Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT7 ligands and role of the aromatic substituents in binding to the target receptor

Article abstract of DOI:10.1016/j.bmc.2013.02.038

It has been reported that 5-HT₇ receptors are promising targets of depression and neuropathic pain. 5-HT₇ receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT₇ modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT₇ receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT₇ receptor with K_i values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT₇ receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH₃ substituents within the arylpiperazine and the other for biphenyl methoxy group.

Full text of DOI:10.1016/j.bmc.2013.02.038

Bioorganic & Medicinal Chemistry 21 (2013) 2568–2576
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds
for 5-HT7 ligands and role of the aromatic substituents in binding to
the target receptor
Youngjae Kim a,b, , Jeeyeon Kim a,c, , Jinsung Tae c, Bryan L. Roth d,e, Hyewhon Rhim f, Gyochang Keum a,
Ghilsoo Nam a, ,à, Hyunah Choo a,b,
⇑
⇑
,à
a Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Hwarangro 14-gil-5, Seoul 136-791, Republic of Korea
b Department of Biological Chemistry, University of Science and Technology, Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea
c Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Republic of Korea
d National Institute of Mental Health Psychoactive Drug Screening Program, Division of Medicinal Chemistry and Natural Products, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599, United States
e Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
f Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been reported that 5-HT7 receptors are promising targets of depression and neuropathic pain. 5-
HT7 receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented
potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT7 modulators,
we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphe-
nyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affin-
ities to the 5-HT7 receptor depending upon the substituents attached to the biphenyl and aryl
functionalities. Among those synthesized compounds, the compounds 1–24 and 1–26 showed the best
binding affinities to the 5-HT7 receptor with Ki values of 43.0 and 46.0 nM, respectively. Structure–activ-
ity relationship study in conjunction with molecular docking study proposed that the 5-HT7 receptor
might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH3 substituents
within the arylpiperazine and the other for biphenyl methoxy group.
Received 1 February 2013
Revised 13 February 2013
Accepted 15 February 2013
Available online 6 March 2013
Keywords:
5-HT7 receptor
Agonist
Antagonist
Biphenyl
Arylpiperazine
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
HT7 receptor may play a role in control of circadian rhythms, sleep,
cognitive processes, pain and migraine, as well as in the patho-
As a neurotransmitter, serotonin (5-HT) interacts with various
serotonin receptors to effect on the central and peripheral nervous
system. The serotonin receptors are classified into seven families
(5-HT1–5-HT7) according to sequence similarity and function. Most
5-HT receptors (except 5-HT3 receptor) are G protein-coupled
receptors (GPCRs),1 and dysfunction of this system has been impli-
cated in cardiovascular, digestive, and psychiatric disorders.2,3
Among the seven 5-HT receptor subtypes, 5-HT7 receptor has been
most recently cloned,4 and studies on the localization of the 5-HT7
receptor gave important indications on its pathophysiological
roles; the 5-HT7 receptor mRNA is distributed in the central ner-
vous system and particularly high levels have been detected in
thalamus, hippocampus and hypothalamus (especially within the
suprachiasmatic nucleus).5,6 It has also been reported that the 5-
physiology of many psychiatric disorders including depression
and anxiety.4 Therefore, chemical entities which can modulate
the 5-HT7 receptor have been actively pursued,7,8 but to date only
a few selective 5-HT7 receptor antagonists (SB-258719 and SB-
269970)9,10 and agonists (AS-19)11 have been discovered (Fig. 1).
These 5-HT7 receptor modulators showed interesting physio-
logical effects in animal model studies. While the 5-HT7 selective
antagonist SB-269970 exhibited antidepressant-like activity,12–14
systemic administration of the 5-HT7 receptor agonist AS-19 sig-
N
N
O
O
N
N
S
S
O
O
N
N
⇑
Corresponding authors. Tel.: +82 2 958 5157; fax: +82 2 958 5189 (H.C.).
E-mail addresses: gsnam@kist.re.kr (G. Nam), hchoo@kist.re.kr (H. Choo).
The first two authors contributed equally to this work.
These two corresponding authors contributed equally to this work.
N
OH
SB-258719
5-HT7 Ki 31.6 nM
SB-269970
5-HT7 Ki 1.26 nM
AS-19
à
5-HT7 Ki 0.6 nM
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.02.038
Figure 1. 5-HT7 receptor antagonists and an agonist.

Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
2569
Figure 2. Docking mode of compound 1-1 (red stick) to the ligand binding site of the modeled 5-HT7 receptor in comparison with that of AS-19 (green stick).
nificantly inhibited mechanical hypersensitivity and thermal
hyperalgesia in the neuropathic pain animal model.15 These results
suggest that the 5-HT7 receptor antagonists and agonists can be
used for treatment of depression and neuropathic pain, respec-
tively. In the course of our ongoing efforts to discover novel 5-
HT7 modulators, we designed an arylpiperazine scaffold with a
substituted biphenyl-2-ylmethyl group. Herein we report design,
synthesis and biological evaluation of the biphenyl-2-yl-aryl-
piperazinylmethane derivatives to the 5-HT7 receptor.
phenylpiperazinylmethane 1-1 was anticipated to serve as a novel
scaffold to show potent binding affinity to the 5-HT7 receptor.
Moreover, introduction of various aromatic substituents on the
biphenyl as well as the piperazinylphenyl functionalities would
provide in depth information about the two hydrophobic pockets
located in the ligand binding site of the 5-HT7 receptor. Thus, as
shown in Figure 3, a focused chemical library was designed
through modifications on both of the aromatic groups of the com-
pound 1-1.
2.2. Chemistry
2. Results and discussion
2.1. 5-HT7 ligand design
The title compounds, aryl-biphenyl-2-ylmethylpiperazines 1,
were synthesized in three steps from commercially available 2-
bromobenzaldehyde 2 and arylboronic acid 3 (Scheme 1). Suzuki
coupling of 2 with arylboronic acids 3 (R1 = H, halogen, CH3, or
OCH3) was performed in the presence of catalytic amount of
Pd(PPh3)4 and Na2CO3 in refluxing DMF to afford biphenyl-2-car-
baldehydes 4 in 60–70% yields.17 Biphenyl-2-carbaldehydes 4 were
reacted with various arylpiperazines 5 under reductive amination
conditions to afford the title compounds 1.18 Total 26 aryl-biphe-
nyl-2-ylmethylpiperazines 1 were synthesized.
