An efficient synthesis of arylated pyridines from conjugated acetylenes and substituted benzylamines catalyzed by base

Article abstract of DOI:10.3390/molecules22081277

An efficient base-catalyzed synthesis of arylated pyridines has been disclosed. This reaction involving conjugated acetylenes and substituted benzylamines proceeded smoothly, giving rise to tri-aryl substituted pyridines which are biologically relevant co

Full text of DOI:10.3390/molecules22081277

molecules
Communication
An Efficient Synthesis of Arylated Pyridines from
Conjugated Acetylenes and Substituted
Benzylamines Catalyzed by Base
Mengping Guo 1,2,
*
ID , Bo Chen 1,2, Qiming Zhu 1, Hua Jin 1, Qiuling Peng 1 and Yanping Kang 1
1
College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, Jiangxi, China;
chenbo25719@163.com (B.C.); Zhqm18@163.com (Q.Z.); 18079573672@163.com (H.J.);
ycxypql@163.com (Q.P.); mkyp@sina.com (Y.K.)
Engineering Center of Jiangxi University for Lithium Energy, Yichun University, Yichun 336000,
Jiangxi, China
2
*
Correspondence: guomengping65@163.com; Tel.: +86-0795-320-0535
Received: 29 June 2017; Accepted: 29 July 2017; Published: 31 July 2017
Abstract: An efficient base-catalyzed synthesis of arylated pyridines has been disclosed. This reaction
involving conjugated acetylenes and substituted benzylamines proceeded smoothly, giving rise to
tri-aryl substituted pyridines which are biologically relevant compounds in good to excellent yields
in N,N-dimethylformamide (DMF) under air at 140 ◦C with K2CO3 as catalyst.
Keywords: arylated pyridines; synthesis; transition-metal-free; base; catalysis
1. Introduction
The importance of pyridine motif comes from its unique biological activity in natural products [
1–3],
pharmaceutical compounds [
4–8
] and agrochemicals [
9]. In addition, pyridine derivatives are widely
applied in organometallic chemistry [10
,
11], catalysis [12], material science [13–15] and supramolecular
chemistry [16–18]. Therefore, the more efficient synthesis of pyridine derivatives is still an important
topic [19 20]. However, there are only very few examples reported on this topic: in 1974, Chalk [21
,
]
reported a new pyridine synthesis from conjugated acetylenes and substituted methylamines, leading
to 51% of 2-p-tolyl-3,6-diphenylpyridine and 38% of 2-p-tolyl-3,6-diphenylpyridine N-oxide at 145 ◦C
under nitrogen with dimethylsulfoxide as solvent. In 2013, Shaand coworkers [22] disclosed a facile
synthetic method for the preparation of trisubstituted pyridines with high regioselectivity through
a three-component assembly strategy of arynes, isocyanides, and 3-bromo- or 3-acetoxypropynes,
leading to 65% of 2-(4-fluorophenyl)-3,6-diphenylpyridine. In recent years, transition-metal-catalyzed
C-C cross-coupling reaction has been applied to a diverse array of fields. Peter [3] recently reported the
site-selective arylation of commercially available 2,3,5,6-tetrachloropyridine using the Suzuki–Miyaura
reaction, allowing the selective synthesis of mono-, di-, tri- and tetraarylated pyridines in good to
quantitative yields. In this context, based on the advantages of conjugated acetylenes, which are readily
prepared by the catalytic oxidative coupling of terminal alkynes [23], studying more efficient synthesis
of pyridine derivatives between conjugated acetylenes and substituted methylamines is still highly
desirable and challenging.
2. Resultsand Discussion
Our interest in increasing the synthetic yield of arylated pyridines from conjugated acetylenes
