A new oxidation system for the oxidation of Hantzsch-1,4-dihydropyridines and polyhydroquinoline derivatives under mild conditions

Article abstract of DOI:10.1039/c5ra20977c

A new oxidation system (Na₂S₂O₄/TBHP) to prepare pyridine derivatives has been developed by the oxidation of 1,4-dihydropyridine derivatives and polyhydroquinoline derivatives in good to excellent yields. The procedures of the reaction were green, convenient, mild and easy work-up.

Full text of DOI:10.1039/c5ra20977c

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A new oxidation system for the oxidation of Hantzsch-1,4-
dihydropyridines and polyhydroquinoline derivatives under
mild conditions
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
b
a
DOI: 10.1039/x0xx00000x
Cui-Bing Bai, Nai-Xing Wang,* Yan-Jing Wang, Xing-Wang Lan, Yalan Xing* and Jia-Long Wen
www.rsc.org/
1
3
14
15
16
17
A new oxidation system (Na
2
S
2
O
4
/TBHP) to prepare pyridine MnO
2
,
Mn(OAc)
3
,
FeCl
and others. For the development of more
dihydropyridine derivatives and polyhydroquinoline derivatives in environmentally friendly aromatizations of 1,4-DHPs, recent efforts
good to excellent yield. The procedures of the reaction showed have focused on the use of O , 3,4-dihydro-2H-pyran and TBHP
(tert-butylhydroperoxide) as the oxidants in the presence of
3
·6H
2
O,
3 6
K [Fe(CN) ], Pd-C/AcOH,
18
3 4
derivatives has been developed by the oxidation of 1,4- Zr(NO ) ,
2
green, convenient, mild and easy work-up.
1
9-21
suitable catalysts.
For example, Rajendra has developed a
Introduction
protocol of conversion of 1,4-DHPs to the pyridines using TBHP in
2
2
1
998. However, this method suffered from a number of
Pyridines are among the most important heterocycles which are
important moieties in a wide range of biologically active molecules
and are found in many natural products, pharmaceuticals and
disadvantages: the oxidation of 1,4-DHPs bearing alkyl substituents
at 4-position gave only dealkylated pyridine derivatives, high
temperature was needed and only a few of substrates were tested.
Also, no possible reaction mechanism was reported. Recently,
Vladimir’s group described aromatization of 1,4-DHPs with TBHP
1
2
dyes. They are not only privileged scaffolds for drug discovery, but
also used as reagents, building blocks and ligands in organic
1
chemistry. Synthesis of pyridines receives much attention from
23
catalyzed by iron(III) phthalocyanine chloride. Although they
1,3
synthetic organic community. Oxidation of the corresponding
Hantzsch-1,4-dihydropyridines (1,4-DHPs), synthesized by the
reaction of β-ketoesters, aldehydes and ammonia (Hantzsch
reaction), is one of the most popular methods for the preparation
of pyridines. Oxidation of 1,4-DHPs is of great interest in recent
years, because it not only can be used for the synthesis of pyridines,
but also can be used in coenzymes NADH and NADPH mediated
4
,5
hydrogen transfer reactions in biological systems. The oxidation
of 1,4-DHPs into pyridines is one of the main metabolic pathways of
many drugs, such as nicardipine, felodipine and amlodipine, and
this process is catalyzed by the cytochrome P450 (CYP) 3A4
6
isoform. Therefore, in order to develop a useful synthetic approach
to polysubstituted pyridines and understand these biological
processes, tremendous efforts have been made to develop efficient
7
reagents for oxidative aromatization of 1,4-DHPs.
From current voluminous literatures, we divide numerous
oxidants into two categories as shown in Figure 1: 1) strong described a new oxidation system, non-environmentally friendly
8
9
10
oxidants such as KMnO
4
, HNO
3
, and K
2
S
2
O
8
etc. 2) Transition transition metal was still used in the aromatization reaction.
