O-iodoxybenzoic acid in water: Optimized green alternative for multicomponent one-pot synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridines

Article abstract of DOI:10.1590/S0103-50532012000500024

A multicomponent one-pot reaction of aromatic aldehyde, malononitrile and thiophenol in the presence of iodoxybenzoic acid (IBX) in aqueous media furnished 2-amino-3,5-dicarbonitrile-6-thiopyridine in good to excellent yield. Eventually, a catalyst could

Full text of DOI:10.1590/S0103-50532012000500024

J. Braz. Chem. Soc., Vol. 23, No. 5, 966-969, 2012.
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Short Report
S
O-Iodoxybenzoic Acid in Water: Optimized Green Alternative for Multicomponent
One-Pot Synthesis of 2-Amino-3,5-dicarbonitrile-6-thiopyridines
Santosh Takale,a Jaidas Patil,a Vikas Padalkar,b Rajaram Pisala and Atul Chaskar*,c
aChangu Kana Thakur Research Centre, 410206 Navi Mumbai, India
bInstitute of Chemical Technology, Matunga, 400019 Mumbai, India
cDepartment of Chemistry, National Taiwan University, 10617 Taipei, Taiwan
Uma reação multicomponente do tipo one-pot de aldeído aromático, melanonitrilo e tiofenol
na presença de ácido iodoxibenzóico (IBX) em meio aquoso forneceu 2-amino-3,5-dicarbonitrilo-
6-tiopiridina em bons a excelentes rendimentos. Eventualmente, um catalisador poderia ser
facilmente recuperado e reutilizado sem perda de sua propriedade catalítica.
A multicomponent one-pot reaction of aromatic aldehyde, malononitrile and thiophenol in the
presence of iodoxybenzoic acid (IBX) in aqueous media furnished 2-amino-3,5-dicarbonitrile-
6-thiopyridine in good to excellent yield. Eventually, a catalyst could be easily recovered and
reused without loss of its catalytic property.
Keywords: O-iodoxybenzoic acid, green catalyst, thiopyridines, aqueous media,
multicomponent reactions
Introduction
octane),5,12 morpholine, thiomorpholine, pyrrolidine,
N,N-DIPEA (N,N-diisopropylethylamine), pyridine,
2,4,6-collidine (2,4,6-trimethylpyridine), DMAP
(4-dimethylaminopyridine), aniline, N-methylaniline,
N,N-dimethylaniline and N,N-diethylaniline have been
employed for this multicomponent reaction.12 In addition,
basic ionic liquids 1-methyl-3-butylimidazolium hydroxide,
[bmim]OH,12 DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene)12 and TBAH (tetrabutylammonium hydroxide)12 have
also been used for this reaction. Sridhar et al.13 showed that
this reaction can be carried out using Lewis acid catalyst
(ZnCl2), which shows better results than base catalyzed
reactions. Recently, boric acid in combination with cetyl
trimethyl ammonium bromide (surfactant) has also been
employed for this reaction.14
In view of the increasingly strict environment
legislation, the present day catalysis research is drifted
towards the development of heterogeneous catalysts in
aqueous media which are paving the way towards the
realization of environmental and eco-friendly synthetic
protocols, consequently transforming into greener
technology. Iodoxybenzoic acid (IBX) has been drawing
attention in synthetic organic chemistry for its promising
role as oxidant. Though moderately soluble in organic
solvents, it aids in oxidation of alcohols into carbonyl
The nitrogen heterocycles have been intensively
investigated in past decades due to their ubiquitous presence
in biologically active compounds and multifarious natural
products. Pyridine ring system represents the major class
of nitrogen heterocycles and its analogues exhibited diverse
biological and physiological activities, such as antibacterial,
antiviral, anti-inflammatory, antitumoural and antioxidant.
These potential therapeutic applications made it as a
privileged scaffold.1-3
2-Amino-3,5-dicarbonitrile-6-thiopyridine derivatives
are not only used as anti-prion,4,5 anti-hepatitis B virus,6
anti-bacterial7 and anti-cancer8 agents but also are used
as potassium channel openers for the treatment of urinary
incontinence.9
Recently, it is being used in treatment of Parkinson’s
disease, hypoxia, asthma, kidney disease, epilepsy,
cancer10 and creutzfeldt-jacob disease.11 In view of
their high significance, many methodologies have
been developed for the construction of the pyridine
skeleton. Various basic catalysts like piperidine, Et3N
(N(CH2CH3)3), DABCO (1,4-diazabicyclo[2.2.2]
*e-mail: achaskar25@gmail.com

