Sustainable Four-Component Annulation for the Synthesis of 2,3,4,6-Tetraarylpyridines

Article abstract of DOI:10.1021/acs.joc.0c02764

A one-pot, four-component annulation of 2,3,4,6-tetraarylpyridines from aromatic aldehydes, methyl ketones, diaryl ethanones, and ammonium acetate is described. The reaction features high functional group compatibility in air under solvent-free conditions without any additive and only water as the nontoxic byproduct, providing a strategy for the facile, economical, and eco-friendly construction of multiaryl-substituted pyridines from simple and readily available reactants.

Full text of DOI:10.1021/acs.joc.0c02764

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Article
Sustainable Four-Component Annulation for the Synthesis of
2,3,4,6-Tetraarylpyridines
Yuxin Ding, Renchao Ma, Xu-Qiong Xiao, Lei Wang, Zhiming Wang, and Yongmin Ma*
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ABSTRACT: A one-pot, four-component annulation of 2,3,4,6-tetraarylpyridines from aromatic aldehydes, methyl ketones, diaryl
ethanones, and ammonium acetate is described. The reaction features high functional group compatibility in air under solvent-free
conditions without any additive and only water as the nontoxic byproduct, providing a strategy for the facile, economical, and eco-
friendly construction of multiaryl-substituted pyridines from simple and readily available reactants.
catalyzed by palladium (Scheme 1a).8i Cui et al. reported a
INTRODUCTION
■
one-pot base-promoted synthesis of the pyridines from 1-
Pyridine represents one of the most important heterocycles in
organic chemistry, as the pyridine framework frequently occurs
arylethylamines and ynones through the direct β-C(sp3)−H
functionalization of enaminones (Scheme 1b).12 Dong et al.
utilized N-sulfonyl ketimines and alkynes as starting materials
to build the pyridine framework, in which the N−S bond was
used as an internal oxidant and the process underwent a C−C/
C−N bond formation along with desulfonylation (Scheme
1c).13 More recently, Yoshikai et al. reported a copper-
catalyzed condensation of oximes and α,β-unsaturated
ketimines to afford such pyridines (Scheme 1d).14 However,
the above reactions suffer from one or more drawbacks, such as
multistep preparation of starting materials, expensive catalysts,
and harsh reaction conditions.
Multicomponent reactions (MCRs) are useful tools for
constructing diverse compounds from simple and readily
available reactants, although the selectivity control of MCRs
can be a problem due to the many reactive functional groups in
the substrates.15 Herein, we report an efficient, atom-
economical, and environmentally friendly method for the
synthesis of 2,3,4,6-tetraaryl pyridines via a four-component
reaction from one aldehyde, two distinct ketones, and
as a core structural motif in many natural products,1 functional
materials,2 electrochemicals,3 agrochemicals,4 pharmaceutical
drugs,5 organocatalysis,6 as well as various valuable ligands.7
Consequently, extensive research has focused on building this
motif in modern heterocyclic chemistry, and as a result, a large
number of efficient and regioselective syntheses of this
compound class, especially transition-metal-catalyzed C−H
functionalization and annulation reactions, have been estab-
lished,8 among which the condensation of carbonyl com-
pounds with amines or ammonia is well-documented as the
traditional method.9 However, this condensation usually gives
symmetrically substituted pyridines, typically 2,4,6-trisubsti-
tuted pyridines.9d−g,k Only a few reports demonstrate the
synthesis of unsymmetrically multisubstituted pyridines up to
now, for example by condensation of 3-oxopropanenitriles or
1,3-diones with an aromatic aldehyde, a ketone, and a “N”
source.10 Very recently, Samanta et al. reported the synthesis of
unsymmetrical pyridines from N-sulfonyl ketimines, aromatic
aldehydes, and ammonium acetate under neat conditions.11
Consequently, it is still desirable to explore new, efficient
methods for the construction of unsymmetrically multi-
substituted pyridines.
Received: November 18, 2020
Published: February 17, 2021
Despite the numerous studies and applications of multi-
substituted pyridine synthesis appearing in the literature, very
few reports on the synthesis of 2,3,4,6-tetraarylpyridines exist.
Yudin and co-workers developed a two-step procedure for the
preparation of the multisubstituted pyridines by utilizing
amino allenes, aldehydes, and aryl iodides as building blocks
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the substrates (1 mmol of each) were treated with ammonium
acetate (3 equiv) in DMSO (3 mL) at 120 °C for 22 h under
an air atmosphere (entry 1). A preliminary survey of solvents
demonstrated that DMSO was the best solvent for the MCR
(entries 1−4). Interestingly, the reaction in the absence of any
solvent under such entry 1 conditions led to an elevated yield
of the desired product 4aaa (87%, entry 5). To improve the
efficiency, various nitrogen sources including ammonium
formate, ammonium chloride, benzylamine, and aqueous
ammonia were investigated. However, all the tested nitrogen
sources gave significantly lower yields than that of ammonium
acetate (entries 6−9). The product yield was considerably
influenced by the molar ratio of NH4OAc to 1a (entries 5 and
10−12), and the optimal ratio of NH4OAc to 1a was found to
be 3:1. Furthermore, attempts to decrease the reaction
temperature sharply reduced the yield (entries 13 and 14).
On the other hand, increasing the reaction temperature from
120 to 140 °C did not markedly increase the yield (entry 15).
On the basis of the above results, the optimal reaction
conditions were set up as in entry 5 of Table 1.
Scheme 1. Previous and Present Work for the Synthesis of
2,3,4,6-Tetraaryl Pyridines
With the optimal reaction conditions in hand, we explored
the scope and limitations of this transformation using various
substituted aldehydes, methyl ketones, and diaryl ethanones
containing both electron-donating groups (EDGs) and
electron-withdrawing groups (EWGs). We first investigated
the scope of different substituted aromatic ketones 1 reacting
with benzaldehyde 2a and 1,2-diphenylethanone 3a (Table 2).
ammonium acetate without any additive, in a solvent-free
system.
a
Table 2. Substrate Scope Based on Ketones 1
RESULTS AND DISCUSSION
■
Initially, acetophenone 1a, benzaldehyde 2a, and 1,2-
diphenylethanone 3a were chosen as the model substrates to
optimize the reaction conditions with regard to solvents,
nitrogen sources, amounts of nitrogen source, and reaction
temperatures (Table 1). The desired 2,3,4,6-tetraphenyl-
substituted pyridine 4aaa was obtained in 71% yield when
a
Table 1. Optimization of Reaction Conditions
entry
solvent
“N” source (equiv)
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DMSO
DMF
CH3CN
PhMe
NH4OAc (3)
NH4OAc (3)
NH4OAc (3)
NH4OAc (3)
NH4OAc (3)
HCOONH4 (3)
NH4Cl (3)
120
120
reflux
reflux
120
120
120
120
120
120
120
120
≤100
110
140
71
16
23
21
87
26
19
21
20
67
73
88
0
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3(1 mmol), NH4OAc
(3 mmol), 120 °C, 22 h.
-
-
-
-
-
-
-
-
-
-
-
Generally, aromatic methyl ketones bearing either an EDG or
an EWG at the ortho-, meta-, or para-position of the ring
(except 1q which contains a nitro group) undergo the
annulation reaction, providing the desired products 4aaa−
4paa in good yields. It is worth noting that the methyl ketones
bearing a hydroxyl group were found to be well tolerated and
gave the desired products (4iaa and 4naa) in good yields. The
hydroxyl group and the C−X bond on the phenyl ring of the
products 4 provide a potential for further derivatization.
Slightly lower yields (63−71%) of the expected products
(4raa−4taa) were observed when heteroaryl methyl ketones
(1r−1t) were employed as the substrates. In addition,
propiophenone (1u) was also examined under the same
BnNH2 (3)
NH3·H2O (3)
NH4OAc (1)
NH4OAc (2)
NH4OAc (4)
NH4OAc (3)
NH4OAc (3)
NH4OAc (3)
23
89
a
Reaction conditions: a mixture of 1a (1 mmol), 2a (1 mmol), 3a (1
mmol), and a nitrogen source at the indicated amount in a sealed tube
at the indicated reaction conditions for 22 h.
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a
optimal reaction conditions, and a 74% yield of 2,3,4,5,6-penta-
substituted pyridine (4uaa) was afforded. Aliphatic methyl
ketones such as pinacolone (1v) were also investigated, and
the target product 4vaa was obtained in 73% yield. However,
acetone failed to give the corresponding pyridine under the
standard conditions.
Table 4. Substrate Scope Based on Diaryl Ethanones
Having exhibited a broad scope for the ketones 1, a series of
substituted aromatic aldehydes 2 were also investigated for
their reaction with acetophenone 1a and 1,2-diphenylethanone
3a under the same optimized conditions (Table 3). Aromatic
a
Table 3. Substrate Scope Based on Aromatic Aldehydes 2
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (1 mmol),
NH4OAc (3 mmol), 120 °C, 22 h.
providing the desired pyridines 4aab−4aai in good to excellent
yields.
In addition, formaldehyde attempted to react with 1a and 3a
under the standard conditions, but the desired 2,3,6-triphenyl-
substituted pyridine was not afforded. Instead, a 2,3,5,6-
tetraphenyl pyridine was obtained at 77% yield (Scheme 2a).
