Three Step Synthesis of Fully and Differently Arylated Pyridines

Article abstract of DOI:10.1002/ejoc.201901663

Condensation of β-(2-pyridyl)enamine and α,β-unsaturated ketone in the presence of FeCl₃ under air afforded highly substituted pyridines. In this transformation, FeCl₃ acted as not only an acid catalyst but also an oxidant for the in

Full text of DOI:10.1002/ejoc.201901663

A Journal of
Accepted Article
Title: Three Step Synthesis of Fully and Differently Arylated Pyridines
Authors: Mao Arita, Soichi Yokoyama, Haruyasu Asahara, and
Nagatoshi Nishiwaki
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10.1002/ejoc.201901663
European Journal of Organic Chemistry
FULL PAPER
Three Step Synthesis of Fully and Differently Arylated Pyridines
Mao Arita,[a] Soichi Yokoyama,[a,b] Haruyasu Asahara,*[a,b,c] and Nagatoshi Nishiwaki*[a,b]
Abstract: Condensation of b-(2-pyridyl)enamine and a,b-unsaturated
ketone in the presence of FeCl3 under air afforded highly substituted
pyridines. In this transformation, FeCl3 acted as not only an acid
catalyst but also an oxidant for the intermediate dihydropyridine. The
substituents could be easily modified by altering the substrates to
obtain tri- and tetraarylpyridines including bipyridines and terpyridine.
Synthesis of differently substituted pentaarylpyridines was
consequently achieved via only three steps from commercially
available reagents with simple experimental manipulations.
poor availability of the corresponding substrates, and need for
separation of spontaneously formed regioisomers. Hence, there
is great demand for a simple method to synthesize diverse
arylated pyridines.
In our previous work,[11] we demonstrated an efficient synthetic
method for polysubstituted nicotinates via the condensation of an
enamino ester with an α,β-unsaturated carbonyl compound in the
presence of FeCl3. This protocol facilitates the introduction of
different alkyl/aryl groups at the desired positions of the pyridine
framework by simply altering the starting materials. This
advantage prompted us to employ β-pyridylenamine 1 as a push-
pull alkene instead of the enamino ester, which afforded fully
arylated pyridines via only three steps including the synthesis of
substrates 1 and 2 (Scheme 1).
Introduction
Polyarylpyridines are widely used in various applications, such as
synthetic
intermediates
for
medicines,[1]
ligands
for
organometals,[2] and fluorophorescent chemosensors.[3] In recent
years, they have also been found to play an important role in
materials science because of their specific electronic properties.[4]
While the utility of polyarylpyridines has increased, introduction of
the desired aryl/alkyl group at the desired position remains difficult,
and considerable efforts have been undertaken in this regard.[5–
Ar4
Ar4
Ar5
Ar5
Ar6
N
FeCl3
microwave
N
Ar2
Ar6
N
O
Ar2
H2N
1
2
3
10]
Although Suzuki-Miyaura coupling is usually employed for
arylation of the pyridine framework,[6] different leaving groups
should be introduced in advance for site-selective arylation via
multistep reactions, which increases the difficulty of synthesis
and decreases the total yields. Indeed, there are only three
papers reporting fully and differently arylated pyridines.[7–10] In
2014, Schmitt et al. synthesized pyridines possessing five
different aryl groups for the first time via 13 steps, which included
regiocontrolled modification of the pyridine ring and subsequent
Suzuki-Miyaura coupling reactions.[7] Later, Yamaguchi et al.
succeeded in reducing the number of reaction steps by adopting
Diels-Alder-type ring transformation as the key step.[8,9] Despite
the successful synthesis of fully and differently arylated pyridines,
the substituents could not be readily altered to other aryl or alkyl
groups readily because of the tedious experimental manipulations,
Scheme 1. Synthesis of fully and differently arylated pyridines 3.
Results and Discussion
β-(2-Pyridyl)enamines 1A–D were efficiently prepared as a single
isomer by the condensation of benzonitriles with 2-
methylpyridine[12] (Table 1, Entries 1–4). On the other hand,
condensation using 4-methylpyridine afforded only the hydrolysis
product of 1E (Entry 5). In the case of p-nitrotoluene, a complex
mixture was obtained without any detectable formation of 1F
(Entry 6). Hence, the 2-pyridyl group is considered to stabilize
1
enamine 1 by intramolecular hydrogen bonding. Indeed, the H
NMR spectrum showed a signal due to one of the NH hydrogens
at d ~6 ppm, but a signal due to the other hydrogen was not
observed because of exchange with water present in the solvent.
Enones 2a–l were easily prepared by simply mixing the
corresponding aldehydes and ketones under alkaline conditions,
respectively. For the preparation of a,b-disubstituted enones 2m–
t, it was more effective to heat a solution of an aldehyde and a
ketone in toluene using Dean-Stark apparatus in the presence of
piperidinium acetate.
[a]
Mr. M. Arita, Dr. S. Yokoyama, Dr. H. Asahara, Prof. N. Nishiwaki
School of Environmental Science and Engineering
Kochi University of Technology
Tosayamada, Kami Kochi 782-8502, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
URL: http://www.env.kochi-tech.ac.jp/naga/nishiwaki-lab.html
Dr. S. Yokoyama, Dr. H. Asahara, Prof. N. Nishiwaki
Research Center for Material Science and Engineering
Kochi University of Technology
[b]
[c]
Dr. H. Asahara
Graduate School of Pharmaceutical Sciences
Osaka University
Yamadaoka 1-6, Suita, Osaka 565-0871, Japan
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Next, we attempted the synthesis of fully substituted pyridines
using α,β-disubstituted enones 2o–r. In the case of α-methylated
enone 2o, pyridine 3Bo was obtained in a similar yield as 3Bg
(Entries 11 and 19). When α-arylated enone 2p was used, fully
and differently substituted pentaarylpyridine 3Bp was obtained,
although the yield was considerably decreased (Entry 20). The
low reaction efficiency of 2p was considered to be due to the
instability caused by the disturbed conjugation. Structural
optimization by DFT calculations [B3LYP/6-31g(d,p)] indicated
that both chlorophenyl and benzoyl groups were distorted by
around 40° angles as a result of steric repulsion with the α-aryl
group, and the α-aryl group itself was distorted by around 85°
angle from the enone plane (Figures 1 and S1). Indeed, when
enone 2p was subjected to the reaction conditions in the absence
of 1B, 82% of 2p was decomposed to afford a complex mixture.
This problem was overcome by increasing the molar ratio (2p:1B)
from 1:5 to 1:2 (Entries 20 and 21). Consequently,
pentaarylpyridines 3Bp–r were synthesized in only three steps,
among which the structure of 3Br was confirmed by X-ray
crystallography (Entries 20–23 and Figure 2). With this method,
the aryl groups could be easily modified by altering benzonitriles,
benzaldehyde, and benzyl phenyl ketones.
Table 1. Preparation of enamines 1.
N
NH2
Y
Z
C
LDA
Y
Z
X
THF
H3C
X
R
-78 °C to rt
R
1
Enamine 1
Entry
R
X
Y
Z
Yield/%
98
1
2
3
4
5
6
7
H
CH
CH
CH
CH
CH
CH
N
N
CH
CH
CH
CH
N
1A
1B
1C
1D
1E
1F
1G
Me
Cl
N
91
N
94
CF3
Me
Me
H
N
86
CH
CH
N
0[a]
0
C-NO2
CH
Cl
Cl
Cl
78
[a] 1-(4-Methylphenyl)-2-(4-pyridyl)ethanone was obtained in 75% yield.
NO2
1.4°
4.4°
41.3°
25.5°
45.4°
45.2°
Me
85.6°
O
O
O
When benzylideneacetone 2a was reacted with β-(2-
pyridyl)enamine 1A in the presence of FeCl3 in a sealed tube at
180 °C under microwave irradiation, 6-methyl-2,4-diphenyl-3-(2-
pyridyl)pyridine (3Aa) was isolated in 84% yield (Table 2, Entry 1).
This reaction was not suppressed by the presence of the bulky
naphthyl group at the reaction site (Entry 2). While an electron-
donating methyl group on the α-phenyl group (R2) of 1 facilitated
the condensation, electron-withdrawing groups slightly decreased
the yields of pyridines 3, presumably due to the decreased
nucleophilicity of enamines 1C and 1D (Entries 3–5).
2g
2o
2p
Figure 1. optimized structures of 2g, 2o and 2p.
Chalcone derivatives 2c–l were more easily treatable than methyl
ketones 2a and 2b, and underwent the condensation to afford
2,3,4,6-tetraarylpyridines, which facilitated the modification of the
substituents at the 4-, 5- and 6-positions of the pyridine framework
(Entries 6–20). The reaction using enones 2c–f readily proceeded
without any notable effect of the electronic nature of R4 to give the
corresponding products 3Bc–f and 3Ce respectively (Entries 6–
10). On the contrary, this reaction was considerably affected by
the substituent on the phenyl group (R6) (Entries 11–13). Since
both electron-donating and electron-withdrawing groups
decreased the yields of products 3Bh and 3Bi, the low reactivity
was considered to be due to the poor solubility of enones 2h and
2i. Indeed, 2-methoxyphenyl ketone 2j showed higher reactivity
than 2i because of its increased solubility (Entries 13 and 14).
Furthermore, 2,3,5,6-tetraarylpyridines 3Bm and 3Bn could be
prepared by using α-arylated enones 2m and 2n were used
(Entries 17 and 18).
Figure 2. ORTEP of the single crystal structure of 3Br. Ellipsoids are shown at
the 50% probability level.
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Table 2. Synthesis of polyarylated pyridines 3.
R4
R4
R5
R6
R5
R6
FeCl3 (1 equiv.)
N
N
+
MeCN
180 °C, 1 h
microwave
R2
R2
NH2
O
N
2
1 (5 equiv.)
