Solvent-free synthesis of 2,4,6-triaryl pyridines

Article abstract of DOI:10.1515/znb-2004-0522

A modified method to prepare 1,3,5-triarylpyridines by a [3+2+1] ring annulation reaction is described. Three-component condensation of neat reactants when subjected to microwaves afforded the required product in shorter reaction time with higher yield in

Full text of DOI:10.1515/znb-2004-0522

Solvent-Free Synthesis of 2,4,6-Triaryl Pyridines
Mazaahir Kidwai, Shweta Rastogi, Ruby Thakur, and Shilpi Saxena
Department of Chemistry, University of Delhi, Delhi-110007, India
Reprint requests to Dr. M. Kidwai. E-mail: mkidwai@mantraonline.com. Fax: (91 11) 27666235
Z. Naturforsch. 59b, 606 – 608 (2004); received December 12, 2003
A modified method to prepare 1,3,5-triarylpyridines by a [3+2+1] ring annulation reaction is de-
scribed. Three-component condensation of neat reactants when subjected to microwaves afforded the
required product in shorter reaction time with higher yield in comparison to conventional method-
ologies. The microwave accelerated reaction technique without external solvent renders the whole
synthesis into a truly ecofriendly protocol.
Key words: Pyridine, Microwaves, Environmentally Benign
Introduction
provides an opportunity to conduct selective organic
functional group transformations more efficiently and
expeditiously.
Industrial chemistry in the new millennium is
widely accepting the concept of “green chemistry” to
meet the fundamental challenges of environment pro-
tection [1]. The emerging area of green chemistry en-
visages minimum hazard and designing of new chem-
ical processes. One of the thrust areas for achieving
this target of environmentallybenign synthesis is to ex-
plore alternative reaction conditions and reaction me-
dia to accomplish the desired transformations with
minimised by-products or waste as well as eliminat-
ing the use of conventional organic solvents, if possi-
ble [2].
The basic skeleton of chalcones that possess α,β-
unsaturated carbonyl group is a useful synthon for
various heterocyclic compounds of pharmacological
importance such as pyrazolines [7], thiophenes [8],
etc. Further, the importance of pyridine [9 – 11] in
pharmaceutical and biological fields is well estab-
lished. Numerous routes to the pyridine ring are known
such as [3+3] pyridine synthesis from iminophospho-
ranes [12], Chichibabin syntheses [13] which gener-
ally results in the formation of mixture of substituted
pyridines. Substituted phenacyl isoquinolinium bro-
mide [14] or pyridinium ylide [15] upon reaction with
various benzylidene acetophenones also afford 2,4,6-
triarylpyridines. The reactants used in the above men-
tioned methods are not readily available and some re-
quire synthesis even at the precursor stage. The synthe-
sis of pyridine ring has been reported widely through
conventional heating, however, alternative strategies
that are more ecofriendly than traditional ones are be-
ing sought due to the increasing concern about the im-
pacts of chemicals on the environment. With a view to
explore the studies on reactivity of α-methyl-ketones
and benzylidene-acetophenones, significant therapeu-
tic value of pyridines, and the environmentally be-
nign role of solventless synthesis with microwave heat-
ing, it was considered worthwhile to explore the syn-
thesis of 2,4,6-triarylprydines by a [3+2+1] ring for-
mation using microwave heating under solvent-free
conditions.
Among the important tools, the use of microwave
(MW) as an alternative energy source is now becom-
ing an attractive technique [3]. One of the advances in
this area where substantial progress has been made is
the MW assisted solid support synthesis [4]. It offers
the advantages of high product yield and reaction rate
enhancement [5]. But the minute observation of this
reveals that an appreciable amount of solvent is still
required for the adsorption of reactants and elution of
product. Another alternative approach which aims at
complete elimination of solvent is the “neat reaction”
[6] technique in which a mixture of reactants in the ab-
sence of solvent is exposed to microwaves. It is associ-
ated with the benefits of shorter reaction time, remark-
able rate enhancement, high product yield and easier
work-up. These no-solvent reactions prove to be ad-
vantageous for environmental reasons especially when
coupled with microwaves. The solventless approach
c
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M. Kidwai et al. · Solvent-Free Synthesis of 2,4,6-Triaryl Pyridines
607
Table 1. Comparison of reaction time and yield of com-
pounds 3a – f.
