Aromatization of Hantzsch 1,4-dihydropyridines with I2-MeOH

Article abstract of DOI:10.1055/s-2000-7613

4-Alkyl or aryl substituted Hantzsch 1,4-dihydropyridines are aromatized to the corresponding pyridines in high yields by iodine in refluxing methanol. The method tolerates several substituents such as alkyl, benzyl, aryl and heterocyclic groups present i

Full text of DOI:10.1055/s-2000-7613

1532
SHORT PAPER
Aromatization of Hantzsch 1,4-Dihydropyridines with I2-MeOH#
Jhillu S. Yadav,* Basi V. Subba Reddy, Gowravaram Sabitha, Garudammagari S. Kiran Kumar Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 26 February 2000; revised 8 June 2000
Several 1,4-DHPs are aromatized to the corresponding
Abstract: 4-Alkyl or aryl substituted Hantzsch 1,4-dihydropy-
ridines are aromatized to the corresponding pyridines in high yields
by iodine in refluxing methanol. The method tolerates several sub-
stituents such as alkyl, benzyl, aryl and heterocyclic groups present
in the 4-position of pyridines.
pyridines in high yields by simply refluxing with iodine in
methanol. The results, summarized in the Tables 1 and 2,
indicate the scope of the reaction with respect to various
DHPs. In general, the reactions are very clean, high yield-
ing, and are completed within 4-10 hours. The method is
mild and tolerates several substituents like alkyl, benzyl,
aryl, and heterocyclic groups in the 4-position of dihydro-
pyridines. No debenzylation or dealkylation was observed
under the present reaction conditions, which are normally
encountered in aromatization by the oxidants.5 Also, no
side products are formed during the aromatization by I2-
MeOH whereas, nitrated side products are generally ob-
served in the aromatization of DHPs with metallic ni-
trates.5f
Key words: Hantzsch 1,4-dihydropyridines, iodine-MeOH, aroma-
tization
Hantzsch 1,4-dihydropyridines (1,4-DHPs) have attracted
considerable attention as calcium channel blockers for the
treatment of cardiovascular diseases1 and are oxidatively
transformed into the corresponding pyridine derivatives
by the action of cytochrome p-450 in the liver.2 Some of
Hantzsch 1,4-DHPs act as NADH mimics which can re-
duce the carbonyl compounds.3 Furthermore, the aromati-
zation of 1,4-DHPs provides an easy access to pyridine
derivatives.
It is of interest to observe that the reaction rates and yields
are dramatically increased by the addition of bases like al-
kali hydroxides, alkali fluorides, and organic bases (Table
1). Among various bases studied, alkali hydroxides are
found to be more efficient in this transformation. This
may be attributed to the in situ formation of hypoiodous
acid (HOI), which is deprotonated by the base. The result-
ing hypoiodite would dehydrogenate the dihydropyridine
to the corresponding pyridine.
Aromatization of 1,4-DHPs has been achieved by using
various oxidants.4 However, most of the oxidative meth-
ods suffer from the use of strong oxidants like CrO3,4a
KMNO4,5a HNO3,5b etc, and require drastic reaction
conditions6 or the need of excess oxidant.4b,d Consequent-
ly, there is a need to develop a mild and high yielding pro-
tocol for the aromatization of Hantzsch 1,4-
dihydropyridines. The use of iodine as oxidant for various
transformations like the oxidation of cyclohexenones to
anisoles7a,b and aldehydes to acids7c has been reported.
Herein, we report a new and efficient method for the aro-
matization of Hantzsch 1,4-dihydropyridines using the in-
expensive and readily available reagent iodine in
methanol.
In conclusion, the paper describes a novel and mild meth-
od for the aromatization of Hantzsch 1,4-dihydropy-