1
1
12
metal containing oxidizing agents such as CrO
2
,
BaMnO
4
,
Fig. 1 Oxidation of Hantzsch-1,4-dihydropyridines (1,4-DHPs).
Although many of these methods were effective for the
preparation of the desired aromatization products, most of them
suffered from disadvantages, such as using toxic organic solvents,
harsh reaction conditions, tedious work-up, low catalytic efficiency,
inconvenient preparation of catalyst and formation of side
products, that significantly lower their appeal. Therefore,
a.
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China. E-
mail: nxwang@mail.ipc.ac.cn.
Department of Chemistry, William Paterson University of New Jersey, 300 Pompton Road, Wayne, New
b.
Jersey 07470, United States. E-mail: xingy@wpunj.edu.
Electronic Supplementary Informaꢀon (ESI) available: details of any
†
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 |
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development of new oxidation systems to overcome these afforded the corresponding products in good to excellent yields
2
4
drawbacks is a challenging task to organic chemists.
As we all know, Na (sodium dithionite) is one of the most substituted 1,4-DHPs, whose aromatization failed by reported
widely used strong reducing agents in organic chemistry. For method,
example, in the synthesis of the chiral NADH models, Na is optimized conditions (entries 11 and 12). We also studied the
(entries7-12). Furthermore, even relatively inert nitrophenyl-
2 2 4
S O
2
0,27
obtained the desired products in good yields under the
2 2 4
S O
often used as the most effective reducing agent in the final key step reactivity of heterocycle Hantzsch 1,4-DHPs and the desired
as shown in Figure 1(b). As part of our ongoing studies with regards pyridine derivatives were gave in good yields at room temperature
25
to the development of new chiral NADH models, in an accidental
opportunity, we found that Na /TBHP can oxidize 1,4-DHPs 1a
2 2 4
S O
to corresponding pyridines. Hence, we examined the possibility of
oxidative aromatization of 1,4-DHPs using a new oxidation system.
In this paper, we would like to report a new, efficient and
environmentally friendly oxidation system, oxidation of 1,4-DHPs
and polyhydroquinoline derivatives (PHQs), which gave the
corresponding pyridines in good to excellent yield at room
temperature. To our best knowledge, it is the first report of the
oxidation of the 1,4-DHPs and PHQs using this new oxidation
system.
2 2 4
Table 1 Oxidation of 1,4-DHPs by Na S O /TBHP
a
Time
h)
Yield
Entry
1
R
1
R
2
2
b
(
(%)
1
2
3
4
5
6
1a
1b
CH
3
H
H
2a
2b
2c
2d
2e
2f
2
2
2
3
3
4
96
95
93
96
90
91
2 5
C H
Results and discussion
1c CH(CH3)2
H
1d
1e
1f
C
2
H
5
Ph
CH3
Inspired by transition metal catalyzed cross couplings in the
C2H5
C2H5
26
presence of TBHP in our laboratory, we planned to study the
conversion of 1,4-DHPs to corresponding pyridines employing
n-propyl
p-
7
1g
C
2
H
5
2g
5
87
aqueous TBHP with Na
obtain a more efficient and green oxidation system. It was very
pleased that we obtained the product in 52% yield when Na (1
2
S
2
O
4
. Thus, we used TBHP in the reaction to
OCH C H
3
6
4
8
1h
1i
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
p-OHC H
6
4
2h
2i
6
5
5
5
5
4
5
5
83
81
79
73
80
85
80
76
2
S
2
O
4
9
p-BrC H
6
6
4
equiv) and TBHP (1 equiv) were simultaneously added to the
reaction system (see Supporting Information Table S1, entry 1).