Scheme 2. Additional Multicomponent Reaction
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol),
b
NH4OAc (3 mmol), 120 °C, 22 h. Reaction at 140 °C.
aldehydes bearing different EWG substitution patterns at the
para- or meta-position including −Cl, −Br, −F, and −CF3 were
found to be well tolerated and smoothly gave the desired
products 4aga−4aha and 4aja−4ama in good yields. On the
other hand, aromatic aldehydes bearing EWGs at the ortho-
position gave the corresponding desired products in only
moderate yields (4aba−4ada). It should be noted that the
desired products were not isolated with aromatic aldehydes
bearing EDGs such as 2-OMe, 2-Me, 3-Me, and 4-Me under
the optimal conditions. When the reaction temperature was
increased to 140 °C, moderate yields of the desired products
(4aia and 4ana) were achieved for meta- and para-methyl-
substituted aldehydes and only 17% of 4aea for the ortho-
methyl analogue. There was no expected product (4afa)
detected for the ortho-methoxy aldehyde even at 140 °C, and
only unidentified complexes were afforded under these
conditions. In addition, 2-furfural (2o) and 2-thiophenecar-
boxaldehyde (2p) proceeded smoothly and gave the desired
pyridines 4aoa and 4apa in good yields (79% and 81%,
respectively). Aliphatic aldehydes such as butyraldehyde were
also examined for reaction under standard conditions.
Unfortunately, only a trace amount of the expected 4-propyl-
2,3,6-triphenylpyridine was detected by GC-MS.
This structure was confirmed by the NMR spectra, and the
data are consistent with a previous report.16 On the other
hand, benzoylacetonitrile (3j) was investigated to replace
diphenylethanone (3a) under the standard reaction conditions.
The result showed that this compound could undergo the
annulation reaction to provide the corresponding product in
76% yield (Scheme 2b). The formed product contains a cyano
group which has the potential for further transformation. When
the diaryl ethanone was replaced by 2-phenylacetaldehyde (3l)
or propiophenone (1u), the desired 2,4,5-triphenyl or 3-
methyl 2,4,6-triphenyl pyridine failed to form, and indeed
2,4,6-triphenyl pyridine 6aa was obtained at 69% and 75%
To further explore the universality of this reaction, diaryl
ethanones 3 with different substituted groups on the aromatic
ring were reacted with acetophenone 1a and benzaldehyde 2a
under the same optimized reaction conditions. The results are
presented in Table 4. It can be seen that diaryl ethanones 3
bearing either EWG or EDG at the ortho-, meta-, or para-
position can undergo the multicomponent annulation reaction,
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yield, respectively (Schemes 2c and 2d). This phenomenon
reveals that the reactants 3l and 1u cannot enter the reaction.
In the absence of diaryl ethanone, the reaction of methyl
ketone 1a and aromatic aldehyde 2n with ammonium acetate
was performed under the same conditions, affording the 2,4,6-
triaryl-substituted pyridine 6an in a moderate yield (Scheme
2e). This result is consistent with those presented in Schemes
2c and 2d. The reaction of 2n and 3a with ammonium acetate
in the absence of methyl ketone 1 was also attempted but
failed, most likely due to the steric effect (Scheme 2f).
Scheme 4. Plausible Reaction Mechanism
By the aforesaid reaction, 2,3,4,6-tetraaryl pyridines with all
four different substituents on the aryl ring are easily
synthesized from aldehydes, ketones, and diaryl ethanones
with different substituents on the aromatic rings, leading to the
production of diverse pyridines. For example, when 4-
methoxyacetophenone 1l and 3-chlorobenzaldehyde 2h were
reacted with 1-phenyl-2-(p-tolyl)ethanone 3k under standard
conditions, product 4lhk was smoothly afforded in 87% yield
(Scheme 3). In addition, to demonstrate the suitability of the
Scheme 3. Synthesis of Different 2,3,4,6-Tetra-Substituted
Pyridines
compound 6 is carried out from the intermediate J via an
intramolecular annulation followed by an oxidization. Based on
our experimental results shown in Tables 2−4, we tend to the
path a mechanism, as otherwise compound 6 should have been
obtained even in the presence of diaryl ethanone 3.
CONCLUSION
■
In summary, for the first time, multicomponent reaction of
methyl ketones, aldehydes, and diaryl ethanones with
ammonium acetate has been established in the air under
solvent-free conditions without any additive. Good yields of a
total of 48 target tetraarylpyridine products are achieved with
37 new compounds. This new transformation is convenient,
efficient, economical, and eco-friendly, rendering the “greener”
methodology as potential applications in both chemical and
pharmaceutical industries.
new synthetic method on an enlarged scale, the reaction of 1l,
2h, and 3k at 10 mmol, respectively, with ammonium acetate
at 18 mmol under the standard conditions was performed, and
84% yield of the corresponding product 4lhk was obtained.
In order to confirm the structures, two tetraarylpyridines
(4haa, CCDC 2009822 and 4aag, CCDC 2009821) with
different substituents on the phenyl rings were analyzed by X-
ray crystallography. The data supported that the formation of
the C−C bonds of the pyridine ring was formed from the
formyl carbon of the aldehydes and the CH2/CH3 of the diaryl
ethanones and methyl ketones, respectively. The C−N bonds
were formed between ammonium acetate and the keto carbon
of the diaryl ethanones and aromatic methyl ketones. The
structural details are listed in the Supporting Information.
On the basis of previous literature reports,9k,11,17 two
possible reaction pathways are proposed as shown in Scheme
4. In path a, Knoevenagel condensation of diaryl ethanone 3
and aldehyde 2 leads to the formation of chalcone A.
Intermediate A can perform a Michael addition with enamine
C which was generated from condensation of methyl ketone 1
and ammonia, to afford intermediate D. The resulting
intermediate D undergoes an intramolecular annulation to
give intermediate E, which is followed by an oxidization under
an air atmosphere to provide the final aromatic product 4.
Alternatively, the reaction of diaryl ethanone 3 with ammonia
affords enamine G. The Michael addition of the intermediate
G with chalcone H which was generated from the
condensation of the methyl ketone 1 and aldehyde 2 yields
intermediate I. The intermediate I undergoes the annulation
followed by oxidization to give the product 4 (bath b). In the
absence of the diaryl ethanone 3, the intermediate H is
coupled with the intermediate C via the Michael addition to
afford intermediate J. In a similar fashion, the production of
EXPERIMENTAL SECTION
■
General Methods. All reagents and solvents were used from
commercial sources unless otherwise stated. All raw materials
including ketones 1, aldehydes 2, and diphenyl ethenone 3a were
obtained from the commercial sources. Compounds 3b−3i are known
compounds and were prepared according to the literature report.18 All
experiments were conducted in the air. All the reactions were
monitored by thin-layer chromatography (TLC). TLC was performed
on precoated silica gel plates (Qingdao Haiyang Chemical Co., Ltd.,
China). Column chromatography was performed on silica gel (240−
1
400 mesh) with petroleum ether and ethyl acetate as eluent. H and
13C NMR (400 and 101 MHz) spectra were recorded on a Bruker
Avance 400 MHz using CDCl3 as solvent with tetramethylsilane as
the internal standard. Melting points are determined using a WRS-1B
apparatus and are uncorrected. High-resolution mass spectra were
obtained with the Q-TOF-Premier mass spectrometer. Reactions were
monitored by TLC and visualized with ultraviolet light.
Typical Experimental Procedure for the Synthesis of
2,3,4,6-Tetraarylpyridines (4aaa as an Example). Acetophenone
(120 mg, 1 mmol), benzaldehyde (106 mg, 1 mmol), 1,2-
diphenylethanone (196 mg, 1 mmol), and ammonium acetate (231
mg, 3 mmol) were added to a tube, and the reaction mixture was
stirred in a sealed tube at 120 °C in an oil bath for 22 h. The reaction
was monitored by TLC. Once the reaction was completed, the
reaction mixture was treated with H2O (10.0 mL) and EtOAc (8.0
mL). The organic and aqueous layers were then separated, and the
aqueous layer was extracted with EtOAc (3 × 8 mL). The combined
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organic extracts were dried (Na2SO4); the solvent was removed under
reduced pressure; and the remaining residue was purified by column
chromatography. Compound 4aaa (333 mg, 87% yield) was obtained
as a white solid.
2,3,4-Triphenyl-6-(m-tolyl)pyridine (4haa). Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (345 mg, 88%); mp 126−
127 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.94 (d, J = 7.6
Hz, 1H), 7.76 (s, 1H), 7.41−7.33 (m, 3H), 7.23−7.17 (m, 7H),
7.15−7.11 (m, 2H), 7.09−7.02 (m, 3H), 6.93−6.89 (m, 2H), 2.44 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.0, 155.8, 150.6, 141.1,
139.9, 139.1, 138.3, 137.9, 132.8, 131.5, 130.2, 129.8, 129.4, 128.6,
127.9, 127.8, 127.7, 127.5, 127.4, 127.3, 126.6, 124.2, 120.5, 21.6.
HRMS (ESI): calcd for C30H24N [M + H]+ 398.1903; found
398.1913.
2,3,4,6-Tetraphenylpyridine (4aaa).19 Petroleum ether/ethyl
acetate (100:1) as eluent. White solid (306 mg, 87%); mp 177−179
°C. 1H NMR (400 MHz, CDCl3) δ 8.18−8.15 (m, 2H), 7.78 (s, 1H),
7.49 (t, J = 7.2 Hz, 2H), 7.44−7.37 (m, 3H), 7.24−7.19 (m, 6H),
7.14−7.12 (m, 2H), 7.09−7.04 (m 3H), 6.93−6.91 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.0, 154.6, 150.6, 141.0, 139.9, 139.1,
137.9, 132.9, 131.4, 130.2, 129.3, 129.0, 128.7, 127.9, 127.7, 127.5,
127.4, 127.4, 127.1, 126.6, 120.4. ESI-MS: m/z [M + H]+ 384.