3
in a sealed tube
Entry
Enamine 1
R2
Enone 2
Product
Yield/%
R4
R5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R6
1
Ph
1A
1B
1B
1C
1D
1B
1B
1B
1C
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
Ph
Me
2a
2b
2a
2a
2a
2c
2d
2e
2e
2f
3Aa
3Bb
3Ba
3Ca
3Da
3Bc
3Bd
3Be
3Ce
3Bf
84
66
86
71
69
56
67
64
76
76
72
35
39
61
57
29
51
38
62
13
26
21
10
2
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-F3CC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-Naphthyl
Me
3
Ph
Ph
Ph
Me
4
Me
5
Me
6
4-MeOC6H4
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
7
8
4-FC6H4
4-FC6H4
4-NCC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-tert-BuC6H4
4-MeOC6H4
H
9
10
11
12
13
14
15
16
17
18
19
20
21[a]
22[a]
23[a]
2g
2h
2i
3Bg
3Bh
3Bi
4-O2NC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-O2NC6H4
Ph
2j
3Bj
2k
2l
3Bk
3Bl
4-O2NC6H4
4-O2NC6H4
Me
2m
2n
2o
2p
2p
2q
2r
3Bm
3Bn
3Bo
3Bp
3Bp
3Bq
3Br
H
4-MeOC6H4
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Ph
Ph
Ph
4-ClC6H4
4-BrC6H4
[a] 2 Equiv. of enamine 1B were used.
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When the reaction atmosphere was changed from air to argon,
the yield of 3Ba decreased to 64%, which indicated that oxygen
is necessary for the efficient reaction (Table 3, Entries 1 and 2).
However, a complicated mixture of compounds was obtained
when the reaction was conducted under oxygen (Entry 3), and
decomposition of the substrates was observed. When a catalytic
amount of FeCl3 was used under argon atmosphere, the reaction
was considerably suppressed; however, the same reaction under
air afforded 3Ba in 72% yield (Entries 4 and 5).
Ph
Ph
H
Py
Py
Tol
Tol
+
NH2
+
NH2
Me
O
Me
O
_
_
1B
FeCl3 2a'
FeCl3
Ph
Py
Ph
Py
Tol
Tol
Me
OH
NH2
Me
O
N
H
Table 3. Study on reaction atmosphere and catalyst loading in the reaction of
1B and 2a.
Ph
Entry
FeCl3/equiv.
Atmosphere
Air
Yield of 3Ba/%
Py
Tol
3Ba
Fe2+
1
2
3
4
5
6
7
1
86
64
69
39
72
69
78
Fe3+
O2
N
Me
4
1
Argon
Oxygen
Argon
Air
1
Scheme 2. A plausible mechanism.
0.2
0.2
0.2[a]
0.2[b]
Ph
Ph
Py
Tol
Py
Tol
Air
+
NH2
N
Me
O
Me
Air
_
1B
FeCl3
2a'
[a] Molecular sieves 3A (100 mg) was added. [b] p-Benzoquinone (1 equiv.) was
added.
Ph
Py
Tol
3Ba
Fe2+
Fe3+
O2
A plausible mechanism for the reaction is shown in Scheme 2.
The reaction is initiated by the attack of 1B onto enone 2a’
activated by FeCl3. After cyclization and dehydration, the resulting
dihydropyridine 4 was oxidized by FeCl3 to afford 3Ba, and
oxygen in the air reoxidized the reduced iron species, and the
reaction proceeded with a catalytic amount of FeCl3. Another
reaction mechanism initiated by imine formation is also
acceptable (Scheme 3). We consider the former mechanism is
more plausible based on our insights obtained from the study
using push-pull alkenes, β-nitroenamines.[13]
N
Me
4’
Scheme 3. Another acceptable reaction mechanism.
Tol
H
O
In both reaction mechanisms, a water is eliminated during the
condensation between an amino and a carbonyl group, which
might cause the competitive hydrolysis of the substrates.
However, no effect was observed even when the reaction was
conducted in the presence of molecular sieves (Table 3, Entry 6).
This is presumably due to the reversible releasing of water under
the employed conditions. Furthermore, p-benzoquinone was
added to facilitate the oxidation of intermediately formed
dihydropyridine 4 or 4’, which increased the yield of 3Ba to 78%
(Entry 7), which indicates a possibility to establish an efficient
catalytic system for synthesis of polysubstituted pyridines.
N
N
N
NH2
1B
NH2
2s
Tol
N
InCl3
(1 equiv.)
FeCl3
(1 equiv.)
1G
(5 equiv.)
(5 equiv.)
MeCN
180 °C, 1 h
microwave
Me
Me
in a seald tube
H
N
H
N
N
N
N
N
3Bs 50%
Scheme 4. Synthesis of oligopyridines 3Bs and 3Gs.
N
Me
3Gs 65%
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performed on Rigaku/R-AXIS RAPID (CuKα
λ = 1.54187 Å) and
Our protocol facilitated the synthesis and molecular design of
multiply substituted pyridines 3 by simple alteration of substrates
1 and 2. This advantage prompted us to synthesize substituted
bipyridine 3Bs and terpyridine 3Gs (Scheme 4). Enamine 1B
reacted with enone 2s to furnish bipyridine 3Bs. However, α-(2-
pyridyl)enamine 1G did not undergo the reaction at all; this is
thought to be due to the formation of a complex of 1G with FeCl3
because the reaction mixture became purple immediately after
the addition of FeCl3. This abovementioned problem was
overcome by replacing the Lewis acid from FeCl3 to the non-
coordinating InCl3, and terpyridine 3Gs was successfully
produced although 1 equiv. InCl3 was necessary for the efficient
reaction. Furthermore, fully arylated bipyridine 3Ct could be
synthesized in 17% yield by the condensation of enamine 1C with
(α,β-diaryl)ethenyl pyridyl ketone 2t in the presence of FeCl3
(Figure 3).
Rigaku/XtaLAB Synergy-S/Cu (CuKα λ = 1.54187 Å) diffractometers. The
single crystal of 3Br was obtained by recrystallization from CHCl3–Hexane.
The X-ray measurement was performed at −150 °C. The structures were
solved by direct methods (SHELXT) and refined through full-matrix least-
squares techniques on F2 using SHELXL and OLEX2 crystallographic
software packages.[14−16] All non-hydrogen atoms were refined with
anisotropic displacement parameters and hydrogen atoms were placed at
calculated positions and refined “riding” on their corresponding carbon
atoms. The geometrical optimization was carried out for at the B3LYP/6-
31g(d,p) level of theory implemented on Gaussian 09 package.[17]
Synthesis of enamines 1. Enamines 1 were prepared according to the
method described in literature.[12] To a solution of diisopropylamine (1.0 g,
10 mmol) in tetrahydrofuran (10 mL), a solution of butyllithium (11 mmol)
was added at -70 °C. After stirring for 0.5 h at the same temperature, 2-
methylpyridine (0.73 g, 10 mmol) was added dropwise, and the resultant
mixture was stirred for further 1 h. Benzonitrile (1.0 g, 10 mmol) was
gradually added to the solution, and stirred at -70 °C for 1 h. After elevating
the reaction temperature, the solution was stirred at room temperature for
further 1 h. After quenching the reaction with water, the mixture was
extracted with ethyl acetate (30 mL ´ 3). The organic layer was dried over
magnesium sulfate, and concentrated under reduced pressure. The
residue was washed with hexane (30 mL) to afford 1-amino-1-phenyl-2-(2-
pyridyl)ethene (1A)[12] as a yellow solid (1.92 g, 9.8 mmol, 98%). 1H NMR
(400 MHz, CDCl3) δ 8.44 (1H, ddd, J = 4.8, 2.0, 1.2 Hz), 7.63–7.61 (2H,
m), 7.48 (1H, ddd, J = 8.0, 8.0, 2.0 Hz), 7.39–7.36 (3H, m), 7.00 (1H, ddd,
J = 8.0, 1.2, 1.2 Hz), 6.84 (1H, ddd, J = 8.0, 4.8, 2.0 Hz), 6.90–6.63 (1H,
br), 5.48 (1H, s). Other enamines 1B–D and 1G were prepared by
condensation of the corresponding benzonitrile derivatives and
methylarenes in the same way.
NO2
N
N
N
Cl
3Ct 17%
Figure 3. Fully arylated bipyridine 3Ct.
1-Amino-1-(4-methylphenyl)-2-(2-pyridyl)ethene (1B).[18] Yellow solid
(1.91 g, 9.1 mmol, 91%). 1H NMR (400 MHz, CDCl3) δ 8.44 (1H, ddd, J =
4.8, 1.2, 0.8 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.49 (1H, ddd, J = 8.4, 8.4, 1.6
Hz), 7.21 (2H, d, J = 8.0 Hz), 7.00 (1H, ddd, J = 8.4, 0.8, 0.8 Hz), 6.84 (1H
ddd, J = 8.4, 4.8, 1.2 Hz), 6.93–6.67 (1H, br), 5.47 (1H, s), 2.38 (3H, s).
Conclusions
We have demonstrated the synthesis of polyarylpyridines by the
condensation of b-(2-pyridyl)enamine 1 and a,b-unsaturated
ketone 2 in the presence of FeCl3 under air. In this reaction, FeCl3
plays the role of not only an acid catalyst but also an oxidant for
the intermediate dihydropyridine. The substituents can be easily
modified by altering the substrates to obtain tri-, tetra- and
pentaarylpyridines 3 from commercially available reagents via
only three steps. Moreover, this protocol is applicable to the
synthesis of polyarylated bipyridines and terpyridine.
1-Amino-1-(4-chlorophenyl)-2-(2-pyridyl)ethene (1C).[18] Yellow solid
(2.17 g, 9.4 mmol, 94%). 1H NMR (400 MHz, CDCl3) δ 8.45 (1H, ddd, J =
6.0, 1.6, 1.2 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.49 (1H, ddd, J = 8.0, 1.6, 1.6
Hz), 7.36 (2H, d, J = 8.4 Hz), 7.00 (1H, ddd, J = 8.0, 1.2, 1.2 Hz), 6.84 (1H
ddd, J = 8.0, 6.0, 1.6 Hz), 6.83–6.65 (1H, br), 5.45 (1H, s).