Encouraged by the good results, we made further efforts to
optimize the reaction conditions. The results are shown in
Supporting Information Table S1. It was found that the reactivity of
the oxidation reaction was the best when molar ratio of
10
11
12
13
14
15
1j
p-ClC H
2j
4
1k
1l
2
6 4
p-NO C H
2k
2l
2
6 4
m-NO C H
1m
1n
1o
2-Furyl
2-Thienyl
2-Pyridyl
2m
2n
2o
a
Na
to lower reactivity (Table S1, entry 5). After monitoring the reaction
with various solvents such as CH CN, CH Cl , C OH, THF,
cyclohexane, dioxane, EtOAc and H O, the best yield was observed
2 2 4
S O /TBHP/substrate was 2:4:1 while decreasing of the ratio led
Reaction conditions: 1 (0.2 mmol), TBHP (0.8 mmol) and
Na S O (0.4 mmol) in EtOAc (5 mL) were stirred at room
2
2
4
3
2
2
2 5
H
temperature. TBHP = tert-butyl hydroperoxide, 70% in water.
2
(
entries 13-15). Notably, the desired bipyridine product was
using EtOAc (Table S1, entries 8-16). Hence, EtOAc was considered
as a suitable solvent. Further control experiments confirmed that
isolated in 76% yield (entry 15)
.
the substrates were unreactive in the absence of either Na
TBHP. The fact indicated that both Na and TBHP were essential
for the oxidation (Table S1, entries 6 and 7).
2 2 4
S O or
Although the new oxidation system prompted the oxidation of
a range of 1,4-DHPs for the formation of corresponding pyridine
derivatives with good yields, the above reactions only dealt with
structurally symmetrical 1,4-DHPs. To broaden the scope of
application, the oxidation of structurally unsymmetrical 1,4-DHPs,
such as polyhydroquinoline derivatives (PHQs) which should be of
2 2 4
S O
With the optimized conditions established, we employed
various 1,4-DHPs to test the generality of this reaction. In general,
various 1,4-DHPs were almost quantitatively transformed into the
corresponding pyridine derivatives in the presence of Na
Table 1). To our delight, the desired aromatization product 2a was
isolated in 96% yield under air atmosphere at room temperature
entry 1). When we changed the R group into C and CH(CH
respectively, the pyridine product was also obtained in high yield
entry 2 and 3). 4-alkyl-1,4-DHPs were also examined, and good to
2 2 4
S O /TBHP
2
8
more synthetic value but few has been reported, was carried out
for the first time in this new oxidation system. As shown in Figure 2,
the PHQs possessing a variety of substituents were oxidized to the
corresponding pyridine derivatives (4a-4i) in good yield. It means
(
(
1
2
H
5
3 2
)
that the Na
this process.
2
S
2
O
4
/TBHP system also exhibited high performance in
(
excellent yields were obtained (entries 5 and 6). It is important to
note that dealkylated pyridine derivative was not generated in the
reaction. At the same time, because 4-alkyl-1,4-DHPs aromatization
was achieved in shorter reaction time, they were more reactive
than 4-aryl-1,4-DHPs. It was showed in Table 1 that both electron-
donating and electron-withdrawing substituents on the 1,4-DHPs
2
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9
this reaction. Firstly, one electron transferring from 1,4-DHPs to
the radical anion A gave a radical cation B. Then, B lost a proton to
form intermediate C. The intermediate D was formed by one
electron transferring to the radical anion A. At last, D lost a proton
to form the aromatized product.
Conclusions
In conclusion, we have demonstrated that a new oxidation system
which promoted oxidation of 1,4-DHPs and PHQs to the
corresponding aromatized pyridine derivatives in good to excellent
yield, respectively. Due to its green, convenient, mild and easy
work-up procedures, we believe that the new oxidation system
surpasses previously reported systems and it enriches the
methodologies of oxidation reaction. Related experiments on the
selective oxidation and detailed mechanistic studies are currently
underway in our laboratory.
Acknowledgements
This work was supported financially by the Natural Science
Foundation of China (21172227).
Notes and references
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Table of Contents
An oxidation system to synthesize pyridine derivatives has been
developed by oxidation of 1,4-dihydropyridines and polyhydroquinoline
derivatives in good yield.