Synthesis of multiply arylated pyridines

Article abstract of DOI:10.1016/j.tet.2017.03.095

We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyrid

Full text of DOI:10.1016/j.tet.2017.03.095

Accepted Manuscript
Synthesis of multiply arylated pyridines
Takashi Asako, Wakana Hayashi, Kazuma Amaike, Shin Suzuki, Kenichiro Itami, Kei
Muto, Junichiro Yamaguchi
PII:
S0040-4020(17)30363-0
10.1016/j.tet.2017.03.095
TET 28601
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 January 2017
Revised Date: 26 March 2017
Accepted Date: 31 March 2017
Please cite this article as: Asako T, Hayashi W, Amaike K, Suzuki S, Itami K, Muto K, Yamaguchi J,
Synthesis of multiply arylated pyridines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.095.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis of Multiply Arylated Pyridines
Leave this area blank for abstract info.
a
b
b
Takashi Asako , Wakana Hayashi , Kazuma Amaike ,
b
b,c
a
a,*
Shin Suzuki , Kenichiro Itami , Kei Muto , and Junichiro Yamaguchi
a
b
Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan. Department of Chemistry, Graduate School of
c
Science and Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan. JST, ERATO, Itami
Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Multiply Arylated Pyridines
a
b
b
b
b,c
a
Takashi Asako , Wakana Hayashi , Kazuma Amaike , Shin Suzuki , Kenichiro Itami , Kei Muto , and
a,*
Junichiro Yamaguchi
a
Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan.
Department of Chemistry, Graduate School of Science and Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-
b
8
602, Japan.
c
JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
We have achieved a synthesis of multiply arylated pyridines by using a [4+2] cycloaddition of
2,4-diaryl-5-chloroxazoles and cinnamic acids as key reaction. The resulting
a
Received in revised form
Accepted
Available online
hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and
pentaarylpyridines by sequential cross-couplings. This synthetic method allows for facile and
rapid access to highly arylated pyridines with different aryl substituents.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
pyridine
cross-coupling
ring transformation
palladium
heterocyclic compound
1
. Introduction
Multiply arylated pyridines are extremely useful as
1
pharmaceutical cores, ligands and organic materials. Therefore,
the development of efficient and flexible synthetic methods
toward these molecules with controlled regioselectivity would be
necessary for the correlation of structures to physical properties,
as well as the construction of diversified chemical libraries. A
number of methods has been established for the synthesis of
multiply arylated pyridines (e.g., cyclization, cycloaddition, and
2
coupling), however, the synthesis of pentaarylpyridines, which
are fully aryl-substituted pyridines (especially with different aryl
3–6
groups), is still rare.
In 2014, Schmitt and co-workers accomplished the first
synthesis of pentaarylpyridine (1) with five different aryl groups
by sequential halogenations and cross-couplings starting from 2-
5
chloro-3-hydroxypyridine (Scheme 1A). Although this method
can introduce aryl substituents on pyridine with complete
regioselectivity, many synthetic operations (13 steps) are
required. In the following year, our group successfully
demonstrated the synthesis of multiply arylated arenes including
6
1
by
a
coupling/ ring transformation approach.
Tetraarylthiophene S-oxides, prepared by regioselective cross-
couplings and C–H couplings followed by oxidation of the sulfur
atom, underwent [4+2] cycloaddition with an arylnitrile to afford
Scheme 1. (A) Synthesis of pentaarylpyridines with different aryl groups.
(B) Synthesis of triarylpyridines by a coupling/ring transformation approach.
(C) Synthesis of pentaarylpyridines by a ring transformation/coupling
approach.
1
as a 1:1 mixture of regioisomers (8 steps). Very recently, our
group also used a similar synthetic approach to synthesize 2,3,6-
7
triarylpyridines (Scheme 1B).

2
Tetrahedron
Phenyl oxazole-4-carboxylate was coupled w
A
ith
C
t
C
woEPar
T
yla
E
ti
D
ng MATa
N
ble
U
1.
S
[4
C
+2
R
] C
I
ycloaddition of 2,4-diaryloxazole 5 and cinnamic acid
P
T
agents by nickel-catalyzed decarbonylative coupling to afford
derivatives 6.
8
2
,4-diaryloxazoles, and subsequently, [4+2] cycloaddition of the
resulting diaryloxazoles with cinnamic acid derivatives provided
,3,6-triarylpyridines with complete regioselectivity. Motivated
by a challenge to generate a new synthesis of pentaarylpyridines
1) with five different aryl groups, we planned to introduce a
2
(
functional group handle on 2,3,6-triarylpyridine (Scheme 1C).
Thus, we selected 5-chloro-2,4-diaryloxazole as the starting
material and [4+2] cycloaddition with cinnamic acids would
produce hydroxylated triarylpyridines. Then, halogenation and
cross-couplings would give 1 in a fewer number of steps. Herein,
we report the synthesis of multiply arylated pyridines such as
triarylpyridine, tetraarylpyridine, and pentaarylpyridine with
different aryl substituents.
Entry
1
2
3
4
5
6/ X (equiv)
6a/ 4.0
6a/ 4.0
6a/ 4.0
6b/ 4.0
6c/ 4.0
6a/ 2.5
Additive
7/% yield
8/% yield
a
–
–
<5
11
43
0
0
43
<1
5
18
0
0
17
2
i-Pr NEt
i-Pr NEt
2
2
i-Pr NEt
2
. Results and Discussion
6
i-Pr NEt
2
a
o-Dichlorobenzene was used as the solvent.
2
.1. Synthesis of hydroxytriarylpyridines
The synthesis of hydroxytriarylpyridines, which is a key
2
.2. Synthesis of triarylpyridines and tetraarylpyridines
-Hydroxy-2,5,6-triarylpyridine and 3-hydroxy-2,4,6-
triarylpyridine 8 can be converted to the corresponding
triarylpyridines (Scheme 3). After converting 7 and 8 to triflates
and 10, reduction of both triflates under palladium catalysis
Pd(OAc)2/ dppp:1,3-bis(diphenylphosphino)propane] using
intermediate in our synthetic plan, commenced with condensation
of commercially available bromoacetophenone (2) and 4-
methoxybenzamide (3) (Scheme 2). Treatment of a mixture of 2
and 3 with stoichiometric silver triflate in ethyl acetate gave 2,4-
3
7
9
[
7,10
diaryloxazole 4 in 64% yield. Subsequently, chlorination of 4
using N-chlorosuccinimide (NCS) afforded 5-chloro-2,4-
diaryloxazole 5 in excellent yield.
formic acid/NEt3 as the hydrogen source afforded the
corresponding triarylpyridines 11 and 12 in 98% and 89% yield,
8
respectively.
Scheme 2. Synthesis of 5-chloro-2,4-diaryloxazole 5.
ꢀ
Then, a [4+2] cycloaddition of the resulting 5-chloro-2,4-
diaryloxazole 5 and cinnamic acid derivatives 6 was carried out
9
(
3
Table 1). Compound 5 was reacted with 4.0 equivalents of (E)-
-(3-(trifluoromethyl)phenyl)acrylic acid (6a) according to our
reported procedure (180 ºC in o-dichlorobenzene as a solvent),
but this resulted in trace product (entry 1). Then, the reaction was
conducted without solvent to furnish the desired 3-hydroxy-
2
3
,5,6-triarylpyridine 7 in 11% yield, along with its regioisomer,
-hydroxy-2,4,6-triarylpyridine 8, in 5% yield (entry 2). This
reaction likely occurs by [4+2] cycloaddition of 5 and 6a to
produce six-membered cycloadduct, followed by
Scheme 3. Synthesis of triarylpyridines 11 and 12.
a
The intermediate triflates 9 and 10 can also be converted to
tetraarylpyridines 13 and 14 with four different aryl groups by
Suzuki–Miyaura cross-coupling (Scheme 4). Triflate 9 was
coupled with a variety of arylboronic acids in the presence of
decarboxylation and loss of HCl. As a scavenger of HCl, addition
of diisopropylethylamine was effective, as both product 7 and 8
were obtained with increased yields (43% and 18%,
respectively), but the regioselectivity did not change (entry 3).