6-(2-Bromophenyl)-2,3,4-triphenylpyridine (4baa). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (374 mg, 81%);
3-(4,5,6-Triphenylpyridin-2-yl)phenol (4iaa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (243 mg, 61%);
1
mp 165−167 °C. H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.72
(dd, J = 2.6, 1.6 Hz, 1H), 7.67−7.64 (m, 1H), 7.38−7.32 (m, 3H),
7.24−7.20 (m, 6H), 7.16−7.11 (m, 2H), 7.10−7.02 (m, 3H), 6.93−
6.89 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.1, 156.2,
155.2, 150.8, 140.8, 139.7, 137.7, 133.2, 131.4, 130.2, 129.9, 129.3,
128.6, 128.0, 127.7, 127.6, 127.5, 127.4, 126.7, 120.7, 119.3, 116.3,
114.1. HRMS (ESI): calcd for C29H22NO [M + H]+ 400.1696; found
400.1695.
1
mp 193−195 °C. H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.6,
1.7 Hz, 1H), 7.73−7.68 (m, 2H), 7.46−7.41 (m, 1H), 7.37−7.31 (m,
2H), 7.28 (d, J = 1.7 Hz, 1H), 7.24−7.16 (m, 6H), 7.16−7.12 (m,
2H), 7.12−7.05 (m, 3H), 6.98−6.92 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.0, 156.6, 156.6, 149.6, 141.0, 140.7, 139.4, 137.6,
133.5, 133.0, 131.9, 131.5, 130.1, 129.8, 129.5, 128.0, 127.8, 127.6,
127.5, 127.4, 126.7, 124.7, 122.1. HRMS (ESI): calcd for C29H21BrN
[M + H]+ 462.0852; found 462.0856.
6-(4-Bromophenyl)-2,3,4-triphenylpyridine (4jaa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (383 mg, 83%); mp
1
164−166 °C. H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz,
6-(2-Chlorophenyl)-2,3,4-triphenylpyridine (4caa). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (346 mg, 83%);
2H), 7.75 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.38−7.33 (m, 2H),
7.24−7.20 (m, 6H), 7.15−7.03 (m, 5H), 6.94−6.88 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 154.4, 150.8, 140.8,
139.7, 138.0, 137.7, 133.3, 131.9, 131.4, 130.2, 129.3, 128.6, 128.0,
127.8, 127.6, 127.5, 127.5, 126.7, 123.5, 120.1. HRMS (ESI): calcd
for C29H21BrN [M + H]+ 462.0852; found 462.0841.
1
mp 185−186 °C. H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.6,
1.8 Hz, 1H), 7.74 (s, 1H), 7.50 (dd, J = 7.8, 1.4 Hz, 1H), 7.39 (td, J =
7.5, 1.5 Hz, 1H), 7.36−7.32 (m, 3H), 7.23−7.16 (m, 6H), 7.15−7.05
(m, 5H), 6.96−6.92 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
158.2, 155.2, 149.7, 140.7, 139.4, 139.0, 137.6, 133.0, 132.4, 131.9,
131.4, 130.2, 130.1, 129.6, 129.5, 127.9, 127.8, 127.6, 127.4, 127.4,
127.1, 126.7, 124.8. HRMS (ESI): calcd for C29H21ClN [M + H]+
418.1357; found 418.1345.
6-(4-Chlorophenyl)-2,3,4-triphenylpyridine (4kaa).13 Petro-
leum ether/ethyl acetate (100:1) as eluent. White solid (356 mg,
1
85%); mp 154−157 °C. H NMR (400 MHz, CDCl3) δ 8.12 (d, J =
8.4 Hz, 2H), 7.74 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.39−7.34 (m,
2H), 7.24−7.20 (m, 6H), 7.15−7.03 (m, 5H), 6.94−6.88 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.1, 154.3, 150.8, 140.8,
139.7, 137.7, 137.5, 135.1, 133.2, 131.4, 130.2, 129.3, 128.9, 128.3,
128.0, 127.8, 127.6, 127.5, 127.5, 126.7, 120.1. ESI-MS: m/z [M +
H]+ 418.
6-(2-Methoxyphenyl)-2,3,4-triphenylpyridine (4daa). Petro-
leum ether/ethyl acetate (100:1) as eluent. White solid (318 mg,
77%); mp 180−182 °C. 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J =
7.6, 1.8 Hz, 1H), 7.92 (s, 1H), 7.41−7.31 (m, 3H), 7.23−7.19 (m,
3H), 7.18−7.16 (m, 3H), 7.15−7.10 (m, 3H), 7.09−7.06 (m, 3H),
7.05−7.01 (m, 1H), 6.96−6.90 (m, 2H), 3.92 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.9, 157.2, 154.4, 149.4, 141.2, 140.0, 138.1,
132.4, 131.6, 131.5, 130.2, 130.0, 129.5, 128.9, 127.8, 127.7, 127.5,
127.2, 127.2, 126.5, 125.0, 121.2, 111.3, 55.7. HRMS (ESI): calcd for
C30H24NO [M + H]+ 414.1852; found 414.1860.
2,3,4-Triphenyl-6-(o-tolyl)pyridine (4eaa). Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (353 mg, 89%); mp 180−
181 °C. 1H NMR (400 MHz, CDCl3) δ 7.61−7.58 (m, 1H), 7.47 (s,
1H), 7.35−7.27 (m, 5H), 7.23−7.15 (m, 6H), 7.15−7.04 (m, 5H),
6.97−6.92 (m, 2H), 2.58 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 158.5, 157.7, 150.0, 140.9, 140.1, 139.6, 137.8, 136.2, 132.2, 131.5,
130.9, 130.1, 129.9, 129.4, 128.3, 127.9, 127.7, 127.5, 127.4, 127.3,
126.6, 125.9, 124.0, 20.8. HRMS (ESI): calcd for C30H24N [M + H]+
398.1903; found 398.1907.
6-(4-Methoxyphenyl)-2,3,4-triphenylpyridine (4laa). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (351 mg, 85%);
mp 162−163 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz,
2H), 7.71 (s, 1H), 7.41−7.33 (m, 2H), 7.24−7.18 (m, 6H), 7.16−
7.10 (m, 2H), 7.10−6.98 (m, 5H), 6.94−6.88 (m, 2H), 3.88 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 157.8, 155.3, 150.6,
141.1, 140.0, 138.0, 132.2, 131.7, 131.5, 130.2, 129.4, 128.4, 127.9,
127.7, 127.5, 127.4, 127.3, 126.5, 119.6, 114.1, 55.4. HRMS (ESI):
calcd for C30H24NO [M + H]+ 414.1852; found 414.1855.
2,3,4-Triphenyl-6-(p-tolyl)pyridine (4maa). Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (349 mg, 88%); mp 167−
168 °C. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 2H), 7.75
(s, 1H), 7.40−7.35 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.23−7.19 (m,
6H), 7.15−7.10 (m, 2H), 7.08−6.99 (m, 3H), 6.92−6.90 (m, 2H),
2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.9, 155.6,
150.6, 141.1, 140.0, 139.0, 138.0, 136.3, 132.6, 131.5, 130.2, 129.4,
129.4, 127.9, 127.7, 127.5, 127.3, 127.3, 126.9, 126.5, 120.0, 21.4.
HRMS (ESI): calcd for C30H24N [M + H]+ 398.1903; found
398.1895.
6-(3-Bromophenyl)-2,3,4-triphenylpyridine (4faa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (379 mg, 82%); mp
1
214−215 °C. H NMR (400 MHz, CDCl3) δ 7.44−7.38 (m, 3H),
7.20−7.15 (m, 5H), 7.01−6.98 (m, 5H), 6.95−6.86 (m, 6H), 6.79−
6.76 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.5, 150.3,
140.9, 138.5, 138.2, 133.7, 132.4, 131.3, 131.0, 130.4, 130.2, 130.0,
129.3, 128.7, 128.0, 127.7, 127.6, 127.5, 127.4, 127.4, 127.0, 126.3,
126.2. HRMS (ESI): calcd for C29H21BrN [M + H]+ 462.0852; found
462.0850.
4-(4,5,6-Triphenylpyridin-2-yl)phenol (4naa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (315 mg, 79%);
mp 224−226 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz,
2H), 7.68 (s, 1H), 7.36−7.34 (m, 2H), 7.24−7.15 (m, 6H), 7.14−
7.08 (m, 2H), 7.08−7.01 (m, 3H), 6.93−6.88 (m, 2H), 6.86 (d, J =
8.8 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.9, 156.9,
155.5, 150.7, 140.9, 139.9, 137.8, 132.3, 131.5 (2C), 130.2, 129.3,
128.6, 127.9, 127.7, 127.5, 127.4, 127.4, 126.5, 120.0, 115.7. HRMS
(ESI): calcd for C29H22NO [M + H]+ 400.1696; found 400.1708.
4-(4,5,6-Triphenylpyridin-2-yl)benzonitrile (4oaa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (298 mg, 73%); mp
6-(3-Methoxyphenyl)-2,3,4-triphenylpyridine (4gaa). Petro-
leum ether/ethyl acetate (100:1) as eluent. White solid (343 mg,
1
83%); mp 125−127 °C. H NMR (400 MHz, CDCl3) δ 7.78−7.70
(m, 3H), 7.43−7.34 (m, 3H), 7.25−7.17 (m, 6H), 7.17−7.11 (m,
2H), 7.11−7.03 (m, 3H), 7.00−6.96 (m, 1H), 6.95−6.88 (m, 2H),
3.90 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.1, 157.9,
155.4, 150.9, 150.6, 140.9, 139.8, 137.9, 133.0, 131.4, 130.2, 129.7,
129.3, 127.9, 127.7, 127.5, 127.4, 126.6, 121.6, 120.5, 119.5, 114.8,
112.5, 55.4. HRMS (ESI): calcd for C30H24NO [M + H]+ 414.1852;
found 414.1859.
