Metal-Free Synthesis of Biaryl- and Teraryl-Cored Diarylmethanes by Ring Transformation of 2 H -Pyran-2-ones

Article abstract of DOI:10.1055/s-0037-1610332

An efficient metal-free approach for the synthesis of functionalized biaryl-cored diarylmethanes is described by the ring transformation of 2 H -pyran-2-ones using 4-phenylbutan-2-one as carbanion source. Moreover, 2 H -pyran-2-ones were reacted with 1,3-

Full text of DOI:10.1055/s-0037-1610332

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
en
F. V. Singh, P. B. Kole
Paper
Synthesis
Metal-Free Synthesis of Biaryl- and Teraryl-Cored Diarylmethanes
by Ring Transformation of 2H-Pyran-2-ones
Fateh V. Singh*
Priyanka B. Kole
0
0
0
0-0
0
0
2-
6
3
5
8-4
4
0
8
O
N
N
O
N
Ph
Ph
R
CN
Me
Ph
Me
R
CN
O
R
CN
O
Chemistry Division, School of Advanced Science,
VIT University, Chennai Campus, Chennai
600127, Tamil Nadu, India
Ph
KOH, DMF
rt, 10–14 h
14 examples
KOH, DMF
rt, 10–15 h
Ar
Ar
Ar
fatehveer.singh@vit.ac.in
Ph
Ph
78–94%
11 examples
74–95%
Ar = C6H5, 4-BrC6H4, 4-ClC6H4, 4-MeC6H4, 4-OMeC6H4, 2-naphthyl, 2-thienyl; R = H, Me
Received: 06.09.2018
Accepted after revision: 26.10.2018
Published online: 30.11.2018
ticancer activities.14 Recently diarylmethane derivatives
have been used as an important precursors in several dye
preparations.15
DOI: 10.1055/s-0037-1610332; Art ID: ss-2018-z0598-op
NH2
Abstract An efficient metal-free approach for the synthesis of func-
tionalized biaryl-cored diarylmethanes is described by the ring transfor-
mation of 2H-pyran-2-ones using 4-phenylbutan-2-one as carbanion
source. Moreover, 2H-pyran-2-ones were reacted with 1,3-diphenylace-
tone in the presence of base to achieve functionalized teraryl-cored dia-
rylmethanes. All the ring transformation reactions were performed un-
der mild reaction conditions to afford the biaryl- and teraryl-cored
reaction products in high yields.
OMe
N
Me
O
Et
O
OEt
Cl
H2N
N
OMe
OMe
2: Trimethoprim
1: Beclobrate
HO
OMe
MeO
Key words biaryl-cored diarylmethanes, teraryl-cored diarylmeth-
anes, 2H-pyran-2-ones, carbanion, ring transformation reactions, 4-
phenylbutan-2-one, 1,3-diphenylacetone
Br
OMe
OMe
Br
OH
OH
N
OH
Functionalized diarylmethanes are important scaffolds
found in various biologically active synthetic and naturally
occurring compounds.1 Diarylmethane-cored compounds
are known to exhibit various biological activities such as
antibreast cancer,2 thyroid hormone and histamine H1-re-
ceptor antagonist,3,4 antiviral,5 antiallergic,6 and antidiabet-
ic activities.7 Molecules embedded with diarylmethane
units are widely found in various biologically active com-
pounds (Figure 1). Beclobrate (1) has been introduced as
potent cholesterol and triglyceride-lowering drug.8 Tri-
methoprim (2) has been developed as effective antibiotic
and used for the treatment of urinary tract infections.9 In
addition, naturally occurring compound avrainvilleol (3) is
isolated from red algae and found to exhibit antioxidant ac-
tivity.10 Moreover, the alkaloid papaverine (4), isolated from
Papaver somniferum L., exhibits diverse biological activities
such as antiplasmodic activity,11 cerebral vasodilator,12 and
non-selective phosphodiesterase inhibitory activity.13 In
addition, various tetronic acid derived chiral analogues of
diarylmethanes have been found to show anti-HIV and an-
4: Papaverine
3: Avrainvilleol
Figure 1 Structures of synthetic and natural products of biological im-
portance with diarylmethane units
There are several methods available in literature for the
synthesis of diarylmethanes, but most of them are associat-
ed with transition-metal-catalyzed coupling reactions such
as Pd-catalyzed Suzuki type cross-coupling reactions of
benzylic halides with arylboranes.16 In 2015, Yoshikai and
co-workers reported the synthesis of diarylmethanes by
ortho-CH benzylation of arylimines using Cobalt-Pyphos cat-
alytic system.17 In 2016, Zhang and co-workers described a
one-pot synthesis of diarylmethanes from benzyl chlorides
by a Ni-catalyzed reductive cross-coupling reactions.18
Furthermore, synthesis of allyldiarylmethanes was ac-
complished via 1,6-conjugate allylation of p-qui-
nonemethides using B(C6F5)3 as catalyst.19 In 2016, Heme-
laere and co-workers developed the synthesis of diaryl-
methanes by Friedel–Crafts reaction of benzyl fluorides in
the presence of TFA.20 Furthermore, the synthesis of diaryl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
F. V. Singh, P. B. Kole
Paper
Synthesis
methanes was achieved through transition-metal-free
cross-coupling reaction of benzylic bromides with arylbo-
ronic acids in the presence of Cs2CO3 using the solvent com-
bination BTF/H2O (10:1).21
Most of the existing approaches are associated with
some limitations such as the use of toxic transition-metal
catalysts and harsh reaction conditions. Despite the avail-
ability of several existing approaches, there is still scope to
develop a new approach that could overcome the problems
associated with them and offers the flexibility of introduc-
ing a wide range of functional groups in the diarylmethane
architecture.
Herein, we report a metal-free approach for the synthe-
sis of functionalized biaryl-cored diarylmethanes 9 in high
yields by the ring transformation of 6-aryl-2H-pyran-2-
ones 8 using 4-phenylbutan-2-one (6) as a source of nucle-
ophile. The parent precursors 5 were synthesized by the re-
action of methyl 2-cyano-3,3-dimethylsulfanylacrylate
with functionalized acetophenones in DMSO at room tem-
perature under alkaline conditions.22 Furthermore, the sub-
strates 5 were reacted with secondary amines in methanol
at reflux temperature to synthesize 6-aryl-4-amino-2H-
pyran-2-ones 8.22
Table 1 Ring Transformation of 6-Aryl-4-(methylthio)-2-oxo-2H-
pyran-3-carbonitriles 5a–c with 4-Phenylbutan-2-one (6)
SMe
SMe
O
CN
CN
Me
KOH
+
Ph
Me
DMF, rt, 10–12 h
Ar
O
O
Ar
Ph
7: 50–57%
5
6
Entry
Ar
Ph
Reaction time (h)
Yield (%) of 7
1
2
3
10
12
10
50
52
57
4-BrC6H4
4-MeOC6H4
strates 6-phenyl-4-amino-2H-pyran-2-ones 8 were synthe-
sized.22 Further, to know the influence of amino functional-
ity in the ring transformation reaction, the substrate 2-oxo-
6-phenyl-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (8a)
was treated with the same ketone 6 under similar reaction
conditions and a significant improvement was observed in
the yield of ring-transformed product 9a (Scheme 1).
