An efficient procedure for the synthesis of substituted pyridines using KF·Al2O3

Article abstract of DOI:10.1002/jhet.206

(Chemical Equation Presented) Three-component coupling of aldehydes, malononitrile, and thiophenols has efficiently been carried out at room temperature using potassium fluoride on alumina (KF·Al₂O ₃) as a catalyst to furnish highly substituted pyridines in high yields.

Full text of DOI:10.1002/jhet.206

1208
An Efficient Procedure for the Synthesis of Substituted Pyridines
Using KFꢀAl2O3
Vol 46
Biswanath Das,* Bommena Ravikanth, Avula Satya Kumar,
and Boddu Shashi Kanth
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007,
Andhra Pradesh, India
*E-mail: biswanathdas@yahoo.com
Received July 11, 2008
DOI 10.1002/jhet.206
Published online 5 November 2009 in Wiley InterScience (www.interscience.wiley.com).
Three-component coupling of aldehydes, malononitrile, and thiophenols has efficiently been carried
out at room temperature using potassium fluoride on alumina (KFꢀAl2O3) as a catalyst to furnish highly
substituted pyridines in high yields.
J. Heterocyclic Chem., 46, 1208 (2009).
INTRODUCTION
the substituted pyridines at room temperature.
(Scheme 1).
Pyridine moiety in highly substituted form is fre-
quently observed in various bioactive compounds [1–3].
This ring exists in both naturally occurring and synthetic
drugs. The substituted pyridines of the common struc-
ture 1 possess significant antibacterial and anti-infective
properties [4] and are useful for the development of
other bioactive agents [5]. Thus, a number of methods
for the synthesis of substituted pyridines have been
reported [6–14]. One of the convenient methods involv-
ing three-component coupling of aldehydes, malononi-
trile, and thiols using bases, such as 1,4-diaza bicyclo
[2,2,2,] octane and Et3N, in ethanol under reflux led to
the direct formation of 1 [8]. However, the yields of the
products are unsatisfactory (20–48%), and the reactions
are conducted at high temperature. The yields were
improved by performing the reaction in the presence of
an oxidizing agent [9]. Very recently, the similar
method using ionic liquid has also been reported [12].
A series of 2-amino-4-aryl-3,5-dicyano-6-sulfanyl pyr-
idines have been prepared from various aromatic
aldehydes following the aforementioned procedure
(Table 1). The aldehydes containing both electron-donat-
ing and electron-withdrawing groups underwent the con-
version smoothly. Different functionalities, such as
hydroxyl, ether, halogen, and nitro, remained unchanged.
The conversion was complete within 0.5–1 h and the sub-
stituted pyridines were formed in high yields (84–95%).
However, with aliphatic aldehydes and thiols, the reaction
was not successful. The structures of the products were
established from their spectral (1H NMR, IR, and MS)
data.
KFꢀAl2O3 has recently emerged as a valuable solid-
phase catalyst for various organic transformations
[18,19]. It possesses interesting catalytic activity. It can
easily be handled and removed from the reaction mix-
ture. It has been used here for the first time for the
Scheme 1
RESULTS AND DISCUSSION
In continuation of our work [15–17] on the develop-
ment of useful synthetic methodologies, we have
observed that the condensation of aldehydes, malononi-
trile, and thiols can efficiently be accomplished using
potassium fluoride on alumina (KFꢀAl2O3) to produce
C
V
2009 HeteroCorporation

