4.05
2
NE
DA
Ph-3-COMe
Ph-4-NO2
1-Naphthyl
Ph
3.08
1.35
>10
3.03
5.1
14.6
1.98
>10
4.02
3.74
5.04
>10
>10
3.29
6.55
5.18
8.32
1d
1q
2a
2b
2c
Ph-3-CF3
Ph-3-COMe
Ph-4-NO2
Ph-4-OMe
Ph-4-F
3
5.02
5.52
2.28
3.96
3.59
2.58
2d
2e
2h
2i
Ph-2-Cl
Ph-3-Cl
Ph-4-Cl
1.32
1.35
3.13
2j
2k

3
3
3
3
-
Ph-2-Br
5.13
>10
3.96
0.31
0.20
-
3.46
4.34
3.45
2.51
2.55
3.24
0.11
>10
>10
>10
6
2l
Ph-3-Br
2m
Ph-2,3-Cl2
2o
1-Naphthyl
2q
Venlafaxine HCl
Bupropion
GBR12909
-
-
-
-
1.20
0.04
-
-
-
Compound 2q, with a 1-naphthyl substitution and a longer linker, was the most potent 5-
HT reuptake inhibitor among the synthesized compounds (IC50 = 0.31 µM). A compound
without any substitution in phenyl ring 2a (IC50 = 0.88 µM) had greater 5-HT reuptake inhibitory
activity than did substituted compounds, except for 3-acetophenyl derivative, 2c (IC50 = 0.54
µM). The IC50 for 5-HT reuptake inhibition of monohalogen-substituted compounds ranged from
1.32 to >10 µM, and they are listed here in increasing order: 2-Cl (2i) > 3-Cl (2j) > 4-F (2h) > 4-
Cl (2k) > 2-Br (2l) > 3-Br (2m). Interestingly, the activities of 1-naphthyl compounds (2q, IC50 =
0.31 µM) increased 30-fold when the length of the linker was extended from two to three
carbons (1q, IC50 > 10 µM). Likewise, the 4-nitro derivative (1d) displayed the greatest NE
reuptake inhibitory activity among the synthesized compounds (IC50 = 1.35 µM). The majority of
benzylpiperidine—tetrazoles exhibited equipotent or more potent inhibition of NE reuptake (IC50
= 1.35–5.51 µM) than standard drug, bupropion. The compound with a 1-naphthyl substitution
(1q) showed the lowest (IC50 > 10 µM). Furthermore, the compound demonstrating the highest
DA reuptake inhibition was the 4-nitro derivative 1d (IC50 = 1.98 µM). A compound with a 4-F
substitution 2h (IC50 = 3.29 µM) was superior in DA reuptake activity than those with a Cl
substitution 2i–2k (IC50 = 5.18–8.31 µM) or a Br substitution 2l and 2m (IC50 > 10 µM).
3.2. Docking study

A hypothetical binding mode of SERT and compound 2q, the most potent 5-HT reuptake
inhibitor among the compounds synthesized in this study, was generated to identify the
interaction responsible for SERT inhibition. 5-HT reuptake inhibitors, like paroxetine, reside at
the central binding site and block 5-HT binding (Fig. 4A). The 5-HT reuptake inhibitor locks
SERT into an outward-open conformation. In this conformation, the central binding site is
situated halfway across the cell membrane-spanning region of SERT. The central binding site
connects to the vestibule and opens into the extracellular space. A second molecule of
neurotransmitter reuptake inhibitor (maltose in case of PDB ID: 5I6X) also binds to the allosteric
site at the extracellular periphery of the vestibule. The additional inhibitor caps the vestibule and
prevents dissociation of the inhibitor from the central binding site.
The 5-HT reuptake inhibition potency of a compound is dependent upon the nature and
extent of its interaction with SERT. The docking study shows that the compound 2q interacted
with SERT in the same unique manner as paroxetine. The 4-benzylpiperidine moiety of the
compound occupied the central binding site, creating a hydrophobic interaction with Ile172,
Tyr176, and Phe341 (Fig. 4B). The 3-carbon linker was particularly important as it bent the
compound into an optimal placement in the L-shaped pocket. The tetrazole group of the
compound, as expected earlier, interacted with Tyr175 and Thr497 through H-bonds. The
naphthalene group, that projected the allosteric site, stacked parallel to the ring of Phe335.

Figure 4. (A) Binding mode of hSERT-paroxetine (PDB ID: 5I6X). (B) Hypothetical binding
mode of hSERT-2q. H-bonds are displayed as brown discontinuous lines and ionic bond as solid
red lines.
4. Conclusion
In conclusion, based upon the docking study we designed and synthesized several
benzylpiperidine—tetrazole compounds. As expected, molecules containing three-carbon units in
the linker showed potent monoamine reuptake inhibition. For an explanation of the 5-HT
reuptake inhibitory activity of 2q, docking studies were performed using the Surflex-dock
program to provide a reasonable binding mode of the compound with the human 5-HT
transporter. The SAR data and docking models from this study can help guide the design of safer,
more effective therapeutic agents for CNS 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, Varian Unity Inova 500 MHz and Bruker BioSpin GmbH spectrometers were used to
obtain 1H 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, multiplicity (s: singlet, d:
doublet, t: triplet, q: quartet, quin: quintet, m: multiplet, dd: doublet of doublets), coupling
constant in Hz and number of protons. Mass spectra were obtained using an Advion Expression
CMS, and recorded in a positive ion mode with an electrospray (ESI) source. 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-Phenyl-1H-tetrazole (4a)
A mixture of a benzonitrile, 3a (310 mg, 3 mmol), sodium azide (586 mg, 9 mmol), and
triethylamine hydrochloride (1.24 g, 9 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. Precipitation occurred, which was filtered off and washed
1
with water to provide 4a as white solid (395 mg, 90%). Mp: 214–216 ℃. H NMR (500 MHz,
DMSO-d6): δ 8.04–7.02 (m, 2H), 7.62–7.57 (m, 3H).
5.1.2. 5-(3-(Trifluromethyl)phenyl)-1H-tetrazole (4b)
The procedure described for the preparation of 3a was used with compound 3b (513 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4b as white solid (514 mg, 80%). Mp: 156–157 ℃. H NMR (300
MHz, DMSO-d6): δ 8.35–8.33 (m, 2H), 7.97–7.95 (m, 1H), 7.88–7.85 (m, 1H).
5.1.3. 1-(3-(1H-Tetrazole-5-yl)phenyl)ethanone (4c)

The procedure described for the preparation of 4a was used with compound 3c (436 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4c as white solid (511 mg, 90%). Mp: 189–191 ℃. H NMR (300
MHz, DMSO-d6): δ 8.17–8.15 (m, 2H), 8.12–8.12 (m, 2H), 2.61 (s, 3H).
5.1.4. 5-(4-Nitrophenyl)-1H-tetrazole (4d)
The procedure described for the preparation of 4a was used with compound 3d (445 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4d as yellow solid (459 mg, 80%). Mp: 218–220 ℃. H NMR (300
MHz, DMSO-d6): δ 8.47–8.42 (m, 2H), 8.28–8.32 (m, 2H).
5.1.5. 5-(4-Methoxyphenyl)-1H-tetrazole (4e)
The procedure described for the preparation of 4a was used with compound 3e (400 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4e as white solid (449 mg, 85%). Mp: 229–230 ℃. H NMR (300
MHz, DMSO-d6): δ 8.00–7.95 (m, 2H), 7.16–7.11 (m, 2H), 3.82 (s, 3H).
5.1.6. 5-(2-Flurophenyl)-1H-tetrazole (4f)
The procedure described for the preparation of 4a was used with compound 3f (363 mg, 3 mmol),
sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in toluene
1
(80 mL) to provide 4f as white solid (295 mg, 60%). Mp: 158–160 ℃. H NMR (500 MHz,
DMSO-d6): δ 16.50 (br, NH), 8.06 (m, 1H), 7.68 (m, 1H), 7.50 (m, 1H), 7.45 (m, 1H).
5.1.7. 5-(3-Flurophenyl)-1H-tetrazole (4g)
The procedure described for the preparation of 4a was used with compound 3g (363 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
toluene (80 mL) to provide 4g as white solid (320 mg, 65%) which was used for next reaction

1
without purification. Mp: 142–144 ℃. H NMR (300 MHz, DMSO-d6): δ 7.78–7.71 (m, 2H),
7.57–7.40 (m, 2H).
5.1.8. 5-(4-Flurophenyl)-1H-tetrazole (4h)
The procedure described for the preparation of 4a was used with compound 3h (363 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4h as yellow solid (345 mg, 70%). Mp: 112–114 ℃. H NMR (300
MHz, DMSO-d6): δ 8.11–8.03 (m, 2H), 7.48–7.40 (m, 2H).
5.1.9. 5-(2-Chlorophenyl)-1H-tetrazole (4i)
The procedure described for the preparation of 4a was used with compound 3i (413 mg, 3 mmol),
sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in toluene
1
(80 mL) to provide 4i as white solid (325 mg, 60%). Mp: 172–174 ℃. H NMR (300 MHz,
DMSO-d6): δ 7.83–7.80 (m, 1H), 7.72–7.69 (m, 1H), 7.65–7.52 (m, 2H).
5.1.10. 5-(3-Chlorophenyl)-1H-tetrazole (4j)
The procedure described for the preparation of 4a was used with compound 3j (413 mg, 3 mmol),
sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in toluene
1
(80 mL) to provide 4j as white solid (460 mg, 85%). Mp: 139–140 ℃. H NMR (300 MHz,
CDCl3): δ 16.90 (br, NH), 7.75 (m, 1H), 7.70 (m, 1H), 7.61 (m, 1H), 7.50 (m, 1H).
5.1.11. 5-(4-Chlorophenyl)-1H-tetrazole (4k)
The procedure described for the preparation of 4a was used with compound 3k (413 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4k as white solid (514 mg, 95%). Mp: 252–254 ℃. H NMR (300
MHz, DMSO-d6): δ 8.05 (d, J = 8.4 Hz, 2H), 7.69 (d J = 8.4 Hz, 2H).

5.1.12. 5-(2-Bromophenyl)-1H-tetrazole (4l)
The procedure described for the preparation of 4a was used with compound 3l (546 mg, 3 mmol),
sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in toluene
1
(80 mL) to provide 4l as white solid (405 mg, 60%). Mp: 174–176 ℃. H NMR (500 MHz,
DMSO-d6): δ 16.70 (br, NH), 7.85 (dd, J = 8.0, 4.0 Hz, 1H), 7.68 (dd, J = 8.8, 4.0 Hz, 1H), 7.55
(m, 2H).
5.1.13. 5-(3-Bromophenyl)-1H-tetrazole (4m)
The procedure described for the preparation of 4a was used with compound 3m (546 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4m as white solid (459 mg, 68%). Mp: 155–156 ℃. H NMR (300
MHz, DMSO-d6): δ 8.22 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H) 7.50 (m, 1H),
7.52 (m, 1H).
5.1.14. 5-(4-Bromophenyl)-1H-tetrazole (4n)
The procedure described for the preparation of 4a was used with compound 3n (546 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4n as white solid white solid (540 mg, 80%). Mp: 259–261 ℃. H
NMR (300 MHz, DMSO-d6): δ 8.00–7.96 (m, 2H), 7.85–7.81 (m, 2H).
5.1.15. 5-(2,3-Dichlorophenyl)-1H-tetrazole (4o)
The procedure described for the preparation of 4a was used with compound 3o (516 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4o as white solid (516 mg, 80%). Mp: 180–182 ℃. H NMR (300

MHz, DMSO-d6): δ 7.92 (dd, J = 8.1, 1.7 Hz, 1H), 7.79 (dd, J = 8.1, 1.7 Hz 1H), 7.59 (t, J = 8
Hz, 1H)
5.1.16. 5-([1,1’-Biphenyl]-4-1yl-1H-tetrazole (4p)
The procedure described for the preparation of 4a was used with compound 3p (538 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
toluene (80 mL) to provide 4p as white solid as white solid (473 mg, 70%). Mp: 247–249 ℃. 1H
NMR (300 MHz, DMSO-d6): δ 7.46 (d, J = 4 Hz, 2H), 7.44 (d, J = 12.4 Hz, 2H), 7.32 (s, 2H),
7.23 (t, J = 6.4 Hz, 1H), 6.68 (d, J = 8 Hz, 2H).
5.1.17. 5-(Naphthalen-1yl)-1H-tetrazole (4q)
The procedure described for the preparation of 4a was used with compound 3q (460 mg, 3
mmol), sodium azide (586 mg, 9 mmol), and triethylamine hydrochloride (1.24 g, 9 mmol) in
1
toluene (80 mL) to provide 4q as white solid (477 mg, 81%). Mp: 212–214 ℃. H NMR (300
MHz, DMSO-d6): δ 8.59–8.56 (m, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.10–8.06 (m, 1H), 7.99 (d, J =
7.2, 1.2 Hz, 1H) 7.73–7.62 (m, 3H).
5.1.18. 1-(2-Chloroethyl)-5-phenyl-1H-tetrazole (5a)
Compound 4a (200 mg, 1.36 mmol) was dissolved in acetone (10 mL), potassium carbonate
(K2CO3, 376 mg, 2.72 mmol) was added and followed by dropwise addition of 1-bromo-2-
chloroethane (0.17 mL, 2.04 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) = 5:1 to obtain 5a
1
(140 mg, 49%) as clear liquid. Retention factor (Rf) = 0.74 (n-hexane: EtOAc = 1:1). H NMR
(300 MHz, CDCl3): δ 8.17–8.13 (m, 2H), 7.54–7.44 (m, 3H), 4.96 (t, J = 6.3 Hz, 2H), 4.08 (t, J =
6.3 Hz, 2H).