For the purpose of designing novel ligands with potent binding
affinity to 5-HT7 receptor, various 5-HT7 ligands previously re-
ported in the literature were structurally investigated.7,8 Based
on this study, a combination of a biphenyl group and an arylpiper-
azine moiety, a structural mimic for the known 5-HT7 ligand AS-19,
biphenylpiperazines8h and phenylpyrroles,8g was proposed to
serve as a novel scaffold for 5-HT7 ligand. This hypothesis was then
evaluated by computational docking study of a biphenyl-2-yl-
methyl-phenylpiperazine (1-1, Fig. 2) to the modeled structure of
the 5-HT7 receptor in comparison with AS-19 (Fig. 2). The homol-
ogy model structure of the 5-HT7 receptor was constructed
through the SwissModel server, and the geometry-optimized
structures of the designed compound 1-1 and a 5-HT7 agonist
AS-19 were docked to the receptor by Glide 4.0 implemented in
Maestro 7.5 (Schrödinger, Inc.) using the previously developed
protocols.16
Overall, the biphenyl-2-ylmethylpiperazinyl moiety of the com-
pound 1-1 showed similar docking mode as the phenylpyrazole
group of AS-19. In particular, a characteristic salt bridge between
the 5-HT7 ligand and an aspartate residue of 5-HT7 (Asp162) was
commonly observed in the docking modes of the piperazine group
and the dimethylamino group forming the cationic ammonium ion
in compound 1-1 and AS-19, respectively. In addition, the biphenyl
functionality of the compound 1-1 was found to serve as a mimic
for the phenylpyrazole group of AS-19 with the terminal phenyl
ring projecting toward a hydrophobic pocket formed by Ile233,
Gln235, Thr240, and Thr244 (Fig. 2). In contrast, a marked differ-
ence in the binding modes of the two compounds was observed
in the hydrophobic pocket located on the opposite side of the li-
gand binding site which was composed of Phe158, Trp148,
Thr141, Asp142, Val138, and Arg367 (Fig. 2). While the phenylpip-
erazinyl group of the compound 1-1 was located in the middle of
pocket, the relatively small dimethylamino group of AS-19 was
not able to fill this hydrophobic space. Taken together, due to the
structural similarity to the known 5-HT7 ligand (AS-19) as well
as possible additional hydrophobic interactions, biphenyl-2-yl-
2.3. Biological results
The synthesized aryl-biphenyl-2-ylmethylpiperazines 1 were
biologically evaluated against the 5-HT7 receptor by [3H]LSD radi-
oligand binding assays in transfected CHO-K1 cells and the results
are summarized in Table 1.19–21
The binding affinity of the initially designed compound 1-1 with
no aromatic substituent on either biphenyl or piperazinylphenyl
moiety was first evaluated to show moderate Ki value of 537 nM
(Table 1). Then, in order to understand the role of the piperazinyl-
phenyl substituent R2 in binding affinity of the corresponding aryl-
biphenyl-2-ylmethylpiperazine derivatives, a series of analogues
(1-2 to 1-20) with the unsubstituted biphenyl moiety (R1 = H)
and variously substituted piperazinylphenyl group (R2 – H) were
R1
N
N
R2
1
R1 = H, F, Cl, Me, and OMe
R2 = H, F, Cl, Me, diMe, OMe, and diOMe,
Figure 3. A designed focused chemical library.

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Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
R1
Br
a) Pd(PPh3)4, Na2CO3,
R1
DMF, reflux
CHO
+
CHO
60~75%
B(OH)2
2
3
4 R1 = H, F, Cl, Me, or OMe
b) NaBH(OAc)3, MeOH, rt
HN
N
R2
5
21~79%
R1
N
N
R2
1
Scheme 1. Synthesis of aryl-biphenyl-2-ylmethylpiperazines 1.
tested for 5-HT7 binding. First, a fluorine atom (R2 = F) demolished
the binding affinities of the resulting derivatives (1-2 to 1-4) to the
target receptor (Ki >10,000 nM) regardless of its site of substitution
on the aromatic ring. Considering the similar sizes of hydrogen and
fluorine, this striking difference in binding affinities suggests
hydrophobic nature of the aromatic-binding site of the 5-HT7
receptor, to which a highly electronegative fluorine atom might
not be suitable for binding. Electronegativity of chlorine, though
chlorine is bigger than both hydrogen and fluorine, seems to be
responsible for the lack of binding affinities of the chlorine-substi-
tuted derivatives (1-5 and 1-6; Ki >10,000 nM). Among the com-
pounds 1-7 to 1-9 with methoxy substituents, the compound 1-7
with ortho-methoxy substituent only showed good binding affinity
with a Ki value of 432 nM and the compound 1-10 with 3,4-dime-
thoxy substituent showed marginal binding affinity. The com-
pounds 1-11 to 1-13 with methyl substituents showed only
marginal binding affinities with Ki values of 1750, 1200, and
2760 nM for ortho-, meta-, and para-position, respectively. The
compounds 1-14 to 1-17 with two methyl substituents showed
no binding affinities against 5-HT7 receptors. The compound 1-18
with meta-trifluoromethyl substituent showed only marginal bind-
ing affinity. Taken together, these data strongly suggest that the 5-
HT7 receptor has a specific aryl binding pocket with an open cavity
at the site corresponding to the 2-position of the aryl ring, which is
as large as a methoxy group. This hypothesis of a methoxy open
cavity inside of the aryl binding pocket is supported by ꢀ4 times
lower binding affinity of 2-CH3 substituted derivative 1-11
(R2 = 2-CH3; Ki = 1750 nM) compared with that of 1-7 (R2 = 2-
OCH3; Ki = 432 nM). At this point, it is worth to note that the syn-
thesized aryl-biphenyl-2-ylmethylpiperazines are much weaker
binders to the 5-HT7 receptor compared with the known 5-HT7 li-
gand, AS-19 (Ki = 0.6 nM).11 Considering the major structural dif-
ference of title compounds compared with AS-19 is located at
the steric bulk around the aryl-substituted piperazinyl moiety,
the aforementioned aryl binding pocket does not seem to be big
enough to accommodate the aryl-substituted piperazinyl moiety.
By the same token, 8-fold lower binding affinity of the phenylpyr-
role with an arylpiperazinyl group (Ki = 4.7 nM)8g compared with
AS-19 provides another evidence that the aryl-substituted pipera-
zine moiety gives some negative effect on binding at the aryl bind-
ing pocket of 5-HT7 receptor. This hypothesis can be further
supported by the potent 5-HT7-binding affinities of biphenylpiper-
azines of which piperazinyl moiety was left unsubstituted.8h
Table 1
Binding affinities (Kis) to the 5-HT7 receptor
R1
N
N
R2
1
Entry
Compd
R1
R2
pKi
Ki (nM)
1
2
3
4
5
6
7
8
1-1
1-2
1-3
1-4
1-5
1-6
1-7
1-8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-F
3-F
4-F
2-Cl
4-Cl
2-OCH3
3-OCH3
4-OCH3
3,4-diOCH3
2-CH3
6.27 0.08
537
a
—
—
—
—
>10000
>10000
>10000
>10000
>10000
432
>10000
>10000
1850
1750
1200
2760
>10000
>10000
>10000
>10000
1660
658
297
219
220
311
43.0
77
46.0
11.0
a
a
a
a
—
6.36 0.09
a
—
—
a
9
1-9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1-10
1-11
1-12
1-13
1-14
1-15
1-16
1-17
1-18
1-19
1-20
1-21
1-22
1-23
1-24
1-25
1-26
5.73 0.09
5.76 0.09
5.9 0.1
3-CH3
4-CH3
5.56 0.08
a
2,3-diCH3
2,4-diCH3
2,5-diCH3
3,5-diCH3
3-CF3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
—
—
—
—
a
a
a
H
H
2-F
2-Cl
3-Cl
4-Cl
2-CH3
2-OCH3
3-OCH3
4-OCH3
5.78 0.07
6.18 0.05
6.53 0.08
6.66 0.08
6.7 0.1
6.51 0.08
7.37 0.06
7.1 0.1
7.34 0.08
7.97 0.09
Chlorpromazine
a
Not available or determined.

Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
2571
Table 2
Docking results of the selected compounds to the model structure of 5-HT7 receptor
c
d
e
Compd
R1
R2
Ki (nM)
G-Scorea
HBndb
Eelec+vdW
Eelec
EvdW
1-24
1-26
1-25
1-20
1-7
1-1
1-11
1-5
2-OCH3
4-OCH3
3-OCH3
2-Cl
H
H
H
H
2-OCH3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
H
43
46
77
297
432
537
1750
>10,000
ꢁ7.64
ꢁ7.56
ꢁ7.60
ꢁ6.87
ꢁ6.52
ꢁ6.21
ꢁ6.27
ꢁ5.71
1
1
1
1
1
1
0
0
ꢁ39.00
ꢁ46.63
ꢁ46.46
ꢁ30.75
ꢁ32.44
ꢁ31.01
ꢁ23.41
ꢁ20.57
ꢁ2.90
ꢁ3.88
ꢁ3.67
ꢁ2.55
ꢁ1.99
ꢁ2.83
ꢁ3.16
+0.10
ꢁ36.09
ꢁ42.75
ꢁ42.79
ꢁ28.20
ꢁ32.44
ꢁ28.18
ꢁ20.25
ꢁ20.67
2-CH3
2-Cl
a
b
c
Glide Score.
Number of hydrogen bonds between ligands and 5-HT7 receptor.
Total binding energy of the ligands to 5-HT7 receptor.
Electrostatic component of the total binding energy of the ligands to 5-HT7 receptor.
Hydrophobic component of the total binding energy of the ligands to 5-HT7 receptor.
d
e
Figure 4. Docking modes of (a) 1-24 and (b) 1-26 to the model structure of 5-HT7 receptor with the binding pockets for piperazinylphenyl 2-OCH3 (right) and biphenyl
methoxy (left) groups.
Among the series, 1-(2-biphenyl)piperazine showed the best bind-
ing affinity with a Ki value of 1.4 nM, which is comparable to that of
AS-19.
docked to the previously constructed homology model structure
of the 5-HT7 receptor by Glide 4.0 implemented in Maestro 7.5
(Schrödinger, Inc.) using the previously developed protocols.16
The docking results are summarized in Table 2, which shows a
good correlation between the binding affinities (Ki) and docking
scores (Glide scores) of the 5-HT7 ligands. While ligands with mod-
erate to potent binding affinities were docked to the target recep-
Also noteworthy in those 1-biphenylpiperazines was that the
substituents such as 2-OCH3 and 4-OCH3 attached to the biphenyl
moiety endowed the corresponding derivatives with good binding
affinities. Thus, we then attempted to optimize the binding affinity
of the title compound through introduction of a substituent (R1) at
the biphenyl moiety (1-19 to 1-26). The compounds 1-19 to 1-23
with halogen and methyl susbstituents showed good binding affin-
ities with Ki values between 219 and 658 nM. The activities are not
much improved compared with that of the compound 1-7. Surpris-
ingly, the alkoxy group was also found to be a substituent of choice
for the biphenyl group to significantly enhance the binding affinity
of the resulting bis-methoxypiperazinyl derivatives (1-24 to 1-26;
Ki = 43, 77, and 46 nM). However, unlike the phenyl group which
showed exclusive selectivity for 2-alkoxy substituent, the binding
affinities of the alkoxy-biphenylmethylpiperazines (1-24 to 1-26)
were not sensitive to the position of the alkoxy group, which sug-
gests that the biphenyl-binding pocket of the 5-HT7 receptor might
be larger than the aryl-binding pocket.
tor with formation of
a critical hydrogen bond to Asp162
(HBnd = 1, Table 2),16 two weak binders (1-11 and 1-5) show abor-
tive binding modes lacking the hydrogen bond (HBnd = 0). Also,
analysis of the total binding energies (EvdW+elec) reveals that hydro-
phobic interaction (EvdW) determines the binding affinities of the
5-HT7 ligands to the receptor. In particular, comparison of the
hydrophobic energies of 1-7 with those of 1-1, 1-11, and 1-5 shows
that the 2-OCH3 group at the piperazinylphenyl moiety (R2 = 2-
OCH3) is a stronger contributor to the hydrophobic interaction en-
ergy (EvdW) than 2-CH3 or 2-Cl substituent. Also noteworthy is that
the total hydrophobic interaction energy between the ligands and
the 5-HT7 receptor can be significantly enhanced by combination
with the second methoxy substituent at the biphenyl ring
(R1 = 2-OCH3, 3-OCH3, or 4-OCH3).
Docking modes of the two most potent 5-HT7 ligands, 1-24 and
1-26, show that the 2-OCH3 group on the piperazinylphenyl ring
and the biphenyl methoxy group bind to the corresponding bind-
ing pockets separated by Ile233 (Fig. 4). Due to the difference in
size, the smaller piperazinylphenyl binding pocket seems to be
specific for 2-OCH3 while the biphenyl binding pocket can accom-
modate both 2-OCH3 (Fig. 4a) and 4-OCH3 (Fig. 4b).
2.4. Molecular modeling
These biphenyl- and aryl-binding pocket hypotheses were then
tackled by molecular docking study. The geometry-optimized
structures of several ligands with a broad spectrum of binding
affinities (1-1, 1-5, 1-7, 1-11, 1-20, 1-24, 1-25, and 1-26) were

2572
Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
phosphine)-palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
3. Conclusion
4.05 mmol) in DMF (20 ml) gave the title compound 4b (536 mg,
2.68 mmol, 99% yield). 1H NMR (300 MHz, CDCl3) d 9.92 (s, 1H),
8.05 (dd, J = 7.7, 1.5 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.55 (m,
1H), 7.49–7.40 (m, 2H), 7.35 (td, J = 7.5, 1.9 Hz, 1H), 7.27 (td,
J = 7.2, 1.1 Hz, 1H), 7.19 (td, J = 8.2, 1.1 Hz, 1H).
A series of aryl-biphenyl-2-ylmethylpiperazines 1 were de-
signed, synthesized, and biologically evaluated against the 5-HT7
receptor. Total 31 compounds were prepared and those com-
pounds showed a broad spectrum of binding affinities to the 5-
HT7 receptor depending upon the substituents attached to the
biphenyl and aryl functionalities. Among those, the compounds
1-24 and 1-26 showed the best binding affinities to the 5-HT7
receptor with Ki values of 43.0 and 46.0 nM, respectively. Struc-
ture-activity relationship study in conjunction with molecular
docking study proposed that the 5-HT7 receptor might have two
distinctive hydrophobic binding sites, one specific for aromatic 2-
OCH3 within the arylpiperazine and the other for biphenyl meth-
oxy group. With the most potent compounds 1-24 and 1-26, fur-
ther evaluations such as functionality, selectivity over other
serotonin receptor subtypes, and pharmacokinetics are in progress.
4.2.3. 20-Chloro-[1,10-biphenyl]-2-carbaldehyde (4c)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (277 ll, 2.37 mmol), 2-chloro-
phenylboronic acid (446 mg, 2.85 mmol), tetrakis-(triphenylphos-
phine)-palladium (27 mg, 0.024 mmol), and Na2CO3 (377 mg,
3.56 mmol) in DMF (20 ml) gave the title compound 4c (189 mg,
0.87 mmol, 37% yield). 1H NMR (400 MHz, CDCl3) d 9.81 (s, 1H),
8.06 (dd, J = 7.6, 1.3 Hz, 1H), 7.68 (td, J = 7.6, 1.5 Hz, 1H), 7.58–
7.50 (m, 2H), 7.43–7.33 (m, 4H).