November 2009 An Efficient Procedure for the Synthesis of Substituted Pyridines Using KFꢀAl2O3
1209
Table 1
Synthesis of substituted pyridines using KFꢀAl2O3.a
Entry
a
Aldehyde (2)
Thiol (3)
Product (1)
Time (min) Isolated yield (%) Mp (ꢁC) [reference]
30
87
216–218 [11]
b
40
90
208–211 [11]
c
35
92
222–224 [11]
d
40
88
315–316 [11]
e
30
90
228–230 [11]
f
35
85
224–225 [11]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1210
B. Das, B. Ravikanth, A. S. Kumar, and B. S. Kanth
Vol 46
Table 1
(Continued)
Entry
Aldehyde (2)
Thiol (3)
Product (1)
Time (min) Isolated yield (%) Mp (ꢁC) [reference]
g
50
89
238–240 [11]
h
30
92
218–220 [11]
i
40
30
35
87
95
91
252–254
319–320 [11]
261–263 [10]
j
k
l
40
95
273–275
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 An Efficient Procedure for the Synthesis of Substituted Pyridines Using KFꢀAl2O3
1211
Table 1
(Continued)
Entry
m
Aldehyde (2)
Thiol (3)
Product (1)
Time (min) Isolated yield (%) Mp (ꢁC) [reference]
55
84
287–289 [11]
n
60
85
279–281
o
45
90
193–195 [11]
a The structures of the products were settled from their spectral (1H NMR, IR, and MS) values.
preparation of substituted pyridines. In the absence of
this catalyst, the reaction did not proceed.
an oxidant under the reaction conditions, and no addi-
tional oxidant was required [9,11,12].
The formation of substituted pyridines in impressive
yields in the present reaction can be explained by a
mechanism (Scheme 2) related to that described by
Ranu et al. [12] for their high-yielding synthesis of pyri-
dines through a similar reaction in the presence of a ba-
sic ionic liquid. In both the cases, air played the role of
In conclusion, we have improved the process of syn-
thesis of the substituted pyridines from aldehydes, malo-
nonitrile, and thiols using KFꢀAl2O3 at room tempera-
ture. The use of (i) inexpensive solid-phase catalyst, (ii)
mild reaction conditions, (iii) impressive yields, and (iv)
operational simplicity are the notable advantages of the
present procedure.
Scheme 2
General Procedure for the Synthesis of Substituted
Pyridines. To a mixture of an aldehyde (0.5 mmol),
malononitrile (1 mmol) and thiophenol (0.5 mmol) dis-
solved in EtOH (5 mL) KFꢀAl2O3 (prepared by reported
method [15]) (10 mol%) was added, and the mixture
was stirred at room temperature. The reaction was moni-
tored by thin layer chromatography. After completion,
the mixture was filtered, and the filtrate was concen-
trated. The residue was purified by column chromatogra-
phy (silica gel, hexane-EtOAc) to obtain pure pyridine
derivative.
The spectral (IR, 1H NMR, and MS) data of the
unknown products are given.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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B. Das, B. Ravikanth, A. S. Kumar, and B. S. Kanth
Vol 46
1
1i: IR (KBr): 3427, 2209, 1614, 1543 cmꢂ1; H NMR
[3] Ma, X.; Gang, D. R. Nat Prod Rep 2004, 21, 752.
þ
[4] Levy, S. B.; Alekshun, M. N.; Podlogar, B. L.; Ohemeng,