1-Amino-2-(2-pyridyl)-1-[4-(trifluoromethyl)phenyl]ethene
(1D).
Yellow solid (2.28 g, 8.6 mmol, 86%). Mp 120.3–120.7 °C. 1H NMR (400
MHz, CDCl3) δ 8.48 (1H, ddd, J = 4.8, 1.2, 0.8 Hz), 7.75 (2H, d, J = 8.0
Hz), 7.65 (2H, d, J = 8.0 Hz), 7.53 (1H, ddd, J = 8.0, 8.0, 1.6 Hz), 7.05 (1H,
ddd, J = 8.0, 0.8, 0.8 Hz), 6.91 (1H ddd, J = 8.0, 4.8, 1.2 Hz), 6.99–6.67
(1H, br), 5.52 (1H, s), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.3
(C), 148.6 (C), 147.6 (CH), 143.5 (C), 135.8 (CH), 130.5 (C, q, J = 136.0
Hz), 126.4 (CH), 125.6 (CH, q, J = 3.8 Hz), 125.5 (C, q, J =271.0 Hz), 122.6
(CH), 118.0 (CH), 97.19 (CH); IR (KBr/cm-1) 3466, 1733, 1618, 1473, 1335,
1168, 1112, 1077, 845, 800, 749; HRMS (ESI/TOF) calcd. for [M+H]+
C14H12F3N2: 265.0947, found: 265.0945.
Experimental Section
General. All reagents were purchased from commercial sources and used
without further purification. Dry acetonitrile was also purchased from
commercial source and used as received. 1H and 13C NMR spectra were
recorded on Bruker DPX-400 spectrometer (400 MHz and 100 MHz,
respectively) in CDCl3 using TMS as an internal standard. When
stereoisomers were obtained as a mixture, integral value for the E isomer
was indicated as HE, and that for the Z isomer was indicated as HZ in the
1H NMR. The assignments of the 13C NMR were performed by DEPT
1-Amino-1,2-bis(2-pyridyl)ethene (1G).[19] Yellow solid (1.53 g, 7.8 mmol,
78%). 1H NMR (400 MHz, CD3CN) δ 8.59 (1H, ddd, J = 4.8, 2.0, 1.2 Hz),
8.46 (1H, ddd, J = 4.8, 2.0, 0.8 Hz), 7.88 (1H, ddd, J =8.4, 0.8, 0.8), 7.76
(1H, ddd, J = 8.4, 8.4, 2.0 Hz), 7.56 (1H, ddd, J = 8.0, 8.0, 2.0 Hz), 7.30
(1H, ddd, J = 8.4, 4.8, 0.8 Hz), 7.13 (1H, ddd, J = 8.0, 0.8, 0.8 Hz), 6.91
(1H, ddd J = 8.0, 4.8, 2.0 Hz), 6.83–6.65 (1H, br), 5.99 (1H, s).
experiments. IR spectra were recorded on
a JASCO FT/IR-4200
spectrometer equipped with an ATM detector. High-resolution mass
spectra were obtained on an AB SCEIX Triplet TOF 4600 mass
spectrometer. Melting points were recorded on an SRS-Optimelt
automated melting point system and were uncorrected. Microwave heating
was performed by Anton-Paar Microwave 300 (850 W, 2455 MHz) using
10 mL glass vessel. Data collection for X-ray crystal analysis was
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10.1002/ejoc.201901663
European Journal of Organic Chemistry
FULL PAPER
Synthesis of enones 2. Enones 2 were prepared by aldol condensation
by Method a or Method b except for commercially available 2a.
1-(4-Chlorophenyl)-3-[4-(1,1-dimethylethyl)phenyl]-2-propen-1-one
(2k).[27] Colorless solid (1.97 g, 6.6 mmol, 66%). 1H NMR (400 MHz,
CDCl3) δ 7.96 (2H, d, J = 8.8 Hz), 7.80 (1H, d, J = 15.6 Hz), 7.58 (2H, d, J
= 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.45 (1H, d, J = 15.6 Hz), 7.44 (2H, d,
J = 8.8 Hz), 1.35 (9H, s).
Method a: To a methanol solution (30 mL) of 2-napthaldehyde (1.56 g, 10
mmol) and acetone (0.74 mL, 10 mmol), 0.5 M aqueous solution of
potassium hydroxide (20 mL, 10 mmol) was added. The resultant mixture
was stirred at room temperature for 0.5 h. Precipitated solid was collected
by filtration to afford 4-(2-naphthyl)-3-buten-2-one (2b)[20] as a colorless
solid (1.96 g, 10 mmol, quant.). The product was used for the subsequent
condensation with enamine 1 without further purification. 1H NMR (400
MHz, CDCl3) δ 7.94 (1H, s), 7.86–7.81 (3H, m), 7.68–7.64 (1H, m), 7.65
(1H, d, J = 16.4 Hz), 7.52–7.50 (2H, m), 2.41 (3H, s). Other enones 2c–l
were prepared in the same way. When product was formed as an oil, the
mixture was extracted with dichloromethane (30 mL ´ 3), and the organic
layer was dried over magnesium sulfate, and concentrated. The residual
oil was used for the subsequent condensation with enamine 1 without
further purification. For the preparation of a,b-disubstituted enones,
Method b was effective rather than Method a.
3-(4-Methoxyphenyl)-1-(4-nitrophenyl)-2-propen-1-one (2l).[28] Yellow
solid (2.07 g, 7.3 mmol, 73%). 1H NMR (400 MHz, CDCl3) δ 8.34 (2H, d, J
= 9.2 Hz), 8.13 (2H, d, J = 9.2 Hz), 7.82 (1H, d, J = 15.6 Hz), 7.62 (2H, d,
J = 8.4 Hz), 7.35 (1H, d, J = 15.6 Hz), 6.96 (2H, d, J = 8.4 Hz), 3.87 (3H,
s).
Method b: To a toluene solution (50 mL) of 4-chlorobenzaldehyde (1.40 g,
10 mmol) and propanoylbenzene (1.34 g, 10 mmol), piperidine (0.20 mL,
2.0 mmol) and acetic acid (0.11 mL, 2.0 mmol) were added. The resultant
mixture was heated under reflux using Dean-Stark apparatus for 1 d. After
concentration, the residue was treated with column chromatography on
silica gel to afford 3-(4-chlorophenyl)-2-methyl-1-phenyl-2-propen-1-one
(2o)[29] as colorless needles (1.05 g, 4.1 mmol, 41%). 1H NMR (400 MHz,
CDCl3) δ 7.74–7.72 (2H, m), 7.55 (1H, ddd, J = 7.6, 0.6, 0.6 Hz), 7.47–
7.44 (2H, m), 7.38–7.32 (4H, m), 7.10 (1H, d, J = 1.2 Hz), 2.23 (3H, d, J =
1.2 Hz). Other enones 2m–t were prepared in the same way.
3-(4-Methoxyphenyl)-1-(4-methylphenyl)-2-propen-1-one
(2c).[21]
Colorless solid (1.01 g, 4.0 mmol, 40%). 1H NMR (400 MHz, CDCl3) δ 7.93
(2H, d, J = 8.4 Hz), 7.77 (1H, d, J = 15.6 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.34
(1H, d, J = 15.6 Hz), 7.29 (2H, d, J = 8.4 Hz), 6.93 (2H, J = 8.8 Hz), 3.85
(3H, s), 2.43 (3H, s).
2-(4-Nitrophenyl)-1-phenyl-2-propen-1-one (2m).[30] Yellow oil (1.24 g,
4.9 mmol, 49%). 1H NMR (400 MHz, CDCl3) δ 8.22 (2H, d, J = 8.8 Hz),
7.90–7.87 (2H, m), 7.62 (2H, d, J = 8.8 Hz), 7.49–7.45 (3H, m), 6.26 (1H,s),
5.88 (1H, s).
1-(4-Methylphenyl)-3-phenyl-2-propen-1-one (2d).[21] Yellow oil (2.00 g,
9.0 mmol, 90%). 1H NMR (400 MHz, CDCl3) δ 7.93 (2H, d, J= 8.4 Hz), 7.79
(1H, d, J = 15.6 Hz), 7.64–7.62 (2H, m), 7.52 (1H, d, J = 15.6 Hz), 7.41–
7.39 (3H, m), 7.29 (2H, d, J = 8.4 Hz), 2.42 (3H, s).
1-(4-Methoxyphenyl)-2-(4-nitrophenyl)-2-propen-1-one (2n). Yellow oil
(2.21 g, 7.8 mmol, 78%). 1H NMR (400 MHz, CDCl3) δ 8.20 (2H, d, J = 9.2
Hz), 7.90 (2H, d, J = 9.2 Hz), 7.61 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8
Hz), 6.18 (1H, s), 5.79 (1H, s), 3.88 (3H, s); 13C NMR (100 MHz, CDCl3) δ
194.8 (C), 164.1 (C), 147.6 (C), 146.5 (C), 143.5 (C), 132.4 (CH), 129.3
(C), 127.9 (CH), 123.9 (CH), 123.0 (CH2), 113.9 (CH), 55.57 (CH3); IR
(ATR/cm-1) 1654, 1593, 1512, 1342, 1257, 1165, 848, 705; HRMS
(ESI/TOF) calcd. for [M+H]+ C16H14NO4: 284.0917, found: 284.0909.
3-(4-Fluorophenyl)-1-(4-methylphenyl)-2-propen-1-one
(2e).[22]
Colorless solid (2.11 g, 8.8 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ 7.93
(2H, d, J = 8.0 Hz), 7.76 (1H, d, J = 16.0 Hz), 7.65–7.61 (2H, m), 7.45 (1H,
d, J = 16.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.13–7.08 (2H, m), 2.44 (3H, s).
3-(4-Cyanophenyl)-1-(4-methylphenyl)-2-propen-1-one
(2f).[23]
Colorless solid (1.21 g, 4.9 mmol, 49%). 1H NMR (400 MHz, CDCl3) δ 7.93
(2H, d, J = 8.0 Hz), 7.76 (1H, d, J = 18.0 Hz), 7.41–7.69 (4H, m), 7.60 (1H,
d, J = 18.0 Hz), 7.32 (2H, d, J = 8.0Hz), 2.45 (3H, s).