Other cinnamic acid derivatives such as methyl ester 6b and
phenyl ester 6c did not work at all (entries 4 and 5). The amount
of 6a can be decreased to 2.5 equivalents to furnish
triarylpyridines 7 and 8 in 60% total yield (1.3 g scale). However,
even with an extensive screening of additives and solvents, the
regioselectivity did not improve. Since 7 and 8 can be easily
separated by column chromatography, we moved onward to the
synthesis of multiply arylated pyridines.
catalytic Pd(PPh ) and K PO in 1,4-dioxane at 110 ºC to afford
3 4
3
4
the corresponding 2,3,5,6-tetraarylpyridines 13a–13d in excellent
yields. When subjected to the same procedure, triflate 10 was
transformed to the corresponding 2,3,4,6-tetraarylpyridines 14a–
1
4d. The molecular structure of 13a was determined by X-ray
crystallography, thereby confirming the presence of four different
aryl groups on the pyridine core.

3
(
HO)
2
B
Ar
ACCEPTED MAN
T
U
abl
S
e
C
2. B
R
ro
I
mo-selective Suzuki–Miyaura coupling of aryl bromide 15
P
T
and arylboronic acids.
(
3.0 equiv)
Ar
OTf
5 mol% Pd(PPh3)4
K
F
3
C
3
F C
3 4
PO (3.5 equiv)
N
1,4-dioxane
10 °C
N
1
MeO
MeO
9
1
1
1
1
3a Ar = 4-tolyl
3b Ar = 4-NO
3c Ar = 3-thienyl
3d Ar = 4-acetylC
[quant]
[quant]
[96%]
[99%]
2 6 4
C H
6
H
4
(
HO)
2
B
Ar
3
F C
F
3
C
c
(
3.0 equiv)
mol% Pd(PPh
PO (3.5 equiv)
Entry
1
Ar
Pd/ mol%
Pd(PPh /5
Ligand/
mol%
–
Base
PO
16 /%
5
3 4
)
Ar
OTf
K
3
4
3-thienyl
3-thienyl
4-tolyl
4-tolyl
3-thienyl
)
3 4
K
3
4
14 (16a)
NaOH 69 (16a)
NaOH 13 (16b)
1
,4-dioxane
110 °C
a
N
N
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
(dba)
3
/2.5 Pt-Bu
/2.5 Pt-Bu
/2.5 Pt-Bu
/2.5 Pt-Bu
/2.5 Pt-Bu
3
/10
/10
/5
/5
/5
a
3
(dba)
(dba)
(dba)
(dba)
3
3
3
3
3
MeO
MeO
b
10
4
5
3
K
K
K
3
3
3
PO
PO
PO
4
4
4
73 (16b)
82 (16a)
84 (16c)
b
3
1
1
1
1
4a Ar = 4- tolyl
[84%]
[88%]
[97%]
[96%]
b
4b Ar = 4-NO
2
C
6
H
4
6
4-EtOC
H
6 4
3
4c Ar = 3-thienyl
4d Ar = 4-acetylC
a
b
1
,4-Dioxane/H
2
O was used as the solvent. Toluene/H
2
O was used as the
6 4
H
solvent.
With triflated tetraarylpyridines 16 in hand, the introduction of
the final aryl group was carried out (Scheme 5). Compounds 16
were coupled with arylboronic acids in the presence of a
palladium catalyst [Pd(PPh ) ] and K PO in 1,4-dioxane at 110
ºC to give a variety of pentaarylpyridines 1a–1e in good to
moderate yields. The molecular structure of 1a was determined
by X-ray crystallography, unambiguously establishing the
connection of five different aryl groups onto the central pyridine.
Me
F
3
C
3
4
3
4
N
MeO
13a
X-ray crystal structure of 13a
Scheme 4. Synthesis of tetraarylpyridines 13 and 14. In the ORTEP drawing
of tetraarylpyridine 13a, hydrogen atoms are omitted for clarity and thermal
ellipsoids are drawn at 50% probability.
(HO)2B
Ar
Ar
Ar
(
3.0 equiv)
Ar
OTf
10 mol% Pd(PPh )
K3PO4 (3.5 equiv)
F3C
3
4
F3C
N
1
,4-dioxane
N
2
.3. Synthesis of pentaarylpyridines
-Hydroxy-2,5,6-triarylpyridine 7 was then used in the
1
10 °C
MeO
MeO
1
6
1
3
synthesis of pentaarylpyridines. Treatment of 7 with N-
bromosuccinimide (NBS) afforded a C4-brominated pyridine,
then triflation led to bromopyridinetriflate 15 in 41% overall
yield. Next, a bromo-selective Suzuki–Miyaura cross-coupling
was performed (Table 2). When compound 15 was coupled with
S
O
Me
F C
3
N
3
-thienylboronic acid using a standard palladium catalyst and a
MeO
base [Pd(PPh ) , K PO ], the desired coupling product 16a was
3
4
3
4
1
a :49%
obtained in very low yield (entry 1). Under these reaction
conditions, no bromo-selectivity was observed, and by-products
resulting from reaction with triflate, as well as dibromo-
detriflated product and recovered starting material were obtained.
In contrast, when the catalyst was changed to Pd (dba) /Pt-Bu
S
S
OMe
Me
F3C
F3C
OMe
2
3
3,
N
N
the reaction proceeded smoothly to produce 16a in 69% yield
with complete bromo-selectivity (entry 2). However, when the
arylboronic acid was changed to 4-tolylboronic acid, the yield of
coupling product 16b decreased to 13% yield (entry 3). To
MeO
MeO
1b: 61%
1c: 89%
Me
Me
O
12
overcome this problem, the ratio of Pd/ligand was critical.
OEt
Me
When the ratio of Pd/ligand was 1/2, the product was produced in
low yield, whereas a 1/1 ratio dramatically increased the yield of
F3C
F3C
N
N
1
6b to 73% (entry 4). This protocol can be used not only for 4-
tolylboronic acid, but also for 3-thienylboronic acid and for 4-
ethoxyphenyl)boronic acid: the coupling reaction of these
MeO
MeO
1
e: 86%
1
d: 75%
(
Scheme 5. Synthesis of pentaarylpyridines 1. In the ORTEP drawing of
pentaarylpyridine 1a, hydrogen atoms are omitted for clarity and thermal
ellipsoids are drawn at 50% probability.
arylboronic acids with 15 produced the corresponding coupling
products 16a and 16c in 82% and 84% respectively, with
complete bromo-selectivity (entries 5 and 6).
3
. Conclusion
In summary, we have demonstrated the synthesis of
pentaarylpyridines with five different aryl groups by a ring
transformation/coupling approach. 5-Chloro-2,4-diaryloxazole is

4
Tetrahedron
2] MAN
a convenient precursor to hydroxypyridines b
A
y u
C
til
C
iz
E
ing
P
a
T
[
E
4+
D
T
U
o
S
a
C
scr
R
ewIP
c
T
ap test tube containing a magnetic stirring bar
cycloaddition. The introduction of all the aryl groups is flexible,
as all the aryl groups are theoretically modifiable. The key
hydroxytriarylpyridine intermediate can also lead to
triarylpyridines and tetraarylpyridines in a two-step sequence.
This combined pyridine synthesis/substitution route allows for a
rapid structural diversification that bodes well for applications in
organometallic, pharmaceutical and materials chemistry.
were added
5 (1.29 g, 4.5 mmol, 1.0 equiv), 3-
(trifluoromethyl)cinnamic acid (6a: 2.43 g, 11.25 mmol, 2.5
equiv), and N,N-diisopropylethylamine (582 mg, 4.5 mmol, 1.0
equiv). The tube was sealed with a screw cap and heated at 180
°C for 24 hours. After cooling, the mixture was diluted with
EtOAc and treated with Na CO aq for 30 min. The water phase
was extracted three times with EtOAc. The combined organic
phase was washed with brine, and then dried over Na SO ,
filtered, and concentrated in vacuo. After removing highly polar
2
3
2
4
4
. Experimental
impurities by a short silica-gel pad with EtOAc as an eluent, the
crude mixture was purified by Isolera (hexane/EtOAc = 20:1 to
Unless otherwise noted, all reactants or reagents including dry
solvents were obtained from commercial suppliers and used as
received. Unless otherwise noted, all reactions were performed
®
5
:1) to afford triaryl hydroxypyridines 7 (813 mg, 43% yield) and
8
(321 mg, 17% yield).
with dry solvents under an atmosphere of argon and N in dried
2
glassware using standard vacuum-line techniques. All cross-
coupling reactions were performed in 8-mL glass tubes equipped
with screw cap and heated in an oil bath unless otherwise noted.
