A facile one-pot synthesis of 2,4,6-triarylpyridine in DMSO

Article abstract of DOI:10.14233/ajchem.2014.16841

A facile, efficient and practical method for the one-pot synthesis of 2,4,6-triarylpyridines starting from acetophenones, aryl aldehydes and ammonium acetate by the use of catalytic amounts of 40 % potassium hydroxide in dimethyl sulfoxide is presented. T

Full text of DOI:10.14233/ajchem.2014.16841

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 7977-7980
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16841
A Facile One-Pot Synthesis of 2,4,6-Triarylpyridine in DMSO
*
ZHEN-LI MIN , TING-ZI YIN and XIA-MIN HU
Department of Pharmacology, Medical College of Wuhan University of Science and Technology, Wuhan 430080, P.R. China
*Corresponding author: Tel: +86 27 68893640; E-mail: mchust@126.com
Received: 9 December 2013;
Accepted: 9 April 2014;
Published online: 15 November 2014;
AJC-16276
A facile, efficient and practical method for the one-pot synthesis of 2,4,6-triarylpyridines starting from acetophenones, aryl aldehydes and
ammonium acetate by the use of catalytic amounts of 40 % potassium hydroxide in dimethyl sulfoxide is presented. The present methodology
offers attractive features such as the ease of workup, short reaction time and good yields of the products and it does not need any complex
catalyst.
Keywords: One-pot reaction, Multi-component reaction, 2,4,6-Triaryl pyridine, Dimethyl sulfoxide.
the key intermediate which is produced by an Aldo conden-
sation of acetophenones with aryl aldehydes to form the
corresponding Aldo product, then the product further under-
goes a Michael addition reaction with another molecule of
acetophenone10. Then, the 1,5-diketone with insertion of
nitrogen atom is cyclized to dihydropyridine which on aroma-
tization and oxidation leads to pyridine. The highly dipolar
aprotic media have a profound rate accelerating on certain
aldol reactions and recently dimethyl sulfoxide as a solvent
has been reported to improving the reaction rates and yields
of the products in someAldol and Michael addition reactions11.
This background prompted us to attempt the synthesis of 2,4,6-
triaryl pyridine in DMSO. Herein, we would like to report a
new, efficient and practical one-pot three-component reaction
with a variety of aromatic aldehydes, acetophenones and
ammonium acetate in DMSO for the preparation of 2,4,6-
triarylpyridines (Scheme-I).
INTRODUCTION
Pyridine ring system, particularly 2,4,6-triarylpyridine,
is of considerable interest as it is usually the skeletal moiety
in a wide range of important compounds with biological
activities such as antimalerial1 and antitumor2. In addition,
some of 2,4,6-triaryl pyridines were used as synthons in
supramolecular chemistry due to their π-stacking ability along
with directional H-bonding capacity3 and these pyridines have
also instigated a growing interest for their use as monomeric
building blocks in thin films and organometallic polymers4.
Therefore, the syntheses of 2,4,6-triarylpyridines have gained
significant attentions of chemists and many preparing protocols
from different start materials have been proposed5.
In recent years, one-pot multi-component reactions (MCRs)
as well as domino reactions6 has been widely used to produce
many biologically active compounds because of their synthetic
efficiency, intrinsic atom economy and procedural simplicity
to construct highly complex molecules. A few one-pot multi-
component reactions for the syntheses of 2,4,6-triarylpyridines
between acetophenones, aryl aldehydes and ammonium acetate
have been described. The reaction proceeded under different
conditions, such as microwave irradiation7, ionic liquid
mediated synthesis8, catalyzed by Preyssler type heteropoly
acid H14[NaP5W30O110], bismuth triflate9. However, these proto-
cols are having one or more drawbacks such as long reaction
time, expensive catalyst and special care in handling. Thus,
there is still a need to develop efficient and practical methods
for the synthesis of 2,4,6-triaryl pyridine.