4.2.4. 30-Chloro-[1,10-biphenyl]-2-carbaldehyde (4d)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (277 ll, 2.37 mmol), 3-chloro-
4. Experimental section
4.1. General
phenylboronic acid (446 mg, 2.85 mmol), tetrakis-(triphenylphos-
phine)-palladium (27 mg, 0.024 mmol), and Na2CO3 (377 mg,
3.56 mmol) in DMF (20 ml) gave the title compound 4d (345 mg,
1.59 mmol, 67% yield). 1H NMR (300 MHz, CDCl3) d 9.99 (s, 1H),
8.04 (dd, J = 8.3, 1.5 Hz, 1H), 7.66 (td, J = 7.5, 1.5 Hz, 1H), 7.54 (t,
J = 7.9 Hz, 1H), 7.47–7.39 (m, 4H), 7.28–7.24 (m, 1H).
All reactions were carried out under dry nitrogen or argon un-
less otherwise indicated. Commercially available reagents were
used without further purification. Solvents and gases were dried
according to standard procedures. Organic solvents were evapo-
rated with reduced pressure using a rotary evaporator. Analytical
thin layer chromatography (TLC) was performed using glass plates
precoated with silica gel (0.25 mm). TLC plates were visualized by
exposure to UV light (UV), and then were visualized with a KMnO4
stain followed by brief heating on hot plate. Flash column chroma-
tography was performed using silica gel 60 (230–400 mesh, Merck)
with the indicated solvents. 1H and 13C spectra were recorded on
Bruker 300, Bruker 400 or Varian 300 NMR spectrometers. 1H
NMR spectra are represented as follows: chemical shift, multiplic-
ity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublet, td = triplet of doublet, br s = broad singlet,
br t = broad triplet), integration, and coupling constant (J) in Hertz
(Hz). 1H NMR chemical shifts are reported relative to CDCl3
(7.26 ppm). 13C NMR was recorded relative to the central line of
CDCl3 (77.0 ppm). LC/MS analyses were performed on either
Micromass QUATTRO micro™ or Agilent 6410 Triple Quad system.
4.2.5. 40-Chloro-[1,10-biphenyl]-2-carbaldehyde (4e)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (277 ll, 2.37 mmol), 4-chloro-
phenylboronic acid (446 mg, 2.85 mmol), tetrakis-(triphenylphos-
phine)-palladium (27 mg, 0.024 mmol), and Na2CO3 (377 mg,
3.56 mmol) in DMF (20 ml) gave the title compound 4e (281 mg,
1.30 mmol, 55% yield). 1H NMR (300 MHz, CDCl3) d 9.99 (s, 1H),
8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.66 (td, J = 7.5, 1.5 Hz, 1H), 7.56–
7.41 (m, 4H), 7.35–7.31 (m, 2H).
4.2.6. 20-Methyl-[1,10-biphenyl]-2-carbaldehyde (4f)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (315 ll, 2.70 mmol), 2-meth-
ylphenylboronic acid (439 mg, 3.24 mmol), tetrakis-(triphenyl-
phosphine)-palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 ml) gave the title compound 4f (432 mg,
2.20 mmol, 82% yield). 1H NMR (300 MHz, CDCl3) d 9.83 (s, 1H),
8.03 (dd, J = 7.8, 1.2 Hz, 1H), 7.64 (td, J = 7.5, 1.5 Hz, 1H), 7.53–
7.47 (m, 1H), 7.34–7.24 (m, 4H), 7.21–7.18 (m, 1H), 2.10 (s, 3H).
4.2. Synthesis of biphenyl-2-carbaldehydes (4) derivatives
4.2.1. Representative procedure for synthesis of [1,10-biphenyl]-
2-carbaldehyde (4a)
4.2.7. 20-Methoxy-[1,10-biphenyl]-2-carbaldehyde (4g)
To a solution of 2-bromobenzaldehyde (315 ll, 2.70 mmol) in
Following the same procedure used for the synthesis of 4a, the
DMF (20 ml) was added phenyl boronic acid (395 mg, 3.24 mmol),
tetrakis-(triphenylphosphine)-palladium (31 mg, 0.027 mmol) and
Na2CO3 (430 mg, 4.05 mmol). The result solution was stirred and
refluxed for 6 h. After the reaction completed, the solution was
cooled to room temperature, then partitioned between satd NaH-
CO3 and EtOAc, and the mixture was extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography (hexane/diethyl ether = 8:1) to afford the
product (369 mg, 2.03 mmol, 75% yield). 1H NMR (400 MHz, CDCl3)
d 10.00(s, 1H), 8.05 (dd, J = 6.6, 1.2 Hz, 1H), 7.65 (dd, J = 6.1, 1.4 Hz,
1H), 7.51–7.46 (m, 5H), 7.40 (dd, J = 5.9, 2.0 Hz, 2H).
reaction of 2-bromobenzaldehyde (315 ll, 2.70 mmol), 2-meth-
oxyphenylboronic acid (492 mg, 3.24 mmol), tetrakis-(triphenyl-
phosphine)-palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 ml) gave the title compound 4g (350 mg,
1.65 mmol, 61% yield). 1H NMR (400 MHz, CDCl3) d 9.79 (s, 1H),
8.00 (dd, J = 7.8, 1.3 Hz, 1H), 7.65 (td, J = 7.5, 1.5 Hz, 1H), 7.48 (t,
J = 7.6 Hz, 1H), 7.42 (td, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 7.7 Hz,
1H), 7.29(dd, J = 7.5, 1.7 Hz, 1H), 7.09 (td, J = 7.5, 1.0 Hz, 1H), 6.98
(d, J = 7.8 Hz, 1H), 3.74 (s, 3H).
4.2.8. 30-Methoxy-[1,10-biphenyl]-2-carbaldehyde (4h)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (145 ll, 1.24 mmol), 3-meth-
4.2.2. 20-Fluoro-[1,10-biphenyl]-2-carbaldehyde (4b)
oxyphenylboronic acid (227 mg, 1.49 mmol), tetrakis-(triphenyl-
phosphine)-palladium (14 mg, 0.012 mmol), and Na2CO3 (197 mg,
1.86 mmol) in DMF (10 ml) gave the title compound 4h (200 mg,
0.94 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) d 10.00 (s, 1H),
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (315
ll, 2.70 mmol), 2-fluor-
ophenylboronic acid (454 mg, 3.24 mmol), tetrakis-(triphenyl-

Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
2573
8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.64 (td, J = 7.5, 1.5 Hz, 1H), 7.53–7.44
(m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.00–6.94 (m, 3H), 3.85 (s, 3H).
4.3.4. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(4-
fluorophenyl)piperazine (1-4)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(4-fluorophenyl)piperazine (296 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-4 (96 mg, 0.28 mmol, 34% yield). 1H NMR (300 MHz,
CDCl3) d 7.64–7.33 (m, 9H), 7.05–6.89 (m, 4H), 3.65 (s, 2H), 3.13
(br t, J = 4.8 Hz, 4H), 2.68 (br t, J = 4.8 Hz, 4H); 13C NMR
(100 MHz, CDCl3) d 157.12 (d, J = 230 Hz), 148.18, 142.88, 141.52,
135.59, 130.16 (d, J = 16.6 Hz), 129.62, 128.91, 127.94, 127.21,
126.99, 117.78, 117.71, 115.51(d, J = 4 Hz), 59.88, 52.83, 50.30;
LC/MS (ESI+): m/z: calcd for C23H23FN2: 346.45, [M+H]+; found:
347.30.
4.2.9. 40-Methoxy-[1,10-biphenyl]-2-carbaldehyde (4i)
Following the same procedure used for the synthesis of 4a, the
reaction of 2-bromobenzaldehyde (315 ll, 2.70 mmol), 4-meth-
oxyphenylboronic acid (492 mg, 3.24 mmol), tetrakis-(triphenyl-
phosphine)-palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 ml) gave the title compound 4i (535 mg,
2.52 mmol, 93% yield). 1H NMR (300 MHz, CDCl3) d 10.00 (s, 1H),
8.01 (dd, J = 7.9, 1.2 Hz, 1H), 7.62 (td, J = 7.5, 1.2 Hz, 1H), 7.49–
7.43 (m, 2H), 7.34–7.28 (m, 2H), 7.03–6.98 (m, 2H), 3.88 (s, 3H)
4.3. Synthesis of aryl-biphenyl-2-ylmethylpiperazines (1)
4.3.1. 1-([1,10-Biphenyl]-2-ylmethyl)-4-phenylpiperazine (1-1)
To a solution of 1-phenylpiperazine (266 mg, 1.64 mmol) in
methanol (10 ml) was added [1,10-biphenyl]-2-carbaldehyde
(150 mg, 0.82 mmol). The reaction mixture was stirred at room
temperature for 2 h, and NaBH(OAc)3 (529 mg, 2.46 mmol) was
added. The resulting mixture was stirred for 8 h. After termination
of the reaction, the solution was partitioned between sat. NaHCO3
and CH2Cl2, and the mixture was extracted with CH2Cl2. The organ-
ic layer was washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (hexane/diethyl ether = 8:1) to afford the product
(50 mg, 0.15 mmol, 18% yield). 1H NMR (300 MHz, CDCl3) d 7.76 (d,
J = 6.9 Hz, 1H), 7.64–7.44 (m, 8H), 7.21–7.01 (m, 4H), 3.65 (s, 2H),
3.20 (br s, 4H), 2.71 (br s, 4H); 13C NMR (75 MHz, CDCl3) d
151.49, 142.88, 141.53, 135.61, 130.21, 130.12, 130.07, 129.60,
129.19, 129.11, 127.19, 126.94, 119.57, 116.03, 59.9, 52.84,
49.28; LC/MS (ESI+): m/z: calcd for C23H24N2: 328.46, [M+H]+;
found: 329.30.
4.3.5. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2-
chlorophenyl)piperazine (1-5)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-chlorophenyl)piperazine (382 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-5 (60 mg, 0.17 mmol, 21% yield). 1H NMR (300 MHz,
CDCl3) d 7.60 (d, J = 6.6 Hz, 1H), 7.52–7.31 (m, 9H), 7.27–7.21 (m,
1H), 7.06 (dd, J = 8.1 Hz, 1.5 Hz, 1H), 6.98 (td, J = 7.5 Hz, J = 1.5 Hz,
1H), 3.53 (s, 2H), 3.05 (br s, 4H), 2.59 (br s, 4H) ; 13C NMR
(75 MHz, CDCl3) d 149.49, 142.84, 141.51, 135.74, 130.65, 130.17,
130.07, 129.62, 128.79, 127.90, 127.56, 127.15, 126.61, 126.87,
123.54, 120.39, 59.87, 53.00, 51.40, 29.76; LC/MS (ESI+): m/z: calcd
for C23H23ClN2: 362.90, [M+H]+; found: 363.20.
4.3.6. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(4-
chlorophenyl)piperazine (1-6)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(4-chlorophenyl)piperazine (382 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-6 (20 mg, 0.06 mmol, 7% yield). 1H NMR (300 MHz,
CDCl3) d 7.63–7.23 (m, 11H), 6.89–6.85 (m, 2H), 3.54 (s, 2H), 3.16
(br t, J = 5.1 Hz, 4H), 2.57 (br t, J = 5.1 Hz, 4H); 13C NMR (75 MHz,
CDCl3) d 150.09, 142.87, 141.50, 135.51, 130.22, 129.57, 127.91,
127.19, 126.98, 126.94, 124.32, 117.15, 59.85, 52.66, 49.27; LC/
MS (ESI+): m/z: calcd for C23H23ClN2: 362.90, [M+H]+; found:
363.20.
4.3.2. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2-
fluorophenyl)piperazine (1-2)
Following the same procedure used for the synthesis of 1-1,
the
reaction
of
1-(2-fluorophenyl)piperazine
(296 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 5–2 (20 mg, 0.06 mmol, 7% yield). 1H NMR
(300 MHz, CDCl3) d 7.76 (d, J = 6.9 Hz, 1H), 7.64–7.44 (m, 8H),
7.21–7.01 (m, 4H), 3.65 (s, 2H), 3.20 (br s, 4H), 2.71 (br s, 4H);
13C NMR (75 MHz, CDCl3) d 155.89 (d, J = 244.5 Hz), 143.01,
141.65, 140.48 (d, J = 8.25 Hz), 135.77, 130.33, 130.26, 129.74,
128.60, 128.04, 127.30, 124.58 (d, J = 3.75 Hz), 122.39 (d,
J = 7.5 Hz), 119.09, 119.05, 116.22 (d, J = 21 Hz), 60.03, 53.01,
50.85, 50.81; LC/MS (ESI+): m/z: calcd C23H23FN2: 346.45,
[M+H]+; found:.347.30
4.3.7. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2-
methoxyphenyl)piperazine (1-7)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (211 mg, 1.10 mmol),
[1,10-biphenyl]-2-carbaldehyde (100 mg, 0.55 mmol), and NaB-
H(OAc)3 (355 mg, 1.65 mmol) in methanol (10 ml) gave the title
compound 1-7 (74 mg, 0.21 mmol, 38% yield). 1H NMR (300 MHz,
CDCl3) d 7.59 (d, J = 6.8 Hz, 1H), 7.48–7.29 (m, 8H), 7.04–6.86 (m,
4H), 3.86 (s, 3H), 3.51 (s, 2H), 3.06 (br s, 4H), 2.60 (br s, 4H); 13C
NMR (75 MHz, CDCl3) d 152.32, 142.87, 141.53, 135.77, 130.17,
130.13, 129.64, 127.84, 127.10, 126.84, 122.76, 120.96, 118.20,
111.22, 59.87, 55.35, 53.04, 50.83; LC/MS (ESI+): m/z: calcd for
4.3.3. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3-
fluorophenyl)piperazine (1-3)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(3-fluorophenyl)piperazine (296 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-3 (80 mg, 0.23 mmol, 28% yield). 1H NMR (300 MHz,
CDCl3) d 7.60–7.57 (m, 1H), 7.50–7.30 (m, 8H), 7.24–7.16 (m,
1H), 6.69–6.51 (m, 3H), 3.50 (s, 2H), 3.17 (br t, J = 4.8 Hz, 4H),
2.53 (br t, J = 5.1 Hz, 4H); 13C NMR (75 MHz, CDCl3) d 163.94 (d,
J = 240.75 Hz), 153.12 (d, J = 6.75 Hz), 153.06, 142.88, 141.51,
135.51, 130.25, 130.17, 130.04, 129.59, 127.94, 127.23, 126.00 (d,
J = 3.75 Hz), 111.09, 111.06, 105.64 (d, J = 21.75 Hz), 102.57 (d,
J = 25.5 Hz), 60.45, 52.62, 48.75; LC/MS (ESI+): m/z: calcd for
C
24H26N2O: 358.48, [M+H]+; found: 359.30.
4.3.8. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3-
methoxyphenyl)piperazine (1-8)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(3-methoxyphenyl)piperazine (315 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-8 (124 mg, 0.35 mmol, 43% yield). 1H NMR
(400 MHz, CDCl3) d 7.55–7.51 (m, 1H), 7.40–7.26 (m, 8H), 7.12 (t,
C
23H23FN2: 346.45, [M+H]+; found: 347.20.

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Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
J = 8.0 Hz, 1H), 6.49–6.35 (m, 3H), 3.72 (s, 3H), 3.44 (s, 2H), 3.10 (br
t, J = 5.1 Hz, 4H), 2.47 (br t, J = 5.0 Hz, 4H) ; 13C NMR (100 MHz,
CDCl3) d 160.67, 152.93, 142.91, 141.57, 135.66, 130.27, 130.12,
129.83, 129.65, 127.98, 127.25, 127.01, 108.89, 104.35, 102.48,
59.96, 55.22, 52.84, 49.23; LC/MS (ESI+): m/z: calcd for
4.3.13. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(4-
methylphenyl)piperazine (1-13)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(4-methylphenyl)piperazine (155 mg, 0.88 mmol),
[1,10-biphenyl]-2-carbaldehyde (80 mg, 0.44 mmol), and NaB-
H(OAc)3 (284 mg, 1.32 mmol) in methanol (5 ml) gave the title
compound 1-13 (70 mg, 0.21 mmol, 48% yield). 1H NMR
(300 MHz, CDCl3) d 7.75–7.70 (m, 1H), 7.61–7.41 (m, 8H), 7.32–
7.28 (m, 2H), 7.18–7.09 (m, 2H), 3.64 (s, 2H), 3.03 (br t,
J = 4.5 Hz, 4H), 2.68 (br s, 4H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 149.49, 142.92, 141.59, 135.72, 130.29, 129.72, 129.69,
129.09, 127.99, 127.26, 127.01, 116.46, 59.98, 52.95, 49.92,
20.59; LC/MS (ESI+): m/z: calcd for C24H26N2: 342.49, [M+H]+;
found: 343.30.
C
24H26N2O: 358.48, [M+H]+; found: 359.30.
4.3.9. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(4-
methoxyphenyl)piperazine (1-9)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(4-methoxyphenyl)piperazine (212 mg, 1.10 mmol),
[1,10-biphenyl]-2-carbaldehyde (100 mg, 0.55 mmol), and NaB-
H(OAc)3 (355 mg, 1.65 mmol) in methanol (5 ml) gave the title
compound 1-9 (128.8 mg, 0.36 mmol, 65% yield). 1H NMR
(300 MHz, CDCl3) d 7.60–7.57 (m, 1H), 7.45–7.26 (m, 9H), 6.93–
6.84 (m, 3H), 3.80 (s, 3H), 3.50 (s, 2H), 3.07 (br t, J = 4.2 Hz, 4H),
2.56 (br t, J = 4.5 Hz, 4H); 13C NMR (75 MHz, CDCl3) d 153.78,
145.99, 142.93, 141.60, 135.73, 130.31, 130.20, 129.72, 128.02,
127.28, 127.04, 118.20, 114.51, 59.99, 55.63, 53.03, 50.83; LC/MS
(ESI+): m/z: calcd for C24H26N2O: 358.48, [M+H]+; found: 359.30.
4.3.14. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2,3-
dimethylphenyl)piperazine (1-14)
Following the same procedure used for the synthesis of 1-1, the
reaction
of
1-(2,3-dimethylphenyl)piperazine
(312 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 1-14 (53 mg, 0.15 mmol, 18% yield). 1H NMR
(300 MHz, CDCl3) d 7.57 (d, J = 6.9 Hz, 1H), 7.44–7.03 (m, 7H),
7.05 (t, J = 7.5 Hz, 2H), 6.88 (t, J = 7.2 Hz, 2H), 3.47 (s, 2H), 2.84
(br t, J = 4.5 Hz, 4H), 2.52 (br s, 4H), 2.24 (s, 3H), 2.17 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 151.80, 142.81, 141.59, 137.95, 135.89,
131.30, 130.19, 130.08, 129.67, 127.92, 127.17, 126.92, 126.85,
125.85, 124.87, 116.67, 60.04, 53.46, 52.36, 20.70, 14.04; LC/MS
(ESI+): m/z: calcd for C24H26N2: 356.51, [M+H]+; found: 357.30.
4.3.10. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3,4-
dimethoxyphenyl)piperazine (1-10)
Following the same procedure used for the synthesis of 1-1, the
reaction
of
1-(3,4-dimethoxyphenyl)piperazine
(245 mg,
1.10 mmol), [1,10-biphenyl]-2-carbaldehyde (100 mg, 0.55 mmol),
and NaBH(OAc)3 (355 mg, 1.65 mmol) in methanol (5 ml) gave
the title compound 1-10 (167.9 mg, 0.43 mmol, 79% yield). 1H
NMR (300 MHz, CDCl3) d 7.60 (d, J = 6.3 Hz, 1H), 7.45–7.30 (m,
8H), 6.82 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.47 (dd,
J = 8.7 Hz, J = 2.7 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.54 (s, 2H),
3.09 (br t, J = 4.5 Hz, 4H), 2.57 (br t, J = 4.5 Hz, 4H); 13C NMR
(75 MHz, CDCl3) d 149.51, 146.50, 143.47, 142.89, 141.52, 135.50,
130.26, 130.18, 129.66, 127.98, 127.24, 127.04, 126.99, 112.07,
107.95, 102.89, 59.84, 56.33, 55.86, 52.92, 50.84; LC/MS (ESI+):
m/z: calcd for C25H28N2O2: 388.51, [M+H]+; found: 389.30.
4.3.15. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2,4-
dimethylphenyl)piperazine (1-15)
Following the same procedure used for the synthesis of 1-1, the
reaction
of
1-(2,4-dimethylphenyl)piperazine
(312 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 1-15 (202 mg, 0.57 mmol, 69% yield). 1H
NMR (300 MHz, CDCl3) d 7.78–7.75 (m, 1H), 7.62–7.42 (m, 8H),
7.14–7.06 (m, 3H), 3.67 (s, 2H), 3.01 (br t, J = 3.9 Hz, 4H), 2.69 (br
s, 4H), 2.42 (s, 3H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) d
149.37, 142.94, 141.68, 135.74, 132.56, 132.43, 131.92, 130.29,
130.27, 129.75, 128.05, 127.30, 127.18, 127.04, 119.06, 60.01,
53.50, 52.15, 20.88, 17.89; LC/MS (ESI+): m/z: calcd for C24H26N2:
356.51, [M+H]+; found: 357.30.