The ring transformation of 2H-pyran-2-ones has been
used to synthesize various arenes,23 heteroarenes,24 and
fused cyclic systems.25 Recently, we have reported the ul-
trasound-assisted synthesis of functionalized 2-tetralones
via ring transformation of 2H-pyran-2-ones.26
N
N
O
CN
O
CN
Me
KOH
+
Ph
Me
DMF, rt, 10 h
Ph
O
Ph
Our approach to prepare functionalized biaryl-cored di-
arylmethanes 9 was based on the ring transformation of 6-
aryl-2H-pyran-2-ones 5 and 8 using 4-phenylbutan-2-one
(6) as a carbanion source. Both substrates 5 and 8 have
three electrophilic centers at C-2, C-4, and C-6. The pres-
ence of the electron-withdrawing substituent at C-3 posi-
tion of pyran ring and the extended conjugation makes the
latter position to be more reactive towards nucleophiles.
Initially, our studies were focused on the ring transfor-
mation of 3-cyano-4-methylsulfanyl-2H-pyran-2-ones (5a)
with 4-phenylbutan-2-one (6). The ring transformation of
substrate 5a with 6 was performed in DMF in the presence
of KOH at room temperature (Table 1, entry 1). Unfortu-
nately, the reaction suffered from several unwanted side re-
actions and ring transformed product 7a was obtained in
50% yield. When other substrates 5b and 5c were used in
similar reactions and the desired products were observed in
slightly improved yields (entries 2 and 3). Probably, the
presence of SMe group at C-4 position of lactone ring in
substrate 5 makes this position more susceptible for nucle-
ophilic attack, which leads to various undesired side products.
Next, our efforts were directed to limit the reactivity of
2H-pyran-2-ones 5 at C-4 position towards the nucleophile.
In order to limit the reactivity at C-4 position, the leaving
group SMe in substrates 5 was replaced with tert-amino
functionality by treating with cyclic amines and new sub-
Ph
9a: 85%
8a
6
Scheme 1
After that our efforts were directed towards the screen-
ing of different solvents using 8a as model substrate. Vari-
ous polar and nonpolar solvents were employed for the ring
transformation of model substrate 8a to the corresponding
synthesis of diarylmethane derivative 9a using ketone 6 as
source of carbanion and the results obtained are summa-
rized in Table 2. Initially, the ring transformation reaction of
8a was performed in polar and aprotic solvents DMF and
DMSO, and the reaction product 9a was isolated in 85% and
82% yield, respectively (Table 2, entries 1 and 2). The yield
of ring transformed product was slightly lowered when ace-
tonitrile was used as solvent (entry 3). The yield was fur-
ther reduced up to 69% yield in EtOAc (entry 4). Additional-
ly, the ring transformation reaction was performed in polar
and protic solvents but could not proceed (entries 5–7). The
ring transformation reaction could proceed in dichloro-
methane but desired product 9a was obtained in moderate
yield (entry 8). The course of reaction was investigated in
aprotic and nonpolar solvents such as benzene and toluene.
The ring transformed product was formed in toluene but
was observed only in traces in benzene (entries 9 and 10).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
F. V. Singh, P. B. Kole
Paper
Synthesis
Finally, the reaction was performed in THF, diethyl ether,
and 1,4-dioxane but the reaction did not proceed in any of
these solvents (entries 11–13).
Table 3 Base Optimization for the Ring Transformation of 6-Phenyl-
2H-pyran-2-one 8a to Diarylmethane Derivative 9a
O
N
Table 2 Solvent Optimization for the Ring Transformation of 6-Phenyl-
2H-pyran-2-one 8a to Diarylmethane Derivative 9a
N
CN
Me
CN
O
Me
base
+
DMF, rt
Ph
Ph
O
Ph
O
N
N
8a
6
9a
CN
Me
CN
O
Me
KOH
+
Entry
Base
Reaction time (h) 9a Yield (%)
solvent, rt
Ph
Ph
O
1
2
3
4
5
KOH
10
12
15
15
15
85
75
65
60
63
Ph
8a
6
9a
NaHCO3
K2CO3
Cs2CO3
LiOH
Entry
Solvent
Reaction time (h) 9a Yield (%)
1
2
DMF
10
10
10
10
14
14
14
12
12
12
12
14
14
85
82
79
69
–
DMSO
MeCN
EtOAc
AcOH
3
with 4-phenyl-butan-2-one (6) in DMF in the presence of
KOH for 10–14 hours at room temperature (Table 4, entries
1–11). The ring transformation reaction proceeded well
with both electron-withdrawing and electron-donating
groups on the aromatic ring of 6-aryl-2H-pyran-2-ones 8.
Notably, the ring transformation products 9f–h were ob-
4
5
6
MeOH
EtOH
–
7
–
8
CH2Cl2
toluene
benzene
Et2O
58
30
–
9
10
11
12
13
Table 4 Synthesis of Biaryl-Cored Diarylmethanes 9a–k via Ring Trans-
formation of 6-Aryl-2H-pyran-2-ones 8a–k
–
THF
–
1,4-dioxane
–
N
O
N
O
R
CN
O
R
CN
Me
After determining the optimal solvent, our aim was to
screen the different bases for the same ring transformation
reaction. Several bases were employed for the ring transfor-
mation of 8a to the desired product 9a and results are listed
in Table 3. Initially, the reaction was carried out with KOH
in DMF and ring transformation product was obtained in
85% yield (Table 3, entry 1). Similarly, the reaction was test-
ed with NaHCO3 under the same reaction condition and the
product 9a was isolated in 75% yield (entry 2). Additionally,
K2CO3 and Cs2CO3 were also used as base for same reaction
and desired product 9a was achieved in 65% and 60% yield,
respectively (entries 3 and 4). The course of reaction was
quite similar with LiOH and the reaction product 9a was
isolated in 63% yield (entry 5).
After the optimization studies, the presence of KOH as
base and DMF as solvent at room temperature for 10 hours
was found as the best reaction conditions for the ring trans-
formation of 6-phenyl-2H-pyran-2-one 8a to 2-benzyl-3-
methyl-5-(piperidin-1-yl)[1,1′-biphenyl]-4-carbonitrile (9a).
After achieving the best reaction conditions, a series of
biaryl-cored diarylmethanes 9a–k were synthesized in 78–
94% yields by the reaction of various 2H-pyran-2-ones 8a–k
KOH
+
Ph
Me
DMF, rt, 10–14 h
Ar
Ar
Ph
9: 78–94%
8
6
Entry Ar
R
Time 9 Yield
(h) (%)
N
1
2
Ph
Ph
H
H
H
H
H
H
H
H
H
Me
H
piperidin-1-yl
10
85
4-phenylpiperazin-1-yl
piperidin-1-yl
10
14
12
12
10
10
10
10
12
10
82
78
82
80
94
90
92
88
78
83
3
4-ClC6H4
4-BrC6H4
4-BrC6H4
4
piperidin-1-yl
5
4-phenylpiperazin-1-yl
piperidin-1-yl
6
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
2-naphthyl
Ph
7
piperidin-1-yl
8
4-phenylpiperazin-1-yl
piperidin-1-yl
9
10
11
4-phenylpiperazin-1-yl
piperidin-1-yl
2-thienyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
F. V. Singh, P. B. Kole
Paper
Synthesis
Table 5 Synthesis of Teraryl-Cored Diarylmethanes 11a–j and 11l via
Ring Transformation of 6-Aryl-2H-pyran-2-ones 8a–j and 8l
SMe
SMe
CN
CN
O
KOH
Ph
Ph
+
Ph
DMF, rt, 12 h
Ph
O
Ph
O
Ph
12a: 62%
N
N
5a
10
R
CN
R
CN
O
KOH
Ph
Ph
Scheme 2 The ring transformation of 2H-pyran-2-ones 5a with 1,3-di-
phenylacetone (10)
+
Ph
DMF, rt, 10–15 h
Ar
O
Ar
O
Ph
8
10
11: 74–95%
ing electron-donating functionalities (Table 5, entries 6–8).
