β-Cyclodextrin-catalyzed mild aromatization of hantzsch 1,4-dihydropyridines with o-iodoxybenzoic acid in water/acetone

Article abstract of DOI:10.1080/00397910902788133

Hantzsch 1,4-dihydropyridines undergo smooth aromatization oxidized by o-iodoxybenzoic acid (IBX) in water/acetone in the presence of-cyclodextrin (-CD) to afford the corresponding pyridine derivatives in excellent yields. The IBX and-CD can be recycled and reused.

Full text of DOI:10.1080/00397910902788133

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β-Cyclodextrin-Catalyzed Mild
Aromatization of Hantzsch
1,4-Dihydropyridines with o-
Iodoxybenzoic Acid in Water/
Acetone
Jiang-Min Chen a & Xiao-Mei Zeng a b
a College of Biological and Chemical Engineering,
Jiaxing University, Jiaxing, China
b State Key Laboratory for Chemical Fibers
Modification and Polymer Materials, Donghua
University, Shanghai, China
Published online: 04 Sep 2009.
To cite this article: Jiang-Min Chen & Xiao-Mei Zeng (2009): β-Cyclodextrin-Catalyzed
Mild Aromatization of Hantzsch 1,4-Dihydropyridines with o-Iodoxybenzoic Acid
in Water/Acetone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:19, 3521-3526
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Synthetic Communications1, 39: 3521–3526, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902788133
b-Cyclodextrin-Catalyzed Mild Aromatization
of Hantzsch 1,4-Dihydropyridines with
o-Iodoxybenzoic Acid in Water/Acetone
Jiang-Min Chen1 and Xiao-Mei Zeng1,2
1College of Biological and Chemical Engineering, Jiaxing University,
Jiaxing, China
2State Key Laboratory for Chemical Fibers Modification and Polymer
Materials, Donghua University, Shanghai, China
Abstract: Hantzsch 1,4-dihydropyridines undergo smooth aromatization
oxidized by o-iodoxybenzoic acid (IBX) in water=acetone in the presence of b-
cyclodextrin (b-CD) to afford the corresponding pyridine derivatives in excellent
yields. The IBX and b-CD can be recycled and reused.
Keywords: Aromatization, b-cyclodextrin, Hantzsh 1,4-dihydropyridines, o-iodo-
xybenzoic acid (IBX), pyridine derivatives
Solvent usage is often an integral part of a chemical or manufacturing
process. The unavoidable choice of a specific solvent for a desired chemi-
cal reaction can have profound economical, environmental, and societal
implications. The pressing need to develop alternative solvents to some
extent originates from these implications and constitutes an essential
strategy in the emerging field of green chemistry.[1,2] The 12 principles
are as follows: prevention, atom economy, less hazardous chemical synth-
esis, safer chemicals, safer solvents, energy efficiency, use of renewable
feedstocks, reduction of derivatives, catalysis, design for degradation,
real-time analysis for pollution prevention, and inherently safer chemistry
Received August 6, 2008.
Address correspondence to Jiang-Min Chen, College of Biological and
Chemical Engineering, Jiaxing University, Jiaxing 314001, China. E-mail:
chenjm@mail.zjxu.edu.cn
3521

3522
J.-M. Chen and X.-M. Zeng
for accident prevention. To meet this end, organic reactions in aqueous
medium could reduce the harmful effects of organic solvents.
Supramolecule catalysts, such as b-cyclodextrin,[3] employed in this kind
of reaction might become more sophisticated.
Hantzsch 1,4-dihydropyridines (1, Hantzsch 1,4-DHPs) are widely
used as calcium-channel blockers for the treatment of cardiovascular
disorder including angina, hypertension, and cardiac arrhythmias.[4]
These compounds are oxidized to pyridine derivatives by the action of
cytochrome P-450 in the liver.[5] In this respect, a convenient preparation
of pyridines from 1,4-DHPs is important for the identification of metabo-
lites. Furthermore, the oxidation of Hantzsch 1,4-DHPs provides easy
access to pyridine derivatives. Up to now, the aromatization of Hantzsch
1,4-dihydropyridines were well documented.[6] However, most of these
reactions were completed in organic solvents or used metal salts in an
aqueous medium at elevated temperatures.
o-Iodoxybenzoic acid (IBX), a well-known hypervalent iodine
reagent, is stable against moisture and highly efficient. Even though it
was discovered some time ago, its significant utilization as a reagent is
of recent origin as a result of its insolubility in most solvents except
dimethylsulfoxide (DMSO, the only solvent in which it does dissolve).[7]
The limited solubility of IBX has also led to many variations.[8] Among
these, the method developed by K. Surendra[3b] and coworkers, which
includes the use of b-cyclodextrin, may be of most interest. In continua-
tion of our study on the applications of hypervalent iodine reagents in
organic synthesis,[9] herein we report a mild and efficient aromatization
of Hantzsch 1,4-DHPs with IBX in the presence of b-cyclodextrin
(Scheme 1). The present method has advantages such as mild reaction
conditions, convenient manipulation, and good yields. The oxidation
reagent and catalyst could be regenerated and reused.
The reactions were carried out by dissolving b-cyclodextrin in water
at room temperature followed by the addition of Hantzsch 1,4-DHPs and
then IBX. The mixture was stirred at room temperature overnight to give
the corresponding pyridines. In all cases, excellent yields of pyridines 2
were obtained. 4-Aryl substrates 1a–g (entries 1a–1g) and 4-H-
1, 4-DHP derivatives, where R2 ¼ H, 1h–i respectively (entries 1h–1i),
Scheme 1. Aromatization of Hantzsch 1,4-dihydropyridines with IBX in the pre-
sence of b-cyclodextrin.

b-Cyclodextrin-Catalyzed Aromatization
3523
Table 1. b-Cyclodextrin-catalyzed aromatization of Hantzsch 1,4-dihydropyri-
dines with IBX in water=acetone
Entry R1
R2
Producta Yield (%)b Mp (ꢀC)c Lit. Mp (ꢀC)
1a
1b
1c
1d
1e
1f
Et C6H5
Et 2-Furyl
Et 4-MeOC6H4
Et 4-ClC6H4
Me C6H5
2a
2b
2c
2d
2e
2f
90
89
94
91
95
93
90
92
96
89
62–63
Liquid
51–52
61–62[6i]
Liquid[6i]
49–50[6i]
65–67
65–66[6i]
135–137
114–116
137–139
71–73
100–102
62–63
137[6h]
Me 4-MeOC6H4
Me 4-ClC6H4
115–117[6h]
138–140[6h]
70–71[6i]
1g
1h
1i
1ad
2g
2h
2i
Et
Me
H
H
101–103[6f]
61–62[6i]
Et C6H5
2a
aAll the products were characterized by melting points, H NMR, and IR and
compared with literature reports.
1
bYields are isolated and unoptimized.
cMelting points are uncorrected.
dRecycled IBX was used.
gave the products of oxidative aromatization 2a–i. This observation is in
accord with the reported behavior of these derivatives under other
oxidative conditions[6] (Table 1).
In these reactions, iodosobenzoic acid (IBA) obtained from the
reduction of IBX has been recycled by oxidation to IBX.[10] Cyclodextrin
has also been recovered and reused.
In conclusion, we have presented a mild and simple methodology for
the oxidation of a variety of Hantzsch 1,4-DHPs using IBX at room
temperature in water=acetone under supramolecular catalysis. The IBX
and b-CD can be recycled and reused.
EXPERIMENTAL
Melting points were uncorrected. 1H NMR spectra were recorded at
400 MHz in CDCl3 at 25ꢀC using a Bruker Avance 400 spectrometer in
CDCl3 with tetramethylsilane (TMS) as the internal standard and are
reported in parts per million (ppm). 13C NMR spectra were recorded
at 100 MHz in CDCl3 at 25ꢀC using a Bruker Avance 400 spectrometer
in CDCl3 with TMS as the internal standard and are reported in ppm.
Infrard (IR) spectra were recorded on a Shimadzu IR-408 spectrometer.
b-Cyclodextrin, a commercially available reagent, were used without
further purification. IBX[10] and Hantzsch 1,4-DHPs[11] were synthesized

3524
J.-M. Chen and X.-M. Zeng
followed the methods in literature. ‘‘In vacuo’’ refers to evaporation at
reduced pressure using a rotary evaporator and diaphragm pump,
followed by the removal of trace volatiles using a vacuum (oil) pump.
All the known products’ physical and spectroscopic data were compared
with those reported in the literature.
General Procedure for Aromatization
Hantzsch 1,4-DHP (1 mmol) in acetone (2 mL), was added to a solution
of b-cyclodextrin (0.1 mmol) in distilled water (15 mL), followed by IBX
(1.2 mmol) at room temperature. The reaction mixture was stirred at
room temperature for 12 h, and then the product was extracted with ethyl
acetate (3 ꢁ 15 mL). The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product thus obtained
was purified by column chromatography on silica gel (60–120 mesh)
using ethyl acetate=hexane (1:3) as eluent. After extraction with ethyl
acetate, the reaction mixture was filtered to isolate IBA, and the aqueous
phase was lyophilized to obtain the b-CD.
ACKNOWLEDGMENTS
We are grateful to the Foundation of Jiaxing University (Project No.
70105005).
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