and substituted benzylamines under optimum conditions stemmed from the fact that Chalk’s [24
]
work gave only a 70% yield of 2,3,6-triphenylpyridine fromsolutions of 1,4-diphenylbutadiyne in
benzylamine (1:6.13 mmol) after two to three hours at 180 ◦C under nitrogen. Initially, we tested the
Molecules 2017, 22, 1277; doi:10.3390/molecules22081277
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Molecules 2017, 22, 1277
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◦
1 (1 mmol) and benzylamine 2 (6 mmol) in DMSO at 140 C in
reaction of 1,4-diphenylbutadiyne
the presence of K2CO3 (0.5 mmol) under air. To our delight, 2,3,6-triphenylpyridine 3c was obtained
in 85% isolated yield (Table 1, entry 3). Then, the effects of the ratio of starting materials were
examined (Table 1, entries 1–5). The yield of improved to 96% with a ratio of 1:8 or 1:10 (Table 1,
1:2
3
1:2
entries 1–2). This result really encouraged us and extensive exploration of the conditions was further
carried out. When the reaction temperature was dropped from 120 ◦C to 80 ◦C, 70% and 30% of the
desired product
3 were obtained respectively (Table 1, entries 6–7). Subsequent solvent screening
suggested that N,N-dimethylformamide (DMF) was the optimal one with 1,4-diphenylbutadiyne
1
(1 mmol) and benzylamine
2 (8 mmol) catalyzed by K2CO3 (0.5 mmol), and the desired product 3 was
obtained in 99% isolated yield without any byproducts at 140 ◦C under air. It is worth noting that
the reaction could proceed without a base, also as a catalyst, rendering the desired product in 38%
isolated yield (Table 1, entry 11), which demonstrated that the yield of desired product
3 depends on
the catalytic activity of the base. To demonstrate the catalytic value of a variety of bases, the synthetic
reactions of 2,3,6-triphenylpyridine between 1,4-diphenylbutadi◦yne
1 (1 mmol) and benzylamine 2
(8 mmol) were carried out in DMF using different bases at 140 C for 10 h with 0.5 mmol catalyst
loading under air (Table 1, entries 12–20). The almost quantitative yield (99%) was obtained by using
K2CO3 as the catalyst (Table 1, entry 8). Use of other bases, such as Na2CO3, NaOH, KOH and KHCO3
also gave good yields (Table 1, entries 13–15, 17). Under similar reaction conditions, Cs2CO3, NaF,
NaH2PO4, KH2PO4 and CH3COONa afforded only moderate yield (Table 1, entries 12, 16, 18–20).
These resultsindicate that K2CO3 is very effective in promoting the synthesis of arylated pyridines
from conjugated acetylenes and substituted benzylamines under facile conditions.
Table 1. Optimization of the reaction conditions a.
Yield(%) b
Entry
Ratio of 1:2 Temperature
Solvent
Catalyst
◦
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1:10
1:8
1:6
1:5
1:4
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
1:8
140
140
140
140
140
120
80
140
140
140
140
140
140
140
140
140
140
140
140
140
C
C
C
C
C
C
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMAc
PEG400
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
_
96
96
85
80
70
70
30
99
94
50
38
65
81
86
88
65
87
53
61
63
◦
◦
◦
◦
◦
◦
C
◦
◦
◦
◦
◦
◦
◦
◦
◦
◦
◦
◦
◦
C
C
C
C
C
C
C
C
C
C
C
C
C
Cs2CO3
Na2CO3
NaOH
KOH
NaF
NaHCO3
NaH2PO4
KH2PO4
CH3COONa
a The reactions were conducted with 1,4-diphenylbutadiyne and benzylamine, and base (0.5 mmol), solvent (0.5 mL),
10 h; b Isolated yield.
Under the optimized reaction conditions, the scope of this synthetic protocol was evaluated
to test the compatibility of varying symmetrical 1,4-diarylbuta-1,3-diynes as starting materials
(Table 2). The 1,4-diarylbuta-1,3-diyne bearing two methyl groups at the 1- and 4-position was