ridines using the inexpensive and easily available reagent
iodine in refluxing methanol. Due to the mild reaction
conditions, high yields of products, and compatibility of
various substituents, the procedure is highly advantageous
over existing methods.
Scheme
Synthesis 2000, No. 11, 1532–1534 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Aromatization of Hantzsch 1,4-Dihydropyridines with I2-MeOH
1533
Table 1 Aromatization of Hantzsch 1,4-dihydropyridines with I2-MeOH
Entry
Substrate
Reaction time & Yield (%)a
In absence of KOH
Melting points
In presence of KOH
25 min (97)
30 min (95)
15 min (93)
10 min (98)
15 min (96)
35 min (90)
20 min (88)
25 min (91)
30 min (93)
35 min (90)
20 min (87)c
25 min (89)c
20 min (92)
30 min (95)
Found/Literature4
a
b
c
d
e
f
C6H5
6 h (90)
8 h (91)
7 h (89)
4 h (93)
5 h (91)
10 h (86)
8 h (84)
6 h (87)
8 h (89)
10 h (89)
7 h (81)
8 h (85)
6 h (87)
7 h (84)
62–63
63–64
72–73
51–53
liquid
4-CH3C6H4
4-MeOC6H4
2-Thienyl
71–73
51–53
liquid
2-Furyl
liquid
liquid
4-NO2C6H4
C6H5CH=CH
2-CIC6H4
113–115
163–164
61–62
62–63
172–173
liquid
114–115
162–165
62
g
h
i
3-NO2C6H4
4-HOC6H4
C6H5CH2
61–63
171–173
liquid
j
k
l
(CH3)2CH
CH3(CH2)4CH2
CH3(CH2)8CH2
liquid
liquid
m
n
liquid
liquid
liquid
liquid
a Isolated yields after purification.
b All products were characterized by 1H NMR, IR spectra and melting points were uncorrected.
c Debenzylation and dealkylation were observed in the presence of base.
References
Pyridines 2a-n; General Procedure
#IICT Communication No. 4424
(1) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
Method A
A mixture of Hantzsch dihydropyridine (2 mmol) and I2 (2 mmol)
in MeOH (10 mL) was refluxed for 4-10 h. After complete conver-
sion, as indicated by TLC, the mixture was diluted with H2O and
extracted with EtOAc (2 ¥ 15 mL). The combined organic layers
were washed with 10% sodium thiosulfate and dried (Na2SO4). The
solvent was removed in vacuo and the resulting product was puri-
fied on silica gel column chromatography (Aldrich, 60-120 mesh,
EtOAc/hexane, 3:7) to afford the corresponding pyridine.
Janis, R. A.; Triggle, D. J. J. Med. Chem. 1983, 25, 775.
Wei, X. Y.; Rulledge, A.; Triggle, D. J. J. Mol. Pharmacol.
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Bocker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 28,
1596.
(2) Guengerich, F. P.; Brian, W. R.; Iwasaki, M.; Sari, M. A.;
Baarhielm, C.; Berntsson, P. J. Med. Chem. 1991, 34, 1838.
(3) Meyrs, A. I.; Brown, J. D. J. Am. Chem. Soc. 1987, 109, 3155.
(4) a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291.
b) Van-der Eynde, J. J.; Mayence, A.; Maquestiau, A.
Tetrahedron 1992, 48, 463.
Method B
To solutions of dihydropyridine (2 mmol) in MeOH (10 mL), a so-
lutions of I2 (2 mmol) and KOH (4 mmol) in MeOH (each 2 mL)
were successively added at 0 °C, and stirred for 15-35 min. On
completion, the mixture was diluted with H2O and extracted with
EtOAc (2 ¥ 15 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The result-
ing product was purified by column chromatography on silica gel
(Aldrich, 60-120 mesh, EtOAc/hexane, 3:7) to afford the corre-
sponding pyridine.
c) Ko, K. -Y.; Park, J. -Y. Bul. Korean. Chem. Soc. 1995, 16,
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d) Pfister, J. R. Synthesis 1990, 689.
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Haverbeke, Y. Tetrahedron 1995, 51, 6511. f) Mashraqui, S.
H.; Karnik, M. A. Synthesis 1998, 713.
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Lett. 1995, 36, 2269.
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Tetrahedron Lett. 2000, 41, 257.
Synthesis 2000, No. 11, 1532–1534 ISSN 0039-7881 © Thieme Stuttgart · New York