3-(4-Chlorophenyl)-2-(4-nitrophenyl)-1-phenyl-2-propen-1-one (2p).
Colorless needles (1.49 g, 4.1 mmol, 41%). Mp 133.9–134.2 °C. 1H NMR
(400 MHz, CDCl3) δ 8.22 (2H, d, J = 8.8 Hz), 7.85–7.83 (2H, m), 7.61–7.57
(1H, m), 7.51–7.45 (4H, m), 7.32 (1H, s), 7.19 (2H, d, J = 8.4 Hz), 6.98 (2H,
d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 196.2 (C), 147.6 (C), 143.2
(C), 140.9 (CH), 139.1 (C), 137.4 (C), 135.7 (C), 132.7 (CH), 132.3 (C),
131.4 (CH), 130.9 (CH), 129.7, (CH), 128.9 (CH), 128.6 (CH), 124.1 (CH);
IR (KBr/cm-1) 1725, 1650, 159, 1518, 1254, 1091, 854, 752, 700; HRMS
(ESI/TOF) calcd. for [M+H]+ C21H15ClNO3: 364.0735, found: 364.0723.
3-(4-Chlorophenyl)-1-phenyl-2-propen-1-one (2g).[24] Yellow solid (1.65
g, 6.8 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 8.03–8.00 (2H, m), 7.75
(1H, d, J = 16.0 Hz), 7.56–7.57 (3H, m), 7.52–7.48 (2H, m), 7.39 (2H, d, J
= 8.4 Hz).
3-(4-Chlorophenyl)-1-(4-nitrophenyl)-2-propen-1-one (2h).[25] Yellow
solid (2.88 g, 10 mmol, quant.) 1H NMR (400 MHz, CDCl3) δ 8.35 (2H, d,
J = 8.8 Hz), 8.12 (2H, d, J = 8.8 Hz), 7.80 (1H, d, J =16.4 Hz), 7.59 (2H, d,
J = 8.4 Hz), 7.45 (1H, d, J = 16.4 Hz), 7.42 (2H, d, J = 8.4 Hz).
2-(4-Nitrophenyl)-1,3-diphenyl-2-propen-1-one (2q). White powder
(2.37 g, 7.2 mmol, 72%, E/Z = 61/39). Mp 157.2—158.0 °C. 1H NMR (400
MHz, CDCl3) δ 8.22–8.19 (2HE, m), 8.22–8.19 (2HZ, m), 7.96–7.94 (2HZ,
m), 7.86–7.84 (2HE, m), 7.62 (2HZ, d, J = 6.8 Hz), 7.61–7.57 (1HE, m),
7.51–7.46 (2HE, m), 7.51–7.46 (2HZ, m), 7.39–7.19 (6HE, m), 7.39–7.19
(7HZ, m), 7.04 (2HE, d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 198.3
(C), 196.6 (C), 147.4 (C), 147.3 (C), 144.3 (C), 143.7 (C), 142.7 (CH),
138.64 (C), 138.62 (C), 137.7 (C), 135.8 (C), 134.5 (C), 134.2 (CH), 133.8
(C), 133.6 (CH), 132.6 (CH), 131.0 (CH), 130.3 (CH), 129.8 (CH), 129.7
(CH), 129.6 (CH), 129.2 (CH), 128.9 (CH), 128.6 (CH), 128.5 (CH), 127.1
(CH), 124.2 (CH), 123.9 (CH) Signals for these isomers could not be
distinguished, and a CH signal is lacked presumably due to overlapping;
IR (KBr/cm-1) 1594, 1647, 1517, 1344, 1253, 848, 695; HRMS
(ESI/TOF) calcd. for [M+H]+ C21H16NO3: 330.1124, found: 330.1113.
3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-propen-1-one
(2i).[25]
Yellow solid (1.80 g, 6.6 mmol, 66%). 1H NMR (400 MHz, CDCl3) δ 8.03
(2H, d, J = 8.8 Hz), 7.74 (1H, d, J = 16.0 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.50
(1H, d, J = 16.0 Hz), 7.38 (2H, J = 8.4 Hz), 6.98 (2H, d, J = 8.6 Hz), 3.89
(3H, s).
3-(4-Chlorophenyl)-1-(2-methoxyphenyl)-2-propen-1-one
(2j).[26]
Yellow oil (2.62 g, 9.6 mmol. 96%). 1H NMR (400 MHz, CDCl3) δ 7.62 (1H,
dd, J = 7.6, 1.6 Hz), 7.57 (1H, d, J = 16.0 Hz), 7.50–7.46 (3H, m), 7.38–
7.35 (2H, m), 7.35 (1H, d, J = 16.0 Hz), 7.05 (1H, ddd, J = 7.6, 7.6, 1.2 Hz),
7.00 (1H, d, J = 8.4 Hz), 3.91 (3H, s).
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10.1002/ejoc.201901663
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1-(Bromophenyl)-3-(4-chlorophenyl)-2-(4-nitrophenyl)-2-propen-1-
one (2r). Yellow powder (2.86 g, 6.5 mmol, 65%, E/Z = 70/30). Mp 168.7—
169.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.24–8.20 (2HE, m), 8.24–8.20 (2HZ,
m), 7.79 (2HZ, d, J = 8.8 Hz), 7.69 (2HE, d, J = 8.8 Hz), 7.62 (2HE, d, J =
8.8 Hz), 7.59 (2HZ, d, J = 9.2 Hz), 7.53 (2HZ, d, J = 9.2 Hz), 7.44 (2HE, d,
J = 8.8 Hz), 7.31 (1HE, s), 7.29 (1HZ, s), 7.22–7.19 (2HE, m), 7.22–7.19
(2HE+2HZ, m), 6.97 (2HZ, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ
197.0 (C), 195.1 (C), 147.6 (C), 143.6 (C), 142.9 (C), 141.2 (CH), 138.8
(C), 138.7 (C) 136.2 (C), 136.0 (C), 134.4 (C), 132.8 (C), 132.5 (CH), 132.3
(CH), 132.0 (C), 131.9 (CH), 131.5 (CH), 131.2 (CH), 130.9 (CH), 130.8
(CH), 130.3 (CH), 129.1 (CH), 129.0 (CH), 127.9 (C), 127.1 (CH), 124.3
(CH), 124.1 (CH) three quaternary carbon signals could not be observed;
IR (KBr/cm-1)1657, 1585, 1515, 1346, 1251, 1017, 1010, 852, 819; HRMS
(ESI/TOF) calcd. for [M+H]+ C21H14BrClNO3: 441.9840, found: 441.9834.
MHz, CDCl3) δ 157.9 (C), 157.9 (C), 157.8 (C), 150.0 (C), 148.9 (CH),
139.5 (C), 137.8 (C), 137.1 (C), 135.3 (CH), 131.0 (C), 129.5 (CH),
129.0(CH), 128.4 (CH), 127.9 (CH), 127.3 (CH), 126.8 (CH), 122.8 (CH),
121.2 (CH), 24.6 (CH3), 21.1 (CH3); IR (ATR/cm-1) 1587, 1565, 1539, 1444,
1019, 700; HRMS (ESI/TOF) calcd. for [M+H]+ C24H21N2: 337.1699, found:
337.1708.
2-(4-Methylphenyl)-6-methyl-4-(2-naphthyl)-3-(2-pyridyl)pyridine
(3Bb). Yellow solid (25.5 mg, 0.066 mmol, 66%). Mp 107.3–107.8 °C. 1H
NMR (400 MHz, CDCl3) δ 8.35 (1H, dd, J = 5.2, 2.0 Hz), 7.75–7.69 (3H,
m), 7.60 (1H, d, J = 8.4 Hz), 7.45–7.43 (2H, m), 7.34–7.29 (1H, ddd, J =
7.6, 7.6, 1.2 Hz), 7.32 (1H, s), 7.20 (2H, d, J = 8.0 Hz), 7.10 (1H, dd, J =
8.4, 1.6 Hz), 6.98 (2H, d, J = 8.4 Hz), 6.95 (1H, d, J = 7.6 Hz), 6.93 (1H, d,
J = 7.6 Hz), 2.72 (3H, s), 2.26 (3H, s); 13C NMR (100 MHz, CDCl3) δ 157.9
(C), 157.8 (C), 149.9 (C), 148.9 (CH), 137.8 (C), 137.1 (C), 137.3 (CH),
135.4 (CH), 133.0 (C), 133.3 (C), 132.3 (C), 131.2 (C), 129.6 (CH), 128.5
(CH), 128.4 (CH), 127.5 (CH), 127.3 (CH), 126.9 (CH), 126.8 (CH), 126.2
(CH), 126.1 (CH), 123.1 (CH), 121.3 (CH), 24.5 (CH3), 21.2 (CH3) One
signal (C) was not observed presumably due to overlapping; IR (ATR/cm-
1) 1586, 1539, 1508, 1470, 1435, 822, 802, 748; HRMS (ESI/TOF) calcd.
for [M+H]+ C28H23N2: 387.1855, found: 387.1841.