1
149−150 °C. H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz,
2H), 7.81 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.34−7.37 (m, 2H),
3901
https://dx.doi.org/10.1021/acs.joc.0c02764
J. Org. Chem. 2021, 86, 3897−3906

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.18−7.24 (m, 6H), 7.05−7.13 (m, 5H), 6.91 (d, J = 7.6 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 153.2, 151.0, 143.2,
140.5, 139.3, 137.4, 134.2, 132.5, 131.3, 130.1, 129.2, 128.0, 127.8,
127.6, 127.6, 127.6, 127.5, 126.9, 120.8, 118.9, 112.4. HRMS (ESI):
calcd for C30H21N2 [M + H]+ 409.1699; found 409.1708.
4-(2-Chlorophenyl)-2,3,6-triphenylpyridine (4aca). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (179 mg, 43%);
mp 120−121 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz,
2H), 7.71 (s, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.44−7.41 (m, 3H), 7.33
(d, J = 7.6 Hz, 1H), 7.22−7.14 (m, 4H), 7.08 (d, J = 7.6 Hz, 1H),
7.04−6.96 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.9,
155.2, 148.5, 140.7, 138.9, 138.7, 137.6, 133.5, 132.7, 131.3, 130.8,
130.3, 129.4, 129.1, 128.9, 128.7, 127.5, 127.5, 127.1, 126.7, 126.1,
120.3. HRMS (ESI): calcd for C29H21ClN [M + H]+ 418.1357; found
418.1362.
Methyl 4-(4,5,6-Triphenylpyridin-2-yl)benzoate (4paa). Pe-
troleum ether/ethyl acetate (100:1) as eluent. White solid (318 mg,
1
72%); mp 206−207 °C. H NMR (400 MHz, CDCl3) δ 8.25 (d, J =
8.0 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.36−7.38 (m,
2H), 7.20−7.24 (m, 6H), 7.04−7.14 (m, 5H), 6.91 (d, J = 8.0 Hz,
2H), 3.94 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 158.3,
154.3, 150.8, 143.2, 140.7, 139.6, 137.6, 133.7, 131.3, 130.3, 130.1,
130.0, 129.3, 128.0, 127.7, 127.6, 127.5, 127.5, 126.9, 126.7, 120.8,
52.2. HRMS (ESI): calcd for C31H24NO2 [M + H]+ 442.1802; found
442.1791.
4-(2-Fluorophenyl)-2,3,6-triphenylpyridine (4ada). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (245 mg, 61%);
mp 134−136 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2 Hz,
2H), 7.70 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H),
7.44−7.40 (m, 3H), 7.22−7.19 (m, 3H), 7.14−6.98 (m, 8H).
4,5,6-Triphenyl-2,2′-bipyridine (4raa). Petroleum ether/ethyl
acetate (10:1) as eluent. White solid (260 mg, 68%); mp 140−142
°C. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.8 Hz, 1H), 8.61 (d,
J = 8.0 Hz, 1H), 8.47 (s, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.39 (dd,
J = 6.7, 3.0 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.24−7.18
(m, 6H), 7.18−7.13 (m, 2H), 7.10−7.04 (m, 3H), 6.95−6.91 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.7, 156.1, 154.4, 150.9,
149.1, 141.0, 139.7, 137.9, 136.9, 134.4, 131.4, 130.2, 129.5, 127.8,
127.8, 127.6, 127.5, 127.3, 126.7, 123.8, 121.6, 121.0. HRMS (ESI):
calcd for C28H21N2 [M + H]+ 385.1699; found 385.1693.
4,5,6-Triphenyl-2,3′-bipyridine (4saa). Petroleum ether/ethyl
acetate (10:1) as eluent. White solid (273 mg, 87%); mp 180−182
°C. 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.66 (d, J = 4.8 Hz,
1H), 8.49 (dt, J = 8.0, 2.0 Hz, 1H), 7.79 (s, 1H), 7.60−7.32 (m, 4H),
7.23−7.21 (m, 5H), 7.17−7.02 (m, 5H), 6.97−6.81 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 153.0, 151.0, 149.9,
148.3, 140.6, 139.4, 137.5, 134.6, 133.7, 131.4, 130.1, 129.3, 128.1,
127.8, 127.6, 127.6, 126.8, 123.9, 123.7, 123.6, 120.4. HRMS (ESI):
calcd for C28H21N2 [M + H]+ 385.1699; found 385.1696.
13C{1H} NMR (101 MHz, CDCl3) δ 159.18 (C−F, 1JC−F = 245 Hz),
3
157.8, 155.4, 145.2, 140.8, 138.9, 137.7, 133.9, 131.3 (C−F, JC−F
=
2
3.6 Hz), 130.8, 130.2, 129.6 (C−F, JC−F = 8.1 Hz), 129.1, 128.7,
127.6, 127.6, 127.5, 127.5, 127.1, 126.7, 123.7 (C−F, 3JC−F = 4.0 Hz),
2
120.6, 115.5 (C−F, JC−F = 21.9 Hz). HRMS (ESI): calcd for
C29H21FN [M + H]+ 402.1653; found 402.1645.
4-(o-Tolyl)-2,3,6-triphenylpyridine (4aea). Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (67 mg, 17%); mp 127−
128 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 2H), 7.68
(d, J = 2.0 Hz, 1H), 7.50−7.40 (m, 5H), 7.22−7.13 (m, 4H), 7.09−
6.98 (m, 6H), 6.91−6.87 (m, 2H), 2.03 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 157.8, 155.1, 151.0, 141.0, 139.5, 139.0, 137.9, 135.2,
133.5, 131.0, 130.3, 129.9, 129.8, 129.0, 128.7, 127.6, 127.6, 127.5,
127.4, 127.0, 126.5, 125.2, 120.2, 20.2. HRMS (ESI): calcd for
C30H24N [M + H]+ 398.1903; found 398.1911.
4-(3-Bromophenyl)-2,3,6-triphenylpyridine (4aga). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (383 mg, 83%);
mp 155−157 °C. 1H NMR (400 MHz, CDCl3) δ 8.19−8.15 (m, 2H),
7.74 (s, 1H), 7.50 (t, J = 8.4 Hz, 2H), 7.46−7.42 (m, 1H), 7.39−7.35
(m, 4H), 7.23−7.18 (m, 3H), 7.14−7.03 (m, 4H), 6.97 (dt, J = 7.8,
1.4 Hz, 1H), 6.94−6.89 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 158.1, 155.8, 149.1, 141.9, 140.7, 138.9, 137.4, 132.7, 132.2, 131.3,
130.4, 130.2, 129.4, 129.2, 128.8, 128.1, 127.9, 127.6, 127.5, 127.1,
126.9, 122.1, 120.0. HRMS (ESI): calcd for C29H21BrN [M + H]+
462.0852; found 462.0858.
4-(3-Chlorophenyl)-2,3,6-triphenylpyridine (4aha). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (347 mg, 83%);
mp 147−148 °C. 1H NMR (400 MHz, CDCl3) δ 8.19−8.15 (m, 2H),
7.74 (s, 1H), 7.53−7.43 (m, 3H), 7.41−7.36 (m, 2H), 7.24−7.17 (m,
5H), 7.15−7.07 (m, 4H), 6.95−6.91 (m, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.6, 158.1, 155.8, 141.6, 140.7, 138.9, 137.4, 133.9,
132.7, 131.3, 130.2, 129.3, 129.2, 129.1, 128.8, 128.4, 127.9, 127.6,
127.6, 127.5, 127.1, 126.9, 120.0. HRMS (ESI): calcd for C29H21ClN
[M + H]+ 418.1357; found 418.1353.
2,3,4-Triphenyl-6-(thiophen-2-yl)pyridine (4taa). Petroleum
ether/ethyl acetate (10:1) as eluent. White solid (245 mg, 63%); mp
1
175−177 °C. H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.8 Hz,
1H), 7.77 (dd, J = 5.1, 1.2 Hz, 1H), 7.63 (s, 1H), 7.39−7.35 (m, 3H),
7.23−7.16 (m, 6H), 7.12−7.10 (m, 2H), 7.08−6.99 (m, 3H), 6.94−
6.84 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.0, 151.9,
150.7, 142.1, 140.9, 139.8, 137.9, 132.6, 131.5, 130.3, 129.3, 128.0,
127.8, 127.6, 127.4, 127.4, 126.6, 126.5, 126.2, 124.0, 120.2. HRMS
(ESI): calcd for C27H20NS [M + H]+ 390.1311; found 390.1316.
3-Methyl-2,4,5,6-tetraphenylpyridine (4uaa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (294 mg, 74%);
mp 180−182 °C. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.0 Hz,
2H), 7.47 (t, J = 7.4 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.35−7.30 (m,
2H), 7.21 (t, J = 7.2 Hz, 2H), 7.18−7.11 (m, 4H), 7.06−7.00 (m,
2H), 7.00−6.96 (m, 3H), 6.91−6.83 (m, 2H), 2.13 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 157.9, 154.7, 151.2 141.3, 140.9, 139.0,
138.5, 133.7, 131.2, 130.1, 129.5, 129.4, 128.1, 127.9, 127.7, 127.5,
127.3, 127.1, 126.8, 126.2, 18.7. HRMS (ESI): calcd for C30H24N [M
+ H]+ 398.1903; found 398.1905.