Molecules 2017, 22, 1277
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easily converted to give the desired products with excellent yield (90%) in the synthesis of arylated
pyridines using benzylamine (3cbb). However, 1,4-bis(4-butylphenyl)buta-1,3-diyne was slightly
less reactive, giving the desired product with 60% yield under the same conditions, and this result
clearly demonstrated that steric hindrance has an effect on the yield of desired product (3cfb).
The reaction using sterically hindered 1,4-di-o-tolylbuta-1,3-diyne and 1,4-di-m-tolylbuta-1,3-diyne
led to 77% and 78% yields, respectively (3ccb, 3cdb).Investigations of substituted benzylamines in
the synthesis of arylated pyridines using 1,4-diphenylbutadiyne were also conducted. The reaction
with substituted benzylamine having an electron-donating group was carried out efficiently, affording
almost quantitative yield (99%) (3cac).Various substituted benzylamines bearing electron-withdrawing
groups, such as -F, -Cl, and -CF3, provided the corresponding products in moderate to good yields
(3cad, 3cae, 3caf). The steric and electronic effects of the substrate bearing electron-withdrawing
substituent in the 3-position of benzylamine remarkably affected the reaction yield: upon using
[3-(trifluoromethyl)phenyl]methanamine, product 3,6-diphenyl-2-[3-(trifluoromethyl)phenyl]pyridine
was obtained in 50% yield (3caf).
Table 2. Synthesis of arylated pyridines from conjugated acetylenes and substituted benzylamines
a
under optimized conditions.
NH2
R1
K CO /DMF
R1
2
3
N
+
140 0C/10 h
R1
R1
R2
R2
1a
2b
3c
Yield(%) b
Entry
Acetylene
Benzylamine
Product
N
NH2
1
2
99
3cab
N
NH2
99
73
3cac
N
NH2
3
4
F
F
3cad
N
NH2
62
50
Cl
Cl
3cae
N
NH2
5
CF3
CF3
3caf

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Table 2. Cont.
Benzylamine
Yield(%) b
Entry
Acetylene
Product
N
NH2
6
90
3cbb
N
NH2
7
8
9
99
77
78
3cbc
N
NH2
3ccb
N
NH2
3cdb
N
NH2
10
63
F
F
3ccd
N
NH2
11
12
65
45
3cec
3ced
N
NH2
F
F
N
NH2
13
14
48
60
Cl
Cl
3cee
4
4
4
N
NH2
4
3cfb
a
Reaction conditions: conjugated acetylene (1a) (0.25 mmol), substituted benzylamine (2b) (2.0 mmol), K2CO3
(0.5 mmol), DMF (0.5 mL), 140 ◦C, 10 h; b Isolated yield.