3-(4-Methylphenyl)-1-(2-pyridyl)-2-propen-1-one (2s).[31] Dark brown
solid (0.71 g, 3.2 mmol, 32%). 1H NMR (400 MHz, CDCl3) δ 8.73 (1H, ddd,
J = 4.8, 1.2, 0.8 Hz), 8.25 (1H, d, J = 16.0 Hz), 8.18 (1H, ddd, J = 8.0, 1.2,
1.2 Hz), 7.93 (1H, d, J = 16.0 Hz), 7.88 (1H, ddd, J = 8.0, 8.0, 1.2 Hz), 7.64
(2H, d, J = 8.0 Hz), 7.48 (1H, ddd, J = 8.0, 4.8, 1.2 Hz), 7.22 (2H, d, J =
8.0 Hz), 2.39 (3H, s).
2-(4-Nitrophenyl)-3-phenyl-1-(2-pyridyl)-2-propen-1-one (2t). Brown oil
(1.55 g, 4.7 mmol, 47%). 1H NMR (400 MHz, CDCl3) δ 8.25 (1H, ddd, J =
4.8, 1.6, 0.8 Hz), 8.20 (2H, d, J = 8.8 Hz), 7.96–7.94 (2H, m), 7.71 (2H, d,
J = 8.8 Hz), 7.62 (1H, ddd, J = 8.0, 8.0, 1.2 Hz), 7.48 (1H, tt, J = 7.2, 1.2
Hz), 7.39–7.33 (3H, m), 7.27 (1H, s), 7.04 (1H, ddd, J = 8.0, 4.8, 1.2 Hz);
13C NMR (100 MHz, CDCl3) δ 197.1 (C), 152.4 (C), 148.9 (CH), 147.6 (C),
143.3 (C), 141.9 (C), 137.1 (C), 136.6 (CH) 133.0 (CH), 130.7 (CH), 128.7
(CH), 128.6 (C), 127.3 (CH), 124.5 (CH), 124.2 (CH), 122.7 (CH); IR
(KBr/cm-1) 1668, 1595, 1516, 1343, 1222, 1109, 854, 719; HRMS
(ESI/TOF) calcd. for [M+H]+ C20H15N2O3: 331.077, found: 331.1075.
4-(4-Methoxylphenyl)-2,6-bis(4-methylphenyl)-3-(2-pyridyl)pyridine
(3Bc). Yellow solid (24.8 mg, 0.056 mmol, 56%). Mp 72.3–72.8 °C. 1H
NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 8.07 (2H, d,
J = 8.4 Hz), 7.72 (1H, s), 7.41 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.27 (2H, d,
J = 8.4 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 6.4 Hz), 7.04 (1H,
ddd, J = 7.6, 4.8, 1.6 Hz), 6.99 (2H, d, J = 8.0 Hz), 6.97 (1H, ddd, J = 8.6,
4.8, 4.8 Hz), 6.72 (2H, d, J = 8.8 Hz), 3.76 (3H, s), 2.41 (3H, s), 2.28 (3H,
s); 13C NMR (100 MHz, CDCl3) δ 158.9 (C), 158.1 (C), 157.8 (C), 156.2
(C), 150.2 (C), 149.0 (CH), 139.0 (C), 138.1 (C), 137.2 (C), 136.4 (C),
135.5 (CH), 131.9 (C), 131.8 (C), 130.3 (CH), 129.8 (CH), 129.4 (CH),
128.4 (CH), 127.0 (CH), 126.8 (CH), 121.4 (CH), 119.6 (CH), 113.4 (CH),
55.2 (CH3), 21.3 (CH3), 21.2 (CH3); IR (KBr/cm-1) 1510, 1462, 1442, 1370,
1112, 1021, 736, 622; HRMS (ESI/TOF) calcd. for [M+H]+ C31H27N2O:
443.2117, found: 443.2106.
General method of synthesis of polysubstitued pyridines 3. To a
solution of 1-amino-1-phenyl-2-(2-pyridinyl)ethene (1A) (98.1 mg, 0.5
mmol) in dry acetonitrile (15 mL), were added 4-phenyl-3-buten-2-one (2a)
(15.0 mg, 0.1 mmol) and iron(III) chloride (12.7 mg, 0.1 mmol), and the
resultant solution was heated at 180 °C for 1 h under microwave irradiation.
After evaporation of the solvent, the residue was dissolved in ethyl acetate
(10 mL). The solution was filtered through silica gel short column, and was
further eluted with ethyl acetate (30 mL). The eluted solution was dried
over magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by flash column chromatography on
silica gel (eluent: hexane/ethyl acetate = 8/2) to afford polysubstituted
pyridine 3Aa (27.1 mg, 0.084 mmol, 84%) as a yellow oil. When other
enamines 1B–D and enones 2b–t were used, reactions were performed in
the same way.
2,6-Bis(4-methylphenyl)-4-phenyl-3-(2-pyridyl)pyridine (3Bd). Yellow
solid (27.7 mg, 0.067 mmol, 67%). Mp 69.1–70.1 °C. 1H NMR (400 MHz,
CDCl3) δ 8.41 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 8.07 (2H, d, J = 8.4 Hz), 7.74
(1H, s), 7.40 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.29–7.26 (4H, m), 7.23–7.21
(3H, m), 7.15–7.14 (2H, m), 7.03–7.00 (3H, m), 6.96 (1H, ddd, J = 7.6, 0.8,
0.8 Hz), 2.41 (3H, s), 2.28 (3H, s);13C NMR (100 MHz, CDCl3) δ 157.9 (C),
157.8 (C), 156.3 (C), 150.6 (C), 148.9 (CH), 142.0 (C), 139.7 (C), 139.1
(C), 137.9 (C), 137.3 (C), 136.3 (C), 135.4 (CH), 129.8 (CH), 129.4 (CH),
129.1 (CH), 128.4 (CH), 127.9 (CH), 127.3 (CH), 127.0 (CH), 126.8 (CH),
121.4 (CH), 119.6 (CH), 21.3 (CH3), 21.2 (CH3); IR (KBr/cm-1) 1587, 1531,
1508, 1292, 1248, 1180, 826, 803; HRMS (ESI/TOF) calcd. for [M+H]+
C30H25N2: 413.2012, found: 413.2012.
6-Methyl-2,4-diphenyl-3-(2-pyridyl)pyridine (3Aa). Yellow oil (27.1 mg,
0.084 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 8.36 (1H, ddd, J = 4.9,
1.6, 0.9 Hz), 7.34 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.27–7.26 (2H, m), 7.23
(1H, s), 7.20–7.16 (6H, m), 7.10–7.07 (2H, m), 6.96 (1H, ddd, J = 7.7, 4.9,
0.9 Hz), 6.89 (1H, ddd, J = 7.7, 0.9, 0.9 Hz), 2.70 (3H, s); 13C NMR (100
MHz, CDCl3) δ 157.8 (C), 157.7 (C), 157.6 (C), 151.2 (C), 150.0 (C), 148.9
(CH), 140.7 (C), 139.3 (CH), 135.2 (CH), 131.2 (C), 129.6 (CH), 129.0
(CH), 127.9 (CH), 127.7 (CH), 127.3 (CH), 126.7 (CH), 123.0 (CH), 121.2
(CH), 24.5 (CH3); IR (ATR/cm-1) 1589, 1539, 1280, 1029, 748, 698; HRMS
(ESI/TOF) calcd. for [M+H]+ C23H19N2: 323.1542, found: 323.1540.
4-(4-Fluorophenyl)-2,6-bis(4-methylphenyl)-3-(2-pyridyl)pyridine
(3Be). Yellow plates (30.6 mg, 0.071 mmol, 71%). Mp 163.6–164.3 °C. 1H
NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 8.07 (2H, d,
J = 8.0 Hz), 7.71 (1H, s), 7.41 (1H, ddd, J = 7.6, 7.6, 2.0 Hz), 7.27–7.26
(4H, m), 7.13 (2H, m), 7.05–6.99 (3H, m), 6.94 (1H, ddd, J = 7.6, 2.0, 2.0
Hz), 6.92–6.88 (2H, m), 2.41 (3H, s), 2.29 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 162.1 (C, d, J = 245.0 Hz), 157.9 (C), 157.8 (C), 156.4 (C), 149.6
(C), 149.1 (CH), 139.2 (C), 137.9 (C), 137.4 (C), 136.2 (C), 135.7 (C, d, J
= 3.1 Hz), 135.5 (CH), 131.8 (C), 130.8 (CH, d, J = 8.1 Hz), 129.8 (CH),
129.4 (CH), 128.4 (CH), 127.0 (CH), 126.7 (CH), 121.5 (CH), 119.5 (CH),
115.1 (CH, d, J = 21.2 Hz), 21.3 (CH3), 21.2 (CH3); 19F NMR (376 MHz,
CDCl3) δ -114.58 (tt, J = 5.6, 2.6 Hz); IR (ATR/cm-1) 1724, 1585, 1504,
1275, 1118, 1018, 821, 802, 756; HRMS (ESI/TOF) calcd. for [M+H]+
C30H24FN2: 431.1918, found: 431.1928.
6-Methyl-2-(4-methylphenyl)-4-phenyl-3-(2-pyridyl)pyridine
(3Ba).
Yellow solid (29.0 mg, 0.086 mmol, 86%). Mp 58.2–58.8 °C. 1H NMR (400
MHz, CDCl3) δ 8.37 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.35 (1H, ddd, J = 7.6,
7.6, 1.2 Hz), 7.20–7.15 (6H, m), 7.09–7.07 (2H, m), 6.99–6.96 (3H, m) 6.89
(1H, ddd, J = 8.0, 1.2, 1.2 Hz), 2.69 (3H, s), 2.26 (3H, s); 13C NMR (100
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4-(4-Cyanophenyl)-2,6-bis(4-methylphenyl)-3-(2-pyridyl)pyridine
(3Bf). Yellow solid (33.3 mg, 0.076 mmol, 76%). Mp 118.3–119.1 °C. 1H
NMR (400 MHz, CDCl3) δ 8.40 (1H, ddd, J = 4.0, 1.8, 0.8 Hz), 8.07 (2H, d,
J = 8.0 Hz), 7.69 (1H, s), 7.51 (2H, d, J = 8.4 Hz), 7.42 (1H, ddd, J = 7.6,
7.6, 1.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.28–7.24 (4H, m), 7.05 (1H, ddd, J
= 7.6, 4.8, 1.2 Hz), 7.02 (2H, d, J = 7.9 Hz), 6.95 (1H, ddd, J = 7.6, 0.8, 0.8
Hz), 2.42 (3H, s), 2.29 (3H, s); 13C NMR (100 MHz, CDCl3) δ 158.0 (C),
157.1 (C), 156.6 (C), 149.2 (CH), 148.9 (C), 144.7 (C), 139.5 (C), 137.7
(C), 137.4 (C), 135.8 (C), 135.7 (CH), 131.7 (CH), 131.5 (C), 129.8 (CH),
129.8 (CH), 129.5 (CH), 128.5 (CH), 127.0 (CH), 126.7 (CH), 121.7 (CH),
118.8 (CH), 118.6 (C), 111.3 (C), 21.3 (CH3), 21.2 (CH3); IR (ATR/cm-1)
2228, 1724, 1586, 1503, 1421, 1370, 1184, 1115, 1021, 826, 803, 624 ;
HRMS (ESI/TOF) calcd. for [M+H]+ C31H24N3: 438.1964, found: 438.1944.