4-(m-Tolyl)-2,3,6-triphenylpyridine (4aia).13 Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (266 mg, 67%); mp 136−
137 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 2H), 7.77
(s, 1H), 7.47 (t, J = 7.2 Hz, 2H), 7.42−7.37 (m, 3H), 7.19−7.17 (m,
3H), 7.09−7.01 (m, 5H), 6.98 (s, 1H), 6.93−6.90 (m, 2H), 6.87 (d, J
= 7.2 Hz, 1H), 2.24 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
158.0, 155.7, 150.9, 141.2, 139.9, 139.3, 138.1, 137.7, 133.0, 131.5,
130.4, 130.2, 129.1, 128.8, 128.2, 127.9, 127.8, 127.6, 127.5, 127.2,
126.7, 126.6, 120.4, 21.5. ESI-MS: m/z [M + H]+ 398.
6-(tert-Butyl)-2,3,4-triphenylpyridine (4vaa). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (265 mg, 73%);
mp 147−149 °C. 1H NMR (400 MHz, CDCl3) δ 7.34−7.30 (m, 3H),
7.21−7.14 (m, 6H), 7.09−0.01 (m, 5H), 6.89−6.85 (m, 2H), 1.47 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.7, 156.3, 149.8, 141.3,
140.4, 138.3, 131.5, 131.1, 130.3, 129.4, 127.8, 127.6, 127.3, 127.1,
127.0, 126.3, 118.9, 37.6, 30.3. HRMS (ESI): calcd for C27H26N [M +
H]+ 364.2060; found 364.2064.
4-(2-Bromophenyl)-2,3,6-triphenylpyridine (4aba). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (226 mg, 47%);
mp 107−109 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.76 (s, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.44−7.39 (m, 3H),
7.23−7.20 (m, 4H), 7.10−7.01 (m, 5H), 6.98−6.94 (m, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 157.9, 155.1, 150.0, 140.7,
140.6, 139.0, 137.5, 133.2, 132.6, 131.3, 130.9, 130.3, 129.1, 129.0,
128.7, 127.5, 127.5, 127.1, 126.7, 122.8, 120.4. HRMS (ESI): calcd
for C29H21BrN [M + H]+ 462.0852; found 462.0843.
4-(4-Bromophenyl)-2,3,6-triphenylpyridine (4aja).13 Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (374 mg, 81%);
mp 152−153 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz,
2H), 7.73 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H),
7.39−7.33 (m, 4H), 7.21−7.18 (m, 3H), 7.16−7.06 (m, 3H), 7.00 (d,
J = 8.0 Hz, 2H), 6.91 (dd, J = 7.6, 1.6 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.2, 155.8, 149.4, 140.8, 138.9, 138.8, 137.5, 132.7,
131.4, 131.2, 131.0, 130.2, 129.2, 128.8, 128.0, 127.6, 127.5, 127.1,
126.8, 121.8, 120.0. ESI-MS: m/z [M + H]+ 462.
4-(4-(Trifluoromethyl)phenyl)-2,3,6-triphenylpyridine
(4aka). Petroleum ether/ethyl acetate (100:1) as eluent. White solid
1
(370 mg, 82%); mp 113−115 °C. H NMR (400 MHz, CDCl3) δ
3902
https://dx.doi.org/10.1021/acs.joc.0c02764
J. Org. Chem. 2021, 86, 3897−3906

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
8.16 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.52−7.41 (m, 5H), 7.40−7.34
(m, 2H), 7.27−7.17 (m, 5H), 7.14−7.04 (m, 3H), 6.93−6.89 (m,
8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.0, 155.9, 150.7, 140.7, 139.5, 138.9, 136.5, 132.7, 132.7,
131.6, 130.2, 129.3, 129.2, 128.8, 128.2, 128.1, 127.7, 127.6, 127.6,
127.1, 120.4. HRMS (ESI): calcd for C29H21ClN [M + H]+ 418.1357;
found 418.1344.
3-(4-Bromophenyl)-2,4,6-triphenylpyridine (4aad). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (397 mg, 86%);
mp 212−214 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.76 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H),
7.36−7.34 (m, 2H), 7.26−7.22 (m, 6H), 7.19 (d, J = 8.4 Hz, 2H),
7.12−7.10 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.0, 155.9, 150.6, 140.7, 139.5, 138.9, 137.0, 133.1,
131.6, 131.0, 130.2, 129.3, 129.2, 128.8, 128.2, 127.8, 127.6, 127.6,
127.1, 120.9, 120.4. HRMS (ESI): calcd for C29H21BrN [M + H]+
462.0852; found 462.0855.
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 155.9, 149.2, 143.6,
2
140.6, 138.8, 137.3, 132.7, 131.3, 130.2, 129.7, 129.5 (C−F, JC−F
=
32.2 Hz), 129.2, 128.8, 128.0, 127.6, 127.6, 127.1, 127.0, 124.9 (C−F,
3JC−F = 3.7 Hz), 122.7 (C−F, JC−F = 271 Hz), 120.0. HRMS (ESI):
1
calcd for C30H21F3N [M + H]+ 452.1621; found 452.1624.
4-(4-Chlorophenyl)-2,3,6-triphenylpyridine (4ala).13 Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (338 mg, 81%);
mp 163−165 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.73 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H),
7.38−7.36 (m, 2H), 7.21−7.19 (m, 5H), 7.12−7.05 (m, 5H), 6.92−
6.90 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 155.8,
149.4, 140.8, 138.9, 138.3, 137.6, 133.6, 132.7, 131.4, 130.7, 130.2,
129.1, 128.8, 128.2, 127.9, 127.6, 127.5, 127.1, 126.8, 120.1. ESI-MS:
m/z [M + H]+ 418.
3-(3-Bromophenyl)-2,4,6-triphenylpyridine (4aae). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (374 mg, 81%);
mp 125−127 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.78 (s, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H),
7.38−7.35 (m, 2H), 7.27−7.21 (m, 7H), 7.14−7.11 (m, 2H), 7.06 (t,
J = 1.8 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.84 (dt, J = 7.7, 1.4 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.0, 156.0, 150.7, 140.5,
140.1, 139.3, 138.9, 134.3, 131.3, 130.2, 130.1, 129.7, 129.3, 129.2,
128.8, 128.1, 127.8, 127.7, 127.7, 127.7, 127.1, 121.7, 120.3. HRMS
(ESI): calcd for C29H21BrN [M + H]+ 462.0852; found 462.0846.
3-(2-Bromophenyl)-2,4,6-triphenylpyridine (4aaf). Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (356 mg, 77%); mp
4-(4-Fluorophenyl)-2,3,6-triphenylpyridine (4ama). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (333 mg, 83%);
mp 175−177 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.74 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H),
7.38−7.36 (m, 2H), 7.21−7.18 (m, 3H), 7.11−7.06 (m, 5H), 6.93−
6.89 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.10 (C−F,
1JC−F = 246 Hz), 158.1, 155.7, 149.6, 140.9, 139.0, 137.7, 135.8, 132.9
4
3
(C−F, JC−F = 3.5 Hz), 131.4, 131.1 (C−F, JC−F = 8 Hz), 130.2,
129.1, 128.8, 127.9, 127.6, 127.5, 127.1, 126.8, 120.3, 115.0 (C−F,
2JC−F = 21.3 Hz). HRMS (ESI): calcd for C29H21FN [M + H]+
402.1653; found 402.1657.
1
4-(p-Tolyl)-2,3,6-triphenylpyridine (4ana).20 Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (282 mg, 71%); mp 180−
182 °C. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.2 Hz, 2H), 7.76
(s, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.43−7.36 (m, 3H), 7.21−7.16 (m,
3H), 7.11−7.02 (m, 7H), 6.95−6.91 (m, 2H), 2.30 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.1, 155.6, 150.6, 141.2, 139.2, 138.1,
137.2, 136.9, 132.9, 131.5, 130.3, 129.3, 129.0, 128.7, 127.8, 127.6,
127.4, 127.1, 126.6, 120.5, 21.2. HRMS (ESI): calcd for C30H24N [M
+ H]+ 398.1903; found 398.1899.
165−167 °C. H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.2 Hz,
2H), 7.79 (s, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.44−7.41 (m, 3H), 7.34
(d, J = 8.4 Hz, 1H), 7.24−7.17 (m, 8H), 7.10−7.04 (m, 2H), 7.01−
6.97 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.0, 156.3,
150.9, 140.7, 139.4, 139.1, 139.0, 133.3, 132.5, 131.9, 129.7, 129.2,
129.0, 128.8, 128.7, 127.9, 127.7, 127.6, 127.5, 127.2, 126.8, 125.1,
120.1. HRMS (ESI): calcd for C29H21BrN [M + H]+ 462.0852; found
462.0849.
3-(2-Chlorophenyl)-2,4,6-triphenylpyridine (4aag). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (334 mg, 80%);
mp 153−155 °C. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.2 Hz,
2H), 7.79 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.45−7.39 (m, 3H),
7.24−7.19 (m, 6H), 7.19−7.14 (m, 3H), 7.10−7.06 (m, 1H), 7.04−
7.00 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 156.3,
151.1, 140.7, 139.4, 139.0, 137.2, 134.4, 133.2, 130.3, 129.6, 129.2,
129.2, 128.9, 128.7, 127.9, 127.7, 127.6, 127.5, 127.2, 126.2, 120.0.
HRMS (ESI): calcd for C29H21ClN [M + H]+ 418.1357; found
418.1354.