Compound
R
Method A
Method B
time (h) / yield (%) time (min) / yield (%)
3a
3b
3c
3d
3e
3f
H
4-Cl
4-Br
4-CH3
2-OH
4-NH2
12/60
10/58
10/55
8/65
15/55
12/63
5/82
6/75
5/77
4/85
8/78
7.5/80
which acts as the nitrogen source as well as the
cyclisation agent to afford 2,4,6-trisubstituted
pyridines.
Results and Discussion
The so-called [3+2+1] pyridine ring synthesis
utilises the enone functionality as the three-carbon
component, differently substituted α-methyl-ketones
as the two-carbon component, and ammonium acetate
as a one-carbon component and has the potential to
meet our goals efficiently. Following the classical pro-
cedure [16], 2,4,6-triarylpyridines 3a – f are obtained
in 55 – 65% yield (Table 1) by refluxing enone 1 with
different α-methyl-ketones 2 and ammonium acetate
as the cyclisation agent in acetic acid under reflux for
10 – 15 h. This procedure employs acetic acid as a cor-
rosive organic reagent, requires long reaction time and
gives unsatisfactory yield. Thus, we herein describe the
MW accelerated solventless neat synthesis of pyridines
3a – f with a view to improve the yield and applica-
bility of the desired transformation. In the solventfree
technology, appropriate amounts of the neat reactants
were mixed and irradiated under microwaves to afford
pyridines 3a– f in 75– 85% yield in 4 – 8 min (Ta-
ble 1). This approach eliminates the usage of solid sup-
port as well as the solvent from the reaction. These
no-solvent conditions prove to be advantageous for en-
vironmental reasons and offer the benefits of shorter
reaction times and high product yield especially when
coupled with microwaves. Further, it is observed that
the amount of ammonium acetate required in which
ammonium ion acts as the nitrogen source in the case
of neat synthesis under microwave is just 1.5 g instead
of 3 g as used in the conventional heating procedure.
This highlights the role of MW which is attributed to
homogenous heating effects [17]. The structures of the
resulting pyridines are established on the basic of spec-
troscopic data and elemental analyses.
Conclusion
We have described a [3+2+1] pyridine synthe-
sis starting from an enone functionality. A novel,
facile and highly efficient MW-accelerated modifica-
tion of the conventional reaction conditions is intro-
duced that allows the rapid assembly of structurally
diverse pyridines. The advantages of this multicom-
ponent ecofriendly condensation reaction includes a
simple reaction set up, good product yield, short re-
action time and above all, complete elimination of
solvent.
Experimental Section
Melting points were determined with a electrothermal
melting point apparatus and are uncorrected. Infrared spec-
tra (in KBr) were recorded on a 1710 Perkin Elmer FT in-
frared spectrophotometer. 1H NMR spectra were recorded on
a FT NMR Hitachi R-600 (60 MHz) spectrometer. Elemen-
tal analyses were performed on Heraeus CHN-Rapid Ana-
lyzer. For microwave irradiation a Kenstar microwave oven,
Model no. OM9925E (2450 MHz, 800 W) was used. The pu-
rity of compounds was checked on silica gel coated Al plates
(Merck).