Additionally, the reaction was found to be slightly slower
when substrates 8j and 8l having methyl group at C-5 posi-
tion were used and reaction products were obtained in 74%
and 79% yield, respectively (entries 10 and 11). All the syn-
thesized compounds were characterized by spectroscopic
analysis.
Entry Ar
R
Time 11 Yield
(h) (%)
N
1
2
Ph
Ph
H
H
H
H
H
H
H
H
H
piperidin-1-yl
10
88
4-phenylpiperazin-1-yl
piperidin-1-yl
10
15
12
12
10
10
10
10
12
12
82
79
82
80
95
92
93
90
74
79
3
4-ClC6H4
4-BrC6H4
4-BrC6H4
Finally, the reaction of substrate 5a was performed with
1,3-diphenylacetone (10) under similar reaction conditions.
Expectedly, the reaction suffered from some undesired side
reactions probably due to the presence of good leaving SMe
at C-4 position in substrate 5a, which makes this position
more vulnerable towards the nucleophile. The ring trans-
formation product 12a was isolated in 62% yield (Scheme
2). Unfortunately, we could not isolate any side product
from the reaction mixture. The isolated compound 12a was
characterized as 3′-benzyl-5′-(methylthio)-[1,1′:2′,1′′-ter-
phenyl]-4′-carbonitrile by its spectroscopic analysis.
The possible mechanism for the ring transformation of
2H-pyran-2-ones 8 with 4-phenylbutan-2-one (6) to diaryl-
methanes 9 is described in Scheme 3.27 Initially, the forma-
tion of bicyclic intermediate 13 takes place by the nucleop-
hilic attack of anion generated from ketone 6 to the C-6 po-
sition of 2H-pyran-2-ones 8, followed by intramolecular
cyclization involving the carbonyl functionality of 6 and C-3
of the pyranone ring. Furthermore, the bicyclic intermedi-
ate 13 transforms to final product 9 on decarboxylation fol-
lowed by dehydration.
In conclusion, we have developed a facile metal-free
synthetic methodology for the synthesis of functionalized
biaryl-cored diarylmethanes 9 through carbanion-induced
ring transformation of 6-aryl-2H-pyran-2-ones 8 in good
yields. In addition, the same approach was employed to
achieve the synthesis of teraryl-cored diarylmethanes 11.
Our methodology for the synthesis of functionalized diaryl-
methanes is simple, economical and does not require any
toxic transition metal. Further investigations about this ring
transformation approach are currently in progress.
4
piperidin-1-yl
5
4-phenylpiperazin-1-yl
piperidin-1-yl
6
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
2-naphthyl
Ph
7
piperidin-1-yl
8
4-phenylpiperazin-1-yl
piperidin-1-yl
9
10
11
Me
Me
4-phenylpiperazin-1-yl
piperidin-1-yl
Ph
tained in slightly higher yields when the reactions were
performed with the substrates 8f–h (entries 6–8) having
electron-donating groups compared to substrates with
electron-withdrawing groups 8c–e (entries 3–5). Further-
more, the ring transformation reaction proceeded well with
substrate 8i having naphthyl group at C-6 position and the
desired product 9i was isolated in 88% yield (entry 9). Addi-
tionally, the course of reaction was also investigated with
the substrate 8j having methyl group at C-5 position and re-
action proceeded well with up to 78% yield (entry 10). The
course of reaction was also evaluated with the substrate 8k
containing thiophene functionality at C-6 position and re-
action worked well with up to 83% yield (entry 11).
In order to generalize this approach, the same synthetic
protocol was applied to construct teraryl-cored diarylmeth-
anes 11. To achieve the synthesis of teraryl-cored diaryl-
methanes 11, the similar substrates 6-aryl-2H-pyran-2-
ones 8 were treated with 1,3-diphenylacetone (10) in DMF
in the presence of KOH at room temperature and teraryl-
cored diarylmethanes 11 were obtained 74–95% yields (Ta-
ble 5, entries 1–11). Various functional groups were suc-
cessfully tolerated during these ring transformations.
It was observed that the course of reaction was quite
similar with both electron-donating and -withdrawing
cored substrates but ring transformation products were ob-
tained in slightly higher yields in the case of substrates hav-
Melting points were measured with REMI DDMS 2545 melting point
apparatus. IR spectra were recorded with a Thermo Scientific Nicolet
Nexus 470FT-IR spectrophotometer and band positions are reported
in reciprocal centimeters. Samples were subjected to ATR mode to re-
cord the IR data. 1H NMR and 13C NMR spectra were recorded on a
Bruker AV-400 spectrometer using the solvents indicated at 400 and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
F. V. Singh, P. B. Kole
Paper
Synthesis
O
O
CN
N
N
CN
O
O
O
O
N
OH
CN
KOH
DMF
CH3
+
Ph
CH3
CH3
Ar
Ar
O
O
Ar
H
Ph
Ph
8
6
13
12
–CO2
–H2O
N
CN
N
CN
CH3
Ar
CH3
Ar
Ph
Ph
9
14
Scheme 3 Proposed mechanism for the synthesis of diarylmethanes 9 by the ring transformation of 2H-pyran-2-ones 8 with 4-phenylbutan-2-one (6)
100 MHz, respectively. Mass spectra (m/z) were recorded under the
conditions of electron ionization (EI). All reactions were monitored by
TLC that was performed on pre-coated sheets of silica gel 60 and col-
umn chromatography was performed with Al2O3 (neutral, 95%) (Avra
synthesis Pvt. Ltd.). Hexane and EtOAc were used as eluting solvents
and bought from Avra Synthesis Pvt. Ltd. DMF was bought from Avra
Synthesis Pvt. Ltd and was used without further purification.
Anal. Calcd for C22H19NS: C, 80.20; H, 5.81; N, 4.25; S, 9.73. Found: C,
79.75; H, 5.83; N, 4.20; S, 9.06.
2-Benzyl-4′-bromo-3-methyl-5-(methylthio)[1,1′-biphenyl]-4-
carbonitrile (7b)
White solid; yield: 212 mg (0.52 mmol, 52%); mp 150–152 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2214 cm–1 (C≡N).
Diarylmethanes 7a–c; General Procedure
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H, CH3), 2.46 (s, 3 H, SCH3),
3.86 (s, 2 H, CH2), 6.79 (d, J = 6.8 Hz, 2 H, ArH), 6.94 (s, 1 H, ArH), 6.97
(td, J1 = 8.8 Hz, J2 = 2.0 Hz, 2 H, ArH), 7.07–7.20 (m, 3 H, ArH), 7.38 (td,
J1 = 8.8 Hz, J2 = 2.0 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 15.8, 18.9, 35.7, 112.4, 116.5, 122.2,
125.1, 126.3, 127.6, 128.7, 130.2, 131.5, 133.6, 139.3, 139.4, 141.5,
143.4, 146.5.
