Aromatization of 1,4-dihydropyridines with selenium dioxide

Article abstract of DOI:10.1139/v05-058

1,4-Dihydropyridines were aromatized to corresponding pyridines using stoichiometric selenium dioxide at ambient temperature in a yield of 87%-98%.

Full text of DOI:10.1139/v05-058

273
RAPID COMMUNICATION / COMMUNICATION RAPIDE
Aromatization of 1,4-dihydropyridines with
selenium dioxide
Xiao-hua Cai, Hai-jun Yang, and Guo-lin Zhang
Abstract: 1,4-Dihydropyridines were aromatized to corresponding pyridines using stoichiometric selenium dioxide at
ambient temperature in a yield of 87%~98%.
Key words: 1,4-dihydropyridines, aromatization, oxidation, pyridine derivatives, selenium dioxide.
Résumé : Les 1,4-dihydropyridines sont aromatisés en pyridines correspondantes avec des rendements allant de 87 %-
98 % par traitement avec une quantité stoechiométrique de dioxyde de sélénium, à la température ambiante.
Mots clés : 1,4-dihydropyridines, aromatisation, oxydation, dérivés de la pyridine, dioxyde de sélénium.
[Traduit par la Rédaction] Cai et al. 275
Introduction
Scheme 1.
1,4-Dihydropyridines are calcium antagonists (1), antitu-
bercular agents (2), and neuropeptide Y Y1 receptor antagonists
(3). They possess neuroprotective (4), platet anti-aggregration
(5), and antidiabetic (6) activities. Aromatization of 1,4-
dihydropyridines has received considerable attention owing
to the fact that 1,4-dihydropyridine-based calcium channel
blockers are oxidatively converted to pyridine derivatives by
the action of cytochrome P-450 in the liver (7). In addition,
the corresponding pyridine derivatives show antihypoxic and
antiischemic activites (8). 1,4-Dihydropyridines can easily
be synthesized by Hantzsch condensation of aldehydes, β-
keto esters, and ammonia or ammonium acetate (7b, 9). 1,4-
Dihydropyridines have been aromatized to pyridines by vari-
ous reagents such as KMnO4 (10), HNO3 (11), DDQ (12),
NaNO2 (13), Zr(NO3)4 (14), Cu(NO3) (15), Bi(NO3)·5H2O
(16), Mn(OAc)3 (17), (NH4)4Ce(NO3)6 (18), urea nitrate and
K2S2O8–Co2+ (19), Pd/C (20), Pt(II) complex – hν (21),
GSNO (22), and O2 – activated carbon (23). Despite these
intensive efforts, most of the reported oxidation procedures
require long reaction time, utilize strong oxidants in large
excess, and afford products with only modest yields. In par-
ticular, the aromatization reaction with these reagents leads
to dealkylation of the 4-position or formation of side prod-
ucts (11, 24). Therefore, the development of more effective
methods for aromatization of 1,4-dihydropyridines is still
necessary.
Selenium dioxide was widely used for the oxidation of a
methylene group activated allyically or benzylically, or by
an adjacent carbonyl group (25). Here, we wish to describe a
simple and efficient precodure for the aromatization of 1,4-
dihydropyridines with selenium dioxide at room temperature
(Scheme 1).
Our initial attempts to aromatize 1,4-dihydropyridines
(1a) as a test case in EtOH, CH3CN, or THF at ambient or
thermal conditions led to corresponding pyridine 2a in very
low yield (<40%). But the aromatization of 1a in acetic acid
occurred smoothly to give the expected pyridine at room
temperature in 96% yield. The success of this reaction
prompted us to examine the aromatization of some 4-alkyl,
aryl, and alkenyl 1,4-dihydropyridines under the same condi-
tions. All reactions proceeded efficiently within 20~60 min to
provide the corresponding pyridines in good yields
