Modern Research in Catalysis, 2013, 2, 42-46

http://dx.doi.org/10.4236/mrc.2013.22007 Published Online April 2013 (http://www.scirp.org/journal/mrc)

Montmorillonite K10 Clay Catalyzed One Pot

Synthesis of 2,4,6-Tri Substituted Pyridine
under Solvent Free Condition
Vellayan Kannan1*, Krishnapillai Sreekumar2
1
Department of Chemistry, Government College Kattappana, Kattappana, India
2
Department of Applied Chemistry, Cochin University of Science and Technology, Cochin, India
Email: *kannanpvl@gmail.com

Received January 11, 2013; revised February 27, 2013; accepted March 11, 2013

Copyright © 2013 Vellayan Kannan, Krishnapillai Sreekumar. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

ABSTRACT
Montmorillonite K10 catalyzed synthesis of 2,4,6 triaryl pyridine under solvent free condition is described. Montmoril-
lonite effectively catalyzed the reaction in good to excellent yields. Using this solid catalyst, the reactions could be car-
ried out in a short period of time with very good yield of triaryl pyridines, up to 97% under solvent free condition. This
catalyst could be recycled very easily, which makes this methodology environmentally benign. The catalyst is active
over three cycles.

Keywords: Clay Catalyst; Solvent Free Synthesis; Substituted Pyridine

1. Introduction [12]. More recently, many improved methods for pre-

paration of 2,4,6-triaryl pyridines have been reported
One-pot multicomponent coupling reactions (MCRs),
such as reaction of α-ketoketene dithioacetals with me-
where several organic moieties are coupled in one step,
thyl ketones in the presence of ammonium acetate [13],
for carbon-carbon and carbon-heteroatom bond forma-
reaction of N-phosphinylethanimines with aldehydes [14],
tion is an attractive synthetic strategy for the synthesis of
addition of lithiated β-enaminophosphonates to chalcones
small-molecule libraries with several degrees of structu-
[15], condensation of acetophenones, benzaldehydes and
ral diversities [1]. Multiaryl substituted pyridine deriva-
NH4OAc in the presence of NaOH under solvent free
tives are recently reported as electron transport materials
condition [16], one pot reaction of acetophenones, ben-
[2]. The highly substituted pyridine derivatives, like2-
zaldehydes and NH4OAc without catalyst under micro-
amino-4-aryl-3,5-dicyano-6-sulfanylpyridines have sig-
wave irradiation [17] etc. Due to the non corrosive, easy
nificant and diverse medicinal utility. Essentially, these
to handle, thermally robust, inexpensive and environmen-
compounds serve as high-potency agonists for the human
tal friendly nature of clays have gained importance in or-
adenosine receptors and act as potential therapeutic
ganic synthesis as solid acid catalysts. Montmorillonite
agents for the treatment of Creutzfeldt-Jacob disease, Par-
kinson’s disease, hypoxia, asthma, cancer, kidney disease K10 has proved to be an efficient catalyst in promoting va-
and prion disease [3-5]. Due to their п-stacking ability, rious organic reactions such as addition reaction [18], Kno-
some pyridines are used in supramolecular chemistry [6- venagal condensation [19], Aza-Diels Alder reaction [20],
8]. Previously, 2,4,6-triarylpyridines have been prepar- Esterification [21], isomerisation reaction [22] etc. How-
ed by the condensation of 1,5-diketones with forma- ever, the utility of this catalyst for the synthesis of trisub-
mide-formic acid [9], reaction of (aroylmethylene) iso- stituted pyridines under solvent free condition has not been
quinolinium ylide with α, β-unsaturated ketones [10,11], explored before. In continuation of our efforts to explore
and reaction of N-phenacylpyridinium salts with α, β-un- the catalytic activity of clays for various organic transfor-
saturated ketones in the presence of ammonium acetate mations, a one-pot solvent free synthesis of 2,4,6trisub-
stituted pyridines by condensation of various aldehydes,
*
Corresponding author. ketones and ammonium acetate have been attempted.