A mixture of 3-cyano-4-methylsulfanyl-2H-pyran-2-one 5 (1.0 mmol,
1.0 equiv), 4-phenylbutan-2-one (6; 0.18 mL, 1.2 mmol, 1.2 equiv),
and powdered KOH (84 mg, 1.5 mmol, 1.5 equiv) in DMF (5 mL) was
stirred at r.t. for 10–12 h. The course of reaction was monitored by
TLC. On completion of the reaction, few ice pieces were added to the
reaction mixture and neutralized with aq 2 M HCl. The mixture was
extracted with EtOAc (3 × 10 mL), the combined organic layers were
dried (anhyd Na2SO4), filtered, and concentrated under vacuum. The
crude residue was purified by neutral alumina column chromatogra-
phy using EtOAc–hexane (1:49) as an eluent and isolated products
were characterized as diarylmethanes 7 by their spectroscopic analy-
sis (Table 1).
GC-MS: m/z = 409 [M + 1]+, 410 [M + 2]+.
Anal. Calcd for C22H18BrNS: C, 64.71; H, 4.44; N, 3.43; S, 7.85. Found:
C, 64.69; H, 4.50; N, 3.39; S, 7.81.
2-Benzyl-4′-methoxy-3-methyl-5-(methylthio)[1,1′-biphenyl]-4-
carbonitrile (7c)
2-Benzyl-3-methyl-5-(methylthio)[1,1′-biphenyl]-4-carbonitrile
(7a)
White solid; yield: 204 mg (0.57 mmol, 57%); mp 144–146 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2214 cm–1 (C≡N).
White solid; yield: 164 mg (0.5 mmol, 50%); mp 148–150 °C; Rf = 0.5
(EtOAc–hexane 1:49).
1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 2.46 (s, 3 H, SCH3),
3.73 (s, 3 H, OCH3), 3.90 (s, 2 H, CH2), 6.78 (td, J1 = 8.8 Hz, J2 = 2.0 Hz, 2
H, ArH), 6.82 (d, J = 7.2 Hz, 2 H, ArH), 6.98 (s, 1 H, ArH), 7.03 (td, J1 =
8.8 Hz, J2 = 2.0 Hz, 2 H, ArH), 7.08–7.20 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 15.9, 18.9, 35.8, 55.3, 111.8, 113.7,
116.7, 125.6, 126.1, 127.7, 128.6, 129.7, 132.9, 133.9, 139.7, 141.1,
143.3, 147.5, 159.3.
IR (ATR): 2212 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3 H, CH3), 2.46 (s, 3 H, SCH3),
3.88 (s, 2 H, CH2), 6.81 (d, J = 7.2 Hz, 2 H, ArH), 6.98 (s, 1 H, ArH), 7.05–
7.20 (m, 5 H, ArH), 7.22–7.28 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 15.9, 18.9, 35.8, 112.1, 116.6, 125.4,
126.1, 127.7, 127.9, 128.3, 128.5, 128.6, 133.8, 139.6, 140.6, 141.2,
143.3, 147.8.
GC-MS: m/z = 360 [M + 1]+.
GC-MS: m/z = 330 [M + 1]+.
Anal. Calcd for C23H21NOS: C, 76.85; H, 5.89; N, 3.90; S, 8.92. Found: C,
76.10; H, 5.84; N, 3.84; S, 8.58.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

F
F. V. Singh, P. B. Kole
Paper
Synthesis
Biaryl-Cored Diarylmethanes 9a–k; General Procedure
13C NMR (100 MHz, CDCl3): δ = 18.9, 24.1, 26.2, 35.6, 53.5, 107.7,
117.9, 118.2, 126.0, 127.7, 128.4, 128.6, 129.4, 129.9, 133.7, 139.8,
140.0, 143.5, 146.9, 155.7.
A mixture of 2H-pyran-2-one 8 (1.0 mmol, 1.0 equiv), 4-phenylbu-
tan-2-one (6; 0.18 mL, 1.2 mmol, 1.2 equiv), and powdered KOH (84
mg, 1.5 mmol, 1.5 equiv) in DMF (5 mL) was stirred at r.t. for 10–14 h.
The course of reaction was monitored by TLC. On completion of the
reaction, few ice pieces were added to the reaction mixture and neu-
tralized with aq 2 M HCl. The reaction mixture was extracted with
EtOAc (3 × 10 mL), the combined organic layers were dried (anhyd
Na2SO4), filtered, and concentrated under vacuum. The crude residue
was purified by neutral alumina column chromatography using EtO-
Ac–hexane (1:49) as an eluent and isolated products were character-
ized as biaryl-cored diarylmethanes 9 by their spectroscopic analysis
(Table 4).
GC-MS: m/z = 401 [M + 1]+, 402 [M + 2]+.
Anal. Calcd for C26H25ClN2: C, 77.89; H, 6.28; N, 6.99. Found: C, 77.39;
H, 6.41; N, 6.43.
2-Benzyl-4′-bromo-3-methyl-5-(piperidin-1-yl)[1,1′-biphenyl]-4-
carbonitrile (9d)
White solid; yield: 364 mg (0.82 mmol, 82%); mp 116–118 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2217 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.47–1.56 (m, 2 H, CH2), 1.66–1.73 (m,
4 H, 2 × CH2), 2.30 (s, 3 H, CH3), 3.06 (t, J = 4.8 Hz, 4 H, 2 × NCH2), 3.81
(s, 2 H, CH2), 6.65 (s, 1 H, ArH), 6.80 (d, J = 7.6 Hz, 2 H, ArH), 6.95 (d, J =
8.0 Hz, 2 H, ArH), 7.03–7.19 (m, 3 H, ArH), 7.34 (d, J = 8.0 Hz, 2 H,
ArH).
2-Benzyl-3-methyl-5-(piperidin-1-yl)[1,1′-biphenyl]-4-carboni-
trile (9a)
White solid; yield: 311 mg, 0.85 mmol (85%); mp 114–116 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2215 cm–1 (C≡N).
13C NMR (100 MHz, CDCl3): δ = 18.9, 24.1, 26.2, 35.6, 53.5, 107.7,
117.9, 118.1, 121.9, 126.1, 127.7, 128.6, 129.4, 130.2, 131.3, 140.0,
140.2, 143.6, 146.8, 155.7.
1H NMR (400 MHz, CDCl3): δ = 1.46–1.54 (m, 2 H, CH2), 1.66–1.75 (m,
4 H, 2 × CH2), 2.30 (s, 3 H, CH3), 3.06 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 3.84
(s, 2 H, CH2), 6.70 (s, 1 H, ArH), 6.82 (d, J = 7.6 Hz, 2 H, ArH), 7.03–7.18
(m, 5 H, ArH), 7.20–7.25 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 18.9, 24.1, 26.3, 35.7, 53.6, 107.5,
118.1, 118.4, 125.9, 127.5, 127.8, 128.2, 128.5, 128.6, 129.6, 140.3,
141.4, 143.4, 148.1, 155.6.
