274
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).
References
1. (a) G.W. Zamponi, S.C. Stotz, R.J. Staples, T.M. Andro, J.K.
Nelson, V. Hulubei, A. Blumenfeld, and N.R. Natale. J. Med.
Chem. 46, 87 (2003); (b) S. Visentin, B. Rolando, A. Di Stilo,
R. Frutterro, M. Novara, E. Carbone, C. Roussel, N. Vanthuyne,
and A. Gasco. J. Med. Chem. 47, 2688 (2004); (c) A. Zarghi,
H. Sadeghi, A. Fassihi, M. Faizi, and A. Shafiee. Farmaco, 58,
1077 (2003); (d) R. Peri, S. Padmanabhan, A. Rutledge, S.
Singh, and D.J. Triggle. J. Med. Chem. 43, 2906 (2000).
2. P.S. Kharkar, B. Desai, H. Gaveria, B. Varu, R. Loriya, Y.
Naliapara, A. Shah, and V.M. Kulkarn. J. Med. Chem. 45,
4858 (2002).
3. (a) G.S. Poindexter, M.A. Bruce, J.G. Breitenbucher, M.A.
Higgins, S.-Y. Sit, J.L. Romine, S.W. Martin, S.A. Ward, R.T.
McGovern, W. Clarke, J. Russell, and I. Antal-Zimanyi.
Bioorg. Med. Chem. 12, 507 (2004); (b) G.S. Poinder, M.A.
Bruce, K.L. LeBoulluec, I. Monkovic, S.W. Martin, E.M.
Parker, L.G. Iben, R.T. McGovem, A.A. Ortiz, J.A. Stanley,
G.K. Mattson, M. Kozlowski, M. Arcuri, and I.A. Zimanyi.
Bioorg. Med. Chem. Lett. 12, 379 (2002).
Diethyl 2,6-dimethyl-4-(p-fluorinephenyl)pyridine-3,5-
dicarboxylate (2g)
Yellow solid. IR (KBr, cm–1) νmax: 2989, 2928, 2905,
2856, 1736, 1716, 1607, 1559, 1513, 1446, 1385, 1294,
1
1235, 1163, 1106, 1047, 867, 851, 796. H NMR (CDCl3,
400 MHz) δH: 1.02 (t, 6H, J = 7.2 Hz), 2.62 (s, 6H), 4.06 (q,
4H, J = 7.2 Hz), 7.06~7.10 (m, 2H), 7.23~7.26 (m, 2H). m/z
(ESI): 346 (100%, [M + 1]+), 330 (21%, [M – CH3]+).
Diethyl 2,6-dimethyl-4-(4-hydroxy-3-
methoxyphenyl)pyridine-3,5-dicarboxylate (2m)
Yellow solid. IR (KBr, cm–1) νmax: 3424, 3064, 2997,
2934, 1740, 1721, 1613, 1569, 1514, 1441, 1384, 1281,
1215, 1130, 1043, 1008, 866, 836, 757, 691. 1H NMR
4. V. Klusa. Drugs Fut. 20, 135 (1995).
5. R.G. Bretzel, C.C. Bollen, E. Maeser, and K.F. Federlin. Drugs
Fut. 17, 465 (1992).
© 2005 NRC Canada