A novel indium-catalysed synthesis of tetra-substituted pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.09.144

Indium trichloride was found to be an effective catalyst for the synthesis of various tetra-substituted pyridine derivatives via Michael addition of β-dicarbonyl compounds to α,β-unsaturated oximes and subsequent ring closure.

Full text of DOI:10.1016/j.tetlet.2003.09.144

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8725–8727
A novel indium-catalysed synthesis of tetra-substituted pyridine
derivatives
Promod Saikia,a Dipak Prajapatia,* and Jagir S. Sandhub
aDepartment of Medicinal Chemistry, Regional Research Laboratory, Jorhat 785 006, Assam, India
bDepartment of Chemistry, Punjabi University, Patiala 147 002, India
Received 28 July 2003; revised 3 September 2003; accepted 12 September 2003
Abstract—Indium trichloride was found to be an effective catalyst for the synthesis of various tetra-substituted pyridine
derivatives via Michael addition of b-dicarbonyl compounds to a,b-unsaturated oximes and subsequent ring closure.
© 2003 Published by Elsevier Ltd.
Pyridine derivatives have attracted a great deal of inter-
est, mainly concerning their synthesis, reactions and
biological properties, as this structural motif appears in
a large number of pharmaceutical agents and natural
products.1 They also find application as agrochemicals
and anticancer agents.2 Extensive studies have been
carried out on the synthesis of these valuable com-
pounds. The Vilsmeier–Hack reaction3 of conjugated
oximes is a multi-step process and involves a Beckmann
rearrangement of the starting oximes. In the case of
oximes derived from cyclic a,b-unsaturated ketones
such a reaction is not possible. Recently amidrazone
was reacted with unsymmetrical tricarbonyl compounds
to provide a triazine, which subsequently reacted with
norbornadiene to afford pyridine derivatives.4 Bryce
and co-workers have reported the synthesis of pyridine
derivatives from furan precursors.5 Also, gluteralde-
hyde can be cyclised to give pyridine in up to 53% yield
by using an ammonium salt and malachite green or by
copper(II) or iron(III) salts with halide counterions.6
The reaction of methyl acetoacetate with N-benzylen-
imines in presence of LiI yielded pyridines7 in 30–72%
yield. In a very recent report,8 an enamino ester and
alkynone were reacted via Michael addition–cyclodehy-
dration, catalysed by acetic acid/Lewis acid, but this
Lewis acid-catalysed cyclodehydration is found to be
more sluggish and less efficient than the corresponding
reaction conducted in acetic acid. Therefore, the practi-
cal application of these methods suffer from several
limitations. In view of current general interest in substi-
tuted pyridine derivatives,9 there is a need for the
development of a protocol using readily available and
safe reagents, which leads to high yields of pyridine
derivatives. We have developed a new one-pot reaction
for the synthesis of tetra-substituted pyridine deriva-
tives using InCl3. The reaction proceeds efficiently in
high yields, without the formation of any by-products.
The emergence of indium(III) compounds as efficient
Lewis acid catalysts, presents new and exciting oppor-
tunities for organoindium chemistry.10 It was found
that the low reactivity of trivalent organoindium
reagents can be increased by complex formation with
organolithium compounds.11 The tetra-organo-indates
thus prepared are sufficiently reactive to take part in
reactions at ambient temperature.11a Moreover, indium
metal12 has been found to be an effective reducing
agent and indium(III) halide complexes act13a as
efficient, moisture compatible Lewis acid catalysts in
Mukaiyama
aldol
reactions,
Friedel–Crafts
acylations,12 Diels–Alder reactions13b in water and het-
ero Diels–Alder cycloadditions.13c However, its use in
the Michael addition of b-dicarbonyl compounds to
Scheme 1.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.144