GC-MS: m/z = 446 [M + 1]+, 447 [M + 2]+.
Anal. Calcd for C26H25BrN2: C, 70.11; H, 5.66; N, 6.29. Found: C, 70.03;
H, 5.66; N, 6.11.
2-Benzyl-4′-bromo-3-methyl-5-(4-phenylpiperazin-1-yl)[1,1′-bi-
phenyl]-4-carbonitrile (9e)
GC-MS: m/z = 367 [M + 1]+.
White solid; yield: 417 mg (0.79 mmol, 80%); mp 172–174 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2210 cm–1 (C≡N).
Anal. Calcd for C26H26N2: C, 85.21; H, 7.15; N, 7.64. Found: C, 85.04; H,
7.18; N, 7.52.
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H, CH3), 3.25–3.36 (m, 8 H,
4 × NCH2), 3.84 (s, 2 H, CH2), 6.71 (s, 1 H, ArH), 6.79–6.85 (m, 3 H,
ArH), 6.91 (d, J = 8.0 Hz, 2 H, ArH), 6.97 (td, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H,
ArH), 7.06–7.25 (m, 5 H, ArH), 7.37 (td, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 18.9, 35.6, 49.6, 51.9, 107.8, 116.4,
117.7, 118.1, 120.1, 122.0, 126.1, 127.7, 128.6, 129.2, 130.2, 130.4,
131.4, 139.8, 140.0, 143.9, 147.1, 151.2, 154.2.
2-Benzyl-3-methyl-5-(4-phenylpiperazin-1-yl)[1,1′-biphenyl]-4-
carbonitrile (9b)
White solid; yield: 363 mg (0.82 mmol, 82%); mp 180–182 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2210 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 3.25–3.35 (m, 8 H,
4 × NCH2), 3.86 (s, 2 H, CH2), 6.76 (s, 1 H, ArH), 6.81 (t, J = 7.6 Hz, 3 H,
ArH), 6.89 (d, J = 8.4 Hz, 2 H, ArH), 7.03–7.20 (m, 7 H, ArH), 7.21–7.26
(m, 3 H, ArH).
GC-MS: m/z = 523 [M + 1]+, 524 [M + 2]+.
13C NMR (100 MHz, CDCl3): δ = 19.0, 24.2, 35.7, 49.6, 51.9, 107.6,
116.4, 117.9, 118.3, 120.1, 126.0, 127.7, 127.8, 128.3, 128.5, 128.6,
129.2, 130.6, 140.1, 141.2, 143.8, 148.4, 151.2, 154.1.
Anal. Calcd for C31H28BrN3: C, 71.26; H, 5.40; N, 8.04. Found: C, 71.19;
H, 5.47; N, 7.91.
GC-MS: m/z = 444 [M + 1]+.
2-Benzyl-3,4′-dimethyl-5-(piperidin-1-yl)[1,1′-biphenyl]-4-carbo-
nitrile (9f)
Anal. Calcd for C31H29N3: C, 83.94; H, 6.59; N, 9.47. Found: C, 83.55; H,
6.58; N, 9.37.
White solid; yield: 357 mg (0.94 mmol, 94%); mp 162–164 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2215 cm–1 (C≡N).
2-Benzyl-4′-chloro-3-methyl-5-(piperidin-1-yl)[1,1′-biphenyl]-4-
1H NMR (400 MHz, CDCl3): δ = 1.45–1.56 (m, 2 H, CH2), 1.64–1.75 (m,
4 H, 2 × CH2), 2.26 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.05 (t, J = 5.2 Hz, 4
H, 2 × NCH2), 3.85 (s, 2 H, CH2), 6.70 (s, 1 H, ArH), 6.83 (d, J = 7.6 Hz, 2
H, ArH), 6.95–7.10 (m, 5 H, ArH), 7.14 (t, J = 7.6 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 18.9, 21.2, 24.2, 26.3, 35.7, 53.6, 107.3,
118.1, 118.4, 125.9, 127.8, 128.5, 128.9, 129.7, 137.3, 138.5, 140.4,
143.4, 148.1, 148.2, 155.6.
carbonitrile (9c)
White solid; yield: 312 mg (0.77 mmol, 78%); mp 141–143 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2218 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.46–1.57 (m, 2 H, CH2), 1.66–1.75 (m,
4 H, 2 × CH2), 2.30 (s, 3 H, CH3), 3.06 (t, J = 5.6 Hz, 4 H, 2 × NCH2), 3.81
(s, 2 H, CH2), 6.65 (s, 1 H, ArH), 6.80 (d, J = 7.2 Hz, 2 H, ArH), 7.01 (d, J =
8.4 Hz, 2 H, ArH), 7.04–7.21 (m, 5 H, ArH).
GC-MS: m/z = 381 [M + 1]+.
Anal. Calcd for C27H28N2: C, 85.22; H, 7.42; N, 7.36. Found: C, 84.71; H,
7.42; N, 7.16.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
F. V. Singh, P. B. Kole
Paper
Synthesis
2-Benzyl-4′-methoxy-3-methyl-5-(piperidin-1-yl)[1,1′-biphenyl]-
IR (ATR): 2215 cm–1 (C≡N).
4-carbonitrile (9g)
1H NMR (400 MHz, CDCl3): δ = 1.89 (s, 3 H, CH3), 2.30 (s, 3 H, CH3),
3.18–3.55 (m, 8 H, 4 × NCH2), 3.69 (s, 2 H, CH2), 6.72 (d, J = 7.2 Hz, 2 H,
ArH), 6.79 (t, J = 7.2 Hz, 1 H, ArH), 6.85–6.94 (m, 4 H, ArH), 7.01–7.15
(m, 3 H, ArH), 7.16–7.24 (m, 5 H, ArH).
White solid; yield: 356 mg (0.90 mmol, 90%); mp 172–174 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2213 cm–1 (C≡N).
13CNMR (100 MHz, CDCl3): δ = 16.9, 18.5, 36.6, 50.5, 50.6, 111.7,
116.6, 118.4, 119.9, 125.8, 127.3, 127.8, 128.2, 128.3, 128.5, 129.1,
133.5, 134.3, 139.8, 140.1, 140.2, 148.9, 151.5, 151.8.
1H NMR (400 MHz, CDCl3): δ = 1.45–1.58 (m, 2 H, CH2), 1.66–1.75 (m,
4 H, 2 × CH2), 2.28 (s, 3 H, CH3), 3.05 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 3.71
(s, 3 H, OCH3), 3.86 (s, 2 H, CH2), 6.70 (s, 1 H, ArH), 6.75 (d, J = 8.0 Hz, 2
H, ArH), 6.83 (d, J = 7.2 Hz, 2 H, ArH), 7.02 (d, J = 8.0 Hz, 2 H, ArH),
7.04–7.10 (m, 1 H, ArH), 7.14 (t, J = 7.2 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 18.9, 24.2, 26.3, 35.7, 53.6, 55.3, 107.2,
113.6, 118.2, 118.5, 125.9, 127.8, 128.5, 129.7, 133.8, 140.4, 143.3,
147.9, 155.6, 159.1.
GC-MS: m/z = 458 [M + 1]+.
Anal. Calcd for C32H31N3: C, 83.99; H, 6.83; N, 9.18. Found: C, 83.67; H,
6.87; N, 8.99.