4.3.11. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2-
methylphenyl)piperazine (1-11)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methylphenyl)piperazine (194 mg, 1.10 mmol),
[1,10-biphenyl]-2-carbaldehyde (100 mg, 0.55 mmol), and NaB-
H(OAc)3 (355 mg, 1.65 mmol) in methanol (5 ml) gave the title
compound 1-11 (140.7 mg, 0.41 mmol, 75% yield). 1H NMR
(300 MHz, CDCl3) d 7.76–7.70 (m, 1H), 7.61–7.41 (m, 8H), 7.32–
7.28 (m, 2H), 7.18–7.09 (m, 2H), 3.64 (s, 2H), 3.03 (br t,
J = 4.5 Hz, 4H), 2.68 (br s, 4H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 151.81, 142.89, 141.66, 135.95, 132.68, 131.18, 130.30,
130.17, 129.76, 128.03, 127.28, 127.03, 126.97, 126.69, 123.12,
119.08, 60.12, 53.51, 52.02, 18.10; LC/MS (ESI+): m/z: calcd for
4.3.16. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(2,5-
dimethylphenyl)piperazine (1-16)
Following the same procedure used for the synthesis of 1-1, the
reaction
of
1-(2,5-dimethylphenyl)piperazine
(312 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 1-16 (36 mg, 0.10 mmol, 12% yield). 1H NMR
(300 MHz, CDCl3) d 7.59–7.26 (m, 7H), 7.05 (d, J = 7.5 Hz, 1H),
6.82–6.76 (m, 2H), 3.47 (s, 2H), 2.84 (br t, J = 4.5 Hz, 4H), 2.52 (br
s, 4H), 2.24 (s, 3H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) d
151.54, 142.79, 141.55, 136.06, 135.84, 130.87, 130.17, 130.06,
129.65, 129.30, 127.90, 127.14, 126.90, 126.83, 126.62, 119.76,
59.99, 53.42, 51.90, 21.26, 17.52; LC/MS (ESI+): m/z: calcd for
C
24H26N2: 342.49, [M+H]+; found: 343.30.
4.3.12. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3-
methylphenyl)piperazine (1-12)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(3-methylphenyl)piperazine (289 mg, 1.64 mmol),
[1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol), and NaB-
H(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave the title
compound 1-12 (154 mg, 0.45 mmol, 55% yield). 1H NMR
(300 MHz, CDCl3) d 7.82–7.79 (m, 1H), 7.67–7.51 (m, 8H), 7.36 (t,
J = 7.5 Hz, 1H), 6.95–6.88 (m, 3H), 3.70 (s, 2H), 3.34 (br t,
J = 5.1 Hz, 4H), 2.73 (br t, J = 4.8 Hz, 4H), 2.54 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 151.86, 143.15, 141.84, 135.85, 135.94, 130.52,
130.39, 129.90, 129.26, 128.21, 127.48, 127.27, 127.24, 120.76,
117.14, 113.51, 60.26, 53.17, 49.60, 22..20; LC/MS (ESI+): m/z: calcd
for C24H26N2: 342.49, [M+H]+; found: 343.30.
C
24H26N2: 356.51, [M+H]+; found: 357.30.
4.3.17. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3,5-
dimethylphenyl)piperazine (1-17)
Following the same procedure used for the synthesis of 1-1, the
reaction
of
1-(3,5-dimethylphenyl)piperazine
(312 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave

Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
2575
the title compound 1-17 (58 mg, 0.16 mmol, 20% yield). 1H NMR
(300 MHz, CDCl3) d 7.57–7.54 (m, 1H), 7.47–7.20 (m, 8H), 6.53–
6.50 (m, 3H), 3.45 (s, 2H), 3.10 (br t, J = 4.8 Hz, 4H), 2.49 (br t,
J = 4.8 Hz, 4H), 2.26 (s, 6H); 13C NMR (75 MHz, CDCl3) d 151.66,
142.87, 141.55, 138.60, 135.68, 130.22, 130.07, 129.62, 127.92,
127.19, 126.93, 121.58, 114.09, 59.94, 52.93, 49.48, 21.74; LC/MS
(ESI+): m/z: calcd for C24H26N2: 356.51, [M+H]+; found: 357.30.
111.31, 60.21, 55.38, 52.94, 50.84; LC/MS (ESI+): m/z: calcd for
24H25ClN2O: 392.93, [M+H]+; found: 393.20.
C
4.3.22. 1-((40-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-22)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (497 mg, 2.58 mmol),
40-chlorobiphenyl-2-carbaldehyde (280 mg, 1.29 mmol), and NaB-
H(OAc)3 (832 mg, 3.87 mmol) in methanol (20 ml) gave the title
compound 1-22 (215 mg, 0.55 mmol, 42% yield). 1H NMR
(300 MHz, CDCl3) d 7.61 (dd, J = 6.4 Hz, 2.3 Hz, 1H), 7.51–7.31 (m,
7H), 7.09–6.98 (m, 3H), 6.92 (d, J = 7.2 Hz, 1H), 3.91 (s, 3H), 3.52
(s, 2H), 3.12 (br s, 4H), 2.66 (br s, 4H); 13C NMR (75 MHz, CDCl3)
d 152.41, 141.76, 141.61, 140305, 135.78, 133.04, 121.10, 130.63,
130.15, 128.06, 127.43, 127.14, 122.87, 121.10 ,118.28, 111.43,
60.17, 55.44, 53.08, 50.89; LC/MS (ESI+): m/z: calcd for
C24H25ClN2O: 392.93, [M+H]+; found: 393.20.
4.3.18. 1-([1,10-Biphenyl]-2-ylmethyl)-4-(3-
(trifluoromethyl)phenyl)piperazine (1-18)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(3-trifluoromethylphenyl)piperazine (437 mg,
1.64 mmol), [1,10-biphenyl]-2-carbaldehyde (150 mg, 0.82 mmol),
and NaBH(OAc)3 (529 mg, 2.46 mmol) in methanol (10 ml) gave
the title compound 1-18 (19 mg, 0.05 mmol, 6% yield). 1H NMR
(300 MHz, CDCl3) d 7.57–7.54 (m, 1H), 7.41–7.25 (m, 9H), 7.07–
7.00 (m, 3H), 3.47 (s, 2H), 3.17 (br t, J = 5.1 Hz, 4H), 2.51 (br s,
4H); 13C NMR (75 MHz, CDCl3) d 151.52, 142.85, 141.46, 135.43,
130.21, 129.97, 129.53, 129.49, 127.90, 127.19, 126.99, 126.93,
118.64, 115.60, 112.02, 59.82, 52.57, 48.77; LC/MS (ESI+): m/z:
calcd for C24H23F3N2: 396.46, [M+H]+; found: 397.30.
4.3.23. 1-(2-Methoxyphenyl)-4-((20-methyl-[1,10-biphenyl]-2-
yl)methyl)piperazine (1-23)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (196 mg, 1.02 mmol),
20-methyl-[1,10-biphenyl]-2-carbaldehyde (100 mg, 0.51 mmol),
and NaBH(OAc)3 (329 mg, 1.53 mmol) in methanol (50 ml) gave
the title compound 1-23 (186 mg, 0.50 mmol, 98% yield). 1H
NMR (300 MHz, CDCl3) d 7.58 (dd, J = 7.5 Hz, 1.2 Hz, 1H), 7.35–
7.10 (m, 7H), 6.96–6.86 (m, 3H), 6.79 (d, J = 7.5 Hz, 1H), 3.78 (s,
3H), 3.34 (d, J = 13.5 Hz, 1H), 3.22 (d, J = 13.5 Hz, 1H), 2.98 (br s,
4H), 2.47 (br s, 4H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) d
152.40, 142.13, 141.67, 141.05, 136.46, 136.06, 129.76, 129.68,
129.42, 127.29, 127.21, 126.68, 125.34, 122.84, 121.08, 118.29,
111.34, 59.84, 55.43, 53.48, 53.32, 50.86; LC/MS (ESI+): m/z: calcd
for C25H28N2O: 372.51, [M+H]+; found: 373.30.