Vol. 23, No. 5, 2012
Takale et al.
967
Table 1. Screening of the catalystsa
entry
Catalyst
Reaction temperature / °C
time / h
4.0
Yieldb / %
1
2
3
4
5
6
7
β-cyclodextrin
reflux
reflux
reflux
reflux
reflux
reflux
70
32
38
49
56
58
60
80
ceric ammonium nitrate (CAN)
ceric ammonium sulfate (CAS)
tetrabutyl ammonium hydrogen sulfate (TBHS)
urea-hydrogen peroxide (UHP)
cuprous chloride (CuCl)
4.0
5.0
4.0
3.5
3.0
iodoxybenzoic acid (IBX)
1.5
aCondition: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol (1 mmol), catalyst (10 mol%); bisolated yield.
compounds,15 simple phenols to ortho-quinones,16
polycyclic aromatic phenols to polycyclic aromatic
quinones,17 benzocyclic compounds and amines.18
Besides this, it is also applied for preparation of carbonyl
compounds,18 N-heterocycles18 and in oxidative cleavage
of dithioacetals and dithioketals.18 IBX also offers
selective deprotection of triethylsilyl ethers along with
tert-butyldimethylsilyl (TBDMS) ethers.19
With all these applications of IBX in mind and its
mild, chemo-selective nature and our interest in exploring
its catalytic properties20 prompted us to use it in aqueous
medium for the synthesis of 2-amino-3,5-dicarbonitrile-
6-thiopyridines. The relevance of this methodology
stems from the fact that all the aforementioned protocols
encounter disadvantages, such as prolonged reaction
time, tedious catalyst preparation and workup, formation
of inevitable side or sticky products, exhaustive usage of
energy sources and solvents that lead to lower yield of
desired product and environmental hazard.
sulfate (TBHS), urea-hydrogen peroxide (UHP), cuprous
chloride (CuCl) and iodoxybenzoic acid (IBX). Table 1
displays the effect of the catalysts on the reaction rate and
product yield.
Fast reaction rate and enhanced product yield were
observed in the IBX-mediated reaction presumably due
to the ability of hypervalent iodine for a coordination
complex, resulting into polarization of carbonyl and nitrile
groups which speed up the Knoevenagel condensation and
Michael addition (first two steps of the multicomponent
condensation).
Since IBX is a selective oxidizing agent at its
stoichiometric levels, in order to optimize the catalyst
quantity, the model reaction was carried out with different
quantities of IBX such as 2, 5, 10 and 15 mol%. 10 mol%
of IBX with respect to benzaldehyde was found to be
optimal (Table 2).
Table 2. Optimization of iodoxybenzoic acid (IBX) as catalysta
Here, we disclose an efficient and environmental benign
method for the synthesis of 2-amino-3,5-dicarbonitrile-
6-thiopyridines in presence of IBX as catalyst in good to
excellent yield, as shown in Scheme 1.
entry
Iodoxybenzoic acid / mol%
Yieldb / %
1
2
3
4
2
5
40
68
80
80
10
15
Ar
NC
CN
aCondition: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol
(1 mmol), IBX; bisolated yield.
O
H
IBX, H2O
70 oC
CN
CN
S
2
H2N
N
S
Ar
H
Ar'
Ar'
1
2
3
4 a-n
All the aforementioned results encouraged us to
plan the synthesis of several 2-amino-3,5-dicarbonitrile-
6-thiopyridines by treating various substituted aromatic
aldehydes with malononitrile and thiophenols (Table 3). The
products are accomplished in good to excellent yields and
their physical and spectral data are in agreement with
literature reports.12,14,21 Indeed, the method has the ability to
tolerate functional groups such as methoxy, nitro, halides, etc.
The recovery and reusability of the catalyst are
crucial in environmental benign large scale protocols and
Scheme 1. Synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridines.
Results and Discussion
With a view to find optimum reaction conditions
for the condensation reaction, preliminary efforts were
mainly focused on the evaluation of different catalysts
viz. β-cyclodextrin, ceric ammonium nitrate (CAN), ceric
ammonium sulfate (CAS), tetra butyl ammonium hydrogen