EXPERIMENTAL
All reagents were purchased from commercial suppliers
and used without further purification. Compound 4 was
synthesized according to the literature method12. Dimethyl
sulfoxide was freshly distilled at reduced pressure from calcium
hydride.All melting points were determined on a Mel-TEMP-
II melting point apparatus which was uncorrected. IR spectra
were recorded on a Bruker VERTEX 70 instruments. Proton
magnetic resonance spectra were recorded on a BrukerAV400
instrument. The spectra were recorded in CDCl3 and chemical
shifts are reported in parts per million (ppm) down field from
tetramethyl silane (TMS) as the internal standard. Mass spectra
were recorded on an Agilent 1100 LC/MSD Trap.
In preparation of 2,4,6-triaryl pyridine through the one-
pot multi-component reaction, 1,5-diketone is believed to be

7978 Min et al.
Asian J. Chem.
Ar1
O
O
40%KOH/DMSO
80 °C,2-3h
NH4OAc
Ar2
Ar1
H
Ar2
N
3a-3e
Ar2
1
2
N N
O
N
40%KOH/DMSO
80 °C,2-3h
Cl
NH4OAc
N
Ar2
CHO
Cl
Ar2
N
5a-5g
Ar2
2
Scheme-I: One-pot syntheses of 2,4,6-triarylpyridine
4
General procedure for preparation of 3a-e and 5a-g:
To a solution of benzaldehyde or compound 4 (0.88 g, 4 mmol)
dissolved in dimethyl sulfoxide (20 mL) were added aceto-
phenone (2) (0.93 mL, 8 mmol) and 40 % KOH solution (0.25
mL). The mixture was stirred at room temperature for 10-30
min. Thereafter, NH4OAc (2 g, 26 mmol) was added and the
solution stirred at 80 °C for 1.8-2.5 h. On completion of the
reaction (TLC), the reaction mixture was cooled at room tempe-
rature and poured into ice cold water (100 mL). The resultant
solid was filtered, washed with ice cold water (50 mL) and
recrystallization from ethanol or chromatograph on silica gel
to give the corresponding products 3a-e and 5a-g.
CDCl3) δ: 2.35 (s, 6H, 2CH3), 7.10 (d, 4H, J = 7.7 Hz, ArH),
7.21 (s, 2H, ArH), 7.58 (t, 3H, J = 7.5 Hz, ArH), 8.18 (d, 2H,
J = 7.8 Hz, ArH), 8.36 (d, 4H, J = 7.6 Hz, ArH); ESI-MS: 336
[M + H]+.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6-
diphenylpyridine (5a): IR (KBr, νmax, cm-1): 3030, 1601, 1549,
998; 1H NMR (400 MHz, CDCl3) δ: 2.50 (s, 3H, CH3), 7.47 (t,
J = 6.6 Hz, 3H, ArH), 7.53 (t, J = 7.2 Hz, 6H, ArH), 7.62 (d,
2H, J = 7.6 Hz, ArH), 7.79 (s, 2H, ArH), 8.18 (d, 4H, J = 7.2
Hz, ArH); 13C NMR (400 MHz, CDCl3) δ: 157.41, 148.09,
141.02, 139.43, 138.12, 129.19, 129.12, 128.79, 128.48,
127.18, 125.71, 125.22, 118.76, 117.41, 13.74; ESI-MS: 422
[M + H]+.
Spectroscopic data of compounds 3a-e and 5a-g
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6-di-
(4-methylphenyl)pyridine (5b): IR (KBr, νmax, cm-1): 3028,
1598, 1069, 864; 1H NMR (400 MHz, CDCl3) δ: 2.43 (s, 6H,
CH3), 2.49 (s, 3H, CH3), 7.31 (d, 4H, J = 8 Hz, ArH), 7.44 (t,
1H, J = 14.4 Hz, ArH), 7.52 (t, 2H, J = 15.2 Hz, ArH), 7.61 (d,
2H, J = 8 Hz, ArH), 7.73 (s, 2H, ArH), 8.08 (d, 4H, J = 8 Hz,
ArH); 13C NMR (400 MHz, CDCl3) δ: 153.71, 151.89, 149.48,
148.19, 140.71, 138.12, 129.11, 128.44, 125.63, 125.23,
117.33, 115.80, 110.54, 108.41, 13.98, 13.58; ESI-MS: 450
[M + H]+.