3-Benzyl-2-methyl-6-(piperidin-1-yl)-4-(thiophen-2-yl)benzoni-
trile (9k)
GC-MS: m/z = 397 [M + 1]+.
White solid; yield: 308 mg (0.83 mmol (83%); mp 115–117 °C; Rf = 0.5
(EtOAc–hexane 1:49).
Anal. Calcd for C27H28N2O: C, 81.78; H, 7.12; N, 7.06. Found: C, 81.11;
H, 7.14; N, 6.92.
IR (ATR): 2215 cm–1 (C≡N).
2-Benzyl-4′-methoxy-3-methyl-5-(4-phenylpiperazin-1-yl)[1,1′-
biphenyl]-4-carbonitrile (9h)
1H NMR (400 MHz, CDCl3): δ = 1.49–1.58 (m, 2 H, CH2), 1.67–1.76 (m,
4 H, 2 × CH2), 2.30 (s, 3 H, CH3), 3.07 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.00
(s, 2 H, CH2), 6.78 (ds, J = 3.2 Hz, 1 H, ArH), 6.85–6.91 (m, 4 H, ArH),
7.11 (t, J = 7.2 Hz, 1 H, ArH), 7.14–7.25 (m, 3 H, ArH).
White solid; yield: 435 mg (0.92 mmol, 92%); mp 174–176 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2214 cm–1 (C≡N).
13C NMR (100 MHz, CDCl3): δ = 19.0, 24.1, 26.2, 35.9, 53.5, 107.9,
117.9, 119.2, 126.0, 126.1, 126.9, 127.3, 127.8, 128.6, 130.2, 140.2,
140.4, 142.1, 143.7, 155.5.
1H NMR (400 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 3.25–3.36 (m, 8 H,
4 × NCH2), 3.72 (s, 3 H, OCH3), 3.89 (s, 2 H, CH2), 6.75–6.77 (m, 2 H,
ArH), 6.78 (s, 1 H, ArH), 6.81–6.87 (m, 2 H, ArH), 6.88–6.95 (m, 2 H,
ArH), 7.04 (d, J = 8.8 Hz, 2 H, ArH), 7.06–7.12 (m, 1 H, ArH), 7.13–7.24
(m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 19.0, 35.7, 49.6, 51.9, 55.3, 107.3,
113.7, 116.4, 118.5, 120.1, 126.0, 127.8, 128.5, 128.7, 129.2, 129.7,
130.8, 133.5, 140.2, 143.7, 148.1, 151.2, 154.1, 159.2.
GC-MS: m/z = 373 [M + 1]+.
Anal. Calcd for C24H24N2S: C, 77.38; H, 6.49; N, 7.52; S, 8.61. Found: C,
77.68; H, 6.44; N, 7.43; S, 8.50.
Teraryl-Cored Diarylmethanes 11a–j and 11l; General Procedure
A mixture of 2H-pyran-2-one 8 (1.0 mmol, 1.0 equiv), 1,3-diphenylac-
etone (10; 0.24 mL, 1.2 mmol, 1.2 equiv), and powdered KOH (84 mg,
1.5 mmol, 1.5 equiv) in DMF (5 mL) was stirred at r.t. for 10–15 h. The
progress of the reaction was checked by TLC. On completion of the re-
action, few ice pieces were added to the reaction mixture and neu-
tralized with aq 2 M HCl. The reaction mixture was extracted with
EtOAc (3 × 10 mL), the combined organic layers were dried (anhyd
Na2SO4), filtered, and evaporated under vacuum. The crude residue
was purified by neutral alumina column chromatography using EtO-
Ac–hexane (1:49) as an eluent and compounds were characterized as
teraryl-cored diarylmethanes 11 by their spectroscopic analysis (Ta-
ble 5).
GC-MS: m/z = 474 [M + 1]+.
Anal. Calcd for C32H31N3O: C, 81.15; H, 6.60; N, 8.87. Found: C, 81.02;
H, 7.12; N, 8.71.
3-Benzyl-2-methyl-4-(naphthalen-2-yl)-6-(piperidin-1-yl)benzo-
nitrile (9i)
White solid; yield: 366 mg (0.88 mmol, 88%); mp 162–164 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2213 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.44–1.55 (m, 2 H, CH2), 1.66–1.76 (m,
4 H, 2 × CH2), 2.33 (s, 3 H, CH3), 3.07 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 3.87
(s, 2 H, CH2), 6.79 (s, 1 H, ArH), 6.82 (d, J = 6.8 Hz, 2 H, ArH), 7.07 (d, J =
6.8 Hz, 1 H, ArH), 7.13 (t, J = 7.6 Hz, 2 H, ArH), 7.21 (dd, J1 = 8.4 Hz, J2 =
1.6 Hz, 1 H, ArH), 7.35–7.41 (m, 2 H, ArH), 7.54 (s, 1 H, ArH), 7.58–
7.65 (m, 1 H, ArH), 7.68 (d, J = 8.8 Hz, 1 H, ArH), 7.70–7.78 (m, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 19.0, 24.2, 26.3, 35.8, 53.6, 107.6,
118.1, 118.6, 125.9, 126.3, 126.4, 126.8, 127.5, 127.6, 127.7, 127.8,
128.1, 128.5, 129.8, 132.5, 133.0, 138.9, 140.3, 143.5, 148.1, 155.7.
3′-Benzyl-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-carbonitrile
(11a)
White solid; yield: 376 mg (0.88 mmol, 88%); mp 145–148 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2214 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.49–1.58 (m, 2 H, CH2), 1.69–1.78 (m,
4 H, 2 × CH2), 3.13 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.06 (s, 2 H, CH2), 6.71–
6.81 (m, 3 H, ArH), 6.86 (s, 1 H, ArH), 6.90–6.95 (m, 2 H, ArH), 6.96–
7.10 (m, 9 H, ArH), 7.17–7.26 (m, 1 H, ArH).
GC-MS: m/z = 417 [M + 1]+.
Anal. Calcd for C30H28N2: C, 86.50; H, 6.78; N, 6.72. Found: C, 86.17; H,
6.77; N, 6.60.
13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 38.4, 53.6, 107.2, 118.9,
125.9, 126.8, 126.9, 127.6, 127.7, 128.1, 128.5, 129.4, 130.9, 135.0,
138.1, 138.2, 139.5, 141.1, 144.3, 147.1, 156.8.
2-Benzyl-3,6-dimethyl-5-(4-phenylpiperazin-1-yl)[1,1′-biphenyl]-
4-carbonitrile (9j)
GC-MS: m/z = 429 [M + 1]+.
Anal. Calcd for C31H28N2: C, 86.88; H, 6.59; N, 6.54. Found: C, 86.82; H,
6.69; N, 5.97.
White solid; yield: 356 mg (0.78 mmol, 78%); mp 140–142 °C; Rf = 0.5
(EtOAc–hexane 1:49).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
F. V. Singh, P. B. Kole
Paper
Synthesis
3′-Benzyl-5′-(4-phenylpiperazin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-car-
bonitrile (11b)
13C NMR (100 MHz, CDCl3): δ = 38.5, 49.6, 51.9, 107.6, 116.5, 117.8,
118.7, 120.2, 121.5, 126.1, 127.2, 128.0, 128.2, 128.5, 129.2, 130.7,
130.9, 131.0, 135.8, 137.7, 139.2, 139.7, 145.0, 146.0, 151.2, 155.4.