All work-up and purification procedures were carried out with
reagent-grade solvents in air. Analytical thin-layer
chromatography (TLC) was performed using E. Merck silica gel
4.2.1. 6-(4-Methoxyphenyl)-2-phenyl-5-(3-
(trifluoromethyl)phenyl)pyridin-3-ol (7).
1
White solid. H NMR (400 MHz, CDCl ) δ 7.80 (dd, J = 8.4,
3
1
.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.49–7.44 (m, 3H), 7.41 (d,
J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz,
H), 7.21 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.70 (d, J = 8.4 Hz,
1
13
6
0
F254 precoated plates (0.25 mm). The developed
2H), 6.37 (br s, 1H), 3.72 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
chromatogram was analyzed by UV lamp (254 nm). Flash®
column chromatography was performed with Biotage Isolera
equipped with Biotage SNAP Cartridge KP-Sil columns and
1
1
59.1, 149.0, 148.6, 144.9, 140.2, 136.0, 134.2, 132.9, 131.3,
31.2, 130.6 (q, J = 32.6 Hz), 129.0, 128.7, 128.6, 128.5, 126.1
(q, J = 3.8 Hz), 126.0, 123.9 (q, J = 273 Hz), 123.8 (q, J = 2.9
hexane/EtOAc
as
an
eluent.
Preparative
thin-layer
Hz), 113.3, 55.1; HRMS (ESI) m/z calcd for C H F NO
2
5
19
3
2
+
chromatography (PTLC) was performed using Wakogel B5-F
silica coated plates (0.75 mm) prepared in our laboratory.
Preparative gel permeation chromatography (GPC) was
performed with a JAI LC-9204 instrument equipped with
JAIGEL-1H/JAIGEL-2H columns using chloroform as an eluent.
The high-resolution mass spectra were conducted on Thermo
[
M+H] : 422.1362, found 422.1358.
4
.2.2. 6-(4-Methoxyphenyl)-2-phenyl-4-(3-
(trifluoromethyl)phenyl)pyridin-3-ol (8).
1
Pale yellow solid. H NMR (400 MHz, CDCl ) δ 7.96 (d, J =
3
9.2 Hz, 2H), 7.93 (s, 1H), 7.87–7.81 (m, 3H), 7.69 (d, J = 7.6 Hz,
1H), 7.60 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.53 (t, J = 8.0 Hz,
Fisher Scientific Exactive (ESI). Nuclear magnetic resonance
1
2
H), 7.45 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 9.2 Hz, 2H), 5.57 (s,
(
NMR) spectra were recorded on a JEOL JNM-ECA-400 ( H 400
13
13
MHz, C 100 MHz) and JEOL JMN-ECA-600II with Ultra
1H), 3.83 (s, 3H); C NMR (100 MHz, CDCl
146.1, 145.0, 136.73, 136.67, 135.4, 132.4, 131.6, 131.1 (q, J =
2.5 Hz), 129.14, 129.05, 128.9, 127.7, 126.0 (q, J = 3.8 Hz),
3
) δ 160.0, 149.8,
TM
1
13
COOL
Chemical shifts for H NMR are expressed in parts per million
ppm) relative to tetramethylsilane (δ 0.00 ppm). Chemical shifts
probe ( H 600 MHz, C 150 MHz) spectrometer.
1
3
(
125.1 (q, J = 3.8 Hz), 124.0 (q, J = 274 Hz), 120.0, 114.0, 55.3
13
for C NMR are expressed in ppm relative to CDCl (δ 77.0
(one peak is missing due to overlapping.); HRMS (ESI) m/z calcd
3
+
for C H F NO [M+H] : 422.1362, found 422.1356.
ppm). Data are reported as follows: chemical shift, multiplicity (s
25 19
3
2
=
singlet, d = doublet, dd = doublet of doublets, ddd = doublet of
4
.3. Procedure for the synthesis of 6-(4-methoxyphenyl)-2-
doublets of doublets, t = triplet, dt = doublet of triplets, td =
triplet of doublets, q = quartet, m = multiplet, br s = broad
singlet), coupling constant (Hz), and integration.
phenyl-5-(3-(trifluoromethyl)phenyl)pyridin-3-yl
trifluoromethanesulfonate (9)
In a round-bottom flask, 2,5,6-triaryl-3-hydroxypyridine 7
400 mg, 0.95 mmol, 1.0 equiv) and N,N-diisopropylethylamine
4
.1. Procedure for the synthesis of 5-chloro-2-(4-methoxyphenyl)
(
(
-4-phenyloxazole (5)
245 mg, 1.9 mmol, 2.0 equiv) were dissolved in dry CH Cl (2.0
2
2
10
mL) and cooled to 0 °C. To this mixture was slowly added a
solution of trifluoromethanesulfonic anhydride (402 mg, 1.42
Using a procedure in the literature , 4 was synthesized in
6
4% yield. To a round-bottom flask containing a magnetic
mmol, 1.5 equiv) in CH Cl (1.0 mL). After stirring the mixture
stirring bar and 4 (2.01 g, 8.0 mmol, 1.0 equiv) was added dry
DMF (26 mL). N-Chlorosuccinimide (NCS: 1.07 g, 8.0 mmol,
1
was heated overnight at 50 °C in an oil bath. After cooling to
room temperature, the mixture was diluted with EtOAc and then
washed three times with brine. The organic layer was dried over
Na SO , filtered, and concentrated in vacuo to afford 5 (2.12 g,
9
7
6
2
2
for 1 hour, NaHCO aq. was added. The mixture was extracted
3
three times with CH Cl . The combined organic layer was dried
.0 equiv) was added in one portion, and the resulting mixture
2
2
over Na SO , filtered, and then concentrated in vacuo. This crude
2
4
®
material was purified by Isolera (hexane/EtOAc = 10:1 to 5:1)
to afford 9 (504 mg, 96% yield) as a yellow powder. H NMR
1
(
400 MHz, CDCl ) δ 7.90 (dd, J = 8.0, 2.0 Hz, 2H), 7.72 (s, 1H),
3
2
4
1
7
1
=
.61 (d, J = 7.2 Hz, 1H), 7.57–7.48 (m, 4H), 7.47 (d, J = 7.2 Hz,
3% yield) as a white solid. H NMR (400 MHz, CDCl ) δ 8.01–
3
H), 7.42 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.80 (d, J
.97 (m, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H),
13
13
8.4 Hz, 2H), 3.80 (s, 3H); C NMR (100 MHz, CDCl ) δ
.96 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H); C NMR (100 MHz,
3
1
1
1
60.1, 156.2, 150.3, 142.8, 138.9, 135.0, 133.9, 132.8, 132.4,
31.5, 131.2 (q, J = 32.6 Hz), 130.4, 129.8, 129.4, 129.2, 128.5,
26.1 (q, J = 2.9 Hz), 123.7 (q, J = 273 Hz), 124.7 (q, J = 3.9
CDCl ) 161.6, 159.7, 133.9, 130.0, 129.9, 128.5, 128.1, 127.9,
3
1
26.3, 119.4, 114.2, 55.4; HRMS (ESI) m/z calcd for
+
C H ClNO [M+H] : 286.0629, found 286.0630.
16
13
2
Hz), 118.3 (q, J = 322 Hz), 113.6, 55.2; HRMS (ESI) m/z calcd
for C H F NO S [M+H] : 554.0855, found 554.0855.
4
.2. Procedure for the [4+2] cycloaddition of 5 and cinnamic
+
26
18
6
4
acid 6a

5
4
.4. Procedure for the synthesis of 6-(4-methoxyphenyl)-2-
(q, J = 4.4 Hz), 123.99 (q, J = 274 Hz), 116.3, 116.2, 114.1,
+
ACCEPTED MANUSCRIPT
phenyl-4-(3-(trifluoromethyl)phenyl)pyridin-3-yl
trifluoromethanesulfonate (10)
55.4; HRMS (ESI) m/z calcd for C H F NO [M+H] : 406.1413,
25 19 3
found 406.1413.
In a round-bottom flask, 3-hydroxy-2,4,6-triarylpyridine 8
300 mg, 0.71 mmol, 1.0 equiv) and N,N-diisopropylethylamine
4.6. Procedure for the synthesis of 2,3,5,6-tetraarylpyridine by
Suzuki–Miyaura coupling (13a–13d)
(
(
184 mg, 1.4 mmol, 2.0 equiv) were dissolved in dry CH Cl (1.5
2
2
To a dried screw cap test tube containing a magnetic stirring
mL) and cooled to 0 °C. To this mixture was slowly added a
solution of trifluoromethanesulfonic anhydride (301 mg, 1.1
mmol, 1.5 equiv) in CH Cl (0.75 mL). After stirring the mixture
for 1 hour, the mixture was added NaHCO aq. was added. The
mixture was extracted three times with CH Cl . The combined
organic layer was dried over Na SO , filtered, and then
concentrated in vacuo. This crude material was purified by
Isolera (hexane/EtOAc = 10:1 to 5:1) to afford 10 (374 mg, 95%
yield) as a yellow powder. H NMR (400 MHz, CDCl ) δ 8.09 (d,
bar were added 9 (1.0 equiv), arylboronic acid (3.0 equiv), K PO
3
4
(
3.5 equiv), and Pd(PPh ) (10 mol%). The tube was evacuated in
3 4
2
2
vacuo and refilled with N gas three times. To the tube was added
2
3
dry 1,4-dioxane (0.10 M) under a stream of N gas. The tube was
2
2
2
sealed with a screw cap, and then heated at 110 °C in an oil bath.
Reaction progress was monitored by TLC. After cooling to room
temperature, the mixture was passed through a short silica-gel
pad with EtOAc as an eluent and concentrated in vacuo. The
residue was purified by PTLC to afford 2,3,5,6-tetraarylpyridines
2
4
®
1
3
J = 9.2 Hz, 2H), 8.01–7.86 (m, 3H), 7.82 (d, J = 8.0 Hz, 1H),
7
7
1
3.
.78 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.67 (t, J = 7.6 Hz, 1H),
13
.58–7.46 (m, 3H), 7.01 (d, J = 9.2 Hz, 2H), 3.87 (s, 3H);
C
4.6.1. 2-(4-Methoxyphenyl)-6-phenyl-5-(p-tolyl)-3-(3-
(trifluoromethyl)phenyl)pyridine(13a)
NMR (100 MHz, CDCl ) δ 161.2, 156.4, 153.2, 143.8, 140.1,
3
1
1
1
36.1, 135.5, 132.7, 131.4 (q, J = 32.6 Hz), 129.9, 129.7, 129.5,
28.7, 128.5, 126.3 (q, J = 3.2 Hz), 123.7 (q, J = 273 Hz), 119.9,
17.6 (q, J = 321 Hz), 114.2, 55.4 (two carbon peaks are missing
Purification by PTLC (hexane/EtOAc = 10:1) gave 13a (27
µmol scale, 14.1 mg, quant) as a white solid. H NMR (600
1
MHz, CDCl ) δ 7.72 (s, 1H), 7.60 (s, 1H), 7.54 (d, J = 7.2 Hz,
3
due to overlapping); HRMS (ESI) m/z calcd for C H F NO S
26
18
6
4
1H), 7.53–7.49 (m, 2H), 7.45–7.36 (m, 4H), 7.32–7.24 (m, 3H),
+
[
M+H] : 554.0855, found 554.0857.
7
.16 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 9.0
13
Hz, 2H), 3.79 (s, 3H), 2.35 (s, 3H); C NMR (150 MHz, CDCl3)
4
.5. Procedure for the synthesis of triarylpyridine 11 and 12 by
δ 159.6, 155.8, 154.8, 141.0, 140.9, 139.9, 137.1, 136.5, 134.0,
33.0, 132.3, 131.9, 131.5, 130.9 (q, J = 31.7 Hz), 130.1, 129.4,
Pd-catalyzed reduction using formic acid
1
To a dried screw cap test tube containing a magnetic stirring
bar were added triarylpyridine triflate (9 or 10: 11.2 mg, 20
129.1, 128.7, 127.84, 127.81, 126.2 (q, J = 2.9 Hz), 124.0 (q, J =
271 Hz), 123.9 (q, J = 2.9 Hz), 113.5, 55.3, 21.2; HRMS (ESI)
+
µmol, 1.0 equiv), Pd(OAc) (1.14 mg, 5.1 µmol, 25 mol%), and
m/z calcd for C H F NO [M+H] : 496.1883, found 496.1880.
2
32 25 3
1
,3-bis(diphenylphosphino)propane (dppp: 2.1 mg, 5.1 µmol, 25
4
.6.2. 2-(4-Methoxyphenyl)-5-(4-nitrophenyl)-6-phenyl-3-(3-
mol%). The tube was evacuated in vacuo and refilled with N gas
three times. To this were added formic acid (6.5 mg, 0.14 mmol,
7
DMF (60 µL). The tube was sealed with a screw cap, and then
heated at 110 °C in an oil bath. Reaction progress was monitored
by TLC. After cooling to room temperature, the mixture was
passed through a short silica-gel pad with EtOAc as an eluent and
concentrated in vacuo. The residue was purified by PTLC to
afford triarylpyridines 11 or 12.
2
(trifluoromethyl)phenyl)pyridine (13b)
Purification by PTLC (hexane/EtOAc = 4:1) and then GPC
.0 equiv), triethylamine (20.5 mg, 0.20 mmol, 10 equiv), and
1
gave 13b (36 µmol scale, 19.1 mg, quant) as a white solid. H
NMR (600 MHz, CDCl ) δ 8.16 (d, J = 7.8 Hz, 2H), 7.74 (s, 1H),
7
3
.61 (s, 1H), 7.58 (d, J = 6.6 Hz, 1H), 7.49–7.42 (m, 6H), 7.40 (d,
J = 7.8 Hz, 2H), 7.35–7.26 (m, 3H), 6.80 (d, J = 7.8 Hz, 2H),
13
3
1
1
1
.79 (s, 3H); C NMR (150 MHz, CDCl ) δ 159.9, 156.2, 156.0,
3
47.0, 146.4, 140.7, 140.3, 139.0, 132.9, 132.5, 131.7, 131.5,
31.3, 131.1 (q, J = 33 Hz), 130.4, 130.1, 129.0, 128.5, 128.2,
26.1 (q, J = 2.9 Hz), 124.2 (q, J = 4.2 Hz), 123.9 (q, J = 272
4
.5.1. 2-(4-Methoxyphenyl)-6-phenyl-3-(3-
(trifluoromethyl)phenyl)pyridine (11)
Hz), 123.7, 113.6, 55.3; HRMS (ESI) m/z calcd for C H F N O
[M+H] : 527.1577, found 527.1579.
31
22
3
2
3
+
Purification by PTLC (hexane/EtOAc = 10:1) gave 11 (8.0
1
mg, 98% yield) as a white solid. H NMR (600 MHz, CDCl ) δ
3
4
.6.3. 2-(4-Methoxyphenyl)-5-(4-nitrophenyl)-6-phenyl-3-(3-
8
7
7
.15 (d, J = 7.8 Hz, 2H), 7.76 (s, 2H), 7.56 (s, 1H), 7.54 (d, J =
.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H),
(trifluoromethyl)phenyl)pyridine (13c)
®
13
Purification by Isolera (hexane/EtOAc = 20:1 to 5:1) gave
.41–7.35 (m, 4H), 6.80 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H);
C
1
1
3c (36 µmol scale, 16.9 mg, 96% yield) as a white solid. H
NMR (150 MHz, CDCl ) δ 159.6, 156.4, 156.2, 141.1, 139.3,
1
1
3
NMR (400 MHz, CDCl ) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.58–7.47
3
38.9, 133.0, 132.4, 132.2, 131.5, 130.9 (q, J = 31.7 Hz), 129.1,
28.7, 127.0, 126.1 (q, J = 2.9 Hz), 124.0 (q, J = 270 Hz), 123.8
(m, 3H), 7.42–7.34 (m, 4H), 7.34–7.26 (m, 3H), 7.24–7.12 (m,
2
H), 6.83 (dd, J = 5.2, 1.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 3.78
(q, J = 4.2 Hz), 118.2, 113.5, 55.3 (one peak is missing due to
13
+
(s, 3H); C NMR (100 MHz, CDCl ) δ 159.6, 156.0, 154.9,
1
=
=
1
3
overlapping); HRMS (ESI) m/z calcd for C H F NO [M+H] :
4
25
19 3
40.7, 140.5, 140.0, 139.7, 133.0, 132.4, 131.7, 131.4, 130.9 (q, J
32.5 Hz), 129.8, 128.9, 128.8, 128.6, 128.1, 127.9, 126.1 (q, J
3.8 Hz), 125.6, 123.93 (q, J = 3.8 Hz) 123.92 (q, J = 274 Hz),
23.5, 113.5, 55.2; HRMS (ESI) m/z calcd for C H F NOS
29 21 3
+
06.1413, found 406.1410.