(87%~98%, Table 1). With respect to the yields of the prod-
ucts, a 1:1 mol ratio of 1,4-dihydropyridines and selenium
dioxide in HOAc was optimal. The salient features for this
procedure are milder reaction conditions, shorter reaction
Received 30 September 2004. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on
29 March 2005.
X.-h. Cai. Chengdu Institute of Biology, the Chinese
Academy of Sciences, Chengdu 610041, P.R. China and
Chengdu Institute of Organic Chemistry, the Chinese
Academy of Sciences, Chengdu 610041, P.R. China.
H.-j. Yang, and G.-l. Zhang.1 Chengdu Institute of Biology,
the Chinese Academy of Sciences, Chengdu 610041, China.
1Corresponding author (e-mail: zhanggl@cib.ac.cn).
Can. J. Chem. 83: 273–275 (2005)
doi: 10.1139/V05-058
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Table 1. Aromatization of 1,4-dihydropyridines to pyridines by SeO2 at room temperature.
Producta
R
Time (min)
30
Yield (%)b
96
mp (°C)
2a
C6H5
63–65 (62 to 63 (14))
2b
2c
2d
2e
H
Me
n-Propyl
C6H5-CH2
20
20
40
40
97
97
92
90
71–72 (68 to 69 (14))
Yellow oil (liq (17))
Yellow oil (yellow oil (19))
Yellow oil (liq (26))
2f
C6H5-CH=CH
4-F-C6H5
50
40
50
20
40
60
96
94
98
95
94
89
162–164 (162 to 163 (17))
88–90
2g
2h
2i
4-Cl-C6H5
63–65 (65 to 66 (14))
55–57 (56–58 (19))
172 to 173 (171–173 (17))
72 to 73 (74–76 (27))
4-MeO-C6H5
4-HO-C6H5
2-NO2-C6H5
2j
2k
2l
2m
2-Furyl
4-HO-3-MeO-C6H5
60
50
87
92
Yellow oil (liq (17))
159 to 160
2n
2o
4-MeO-3-OH-C6H5
3,4-2Cl-C6H5
30
40
95
94
140–142
63–65 (66–68 (28))
aAll known compounds were characterized by comparing their spectral data with those reported.
bIsolated yields.
time, higher yield, avoidance of dealkylation or debenzyl-
ation at C-4, and stoichiometric oxidants used. Moreover,
this is a simple procedure for the separation of the products.
(CDCl3, 400 MHz) δH: 1.01 (t, 6H, J = 7.2 Hz), 2.59 (s, 6H),
3.86 (s, 3H, OCH3), 4.06 (q, 4H, J = 7.2 Hz), 5.68 (br s, 1H,
OH), 6.74 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 6.77~6.79
(m, 2H). m/z (ESI): 396 (100%, [M + Na+]), 374 (100%,
[M + 1]+).
Conclusion
An efficient and simple procedure for the aromatization of
1,4-dihydropyridines to correponding pyridine derivatives
with stoichiometric selenium dioxide was developed.
Diethyl 2,6-dimethyl-4-(3-hydroxy-4-
methoxyphenyl)pyridine-3,5-dicarboxylate (2n)
Yellow solid. IR (KBr, cm–1) νmax: 3432, 3045, 2984,
2934, 1738, 1724, 1613, 1559, 1507, 1441, 1382, 1267,
1
1213, 1130, 1045, 1008, 862, 841, 815, 755, 672. H NMR
Experimental
(CDCl3, 400 MHz) δH: 1.02 (t, 6H, J = 7.2 Hz), 2.58 (s, 6H),
3.91 (s, 3H, OCH3), 4.06 (q, 4H, J = 7.2 Hz), 5.62 (br s, 1H,
OH), 6.74 (dd, 1H, J = 8.4 Hz, J = 2.4 Hz), 6.83~6.87 (m,
2H). m/z (ESI): 374 (100%, [M + 1]+).
In a typical procedure, a mixture of 1a (165 mg,
0.5 mmol), selenium dioxide (66 mg, 0.5 mmol), and HOAc
(4 mL) was stirred at room temperature for 30 min. After
completion monitored by TLC, the reaction mixture was
quenched with a satd. aqueous NaHCO3 solution and the red
solid selenium was filtered off. The filtrate was extracted
with Et2O. The organic layer was washed with water, dried
over anhydr. MgSO4, and concentrated to give the pure prod-
uct 2a (156 mg, 96%), mp 63–65 °C (lit. value (14) mp 62
to 63 °C). Under similar conditions, various substituted 1,4-
dihydropyridines were converted to corresponding pyridines
(Table 1).
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