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P. Saikia et al. / Tetrahedron Letters 44 (2003) 8725–8727
a,b-unsaturated oximes has remained unexplored.14,15
In continuation of our studies on indium based
reagents16 we report herein the first example of indium
trichloride mediated synthesis of tetra-substituted pyri-
dine derivatives via Michael addition of b-dicarbonyl
compounds to a,b-unsaturated oximes (Scheme 1).
Attempts to perform the pyridine synthesis at ambient
temperature for 24 h proved fruitless even when a large
excess of InCl3 was used. Further increase of the reac-
tion time gave no significant improvement. Further-
more, the reaction did not proceed in the absence of
indium trichloride and the reaction was ineffective
when indium chloride was replaced with cerium chlo-
ride (CeCl3·7H2O), the corresponding tetra-substituted
pyridine derivatives being obtained in poor yields of
only 20–25%. In most cases, the reaction was complete
within 6–7 h with indium trichloride, however, the
reaction took longer with cerium chloride, approxi-
mately 10–12 h. Increasing the reaction time further
gave no improvement in yields but instead decomposi-
tion of the starting materials occurred. All the com-
pounds obtained were characterised fully by
spectroscopic analysis (IR, 1H NMR, and MS).
Although the detailed mechanism of this reaction is not
clear at this stage, it is likely that the reaction proceeds
through the Michael addition of ethyl acetoacetate to
the enone oxime followed by subsequent ring closure,
dehydration and migration of a proton to form the
N-hydroxy derivatives. Subsequent elimination of a
further water molecule from this N-hydroxy derivative
would provide the substituted pyridine. Further investi-
gations of the scope and mechanism of the reaction are
underway. A tentative mechanism for the formation of
the tetra-substituted pyridine derivative is shown in
Scheme 2.
Reaction of enone oxime 1a with ethyl acetoacetate 2
(R=OEt) in the presence of indium trichloride without
any solvent produced the corresponding tetra-substi-
tuted pyridine17 3a as a pale yellow viscous oil in 80%
yield. Analysis of the crude product did not indicate the
formation of any other products. Similarly other substi-
tuted a,b-unsaturated oximes and b-dicarbonyl com-
pounds were reacted together using indium trichloride
following this procedure. The results are summarised in
Table 1. This new method is fairly general and the
reaction conditions are tolerant of the ether group.
Aromatic halides showed selectivity to give the corre-
sponding tetra-substituted pyridine derivatives without
any products of dehalogenation or complex formation.
However, the reaction was not as effective when acetyl
acetone was used in lieu of ethyl acetoacetate and the
corresponding tetra-substituted pyridine derivatives
were obtained in only 50–60% yields (Table 1). It is
worth mentioning that we have performed the Michael
addition18 of 1,3-dicarbonyl compounds with a,b-unsat-
urated ketones using bismuth trichloride and cadmium
iodide under microwave irradiation. However, this
reaction did not proceed with the enone oximes 1.
Table 1. InCl3-mediated synthesis of various tetra-substituted pyridine derivatives 3
Product
R
R1
R2
Reaction time (h)
Yielda (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CH3
CH3
CH3
CH3
Ph
Ph
CH3
Ph
CH3
CH3
CH3
Ph
Ph
Ph
Ph
CH3
CH3
6
7
7
6
7
7
6
8
8
8
8
80
80
75
80
75
80
75
60
60
50
55
p-ClC6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
3j
3k
a All the yields refer to isolated chromatographically pure compounds.
Scheme 2.