Molecules 2017, 22, 1277
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3. Materials and Methods
3.1. General Conditions
All manipulations were performed under air. All reagents employed in the synthesis were
analytical grade, purchased from J&K Scientific Ltd. (Shanghai, China) and used as received without
any prior purification. The products were isolated by thin layer chromatography on silica gel using
petroleum ether as the eluent. 1H-NMR, 13C-NMR spectra were recorded on a Bruker Avance III
(400 MHz, Bruker Corporation, Billerica, MA, USA) spectrometer using tetramethylsilane as the
internal standard and CDCl3 as the solvent. Chemical shift values are expressed in ppm relative to
external TMS (see Supplementary).
3.2. General Procedure for the Preparation of Arylated Pyridines
1,4-Disubstituted-1,3-diacetylene (0.25 mmol) and K2CO3 (0.5 mmol) were added, under air, to
◦
a solution of appropriate benzylamine (2.0 mmol) in DMSO (0.5 mL) previously heated at 140 C.
The resulting solution was stirred for 10 h at this temperature and washed with saturated aqNaCl,
extracted with ethyl acetate (3
Na2SO4, filtrated and concentrated under vacuum to yield the crude product. The crude product was
purified by thin layer chromatography on silica gel with petroleum ether as eluent.
×
15 mL). The combined organic phase was dried with anhydrous
3.3. Analytical Data of Representative Products
2,3,6-Triphenylpyridine: White crystals (m.p. = 110–111 ◦C, lit [24] 110.5–112 ◦C, lit [25] 111–112 ◦C).
1H-NMR (400 MHz, CDCl3) 8.20 (d, 2H), 7.98–7.75 (m, 2H), 7.50 (dq, 5H), 7.30 (ddd, 8H).13C-NMR
δ
(101 MHz, CDCl3)
128.37, 127.84, 127.18, 127.02, 118.59. lit [25]: H-NMR (400MHz, CDCl3)
(m, 2H), 7.51–7.42 (m, 5H), 7.30–7.21 (m, 9H); 13C-NMR (100 MHz, CDCl3) δ 156.6, 155.6, 140.4, 140.0,
139.4, 139.1, 134.4, 130.2, 129.5, 129.0, 128.7, 128.3, 127.8, 127.1, 127.0, 118.5. HRMS (EI) calcd. for
C23H17N: 307.1361, found: 307.2.
δ
156.64, 155.68, 140.43, 140.01, 139.43, 139.10, 134.43, 130.23, 129.59, 129.01, 128.75,
1
δ 8.16–8.14 (m, 2H), 7.78–7.77
2-(4-Fluorophenyl)-3,6-diphenylpyridine: White solid (m.p. = 115–117 ◦C, lit [22] 115–116 ◦C). 1H-NMR
(400 MHz, CDCl3)
2H). 13C-NMR (101 MHz, CDCl3)
134.31 (JC−F = 4.3 Hz), 132.06, 131.97 (JC−F = 8.2 Hz), 129.55, 129.13, 128.82, 128.53, 127.34, 126.99,
8.13 (d, 2H), 7.77 (s, 2H),
δ
8.19 (d, 2H), 7.82 (d, 2H), 7.52 (dd, 5H), 7.32 (d, 3H), 7.27 (d, 2H), 7.01 (d,
δ
162.53 (JC−F = 245.6 Hz), 155.73, 155.53, 139.81, 139.56, 138.95,
118.70, 114.74(JC−F = 21.5 Hz). lit [22]: 1H-NMR (400 MHz, CDCl3):
δ
7.51–7.42 (m, 5H), 7.31–7.29 (m, 3H), 7.22–7.20 (m, 2H), 6.94 (t, 2H); 13C-NMR (100 MHz, CDCl3): 162.5
(JC−F = 245.6 Hz), 155.7, 155.5, 139.8, 139.5, 138.9, 136.4 (JC−F = 4.3 Hz), 134.2, 131.9 (JC−F = 8.2 Hz),
129.5, 129.0, 128.7, 128.4, 127.2, 126.9, 118.6, 114.7 (JC−F = 21.5Hz). HRMS (EI) calcd. for C23H16FN:
325.1267, found: 325.2.
4. Conclusions
In summary, an efficient protocol for arylated pyridines from conjugated acetylenes and
substituted benzylamines catalyzed by base was developed, which gives a much more convenient
approach to obtain arylated pyridines with good to excellent yields. Compared to the approachreported
by Chalk [21], the advantages of this protocol are inthe absence ofbyproduct detected by GC-MS even
if the reaction was carried out in the air. Efforts to understand this reaction mechanism are in progress
in our laboratory.
Supplementary Materials: Supplementary materials are available online.
Acknowledgments: This research was financially supported by the National Natural Science Foundation of
China (No. 21363026), the Scientific and Technological Landing Project of Higher Education of Jiangxi Province
(No. KJLD13091).

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Author Contributions: M.G. and Q.Z. conceived and designed the experiments; B.C. performed the experiments;
M.G., H.J., Q.P. and Y.K. analyzed the data and contributed with different analysis tools; finally, M.G. and B.C.
wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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