2,4,6-Triphenylpyridine (3a): IR (KBr, νmax, cm-1): 1592,
1
1542, 1033, 871; H NMR (400 MHz, CDCl3) δ: 7.23-7.29
(m, 1H, Ar), 7.51-7.55 (m, 2H, ArH), 7.57-7.62 (m, 2H, ArH),
8.04 (d, 2H, J = 7.4 Hz, ArH), 8.06-8.10 (m, 4H, ArH), 8.33 (s,
2H, ArH), 8.37 (d, 4H, J = 7.6 Hz,ArH); ESI-MS: 308 [M + H]+.
4-(4-Methoxyphenyl)-2,6-diphenylpyridine (3b): IR
(KBr, νmax, cm-1): 3035, 2936, 1596, 1037; 1H NMR (400 MHz,
CDCl3) δ: 3.82 (s, 3H, CH3), 7.1 (d, 2H, J = 7.1 Hz, ArH),
7.48 (d, 2H, J = 7.3 Hz, ArH), 7.50 (t, 4H, J = 6.8 Hz, ArH),
7.61 (t, 4H, J = 6.8 Hz, ArH), 8.03 (d, 2H, J = 7.1 Hz, ArH),
8.14 (s, 2H, ArH), 8.30 (d, 2H, J = 7.3 Hz, ArH), 8.38 (d, 2H,
J = 7.6 Hz, ArH); ESI-MS: 338 [M + H]+.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6-di-
(4-methoxyphenyl)pyridine (5c): IR (KBr, νmax, cm-1): 3032,
1601, 1499, 870; 1H NMR (400 MHz, CDCl3) δ: 2.48 (s, 3H,
CH3), 3.88 (s, 6H, OCH3), 7.04 (d, 4H, J = 7.2 Hz, ArH), 7.43-
7.53 (m, 3H, ArH), 7.62 (d, 2H, J = 7.6 Hz, ArH), 7.66 (s, 2H,
4-(4-Nitrophenyl)-2,6-diphenylpyridine (3c): IR (KBr,
1
νmax, cm-1): 1590, 1540,1380, 1100; H NMR (400 MHz,
13
CDCl3) δ: 7.20-7.66 (6H, m, ArH), 7.85 (2H, s, ArH), 7.87
(2H, d, J = 9 Hz, ArH), 8.08-8.25 (4H, m, ArH), 8.36 (2H, d,
J = 9 Hz, ArH). ESI-MS: 351[M + H]+.
ArH), 8.14 (d, 4H, J = 7.2 Hz, ArH); C NMR (400 MHz,
CDCl3) δ: 160.63, 156.82, 148.14, 140.77, 138.16, 132.23,
129.54, 128.59, 128.47, 128.42, 126.60, 125.56, 125.23,
117.66, 117.43, 114.12, 113.90, 55.40, 13.67; ESI-MS: 482
[M + H]+.
4-Phenyl-2,6-di-(4-chlorophenyl)pyridine (3d): IR
(KBr, νmax, cm-1): 1598, 1544, 1012, 869; 1H NMR (400 MHz,
CDCl3) δ: 7.50-7.61 (m, 7H, ArH), 8.04 (d, 2H, J = 7.7Hz,
ArH) 8.23 (s, 2H, ArH), 8.33 (d, 2H, J = 7.5Hz, ArH), 8.42 (d,
2H, J = 7.6 Hz, ArH); ESI-MS: 377 [M + H]+.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6- di-
(4-ethoxyphenyl)pyridine (5d): IR (KBr, νmax, cm-1): 3031,
1604, 1492, 874; 1H NMR (400 MHz, CDCl3) δ: 1.46 (t, 6H,
J = 10.8 Hz, OCH2CH3), 2.49 (s, 3H, CH3), 4.11 (q, 4H, J = 4
Hz, OCH2CH3), 7.03 (d, 4H, J = 8 Hz, ArH), 7.37-7.53 (m,
4-Phenyl-2,6-di-(4-methylphenyl)pyridine (3e): IR
(KBr, νmax, cm-1): 3063, 1587, 1554, 867; 1H NMR (400 MHz,

Vol. 26, No. 23 (2014)
A Facile One-Pot Synthesis of 2,4,6-Triarylpyridine in DMSO 7979
3H, ArH), 7.62 (d, 2H, J = 7.6 Hz, ArH), 7.66 (s, 2H, ArH),
8.12 (d, 4H, J = 8 Hz, ArH); 13C NMR (400 MHz, CDCl3) δ:
160, 156.81, 148.13, 140.76, 138.15, 131.91, 129.11, 128.45,
128.40, 125.55, 117.77, 117.37, 63.56, 14.85, 13.66; ESI-MS:
510 [M + H]+.