5.1.19. 1-(2-Chloroethyl)-5-(3-(trifluoromethyl)phenyl)-1H-tetrazole (5b)
The procedure described for the preparation of 5a was used with compound 4b (500 mg, 2.33
mmol), K2CO3 (644 mg, 4.66 mmol) and 1-bromo-2-chloroethane (0.29 mL, 3.5 mmol.) to
obtain 5b (567 mg, 88%) as clear liquid. Rf = 0.57 (n-hexane: EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): δ 8.40–8.31 (m, 2H), 7.72–7.58 (m, 2H), 4.99 (t, J = 6 Hz, 2H), 4.11–4.09 (m, 2H).
5.1.20. 1-(3-(1-(2-Chloroethyl)-1H-tetrazol-5-yl)phenyl)ethanone (5c)
The procedure described for the preparation of 5a was used with compound 4b (400 mg, 2.12
mmol), K2CO3 (586 mg, 4.24 mmol) and 1-bromo-2-chloroethane (0.26 mL, 3.18 mmol.) to
obtain 5c (255 mg, 48%) as white solid. Rf = 0.73 (n-hexane: EtOAc = 2:1). Mp = 83-85 ℃. 1H
NMR (500 MHz, CDCl3): δ 8.73–8.72 (m, 1H), 8.38–8.36 (m, 1H), 8.10–8.08 (m, 1H), 7.64–
7.61 (m, 1H), 5.02–5.00 (m, 2H), 4.13–4.11 (m, 2H), 2.71 (s, 3H).
5.1.21. 1-(2-Chloroethyl)-5-(4-nitrophenyl)-1H-tetrazole (5d)
The procedure described for the preparation of 5a was used with compound 4d (200 mg, 1.05
mmol), K2CO3 (289 mg, 2.1 mmol) and 1-bromo-2-chloroethane (0.13 mL, 1.56 mmol.) to
obtain 5d (120 mg, 45%) as clear liquid. Rf = 0.77 (n-hexane: EtOAc = 1:1. 1H NMR (300 MHz,
CDCl3): δ 8.35 (s, 4H), 5.06–5.02 (m, 2H), 4.13 (t, J = 6 Hz, 2H)
5.1.22. 1-(2-Chloroethyl)-5-(4-methoxyphenyl)-1H-tetrazole (5e)
The procedure described for the preparation of 5a was used with compound 4e (300 mg, 1.70
mmol), K2CO3 (470 mg, 3.40 mmol) and 1-bromo-2-chloroethane (0.17 mL, 2.04 mmol.) to
obtain 5e (263 mg, 65%) as clear liquid. Rf = 0.25 (n-hexane: EtOAc = 4:1). 1H NMR (300 MHz,

CDCl3): δ 8.12–8.07 (m, 2H), 7.04–6.99 (m, 2H), 4.96 (t, J = 6.3 Hz, 2H), 4.11–4.06 (m, 2H),
3.88 (s, 3H).
5.1.23. 1-(2-Chloroethyl)-5-(2-flurophenyl)-1H-tetrazole (5f)
The procedure described for the preparation of 5a was used with compound 4f (450 mg, 2.12
mmol), K2CO3 (757 mg, 5.48 mmol) and 1-bromo-2-chloroethane (0.40 mL, 4.11 mmol.) to
obtain 5f (446 mg, 72%) as clear liquid. Rf = 0.62 (n-hexane: EtOAc = 2:1). Mp = 83-85 ℃. 1H
NMR (500 MHz, CDCl3): δ 8.18–8.14 (m, 1H), 7.05–7.46 (m, 1H), 7.31–7.23 (m, 2H), 5.04–
5.01 (m, 2H), 4.12–4.09 (m, 2H).
5.1.24. 1-(2-Chloroethyl)-5-(3-flurophenyl)-1H-tetrazole (5g)
The procedure described for the preparation of 5a was used with compound 4g (300 mg, 1.82
mmol), K2CO3 (503 mg, 3.64 mmol) and 1-bromo-2-chloroethane (0.22 mL, 2.73 mmol.) to
obtain 5g (330 mg, 80%) as clear liquid. Rf = 0.64 (n-hexane: EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): δ 7.95–7.93 (m, 1H), 7.86–7.83 (m, 1H), 7.48–7.44 (m, 1H), 7.19–7.15 (m, 1H), 4.99–
4.97 (m, 2H), 4.09 (t, J = 6 Hz, 2H).
5.1.25. 1-(2-Chloroethyl)-5-(4-flurophenyl)-1H-tetrazole (5h)
The procedure described for the preparation of 5a was used with compound 4h (300 mg, 1.82
mmol), K2CO3 (503 mg, 3.64 mmol) and 1-bromo-2-chloroethane (0.22 mL, 2.73 mmol.) to
obtain 5h (214 mg, 52%) as white solid. Rf = 0.54 (n-hexane: EtOAc = 2:1). Mp = 60-62 ℃. 1H
NMR (500 MHz, CDCl3): δ 8.18–8.14 (m, 2H), 7.22–7.17 (m, 2H), 4.99–4.97 (m, 2H), 4.11–
4.08 (m, 2H).
5.1.26. 1-(2-Chloroethyl)-5-(2-chlorophenyl)-1H-tetrazole (5i)

The procedure described for the preparation of 5a was used with compound 4i (350 mg, 1.93
mmol), K2CO3 (534 mg, 3.86 mmol) and 1-bromo-2-chloroethane (0.24 mL, 2.89 mmol.) to
obtain 5i (328 mg, 70%) as clear liquid. Rf = 0.54 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.98–7.94 (m, 1H), 7.55–7.52 (m, 1H), 7.44–7.35 (m, 2H), 5.03–5.01 (m, 2H), 4.11 (t,
J = 6 Hz, 2H).
5.1.27. 1-(2-Chloroethyl)-5-(3-chlorophenyl)-1H-tetrazole (5j)
The procedure described for the preparation of 5a was used with compound 4j (350 mg, 1.93
mmol), K2CO3 (534 mg, 3.86 mmol) and 1-bromo-2-chloroethane (0.19 mL, 2.31 mmol.) to
1
obtain 5j (352 mg, 75%) as white solid. Rf = 0.60 (n-hexane: EtOAc = 2:1). Mp = 72-74 ℃. H
NMR (500 MHz, CDCl3): δ 8.12–8.09 (m, 2H), 7.50–7.47 (m, 2H), 5.00–4.97 (m, 2H), 4.11–
4.08 (m, 2H).
5.1.28. 1-(2-Chloroethyl)-5-(4-chlorophenyl)-1H-tetrazole (5k)
The procedure described for the preparation of 5a was used with compound 4k (200 mg, 1.10
mmol), K2CO3 (304 mg, 2.20 mmol) and 1-bromo-2-chloroethane (0.13 mL, 1.65 mmol.) to
obtain 5k (147 mg, 52%) as clear liquid. Rf = 0.40 n-hexane: EtOAc = 4:1). 1H NMR (300 MHz,
CDCl3): δ 8.11–8.06 (m, 2H), 7.49–7.44 (m, 2H), 4.97 (t, J = 6.3 Hz, 2H), 4.09 (t, J = 6.3 Hz,
2H).
5.1.29. 1-(2-Chloroethyl)-5-(2-bromophenyl)-1H-tetrazole (5l)
The procedure described for the preparation of 5a was used with compound 4l (400 mg, 1.77
mmol), K2CO3 (489 mg, 3.54 mmol) and 1-bromo-2-chloroethane (0.22 mL, 2.65 mmol.) to
obtain 5l (356 mg, 70%) as clear liquid. Rf = 0.61 (n-hexane: EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): δ 7.85–7.83 (m, 1H), 7.72–7.70 (m, 1H), 7.43–7.39 (m, 1H), 7.33–7.29 (m, 1H), 5.02–
4.99 (m, 2H), 4.10–4.07 (m, 2H).