4.3.19. 1-((20-Fluoro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-19)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (1.2 g, 6.20 mmol), 20-
fluorobiphenyl-2-carbaldehyde (620 mg, 3.10 mmol), and NaB-
H(OAc)3 (2.0 g, 9.30 mmol) in methanol (50 ml) gave the title com-
pound 1-19 (379 mg, 1.01 mmol, 33% yield). 1H NMR (300 MHz,
CDCl3) d 7.64 (dd, J = 6.8 Hz, 1.5 Hz, 1H), 7.44–7.11 (m, 7H), 7.03–
6.92 (m, 3H), 6.86 (d, J = 7.9 Hz, 1H), 3.85 (s, 3H), 3.48 (s, 2H),
3.00 (br s, 4H), 2.52 (br s, 4H); 13C NMR (75 MHz, CDCl3) d
160.69 (d, J = 246 Hz), 152.31, 141.59, 137.10, 136.16, 131.69 (d,
J = 3.5 Hz), 130.32, 129.63, 129.05, 128.91 (d, J = 5.6 Hz), 127.91,
126.71, 123.69 (d, J = 3.5 Hz), 122.72, 120.95, 118.18, 115.28 (d,
J = 22.4 Hz), 111.21, 59.99, 55.33, 53.08, 50.74; LC/MS (ESI+): m/z:
calcd for C24H25FN2O: 376.47, [M+H]+; found: 377.30.
4.3.24. 1-((20-Methoxy-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-24)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (634 mg, 3.30 mmol),
20-methoxybiphenyl-2-carbaldehyde (350 mg, 1.65 mmol), and
NaBH(OAc)3 (1.1 g, 4.95 mmol) in methanol (25 ml) gave the title
compound 1-24 (382 mg, 0.98 mmol, 60% yield). 1H NMR
(400 MHz, CDCl3) d 7.62 (dd, J = 7.6 Hz, 1.0 Hz, 1H), 7.36–7.25 (m,
3H), 7.19–7.15 (m, 2H), 7.00–6.89 (m, 5H), 6.80 (d, J = 7.6 Hz,
1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.46 (d, J = 13.4 Hz, 1H), 3.33 (d,
J = 13.4 Hz, 1H), 2.98 (br s, 4H), 2.48 (br s, 4H); 13C NMR
4.3.20. 1-((20-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-20)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (311 mg, 1.62 mmol),
20-chlorobiphenyl-2-carbaldehyde (175 mg, 0.81 mmol), and NaB-
H(OAc)3 (523 mg, 2.43 mmol) in methanol (15 ml) gave the title
compound 1-20 (69 mg, 0.18 mmol, 22% yield). 1H NMR
(400 MHz, CDCl3) d 7.59 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.46–7.24 (m,
6H), 7.17 (d, J = 7.6 Hz, 1H), 6.99–6.88 (m, 3H), 6.82 (d, J = 7.8 Hz,
1H), 3.81 (s, 3H), 3.44 (d, J = 13.5 Hz, 1H), 3.28 (d, J = 13.5 Hz,
1H), 2.96 (br s, 4H), 2.47 (br s, 4H); 13C NMR (100 MHz, CDCl3) d
152.29, 141.55, 140.14, 139.78, 136.72, 133.53, 131.38, 129.81,
129.45, 129.20, 128.53, 127.87, 126.64, 126.26, 122.76, 120.94,
118.19, 111.14, 59.89, 55.34, 53.17, 50.71; LC/MS (ESI+): m/z: calcd
for C24H25ClN2O: 392.93, [M+H]+; found: 393.30.
(100 MHz, CDCl3)
d 156.60, 152.34, 141.65, 138.95, 137.21,
131.30, 130.44, 130.28, 129.03, 128.38, 127.37, 126.53, 122.79,
121.03, 120.41, 118.25, 111.20, 110.51, 59.83, 55.40, 53.53, 53.25,
50.88; LC/MS (ESI+): m/z: calcd for C25H28N2O2: 388.51, [M+H]+;
found: 389.30.
4.3.25. 1-((30-Methoxy-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-25)
4.3.21. 1-((30-Chloro-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-21)
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol),
30-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol), and
NaBH(OAc)3 (303 mg, 1.41 mmol) in methanol (10 ml) gave the ti-
tle compound 1-25 (176 mg, 0.45 mmol, 96% yield). 1H NMR
(300 MHz, CDCl3) d 7.55–7.53 (m, 1H), 7.34–7.26 (m, 4H), 7.03–
6.80 (m, 7H), 3.80 (s, 6H), 3.48 (s, 2H), 3.02 (br s, 4H), 2.58 (br s,
4H); 13C NMR (75 MHz, CDCl3) d 159.26, 152.38, 142.98, 142.80,
141.61, 135.70, 130.39, 130.10, 128.93, 127.24, 126.93, 122.87,
122.23, 121.07, 118.26, 115.42, 112.60, 111.29, 60.03, 55.42,
55.37, 53.18, 50.91; LC/MS (ESI+): m/z: calcd for C25H28N2O2:
388.51, [M+H]+; found: 389.30.
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (603 mg, 3.14 mmol),
30-chlorobiphenyl-2-carbaldehyde (340 mg, 1.57 mmol), and NaB-
H(OAc)3 (1.0 g, 4.71 mmol) in methanol (25 ml) gave the title com-
pound 1-21 (250 mg, 0.64 mmol, 41% yield). 1H NMR (300 MHz,
CDCl3) d 7.71 (br s, 1H), 7.56–7.52 (m, 1H), 7.43–7.30 (m, 6H),
7.06–6.92 (m, 3H), 6.90 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H), 3.47 (s,
2H), 3.10 (br s, 4H), 2.65 (br s, 4H); 13C NMR (75 MHz, CDCl3) d
152.36, 143.34, 141.63, 141.59, 135.75, 133.70, 130.73, 130.06,
129.07, 127.79, 127.46, 127.17, 126.97, 122.80, 121.03, 118.25,

2576
Y. Kim et al. / Bioorg. Med. Chem. 21 (2013) 2568–2576
4.3.26. 1-((40-Methoxy-[1,10-biphenyl]-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine (1-26)
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Leopoldo, M. J. Med. Chem. 2012, 55, 6375.
Following the same procedure used for the synthesis of 1-1, the
reaction of 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol),
40-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol), and
NaBH(OAc)3 (303 mg, 1.41 mmol) in methanol (10 ml) gave the ti-
tle compound 1-26 (149 mg, 0.38 mmol, 82% yield). 1H NMR
(300 MHz, CDCl3) d 7.53–7.51 (m, 1H), 7.38–7.24 (m, 5H), 6.95–
6.87 (m, 5H), 6.80 (d, J = 7.2 Hz, 1H) 3.80 (s, 3H), 3.79 (s, 3H),
3.46 (s, 2H), 3.02 (br s, 4H), 2.57 (br s, 4H); 13C NMR (75 MHz,
CDCl3) d 158.76, 152.41, 142.66, 141.66, 135.91, 134.00, 130.89,
130.42, 130.39, 126.98, 126.91, 122.88, 121.10, 118.31, 113.39,
111.33, 60.12, 55.44, 55.35, 53.16, 50.95; LC/MS (ESI+): m/z: calcd
for C25H28N2O2: 388.51, [M+H]+; found: 389.30.
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Binding affinities were generously provided by the National
Institute of Mental Health’s Psychoactive Drug Screening Program,
Contract # HHSN-271-2008-00025-C (NIMH PDSP). This research
was supported by Basic Science Research Program through the Na-
tional Research Foundation of Korea (NRF) funded by the Ministry
of Education, Science and Technology (2012–0002547), and Korea
Institute of Science and Technology.
15. Brenchat, A.; Nadal, X.; Romero, L.; Ovalle, S.; Muro, A.; Sanchez-Arroyos, R.;
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