Copyright © 2013 SciRes. MRC

 V. KANNAN, K. SREEKUMAR 43

2. Experimental Procedure O H O CH 3
R1
C C
Commercial clay K10 was purchased from Sigma-Al- Clay catalyst 0.2g

drich India. The clay was activated at 200˚C for 3 h be- R1 2 NH 4 OAc, heat, solvent- free
R2 N
fore use. The reactants were purchased from Merck Ltd. R2 R2

India and were used as such. The products were cha-

racterized by FT-IR, NMR spectral methods and m. p. Scheme 1. K10 catalyzed one pot synthesis of triaryl pyri-
dines.
FT-IR spectra were recorded by the KBr pellet method
on a JASCO FT-IR spectrometer in the range of 400 to
Table 1. Results of recycling studies.
4000 cm−1. High-resolution mass spectra were obtained
with a LC-MS (Q-TOFF) LC (Waters). 1H NMR spectra No. of recycling steps % Yield
were recorded on a Bruker 400 MHZ instrument with te-
1 97
tra methyl silane (TMS) as internal standard in CDCl3.
2 92

2.1. Synthesis of 2,4,6 Triaryl Pyridines 3 88

Reaction condition: benzaldehyde (1 mmol), acetophenone (2 mmol),
A mixture of aldehyde (1 mmol), acetophenone (2 mmol), NH4OAc (1.3 mol%), 0.2 gm catalyst reaction time 4 h. Isolated yield.
1.3 mol% (NH4OAc) and activated K10 clay (0.2 g) was
stirred at 120˚C. The progress of the reaction was moni- of catalyst loading was studied by increasing the catalyst
tored by TLC. After the completion of the reaction, hot concentration from 0.05 g to 0.3 g with an increment of
ethanol was added to the mixture and the insoluble ca- 0.05 g selecting benzaldehyde and acetophenone as sub-
talyst was filtered off. The pure product was obtained by strates for 3 h, the formation of product was found to in-
recrystalisation from the solvent. crease up to 0.2 g further increase did not appreciably af-
fect the yield of the product, optimum catalyst concentra-
2.2. Reusability of the Catalyst tion of 0.2 g was selected for further studies, similarly
At the end of the reaction the catalyst was filtered, wash- temperature was also optimized by varying the tempera-
ed with diethyl ether, dried at 130˚C for 1 h, and reused. ture from 40˚C - 130˚C, optimum temperature obtained
The recycled catalyst was found to be active over three was 120˚C.
cycles without appreciable loss in catalytic activity. Re-
sults are given in Table 1. Spectral Data of Selected Products
All the products are known compounds and were cha- 2,4,6-triphenylpyridine (Entry 1, Table 2). Mp 130˚C -
racterized by comparing IR and 1H NMR spectral data as 132˚C; 1H NMR (CDCl3, 400MHZ): δ 7.2 - 8.2 (m, 17H),
well as melting points with those reported in the litera- LC-MS (m/z): 308.1 (M + 1). FT-IR (KBr): 3032, 1604,
ture. All yields refer to that of isolated pure products. 1544, 1232, 1025 cm−1.
4-phenyl-2,6-dip-tolylpyridine (Entry 2, Table 2) Mp
3. Results and Discussion 156˚C - 158˚C 1H NMR (CDCl3, 400 MHZ): δ 7.2 - 8.2
(m, 15H), 2.4 (s, 6H), LC-MS (m/z): 336.2 (M + 1).
The catalytic efficiency of K10 was evaluated for the syn- FT-IR (KBr): 3030, 1654, 1593, 1330, 1180 cm−1.
thesis of triaryl pyridines by a one pot condensation of 4-(2,6-diphenylpyridin-4-yl) phenol (Entry 4, Table 2).
aldehyde, ketone and NH4OAc under solvent free condi- Mp 197˚C; 1H NMR (CDCl3, 400 MHZ): δ 8.2 (dd, 4H, J
tion (Scheme 1). High yield (97%) was obtained with = 1.2 HZ), 7.8(s, 2H), 7.68(d, 2H, J = 4.4 HZ), 7.4 - 7.6
benzaldehyde and acetophenone. To evaluate the scope (m, 6H), 7 (d, 2H, J = 8.4 HZ), 5 (s, 1H) LC-MS (m/z):
and limitations of the methodology, reactions were car- 324.3 (M + 1). FT-IR (KBr): 3038, 1598, 1517, 1602,
ried out with various substituted benzaldehydes including 1207, 1109 cm−1.
both electron-donating and electron-withdrawing substi- 4-(4-nitrophenyl)-2,6-diphenylpyridine (Entry 5, Ta-
tuents at para position of the aromatic ring (Table 2). The ble 2). Mp 203˚C - 205˚C; 1H NMR (CDCl3, 400MHZ):
results showed that there is no adverse effect of substitu- δ 7.42 - 7.89 (m, 17H), LC-MS (m/z): 353.3 (M + 1).
ents, either electron-donating or electron-withdrawing, on FT-IR (KBr): 3069, 1608, 1528, 1351, 1218 cm−1.
the aromatic ring of benzaldehyde or acetophenone on 4-(4-chlorophenyl)-2,6-diphenylpyridine (Entry 7, Ta-
the product yield. In the case of all the aldehydes, very ble 2). Mp 118˚C - 119˚C; 1H NMR (CDCl3, 400 MHZ):
high yields (>88%) were obtained in comparatively less δ 7.4 - 8.2 (m, 16H) LC-MS (m/z): 342.8 (M + 1). FT-IR
time (2 - 6.5 h). All the products were characterized by (KBr): 3023, 1656, 1600, 1334, 1222 cm−1.
comparing melting points with those of the reported The effect of various ammonia sources was studied. Ef-
compounds. The reaction conditions such as temperature, fect of the different ammonia derivatives on yield of the
time and amount of catalyst were optimized. The effect product were checked, maximum, yield was obtained for