White solid; yield: 414 mg (0.82 mmol, 82%); mp 167–169 °C; Rf = 0.5
(EtOAc–hexane 1:49).
GC-MS: m/z = 585 [M + 1]+, 586 [M + 2]+.
IR (ATR): 2215 cm–1 (C≡N).
Anal. Calcd for C36H30BrN3: C, 73.97; H, 5.17; N, 7.19. Found: C, 74.01;
H, 5.36; N, 6.99.
1H NMR (400 MHz, CDCl3): δ = 3.30–3.38 (m, 8 H, 4 × NCH2), 4.08 (s, 2
H, CH2), 6.72–6.84 (m, 5 H, ArH), 6.88–6.96 (m, 5 H, ArH), 6.99–7.07
(m, 9 H, ArH), 7.20 (t, J = 7.6 Hz, 2 H, ArH).
3′-Benzyl-4-methyl-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-
carbonitrile (11f)
13C NMR (100 MHz, CDCl3): δ = 38.5, 49.6, 52.0, 107.3, 116.5, 117.9,
118.9, 120.1, 126.1, 126.9, 127.1, 127.7, 127.8, 128.2, 128.5, 129.2,
129.4, 130.8, 135.9, 137.9, 139.3, 140.8, 144.7, 147.4, 151.2, 155.3.
White solid; yield: 419 mg (0.95 mmol, 95%); mp 156–158 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2210 cm–1 (C≡N).
GC-MS: m/z = 506 [M + 1]+.
1H NMR (400 MHz, CDCl3): δ = 1.47–1.57 (m, 2 H, CH2), 1.68–1.77 (m,
4 H, 2 × CH2), 2.15 (s, 3 H, CH3), 3.12 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.04
(s, 2 H, CH2), 6.76 (t, J = 8.4 Hz, 4 H, ArH), 6.80–6.87 (m, 5 H, ArH),
6.97–7.10 (m, 6 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.1, 24.1, 26.2, 38.4, 53.6, 106.9,
118.2, 119.0, 125.9, 126.7, 127.7, 128.1, 128.4, 128.5, 129.3, 130.9,
135.0, 136.6, 138.1, 138.4, 139.5, 144.3, 147.1, 156.8.
Anal. Calcd for C36H31N3: C, 85.51; H, 6.18; N, 8.31. Found: C, 85.02; H,
6.24; N, 8.13.
3′-Benzyl-4-chloro-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-car-
bonitrile (11c)
White solid; yield: 365 mg (0.79 mmol, 79%); mp 158–160 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2215 cm–1 (C≡N).
GC-MS: m/z = 443 [M + 1]+.
1H NMR (400 MHz, CDCl3): δ = 1.49–1.57 (m, 2 H, CH2), 1.67–1.78 (m,
4 H, 2 × CH2), 3.12 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.04 (s, 2 H, CH2), 6.70–
6.78 (m, 4 H, ArH), 6.81 (s, 1 H, ArH), 6.85 (d, J = 8.4 Hz, 2 H, ArH),
6.97–7.10 (m, 8 H, ArH).
Anal. Calcd for C32H30N2: C, 86.84; H, 6.83; N, 6.33. Found: C, 86.77; H,
6.82; N, 6.24.
3′-Benzyl-4-methoxy-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-
carbonitrile (11g)
13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 38.4, 53.5, 107.4, 118.0,
118.7, 126.0, 127.0, 127.9, 128.1, 128.5, 128.7, 129.5, 130.7, 130.8,
134.9, 137.9, 139.3, 139.5, 144.6, 145.8, 156.8.
White solid; yield: 421 mg (0.92 mmol, 92%); mp 95–97 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2212 cm–1 (C≡N).
GC-MS: m/z = 464 [M + 1]+, 465 [M + 2]+.
1H NMR (400 MHz, CDCl3): δ = 1.48–1.59 (m, 2 H, CH2), 1.68–1.77 (m,
4 H, 2 × CH2), 3.12 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 3.63 (s, 3 H, OCH3),
4.04 (s, 2 H, CH2), 6.57 (d, J = 8.4 Hz, 2 H, ArH), 6.76 (t, J = 8.4 Hz, 4 H,
ArH), 6.82–6.88 (m, 3 H, ArH), 6.98–7.10 (m, 6 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 24.2, 26.2, 38.5, 53.6, 55.1, 106.8,
113.1, 118.3, 119.0, 125.9, 126.8, 127.8, 128.1, 128.5, 130.6, 130.9,
133.4, 135.0, 138.4, 139.5, 144.3, 146.7, 156.8, 158.5.
Anal. Calcd for C31H27ClN2: C, 80.42; H, 5.88; N, 6.05. Found: C, 80.59;
H, 5.96; N, 5.48.
3′-Benzyl-4-bromo-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-car-
bonitrile (11d)
White solid; yield: 415 mg (0.82 mmol, 82%); mp 150–152 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2217 cm–1 (C≡N).
GC-MS: m/z = 459 [M + 1]+.
1H NMR (400 MHz, CDCl3): δ = 1.49–1.57 (m, 2 H, CH2), 1.68–1.77 (m,
4 H, 2 × CH2), 3.12 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.04 (s, 2 H, CH2), 6.69–
6.79 (m, 6 H, ArH), 6.80 (s, 1 H, ArH), 6.97–7.08 (m, 6 H, ArH), 7.16 (d,
J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 24.1, 26.2, 38.4, 53.5, 107.5, 118.0,
118.7, 121.3, 126.0, 127.0, 127.9, 128.1, 128.5, 130.8, 131.0, 134.8,
137.9, 138.0, 139.3, 140.0, 144.6, 145.7, 156.8.
Anal. Calcd for C32H30N2O: C, 83.81; H, 6.59; N, 6.11. Found: C, 83.08;
H, 6.70; N, 6.07.
3′-Benzyl-4-methoxy-5′-(4-phenylpiperazin-1-yl)[1,1′:2′,1′′-ter-
phenyl]-4′-carbonitrile (11h)
White solid; yield: 497 mg (0.93 mmol, 93%); mp 120–122 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2209 cm–1 (C≡N).
GC-MS: m/z = 508 [M + 1]+, 509 [M + 2]+.
1H NMR (400 MHz, CDCl3): δ = 3.32–3.38 (m, 8 H, 4 × NCH2), 3.64 (s, 3
H, OCH3), 4.07 (s, 2 H, CH2), 6.58 (d, J = 8.8 Hz, 2 H, ArH), 6.77 (t, J = 7.6
Hz, 4 H, ArH), 6.80–6.94 (m, 6 H, ArH), 6.98–7.11 (m, 6 H, ArH), 7.21
(t, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 38.5, 49.6, 52.0, 55.2, 106.9, 113.2,
116.5, 118.1, 118.9, 120.2, 126.0, 126.9, 127.9, 128.1, 128.5, 129.2,
130.6, 130.8, 133.2, 135.9, 138.2, 139.4, 144.7, 147.0, 151.2, 155.3,
158.6.
Anal. Calcd for C31H27BrN2: C, 73.37; H, 5.36; N, 5.52. Found: C, 73.53;
H, 5.44; N, 5.35.
