Iodoxybenzoic acid (IBX): An efficient and novel oxidizing agent for the aromatization of 1,4-dihydropyridines

Article abstract of DOI:10.1055/s-2005-918519

Hantzsch 1,4-dihydropyridines undergo smooth aromatization catalyzed by iodoxybenzoic acid (IBX) to afford the corresponding pyridine derivatives in high yields. All the reactions were carried out in DMSO solvent at 80-85 °C for a period of two to four ho

Full text of DOI:10.1055/s-2005-918519

PAPER
451
Iodoxybenzoic Acid (IBX): An Efficient and Novel Oxidizing Agent for the
Aromatization of 1,4-Dihydropyridines1
I
odoxyben
.
zoic
A
cid S.Yadav,* B. V. S. Reddy, A. K. Basak, G. Baishya, A. Venkat Narsaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax yadavpub@iict.res.in; E-mail: +91(40)27160512
Received 7 July 2005; revised 17 August 2005
of excess oxidant and also the yields reported are far from
satisfactory. Thus, there is a need for the development of
novel reagents that provide beneficial levels of mildness
and efficiency.
Abstract: Hantzsch 1,4-dihydropyridines undergo smooth aromati-
zation catalyzed by iodoxybenzoic acid (IBX) to afford the corre-
sponding pyridine derivatives in high yields. All the reactions were
carried out in DMSO solvent at 80–85 °C for a period of two to four
hours to complete conversion of the substrates.
O
R
O
O
R
O
Keywords: hypervalent iodine reagents, dihydropyridines, aroma-
tization, DMSO, pyridine derivatives
IBX
EtO
Me
OEt
Me
EtO
Me
OEt
Me
DMSO, 80–85 °C
N
H
N
1
2
Hypervalent iodine reagents have recently attracted much
attention as powerful oxidants in organic synthesis be-
cause of their selective and mild oxidizing properties.2
Among the various hypervalent iodine reagents, o-iodoxy-
benzoic acid (IBX) is a versatile oxidizing agent due to its
high efficiency, ease of preparation, mild reaction condi-
tions and its stability against moisture and air. A wide
range of functional group tolerance and high-yielding re-
actions without over oxidation have made IBX very famil-
iar for the oxidation of various alcohols. Recently, the use
of IBX as a mild oxidant has been extended to many other
elegant oxidative transformations by Nicolaou et al.3
Scheme 1
In continuation of our interest in developing new synthetic
methodologies7 herein, we wish to report an efficient pro-
tocol for the aromatization of Hantzsch 1,4-dihydropy-
ridines using the inexpensive and readily available
iodoxybenzoic acid (IBX) as the novel oxidant
(Scheme 1). For instance the treatment of diethyl 2,6-di-
methyl-4-(p-methoxyphenyl)pyridine-3,5-dicarboxylate
with IBX (1.5 equiv) in DMSO at 80–85 °C for 2.5 hours
afforded the corresponding pyridine derivative 2a in 86%
yield. In a similar manner, various Hantzsch 1,4-dihydro-
pyridines were aromatized without any problem. To es-
tablish the generality of this method, various alkyl, aryl
and heterocyclic substituents present on Hantzsch 1,4-di-
hydropyridines were oxidized under these reaction condi-
tions. In all cases, the reactions proceeded readily with
high efficiency. The influence of various solvents on the
yield of the reaction was investigated using EtOAc,
MeCN, CH2Cl2, CHCl3, THF and MeOH. The oxidation
reaction takes place smoothly in DMSO solvent and the
products were obtained in very good yields. This can be
attributed to the enhanced solubilizing power of the sol-
vent for the oxidation as well as the substrate. In general,
the reactions are very clean, high yielding and complete
within two to four hours reaction time.
Hantzsch 1,4-dihydropyridines are often regarded as the
models of the naturally reduced nicotinamine adenine di-
nucleotide [NADH] co-enzyme which functions as redox
reagent for biological reactions. 1,4-Dihydropyridines are
rapidly emerging as the most important class of drugs for
the treatment of cardiovascular disease.4 These com-
pounds generally undergo oxidative metabolism in the
liver by the action of cytochrome p-450 to form the corre-
sponding pyridine derivatives, which exhibit anti-hypoxic
and anti-ischemic activities. Further, metabolism involves
the cleavage of the ester groups. Some of the representa-
tives of this class show acaricidal, insecticidal, bactericid-
al and herbicidal activities. On the other hand, these
compounds are starting materials for the synthesis of anti-
bacterial 1,6-naphthyridines and 1,2-benzisoazalenes.5
The oxidation of Hantzsch 1,4-dihydropyridines is one of
the ubiquitous issues in organic chemistry. Generally,
strong oxidants such as CrO3, HNO3, KMnO4, cupric ni-
trate, ferric nitrate and CAN, and pyridinium chromate
have been used to accomplish this oxidation.6 However,
many of these methods suffer from the use of strong acidic
conditions and require extended reaction times or the need
The possible mechanism for the oxidation reaction using
IBX, proceed via an ionic, concerted pathway or by an en-
suing single electron transfer (SET) from 1,4-dihydropy-
ridine to the iodoxybenzoic acid to afford a nitrogen
radical cation, followed by fragmentation (Scheme 2).
Both of these processes consequently supply the desired
pyridine derivatives along with o-iodosobenzoic acid
(IBA). This method is very mild and tolerates several sub-
stituents present on alkyl, alkoxy, benzyl, cinnamyl and
heterocyclic groups, which were in the 4-position of dihy-
dropyridines. No debenzylation or dealkylation was ob-
SYNTHESIS 2006, No. 3, pp 0451–0454
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918519; Art ID: Z13405SS
© Georg Thieme Verlag Stuttgart · New York