4
.5.2. 2-(4-Methoxyphenyl)-6-phenyl-4-(3-
(trifluoromethyl)phenyl)pyridine (12)
Purification by PTLC (hexane/EtOAc = 10:1) gave 12 (7.3
[M+H] :488.1290, found 488.1293.
1
mg, 89% yield) as a white solid. H NMR (600 MHz, CDCl ) δ
8
7
3
4
.6.4. 1-(4-(6-(4-Methoxyphenyl)-2-phenyl-5-(3-
.20 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 9.0 Hz, 2H), 7.97 (s, 1H),
.92 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.81 (d, J = 1.2
(trifluoromethyl)phenyl)pyridin-3-yl)phenyl)ethan-1-one(13d)
®
Purification by Isolera (hexane/EtOAc = 20:1 to 2:1) gave
Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.52
1
1
3d (36 µmol scale, 18.8 mg, 99% yield) as a white solid. H
(t, J = 7.2 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 9.0 Hz,
13
NMR (400 MHz, CDCl ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H),
7
7
3
2
1
1
H), 3.90 (s, 3H); C NMR (150 MHz, CDCl ) δ 160.7, 157.7,
3
.61 (s, 1H), 7.59–7.53 (m, 1H), 7.47 (dd, J = 8.4, 2.4 Hz, 2H),
.45–7.34 (m, 6H), 7.32–7.24 (m, 3H), 6.80 (d, J = 8.4 Hz, 2H),
57.4, 148.7, 140.1, 139.4, 131.9, 131.6 (q, J = 33.2 Hz), 130.5,
29.6, 129.2, 128.7, 128.4, 127.1, 125.5 (q, J = 3.0 Hz), 124.00

6
Tetrahedron
13
3
.80 (s, 3H), 2.61 (s, 3H); C NMR (100
A
M
C
H
C
z,
E
C
P
D
T
C
E
3
l )
D
δ
MA4.
NU
7.4
. 1
S
-(
C
4-
R
(6-
I
(4-Methoxyphenyl)-2-phenyl-4-(3-
PT
1
1
1
3
97.6, 159.7, 155.9, 155.6, 144.4, 140.8, 140.5, 139.3, 135.8,
32.9, 132.8, 132.4, 131.5, 131.0 (q, J = 32.6 Hz), 130.1, 129.7,
28.9, 128.5, 128.2, 128.0, 126.1 (q, J = 3.9 Hz), 124.1 (q, J =
.8 Hz), 123.9 (q, J = 273 Hz), 113.5, 55.2, 26.6 (one peak is
(trifluoromethyl)phenyl)pyridin-3-yl)phenyl)ethan-1-one (14d)
®
Purification by Isolera (hexane/EtOAc = 20:1 to 2:1) gave
14d (36 µmol scale, 18.2 mg, 96% yield) as a white solid. H
NMR (400 MHz, CDCl ) δ 8.14 (d, J = 9.2 Hz, 2H), 7.71 (s, 1H),
7.67 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H),
7.38–7.29 (m, 3H), 7.29–7.17 (m, 4H), 7.02 (d, J = 9.2 Hz, 2H),
1
3
missing due to overlapping); HRMS (ESI) m/z calcd for
C H F NO [M+H] : 524.1832, found 524.1832.
+
33
25
3
2
1
3
7
.00 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.54 (s, 3H); C NMR
4
.7. Procedure for the synthesis of 2,3,4,6-tetraarylpyridine by
(100 MHz, CDCl ) δ 197.7, 160.8, 157.8, 156.0, 148.9, 142.9,
3
Suzuki–Miyaura coupling (14a–14d)
1
40.3, 140.2, 135.2, 132.5, 131.6, 131.1, 130.9, 130.5 (q, J = 32.5
To a dried screw cap test tube containing a magnetic stirring
bar were added 10 (1.0 equiv), arylboronic acid (3.0 equiv),
K PO (3.5 equiv), and Pd(PPh ) (10 mol%). The tube was
Hz), 130.1, 128.6, 128.4, 127.9, 127.8, 127.7, 126.0 (q, J = 3.8
Hz), 124.3 (q, J = 2.8 Hz), 123.7 (q, J = 274 Hz), 119.0, 114.1,
+
55.4. 26.5; HRMS (ESI) m/z calcd for C33
H
25
F
3
NO
[M+H] :
3
4
3 4
2
evacuated in vacuo and refilled with N gas three times. To the
524.1832, found 524.1834.
2
tube was added dry 1,4-dioxane (0.10 M) under a stream of N2
gas. The tube was sealed with a screw cap, and then heated at 110
4
.8. Procedure for the synthesis of 4-bromo-6-(4-
methoxyphenyl)-2-phenyl-5-(3-(trifluoromethyl)phenyl)pyridin-3-
yl trifluoromethanesulfonate (15)
°
C in an oil bath. Reaction progress was monitored by TLC.
After cooling to room temperature, the mixture was passed
through a short silica-gel pad with EtOAc as an eluent and
concentrated in vacuo. The residue was purified by PTLC to
afford 2,3,4,6-tetraarylpyridines 14.
To a round-bottom flask containing a magnetic stirring bar
and
7
(337 mg, 0.80 mmol, 1.0 equiv) and N,N-
diisopropylethylamine (310 mg, 2.4 mmol, 3.0 equiv) was added
dry CH Cl (9.4 mL). This mixture was cooled to 0 °C, and then
N-bromosuccinimide (285 mg, 1.6 mmol, 2.0 equiv) was added
in one portion. After stirring at 0 °C for 1 hour, NaHCO aq. was
added. The mixture was extracted three times with CH Cl . The
combined organic layer was dried over Na SO , filtered, and then
concentrated in vacuo. The crude material was immediately
purified by Isolera (hexane/EtOAc = 10:1 to 4:1) to afford 4-
bromo-6-(4-methoxyphenyl)-2-phenyl-5-(3-
2
2
4
.7.1. 6-(4-Methoxyphenyl)-2-phenyl-3-(p-tolyl)-4-(3-
(trifluoromethyl)phenyl)pyridine (14a)
3
Purification by PTLC (hexane/EtOAc = 10:1) gave 14a (27
1
2
2
µmol scale, 11.1 mg, 84% yield) as a white solid. H NMR (600
2
4
MHz, CDCl ) δ 8.13 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.48 (d, J
3
=
7.8 Hz, 1H), 7.44–7.36 (m, 3H), 7.33 (t, J = 7.8 Hz, 1H), 7.29
®
(d, J = 7.8 Hz, 1H), 7.24–7.18 (m, 3H), 7.01 (d, J = 9.0 Hz, 2H),
6
2
1
1
.88 (d, J = 7.8 Hz, 2H), 6.75 (d, J = 7.8 Hz, 2H), 3.88 (s, 3H),
(trifluoromethyl)phenyl)pyridin-3-ol (213.9 mg, 53% yield) as a
13
.23 (s, 3H); C NMR (150 MHz, CDCl ) δ 160.6, 158.0, 155.4,
3
white solid. Owing to the instability of this product, this was
quickly used in the next triflation step. The obtained molecule
49.0, 140.91, 140.87, 136.5, 134.2, 132.6, 132.1, 131.5, 131.1,
30.3 (q, J = 31.7 Hz), 130.2, 128.6, 128.3, 127.5, 127.4, 126.2
(213.9
mg,
0.43
mmol,
1.0
equiv)
and
N,N-
(q, J = 2.9 Hz), 123.93 (q, J = 4.4 Hz), 123.89 (q, J = 270 Hz),
diisopropylethylamine (221.0 mg, 1.71 mmol, 4.0 equiv) were
dissolved in dry CH Cl (17.5 mL) and cooled to 0 °C. To this
1
19.1, 114.1, 55.4, 21.1 (one peak is missing due to overlapping);
+
2
2
HRMS (ESI) m/z calcd for C H F NO [M+H] : 496.1883,
32
25 3
mixture was slowly added trifluoromethanesulfonic anhydride
362 mg, 1.28 mmol, 3.0 equiv). After stirring the mixture for 30
min, NaHCO aq. was added. The mixture was extracted three
times with CH Cl . The combined organic layer was dried over
Na SO , filtered, and then concentrated in vacuo. This crude
found 496.1879.