Copyright © 2013 SciRes. MRC

44 V. KANNAN, K. SREEKUMAR

NH4OAc. Results are summarized in Table 3. sation of ammonia with a molecule of chalcone and Mi-
The mechanism of triaryl pyridine synthesis is as chel addition of ammonia to the second molecule of chal-
shown in Scheme 2 [25]. First step involves the conden- cone leads to the formation of 2,4-diaryl-1-azadiene 3 and
the 1:1 adduct 4 probably undergoes a formal [4 + 2] cy-
Ar' cloaddition to form tetrahydro pyridine intermediate 5.
Ar NH
O
+ NH4OAc NH2 +NH4OAc
O
Dehydration to dihydropyridine intermediate 6 and then
Ar Ar'
-AcOH
-H2O
Ar OH
-AcOH Ar Ar' oxidative aromatization with removal of the benzyl side
-H2O
1 Ar' chain would yield 2,4,6-triarylpyridine. According the me-
chanism, the role of NH4OAc is as nitrogen source and
3 4

acetic acid is formed as by-product, the reaction is cata-

Ar' Ar'
Ar' H Ar' Ar' lysed by acid, the presence of acetic acid increases the
NH2 -H2O NH2
-Ar'CH2NH2
acidity of the medium.
Ar N
OH
Ar N
OH
Ar N Ar
The main advantages of the present method in the syn-
H Ar H Ar

5 2
thesis of triarylpyridines are that they are clean reactions
without any side product under solvent free condition
6

Scheme 2. Mechanism of formation of triaryl pyridines. and workup does not require column chromatography.
The catalyst could be recycled efficiently for three cycles
Table 2. Montmorillonite K10 clay catalyzed synthesis of tri- without any appreciable loss in the yield.
aryl pyridinesa.