K.; Verma, A. K.; Warchol, T.; Bhatia, B.; Bowser, T.; Grier, M. US
Pat. Appl. Publ. US 2005124678 A1 20050609, 2005.
[5] Perrier, V.; Wallace, A. C.; Kaneko, K.; Safar, J.; Prusiner,
S. B.; Cohen, F. E. Proc Natl Acad Sci USA 2000, 97, 6073.
[6] Kambe, S.; Satto. K. Synthesis 1981, 531.
(200 MHz, CDCl3 DMSO-d6): d 7.60–7.41 (6H, m),
7.04 (2H, d, J ¼ 8.0 Hz), 6.89 (2H, brs), 3.90 (3H, s);
FABMS: m/z 415, 417 [MþNa]þ. Anal. Calcd. for
C20H13ClN4OS: C 61.14, H 3.31, N 14.26; Found: C
61.82, H 3.43, N 14.38.
1
1l: IR (KBr): 34þ25, 2212, 1621, 1546 cmꢂ1; H NMR
[7] Chang, L. C. W.; von Frijtag Drabbe Kunzel, J. K.;
Mulder-Krieger, T.; Spanjersberg, R. F.; Roerink, S. F.; van den Hout,
G.; Beukers, M. W.; Brussee, J.; Ijzerman, A. P. J Med Chem 2005,
48, 2045.
(200 MHz, CDCl3 DMSO-d6): d 7.56 (2H, d, J ¼ 8.0
Hz), 7.42 (2H, d, J ¼ 8.0 Hz), 7.15 (1H, dd, J ¼ 8.0,
2.0 Hz), 7.06 (1H, d, J ¼ 2.0 Hz), 7.02 (1H, d, J ¼ 8.0
Hz), 6.79 (2H, brs), 3.96 (3H, s); 3.92 (3H, s); FABMS:
m/z 445, 447 [MþNa]þ. Anal. Calcd. for C21H15
ClN4O2S: C 59.64, H 3.55, N 13.25; Found: C 59.84, H
3.67, N 13.13.
[8] Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kor-
nienko, A. Org Lett 2006, 8, 899 and ref. cited therein.
[9] Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin,
M. Yu.; Magedov, I. V.; Kornienko, A. J org Chem 2007, 72, 3443.
[10] Movassaghi, M.; Hill, M. D. J Am Chem Soc 2006, 128, 4592.
[11] Reddy, T. R. K.; Mutter, R.; Heal, W.; Guo, K.; Gillet, V.
J.; Pratt, S.; Chen, B. J Med Chem 2006, 49, 607.
1
1n: IR (KBr): 34þ17, 2214, 1638, 1551 cmꢂ1; H NMR
[12] Ranu, B. C.; Jana, R. Sowmiah, S. J Org Chem 2007, 72,
3152 and ref. cited therein.
(200 MHz, CDCl3 DMSO-d6): d 8.50–8.36 (2H, m),
7.95–7.80 (2H, m), 7.54 (2H, d, J ¼ 8.0 Hz), 7.45 (2H, d,
J ¼ 8.0 Hz), 7.28 (2H, brs); FABMS: m/z 430, 432
[MþNa.]þ. Anal. Calcd. for C19H10ClN5O2S: C 55.95, H
2.45, N 17.17; Found: C 56.32, H 2.57, N 17.28.
[13] Guo, K.; Thompson, M. J.; Reddy, T. R. K.; Mutter, R.;
Chen, B. Tetrahedron 2007, 63, 5300.
[14] Anabha, E. R.; Nirmala, K. N.; Thomas, A.; Asokan, C. V.
Synthesis 2007, 428.
[15] Das, B.; Venkateswarlu, K.; Mahender. G.; Mahender, I.
Tetrahedron Lett 2005, 46, 3041.
Acknowledgments. The authors thank CSIR and UGC,
New Delhi, for financial assistance.
[16] Das, B.; Ramu, R.; Ravikanth, B.; Reddy, K. R. Tetrahe-
dron Lett 2006, 47, 779.
[17] Das, B.; Venkateswarlu, K.; Suneel, K.; Majhi, A. Tetrahe-
dron Lett 2007, 48, 5371.
REFERENCES AND NOTES
[18] Lenardao, E. J.; Ferreira, P. C.; Jacob, R. G.; Perin, G.;
Leite, F. P. L. Tetrahedron Lett 2007, 48, 6763.
[1] Boger, D. L.; Nakahara, S. J org Chem 1991, 56, 880.
[2] Zhang, T. Y.; Stout, J. R.; Keay, J. G.; Scriven, E. F. V.;
Toomey, J. E.; Goe, G. L. Tetrahedron 1995, 51, 13177.
[19] Sharifi, A.; Salimi, R.; Mirzaei, M.; Abaee, M. S. Synth
Commun 2007, 37, 1825 and ref. cited therein.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet