Clinofen-A user-friendly oxidizing agent for very fast oxidation of Hantzsch 1,4-dihydropyridines

Full text of DOI:10.1134/S1070428007090254

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 9, pp. 1408–1410. © Pleiades Publishing, Ltd., 2007.
Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 9, pp. 1412–1413.
SHORT
COMMUNICATIONS
Clinofen—A User-Friendly Oxidizing Agent for Very Fast
Oxidation of Hantzsch 1,4-Dihydropyridines*
M. M. Heravi, Kh. Bakhtiari, H. A. Oskooie, and R. Hekmatshoar
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
e-mail: mmh1331@yahoo.com
Received June 25, 2005
DOI: 10.1134/S1070428007090254
Hantzsch 1,4-dihydropyridines have been exten-
sively utilized as analogs of NAD(P)H coenzymes to
study the mechanism and synthetic potential of various
redox processes [1, 2]. In addition, 1,4-dihydropyri-
dine-based drugs such as Nifedipine and Niguldipine
are widely used as calcium channel blockers for the
treatment of cardiovascular disorders, including steno-
cardia, hypertension, and cardiac arrhythmia [3].
1,4-Dihydropyridines are transformed into the corre-
sponding pyridines in the course of both redox proc-
esses [2] and metabolism [4]. Therefore, aromatization
of 1,4-dihydropyridines continues to attract attention
of researchers from the viewpoint of searching for
milder and general procedures applicable to a wide
range of substrates. A number of methods and reagents
have been reported recently for this purpose. They
generally involve the use of strong inorganic oxidants
such as nitric acid [5], ceric ammonium nitrate (CAN)
[6], iron(III) and copper(II) nitrates [7], potassium per-
manganate [8], chromium(VI) oxide [9], pyridinium
chlorochromate (PCC) [10], bentonite clay-supported
manganese(IV) oxide [11], bismuth nitrate pentahy-
drate [12], clay-supported copper(II) nitrate under
microwave activation [13], iron(III) nitrate on silica
gel (silfen) [14], etc. [15–18]. Disadvantages of these
procedures include the use of strong and toxic oxi-
dants, severe conditions, long reaction times, necessity
of excess reagent, formation of by-products, laborious
work-up, and poor yields of the target products.
In this communication we report a very convenient,
clean, and efficient procedure for the oxidation of
Hantzsch 1,4-dihydropyridines with clinoptilolite–
iron(III) nitrate (clinofen) [19]. Minerals of the clino-
ptilolite series are the most common rock-forming
minerals of sedimentary rocks of volcanic origin, the
latter being a source of natural zeolites. To the best of
our knowledge, this is the first report on the use of
clinoptilolite in organic synthesis. The reactions were
carried out by heating a mixture of 1 mmol of 1,4-di-
hydropyridine I, 1 g of clinoptilolite, and 1 mmol of
iron(III) nitrate in boiling chloroform for a very short
time. As a result, the corresponding pyridines were
formed in excellent yields. The products were isolated
by simple filtration of the reaction mixture, followed
by removal of the solvent. In the absence of clino-
ptilolite, the reaction was sluggish and (what is more
important) molten iron(III) nitrat nonahydrate adhered
to the wall of the reaction vessel. As followed from
spectroscopic data, the oxidation did not involve sub-
stituent in the 4-position of the pyridine ring.
Thus we have proposed a readily accessible reagent
for highly effective oxidation of Hantzsch 1,4-dihydro-
pyridines to the corresponding pyridine derivatives. It
O
R
O
O
R
O
Clinoptilolite–Fe(NO3)3 ·9H2O
CHCl3, reflux, 1–2 min
EtO
OEt
EtO
OEt
Me
N
H
Me
Me
N
Me
Ia–Ig
IIa–IIg
R = H (a), 4-ClC6H4 (b), Et (c), Ph (d), 3-O2NC6H4 (e), 4-MeOC6H4 (f), 2-furyl (g).
* The text was submitted by the authors in English.
1408

CLINOFEN—A USER-FRIENDLY OXIDIZING AGENT
1409
is advantageous due to very short reaction time, easy
and clean work-up, and excellent yields. As far as we
know, Clinofen is the fastest among known oxidants
for 1,4-dihydropyridines, and the proposed procedure
considerably improves their oxidation.
99%, mp 62–63°C; published data [21]: mp 61–63°C.
IR spectrum (KBr), ν, cm–1: 1535–1538, 1560, 1623,
1730, 2965, 3050. 1H NMR spectrum (CDCl3), δ, ppm:
1.1 t (6H, CH3), 2.4 s (6H, CH3), 4.2 q (4H, CH2),
7.7 d (2H, Harom), 8.2 s (1H, Harom), 8.3 m (2H, Harom).
1,4-Dihydropyridines Ia–Ig were synthesized ac-
cording to the procedure described in [20] from the
corresponding aldehydes, ammonia, and ethyl aceto-
acetate. All products were reported previously; their
physical constants and spectral parameters coincided
with those of authentic samples.
Diethyl 4-(4-methoxyphenyl)-2,6-dimethylpyri-
dine-3,5-dicarboxylate (IIf). Reaction time 2 min.
Yield 98%, mp 50°C [22]. IR spectrum (KBr), ν, cm–1:
1115, 1292, 1515, 1615, 1730, 2970. H NMR spec-
trum (CDCl3), δ, ppm: 1.1 t (6H, CH3), 2.4 s (6H,
1
CH3), 3.8 s (3H, CH3O), 4.2 q (4H, CH2), 6.7 d (2H,
H
arom), 7.2 d (2H, Harom).
General procedure for the oxidation of 1,4-dihy-
dropyridines Ia–Ig with iron(III) nitrate–clinoptilo-
lite. Iron(III) nitrate nonahydrate, 0.4 g (1 mmol), was
mixed with 1 g of clinoptilolite in 10 ml of chloroform,
1 mmol of 1,4-dihydropyridine Ia–Ig was added, and
the mixture was heated for 1–2 min under reflux. The
progress of reactions was monitored by TLC using
petroleum ether–ethyl acetate as eluent. When the re-
action was complete, the mixture was filtered, and the
filtrate was evaporated to dryness under reduced pres-
sure. The residue was the corresponding pure pyridine
IIa–IIg.
Diethyl 4-(2-furyl)-2,6-dimethylpyridine-3,5-di-
carboxylate (IIg). Reaction time 2 min. Yield 99%,
oily substance (cf. [23]). IR spectrum (KBr), ν, cm–1:
1
1046, 1107, 1561, 1575, 1730, 2984, 3075. H NMR
spectrum (CDCl3), δ, ppm: 1.1 t (6H, CH3), 2.4 s (6H,
CH3), 4.2 q (4H, CH2), 6.2–6.5 m (2H, furyl), 7.4 s
(1H, furyl).
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1410
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