Entry R1 R2 Time (h) Yield (%)b M.p (˚C) (lit.) 4. Conclusion

[23]
1 H H 4 97 133 - 136(135) A mild, efficient and environmentally friendly approach
2 H 4-CH3 6 93 156 - 158(157 - 158) [25] for the synthesis of 2,4,6-trisubstituted pyridines via cy-
clo condensation of aromatic ketones with aromatic alde-
3 H 4-Br 5 92 194 - 196(192 - 194)[26]
hydes and ammonium acetate in the presence of Montmo-
4 4-OH H 5 97 197 - 198(197 - 198)[23] rillonite K10 clay as a recyclable solid acid catalyst has
5 4-NO2 H 6 91 203 - 205(202 - 203)[23] been developed. The trisubstituted pyridines were pro-
6 2-Cl H 4.5 93 113 - 114(109 - 111)[26] duced with 100% selectivity without formation of any
other side product. The green context of the reaction is
7 4-Cl H 4 94 126 - 127(129 - 130)[23]
the use of non corrosive catalyst under solvent free reac-
8 4-OCH3 H 7 96 101 - 102(98)[25] tion condition and workup procedure does not require co-
9 4-CH3 H 6.5 95 116 - 118(116)[24] lumn chromatography.
10 4-CH3 4-CH3 5 90 177 - 178(178 - 180)[26]
5. Acknowledgements
11 3-NO2 4-Br 5 89 >200
One of the authors VK is thankful to UGC for teacher
12 4-Cl 4-CH3 4 96 199 - 201(200 - 202)[25]
fellowship and SAIF Cochin for 1H NMR analysis.
13 4-Cl 4-Br 5 94 >200
14 Thio H 4 91 168 - 170(68 - 170)[25]
REFERENCES
15 Thio 4-CH3 3.5 88 162 - 163(164 - 165)[25]
[1] A. U. Lesanko and D. G. Hall, “Wanted: New Multicom-
a
Reaction conditions: Temperature 120˚C, Catalyst 0.2 g, aldehyde:NH4OAc: ponent Reactions for Generating Libraries of Polycyclic
ketone:1:1.3:2 mmol. bIsolated yield of product. Natural Products,” Current Opinion in Chemical Biology,
Vol. 9, No. 3, 2005, pp. 266-276.
Table 3. Effect of various ammonia sources on the yield of doi:10.1016/j.cbpa.2005.04.003
producta.
[2] N. Li, P. Wang, S. L. Lai, W. Liu, C. S. Lee, S. T. Lee
Ammonia source Time (h) Yield % b and Z. Liu, “Synthesis of Multiaryl-Substituted Pyridine
Derivatives and Applications in Non-Doped Deep-Blue
NH4OAc 4 97 OLEDs as Electron-Transporting Layer with High Hole-
Blocking Ability,” Advanced Materials, Vol. 22, No. 4,
NH2CONH2 6 40 2010, pp. 527-530. doi:10.1002/adma.200902430
NH2COCH3 5 65 [3] L. C. W. Chang, J. K. Von Frijtag, D. Kunzel, T. M. Mul-
der-Kriegger, R. F. Spangersberg, S. F. Roerink, G. Hout,
NH2CSNH2 4.5 36 M. W. Beukers, J. Brussee and A. P. Ijzerman, “A Series
a
Reaction conditions: Temperature 120˚C, Catalyst 0.2 g, aldehyde:NH4OAc:
of Ligands Displaying a Remarkable Agonistic-Antago-
ketone:1:1.3:2 mmol. bIsolated yield of product. nistic Profile at the Adenosine A1 Receptor,” Journal of