968
O-Iodoxybenzoic Acid in Water
J. Braz. Chem. Soc.
Table 3. Synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridinesa
entry
1
Compound
Ar
Ar’
time / h
1.5
1.5
2.0
2.0
1.5
1.5
1.5
2.0
1.5
2.0
2.0
2.0
2.0
2.5
Yieldb / %
80
mpc / oC
219-220
208-210
242-243
229-230
289-291
258-260
222-223
280-282
255-257
289-290
227-228
243-244
223-225
273-275
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
2
4-Me-Ph
72
3
4-OMe-Ph
3,4-(OMe)2-Ph
4-NO2-Ph
4-NO2-Ph
4-Cl-Ph
Ph
70
4
Ph
78
5
Ph
83
6
2-Br-Ph
Ph
82
7
4g
4h
4i
80
8
2,6-Cl-Ph
4-Br-Ph
2,4,6-Me3-Ph
Ph
75
9
82
10
11
12
13
14
4j
4-Cl-Ph
2,4,6-Me3-Ph
Ph
73
4k
4l
3,4-(OMe)2-Ph
3,4-Me2-Ph
4-Me-Ph
69
2-Me-Ph
2-Me-Ph
4-Cl-Ph
71
4m
70
4n
3,4-(OMe)2-Ph
72
aCondition: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol (1 mmol), IBX (10 mol%), H2O (5 mL), temperature of 70 oC; bisolated yield;
cmp: melting point.
from the industrial point of view. In this protocol, after
completion of the reaction, IBX was recovered by simple
filtration, washed with little quantity of water and then
dried. IBA, the reduction product of IBX obtained upon
completion of reaction, was oxidized back to IBX. Thus,
gained IBX has revealed identical chemical and physical
characteristics to those of standard IBX. In this manner, it
was recovered about 55-60% of IBX and reused for further
three successive reaction cycles offering consistent yield
of products.
spectrophotometer in a KBr disc, and the absorption
1
bands are expressed in cm-1. H NMR (nuclear magnetic
resonance) spectra were recorded on a Varian AS 300 MHz
spectrometer in DMSO-d6, chemical shifts (d) are in ppm
(parts per million) relative to TMS (tetramethylsilane).
General procedure for the synthesis of 2-amino-
3,5-dicarbonitrile-6-thiopyridines
A solution of aldehyde (1 mmol), malononitrile
(2 mmol) and a thiophenol (1 mmol) in water (5 mL)
was stirred at 70 °C in the presence of catalytic amount
of IBX (10 mol%, 0.28 g). The progress of the reaction
was monitored by TLC. After completion of the reaction,
the product was extracted with diethyl ether (2 × 5 mL).
The combined organic layer was then washed with brine
(2 × 5 mL), and dried over MgSO4. The solvent was
evaporated under reduced pressure and the crude product
obtained was purified by column chromatography followed
by recrystallization from ethanol. The catalyst was
recovered from aqueous layer by simple filtration.
Conclusion
The present work highlights IBX as an inexpensive,
non-corrosive and environmentally benign catalyst for the
synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridines.
We anticipate that short reaction time, easy catalyst
recovery, aqueous reaction medium and high yield of
product could make this protocol a good alternative to the
existing protocols.
Experimental
Physical and spectral data of the product
All commercial reagents were used as received without
purification and all solvents were reagent grade. The reaction
was monitored by TLC (thin layer chromatography) using
on 0.25 mm E-Merck silica gel 60 F254 precoated plates,
which were visualized with UV light. Melting points (mp)
were taken in open capillaries on a Veego apparatus and are
uncorrected. Infrared spectra were recorded on a Simadzu
2-Amino-4-(4-methoxyphenyl)-6-(phenylthio)pyridine-
3,5-dicarbonitrile (4c)
IR (KBr) n/cm-1 3437, 3327, 3228, 3074, 2926, 2220,
1
1628, 1529; H NMR (DMSO-d6, 300 MHz) d 3.61 (s,
3H), 7.1 (d, 2H, J 7.8 Hz), 7.18-7.20 (m, 3H), 7.7 (d, 2H,
J 7.8 Hz), 7.45 (d, 2H), 7.78 (s, 2H).

Vol. 23, No. 5, 2012
Takale et al.
969
Supplementary Information
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Pratt, S.; Thompson, M. J.; Chen, B.; Eur. J. Med. Chem.
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1
The spectroscopic H NMR and IR data of selected
compoundareavailablefreeofchargeathttp://jbcs.sbq.org.br
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Acknowledgment
We appreciate the generous support from Dr. S.T. Gadade,
Changu Kana Thakur College, India.
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Submitted: December 11, 2011
Published online: March 27, 2012