base. In accordance with the aforementioned mechanism, this
step involves an Aldo condensation and a Michael addition,
the intermediate 1,3,5-triphenylpentane-1,5-dione was isolated
and the structure was confirmed.
The reaction was initially performed using NaOH pellet
and KOH pellet at room temp. But, even after stirring for 40
min, it was incomplete and only poor yield of intermediate
product was obtained. Changing the base to 10 % aq KOH
caused some improvement in the yields. When the reaction
was carried out under 40 % KOH condition, it proceeded quickly
and was completed in 15 min. After that, excess NH4OAc was
added and the solution was stirred at 80 °C for 2 h. To optimize
the reaction temperature, a series of reactions were carried
out at temperatures ranging from 60 to 110 °C in an increment
of 10 °C each time, the better yields are obtained at 80 °C,
further increase in temperature was found to have an inhibitory
effect on formation of the product.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6- di-
(3,4-dimethylphenyl)pyridine (5e): IR (KBr, νmax, cm-1):
3029, 1602, 1545, 873; 1H NMR (400 MHz, CDCl3) δ: 2.38
(s, 6H, CH3Ph), 2.43 (s, 6H, CH3Ph), 2.52 (s, 3H, CH3), 7.31
(d, 2H, J = 8 Hz, ArH), 7.47-7.57 (m, 3H, ArH), 7.66 (d, 2H,
J = 7.6 Hz, ArH), 7.74 (s, 2H, ArH), 7.92 (d, 2H, J = 7.2 Hz,
ArH), 7.99 (s, 2H, ArH); 13C NMR (400 MHz, CDCl3) δ:
157.51, 148.15, 140.66, 138.16, 137.74, 137.24, 136.89,
130.03, 129.11, 128.44, 128.37, 125.58, 125.23, 124.61,
118.37, 117.66, 20.02, 19.67, 13.64; ESI-MS: 478 [M + H]+.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6-di-
(3,4-methylenedioxyphenyl)pyridine (5f): IR (KBr, νmax, cm-1)
δ: 3032, 1603, 1498, 875; 1H NMR (400 MHz, CDCl3): 2.48
(s, 3H, CH3), 6.02 (s, 4H, OCH2O), 6.93 (d, 2H, J = 8 Hz,
ArH), 7.45 (t, 1H, J = 14.8 Hz, ArH), 7.53 (t, 2H, J = 15.6 Hz,
ArH), 7.60-7.66 (m, 6H, ArH) 7.72 (d, 2H, J = 7.2 Hz, ArH);
13C NMR (400 MHz, CDCl3) δ: 156.42, 150.33, 148.62,
147.53, 144.18, 138.78, 129.72, 128.85, 128.36, 126.67,
125.48, 120.79, 120.21, 118.57, 115.36, 112.98, 101.65, 13.61;
ESI-MS: 510 [M + H]+.
After establishing the reaction conditions, various alde-
hydes were treated with acetophenones to investigate the reaction
scope. Giving the importance of imidazole in medicinal
chemistry, 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbal-
dehyde (4) was chosen to take place of benzaldehyde to synthe-
size a serial of 2,4,6-triarylpyridine bearing imidazole moiety.
