Oxidative aromatization of Hantzsch 1,4-dihydropyridines by sodium chlorite

Article abstract of DOI:10.1016/j.tetlet.2010.05.091

Hantzsch 1,4-dihydropyridines were converted to the corresponding pyridines efficiently by sodium chlorite under mild conditions in excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.05.091

Tetrahedron Letters 51 (2010) 3859–3861
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Oxidative aromatization of Hantzsch 1,4-dihydropyridines by sodium chlorite
Xiali Liao a,b, Wenbin Lin a, Jun Lu a, Chun Wang a,
*
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate School of the Chinese Academy of Sciences, Beijing 100039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Hantzsch 1,4-dihydropyridines were converted to the corresponding pyridines efficiently by sodium
chlorite under mild conditions in excellent yields.
Received 27 April 2010
Revised 19 May 2010
Accepted 21 May 2010
Available online 25 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
To our knowledge, the use of sodium chlorite to oxidize 1,4-DHPs
has never been reported before. Herein, we described an efficient,
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are important car-
diovascular drugs due to their calcium antagonistic effect.1 The
oxidation of 1,4-DHPs into the corresponding pyridines is one of
the main metabolic pathways of these drugs. This process is cata-
lyzed by the cytochrome P450 (CYP) 3A4 isoform.2 In addition, 1,4-
DHPs were also used in modeling the coenzymes NADH in its bio-
logical redox processes.3 In order to understand these biological
systems, as well as to develop new methods for preparing poly-
substituted pyridines, considerable attention has been paid to the
oxidative aromatization of 1,4-DHPs. However, most reported
methods involved strong oxidants, such as HNO3,4 KMnO4,5
CAN,6 and PCC.7 Alternative efforts have been made to electro-
chemical oxidation and catalytic aerobic oxidation using RuCl3,
Pd/C, or activated carbon as catalysts.8–11 These processes still exist
with at least one of the following drawbacks, such as long reaction
time, only modest yields, harsh reaction conditions, expensive or
toxic reagents, inconvenient preparation of reagents and tedious
workup procedures. In particular, the undesirable dealkylation on
4-position or the formation of side products was detectable.12
Therefore, development of efficient, mild, and environmentally
friendly methods for aromatization of 1,4-DHPs are still desirable.
Sodium chlorite (NaClO2) is a relatively inexpensive and green
reagent which is widely used in disinfection of drinking water.
convenient, and economic method for the aromatization of 1,4-
DHPs by sodium chlorite in the presence of hydrochloric acid as
in Scheme 1.
2. Results and discussion
Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicar-
boxylate 1a was chosen as the model compound to establish a gen-
eral procedure for the reaction. A series of solvent systems were
screened with 1.0 equiv of NaClO2 at 20 °C (Table 1, entries 1–6).
Presumably, the oxidation was conducted by chlorine dioxide
(ClO2) which can be readily generated from hydrochloric acid-acti-
vated NaClO2,13 the reaction was designed to run under acidic con-
ditions. The reactions in THF, CH2Cl2, Et2O, and EtOH all proceeded
smoothly to give modest to excellent yields when concd HCl
(12 M) was added. Nonetheless, the use of CH3COOH without HCl
dramatically decreased the yield (Table 1, entry 5), and the use
of water could not afford any product even in the presence of
HCl (Table 1, entry 6). Mixed solvents, EtOH/H2O (1:1) gave an
excellent yield (up to 92%) (Table 1, entry 7). In terms of oxidant
loading, 1.5 equiv of NaClO2 gave the best yield in much shorter
time (Table 1, entry 8).
R
H
R
EtO2C
CO2Et
NaClO2 (1.5 equiv)
EtO2C
CO2Et
EtOH/H2O (1:1), HCl (con.), 20 °C
N
H
1
N
2
Scheme 1. Oxidative aromatization of 1,4-DHPs by sodium chlorite.
* Corresponding author. Tel./fax: +86 28 85225401.
E-mail address: wangchun@cib.ac.cn (C. Wang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.091