Copyright © 2013 SciRes. MRC

 V. KANNAN, K. SREEKUMAR 45

Medicinal Chemistry, Vol. 48, No. 6, 2005, pp. 2045- Salts,” Journal of American Chemical Society, Vol. 103,
2053. doi:10.1021/jm049597+ No. 12, 1981, pp. 3584-3585.
[4] M. W. Beukers, L. W. Chang, J. K. von Frijtag, D. Künzel, http://dx.doi.org/10.1021/ja00402a062
T. Mulder-Krieger, R. F. Spanjersberg, J. Brussee and A. [14] T. Kobayashi, H. Kakiuchi and H. Kato, “On the Reaction
P. I. Jzerman, “New, Non-Adenosine, High-Potency Ago- of N-(Diphenylphosphinyl)-1-phenylethanimine with Aro-
nists for the Human Adenosine A2B Receptor with an Im- matic Aldehydes Giving 4-Aryl-2,6-diphenylpyridine De-
proved Selectivity Profile Compared to the Reference rivatives,” Bulletin of the Chemical Society of Japan, Vol.
Agonist N-Ethylcarboxamidoadenosine,” Journal of Me- 64, No. 2, 1991, pp. 392-395. doi:10.1246/bcsj.64.392
dicinal Chemistry, Vol. 47, No. 15, 2004, pp. 3707-3709. [15] F. Palacios, A. O. Retana and J. A. Oyarzabal, “A ‘One Pot’
doi:10.1021/jm049947s Synthesis of Polysubstituted Pyridines from Metallated
[5] A. D. Pillai, P. D. Rathod, P. X. F. M. Patel, M. Nivsarkar, Alkylphosphonates, Nitriles and α,β-Unsaturated Ketones,”
K. K. Vasu, H. Padh and V. Sudarsanam, “Novel Drug De- Tetrahedron Letters, Vol. 37, No. 26, 1996, pp. 4577-
signing Approach for Dual Inhibitors as Anti-Inflamma- 4580. doi:10.1016/0040-4039(96)00850-7
tory Agents: Implication of Pyridine Template,” Bioche- [16] G. W. V. Cave and C. L. Raston, “Towards Benign SynThe-
mical and Biophys Research Communications, Vol. 301, sis of Pyridines Involving Sequential Solvent Free Aldol
No. 1, 2003, pp. 183-186. and Michael Addition Reactions,” Chemical Communica-
doi:10.1016/S0006-291X(02)02996-0 tions, No. 22, 2000, pp. 2199-2200.
[6] G. W. Cave, M. J. Hardie, B. A. Roberts and C. L. Raston, doi:10.1039/b007431o
“A Versatile Six-Component Molecular Capsule Based [17] S. Tu, T. Li, F. Shi, F. Fang, S. Zhu, X. Wei and Z. Zong,
on Benign Synthons—Selective Confinement of a Hete- “An Efficient Improve for the Kröhnke Reaction: One-
rogeneous Molecular Aggregate,” European Journal of Pot Synthesis of 2,4,6-Triarylpyridines Using Raw Mate-
Organic Chemistry, Vol. 2001, No. 17, 2001, pp. 3227- rials under Microwave Irradiation,” Chemistry Letters,
3231. Vol. 34, No. 5, 2005, pp. 732-733.
doi:10.1002/1099-0690(200109)2001:17<3227::AID-EJO doi:10.1246/cl.2005.732
C3227>3.0.CO;2-V [18] K. Motokura, S. Matsunaga, A. Miyaji, Y. Sakamoto and
[7] R. R. Jetti, A. Nagia, F. Xue and T. C. W. Mak, “Polar Host- T. Baba, “Heterogeneous Allylsilation of Aromatic and Ali-
Guest Assembly Mediated by Halogen…π Interaction: In- phatic Alkenes Catalyzed by Proton-Exchanged Montmo-
clusion Complexes of 2,4,6-Tris (4-halophenoxy)-1,3,5- rillonite,” Organic Letters, Vol. 12, No. 7, 2010, pp. 1508-
triazine (Halo = Chloro, Bromo) with Trihalobenzene 1511. doi:10.1021/ol100228t
(Halo = Bromo, Iodo),” Chemical Communications, No.
[19] K. Motokura, M. Tada and Y. Iwasawa, “Layered Mate-
10, 2001, pp. 919-920. doi:10.1039/b102150h rials with Coexisting Acidic and Basic Sites for Catalytic
[8] Z. C. Watson, N. Bampos and J. M. Sanders, “Mixed Cy- One-Pot Reaction Sequences,” Journal of American Che-