1534
J. S. Yadav et al.
SHORT PAPER
Table 2 Spectroscopic Data for Products 2a–n
Product
Molecular Formula
1H NMRa (CDCl3) d, J (Hz)
IRb n (cm−1)
2a
C19H21NO4
(327)
1.10 (t, 6 H, J = 6.8), 2.62 (s, 6 H), 4.02 (q, 4 H, J = 6.8), 7.25-
7.35 (m, 5 H)
3133, 1735, 1710, 1575, 1235,
1105, 1020
2b
2c
2d
2e
2f
C20H23NO4
(341)
1.15 (t, 6 H, J = 7.0), 2.38 (s, 3 H), 2.58 (s, 6 H), 4.05 (q, 4 H,
J = 7.0), 7.16 (m, 4 H)
3050, 3035, 1743, 1725, 1530,
1220, 1115, 1027
C20H23NO5
(357)
1.23 (t, 6 H, J = 6.8), 2.45 (s, 6 H), 3.65 (s, 3 H), 3.85 (q, 4 H,
J = 6.8), 6.76 (d, 2H, J = 8.0), 7.20 (d, 2H, J = 8.0)
3088, 1740, 1733, 1545, 1240,
1120, 1025
C17H19NO4S
(333)
1.05 (t, 6 H, J = 6.9), 2.55 (s, 6 H), 4.10 (q, 4 H, J = 6.9), 7.05-
7.35 (m, 3 H)
3055, 1745, 1730, 1540, 1240,
1110, 1020
C17H19NO5
(317)
1.20 (t, 6 H, J = 7.0), 2.50 (s, 6 H), 4.05 (q, 4 H, J = 7.0), 6.95-
7.30 (m, 3 H)
3064, 1742, 1737, 1538, 1242,
1112, 1021
C19H20N2O6
(372)
1.05 (t, 6 H, J = 6.9), 2.60 (s, 6 H), 4.01 (q, 4 H, J = 6.9), 7.45
(d, 2 H, J = 8.5), 8.25 (d, 2 H, J = 8.5)
3070, 1750, 1730, 1545, 1235,
1100, 1020
2g
2h
2i
C21H23NO4
(353)
1.13 (t, 6 H, J = 7.1), 2.34 (s, 6 H), 3.90 (q, 4 H, J = 7.1), 6.40
(d, 1 H, J = 16.6), 7.10 (d, 1 H, J = 16.6), 7.24-7.34 (m, 5 H)
3170, 1745, 1730, 1535, 1225,
1110, 1025
C19H20ClNO4
(361)
1.15 (t, 6 H, J = 6.8), 2.55 (s, 6 H) 4.10 (q, 4 H, J = 6.8), 7.15-
7.35 (m, 4 H)
3165, 1738, 1725, 1540, 1220,
1105, 1020
C19H20 N2O6
(372)
1.20 (t, 6 H, J = 7.0), 2.65 (s, 6 H), 4.08 (q, 4 H, J = 7.0), 7.65-
7.85 (m, 3 H), 8.20 (s, 1 H)
3170, 1745, 1730, 1545, 1230,
1120, 1015
2j
C19H21NO5
(343)
1.02 (t, 6 H, J = 6.8), 2.43 (s, 6 H), 3.95 (q, 4 H, J = 6.8), 6.85
(d, 2 H, J = 8.2), 7.20 (d, 2 H, J = 8.2), 9.5 (br s, OH)
3300, 1740, 1720, 1540, 1230,
1100, 1030
2k
2l
C20H23NO4
(341)
1.40 (t, 6 H, J = 6.8), 2.68 (s, 6 H), 4.45 (q, 4 H, J = 6.8), 5.15
(s, 2 H), 7.12-7.31 (m, 5 H)
3175, 3055, 1740, 1720, 1545,
1238, 1120, 1035
C16H23NO4
(293)
0.85 (d, 6 H, J = 6.8), 1.25 (t, 6 H, J = 7.0), 1.55 (m, 1 H), 2.65
(s, 6 H), 4.05 (q, 4 H, J = 7.0)
3098, 1745, 1725, 1540, 1225,
1105, 1020
2m
2n
C19H29NO4
(335)
0.90 (t, 3 H, J = 6.8), 1.25 (t, 6 H, J = 7.0), 1.35 (m, 8 H), 1.52
(t, 2 H, J = 6.8), 2.45 (s, 6 H) 4.10 (q, 4 H, J = 7.0)
3100, 1745, 1725, 1540, 1230,
1128, 1015
C23H37NO4
(391)
0.95 (t, 3 H, J = 6.9), 1.25 (t, 6 H, J = 7.1), 1.35 (m, 16 H), 1.55
(t, 2 H, J = 6.9), 2.45 (s, 6 H), 4.15 (q, 4 H, J = 7.1)
3125, 1740, 1720,1535, 1235,
1120, 1030
a 1H NMR spectra were recorded on a Varian Gemini-200 MHz spectrometer
b IR Spectra were recorded on a Nicolet-740 FTIR using KBr optics
(5) a) Vanden Eynde, J. J.; D Orazio, R.; Van Haverbeke, Y.
Tetrahedron 1994, 50, 2479.
(7) a) Kotis, A. S. Tetrahedron Lett. 1991, 32, 3441.
b) Kotis, A. S. Tetrahedron Lett. 1990, 31, 481.
c) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron
Lett. 1992, 33, 4329.
b) Bocker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 28,
1596.
(6) Kamal, A.; Ahmed, M.; Mohd. N.; Hamid, A. M. Bull. Chem.
Soc. Jpn. 1964, 37, 610.
Article Identifier:
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Synthesis 2000, No. 11, 1532–1534 ISSN 0039-7881 © Thieme Stuttgart · New York