5.1.30. 1-(2-Chloroethyl)-5-(3-bromophenyl)-1H-tetrazole (5m)
The procedure described for the preparation of 5a was used with compound 4m (400 mg, 1.77
mmol), K2CO3 (489 mg, 3.54 mmol) and 1-bromo-2-chloroethane (0.22 mL, 2.65 mmol.) to
obtain 5m (356 mg, 70%) as white solid. Rf = 0.64 (n-hexane: EtOAc = 2:1). Mp = 63-65 ℃. 1H
NMR (500 MHz, CDCl3): δ 8.32–8.31 (m, 1H), 8.10–8.08 (m, 1H), 7.62–7.59 (m, 1H), 7.38–
7.35 (m, 1H), 4.98 (t, J = 6 Hz, 2H), 4.11–4.08 (m, 2H).
5.1.31. 1-(2-Chloroethyl)-5-(4-bromophenyl)-1H-tetrazole (5n)
The procedure described for the preparation of 5a was used with compound 4n (280 mg, 1.16
mmol), K2CO3 (320 mg, 2.32 mmol) and 1-bromo-2-chloroethane (0.14 mL, 1.74 mmol.) to
obtain 5n (185 mg, 52%) as white solid. Rf = 0.70 (n-hexane: EtOAc = 2:1). Mp = 348-350 ℃.
1H NMR (300 MHz, CDCl3): δ 8.05–8.01 (m, 2H), 7.66–7.61 (m, 2H), 4.98 (t, J = 6.3 Hz, 2H),
4.11–4.07 (m, 2H).
5.1.32. 1-(2-Chloroethyl)-5-(2,3-dichlorophenyl)-1H-tetrazole (5o)
The procedure described for the preparation of 5a was used with compound 4o (430 mg, 1.99
mmol), K2CO3 (550 mg, 3.98 mmol) and 1-bromo-2-chloroethane (0.25 mL, 2.99 mmol.) to
obtain 5o (441 mg, 80%) as clear liquid. Rf = 0.77 (n-hexane: EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): δ 7.87–7.84 (m, 1H), 7.63–7.60 (m, 1H), 7.37–7.32 (m, 1H), 5.06–5.02 (m, 2H), 4.11 (t,
J = 6.3 Hz, 2H).
5.1.33. 5-([1,1'-Biphenyl]-4-yl)-1-(2-chloroethyl)-1H-tetrazole (5p)
The procedure described for the preparation of 5a was used with compound 4p (400 mg, 1.79
mmol), K2CO3 (495 mg, 3.58 mmol) and 1-bromo-2-chloroethane (0.18 mL, 2.15 mmol.) to

obtain 5p (357 mg, 70%) as white solid. Rf = 0.51 (n-hexane: EtOAc = 2:1). Mp = 93-95 ℃. 1H
NMR (500 MHz, CDCl3): δ 8.25–8.23 (m, 2H), 7.76–7.73 (m, 2H), 7.67–7.65 (m, 2H), 7.50–
7.46 (m, 2H), 7.41–7.38 (m, 1H), 5.02–4.99 (m, 2H), 4.13–4.10 (m, 2H).
5.1.34. 1-(2-Chloroethyl)-5-(naphthalen-1-yl)-1H-tetrazole (5q)
The procedure described for the preparation of 5a was used with compound 4p (261 mg, 1.01
mmol), K2CO3 (279 mg, 2.02 mmol) and 1-bromo-2-chloroethane (0.12 mL, 1.51 mmol.) to
1
obtain 5q (130 mg, 50%) as clear liquid. Rf = 0.90 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). H
NMR (300 MHz, CDCl3): δ 8.90–8.87 (m, 1H), 8.27 (dd, J = 7.2, 1.2 Hz, 1H), 8.01–7.09 (m,
2H), 7.65–7.53 (m, 3H), 5.07 (t, J = 6.3 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H).
5.1.35. 1-(3-Chloropropyl)-5-phenyl-1H-tetrazole (6a)
The procedure described for the preparation of 5a was used with compound 4a (450 mg, 3.07
mmol), K2CO3 (834 mg, 6.04 mmol) and 1-bromo-3-chloropropane (0.38 mL, 4.60 mmol.) to
obtain 6a (481 mg, 81%) as clear liquid. Rf = 0.56 (n-hexane: EtOAc = 1:1). 1H NMR (500 MHz,
CDCl3): δ 8.16–8.11 (m, 2H), 7.52–7.45 (m, 3H), 4.85 (t, J = 6.6 Hz, 2H), 3.65–3.61 (m, 2H),
2.57–2.48 (m, 2H).
5.1.36. 1-(3-Chloropropyl)-5-(3-(trifluoromethyl)phenyl)-1H-tetrazole (6b)
The procedure described for the preparation of 5a was used with compound 4b (600 mg, 2.80
mmol), K2CO3 (774 mg, 5.60 mmol) and 1-bromo-3-chloropropane (0.41 mL, 4.20 mmol.) to
obtain 6b (757 mg, 93%) as clear liquid. Rf = 0.57 (n-hexane: EtOAc = 2:1). 1H NMR (300 MHz,
CDCl3): δ 8.41–8.31 (m, 2H), 7.74–7.59 (m, 2H), 4.91–4.86 (m, 2H), 3.67–3.63 (m, 2H), 2.60–
2.52 (m, 2H).