clic Trimers of Porphyrins and Dioxoporphyrins: Geome- mical Society, Vol. 131, No. 23, 2009, pp. 7944-7945.
try vs. Electronics in Ligand Recognition,” New Journal doi:10.1021/ja9012003
of Chemistry, Vol. 22, No. 11, 1998, pp. 1135-1138.
[20] M. Nose, T. Mizugaki, K. Jitsukawa and K. Kaneda, “Re-
doi:10.1039/a805504a
usable Montmorillonite-Entrapped Organocatalyst for Asym-
[9] F. Chubb, A. S. Hay and R. B. Sandin, “The Leuckart Re- metric Diels-Alder Reaction,” Tetrahedron Letters, Vol.
action of Some 1,5-Diketones,” Journal of American Che- 49, No. 38, 2008, pp. 5464-5466.
mical Society, Vol. 75, No. 23, 1953, pp. 6042-6044. doi:10.1016/j.tetlet.2008.07.011
doi:10.1021/ja01119a508
[21] S. B. Neji, M. Trabelsi and M. H. Frikha, “Esterification
[10] R. S. Tewari and A. K. Dubey, “Studies on Cycloimmo- of Fatty Acids with Short-Chain Alcohols over Commer-
nium Ylides. Synthesis of Some 2,4,6-Triaryl-Substituted cial Acid Clays in a Semi-Continuous Reactor,” Energies,
Pyridines via Isoquniolinium Ylides,” Journal of Chemi- Vol. 2, No. 4, 2009, pp. 1107-1117.
cal Engineering Data, Vol. 25, No. 1, 1980, pp. 91-92. doi:10.3390/en20401107
doi:10.1021/je60084a032 [22] M. R. Dintzner, Y. A. Mondjnou and D. J. Pileggi, “Mont-
[11] S. P. Kendurkar and R. S. Tewari, “Synthesis of Some morillonite Clay-Catalyzed Cyclotrimerization and Oxida-
New 2,4,6-Triaryl-Substituted Pyridines Via Aroylmethy- tion of Aliphatic Aldehydes,” Tetrahedron Letters, Vol.
lenepyridinium Ylides,” Journal of Chemical Engineer- 51, No. 5, 2010, pp. 826-827.
ing Data, Vol. 19, No. 2, 1974, pp. 184-188. doi:10.1016/j.tetlet.2009.12.009
doi:10.1021/je60061a004 [23] T. Kobayashi, H. Kakiuchi and H. Kato, “On the Reaction
[12] F. Kröhnke, W. Zecher, J. Curtze, D. Drechsler, K. Pfle- of N-(Diphenylphosphinyl)-1-phenylethanimine with Aro-
ghar, K. E. Schnalke and W. Weis, “Syntheses Using the matic Aldehydes Giving 4-Aryl-2,6-diphenylpyridine De-
Michael Adddition of Pyridinium Salts,” Angewandte Che- rivatives,” Bulletin of the Chemical Society of Japan, Vol.
mie International Edition in English, Vol. 1, No. 12, 1962, 64, No. 2, 1991, pp. 392-395. doi:10.1246/bcsj.64.392
pp. 626-632. doi:10.1002/anie.196206261 [24] P. G. Ingole, S. V. Jadhav and H. C. Bajaj, “Ionic Liquid
[13] K. T. Potts, M. J. Cipullo, P. Ralli and G. Theodoridis, “Ke- Mediated One Pot Synthesis of Substituted 2,4,6-Tria-
tenedithioacetals as Synthetic Intermediates. A Versatile rylpyridines,” International Journal of Chemical Tech-
Synthesis of Pyridenes, Polypyridinyls, and Pyrylium nological Research, Vol. 2, No. 1, 2010, pp. 289-294.

Copyright © 2013 SciRes. MRC

46 V. KANNAN, K. SREEKUMAR

[25] M. Adib, H. Tahermansouri, S. A. Koloogani, B. Moham- [26] X. Q. Huang, H. X. Li, J. X. Wang and X. F. Jia, “A
madi and H. R. Bijanzadeh, “Krohnke Pyridines: An Ef- Rapid and Efficient Synthesis of 2,4,6-Triarylpyridines
ficient Solvent Free Synthesis of 2,4,6-triarylpyridines,” under Microwave Irradiation,” Chinese Chemical Letters,
Tetrahedron Letters, Vol. 47, No. 33, 2006, pp. 5957- Vol. 16, No. 5, 2005, pp. 607-608.
5960. doi:10.1016/j.tetlet.2006.01.162

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