(
4
.7.2. 6-(4-Methoxyphenyl)-3-(4-nitrophenyl)-2-phenyl-4-(3-
3
(trifluoromethyl)phenyl)pyridine (14b)
2
2
Purification by PTLC (hexane/EtOAc = 4:1) gave 14b (36
2
4
®
1
material was purified by Isolera (hexane/EtOAc = 10:1 to 4:1)
to afford 15 (211.8 mg, 41% yield in 2 steps) as a white solid. H
NMR (400 MHz, CDCl ) δ 7.83 (d, J = 8.0 Hz, 2H), 7.63 (d, J =
8
µmol scale, 16.7 mg, 88% yield) as a white solid. H NMR (400
1
MHz, CDCl ) δ 8.14 (d, J = 9.2 Hz, 2H), 7.94 (d, J = 9.2 Hz,
3
2
7
H), 7.73 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.39–
.29 (m, 3H), 7.29–7.18 (m, 4H), 7.07 (d, J = 9.2 Hz, 2H), 7.01
3
.0 Hz, 1H), 7.57–7.45 (m, 5H), 7.39 (d, J = 8.0 Hz, 1H), 7.21 (d,
13
13
J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 3.77 (s, 3H); C NMR
100 MHz, CDCl ) δ 160.0, 157.2, 152.3, 141.1, 138.5, 135.4,
(d, J = 9.2 Hz, 2H), 3.87 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
(
1
1
1
1
61.0, 157.8, 156.5, 148.8, 146.4, 145.1, 139.9, 139.8, 132.4,
32.3, 130.80 (q, J = 33.5 Hz), 130.79, 130.0, 129.8, 128.8,
28.5, 128.0, 127.9, 126.0 (q, J = 3.8 Hz), 124.6 (q, J = 2.9 Hz),
3
1
1
1
35.2, 133.9, 131.5, 131.0, 130.9 (q, J = 32.6 Hz), 130.5, 130.1,
29.5, 129.1, 128.5, 127.6 (q, J = 3.8 Hz), 125.1 (q, J = 4.0 Hz),
23.7 (q, J = 275 Hz), 118.0 (q, J = 323 Hz), 113.4, 55.2; HRMS
23.6 (q, J = 273 Hz), 123.1, 119.1, 114.2, 55.3; HRMS (ESI)
+
+
(ESI) m/z calcd for C H BrF NO S [M+H] : 631.9960, found
m/z calcd for C H F N O [M+H] : 527.1577, found 527.1579.
26 17
6
4
31
22
3
2
3
6
31.9961.
4
.7.3. 6-(4-Methoxyphenyl)-2-phenyl-3-(thiophen-3-yl)-4-(3-
4
.9. Procedure for the bromo-selective cross-coupling of 15
(trifluoromethyl)phenyl)pyridine (14c)
®
Purification by Isolera (hexane/EtOAc = 20:1 to 2:1) gave
To a screw cap test tube containing a magnetic stirring bar
1
1
4c (36 µmol scale, 17.1 mg, 97% yield) as a white solid. H
were added 15 (1.0 equiv), arylboronic acid (3.0 equiv),
Pd (dba) ·CHCl (5 mol%), and P(t-Bu) ·HBF (10 mol%). The
tube was evacuated in vacuo and refilled with N gas three times.
To the tube were added degassed K PO aq. (1 M, 2.0 equiv) and
toluene (0.125 M) under a stream of N gas. The tube was sealed
with a screw cap, and then heated overnight at 80 °C in an oil
bath. After cooling to room temperature, water and EtOAc were
added. The mixture was extracted three times with EtOAc. The
combined organic layer was dried over Na SO , filtered, and then
concentrated in vacuo. The residue was purified by PTLC to
afford triflated 2,3,5,6-tetraarylpyridines 16.
NMR (400 MHz, CDCl ) δ 8.12 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H),
3
2
3
3
3
4
7
7
.53 (d, J = 7.2 Hz, 1H), 7.48–7.30 (m, 5H), 7.30–7.18 (m, 3H),
.06 (dd, J = 4.8, 2.4 Hz, 1H), 7.00 (dd, J = 8.4 Hz, 2H), 6.66
2
3
4
(
dd, J = 2.4, 1.6 Hz, 1H), 6.52 (dd, J = 4.8, 1.6 Hz, 1H), 3.86 (s,
13
2
3
1
1
1
5
H); C NMR (100 MHz, CDCl ) δ 160.6, 158.3, 155.6, 149.1,
3
40.8, 140.7, 137.2, 132.3, 131.3, 130.4 (q, J = 32.5 Hz), 129.8,
29.7, 128.5, 128.3, 127.6, 127.1, 125.9 (q, J = 3.9 Hz), 125.4,
25.1, 124.2 (q, J = 3.8 Hz), 123.8 (q, J = 273 Hz), 118.9, 114.1,
2
4
5.3 (one peak is missing due to overlapping); HRMS (ESI) m/z
+
calcd for C H F NOS [M+H] : 488.1290, found 488.1286.
29
21 3

7
4
.9.1. 6-(4-Methoxyphenyl)-2-phenyl-4-(thiophen-3-yl)-5-(3-
(d, J = 9.0 Hz, 2H), 7.24–7.16 (m, 5H), 7.12 (d, J = 7.8 Hz,
ACCEPTED MANUSCRIPT
(trifluoromethyl)phenyl)pyridin-3-yl trifluoromethanesulfonate
1H), 7.04 (d, J = 7.8 Hz, 2H), 6.91 (dd, J = 4.8, 3.0 Hz, 1H), 6.73
(d, J = 9.0 Hz, 2H), 6.51 (d, J = 3.0 Hz, 1H), 6.37 (d, J = 4.8 Hz,
1H), 3.76 (s, 3H), 2.52 (s, 3H); C NMR (150 MHz, CDCl ) δ
197.8, 159.3, 156.8, 156.5, 145.7, 143.9, 140.2, 139.5, 137.1,
135.0, 134.1, 132.6, 132.5, 132.1, 131.5, 131.2, 130.11 (q, J =
31.7 Hz), 130.10, 129.0, 128.1, 127.9 (q, J = 2.9 Hz), 127.8,
127.7, 127.6, 125.2, 124.8, 123.8 (q, J = 272 Hz), 123.2 (q, J =
(16a)
13
Purification by PTLC (hexane/EtOAc = 10:1) gave 16a (63
3
1
µmol scale, 27.2 mg, 82% yield) as a white solid. H NMR (400
MHz, CDCl ) δ 7.89 (d, J = 8.4 Hz, 2H), 7.58–7.45 (m, 3H), 7.42
3
(d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.23–7.16 (m, 5H),
7
5
1
1
1
3
.12 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.68 (dd, J =
13
.2, 1.2 Hz, 1H), 3.75 (s, 3H); C NMR (100 MHz, CDCl ) δ
4.4 Hz), 113.3, 55.2, 26.5; HRMS (ESI) m/z calcd for
3
+
59.7, 156.9, 152.0, 141.5, 141.1, 137.6, 135.9, 134.1, 133.8,
31.9, 131.32, 131.26, 130.4 (q, J = 32.5 Hz), 129.7, 129.5,
28.8, 128.5, 127.74 (q, J = 3.9 Hz), 127.68, 125.8, 124.0 (q, J =
.9 Hz), 123.6 (q, J = 274 Hz), 117.6 (q, J = 322 Hz), 113.4, 55.2
C
37
H
27
F
3
NO
2
S [M+H] : 606.1709, found 606.1709.
4
.10.2. 2-(4-Methoxyphenyl)-6-phenyl-4-(thiophen-3-yl)-5-(p-
tolyl)-3-(3-(trifluoromethyl)phenyl)pyridine (1b)
Purification by PTLC (hexane/EtOAc = 2:1) gave 1b (15.7
µmol scale, 5.5 mg, 61% yield) as a white solid. H NMR (600
MHz, CDCl ) δ 7.40 (dd, J = 7.8, 2.4 Hz, 2H), 7.33 (d, J = 7.8
(one peak is missing due to overlapping); HRMS (ESI) m/z calcd
1
+
for C H F NO S [M+H] : 636.0732, found 636.0730.