4-(Furan-2-yl)-2,3,6-triphenylpyridine (4aoa).13 Petroleum
ether/ethyl acetate (10:1) as eluent. White solid (295 mg, 79%);
1
mp 176−157 °C. H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.19
(d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.45−7.41 (m, 2H),
7.36−7.29 (m, 5H), 7.19−7.14 (m, 5H), 6.23 (dd, J = 3.2, 1.2 Hz,
1H), 5.32 (d, J = 3.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
158.4, 156.2, 150.7, 142.7, 140.9, 139.3, 138.6, 138.4, 130.6, 130.1,
130.0, 129.0, 128.7, 128.6, 127.6, 127.4, 127.3, 127.1, 115.4, 112.6,
111.9. ESI-MS: m/z [M + H]+ 374.
2,3,6-Triphenyl-4-(thiophen-2-yl)pyridine (4apa).13 Petrole-
um ether/ethyl acetate (10:1) as eluent. White solid (315 mg, 81%);
mp 168−170 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.91 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H),
7.37−7.35 (m, 2H), 7.27−7.17 (m, 7H), 7.08−7.06 (m, 2H), 6.89
(dd, J = 5.1, 3.7 Hz, 1H), 6.79 (dd, J = 3.7, 1.2 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.5, 156.0, 143.1, 141.1, 140.9, 139.0,
137.9, 132.3, 131.3, 130.1, 129.1, 128.8, 128.3, 128.2, 127.5, 127.4,
127.3, 127.3, 127.1, 127.1, 119.7. ESI-MS: m/z [M + H]+ 390.
3-(4-Fluorophenyl)-2,4,6-triphenylpyridine (4aab). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (337 mg, 84%);
2,3-Bis(4-bromophenyl)-4,6-diphenylpyridine (4aah). Petro-
leum ether/ethyl acetate (100:1) as eluent. White solid (449 mg,
83%); mp 167−169 °C. H NMR (400 MHz, CDCl3) δ 8.14 (d, J =
7.2 Hz, 2H), 7.77 (s, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz,
1H), 7.36 (d, J = 8.4 Hz, 2H), 7.27−7.21 (m, 7H), 7.11−7.08 (m,
2H), 6.78 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
156.6, 156.1, 150.8, 139.6, 139.3, 138.7, 136.6, 133.0, 131.8, 131.2,
131.0, 130.9, 129.3 129.2, 128.8, 128.2 127.7, 127.0, 122.1, 121.2,
120.6. HRMS (ESI): calcd for C29H20Br2N [M + H]+ 539.9957;
found 539.9952.
1
2,3-Bis(4-methoxyphenyl)-4,6-diphenylpyridine (4aai). Pe-
troleum ether/ethyl acetate (100:1) as eluent. White solid (390 mg,
1
mp 145−147 °C. H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.1
1
Hz, 2H), 7.77 (s, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz,
1H), 7.37−7.34 (m, 2H), 7.25−7.21 (m, 6H), 7.13−7.10 (m, 2H),
6.88−6.85 (m, 2H), 6.76 (t, J = 8.8 Hz, 2H). 13C{1H} NMR (101
88%); mp 173−175 °C. H NMR (400 MHz, CDCl3) δ 8.16 (d, J =
7.2 Hz, 2H), 7.71 (s, 1H), 7.47 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2
Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.24−7.21 (m, 3H), 7.15−7.11 (m,
2H), 6.82 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.63 (d, J =
8.8 Hz, 2H), 3.77 (s, 3H), 3.73 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.9, 158.2, 157.6, 155.2, 150.7, 140.2, 139.2, 133.7, 132.5,
132.2, 131.5, 130.3, 129.3, 128.9, 128.7, 128.0, 127.2, 127.0, 120.0,
113.3, 113.0, 55.2, 55.1. HRMS (ESI): calcd for C31H26NO2 [M +
H]+ 444.1958; found 444.1955.
1
MHz, CDCl3) δ 161.6 (C−F, JC4−F = 249 Hz), 158.1, 155.8, 150.7,
3
140.8, 139.7, 139.0, 133.9 (C−F, JC−F = 3.5 Hz), 133.0 (C−F, JC−F
= 7.9 Hz), 131.8, 130.2, 129.3, 129.1, 128.7, 128.1, 127.7, 127.5 (2C),
2
127.1, 120.4, 114.9 (C−F, JC−F = 21.3 Hz). HRMS (ESI): calcd for
C29H21FN [M + H]+ 402.1653; found 402.1654.
3-(4-Chlorophenyl)-2,4,6-triphenylpyridine (4aac). Petrole-
um ether/ethyl acetate (100:1) as eluent. White solid (351 mg, 84%);
mp 195−197 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz,
2H), 7.77 (s, 1H), 7.51−7.46 (m, 2H), 7.45−7.40 (m, 1H), 7.37−
7.35 (m, 2H), 7.26−7.21 (m, 6H), 7.12−7.10 (m, 2H), 7.04 (d, J =
4-(3-Chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-3-(p-
tolyl)pyridine (4lhk). Petroleum ether/ethyl acetate (100:1) as
1
eluent. White solid (401 mg, 87%); mp 135−137 °C. H NMR (400
MHz, CDCl3) δ 8.12 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.39−7.36 (m,
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Article
2H), 7.23−7.18 (m, 5H), 7.11 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.8 Hz,
2H), 6.91 (dt, J = 8.0, 1.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.77 (d, J
= 8.0 Hz, 2H), 3.87 (s, 3H), 2.24 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.6, 158.0, 155.2, 149.1, 142.0, 141.0, 136.4, 134.4, 133.8,
132.1, 131.6, 131.2, 130.2, 129.3, 129.1, 128.6, 128.3, 127.7, 127.5,
127.4, 119.2, 114.1, 55.4, 21.2. HRMS (ESI): calcd for C31H25ClNO
[M + H]+ 462.1619; found 462.1611.
Renchao Ma − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China
Xu-Qiong Xiao − Key Laboratory of Organosilicon Chemistry
and Material Technology of Ministry of Education,
Hangzhou Normal University, Hangzhou 311121, P R
China; orcid.org/0000-0001-8424-9898
Lei Wang − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China
Zhiming Wang − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; orcid.org/0000-
0002-6583-3826
2,4-Diphenyl-6-(p-tolyl)nicotinonitrile (4maj).10b Petroleum
ether/ethyl acetate (100:1) as eluent. White solid (263 mg, 76%); mp
153−154 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.30−8.32 (m, 2H),
8.15 (s, 1H), 7.99−8.01 (m, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.58−7.62
(m, 3H), 7.55−7.57 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 162.1, 158.7, 155.3, 140.3,
138.4, 137.5, 134.0, 131.1, 130.4, 129.8, 129.8, 129.5, 129.4, 128.9,
128.1, 119.2, 118.3, 104.6, 21.4. ESI-MS: m/z [M + H]+ 347.
2,3,5,6-Tetraphenylpyridine (5).21 Petroleum ether/ethyl ac-
etate (100:1) as eluent. White solid (147 mg, 77%); mp 228−230 °C.
1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.54−7.46 (m, 4H),
7.29−7.21 (m, 16H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.4,
141.2, 140.0, 139.7, 134.4, 130.2, 129.6, 128.4, 127.9, 127.8, 127.3.
ESI-MS: m/z [M + H]+ 384.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02764
Notes
The authors declare no competing financial interest.
2,4,6-Triphenylpyridine (6aa).8i Petroleum ether/ethyl acetate
1
(100:1) as eluent. White solid (106 mg, 69%); mp 125−128 °C. H
ACKNOWLEDGMENTS
■
NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.6 Hz, 4H), 7.91 (s, 2H),
7.77 (d, J = 7.5 Hz, 2H), 7.57−7.45 (m, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 157.5, 150.2, 139.6, 139.1, 129.2, 129.1, 129.0, 128.7,
127.2, 127.2, 117.2. ESI-MS: m/z [M + H]+ 308.
Financial support from the Leading Innovative and Entrepre-
neur Team Introduction Program of Zhejiang (No.
2019R01005) is gratefully acknowledged. We thank Professor
Robert C Hider from King’s College London for his
constructive advice.
2,6-Diphenyl-4-(p-tolyl)pyridine (6an).8i Petroleum ether/
ethyl acetate (100:1) as eluent. White solid (106 mg, 66%); mp
1
113−115 °C. H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz,
4H), 7.76 (s, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 7.6 Hz, 4H),
7.33 (t, J = 7.2 Hz), 7.21 (d, J = 8.0 Hz, 2H). ESI-MS: m/z [M + H]+
322.
REFERENCES
■
(1) (a) Ma, X. Q.; Gang, D. R. The Lycopodium alkaloids. Nat.
Prod. Rep. 2004, 21, 752−772. (b) Vargas, D. F.; Larghi, E. L.;
Kaufman, T. S. The 6 pi-azaelectrocyclization of azatrienes. Synthetic
applications in natural products, bioactive heterocycles, and related
fields. Nat. Prod. Rep. 2019, 36, 354−401. (c) Uredi, D.; Motati, D.
R.; Watkins, E. B. A simple, tandem approach to the construction of
pyridine derivatives under metal-free conditions: a one-step synthesis
of the monoterpene natural product, (−)-actinidine. Chem. Commun.
2019, 55, 3270−3273.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02764.
1H NMR, 13C NMR, and X-ray crystallographic data
(PDF)
(2) (a) Rokesh, K.; Sakar, M.; Do, T.-O. 2-(Aminomethyl
pyridine)SbI5: An emerging visible-light driven organic-inorganic
hybrid perovskite for photoelectrochemical and photocatalytic
applications. Mater. Lett. 2019, 242, 99−102. (b) Hang, X.-C.;
Fleetham, T.; Turner, E.; Brooks, J.; Li, J. Highly efficient blue-
emitting cyclometalated platinum(II) complexes by judicious
molecular design. Angew. Chem., Int. Ed. 2013, 52, 6753−6756.
