Solvent-free, one-pot synthesis of 2,4,6-triarylpyridines using trichloroisocyanuric acid or N-bromosuccinimide as a novel and neutral catalyst

Article abstract of DOI:10.1135/cccc2011021

A simple and benign protocol has been explored for the preparation of 2,4,6-triarylpyridines by a one-pot reaction between aryl aldehydes, enolizable ketones and ammonium acetate in the presence of N-bromosuccinimide or trichloroisocyanuric acid as green and neutral catalysts. The reactions proceed smoothly at 130 °C under solvent-free conditions to provide 2,4,6-triarylpyridines in good yields.

Full text of DOI:10.1135/cccc2011021

One-Pot Synthesis of 2,4,6-Triarylpyridines
1307
SOLVENT-FREE, ONE-POT SYNTHESIS OF 2,4,6-TRIARYLPYRIDINES
USING TRICHLOROISOCYANURIC ACID OR N-BROMOSUCCINIMIDE
AS A NOVEL AND NEUTRAL CATALYST
1,
2
3
Behrooz MALEKI *, Hafezeh SALEHABADI , Zeinalabedin SEPEHR and
4
Mina KERMANIAN
Department of Chemistry, Sabzevar Tarbiat Moallem University, 397 Sabzevar, Iran;
1
2
3
e-mail: maleki@sttu.ac.ir, hafezeh_s6245@yahoo.com, szeinalabedin@yahoo.com,
4
m_kermaniyan@yahoo.com
Received January 26, 2011
Accepted June 3, 2011
Published online October 30, 2011
A simple and benign protocol has been explored for the preparation of 2,4,6-triarylpyridines
by a one-pot reaction between aryl aldehydes, enolizable ketones and ammonium acetate in
the presence of N-bromosuccinimide or trichloroisocyanuric acid as green and neutral cata-
lysts. The reactions proceed smoothly at 130 °C under solvent-free conditions to provide
2,4,6-triarylpyridines in good yields.
Keywords: 2,4,6-Triarylpyridines; Aldehydes; Ketones; Ammonium acetate; N-Bromosuccin-
imide; Trichloroisocyanuric acid; Green chemistry.
In the past few decades, the synthesis of new heterocyclic compounds has
been a subject of great interest due to their wide range applicability. Hetero-
cyclic compounds occur very widely in nature and are essential to life.
Among a large variety of heterocyclic compounds, heterocycles containing
the pyridine moiety receive much interest1–3. 2,4,6-Triarylpyridines known
as Krohnke pyridines are considered as prominent building blocks in supra-
molecular chemistry4. Many naturally occurring derivatives of these com-
pounds such as NAD nucleotides, pyridoxol (vitamin B6), and pyridine
alkaloids posses important biological properties5. In addition, many of
these compounds have been reported in medicinal and pharmaceutical lit-
erature as antimalarial, anticonvulsant, anesthetic, antiinflammatorial, an-
tioxidant, antibacterial, and antiparasitic agents6–10. Also, a number of
2,4,6-triarylpyridines are known as luminescence compounds11.
Hence, in view of their wide range applications as pharmaceutical and in-
dustrial agents as well as in organic synthesis, a good number of methods
have been developed for the synthesis of Krohnke type pyridines12. Tradi-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 11, pp. 1307–1315
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011021