452
J. S. Yadav et al.
PAPER
A. Ionic mechanism:
R
H
R
H
EtO2C
CO2Et
EtO2C
OH
O
R
N
O
N
H
N
I
HO OH
EtO
OEt
HO
I
O
H2O
O
I
O
O
O
O
O
B. SET mechanism:
R
H
R
H
R
R
H
EtO2C
CO2Et
EtO2C
CO2Et
EtO2C
CO2Et
EtO2C
CO2Et
N
H
N
N
I
N
SET
– H2O
HO OH
HO
HO
I
O
HO OH
I
I
O
O
O
O
O
O
O
O
R
N
OH
EtO2C
CO2Et
I
O
H2O
O
Scheme 2 Proposed ionic (A) and single-electron-transfer (B) mechanism leading to the formation of pyridine derivatives mediated by IBX.
Table 1 Aromatization of Hantzsch 1,4-Dihydropyridines with IBX in DMSO
Entry
Substrate
Producta
2a
Reaction Time (h)
Yield (%)b
Mpc
51–52
112–113
62–63
161–162
–
a
b
c
d
e
f
4-MeOC6H4
4-NO2C6H4
C6H5
2.5
3.5
2.0
3.0
2.0
4.0
3.5
4.0
2.5
3.5
3.0
3.5
4.0
3.0
4.0
86
88
90
83
90
84
89
80
90
83
88
82
84
80
82
2b
2c
C6H5CH=CH
2-Furyl
2d
2e
C6H5CH2
2f
–
g
h
i
4-CH3C6H4
CH3(CH2)4CH2
3,4(OCH3)2C6H3
(CH3)2CH
4-ClC6H4
2g
71–72
–
2h
2i
100–101
–
j
2j
k
l
2k
2l
69–72
79–80
73–75
84–86
2-Thienyl
m
n
o
2-NO2C6H4
3-Pyridyl
2m
2n
2o
CH3(CH2)8CH2
a All the products were characterized by 1H NMR, IR and mass spectroscopy and compared with literature reports.5
b Yields are isolated and unoptimized.
c Melting points are uncorrected.
Synthesis 2006, No. 3, 451–454 © Thieme Stuttgart · New York

PAPER
Iodoxybenzoic Acid
453
Diethyl 1,6-Dimethyl-4-n-hexylpyridine-3,5-dicarboxylate (2h)
IR (KBr): 2991, 2879, 1739, 1724, 1576, 1438, 1286, 1221, 1107,
1033, 923, 847, 759 cm–1.
1H NMR (CDCl3): d = 0.98 (t, J = 6.5 Hz, 3 H), 1.28 (t, J = 6.8 Hz,
6 H), 1.33–1.43 (m, 8 H), 1.55 (t, J = 6.5 Hz, 2 H), 2.50 (s, 6 H),
4.17 (q, J = 6.8 Hz, 4 H).
13C NMR (CDCl3): d = 14.8, 23.2, 23.9, 32.3, 33.9, 62.8, 122.0,
126.9, 145.8, 155.6, 169.2.
EIMS: m/z (%) = 335 (41) [M+], 277 (22), 189 (100), 150 (18), 109
(42), 71 (53), 43 (41).
served under the present reaction conditions, which are
normally observed in aromatization of dihydropyridines
by other oxidants. No side-products are formed during the
aromatization by IBX while nitrated side-products are
generally observed in the aromatization of dihydropy-
ridines with metallic nitrates. The results obtained with
various 4-substituted 1,4-dihydropyridines are summa-
rized in the Table 1.
In summary, we showed that IBX could function as an ef-
ficient oxidant for the aromatization of Hantzsch 1,4-di-
hydropyridines. This method offers significant
advantages such as the use of inexpensive, air- and mois-
ture-stable oxidant, mild reaction conditions and compat-
ibility with a variety of substituents present in the
dihydropyridine skeleton, and easy workup procedure for
the isolation of products.
Acknowledgment
AKB and GB thanks to CSIR, New Delhi for the award of fel-
lowship.
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General Procedure
A mixture of Hantzsch dihydropyridine (2 mmol) and IBX (3
mmol) in DMSO (2 mL) was heated at 80–85 °C for 2–4 h
(Table 1). After complete conversion, as indicated by TLC, the re-
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15 mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to obtain the crude products,
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Synthesis 2006, No. 3, 451–454 © Thieme Stuttgart · New York

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PAPER
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Synthesis 2006, No. 3, 451–454 © Thieme Stuttgart · New York