126.7 (CH), 124.4 (CH), 121.5 (CH), 121.2 (CH), 111.5 (CH), 55.7 (CH3),
21.2 (CH3); IR (KBr/cm-1) 1500, 1370, 1112, 1021, 736, 622; HRMS
(ESI/TOF) calcd. for [M+H]+ C30H23ClN2O: 463.1571, found:463.1571.
2-(4-chlororphenyl)-4-[(1,1-dimethylethyl)-phenyl]-6-(4-
methylphenyl)-5-(2-pyridyl)pyridine (3Bk). White solid (27.9 mg, 0.057
mmol, 57%). Mp 118.9–119.7 °C. 1H NMR (400 MHz, CDCl3) δ 8.41 (1H,
ddd, J = 4.9, 1.8, 0.9 Hz), 8.11 (2H, d, J = 8.6 Hz), 7.74 (1H, s), 7.43 (2H,
d, J = 8.6 Hz), 7.39 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.26-7.21 (4H, m), 7.06
(2H, d, J = 8.5 Hz), 7.04–7.00 (3H, m), 6.96 (1H, ddd, J = 7.7, 0.9, 0.9 Hz),
2.28 (3H, s), 1.27 (9H, s); 13C NMR (100 MHz, CDCl3) δ 158.1 (C), 157.7
(C), 154.8 (C), 150.7 (C), 150.5 (C), 149.0 (CH), 137.8 (C), 137.6 (C),
137.3 (C), 136.3 (C), 135.4 (CH), 135.1 (C), 132.4 (C), 129.7 (CH), 128.8
(CH), 128.7 (CH), 128.41 (CH), 128.40 (CH), 126.7 (CH), 124.9 (CH),
121.4 (CH), 119.8 (CH), 34.5 (CH3), 31.2 (C), 21.1 (CH3); IR (ATR/cm-1)
1585, 1531, 1492, 1365, 1091, 1014, 829, 802; HRMS (ESI/TOF) calcd.
for [M+H]+ C33H30ClN2: 489.2092, found: 489.2073.
4-(4-Chlorophenyl)-2-(4-methylphenyl)-6-phenyl-3-(2-
pyridyl)pyridine (3Bg). Yellow solid (31.2 mg, 0.072 mmol, 72%). Mp
154.8–155.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.8, 1.6,
0.8 Hz), 8.18 (2H, d, J = 8.4 Hz), 7.72 (1H, s), 7.50–7.41 (4H, m), 7.26 (2H,
d, J = 8.0 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.04 (1H,
ddd, J = 4.8, 1.2, 1.2 Hz), 7.01 (2H, d, J = 8.0 Hz), 6.94 (1H, ddd, J = 7.6,
4.8, 0.8 Hz), 2.28 (3H, s); 13C NMR (100 MHz, CDCl3) δ 158.0 (C), 157.5
(C), 156.4 (C), 149.5 (C), 149.2 (CH), 138.9 (C), 138.1 (C), 137.7 (C),
137.5 (C), 135.6 (CH), 133.6 (C), 132.0 (C), 130.4 (CH), 129.8 (CH), 129.2
(CH), 128.7 (CH), 128.5 (CH), 128.2 (CH), 127.2 (CH), 126.7 (CH), 121.6
(CH), 119.7 (CH), 21.2 (CH3); IR (ATR/cm-1) 1586, 1531, 1491, 1419, 1371,
1018, 826, 749; HRMS (ESI/TOF) calcd. for [M+H]+ C29H22ClN2: 433.1466,
found: 433.1466.
6-(4-Methoxyphenyl)-2-(4-methylphenyl)-4-(4-nitrophenyl)-3-(2-
pyridyl)pyridine (3Bl). Yellow needles (13.7 mg, 0.029 mmol, 29%). Mp
115.8–116.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (1H, ddd, J = 4.8, 1.6,
0.8 Hz), 8.36–8.31 (4H, m), 7.82 (1H, s) 7.44 (1H, ddd, J = 7.6, 7.6, 2.0
Hz), 7.25 (2H, d, J = 8.4 Hz), 7.09–7.04 (5H, m), 6.98 (1H, ddd, J = 7.6,
0.8, 0.8 Hz) 6.77 (2H, ddd, J = 8.8, 2.8, 2.8 Hz), 3.77 (3H, s), 2.30 (3H, s);
13C NMR (100 MHz, CDCl3) δ 159.3 (C), 158.6 (C), 157.5 (C), 153.6(C),
150.8 (C), 149.2 (CH), 148.2 (C), 145.1 (C), 137.7 (C), 137.5 (C), 135.6
(CH), 133.5 (C), 131.3 (C), 130.3 (CH), 129.7 (CH), 128.5(CH), 127.9 (CH),
126.6 (CH), 123.9 (CH), 121.7 (CH), 120.7 (CH), 113.7 (CH), 55.2 (CH3),
21.2 (CH3); IR (ATR/cm-1) 1512, 1341, 1249, 1179, 1022, 700; HRMS
(ESI/TOF) calcd. for [M+H]+ C30H24N3O3: 474.1812, found: 474.1813.
4-(4-Chlorophenyl)-2-(4-methylphenyl)-6-(4-nitrophenyl)-3-(2-
pyridyl)pyridine (3Bh). Yellow solid (16.7 mg, 0.035 mmol, 35%). Mp
100.9–101.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.38 (1H, ddd, J = 4.9, 2.0,
0.8 Hz), 8.27 (4H, br s), 7.73 (1H, s), 7.37 (1H, ddd, J = 7.7, 7.7, 1.8 Hz),
7.25 (2H, d, J = 7.8 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.09 (2H, d, J = 8.6 Hz),
7.07–7.06 (1H, m), 7.03 (2H, d, J = 7.8 Hz), 6.96 (1H, ddd, J = 7.7, 0.8, 0.8
Hz), 2.30 (3H, s);13C NMR (100 MHz, CDCl3) δ 157.6 (C), 155.9 (C), 152.7
(C), 149.0 (C), 148.2 (CH), 147.3 (C), 143.7 (C), 136.9 (C), 136.5 (C),
136.1 (C), 134.7 (CH), 132.9 (C), 132.4 (C), 129.2 (CH), 128.6 (CH), 127.5
(CH), 127.3 (CH), 126.8 (CH), 125.5 (CH), 122.9 (CH), 120.8 (CH), 119.3
(CH), 20.1 (CH3); IR (ATR/cm-1) 1585, 1516, 1342, 1261, 1091, 1018, 802,
729, 698; HRMS (ESI/TOF) calcd. for [M+H]+ C29H21CN3O2: 478.1316,
found: 478.1301.
2-(4-Methylphenyl)-5-(4-nitrophenyl)-6-phenyl-3-(2-pyridyl)pyridine
(3Bm). White solid (24.4 mg, 0.051 mmol, 51%). Mp 255.5–256.2 °C 1H
NMR (400 MHz, CDCl3) δ 8.71 (1H, ddd, J = 4.4, 1.6, 0.8 Hz), 8.14 (2H, d,
J = 8.8 Hz), 8.09 (1H, s), 7.50 (1H, ddd, J = 8.0, 8.0, 2.0 Hz), 7.46 (2H, d,
J = 8.8 Hz), 7.45 (2H, J = 8.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.30–7.29 (3H,
m), 7.22 (1H, ddd, J = 7.6, 4.8, 1.2 Hz), 7.11–7.08 (3H, m), 2.34 (3H, s);
13C (100 MHz, CDCl3) δ 157.3 (C), 156.7 (C), 156.2 (C), 150.0 (CH), 146.9
(C), 146.7 (C), 140.9 (CH), 139.1 (C), 138.5 (C), 136.5 (C), 135.8 (CH),
133.3 (C), 131.9 (C), 130.4 (CH), 130.1 (CH), 129.9 (CH), 128.9 (CH),
128.5 (CH), 128.2 (CH), 125.3 (CH), 123.6 (CH), 122.2 (CH), 21.3 (CH3);
IR (ATR/cm-1) 1595, 1518, 1427, 750, 701; HRMS (ESI/TOF) calcd. for
[M+H]+ C29H21ClN3O2: 478.1316, found: 478.1301.
4-(4-Chlorophenyl)-6-(4-methoxyphenyl)-2-(4-methylphenyl)-3-(2-
pyridyl)pyridine (3Bi). White solid (13.9 mg, 0.039 mmol, 39%). Mp 79.7–
80.4 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.0, 1.6, 0.8 Hz),
8.13 (2H, d, J = 9.2 Hz), 7.68 (1H, s), 7.41 (1H, ddd, J = 7.6, 7.6, 1.6 Hz),
7.25 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.0 Hz),
7.07–6.99 (5H, m), 6.94 (1H, ddd, J = 7.6, 0.8, 0.8 Hz), 3.87 (3H, s), 2.29
(3H, s); 13C (100 MHz, CDCl3) δ 160.7 (C), 157.8 (C), 157.6 (C), 156.0 (C),
149.4 (C), 149.1 (CH), 138.2 (C), 137.8 (C), 137.4 (C), 135.5 (CH), 133.5
(C), 131.5 (C), 131.3 (C), 130.3 (CH), 129.8 (CH), 128.44 (CH), 128.41
(CH), 128.2 (CH), 126.7 (CH), 121.5 (CH), 118.8 (CH), 114.0 (CH), 55.3
(CH3), 21.1(CH3); IR (KBr/cm-1) 1500, 1370, 1112, 1021, 736, 622; HRMS
(ESI/TOF) calcd. for [M+H]+ C23H17ClN2: 357.1153, found: 357.1147.