(c) Cheng, G.; Weng, Y.; Yang, X.; Cui, X. Base-promoted N-
pyridylation of heteroarenes using N-propargyl enaminones as
equivalents of pyridine scaffolds. Org. Lett. 2015, 17, 3790−3793.
(3) (a) McMillion, N. D.; Wilson, A. W.; Goetz, M. K.; Chang, M.-
C.; Lin, C.-C.; Feng, W.-J.; McCrory, C. C. L.; Anderson, J. S.
Imidazole for pyridine substitution leads to enhanced activity under
milder conditions in cobalt water oxidation electrocatalysis. Inorg.
Chem. 2019, 58, 1391−1397. (b) Shi, H.; Wang, R.; Lou, M.; Jia, D.;
Guo, Y.; Wang, X.; Huang, Y.; Sun, Z.; Wang, T.; Wang, L. A novel
Pt/pyridine ionic liquid polyoxometalate/rGO tri-component hybrid
and its enhanced activities for methanol electrooxidation. Electrochim.
Acta 2019, 294, 93−101. (c) Momblona, C.; Ertl, C. D.; Pertegas, A.;
Junquera-Hernandez, J. M.; Bolink, H. J.; Constable, E. C.; Sessolo,
M.; Orti, E.; Housecroft, C. E. Exploring the effect of the
cyclometallating ligand in 2-(pyridine-2-yl)benzo[d]thiazole-contain-
ing iridium(iii) complexes for stable light-emitting electrochemical
cells. J. Mater. Chem. C 2018, 6, 12679−12688.
Accession Codes
CCDC 2009821−2009822 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Yongmin Ma − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; School of
Pharmaceutical Science, Zhejiang Chinese Medical University,
Hangzhou 310053, P R China; orcid.org/0000-0002-
9521-767X; Email: yongmin.ma@tzc.edu.cn
Authors
Yuxin Ding − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; School of
Pharmaceutical Science, Zhejiang Chinese Medical University,
Hangzhou 310053, P R China
(4) (a) Burriss, A.; Edmunds, A. J. F.; Emery, D.; Hall, R. G.; Jacob,
O.; Schaetzer, J. The importance of trifluoromethyl pyridines in crop
protection. Pest Manage. Sci. 2018, 74, 1228−1238. (b) Guan, A.; Liu,
C.; Chen, W.; Yang, F.; Xie, Y.; Zhang, J.; Li, Z.; Wang, M. Design,
synthesis, and structure-activity relationship of new pyrimidinamine
3904
https://dx.doi.org/10.1021/acs.joc.0c02764
J. Org. Chem. 2021, 86, 3897−3906

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Article
derivatives containing an aryloxy pyridine Moiety. J. Agric. Food Chem.
2017, 65, 1272−1280. (c) Nauha, E.; Kolehmainen, E.; Nissinen, M.
Packing incentives and a reliable N-H•••N-pyridine synthon in co-
crystallization of bipyridines with two agrochemical actives.
CrystEngComm 2011, 13, 6531−6537. (d) Nauha, E.; Nissinen, M.
Co-crystals of an agrochemical active - A pyridine-amine synthon for a
thioamide group. J. Mol. Struct. 2011, 1006, 566−569.
Metal-free synthesis of highly substituted pyridines by formal 2 + 2+2
cycloaddition under mild conditions. Angew. Chem., Int. Ed. 2016, 55,
12864−12867. (e) Wang, Y.; Song, L.-J.; Zhang, X.; Sun, J. Metal-free
2 + 2+2 cycloaddition of ynamides and nitriles: mild and
regioselective synthesis of fully substituted pyridines. Angew. Chem.,
Int. Ed. 2016, 55, 9704−9708. (f) Michlik, S.; Kempe, R.
Regioselectively functionalized pyridines from sustainable resources.
Angew. Chem., Int. Ed. 2013, 52, 6326−6329. (g) Shi, Z.; Loh, T.-P.
Organocatalytic synthesis of highly functionalized pyridines at room
temperature. Angew. Chem., Int. Ed. 2013, 52, 8584−8587. (h) Stark,
D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O'Riordan, T. J. C.;
Smith, A. D. Isothiourea-mediated one-pot synthesis of functionalized
pyridines. Angew. Chem., Int. Ed. 2013, 52, 11642−11646. (i) He, Z.;
Dobrovolsky, D.; Trinchera, P.; Yudin, A. K. Synthesis of multi-
substituted pyridines. Org. Lett. 2013, 15, 334−337. (j) Wu, J.; Xu,
W.; Yu, Z.-X.; Wang, J. Ruthenium-catalyzed formal dehydrative 4 + 2
cycloaddition of enamides and alkynes for the synthesis of highly
substituted pyridines: reaction development and mechanistic study. J.
Am. Chem. Soc. 2015, 137, 9489−9496. (k) Hille, T.; Irrgang, T.;
Kempe, R. Synthesis of meta-functionalized pyridines by selective
dehydrogenative heterocondensation of beta- and gamma-amino
alcohols. Angew. Chem., Int. Ed. 2017, 56, 371−374.
(9) (a) Simon, C.; Constantieux, T.; Rodriguez, J. Utilisation of 1,3-
dicarbonyl derivatives in multicomponent reactions. Eur. J. Org. Chem.
2004, 2004, 4957−4980. (b) Liéby-Muller, F.; Allais, C.;
Constantieux, T.; Rodriguez, J. Metal-free Michael addition initiated
multicomponent oxidative cyclodehydration route to polysubstituted
pyridines from 1,3-dicarbonyls. Chem. Commun. 2008, 4207−4209.
(c) Gao, Y.; Zhou, D.; Ma, Y. Alpha-Csp(3)-H methylenation of
diketones to synthesize methylene-bridged bis-1,3-dicarbonyl com-
pounds and polysubstituted pyridines using the DMSO/selectfluor
system. Chemistryselect 2018, 3, 9374−9377. (d) Han, J.; Guo, X.; Liu,
Y.; Fu, Y.; Yan, R.; Chen, B. One-pot synthesis of benzene and
pyridine derivatives via copper-catalyzed coupling reactions. Adv.
Synth. Catal. 2017, 359, 2676−2681. (e) Huang, H.; Ji, X.; Wu, W.;
Huang, L.; Jiang, H. Copper-catalyzed formal C-N bond cleavage of
aromatic methylamines: assembly of pyridine derivatives. J. Org.
Chem. 2013, 78, 3774−3782. (f) Zhang, X.; Wang, Z.; Xu, K.; Feng,
Y.; Zhao, W.; Xu, X.; Yan, Y.; Yi, W. HOTf-catalyzed sustainable one-
pot synthesis of benzene and pyridine derivatives under solvent-free
conditions. Green Chem. 2016, 18, 2313−2316. (g) Chen, J.; Meng,
H.; Zhang, F.; Xiao, F.; Deng, G.-J. Transition-metal-free selective
pyrimidines and pyridines formation from aromatic ketones,
aldehydes and ammonium salts. Green Chem. 2019, 21, 5201−5206.
(h) Rong, L.; Han, H.; Wang, S.; Zhuang, Q. Efficient synthesis of
polysubstituted pyridine under solvent-free conditions without using
any catalysts. Synth. Commun. 2008, 38, 1808−1814. (i) Wu, P.; Cai,
X.-M.; Wang, Q.-F.; Yan, C.-G. One-pot multicomponent con-
densation reaction of aldehydes with cyclic ketones. Synth. Commun.
2011, 41, 841−850. (j) Li, J.; He, P.; Yu, C. DPTA-catalyzed one-pot
regioselective synthesis of polysubstituted pyridines and 1,4-
dihydropyridines. Tetrahedron 2012, 68, 4138−4144. (k) Adib, M.;
Tahermansouri, H.; Koloogani, S. A.; Mohammadi, B.; Bijanzadeh, H.
R. Krohnke pyridines: an efficient solvent-free synthesis of 2,4,6-
triarylpyridines. Tetrahedron Lett. 2006, 47, 5957−5960.
(5) (a) Prachayasittikul, S.; Pingaew, R.; Worachartcheewan, A.;
Sinthupoom, N.; Prachayasittikul, V.; Ruchirawat, S.; Prachayasittikul,
V. Roles of pyridine and pyrimidine derivatives as privileged scaffolds
in anticancer agents. Mini-Rev. Med. Chem. 2017, 17, 869−901.
(b) Conlon, I. L.; Van Eker, D.; Abdelmalak, S.; Murphy, W. A.;
Bashir, H.; Sun, M.; Chauhan, J.; Varney, K. M.; Godoy-Ruiz, R.;
Wilder, P. T.; Fletcher, S. Krohnke pyridines: rapid and facile access
to Mcl-1 inhibitors. Bioorg. Med. Chem. Lett. 2018, 28, 1949−1953.
(c) Ghobadian, R.; Mahdavi, M.; Nadri, H.; Moradi, A.; Edraki, N.;
Akbarzadeh, T.; Sharifzadeh, M.; Bukhari, S. N. A.; Amini, M. Novel
tetrahydrocarbazole benzyl pyridine hybrids as potent and selective
butryl cholinesterase inhibitors with neuroprotective and beta-
secretase inhibition activities. Eur. J. Med. Chem. 2018, 155, 49−60.
(d) Huang, Y.; Wang, Q.; Wu, Y. An unexpected degradation pathway
of a 1,2,4-triazolo 4,3-alpha pyridine derivative: The formation of 2
cationic pseudodimers of an 11 beta-hydroxysteroid dehydrogenase
type 1 inhibitor drug candidate in a stressed capsule formulation. J.
Pharm. Sci. 2018, 107, 1633−1641. (e) Zhou, Y.; Zhu, X.; Zhang, L.;
Tang, C.; Feng, B. Design, synthesis, and biological evaluation of 2-(4-
(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists.
Chem. Biol. Drug Des. 2019, 93, 67−74.
(6) (a) Bertuzzi, G.; Sinisi, A.; Caruana, L.; Mazzanti, A.; Fochi, M.;
Bernardi, L. Catalytic enantioselective addition of indoles to activated
N-benzylpyridinium salts: nucleophilic dearomatization of pyridines
with unusual C-4 regioselectivity. ACS Catal. 2016, 6, 6473−6477.
(b) Binnani, C.; Rai, R. K.; Tyagi, D.; Mobin, S. M.; Singh, S. K.
Ligand-tuned C-H bond activation/arylation of 2-arylpyridines over
pyridine-based N,O/N,N ligated Ruthenium-arene complexes. Eur. J.
Inorg. Chem. 2018, 2018, 1435−1445. (c) Greve, E.; Porter, J. D.;
Dockendorff, C. DFT-assisted design and evaluation of bifunctional
amine/pyridine-oxazoline metal catalysts for additions of ketones to
unactivated alkenes and alkynes. Synthesis 2019, 51, 450−462.
(d) Ramesh, R.; Arivazhagan, M.; Malecki, J. G.; Lalitha, A. Improved
one-pot, four-component strategy to access functionalized dihydro-
pyridines by using 4-(N,N-dimethylamino)pyridine as a catalyst.
Synlett 2018, 29, 1897−1901. (e) Zhang, Y.; Zhang, Y.; Sun, Y. L.;
Du, X.; Shi, J. Y.; Wang, W. D.; Wang, W. 4-(N,N-Dimethylamino)-
pyridine-embedded nanoporous conjugated polymer as a highly active
heterogeneous organocatalyst. Chem. - Eur. J. 2012, 18, 6328−6334.
(7) (a) Guo, J.; Pan, X.; Li, J.; Wu, W.; Zhang, J. Theoretical
investigation of the vibronic phosphorescence spectra and quantum
yields for iridium(III) complexes with 2-(2,5,2’,3′,4’,5′,6’-heptafluoro-
biphenyl-4-yl)-pyridine as the primary ligand. Spectrochim. Acta, Part
A 2019, 216, 179−189. (b) Meng, X.; Bai, R.; Wang, X.; Pan, F.; He,
L. Red to blue emitting cationic iridium complexes with 2-phenyl-4-
dimethylaminopyridine as the cyclometalating ligand: Synthesis,
characterization and electroluminescent devices. Dyes Pigm. 2019,
165, 458−466. (c) Pearce, B. H.; Ogutu, H. F. O.; Saban, W.; Luckay,
R. C. Synthesis, characterization and use of imidazole and methyl-
pyrazole based pyridine ligands as extractants for nickel(II) and
copper(II. Inorg. Chim. Acta 2019, 490, 57−67. (d) Gunanathan, C.;
Milstein, D. Metal-ligand cooperation by aromatization-dearomatiza-
tion: a new paradigm in bond activation and ″green″ catalysis. Acc.
Chem. Res. 2011, 44, 588−602.
(10) (a) Muthu, M.; Vishnu Priya, R.; Almansour, A. I; Suresh
Kumar, R.; Kumar, R. R. Synthesis of indole-cycloalkyl b pyridine
hybrids via a four-component six-step tandem process. Beilstein J. Org.
Chem. 2018, 14, 2907−2915. (b) Li, N.; Lai, S.-L.; Liu, W.; Wang, P.;
You, J.; Lee, C.-S.; Liu, Z. Synthesis and properties of n-type
triphenylpyridine derivatives and applications in deep-blue organic
light-emitting devices as electron-transporting layer. J. Mater. Chem.
2011, 21, 12977−12985. (c) Tu, S.; Jiang, B.; Yao, C.; Jiang, H.;
Zhang, J.; Jia, R.; Zhang, Y. An efficient and regiospecific synthesis of
new 2,2’-bipyridine derivatives in water. Synthesis 2007, 2007, 1366−
1372.
(8) (a) Chelucci, G. Synthesis and application in asymmetric
catalysis of camphor-based pyridine ligands. Chem. Soc. Rev. 2006, 35,
1230−1243. (b) Loy, N. S. Y.; Singh, A.; Xu, X.; Park, C.-M.
Synthesis of pyridines by carbenoid-mediated ring opening of 2H-
azirines. Angew. Chem., Int. Ed. 2013, 52, 2212−2216. (c) Wei, Y.;
Yoshikai, N. Modular pyridine synthesis from oximes and enals
through synergistic copper/iminium catalysis. J. Am. Chem. Soc. 2013,
135, 3756−3759. (d) Xie, L.-G.; Shaaban, S.; Chen, X.; Maulide, N.
(11) Prakash, M.; Gudimella, S. K.; Lodhi, R.; Guin, S.; Samanta, S.
NH4OAc-promoted domino route to hydroxyarylated unsymmetrical
pyridines under neat conditions. J. Org. Chem. 2020, 85, 2151−2167.
3905
https://dx.doi.org/10.1021/acs.joc.0c02764
J. Org. Chem. 2021, 86, 3897−3906

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(12) Shen, J.; Cai, D.; Kuai, C.; Liu, Y.; Wei, M. e.; Cheng, G.; Cui,
X. Base-promoted β-C(sp3)−H functionalization of enaminones: an
approach to polysubstituted pyridines. J. Org. Chem. 2015, 80, 6584−
6589.
(13) Zhang, Q.-R.; Huang, J.-R.; Zhang, W.; Dong, L. Highly
functionalized pyridines synthesis from N-sulfonyl ketimines and
alkynes using the N−S bond as an internal oxidant. Org. Lett. 2014,
16, 1684−1687.
(14) Tan, W. W.; Ong, Y. J.; Yoshikai, N. Synthesis of highly
substituted pyridines through copper-catalyzed condensation of
oximes and alpha,beta-unsaturated imines. Angew. Chem., Int. Ed.
2017, 56, 8240−8244.
(15) (a) Brauch, S.; van Berkel, S. S.; Westermann, B. Higher-order
multicomponent reactions: beyond four reactants. Chem. Soc. Rev.
2013, 42, 4948−4962. (b) Levi, L.; Mueller, T. J. J. Multicomponent
syntheses of functional chromophores. Chem. Soc. Rev. 2016, 45,
2825−2846. (c) Zhi, S.; Ma, X.; Zhang, W. Consecutive multi-
component reactions for the synthesis of complex molecules. Org.
Biomol. Chem. 2019, 17, 7632−7650. (d) Neochoritis, C. G.; Zhao,
T.; Domling, A. Tetrazoles via multicomponent reactions. Chem. Rev.
2019, 119, 1970−2042. (e) Bao, W.-H.; He, M.; Wang, J.-T.; Peng,
X.; Sung, M.; Tang, Z.; Jiang, S.; Cao, Z.; He, W.-M. Iodine-catalyzed
odorless synthesis of s-thiocarbamates with sulfonyl chlorides as a
sulfur source. J. Org. Chem. 2019, 84, 6065−6071. (f) Gui, Q.-W.; He,
X.; Wang, W.; Zhou, H.; Dong, Y.; Wang, N.; Tang, J.-X.; Cao, Z.;
He, W.-M. The clean preparation of multisubstituted pyrroles under
metal- and solvent-free conditions. Green Chem. 2020, 22, 118−122.
(g) Lu, L.-H.; Wang, Z.; Xia, W.; Cheng, P.; Zhang, B.; Cao, Z.; He,
W.-M. Sustainable routes for quantitative green selenocyanation of
activated alkynes. Chin. Chem. Lett. 2019, 30, 1237−1240.
(16) Zhao, M.-N.; Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H.
Ruthenium-catalyzed cyclization of ketoxime acetates with DMF for
synthesis of symmetrical pyridines. Org. Lett. 2014, 16, 3082−3085.
(17) Pan, X.; Liu, Q.; Chang, L.; Yuan, G. Ammonium iodide-
promoted cyclization of ketones with DMSO and ammonium acetate
for synthesis of substituted pyridines. RSC Adv. 2015, 5, 51183−
51187.
(18) Yu, J.-W.; Mao, S.; Wang, Y.-Q. Copper-catalyzed base-
accelerated direct oxidation of C-H bond to synthesize benzils, isatins,
and quinoxalines with molecular oxygen as terminal oxidant.
Tetrahedron Lett. 2015, 56, 1575−1580.
(19) Tan, W. W.; Ong, Y. J.; Yoshikai, N. Synthesis of highly
substituted pyridines through copper-catalyzed condensation of
oximes and α,β-unsaturated imines. Angew. Chem., Int. Ed. 2017, 56,
8240−8244.
(20) Shibuya, J.; Nabeshima, M.; Nagano, H.; Maeda, K.
Photochemical reaction of 2,4,4,6-tetrasubstituted 1,4-dihydropyr-
idines in deaerated media: photocolouration and photorearrangement
accompanying dehydrogenation. J. Chem. Soc., Perkin Trans. 2 1988,
2, 1607−1612.
(21) Liu, W.; Tan, H.; Chen, C.; Pan, Y. A method to access
symmetrical tetrasubstituted pyridines via iodine and ammonium
persulfate mediated [2 + 2+1 + 1]-cycloaddition reaction. Adv. Synth.
Catal. 2017, 359, 1594−1598.
3906
https://dx.doi.org/10.1021/acs.joc.0c02764
J. Org. Chem. 2021, 86, 3897−3906