The results are summarized in Table-1. All the reactions were
completed in 2-3 h in good to high yields. The first step was
completed in 10-30 min (Time 1 in Table-1) depending on the
reactants. The nature of the substituents on the aromatic ring
showed obvious effects on this conversion, it would take less
time for the electron-withdraw substituent than the electron-
donating one (Entry 3c and 3e). The reaction time for the
second step (Time 2 in Table-1) did not show significant diffe-
rences. The steric nature of substituents on the aromatic ring
of acetophenones affected the yields of the product. As com-
pared with compounds 5a, 5f with more steric group was
associated with lower yield.
4-(5-Chloro-3-methyl-1-phenylpyrazole-4-yl)-2,6-di-
[2-(5-methyl)furyl]pyridine (5g): IR (KBr, νmax, cm-1): 3030,
1606, 1527, 872; 1H NMR (400 MHz, CDCl3) δ: 2.42 (s, 6H,
furyl-CH3), 2.47 (s, 3H, pyrazolyl-CH3), 6.15 (d, 2H, J = 2.8
Hz, furyl-H), 7.11 (d, 2H, J = 2.8 Hz, furyl-H), 7.44 (t, 1H,
J = 14.8 Hz, ArH), 7.50-7.55 (m, 4H, ArH), 7.60 (d, 2H, J = 8
Hz, ArH); 13C NMR (400 MHz, CDCl3): 153.71, 151.89,
149.48, 148.19, 140.71, 138.12, 129.11, 128.44, 125.63,
125.23, 117.33, 115.80, 110.54, 108.41, 13.98, 13.8; ESI-MS:
430 [M + H]+.
From the environmental point of view, DMSO is not an
ideal solvent for the organic syntheses. But, as compared with
the method mentioned above, this method doesn't need harsh
reaction condition, complexly catalyst and it can shorten
reaction time with some other advantages such as the ease of
workup and good yields of the products. It provides a prac-
tically synthetical way for the exploration of the bioactivities
of 2,4,6-triarylpyridine derivatives.
RESULTS AND DISCUSSION
Firstly, benzaldehyde was chosen as a model for the
reaction condition optimization and it was treated with 2 equi-
valents of acetophenone in DMSO as solvent, then a catalytic
amount of strong base was added. The mixture was stirred
at room temp for a few minutes as monitored by TLC. The
reaction was completed in a few minutes depending on the
TABLE-1
SYNTHESIS OF 2,4,6-TRIARYLPYRIDINE IN DMSO
Entry
Ar1
r2
Time 1 (min)
Time 2 (h)
Yielda (%)
m.p. (°C)
Ph
Ph
15
18
10
15
20
15
22
20
20
25
30
20
2.0
2.2
1.8
2.0
2.2
2.0
2.2
2.3
2.3
2.5
2.5
2.5
80
85
70
75
82
90
92
89
86
78
63
72
133-134 (1309a)
99-100 (989a)
187(184-1869a)
179-181 (175-1789b)
143-145 (1409a)
141-142
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
5f
4-MeO-Ph
Ph
4-NO2-Ph
Ph
Ph
Ph
--
4-Cl-Ph
4-Me-Ph
Ph
--
4-Me-Ph
119-121
--
4-MeO-Ph
158-160
--
4-C2H5O-Ph
143-144
--
3,4-(CH3)2-Ph
3,4-O-CH2-O-Ph
2-(5-Methyl)furyl
150
--
196-197
166
--
5g
aIsolated yields based on aromatic aldehyde

7980 Min et al.
Asian J. Chem.
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Conclusion
In summary, a facile, efficient and practical method is
4. P.V. Shinde, V.B. Labade, J.B. Gujar, B.B. Shingate and M.S. Shingare,
Tetrahedron Lett., 53, 1523 (2012).
demonstrated for the one-pot synthesis of 2,4,6-triaryl-
pyridines between acetophenones, aryl aldehydes and ammo-
nium acetate by the use of catalytic amounts of 40 % potassium
hydroxide in dimethyl sulfoxide.
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