6-(4-Methoxyphenyl)-2-(4-methylphenyl)-5-(4-nitrophenyl)-3-(2-
pyridyl)pyridine (3Bn). White solid (18.0 mg, 0.038 mmol, 38%). Mp
234.4–235.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.71 (1H, ddd, J = 4.8, 1.8,
0.9 Hz), 8.16 (2H, d, J = 8.9 Hz), 8.06 (1H, s), 7.50 (1H, ddd, J = 7.7, 7.7,
1.8 Hz), 7.47 (2H, d, J = 8.9 Hz), 7.40 (2H, d, J = 8.9 Hz), 7.39 (2H, d, J =
8.0 Hz), 7.20 (1H, ddd, J = 7.7, 4.8, 0.9 Hz), 7.10 (2H, d, J = 8.0 Hz), 7.07
(1H, ddd, J = 7.7, 0.9, 0.9 Hz), 6.80 (2H, d, J = 8.9 Hz), 3.80 (3H, s), 2.34
(3H, s); 13C NMR (100 MHz, CDCl3) δ 159.9 (C), 157.4 (C), 156.5 (C),
155.7 (C), 151.6 (C), 149.9 (CH), 147.1 (C), 146.8 (C), 141.0 (CH), 138.4
(C), 136.6 (C), 135.7 (CH), 132.8 (C), 131.6 (CH), 131.5 (C), 130.4 (CH),
129.9 (CH), 128.8 (CH), 125.2 (CH), 123.6 (CH), 122.1 (CH), 113.6 (CH),
55.2 (CH3), 21.2 (CH3); IR (ATR/cm-1) 1516, 1504, 1427, 1342, 1249, 1172,
1029, 852, 794, 698; HRMS (ESI/TOF) calcd. for [M+H]+ C30H24N3O3:
474.1812, found: 474.1797.
4-(4-Chlorophenyl)-6-(2-methoxyphenyl)-2-(4-methylphenyl)-3-(2-
pyridyl)pyridine (3Bj). Yellow solid (28.2 mg, 0.061 mmol, 61%). Mp
141.3–141.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.8, 1.6,
0.8 Hz), 8.00 (1H, dd, J = 7.6, 2.0 Hz), 7.87 (1H, s), 7.43–7.36 (2H, m),
7.23 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz),
7.11–6.95 (6H, m), 3.88 (3H, s), 2.27 (3H, s); 13C (100 MHz, CDCl3) δ
157.8 (C), 157.7 (C), 157.3 (C), 155.2 (C), 149.1 (CH), 148.2 (C), 138.3
(C), 137.8 (C), 137.2 (C), 135.6 (CH), 133.4 (C), 131.6 (CH), 130.5 (CH),
130.1 (CH), 129.8 (CH), 128.8 (C), 128.6 (C), 128.4 (CH), 128.1 (CH),
4-(4-Chlorophenyl)-5-methyl-2-(methylphenyl)-6-phenyl-3-(2-
pyridyl)pyridine (3Bo). Yellow solid (27.7 mg, 0.062 mmol, 62%). Mp
86.4–87.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.37 (1H, ddd, J = 4.8, 1.6, 0.8
Hz), 7.65 (2H, ddd, J = 6.8, 1.6, 1.6 Hz), 7.45 (2H, ddd, J = 7.2, 1.2, 1.2
Hz), 7.41–7.32 (2H, m), 7.22–7.17 (4H, m), 7.02–7.01 (2H, brd, J = 7.6
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10.1002/ejoc.201901663
European Journal of Organic Chemistry
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Hz), 6.96–6.93 (3H, m), 6.89 (1H, ddd, J = 7.6, 1.2, 1.2 Hz), 2.24 (3H, s),
2.11 (3H, s); 13C NMR (100 MHz, CDCl3) δ 154.5 (C), 149.7 (C), 148.8
(CH), 141.1 (C), 137.5 (C), 137.1 (C), 137.0 (C), 135.3 (CH), 132.9 (C),
132.8 (C), 130.65 (CH), 130.62 (C), 129.6 (CH), 129.4 (C), 129.2 (C),
128.4 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.2 (CH), 126.3 (CH),
121.2 (CH), 21.1 (CH3), 18.2 (CH3); IR (ATR/cm-1) 1585.4, 1566.2, 1539.2,
1492.9, 1392.6, 1087.8, 1018.4, 8293, 771.5, 744.5, 702.1; HRMS
(ESI/TOF) calcd. for [M+H]+ C30H24ClN2: 447.1622, found: 447.1639.
749; HRMS (ESI/TOF) calcd. for [M+H]+ C29H23N3: 414.1964, found:
414.1964.
2-(4-Chlorolphenyl)-6-methyl-4-phenyl-3-(2-pyridyl)pyridine
(3Ca).
Yellow solid (25.3 mg, 0.071 mmol, 71%). Mp 108.9–109.4 °C. 1H NMR
(400 MHz, CDCl3) δ 8.38 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.37 (1H, ddd, J
= 7.6, 7.6, 2.0 Hz), 7.23 (1H, s), 7.22–7.17 (5H, m), 7.14 (2H, d, J = 8.6
Hz), 7.08—7.06 (2H, m), 7.00 (1H, ddd, J = 7.6, 4.8, 0.8 Hz), 6.88 (1H,
ddd, J = 7.6, 0.8, 0.8 Hz), 2.69 (3H, s); 13C NMR (100 MHz, CDCl3) δ 157.9
(C), 157.3 (C), 156.5 (C), 150.2 (C), 149.1 (CH), 139.2 (C), 139.1 (C),
135.5 (CH), 133.5 (C), 131.2 (C), 130.9 (CH), 129.0 (CH), 128.0 (CH),
128.9 (CH), 127.4 (CH), 126.6 (CH), 123.2 (CH), 121.5 (CH), 24.5 (CH3);
IR (ATR/cm-1) 1577, 1543, 1435, 1377, 1284, 1087, 1014, 844; HRMS
(ESI/TOF) calcd. for [M+H]+ C23H17ClN2: .357.1153, found: 357.1147.
4-(4-Chlorophenyl)-2-(4-methylphenyl)-5-(4-nitrophenyl)-6-phenyl-3-
(2-pyridyl)pyridine (3Bp). Yellow solid (7.2 mg, 0.013 mmol, 13%). Mp
165.3–166.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (1H, ddd, J = 4.8, 1.6,
0.8 Hz), 7.90 (2H, d, J = 8.8 Hz), 7.38 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.33–
7.28 (4H, m), 7.23–7.20 (3H, m), 7.07 (2H, d, J = 8.8 Hz), 7.02–6.98 (3H,
m), 6.95–6.91 (3H, m), 6.77–6.73 (2H, br), 2.28 (3H, s); 13C NMR (100
MHz, CDCl3) δ 157.3 (C), 157.2 (C), 157.1 (C), 149.0 (CH), 148.8 (C),
146.3 (C), 145.5 (C), 139.8 (C), 137.9 (C), 137.0 (C), 135.6 (CH), 133.0
(C), 132.1 (CH), 131.2 (C), 130.1 (CH), 129.8 (CH), 128.5 (CH), 128.0
(CH), 127.9 (CH), 127.7 (CH), 126.3 (CH), 122.8 (CH), 121.6 (CH), 21.2
(CH3), Three signals (CH×1, C×2) were not observed presumably due to
overlapping.; IR (ATR/cm-1) 1585, 1519, 1489, 1388, 1346, 1018, 852, 763,
736, 702; HRMS (ESI/TOF) calcd. for [M+H]+ C35H25ClN3O2: 554.1629,
found: 554.1611.
2-(4-Chlorophenyl)-4-(4-fluorophenyl)-6-(4-methylphenyl)-3-(2-
pyridyl)pyridine (3Ce). Yellow plates (28.9 mg, 0.064 mmol, 64%). Mp
163.4–164.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (1H, ddd, J = 4.8, 1.6,
0.9 Hz), 8.05 (2H, d, J = 8.4 Hz), 7.74 (1H, s), 7.41 (1H, ddd, J = 7.6, 7.6,
1.6 Hz), 7.34–7.29 (4H, m), 7.18 (2H, d, J = 6.8 Hz), 7.13–7.11 (2H, m),
7.07 (1H, ddd, J = 7.6 , 1.6, 1.2 Hz), 6.94–6.89 (3H, m), 2.41 (3H, s); 13
C
NMR (100 MHz, CDCl3) δ 162.8 (C, d, J = 246.3 Hz), 157.3 (C), 156.8 (C),
156.6 (C), 149.8 (C), 149.3 (CH), 139.4 (C), 139.2 (C), 135.9 (C), 135.7
(CH), 135.3 (C, d, J = 3.5 Hz), 133.7 (C), 131.9 (C), 131.2 (CH), 130.8 (CH,
d, J = 8.1 Hz), 129.5 (CH), 127.9 (CH), 126.9 (CH), 126.6 (CH), 121.7 (CH),
119.9 (CH), 115.1 (CH, d, J = 21.3Hz), 21.3 (CH3); 19F NMR (376 MHz,
CDCl3) δ -114.2 (tt, J = 5.3, 3.0 Hz) IR (ATR/cm-1) 1558, 1508, 1419, 1369,
1157, 1087, 1014, 837, 810; HRMS (ESI/TOF) calcd. for [M+H]+
C29H21ClFN2: 451.1371, found: 451.1362.