5.1.37. 1-(3-(1-(3-Chloropropyl)-1H-tetrazol-5-yl)phenyl)ethanone (6c)
The procedure described for the preparation of 5a was used with compound 4c (500 mg, 2.65
mmol), K2CO3 (732 mg, 5.30 mmol) and 1-bromo-3-chloropropane (0.39 mL, 3.98 mmol.) to
obtain 6c (547 mg, 78%) as clear liquid. Rf = 0.42 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 8.73–8.72 (m, 1H), 8.37–8.33 (m, 1H), 8.10–8.06 (m, 1H), 7.64–7.59 (m, 1H), 4.89 (t,
J = 6.6 Hz, 2H), 3.65 (t, J = 6 Hz, 2H), 2.69 (s, 3H),.2.60–2.52 (m, 2H).
5.1.38. 1-(3-Chloropropyl)-5-(4-nitrophenyl)-1H-tetrazole (6d)
The procedure described for the preparation of 5a was used with compound 4d (450 mg, 2.35
mmol), K2CO3 (652 mg, 4.70 mmol) and 1-bromo-3-chloropropane (0.34 mL, 3.53 mmol.) to
obtain 6d (276 mg, 44%) as white solid. Rf = 0.62 (n-hexane: EtOAc = 1:1). Mp = 80-82 ℃. 1H
NMR (300 MHz, CDCl3): δ 8.36–8.30 (s, 4H), 4.95–4.91 (m, 2H), 3.70–3.66 (m, 2H), 2.63–2.54
(m, 2H).
5.1.39. 1-(3-Chloropropyl)-5-(4-methoxyphenyl)-1H-tetrazole (6e)
The procedure described for the preparation of 5a was used with compound 4e (594 mg, 3.37
mmol), K2CO3 (937 mg, 6.74 mmol) and 1-bromo-3-chloropropane (0.49 mL, 5.0 mmol.) to
obtain 6e (732 mg, 86%) as clear liquid. Rf = 0.36 (n-hexane: EtOAc = 4:1). 1H NMR (600 MHz,
CDCl3): δ 8.08–8.05 (m, 2H), 7.01–6.98 (m, 2H), 4.82 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 3.64 (t, J
= 3 Hz, 2H), 2.53–2.49 (s, 2H).
5.1.40. 1-(3-Chloropropyl)-5-(2-fluorophenyl)-1H-tetrazole (6f)
The procedure described for the preparation of 5a was used with compound 4f (450 mg, 2.74
mmol), K2CO3 (757 mg, 5.48 mmol) and 1-bromo-3-chloropropane (0.40 mL, 4.11 mmol.) to
obtain 6f (600 mg, 91%) as clear liquid. Rf = 0.29 (n-hexane: EtOAc = 4:1). Mp = 83–85 ℃. 1H

NMR (300 MHz, CDCl3): δ 8.16–8.10 (m, 1H), 7.51–7.43 (m, 1H), 7.31–7.20 (m, 2H), 4.92–
4.88 (m, 2H), 3.67–3.63 (m, 2H), 2.59–2.51 (m, 2H).
5.1.41. 1-(3-Chloropropyl)-5-(3-fluorophenyl)-1H-tetrazole (6g)
The procedure described for the preparation of 5a was used with compound 4g (480 mg, 2.92
mmol), K2CO3 (807 mg, 5.84 mmol) and 1-bromo-3-chloropropane (0.43 mL, 4.38 mmol.) to
obtain 6g (632 mg, 90%) as clear liquid. Rf = 0.64 (n-hexane: EtOAc = 2:1). 1H NMR (300 MHz,
CDCl3): δ 7.95–7.94 (m, 1H), 7.85–7.81 (m, 1H), 7.49–7.42 (m, 1H), 7.20–7.13 (m, 1H), 4.88–
4.84 (m, 2H), 3.66–3.62 (m, 2H), 2.58–2.49 (m, 2H).
5.1.42. 1-(3-Chloropropyl)-5-(4-fluorophenyl)-1H-tetrazole (6h)
The procedure described for the preparation of 5a was used with compound 4h (200 mg, 1.21
mmol), K2CO3 (334 mg, 2.42 mmol) and 1-bromo-3-chloropropane (0.18 mL, 1.81 mmol.) to
obtain 6h (241 mg, 83%) as clear liquid. Rf = 0.66 (n-hexane: EtOAc = 2:1). 1H NMR (300 MHz,
CDCl3): δ 8.17–8.10 (m, 2H), 7.22–7.14 (m, 2H), 4.85 (t, J = 6.6 Hz, 2H) 2H), 3.66–3.62 (m,
2H), 2.57–2.49 (m, 2H).
5.1.43. 5-(2-Chlorophenyl)-1-(3-chloropropyl)-1H-tetrazole (6i)
The procedure described for the preparation of 5a was used with compound 4i (200 mg, 1.10
mmol), K2CO3 (304 mg, 2.20 mmol) and 1-bromo-3-chloropropane (0.16 mL, 1.65 mmol.) to
obtain 6i (237 mg, 84%) as clear liquid. Rf = 0.54 (n-hexane: EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): δ 7.96–7.93 (m, 1H), 7.55–7.52 (m, 1H), 7.44–7.38 (m, 2H), 4.90 (t, J = 6.6 Hz, 2H),
3.68–3.64 (m, 2H), 2.59–2.50 (m, 2H).
5.1.44. 5-(3-Chlorophenyl)-1-(3-chloropropyl)-1H-tetrazole (6j)

The procedure described for the preparation of 5a was used with compound 4j (520 mg, 2.87
mmol), K2CO3 (793 mg, 5.74 mmol) and 1-bromo-3-chloropropane (0.42 mL, 4.30 mmol) to
obtain 6j (657 mg, 89%) as clear liquid. Rf = 0.50 (n-hexane: EtOAc = 4:1). 1H NMR (300 MHz,
CDCl3): δ 8.11–7.98 (m, 2H), 7.44–7.37 (m, 2H), 4.85 (t, J = 6.6 Hz, 2H), 3.66–3.62 (m, 2H),
2.57–2.48 (m, 2H).
5.1.45. 5-(4-Chlorophenyl)-1-(3-chloropropyl)-1H-tetrazole (6k)
The procedure described for the preparation of 5a was used with compound 4k (637 mg, 3.52
mmol), K2CO3 (972 mg, 7.04 mmol) and 1-bromo-3-chloropropane (0.52 mL, 5.28 mmol.) to
obtain 6k (497 mg, 55%) as clear liquid. Rf = 0.48 n-hexane: EtOAc = 4:1). 1H NMR (600 MHz,
CDCl3): δ 8.08–8.06 (m, 2H), 7.47–7.44 (m, 2H), 4.86–4.84 (m, 2H), 3.64–3.62 (m, 2H), 2.55–
2.51 (m, 2H).
5.1.46. 5-(2-Bromophenyl)-1-(3-chloropropyl)-1H-tetrazole (6l)
The procedure described for the preparation of 5a was used with compound 4l (300 mg, 1.33
mmol), K2CO3 (368 mg, 2.66 mmol) and 1-bromo-3-chloropropane (0.19 mL, 1.9 mmol.) to
obtain 6l (300 mg, 75%) as clear liquid. Rf = 0.64 (n-hexane: EtOAc = 2:1). 1H NMR (300 MHz,
CDCl3): δ 8.28–8.21 (m, 1H), 8.01 (dd, J = 7.8, 1.2 Hz, 1H), 7.56 –7.52 (m, 1H), 7.34–7.28 (m,
1H), 4.84 (t, J = 6.6 Hz, 2H), 3.67–3.62 (m, 2H), 2.56–2.48 (m, 2H).
5.1.47. 5-(3-Bromophenyl)-1-(3-chloropropyl)-1H-tetrazole (6m)
The procedure described for the preparation of 5a was used with compound 4m (250 mg, 1.11
mmol), K2CO3 (460 mg, 3.33 mmol) and 1-bromo-3-chloropropane (0.16 mL, 1.66 mmol.) to
1
obtain 6m (268 mg, 80%) as clear liquid. Rf = 0.61 (n-hexane: EtOAc = 2:1). H NMR (300
MHz, CDCl3): δ 7.85 (ddd, J = 7.5, 1.8, 0.3 Hz, 1H), 7.74–7.71 (m, 1H), 7.45–7.29 (m, 2H), 4.87
(t, J = 6.6 Hz, 2H), 3.67–3.63 (m, 2H), 2.57–2.49 (m, 2H).