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Maleki, Salehabadi, Sepehr, Kermanian:
tionally, Krohnke-type pyridines have been synthesized through the reac-
tion of N-phenacylpyridinium salts with α,β-unsaturated ketones in the
presence of ammonium acetate12,13. The same compounds have also been
synthesized via condensation reaction of 1,5-diketones with formamide-
ammonium formate14 and by other synthetic procedures12.
More recently, one-pot syntheses of 2,4,6-triarylpyridines by three-
component condensation between aromatic ketones, aldehydes, and am-
monium acetate have been reported15–26. However, many of the previously
established methods are subject to certain disadvantages including multi-
step procedures, use of costly and toxic catalysts, acidic media and organic
solvents. To avoid such drawbacks, development of more simple, inexpen-
sive, environmentally benign and efficient protocols are still in demand.
RESULTS AND DISCUSSION
In recent years, solvent-free organic reactions27 have caused great interests,
because they have many advantages such as high efficiency and selectivity,
very facile separation and purification, mild reaction conditions, and bene-
ficial to industry as well as for environment. In continuation of our ongo-
ing endeavour on the application of heterogeneous and solvent-free
conditions for the synthesis of organic compounds28. Herein, we describe a
practical and simple method to prepare 2,4,6-triarylpyridines by a three-
component condensation of aromatic ketones or aldehydes with ammoni-
um acetate under solvent-free conditions at 130 °C using N-bromosuccin-
imide (NBS) or trichloroisocyanuric acid (TCCA) as catalysts (Scheme 1).
SCHEME 1
We have previously examined NBS and TCCA as efficient catalysts in our
various reported transformations29. To the best of our knowledge, the appli-
cation of TCCA and NBS as catalysts in the synthesis of the title com-
pounds has not been previously explored.
Trichloroisocyanuric acid (TCCA) is an inexpensive, eco-friendly and ver-
satile reagent which has been used in the synthesis of various organic com-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 11, pp. 1307–1315