2-(4-Methylphenyl)-5-(4-nitrophenyl)-4,6-diphenyl-3-(2-
pyridyl)pyridine (3Bq). White solid (10.9 mg, 0.021 mmol, 21%). Mp
263.1–263.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.38 (1H, ddd, J = 4.8, 1.6,
0.8 Hz), 7.86 (2H, d, J = 8.8 Hz), 7.35–7.31 (5H, m), 7.22–7.19 (3H, m),
7.06 (2H, d, J = 9.2 Hz), 7.00 (2H, d, J = 8.0 Hz), 6.97–6.92 (5H, m), 6.86–
6.74 (2H, br), 2.28 (3H, s); 13C (100 MHz, CDCl3) δ 157.5 (C), 157.2 (C),
156.9 (C), 150.0 (C), 148.8 (CH), 146.1 (C), 145.9 (C), 140.1 (C), 137.7
(C), 137.3 (C), 137.1 (C), 135.4 (CH), 133.1 (C), 132.2 (CH), 131.4 (C),
130.1 (CH), 129.8 (CH), 128.5 (CH), 128.4 (CH), 127.9 (CH), 127.8 (CH),
127.4 (CH), 126.8 (CH), 126.3 (CH), 122.6 (CH), 121.4 (CH), 21.2 (CH3);
IR (KBr/cm-1) 1586, 1518, 1396, 1345, 1275, 851, 749, 701; HRMS
(ESI/TOF) calcd. for [M+H]+ C35H26N3O2: 520.2019, found: 520.2018.
2-(4-Chlorophenyl)-5-(4-nitrophenyl)-4-phenyl-3,6-bis(2-
pyridyl)pyridine (3Ct). Yellow plates (9.2 mg, 0.017 mmol, 17%). Mp
285.0–285.9 °C, 1H NMR (400 MHz, CDCl3) δ 8.33 (1H, ddd, J = 4.4, 1.6,
0.4 Hz), 8.23 (1H, ddd, J = 4.9, 1.5, 1.0 Hz), 8.25 (2H, d, J = 8.9 Hz), 7.39
(1H, ddd, J = 7.7, 1.8, 1.8 Hz), 7.37–7.32 (4H, m), 7.30 (1H, ddd, J = 7.7,
1.6, 1.6 Hz), 7.27–7.22 (3H, m), 7.18 (2H, d, J = 8.9 Hz), 7.12 (2H, br d, J
= 7.9 Hz), 7.03 (1H, d, J = 7.8 Hz), 6.98 (1H, ddd, J = 4.9, 4.9, 1.0 Hz),
6.91 (1H, ddd, J = 4.9, 4.9, 1.0 Hz), 6.87 (1H, d, J = 7.8 Hz); 13C (100 MHz,
CDCl3) δ 157.4 (C), 156.3 (C), 156.3 (C), 155.9 (C), 149.2 (C), 148.9 (CH),
148.6 (CH), 146.4 (C), 145.2 (C), 139.5 (C), 138.4 (C), 135.6 (CH), 135.3
(CH), 134.3 (C), 132.9 (C), 132.0 (CH), 131.6 (C), 131.3 (CH), 130.0 (CH),
128.2 (CH), 128.1 (CH), 128.0 (CH), 126.5 (CH), 125.7 (CH), 122.7 (CH),
121.8 (CH), 121.7 (CH); IR (KBr/cm-1) 1587, 1518, 1492, 1471, 1396, 1287,
1012, 850, 752, 702 ; HRMS (ESI/TOF) calcd. for [M+H]+ C33H21ClN4O2:
541.1425, found: 541.1399.
6-(4-Bromophenyl)-4-(4-chlorophenyl)-2-(4-methylphenyl)-5-(4-
nitrophenyl)-3-(2-pyridyl)pyridine (3Br). Colorles needles (6.3 mg,
0.010 mmol, 10%). Mp 264.6–265.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.39
(1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.94 (2H, d, J = 8.8 Hz), 7.40 (1H, ddd, J =
7.6, 7.6, 1.6 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 7.6 Hz), 7.21
(2H, d, J = 8.4 Hz), 7.06 (2H, d, J = 8.8 Hz), 7.02–7.00 (3H, m), 6.94 (2H,
d, J = 8.8 Hz), 6.93 (1H, d, J = 7.6 Hz), 6.77–6.73 (2H, br), 2.28 (3H, s);
13C NMR (100 MHz, CDCl3) δ 157.5 (C), 157.0 (C), 155.7 (C), 149.0 (CH),
146.4 (C), 145.1 (C), 138.7 (C), 138.0 (C), 136.8 (C), 135.6 (CH), 135.4
(C), 133.3 (C), 133.1 (C), 132.1 (CH), 131.7 (CH), 131.1 (CH), 129.7 (CH),
128.6 (CH), 127.7 (CH), 126.2 (CH), 123.1 (CH), 122.7 (C), 121.7 (CH),
21.2 (CH3), Three signals (CH×1, C×2) were not observed presumably due
to overlapping.; IR (ATR/cm-1) 1520, 1485, 1346, 1087, 1010, 748; HRMS
(ESI/TOF) calcd. for [M+H]+ C35H24BrClN3O2: 632.0734, found: 632.0708.
CCDC number: 1951931.
2-[(4-Trifluoroethyl)phenyl]-6-methyl-4-phenyl-3-(2-pyridyl)pyridine
(3Da). Yellow solid (27.0 mg, 0.069 mmol, 69%). Mp 132.2–133.1 °C. 1
H
NMR (400 MHz, CDCl3) δ 8.38 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.43 (2H, d,
J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.35 (1H, ddd, J = 7.6, 7.6, 2.0 Hz),
7.28 (1H, s), 7.21–7.19 (3H, m) 7.10–7.08 (2H, m), 7.01 (1H, ddd, J = 7.6,
4.8, 1.2 Hz), 6.89 (1H, ddd, J = 8.0, 0.8, 0.8 Hz), 2.71 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 158.1 (C), 157.1 (C), 156.4 (C), 150.3 (C), 149.1 (CH),
144.4 (C), 138.9 (C), 135.5 (CH), 131.4 (C), 129.9 (CH), 129.4 (C, q, J =
270.3 Hz), 129.0 (CH), 128.0 (CH), 127.5 (CH), 126.7 (CH), 124.7 (CH, q,
J =3.7 Hz), 124.3 (C, q, J =32.2 Hz) 123.6 (CH), 121.6 (CH), 24.5 (CH3);
IR (ATR/cm-1) 1586, 1534, 1491, 1369, 1275, 1242, 1182, 1089, 1020, 827,
805; HRMS (ESI/TOF) calcd. for [M+H]+ C24H18F3N2: 391.1416, found:
391.1431.
2,4-Bis(4-methylphenyl)-3,6-di(2-pyridyl)pyridine (3Bs). White solid
(20.7 mg, 0.050 mmol, 50%). Mp 89.9–90.7 °C. 1H NMR (400 MHz, CDCl3)
δ 8.68 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 8.63 (1H, ddd, J = 7.2, 0.8, 0.8 Hz),
8.61 (1H, s), 8.44 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.81 (1H, ddd, J = 7.6,
7.6, 1.6 Hz), 7.40 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.31 (1H, ddd, J = 7.6,
4.8, 1.2 Hz), 7.27 (2H, d, J = 6.8 Hz), 7.08–6.97 (8H, m), 2.29 (3H, s), 2.28
(3H, s); 13C NMR (100 MHz, CDCl3) δ 157.9 (C), 157.6 (C), 156.1 (C),
154.9 (C), 150.9 (C), 149.1 (CH), 149.0 (CH), 137.9 (C), 137.3 (C), 137.1
(C), 136.8 (CH), 136.4 (C), 135.4 (CH), 133.6 (C), 129.8 (CH), 129.1 (CH),
128.6 (CH), 128.4 (CH), 126.8 (CH), 123.7 (CH), 121.6 (CH), 121.4 (CH),
120.6 (CH), 21.2 (CH3), 21.1 (CH3); IR (ATR/cm-1)1585, 1511, 1260, 793,
4-(4-Methylphenyl)-2,3,6-tris(2-pyridyl)pyridine (3Gs). Brown oil (26.1
mg, 0.065 mmol, 65%). 1H NMR (400 MHz, CDCl3) δ 8.68 (1H, ddd, J =
4.0, 1.6, 0.8 Hz), 8.67 (1H, d, J = 5.2 Hz), 8.53 (1H, s), 8.31 (1H, ddd, J =
4.8, 1.6, 0.8 Hz), 8.29 (1H, ddd, J = 4.8, 1.6, 0.8 Hz), 7.84 (1H, d, J = 8.0
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Hz), 7.80 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.67 (1H, J = 7.6, 7.6, 1.6 Hz),
7.38 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.30 (1H, ddd, J = 7.2, 3.6, 0.8 Hz),
7.10–7.06 (3H, m), 7.59–6.95 (4H, m), 2.28 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 158.8 (C), 157.7 (C), 156.7 (C), 155.9 (C), 154.9 (C), 151.0 (C),
149.1 (CH), 148.5 (CH), 148.1 (CH), 137.3 (C), 136.8 (CH), 136.1 (C),
136.0 (CH), 135.2 (CH), 134.3 (C), 129.2 (CH), 128.7 (CH), 126.7 (CH),
124.8 (CH), 123.8 (CH), 122.0 (CH), 121.7 (CH), 121.6 (CH), 121.1 (CH),
21.5 (CH3); IR (ATR/cm-1) 1585.4, 1562.3, 1535.3, 1512.2, 1473.6, 1415.7,
821.6, 790.8, 740.6; HRMS (ESI/TOF) calcd. for [M+H]+ C27H21N4:
401.1760, found: 401.1764.
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Keywords: Cyclization• Microwave Chemistry •Enones •
Nitrogen heterocycles • Synthetic methods
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Entry for the Table of Contents (Please choose one layout)
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Cl
Mao Arita, Soichi Yokoyama, Haruyasu
Asahara* and Nagatoshi Nishiwaki*
Cl
NO2
NO2
FeCl3
N
N
MW
NH2
Page No. – Page No.
O
N
Only
3
steps!!
Me
Me
Br
Br
Three Step Synthesis of Fully and
Differently Arylated Pyridines
Condensation of b-(2-pyridyl)enamine and a,b-unsaturated ketone in the presence
of FeCl3 under air afforded highly substituted pyridines. Synthesis of differently
substituted pentaarylpyridines was consequently achieved via only three steps from
commercially available reagents with simple experimental manipulations.
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