30
20
6
4 2
3
4
.9.2. 6-(4-Methoxyphenyl)-2-phenyl-4-(p-tolyl)-5-(3-
Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.22–7.15 (m, 5H), 7.11 (d, J =
7.8 Hz, 1H), 6.90 (dd, J = 4.8, 3.0 Hz, 1H), 6.86 (d, J = 8.4 Hz,
(
trifluoromethyl)phenyl)pyridin-3-yl trifluoromethanesulfonate
16b)
(
2
H), 6.80 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H), 6.50 (d, J
Purification by PTLC (hexane/EtOAc = 10:1) gave 16b (31.6
µmol scale, 14.9 mg, 73% yield) as a white solid. H NMR (400
= 3.0 Hz, 1H), 6.38 (d, J = 4.8 Hz, 1H), 3.75 (s, 3H), 2.22 (s,
1
13
3H); C NMR (150 MHz, CDCl ) δ 159.2, 157.0, 155.8, 145.9,
3
MHz, CDCl ) δ 7.89 (dd, J = 8.0, 1.6 Hz, 2H), 7.54–7.44 (m,
140.8, 139.9, 137.6, 136.0, 135.2, 134.2, 133.7, 132.8, 132.1,
131.5, 130.7, 130.2, 130.0 (q, J = 31.5 Hz), 129.3, 128.3, 128.0,
127.5, 127.4, 125.0, 124.2, 123.9 (q, J = 270 Hz), 123.0 (q, J =
4.2 Hz), 113.2, 55.2, 21.2 (one peak is missing due to
3
3
7
H), 7.36 (d, J = 8.0 Hz, 1H), 7.23–7.15 (m, 3H), 7.12 (s, 1H),
.11–6.89 (br s, 5H), 6.73 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H), 2.30
13
(s, 3H); C NMR (100 MHz, CDCl ) δ 159.6, 156.9, 152.0,
3
+
1
1
1
45.8, 141.4, 138.8, 137.6, 136.0, 134.4, 133.9, 131.4, 131.3,
30.5, 130.2 (q, J = 32.6 Hz), 129.64, 129.56, 129.3, 128.7,
28.5, 128.3, 128.1 (q, J = 3.8 Hz), 123.7 (q, J = 2.9 Hz), 123.6
overlapping); HRMS (ESI) m/z calcd for C H F NOS [M+H] :
36
27 3
578.1760, found 578.1757.
4
.10.3. 3-(3,5-Dimethoxyphenyl)-6-(4-methoxyphenyl)-2-phenyl-
(
q, J = 274 Hz), 117.6 (q, J = 322 Hz), 113.4, 55.2, 21.2; HRMS
+
4-(thiophen-3-yl)-5-(3-(trifluoromethyl)phenyl)pyridine (1c)
(ESI) m/z calcd for C H F NO S [M+H] : 644.1325, found
33
24
6
4
Purification by PTLC (hexane/EtOAc = 10:1) gave 1c (31.5
6
44.1322.
1
µmol scale, 17.4 mg, 89% yield) as a white solid. H NMR (400
4
.9.3. 4-(4-Ethoxyphenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(3-
MHz, CDCl ) δ 7.44 (d, J = 6.8 Hz, 2H), 7.34 (d, J = 8.0 Hz,
3
(
trifluoromethyl)phenyl)pyridin-3-yl trifluoromethanesulfonate
1
H), 7.28 (d, J = 9.2 Hz, 2H), 7.25–7.15 (m, 5H), 7.12 (d, J = 8.0
(16c)
Hz, 1H), 6.94 (dd, J = 5.6, 2.8 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H),
6.56 (dd, J = 2.8, 1.2 Hz, 1H), 6.43 (dd, J = 5.6, 1.2 Hz, 1H),
6.19 (t, J = 2.0 Hz, 1H), 6.09 (d, J = 2.0 Hz, 2H), 3.75 (s, 3H),
Purification by PTLC (hexane/EtOAc = 5:1, and then CH Cl )
2
2
1
gave 16c (17.9 mg, 84% yield) as a white solid. H NMR (400
13
MHz, CDCl ) δ 7.89 (d, J = 6.8 Hz, 2H), 7.54–7.43 (m, 3H), 7.37
3.50 (s, 6H); C NMR (100 MHz, CDCl ) δ 159.9, 159.2, 156.9,
3
3
(
8
(
d, J = 8.0 Hz, 1H), 7.24–7.16 (m, 3H), 7.14 (s, 1H), 7.07 (d, J =
.0 Hz, 1H), 7.04–6.91 (br s, 2H), 6.77 (d, J = 8.0 Hz, 2H), 6.73
d, J = 8.8 Hz, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 1.37 (t,
156.0, 145.6, 140.7, 140.0, 139.8, 137.5, 134.2, 133.4, 132.7,
132.0, 131.5, 130.0 (q, J = 32.5 Hz), 129.8, 129.2, 128.0, 127.6,
127.5, 124.9, 124.3, 123.8 (q, J = 274 Hz), 123.1 (q, J = 2.8 Hz),
113.2, 109.3, 99.6, 55.23, 55.20 (one peak is missing due to
13
J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ 159.6, 159.2,
3
+
1
1
1
1
6
56.9, 152.0, 145.5, 141.6, 137.6, 136.0, 134.4, 134.0, 132.0,
31.5, 131.3, 130.3 (q, J = 33.5 Hz), 129.63, 129.56, 128.5,
28.4, 128.2 (q, JC-F = 3.8 Hz), 124.2, 123.69 (q, J = 3.9 Hz),
23.65 (q, J = 273.1 Hz),117.6 (q, J = 321.9 Hz), 114.2, 113.4,
3.4, 55.2, 14.6; HRMS (ESI) m/z calcd for C H F NO S
overlapping); HRMS (ESI) m/z calcd for C H F NO S [M+H] :
37
29
3
3
624.1815, found 624.1810.
4
.10.4. 1-(4-(6-(4-Methoxyphenyl)-2-phenyl-4-(p-tolyl)-5-(3-
(trifluoromethyl)phenyl)pyridin-3-yl)phenyl)ethan-1-one (1d)
34
26
6
5
+
Purification by PTLC (hexane/EtOAc = 10:1) gave 1d (31.1
[
M+H] : 674.1430, found 674.1429.
1
µmol scale, 14.3 mg, 75% yield) as a white solid. H NMR (400
4
.10. Procedure for the synthesis of pentaarylpyridines 1
MHz, CDCl ) δ 7.61 (d, J = 8.8 Hz, 2H), 7.37 (dd, J = 7.6, 2.4 Hz
3
,
2H), 7.31–7.27 (m, 3H), 7.24–7.12 (m, 5H), 7.07 (d, J = 8.0 Hz,
To a dried screw cap test tube containing a magnetic stirring
bar were added 16 (1.0 equiv), arylboronic acid (3.0 equiv),
1
2
1
1
H), 7.02 (d, J = 8.8 Hz, 2H), 6.80–6.50 (br s, 6H), 3.76 (s, 3H),
13
.50 (s, 3H), 2.13 (s, 3H); C NMR (100 MHz, CDCl ) δ 197.9,
3
K PO (3.5 equiv), and Pd(PPh ) (10 mol%). The tube was
3
4
3 4
59.2, 156.7, 156.4, 150.3, 143.9, 140.4, 139.5, 136.5, 134.8,
34.5, 134.1, 132.6, 132.4, 132.0, 131.5, 130.1, 129.8 (q, J = 32.6
evacuated in vacuo and refilled with N gas three times. To the
2
tube was added dry 1,4-dioxane (0.10 M) under a stream of N2
gas. The tube was sealed with a screw cap, and then heated at 110
C in an oil bath. Reaction progress was monitored by TLC.
After cooling to room temperature, the mixture was passed
through a short silica-gel pad with EtOAc as an eluent and
concentrated in vacuo. The residue was purified by PTLC
Hz), 128.3 (q, J = 2.9 Hz), 128.1, 127.9, 127.7, 127.5, 123.8 (q, J
274 Hz), 122.9 (q, J = 3.9 Hz), 113.2, 55.2, 26.5, 21.0 (three
=
°
peaks are missing due to overlapping); HRMS (ESI) m/z calcd
for C H F NO [M+H] : 614.2301, found 614.2299.