3′-Benzyl-4-bromo-5′-(4-phenylpiperazin-1-yl)[1,1′:2′,1′′-terphe-
nyl]-4′-carbonitrile (11e)
White solid; yield: 467 mg (0.80 mmol, 80%); mp 170–172 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2212 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 3.31–3.37 (m, 8 H, 4 × NCH2), 4.06 (s, 2
H, CH2), 6.70–6.83 (m, 7 H, ArH), 6.86 (s, 1 H, ArH), 6.89 (d, J = 8.0 Hz,
2 H, ArH), 6.99–7.09 (m, 6 H, ArH), 7.12–7.23 (m, 4 H, ArH).
GC-MS: m/z = 536 [M + 1]+.
Anal. Calcd for C37H33N3O: C, 82.96; H, 6.21; N, 7.84. Found: C, 82.86;
H, 6.25; N, 7.73.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
F. V. Singh, P. B. Kole
Paper
Synthesis
2-Benzyl-6-(naphthalen-2-yl)-4-(piperidin-1-yl)[1,1′-biphenyl]-3-
carbonitrile (11i)
pieces were added to the reaction mixture and neutralized with aq 2
M HCl. After that the reaction mixture was extracted with EtOAc (3 ×
10 mL). The combined organic layers were dried (anhyd Na2SO4), fil-
tered, and, concentrated under vacuum. The crude product was puri-
fied by neutral alumina column chromatography using EtOAc–hexane
(1:49) as an eluent to afford 12a; white solid; yield: 242 mg (0.62
mmol, 62%); mp 144–146 °C; Rf = 0.4 (EtOAc–hexane 1:49).
White solid; yield: 430 mg (0.90 mmol, 90%); mp 182–184 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2214 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.63–1.71 (m, 2 H, CH2), 1.82–1.90 (m,
4 H, 2 × CH2), 3.28 (t, J = 5.2 Hz, 4 H, 2 × NCH2), 4.22 (s, 2 H, CH2), 6.90–
6.96 (m, 4 H, ArH), 7.08–7.13 (m, 5 H, ArH), 7.14–7.23 (m, 3 H, ArH),
7.42–7.50 (m, 2 H, ArH), 7.56 (d, J = 8.4 Hz, 1 H, ArH), 7.64 (s, 1 H,
ArH), 7.71–7.78 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 24.2, 26.2, 38.4, 53.6, 107.3, 118.2,
119.3, 125.9, 126.1, 126.2, 126.8, 126.9, 127.4, 127.6, 127.8, 127.9,
128.1, 128.4, 128.5, 130.9, 132.1, 132.9, 135.1, 138.2, 138.8, 139.5,
144.5, 147.0, 156.9.
IR (ATR): 2211 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3 H, SCH3), 4.07 (s, 2 H, CH2),
6.72–6.77 (m, 4 H, ArH), 6.90–6.96 (m, 2 H, ArH), 6.98–7.09 (m, 9 H,
ArH), 7.12 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 14.7, 37.3, 110.7, 115.6, 124.4, 125.1,
126.1, 126.2, 126.7, 126.8, 127.1, 127.4, 128.3, 129.5, 136.5, 137.7,
137.8, 139.3, 142.2, 143.1, 145.6.
GC-MS: m/z = 392 [M + 1]+, 393 [M + 2]+.
GC-MS: m/z = 479 [M + 1]+.
Anal. Calcd for C27H21NS: C, 82.83; H, 5.41; N, 3.58; S, 8.19. Found: C,
82.21; H, 5.52; N, 3.42; S, 8.09.
Anal. Calcd for C35H30N2: C, 87.83; H, 6.32; N, 5.85. Found: C, 83.69; H,
6.36; N, 5.58.
3′-Benzyl-6′-methyl-5′-(4-phenylpiperazin-1-yl)[1,1′:2′,1′′-terphe-
nyl]-4′-carbonitrile (11j)
Acknowledgment
White solid; yield: 384 mg (0.74 mmol, 74%); mp 178–180 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2217 cm–1 (C≡N).
Fateh V. Singh is thankful to the SAIF, VIT University, Vellore Campus
for providing spectroscopic analysis. Priyanka B. Kole is grateful to VIT
Chennai Campus for providing a fellowship.
1H NMR (400 MHz, CDCl3): δ = 1.99 (s, 3 H, CH3), 3.22–3.60 (m, 8 H,
4 × NCH2), 3.98 (s, 2 H, CH2), 6.64 (dd, J1 = 7.2 Hz, J2 = 1.6 Hz, 2 H, ArH),
6.78 (dt, J1 = 7.2 Hz, J2 = 1.6 Hz, 5 H, ArH), 6.89–6.96 (m, 5 H, ArH),
6.95–7.09 (m, 6 H, ArH), 7.20 (t, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 17.2, 38.2, 50.5, 50.7, 111.4, 116.6,
118.5, 120.0, 126.0, 126.6, 127.4, 127.7, 128.1, 128.5, 129.1, 129.3,
130.3, 133.9, 138.6, 139.5, 139.6, 139.9, 141.4, 148.2, 151.8, 152.8.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610332.
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GC-MS: m/z = 520 [M + 1]+.
References
Anal. Calcd for C37H33N3: C, 85.51; H, 6.40; N, 8.09. Found: C, 85.38; H,
6.70; N, 8.07.
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3′-Benzyl-6′-methyl-5′-(piperidin-1-yl)[1,1′:2′,1′′-terphenyl]-4′-
carbonitrile (11l)
White solid; yield: 349 mg (0.79 mmol, 79%); mp 156–158 °C; Rf = 0.5
(EtOAc–hexane 1:49).
IR (ATR): 2213 cm–1 (C≡N).
1H NMR (400 MHz, CDCl3): δ = 1.55–1.74 (m, 6 H, 3 × CH2), 1.94 (s, 3
H, CH3), 3.10–3.36 (m, 4 H, 2 × NCH2), 3.96 (s, 2 H, CH2), 6.63 (dd, J1 =
7.6 Hz, J2 = 2.0 Hz, 2 H, ArH), 6.74–6.80 (m, 4 H, ArH), 6.86–6.93 (m, 3
H, ArH), 6.94–7.10 (m, 6 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 16.9, 24.3, 26.9, 38.1, 52.0, 110.5,
118.8, 125.9, 126.4, 126.5, 127.3, 127.6, 128.0, 128.5, 129.4, 130.3,
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GC-MS: m/z = 443 [M + 1]+.
Anal. Calcd for C32H30N2: C, 86.84; H, 6.83; N, 6.33. Found: C, 86.62; H,
6.87; N, 6.11.
3′-Benzyl-5′-(methylthio)[1,1′:2′,1′′-terphenyl]-4′-carbonitrile
(12a)
A mixture of 4-(methylthio)-2-oxo-6-phenyl-2H-pyran-3-carboni-
trile (5a; 243 mg, 1.0 mmol, 1.0 equiv), 1,3-diphenylacetone (10; 0.24
mL, 1.2 mmol, 1.2 equiv), and powdered KOH (84 mg, 1.5 mmol, 1.5
equiv) in DMF (5 mL) was stirred at r.t. for 12 h. The course of the re-
action was monitored by TLC. On completion of the reaction, few ice
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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F. V. Singh, P. B. Kole
Paper
Synthesis
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