5.1.48. 5-(4-Bromophenyl)-1-(3-chloropropyl)-1H-tetrazole (6n)
The procedure described for the preparation of 5a was used with compound 4n (1300 mg, 5.77
mmol), K2CO3 (2392 mg, 17.31 mmol) and 1-bromo-3-chloropropane (0.5 mL, 8.6 mmol.) to
1
obtain 6n (1496 mg, 86%) as clear liquid. Rf = 0.51 (n-hexane: EtOAc = 4:1). H NMR (300
MHz, CDCl3): δ 7.99–7.94 (m, 2H), 7.60–7.56 (m, 2H), 4.86–4.81 (m, 2H), 3.65–3.61 (m, 2H),
2.56–2.47 (m, 2H).
5.1.49. 1-(3-Chloropropyl)-5-(2,3-dichlorophenyl)-1H-tetrazole (6o)
The procedure described for the preparation of 5a was used with compound 4o (215 mg, 1.0
mmol), K2CO3 (276 mg, 2 mmol) and 1-bromo-3-chloropropane (0.14 mL, 1.5 mmol.) to obtain
1
6o (248 mg, 85%) as clear liquid. Rf = 0.54 (n-hexane: EtOAc = 1:1). H NMR (300 MHz,
CDCl3): δ 7.82 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 (dd, J = 8.1, 1.5 Hz, 1H), 7.36–7.31 (m, 1H),
4.94–4.89 (m, 2H), 3.68–3.64 (m, 2H), 2.60–2.51 (m, 2H).
5.1.50. 5-([1,1'-Biphenyl]-4-yl)-1-(3-chloropropyl)-1H-tetrazole (6p)
The procedure described for the preparation of 5a was used with compound 4p (450 mg, 2.02
mmol), K2CO3 (558 mg, 4.04 mmol) and 1-bromo-3-chloropropane (0.30 mL, 3.03 mmol.) to
obtain 6p (471 mg, 78%) as clear liquid. Rf = 0.67 (n-hexane: EtOAc = 2:1). 1H NMR (300 MHz,
CDCl3): δ 8.23–8.19 (m, 2H), 7.74–7.62 (m, 4H), 7.49–7.35 (m, 3H), 4.88–4.84 (m, 2H), 3.66–
3.62 (m, 2H), 2.58–2.50 (m, 2H).
5.1.51. 1-(3-Chloropropyl)-5-(naphthalen-1-yl)-1H-tetrazole (6q)
The procedure described for the preparation of 5a was used with compound 4q (500 mg, 2.54
mmol), K2CO3 (702 mg, 5.08 mmol) and 1-bromo-3-chloropropane (0.37 mL, 3.81 mmol.) to

obtain 6q (457 mg, 66%) as clear liquid. Rf = 0.42 (n-hexane: EtOAc = 4:1). 1H NMR (300 MHz,
CDCl3): δ 8.91–8.18 (m, 1H), 8.26 (dd, J = 7.2, 1.2 Hz, 1H), 8.00–7.90 (m, 2H), 7.64–7.52 (m,
3H), 4.96–4.91 (m, 2H), 3.69–3.65 (m, 2H), 2.63–2.54 (m, 2H).
5.1.52. 4-Benzyl-1-(2-(5-phenyl-1H-tetrazol-1-yl)ethyl)piperidine (1a)
The mixture of compound 5a (140 mg, 0.67 mmol), 4-benzylpiperidine (0.14 mL, 0.80 mmol),
TEA (0.28 mL, 2.01 mmol) and DMSO (1 mL) was stirred at 100 ℃. 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
1
obtain 1a (81 mg, 35%) as liquid. Rf = 0.66 (n-hexane: EtOAc =1:1). H NMR (300 MHz,
CDCl3): δ 8.15–8.12 (m, 2H), 7.52–7.45 (m, 3H), 7.29–7.16 (m, ≈ 5H, overlapped with CHCl3
peak), 4.78–4.73 (m, 2H), 3.01 (t, J = 6.9 Hz, 2H), 2.91 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 6.9 Hz,
2H), 2.08–2.01 (m, 2H), 1.63–1.45 (m, 3H), 1.41–1.30 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
164.9, 140.7, 130.1, 129.0, 128.9, 128.8, 128.1, 127.4, 126.7, 125.7, 56.9, 53.7, 50.7, 43.0, 37.6,
31.9, 29.6. MS (ESI): m/z 348.2 (M+H) +.
5.1.53. 4-Benzyl-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1b)
The procedure described for the preparation of 1a was used with compound 5b (300 mg, 1.08
mmol), 4-benzylpiperidine (0.22 mL, 1.29 mmol), TEA (0.45 mL, 3.24 mmol) and DMSO (2 mL)
1
to obtain 1b (197 mg, 44%) as liquid. Rf = 0.56 (n-hexane: EtOAc = 2:1). H NMR (500 MHz,
CDCl3): δ 8.43 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.74–7.61 (m, 2H), 7.29–7.12 (m, 5H), 4.80–
4.77 (m, 2H), 3.04–3.01 (m, 2H), 2.91 (d, J = 11.5 Hz, 2H), 2.51 (d, J = 7 Hz, 2H), 2.08–2.03 (m,
2H), 1.64–1.47 (m, 3H), 1.30–1.22 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 163.8, 140.5, 131.4
(d, J = 32.5 Hz), 129.9, 129.4, 129.1, 128.2, 126.7 (q, J = 12.5 Hz), 125.8, 123.6 (q, J = 3.7 Hz),
121.6 (d, J = 271.2 Hz), 56.9, 53.8, 51.0, 43.1, 37.7, 32.1. MS (ESI): m/z 416.1 (M+H) +.