One-Pot Synthesis of 2,4,6-Triarylpyridines
1309
pounds. This compound has been reported to effectively promote many
transformations including the synthesis of benzimidazoles30, oxidation of
urazoles31, synthesis of 1,8-dioxooctahydroxanthenes32, synthesis of 2-aryl-
benzothiazoles and bisbenzothiazoles33, and chemoselective dehydration of
2-imidazolines34. It has been also employed in the synthesis of unsymmet-
rical 2,5-disubstituted 1,3,4-oxadiazoles35.
In order to optimize the reaction conditions, effects of catalyst concentra-
tion and reaction temperature were investigated in the synthesis of 2,4,6-
triphenylpyridine (3a) as the model reaction. A mixture of benzaldehyde
(1 mmol), acetophenone (2 mmol) and ammonium acetate (1.3 mmol) was
stirred under various reaction conditions and the resulting data are summa-
rized in Table I. The role of TCCA as a catalyst was evaluated by conducting
the reaction in the absence of TCCA and no formation of the respective
product was noticed after 6 h (entry 1), while good yields were obtained in
the presence of TCCA (entries 2–8). The most effective amount of TCCA to
promote this reaction was found to be 2 mole %, which brings the forma-
tion of the products in highest possible yields (entry 3). The effect of tem-
perature on the reaction was also studied by carrying out the model
reaction in the presence of TCCA (2 mole %) at various temperatures such
as 100, 110, 120, 130, and 140 °C. Among these, 130 °C was found to be
the temperature of choice in terms of yields.
TABLE I
Optimizing the reaction conditions
Entry
Catalyst, mole%
Temperature, °C
Time, h
Yield, %a
1
2
3
4
5
6
7
8
9b
–
120
110
110
110
100
120
130
140
80
5
–
1
2
5
2
2
2
2
2
4
42
64
62
60
70
82
74
24
4
4
4.5
4
4
4
3
a
b
Isolated yield. The reaction was carried out under reflux in EtOH.
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Maleki, Salehabadi, Sepehr, Kermanian:
To develop the scope of reaction, a wide range of aldehydes and ketones
was subjected to TCCA-catalyzed reaction under the optimized conditions
(Table II). In all cases, aromatic aldehydes with substituents carrying either
electron-donating or electron-withdrawing groups reacted successfully and
gave the products in good yields. It was founds that aromatic aldehydes
TABLE II
NBS or TCCA-catalyzed solvent-free synthesis of 2,4,6-triarylpyridines
M.p., °C
Time, h
Yield, %c
I (II)
Productsa
Ar1
Ar2
I (II)b
Found
Reporteda
3a
3b
3c
3d
3e
3f
C6H5
C6H5
C6H5
3.5 (4)
4 (4.5)
88 (82)
82 (64)
66 (52)
78 (64)
72 (54)
82 (68)
86 (62)
80 (62)
84 (72)
88 (74)
88 (70)
74 (60)
76 (64)
84 (62)
88 (70)
90 (76)
92 (82)
90 (80)
82 (80)
132–134
120–122
153–155
178–179
195–196
119–120
152–154
136–138
198–200
112–114
99–100
134–135
122–124
159–160
176–177
197
4-ClC6H4
C6H5
4-CH3C6H4 4 (5)
4-CH3C6H4 4 (5)
4-CH3C6H4
4-OHC6H4
2-CH3C6H4
4-MeOC6H4
C6H5
C6H5
5 (6)
3.5 (5)
120–122
155–157
138–140
199–201
115–116
100–103
165–166
113–114
168–170
166–167
198–200
–
3g
3h
3i
4-CH3C6H4 4 (5)
3 (3.5)
4-N(CH3)C6H4 C6H5
4-ClC6H4
4-ClC6H4
4-MeOC6H4
2-Furyl
4-CH3C6H4 4.5 (6)
4-MeOC6H4 3.5 (5)
3j
3k
3l
C6H5
3 (4.5)
4 (4.5)
3.5 (4)
4 (5)
C6H5
164–165
114–116
172–174
164–166
196–198
248–250
228–230
192–194
3m
3n
3o
3p
3q
3r
2-ClC6H4
2-Thienyl
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-BrC6H4
C6H5
C6H5
C6H5
4 (5)
C6H5
2.5 (3)
2 (3)
4-FC6H4
4-FC6H4
4-FC6H4
2 (3)
–
3s
3 (3.5)
–
a
All isolated products were characterized on the basis of their physical properties and IR, 1H
b
NMR spectral analysis and by direct comparision with authentic materials. The reaction
c
time and yields obtained by trichloroisocyanuric acid are given in parentheses. Isolated
yields. Literature data: 3a–3e10, 3f–3n5, 3o12, 3p24
.
d
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One-Pot Synthesis of 2,4,6-Triarylpyridines
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with electron-withdrawing groups reacted faster than those with electron-
donating groups, as would be expected.
However, despite many advantages allocated to TCCA as a catalyst, the
reactions proceeded with longer times and low yields. In view of these
drawbacks, we were prompted to examine the catalytic capacity of NBS in
the synthesis of 2,4,6-triarylpyridines owing to its previously reported suc-
cessful applications in various organic reactions36.
In our ongoing research on the use of NBS in various transforma-
tions29c,29d, it was found to efficiently catalyze the one-pot synthesis of
2,4,6-triarylpyridines from aldehydes and ketones. We first studied a reac-
tion between benzaldehyde (1 mmol), acetophenone (2 mmol), and ammo-
nium acetate (1.3 mmol) by screening the reaction conditions. In order to
determine the optimum conditions, we examined the influence of reaction
temperature, reaction time, and amount of the catalyst. We noticed that
the best result was obtained with 10 mole % of NBS at 130 °C. Following
optimizing the conditions, we examined generality of these conditions to
other substrates using several aldehydes and ketones (Table II).
We compared results of NBS with TCCA in the synthesis of 2,4,6-triaryl-
pyridines. As shown in Table II, NBS can act as an effective catalyst for the
mentioned transformation.
Since NBS or TCCA contain Br+ or Cl+ atoms which are attached to nitro-
gen atoms, it is very probable that these reagents release Br+ and Cl+, respec-
tively, in situ which can act preparation of an electrophilic species29–35
.
However, we do not believe that traces of Br+ or Cl+ are catalyzing the reac-
tion36f. One explanation for this process is that TCCA or NBS probably gen-
erates small quantities of HBr or HCl in situ, which may be the actual
catalyst for the synthesis of 2,4,6-triarylpyridines reaction (as a protic acid).
This explanation is supported based on our observations that: (i) When the
reaction of benzaldehyde (1 mmol) with acetophenone (2 mmol) and am-
monium acetate (1.3 mmol) was conducted in the presence of a catalytic
amount of saturated HBr instead of NBS, the reaction rate considerably in-
creased and the reaction was completed within 4.5 h giving 42% yield. This
could be due to the presence of larger amount of HBr in the reaction com-
pared with the small amount of HBr generated from NBS when used as the
catalyst. (ii) In an attempt to synthesis of 2,4,6-triphenylpyridine from this
reaction using TCCA as the catalyst in the presence of Br2, only trace
amount of the product was obtained after 6 h. (iii) The pH of reaction was
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 11, pp. 1307–1315