3860
X. Liao et al. / Tetrahedron Letters 51 (2010) 3859–3861
Table 1
Oxidative aromatization of 1a under different conditions
O
O
O
Ph
O
H
Ph
NaClO2, HCl (con.)
Solvent, time, 20°C
EtO
OEt
EtO
OEt
N
H
1a
N
2a
Entrya
Solvent
Oxidant loading (equiv)
Time (min)
Yieldd (%)
1
2
3
4
5
6
7
8
9
THFb
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
2.0
90
90
90
90
90
120
90
20
15
360
85
93
94
75
b
CH2Cl2
Et2Ob
EtOH
CH3COOHc
33
H2Ob
n.r.e
92
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)
EtOH/H2O (1:1)c
96
95
10
n.r.e
a
b
c
Reaction conditions: 1,4-DHP (1 mmol), NaClO2 (designed amount), solvent (5 mL), concd HCl (12 M, 0.2 mL), 20 °C.
0.1 equiv of n-Bu4N+Brꢀ was added.
No concd HCl was added.
Isolated yields.
d
e
No reaction.
2 by the general procedure (see below). The results are summa-
rized in Table 2. Despite varying the substituents with electron-
withdrawing or electron-donating groups, and bulky or small
groups, the yields fell between 89% and 99%. The considerably close
yields revealed that both electronic and steric nature of the substit-
uents on 4-position had no significant influence on the reaction.
It was well known that the reaction between sodium chlorite
and hydrochloric acid generated chlorine dioxide (ClO2, Eq. 1)
and the reaction was catalyzed by chlorine.22 Furthermore, ClO2
can oxidize organic species with the formation of a chlorite ion
(ClO2ꢀ).23 The fact that the reaction yielded undetectable product
without the addition of hydrochloric acid (Table 1, entry 10) sug-
gested that ClO2 played a significant role in the aromatization pro-
cess. Based on our experimental observations, an electron transfer
mechanism promoted by ClO2 is proposed as in Scheme 2.
Table 2
Aromatization of 4-substituted 1,4-DHPsa
Substrate
R
Yield of 2b (%)
Mp (°C)
Ref. mp (°C)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
H
Me
96
99
97
92
89
94
95
98
95
97
99
95
9121
95
60–61
71–72
Oil
62–6315
69–7015
Liquid12b
17116
4-HO–C6H4
4-MeO–C6H4
4-O2N–C6H4
2-O2N–C6H4
4-F–C6H4
4-Cl–C6H4
3-MeO-4-HO–C6H4
3-HO-4-MeO–C6H4
3,4-Cl2–C6H4
3,4,5-(MeO)3–C6H4
2-Furyl
172–173
49–50
115–116
77–78
90–92
64–65
159–160
140–141
63–65
107–108
oil
51–5316
114–11516
74–7617
88–9016
64–6618
159–16019
140–14216
66–6820
no ref.
oil16
a
5NaClO2 þ 4HCl ! 5NaCl þ 4ClO2 þ 2H2O
ð1Þ
Reaction conditions: 1,4-DHP (1 mmol), NaClO2 (1.5 mmol), solvent (5 mL),
concd HCl (12 M, 0.2 mL), 20 °C, 30 min.
b
As demonstrated in Scheme 2, the oxidation of 1,4-DHPs was
initiated by ClO2-promoted single electron transfer to produce
radical cation A and (ClO2ꢀ). This was followed by a proton loss
from 4-position to afford radical B. Further oxidation of radical
B by another molecule of ClO2 resulted in the protonated pyridine
C. The aromatization was accomplished by the loss of a proton
from C.
Isolated yields, and all compounds were characterized by spectroscopic tech-
niques and the data were compared with those reported (except 1m).
To investigate the scope of the reaction, a series of 1,4-DHPs 1
were prepared with a modified Hantzsch reaction procedure,14
and each was converted to the corresponding pyridine derivative
R
H
R
H
R
-
EtO2C
CO2Et
EtO2C
CO2Et ClO2
ClO2
EtO2C
ClO2
CO2Et
-H+
-e
N
N
H
N
H
H
A
B
-
ClO2
R
N
R
-e
EtO2C
CO2Et
EtO2C
CO2Et
-H+
N
H
C
Scheme 2. Proposed mechanism for the aromatization process.

X. Liao et al. / Tetrahedron Letters 51 (2010) 3859–3861
3861
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3.1. General procedure for the aromatization of 1,4-DHPs
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Shide, N. D.; Shingare, M. S. Indian J. Chem. 1995, 34B, 920–922.
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To
a stirred solution of 1,4-DHP (1 mmol) and NaClO2
(1.5 mmol) in EtOH/H2O (1:1) (5 mL), HCl (concd) (12 M, 0.2 mL)
was added dropwise. The mixture was allowed to stir at 20 °C for
specified time (Table 1). The progress of the reaction was moni-
tored by TLC. Upon completion of the reaction, the mixture was
concentrated under reduced pressure. The residue was diluted
with 10% NaHCO3 (5 mL) and extracted with EtOAc. The organic
layer was washed with iced water and brine, dried over anhydrous
Na2SO4, filtered and evaporated to dryness. The crude products
were crystallized from EtOH or EtOH/H2O or chromatographed
on silica gel column to give pure products.
16. Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21–24.
17. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Li, W. Synth. Commun. 2001, 31, 2625–2630.
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Oskooie, H. A. Bioorg. Med. Chem. Lett. 2007, 17, 3305–3309.
19. Cai, X. H.; Yang, H. J.; Zhang, G. L. Can. J. Chem. 2005, 83, 273–275.
20. Wang, B.; Hu, Y.; Hu, H. Synth. Commun. 1999, 29, 4193–4199.
21. Compound 1m: 2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,5-pyridine dicarbo-
xylate; white solid; mp: 107–108 °C, HR-ESI-MS: calcd for C22H28NO7, m/z:
Acknowledgment
The authors are grateful to Professor Guolin Zhang (Chengdu
Institute of Biology, CAS) for valuable advices to this work.
418.1860 [M+H]+, found 418.1854, Err 1.59 ppm; IR (KBr, cmꢀ1
) mmax: 2930,
1726, 1557, 1508, 1465, 1349, 1296, 1232, 1125, 1106, 1047, 1003, 851, 709;
1H NMR (600 MHz, CDCl3): d = 1.00 (t, 6H, J = 7.0 Hz, 6H), 2.60 (s, 6H), 3.82 (s,
6H), 3.85 (s, 3H), 4.08 (q, J = 7.0 Hz, 4H), 6.51 (s, 2H). 13C NMR (150 MHz,
CDCl3): d = 13.7, 22.79, 52.1, 60.9, 61.4, 105.6, 126.8, 131.9, 138.1, 145.7, 153.0,
155.3, 168.0.
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