5.1.54. 1-(3-(1-(2-(4-Benzylpiperidin-1-yl)ethyl)-1H-tetrazol-5-yl)phenyl)ethanone (1c)
The procedure described for the preparation of 1a was used with compound 5c (290 mg, 1.15
mmol), 4-benzylpiperidine (0.24 mL, 1.38 mmol), TEA (0.48 mL, 3.45 mmol) and DMSO (2 mL)
1
to obtain 1c (291 mg, 65%) as liquid. Rf = 0.34 (n-hexane: EtOAc = 2:1). H NMR (300 MHz,
CDCl3): δ 8.71–8.70 (m, 1H), 8.36–8.30 (m, 1H), 8.08–8.05 (m, 1H), 7.63–7.58 (m, 1H), 7.25–
7.03 (m, 5H), 4.80–4.75 (m, 2H), 3.02 (t, J = 6.9 Hz, 2H), 2.91 (d, J = 11.4 Hz, 2H), 2.69 (s, 3H),
13
2.50 (d, J = 6.9 Hz, 2H), 2.09–2.02 (m, 2H), 1.61–1.47 (m, 3H), 1.30–1.23 (m, 2H); C NMR
(125 MHz, CDCl3): 197.5, 164.2, 140.5, 137.7, 133.4, 131.2, 129.8, 129.3, 129.1, 128.2, 128.1,
126.8, 125.8, 56.7, 53.7, 50.9, 43.1, 37.6, 32.0, 26.7. MS (ESI): m/z 390.8 (M+H) +.
5.1.55. 4-Benzyl-1-(2-(5-(4-nitrophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1d)
The procedure described for the preparation of 1a was used with compound 5d (120 mg, 0.47
mmol), 4-benzylpiperidine (0.1 mL, 0.56 mmol), TEA (0.19 mL, 1.41 mmol) and DMSO (1 mL)
to obtain 1d (59 mg, 32%) as liquid. Rf = 0.73 (n-hexane: EtOAc: MeOH = 2.5:1.5:1). 1H NMR
(300 MHz, CDCl3): δ 8.34 (s, 4H), 7.28–7.10 (m, 5H), 4.80–4.76 (m, 2H), 3.03–2.99 (m, 2H),
2.90 (d, J = 10.8 Hz, 2H), 2.50 (d, J = 6.3 Hz, 2H), 2.08–2.01 (m, 2H), 1.63–1.50 (m, 3H), 1.41–
1.28 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 163.1, 148.8, 140.5, 133.4, 129.1, 128.2, 127.3,
125.8, 124.2, 56.8, 53.8, 51.1, 43.1, 37.7, 32.1. MS (ESI): m/z 393.7 (M+H) +.
5.1.56. 4-Benzyl-1-(2-(5-(4-methoxyphenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1e)
The procedure described for the preparation of 1a was used with compound 5e (200 mg, 0.83
mmol), 4-benzylpiperidine (0.18 mL, 0.99 mmol), TEA (0.34 mL, 2.49 mmol) and DMSO (2 mL)
1
to obtain 1e (128 mg, 41%) as solid. Rf = 0.31 (n-hexane: EtOAc = 2:1). Mp = 110–113 °C. H
NMR (500 MHz, CDCl3): δ 8.10–8.07 (m, 2H), 7.29–6.99 (m, 7H), 4.74 (t, J = 7 Hz, 2H), 3.87
(s, 3H), 3.01 (t, J = 7 Hz, 2H), 2.91 (d, J = 11.5 Hz, 2H), 2.51 (d, J = 7.5 Hz, 2H), 2.08–2.03 (m,
2H), 1.63–1.47 (m, 3H), 1.30–1.22 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 164.9, 161.2, 140.5,

129.1, 128.3, 128.2, 125.8, 120.1, 114.3, 57.0, 55.4, 53.8, 50.7, 43.1, 37.7, 32.1, 29.7. MS (ESI):
m/z 378.2 (M+H) +.
5.1.57. 4-Benzyl-1-(2-(5-(3-fluorophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1g)
The procedure described for the preparation of 1a was used with compound 5g (230 mg,
1.01mmol), 4-benzylpiperidine (0.21 mL, 1.21 mmol), TEA (0.42 mL, 3.03 mmol) and DMSO
(2 mL) to obtain 1g (153 mg, 42%) as solid. Rf = 0.41 (n-hexane: EtOAc = 2:1). Mp = 100–
1
103 °C. H NMR (500 MHz, CDCl3): δ 7.96–7.93 (m, 2H), 7.86–7.84 (m, 1H), 7.48–7.12 (m, ≈
6H, overlapped with CHCl3 peak), 4.76 (t, J = 7 Hz, 2H), 3.02–3.0 (m, 2H), 2.91 (d, J = 11.5 Hz,
2H), 2.51 (d, J = 7 Hz, 2H), 2.08–2.03 (m, 2H), 1.63–1.47 (m, 3H), 1.29–1.23 (m, 2H), 13C NMR
(125 MHz, CDCl3): δ 164.0 (d, J = 12.5 Hz), 163.9, 162.1, 140.5, 130.5 (d, J = 12.5 Hz), 129.5
(d, J = 12.5 Hz), 129.1, 128.2, 125.8, 122.4 (d, J = 12.5 Hz), 117.1 (d, J = 12.5 Hz), 113.7 (d, J =
25 Hz), 56.9, 53.8, 50.9, 43.1, 37.7, 32.1. MS (ESI): m/z 366.3 (M+H) +.
5.1.58. 4-Benzyl-1-(2-(5-(4-fluorophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1h)
The procedure described for the preparation of 1a was used with compound 5h (300 mg, 1.32
mmol), 4-benzylpiperidine (0.28 mL, 1.58 mmol), TEA (0.55 mL, 3.96 mmol) and DMSO (2 mL)
to obtain 1h (178 mg, 37%) as liquid. Rf = 0.46 (n-hexane: EtOAc = 1:1). 1H NMR (500 MHz,
CDCl3): δ 8.16–8.12 (m, 2H), 7.29–7.12 (m, 7H), 4.75 (t, J = 7 Hz, 2H), 3.01 (t, J = 7 Hz, 2H),
2.91 (d, J = 11.5 Hz, 2H), 2.52 (d, J = 7 Hz, 2H), 2.08–2.03 (m, 2H), 1.63–1.48 (m, 3H), 1.30–
13
1.22 (m, 2H); C NMR (125 MHz, CDCl3): δ 165.0, 164.2, 163.0, 140.5, 129.1, 128.8 (d, J =
12.5 Hz), 128.2, 125.8, 123.7 (d, J = 12.5 Hz), 116.0 (d, J = 25 Hz), 56.9, 53.8, 50.8, 43.1, 37.7,
32.0. MS (ESI): m/z 366.0 (M+H) +.
5.1.59. 4-Benzyl-1-(2-(5-(3-chlorophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1j)