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Maleki, Salehabadi, Sepehr, Kermanian:
SCHEME 2
measured to be 2.5 proving the presence of an acid. In view of these obser-
vations, we suggest a mechanism for this reaction as shown in Scheme 2.
CONCLUSION
In conclusion, we have developed an efficient and benign procedure for the
synthesis of 2,4,6-triarylpyridines from a one-pot reaction of aldehydes or
ketones, with ammonium acetate in the presence of NBS or TCCA as cata-
lysts. This protocol may be considered as environmentally friendly since no
solvent has been necessarily used in these reactions and the catalysts em-
ployed are regarded as non-polluting reagents.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 11, pp. 1307–1315

One-Pot Synthesis of 2,4,6-Triarylpyridines
1313
EXPERIMENTAL
Solvents, reagents, and chemical materials were obtained from Aldrich (USA), Merck
(Germany) and Fluka (Switzerland) chemical companies and purified prior to use. Melting
points were determined in open capillary tubes in a BI Branstead Electrothermal Cat No.
IA9200 apparatus and are uncorrected. 1H NMR spectra (δ, ppm) were recorded on Jeol FT
NMR 90 MHz using tetramethylsilane (TMS) as an internal standard. IR spectra (ν, cm–1
)
were recorded on a Shimadzu 435-U-04 spectrophotometer (KBr pellets).
Synthesis of 2,4,6-Triarylpyridines. General Procedure
To a stirred mixture of the aldehyde 1a–1o (1 mmol), ketone (2 mmol), and ammonium ace-
tate (1.3 mmol) TCCA (2 mole %) was added at room temperature. The mixture was heated
to 130 °C and the progress of the reaction was followed by TLC. After completion of the re-
action (3–6 h), 96% EtOH (5 ml) was added to the reaction mixture. The mixture was fil-
tered to remove the resulting precipitate, the filtrate was evaporated and the residue was
recrystallized from 96% EtOH (2 × 5 ml) to afford pure 2,4,6-triarylpyridines. In a separate
set of experiments, these reactions were all repeated using NBS (10 mole %) at 130 °C
(Table II).
Spectral Data for New Target Compounds
4-(4-Nitrophenyl)-2,6-bis(4-fluorophenyl)pyridine (3q). A brown solid, m.p. 248–250 °C.
IR (KBr): 3010, 1600, 1582, 1330, 1220, 1160, 1120, 840. 1H NMR (90 MHz, DMSO-d6):
8.72–8.64 (m, 4 H, ArH), 8.52 (s, 2 H, pyridine-H), 8.32–8.14 (m, 5 H, ArH), 7.42–7.26 (m,
3 H, ArH). For C23H14F2N2O2 (388.37) calculated: 71.13% C, 3.63% H, 7.21% N; found:
71.40% C, 3.54% H, 7.24% N.
4-(4-Cyanophenyl)-2,6-bis(4-fluorophenyl)pyridine (3r). A white solid, m.p. 228–230°C.
IR (KBr): 3020, 2225, 1602, 1530, 1490, 1420, 1390, 1225, 1110, 838. 1H NMR (90 MHz,
CDCl3): 8.61–8.52 (m, 4 H, ArH), 8.44 (s, 2 H, pyridine-H), 8.30–8.09 (m, 5 H, ArH),
7.31–7.01 (m, 4 H, ArH). For C24H14F2N2 (368.38) calculated: 78.25 % C, 3.83% H, 7.60% N;
found: 78.18% C, 3.87% H, 7.68% N.
4-(4-Bromophenyl)-2,6-bis(4-fluorophenyl)pyridine (3s). A white solid, m.p. 192–194°C.
IR (KBr): 3030, 1602, 1525, 1492, 1437, 1372, 1220, 828. 1H NMR (90 MHz, CDCl3):
8.41–8.37 (m, 2 H, ArH), 8.24 (s, 2 H, pyridine-H), 8.13–7.78 (m, 6 H, ArH), 7.32–7.06 (m,
5 H, ArH). For C23H14BrF2N (422.27) calculated: 65.42% C, 3.34% H, 3.32% N; found:
65.51% C, 3.36% H, 3.33% N.
Authors wish to thank the University of Sabzevar Tarbiat Moallem in Sabzevar for financial
support to carry out this research. We also thank Ms. N. Rahiminezhad for her assistance.
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