P. Saikia et al. / Tetrahedron Letters 44 (2003) 8725–8727
8727
In conclusion, we have provided a novel and efficient
method for the synthesis of various tetra-substituted
pyridine derivatives employing indium trichloride,
which makes a useful and important addition to exist-
ing methodologies.19 This new procedure has advan-
tages such as the lack of side product formation and
better yields than classical methods.
Chen, D. L.; Lu, Y. Q.; Daberman, J. X.; Mague, J. T. J.
Am. Chem. Soc. 1996, 118, 4216; (c) Paquette, L. A.;
Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931.
13. (a) Loh, T. P.; Pai, J.; Cao, G. Q. J. Chem. Soc., Chem.
Commun. 1996, 1819; (b) Loh, T. P.; Pai, J.; Lin, M. J.
Chem. Soc., Chem. Commun. 1996, 2315; (c) Ali, K.;
Chauhan, K. K.; Frost, C. G. Tetrahedron Lett. 1999, 40,
5621.
14. For reviews on InCl3, see: (a) Ranu, B. C. Eur. J. Org.
Chem. 2000, 2347; (b) Chauhan, K. K.; Frost, C. O. J.
Chem. Soc., Perkin Trans. 1 2000, 3015; (c) Ghosh, R.
Ind. J. Chem. 2001, 550.
Acknowledgements
15. (a) Harada, T.; Ohno, T.; Kobayashi, S.; Mukaiyama, T.
Synthesis 1991, 1216; (b) Yasuda, M.; Miyai, T.; Shibata,
I.; Baba, A.; Nomura, R.; Matsuda, H. Tetrahedron Lett.
1995, 36, 9497; (c) Loh, T. P.; Pai, J.; Cao, G. Q. J.
Chem. Soc., Chem. Commun. 1996, 1819; (d) Babu, G.;
Perumal, P. Tetrahedron Lett. 1997, 38, 5025.
We thank the Department of Science and Technology
(DST), New Delhi for financial support and Director,
Regional Research Laboratory, Jorhat for his encour-
agement to perform this work. One of us (P.S.) thanks
CSIR, New Delhi for the award of a senior research
fellowship.
16. (a) Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Tetra-
hedron Lett. 2000, 41, 8639; (b) Barman, D. C.; Thakur,
A. J.; Prajapati, D.; Sandhu, J. S. Synlett 2001, 515.
17. In a typical case, ethyl acetoacetate (0.13 g, 1 mmol) and
InCl3 (0.22 g, 1 mmol) were added to enone oxime 1a
(0.16 g, 1 mmol) and the reaction mixture was heated
with vigorous stirring to 150–160°C and kept at this
temperature for 6–7 h (monitored by TLC). After that
the unreacted ethyl acetoacetate (if any remains) was
removed under reduced pressure. The residue was then
taken in diethyl ether (25 mL) and the resulting mixture
was extracted with 1 M HCl (3×20 mL). The combined
acidic aqueous extracts were adjusted to pH 9 by means
of aqueous ammonia and extracted with dichloromethane
(2×20 mL). The dichloromethane extract was dried over
anhydrous sodium sulphate and concentrated on a rotary
evaporator to afford the crude tetra-substituted pyridine
derivative 3a in 82% yield which was then purified by
column chromatography on silica gel using chloroform as
eluent to give the pure ethyl 2,6-dimethyl-4-
phenylpyridine-3-carboxylate 3a as a light yellow viscous
oil. 3a: 1H NMR (CDCl3) l 1.01 (t, J=7.3 Hz, 3H,
OCH2CH3), 2.58 (s, 3H, CH3), 2.64 (s, 3H, CH3), 4.11 (q,
J=7.3 Hz, 2H, OCH2CH3), 7.05 (s, 1H, pyridine-H5),
7.25 (m, 5H, aromatics), IR (KBr): 2975, 2920, 1720,
1585, 1265, 1206, 1085, 870, 765, 700 cm−1; lc 169.4,
159.2, 152.5, 150.9, 143.2, 130.46, 128.9, 127.9, 126.4,
121.6, 61.5 (CH2), 24.3(Me), 23.2(Me), 14.0(Me); EI MS
m/z 255. Calcd for C16H17NO2: C,75.29; H, 6,67; N, 5.49.
Found: C, 75.41; H, 6.74; N, 5.32. Similarly other enone
oximes and b-dicarbonyl compounds were reacted in the
presence of indium trichloride and the reaction times and
yields are recorded in Table 1. All the compounds
obtained were characterised fully by spectroscopic analy-
sis (IR, 1H NMR, MS) and finally by comparison with
authentic samples.
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