+
40
31
3
2
4.10.5. 3-(4-Ethoxyphenyl)-6-(4-methoxyphenyl)-2-phenyl-4-(p-
(hexane/EtOAc = 10:1) to afford pentaarylpyridines 1.
tolyl)-5-(3-(trifluoromethyl)phenyl)pyridine (1e)
Purification by PTLC (hexane/EtOAc = 5:1) gave 1e (31.1
µmol scale, 16.5 mg, 86% yield) as a white solid. H NMR (400
4
.10.1. 1-(4-(6-(4-Methoxyphenyl)-2-phenyl-4-(thiophen-3-yl)-5-
1
(3-(trifluoromethyl)phenyl)pyridin-3-yl)phenyl)ethan-1-one (1a)
MHz, CDCl ) δ 7.40 (dd, J = 6.8, 2.8 Hz, 2H), 7.31–7.24 (m,
3
Purification by PTLC (hexane/EtOAc = 2:1) gave 1a (36.7
1
3H), 7.21–7.17 (m, 3H), 7.15–7.10 (m, 2H), 7.06 (d, J = 7.6 Hz,
H), 6.81–6.48 (br s, 4H), 6.78 (d, J = 8.0 Hz, 2H), 6.71 (d, J =
µmol scale, 10.8 mg, 49% yield) as a white solid. H NMR (600
MHz, CDCl ) δ 7.66 (d, J = 7.8 Hz, 2H), 7.38–7.34 (m, 3H), 7.29
1
3

8
Tetrahedron
), MANUSCRIPT
Boruah, R. C. Synlett 2008, 3125; (e) Katritzky, A. R.; Adbel-
Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis
999, 2114; (f) Rajput, P.; Subhashini, N. J. P.; Shivaraj, J. Sci.
9
.2 Hz, 2H), 6.54 (d, J = 8.0 Hz, 2H), 3.89 (q
.75 (s, 3H), 2.14 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); C NMR (100
MHz, CDCl ) δ 159.0, 157.2, 157.1, 155.6, 150.5, 141.0, 139.9,
A
, J
C
=
C
7.
E
2
P
H
T
z,
E
2H
D
1
3
3
1
3
Res. 2010, 2, 337; (g) Pan, X.; Liu, Q.; Chang, L.; Yuan, G. RSC
Adv. 2015, 5, 51183; (h) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc.
2009, 131, 12570; (i) Li, Z.; Huang, X.; Chen, F.; Zhang, C.;
Wang, X.; Jiao, N. Org. Lett. 2015, 17, 584; (j) Wang, S.-W.;
Guo, W.-S.; Wen, L.-R.; Li, M. RSC Adv. 2014, 4, 59218; (k) Ren,
Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan, Z.-H. Org.
Lett. 2011, 13, 5394; (l) Bai, Y.; Tang, L.; Huang, H.; Deng, G.-J.
Org. Biomol. Chem. 2015, 13, 4404; (m) Schipper, D. J.; El-
Salfiti, M.; Whipp, C. J.; Fagnou, K. Tetrahedron 2009, 65, 4977.
3. Reviews: Suzuki, S.; Yamaguchi, J. Chem. Commun. 2017, 53,
1
1
1
1
35.9, 134.7, 134.5, 133.1, 132.9, 132.3, 132.0, 131.5, 130.4,
30.2, 129.7 (q, J = 32.6 Hz), 128.4 (q, J = 3.8 Hz), 127.9, 127.8,
27.5, 127.2, 123.9 (q, J = 274 Hz), 122.7 (q, J = 3.8 Hz), 113.5,
13.1, 63.1, 55.2, 21.0, 14.7 (one peak is missing due to
+
overlapping); HRMS (ESI) m/z calcd for C H F NO [M+H] :
40
33
3
2
6
16.2458, found 616.2457.
Acknowledgments
1
568.
4
.
(a) Palacios, F.; Alonso, C.; Rubiales G.; Ezpeleta, J. M. Eur. J.
Org. Chem. 2001, 2115; (b) Ollagnier, C. M. A.; Perera, S. D.;
Fitchett, C. M.; Draper, S. M. Dalton Trans. 2008, 283; (c) Jiang,
B.; Hao, W.-J.; Wang, X.; Shi F. Tu, S.-J. J. Comb. Chem. 2009,
11, 846. (d) You, X.; Yu, S.; Liu, Y. Organometallics, 2013, 32,
This work was supported by JSPS KAKENHI Grant Nos.
JP16H01011, JP16H01140, JP16H04148 (to J.Y.), JP16H07291
(to K.M), the ERATO program from JST (K.I.), and a JSPS
research fellowship for young scientists (to K.A. and S.S). We
thank Dr. Yasutomo Segawa for assistance with X-ray
crystallography. We also thank Dr. Yoshihiro Ishihara (Vertex
Pharmaceuticals) for fruitful discussion and critical comments.
ITbM is supported by the World Premier International Research
Center (WPI) Initiative, Japan.
5
273; (e) Reimann, S.; Ehlers, P.; Petrosyan, A.; Kohse, S.;
Spannenberg, A.; Surkus, A. E.; Ghochikyan, T. V.; Saghyan, A.
S.; Lochbrunner, S.; Kühnꢁ, O.; Ludwig, R.; Langer, P. Adv.
Synth. Catal. 2014, 356, 1987.
Doebelin, C.; Wanger, P.; Bihel, F.; Humbert, N.; Kenfack, C. A.;
Mely, Y.; Bourguignon, J.-J.; Schmitt, M. J. Org. Chem. 2014, 79,
5
.
9
08.
Suzuki, S.; Segawa, Y.; Itami, K.; Yamaguchi, J. Nat. Chem.
015, 7, 227.
6
7
.
.
Supplementary Material
2
Amaike, K.; Itami, K.; Yamaguchi, J. Chem. Eur. J. 2016, 22,
4384.
1
13
All compounds H and C NMR spectra and data for X-ray
crystallography of 13a and 1a were provided as Supplementary
material.
8. (a) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat.
Commun. 2015, 6, 7508 (b) Amaike, K.; Muto, K.; Yamaguchi, J.;
Itami, K. J. Am. Chem. Soc. 2012, 134, 13573.
9
.
For a [4+2] cycloaddition of 2,4-substituted oxazoles with alkenes,
see: (a) Levin, J. I.; Weinreb, S. M. J. Org. Chem. 1984, 49, 4325.
References and notes
(b) Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. Org. Lett.
1
.
Examples and reviews: (a) Corry, B.; Smith, N. M. Chem.
Commun. 2012, 48, 8958; (b) Tang, B.; Yu, F.; Li, P.; Tong, L.;
Duan, X.; Xie, T.; Wang, X. J. Am. Chem. Soc. 2009, 131, 3016;
2001, 3, 877. (c) Janvier, P.; Sun, X.; Bienaymé, H.; Zhu, J. J. Am.
Chem. Soc. 2002, 124, 2560. (d) Sabot, C.; Oueis, E.; Brune, X.;
Renard, P.-Y. Chem. Commun. 2011, 48, 768. (e) Goodman, S.
N.; Mans, D. M.; Sisko, J.; Yin, H. Org. Lett. 2012, 14, 1604. (f)
Lehmann, J.; Alzieu, T.; Martin, R. E.; Britton, R. Org. Lett. 2013,
15, 3550.
(c) Karki, R.; Thapa, P.; Yoo, H. Y.; Kadayat, T. M.; Park, P.-H.;
Na, Y.; Lee, E.; Jeon, K.-H.; Cho, W.-J.; Choi, H.; Kwon, Y.; Lee,
E.-S. Eur. J. Med. Chem. 2012, 49, 219; (d) Baumann, M.;
Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 2265.
Recent examples for synthesis of multiply arylated pyridines: (a)
Reimann, S.; Parpart, S.; Ehlers, P.; Sharif, M.; Spannenberg, A.;
Langer, P. Org. Biomol. Chem. 2015, 13, 6832; (b) Khajuria, R.;
Kannaboina, P.; Kapoor, K. K.; Gupta, A.; Raina, G.; Jassal, A.
K.; Rana, L. K.; Hundal, M. S.; Das, P. Org. Biomol. Chem. 2015,
10. Bailey, J. L.; Sudini, R. R. Tetrahedron Lett. 2014, 55, 3674.
1. Bera, M. K.; Hommes, P.; Reissig, H.-U. Chem. Eur. J. 2011, 17,
11838.
1
2
.
1
2. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4
020.
1
3, 5944; (c) Xiang, J.-C.; Wang, M.; Cheng, Y.; Wu, A.-X. Org.
Lett. 2016, 18, 24; (d) Borthakur, M.; Dutta, M.; Gogoi, S.;