General procedure for the synthesis of 4-(1,3-benzodioxol-
5-yl)-2-(4-bromophenyl)-6-arylpyridines 3a−f
Method A: Conventional solution phase synthesis
A mixture of 3-(1,3-benzodioxol-5-yl)-1-(4-bromophe-
nyl)-2-propen-1-one 1 (3.32 g, 0.01 mol), α-methyl-ketone
2a – f (0.01 mol) and ammonium acetate (3.08 g, 0.04 mol)
in glacial acetic acid (20 ml) was stirred at reflux tempera-
ture for 8 – 12 h. Upon completion of the reaction, the reac-
tion mixture was cooled, concentrated and left overnight at
room temperature. Ice-cold water was added and the precip-
itate was separated, washed with methanol, dried and recrys-
It is plausible to assume that initially inter-
molecular condensation of the α,β-unsaturated
ketone with an α-methyl-ketone occurs to re-
sult in a 1,5-diketone. This, then undergoes ring
closure in the presence of ammonium acetate tallised from a suitable solvent to yield pure pyridines 3a – f.
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M. Kidwai et al. · Solvent-Free Synthesis of 2,4,6-Triaryl Pyridines
◦
Method B: Microwave assisted solventless synthesis
3c: M. p. 193 – 195 C [15] (CHCl3-MeOH). – IR (KBr
pellets): ν = 3065 (C–H), 1598 (C=N), 1542 (C=C) cm−1. –
A mixture of neat reactants, 3-(1,3-benzodioxol-5-yl)-
1-(4-bromophenyl)-2-propen-1-one 1 (3.32 g, 0.01 mol),
α-methyl-ketone 2a – f (0.01 mol) and ammonium acetate
(1.54 g, 0.02 mol) was taken in an Erlenmeyer flask and
irradiated under microwaves at an interval of 20 sec. The
progress of reaction was monitored by TLC examination.
Upon completion of the reaction, the mixture was cooled,
and methanol was added. During standing at 10 ◦C, a sticky
solid separated which was crystallised from a suitable solvent
to afford products 3a – f in high yield.
1H NMR (60 MHz, CDCl3): δ = 6.0 (s, 2H, OCH2O), 7.0
(s, 2H, pyridyl), 7.3 – 8.3 (m, 11H, Ar-H).
◦
3d: M. p. 160 – 162 C [16] (CHCl3-EtOH). – IR (KBr
pellets): ν = 3068 (C–H), 1599 (C=N), 1543 (C=C) cm−1. –
1H NMR (60 MHz, CDCl3): δ = 2.4 (s, 3H, CH3), 6.0 (s,
2H, OCH2O), 6.9 (s, 2H, pyridyl), 7.2 – 8.1 (m, 11H, Ar-H).
3e: M. p. 122 – 124 ◦C (CHCl3-EtOH). – IR (KBr
pellets): ν = 3425 (OH), 3062 (C–H), 1598 (C=N),
1544 (C=C) cm−1. – H NMR (60 MHz, CDCl3): δ = 5.8
1
(s, 1H, OH), 6.0 (s, 2H, OCH2O), 6.8 (s, 2H, pyridyl), 7.1 –
8.1 (m, 11H, Ar-H).
◦
3a: M. p. 136 – 138 C [18] (CHCl3-C6H12). – IR (KBr
pellets): ν = 3070 (C–H), 1599 (C=N), 1543 (C=C) cm−1. –
1H NMR (60 MHz, CDCl3): δ = 5.9 (s, 2H, OCH2O), 7.0
(s, 2H, pyridyl), 7.2 – 8.1 (m, 12H, Ar-H).
3f: M. p. 190 – 192 ◦C (CHCl3-C6H12). – IR (KBr
pellets): ν = 3143 (NH2), 3071 (C–H), 1599 (C=N),
1543 (C=C) cm−1. – H NMR (60 MHz, CDCl3): δ = 5.9
1
◦
(s, 2H, OCH2O), 4.2 (brs, 2H, NH2), 6.8 (s, 2H, pyridyl),
7.0 – 8.1 (m, 11H, Ar-H).
3b: M. p. 235 – 238 C [14] (CHCl3-MeOH). – IR (KBr
pellets): ν = 3060 (C–H), 1598 (C=N), 1543 (C=C) cm−1. –
1H NMR (60 MHz, CDCl3): δ = 6.0 (s, 2H, OCH2O), 7.1
(s, 2H, pyridyl), 7.4 – 8.3 (m, 11H, Ar-H).
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