The procedure described for the preparation of 1a was used with compound 5j (250 mg, 1.02
mmol), 4-benzylpiperidine (0.22 mL, 1.22 mmol), TEA (0.42 mL, 3.06 mmol) and DMSO (2 mL)
1
to obtain 1j (156 mg, 40%) as solid. Rf = 0.44 (n-hexane: EtOAc = 4:1). Mp = 90–94 °C. H
NMR (300 MHz, CDCl3): δ 8.10–8.06 (m, 2H), 7.48–7.43 (m, 2H), 7.29–7.10 (m, ≈ 5H,
overlapped with CHCl3 peak), 4.77–4.72 (m, 2H), 2.99 (t, J = 6.9 Hz, 2H), 2.90 (d, J = 11.4 Hz,
2H), 2.50 (d, J = 7 Hz, 2H), 2.08–2.01 (m, 2H), 1.63–1.43 (m, 3H), 1.31–1.17 (m, 2H); 13C
NMR (125 MHz, CDCl3): δ 164.1, 140.5, 136.2, 129.1, 129.0, 128.2, 128.1, 126.0, 125.8, 56.9,
53.8, 50.9, 43.1, 37.7, 32.1, 29.7. MS (ESI): m/z 404.9 (M+Na) +.
5.1.60. 4-Benzyl-1-(2-(5-(4-chlorophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1k)
The procedure described for the preparation of 1a was used with compound 5k (250 mg, 1.02
mmol), 4-benzylpiperidine (0.21 mL, 1.22 mmol), TEA (0.42 mL, 3.06 mmol) and DMSO (2 mL)
1
to obtain 1k (148 mg, 38%) as solid. Rf = 0.39 (n-hexane: EtOAc = 1:1). Mp = 92–94 °C. H
NMR (600 MHz, CDCl3): δ 8.09–8.07 (m, 2H), 7.47–7.45 (m, 2H), 7.28–7.11 (m, ≈ 5H,
overlapped with CHCl3 peak), 4.76–4.73 (m, 2H), 3.01–2.98 (m, 2H), 2.90 (d, J = 11.4 Hz, 2H),
13
2.50 (d, J = 7.2 Hz, 2H), 2.06–2.02 (m, 2H), 1.62–1.47 (m, 3H), 1.28–1.21 (m, 2H); C NMR
(125 MHz, CDCl3): δ 164.1, 140.5, 136.2, 129.1, 129.0, 128.2, 128.1, 126.0, 125.8, 56.9, 53.8,
50.9, 43.1, 37.7, 32.1. MS (ESI): m/z 382.0 (M+H)+.
5.1.61. 4-Benzyl-1-(2-(5-(2-bromophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1l)
The procedure described for the preparation of 1a was used with compound 5l (300 mg, 1.04
mmol), 4-benzylpiperidine (0.22 mL, 1.24 mmol), TEA (0.43 mL, 3.12 mmol) and DMSO (2 mL)
to obtain 1l (275 mg, 64%) as liquid. Rf = 0.44 (n-hexane: EtOAc = 2:1). 1H NMR (500 MHz,
CDCl3): δ 7.86–7.84 (m, 2H), 7.74–7.73 (m, 1H), 7.44–7.41 (m, 3H) 7.20–7.16 (m, 1H), 7.13–
7.12 (m, 2H), 4.81–4.78 (m, 2H), 3.04–3.02 (m, 2H), 2.90 (d, J = 11.5 Hz, 2H), 2.51 (d, J = 7.5
Hz, 2H), 2.07–2.02 (m, 2H), 1.62–1.46 (m, 3H), 1.29–1.21 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 164.0, 140.5, 134.0, 131.7, 131.2, 129.1, 128.7, 128.2, 127.4, 125.8, 122.1, 56.9, 53.7,
51.0, 43.1, 37.7, 32.1. MS (ESI): m/z 426.0 (M+H)+.

5.1.62. 4-Benzyl-1-(2-(5-(3-bromophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1m)
The procedure described for the preparation of 1a was used with compound 5m (300 mg, 1.04
mmol), 4-benzylpiperidine (0.22 mL, 1.24 mmol), TEA (0.43 mL, 3.12 mmol) and DMSO (2 mL)
to obtain 1m (310 mg, 70%) as liquid. Rf = 0.50 (n-hexane: EtOAc = 2:1). 1H NMR (600 MHz,
CDCl3): δ 8.30 (s, 1H), 8.08–8.07 (m, 1H), 7.58–7.57 (m, 1H), 7.36–7.10 (m, 6H), 4.75–4.73 (m,
2H), 3.00–2.98 (m, 2H), 2.89 (d, J = 11.4 Hz, 2H), 2.49 (d, J = 7.2 Hz, 2H), 2.05–2.02 (m, 2H),
1.61–1.46 (m, 3H), 1.27–1.20 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 163.7, 140.5, 133.2,
130.4, 129.8, 129.4, 129.1, 128.2, 125.8, 125.3, 122.9, 56.9, 53.8, 50.9, 43.1, 37.7, 32.1. MS
(ESI): m/z 426.5 (M+H) +.
5.1.63. 4-Benzyl-1-(2-(5-(4-bromophenyl)-1H-tetrazol-1-yl)ethyl)piperidine (1n)
The procedure described for the preparation of 1a was used with compound 5n (300 mg, 1.04
mmol), 4-benzylpiperidine (0.22 mL, 1.24 mmol), TEA (0.43 mL, 3.12 mmol) and DMSO (2 mL)
to obtain 1n (168 mg, 38%) as solid. Rf = 0.33 (n-hexane: EtOAc = 1:1). Mp = 104–105 °C. 1H
NMR (600 MHz, CDCl3): δ 8.02–8.00 (m, 2H), 7.63–7.61 (m, 2H), 7.27–7.7.25 (m, ≈ 2H,
overlapped with CHCl3 peak), 7.19–7.16 (m, 1H), 7.12–7.11 (m, 2H), 4.76–4.74 (m, 2H), 3.01–
2.99 (m, 2H), 2.90 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 7.2 Hz, 2H), 2.06–2.02 (m, 2H), 1.61–1.47
(m, 3H), 1.28–1.22 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 164.2, 140.5, 132.1, 129.1, 128.3,
128.2, 126.5, 125.8, 124.6, 56.9, 53.8, 50.9, 43.1, 37.7, 32.1. MS (ESI): m/z 426.1 (M+H) +.
5.1.64. 1-(2-(5-([1,1'-Biphenyl]-4-yl)-1H-tetrazol-1-yl)ethyl)-4-benzylpiperidine (1p)
The procedure described for the preparation of 1a was used with compound 5p (300 mg, 1.05
mmol), 4-benzylpiperidine (0.22 mL, 1.26 mmol), TEA (0.44 mL, 3.15 mmol) and DMSO (2 mL)
to obtain 1p (173 mg, 39%) as solid. Rf = 0.58 (n-hexane: EtOAc = 2:1). Mp = 104–105 °C. 1H
NMR (300 MHz, CDCl3): δ 8.26–8.20 (m, 2H), 7.73–7.71 (m, 2H), 7.65–7.71 (m, 3H), 7.48–
7.45 (m, 1H), 7.39–7.36 (m, 1H), 7.27–7.25 (m, 2H, overlapped with CHCl3 peak), 7.19–7.16 (m,