A simple, efficient, one-pot three-component domino synthesis of Hantzsch pyridines under solvent-free condition

Article abstract of DOI:10.1002/jhet.175

(Chemical Equation Presented) In this article, efficient and simple preparation of Hantzsch pyridine derivatives by reaction of various aldehydes and β-dicarbonyls in the presence of ammonium chlorate under solvent-free condition at 80°C is reported. The advantages of this system are the one-step procedure, high yields of the products, and the ability to carry out large-scale reactions.

Full text of DOI:10.1002/jhet.175

September 2009
A Simple, Efficient, One-Pot Three-Component Domino
Synthesis of Hantzsch Pyridines under Solvent-Free Condition
931
Masoud Nasr-Esfahani,* Bahador Karami, and Masoume Behzadi
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
*E-mail: manas@mail.yu.ac.ir
Received January 23, 2009
DOI 10.1002/jhet.175
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
In this article, efficient and simple preparation of Hantzsch pyridine derivatives by reaction of various
aldehydes and b-dicarbonyls in the presence of ammonium chlorate under solvent-free condition at
80ꢀC is reported. The advantages of this system are the one-step procedure, high yields of the products,
and the ability to carry out large-scale reactions.
J. Heterocyclic Chem., 46, 931 (2009).
INTRODUCTION
[14], tert-butylhydroperoxide [15], photochemical oxida-
tion [16], vanadium(V) salts [17], and biomimetic cata-
lyzed oxidation [18].
Pyridine bases, as representative heteroaromatic ring
compounds, are produced for applications in herbicides,
insecticides, vitamins, nicotinic acid and nicotinic am-
ide, pharmaceuticals, and adhesives [1]. For example,
there are many bioactive pyridine compounds, such as
the prosthetic pyridine nucleotide (NADP) [2], pyridox-
ine (vitamin B6), and nicotine [3], and also many phar-
maceuticals [4] and agrochemicals [5] possessing a pyri-
dine nucleus. Pyridine is used as a basic solvent as well
as a catalyst in industrially important organic reactions
[6]. Thus, new construction methods for multisubstituted
pyridines are still intriguing studies [7,8].
Despite these intensive efforts, most of the reported
oxidation procedures require long reaction time, use of
the strong oxidants in large excess, and afford products
with only modest yields. In particular, the aromatization
reactions with these reagents lead to dealkylation of the
4-position or formation of side products.
It is well known in the protocol of green chemistry
that its main objective is to perform reactions under sol-
ventless conditions using heterogeneous catalysts to gen-
erate environmentally friendly chemical transformations
[19]. In addition, it is important to note that an ideal
synthesis is considered as one in which a target mole-
cule is produced quantitatively in one step, from avail-
able and inexpensive raw materials [20].
Ammonium acetate has been used for the synthesis of
dihydropyridine [21] and pyridine derivatives. 4-Substi-
tuted Hantzsch 1,4-dihydropyridines were synthesized
by replacing ammonium acetate with ammonia in a clas-
sical method, in which the products can be subsequently
oxidized to corresponding pyridines. To the best of our
knowledge, only two articles reported the continuous
synthesis of Hantzsch pyridines by a mixture of benton-
ite clay, b-ketoester, aldehyde, and ammonium nitrate
as the source of ammonia and oxidizing species [22,23].
These results are intriguing as they are somehow contra-
dictory. In one of these reports [22], in the absence of
solvent, the alkylated pyridine was isolated from
the oxidation of 4-isopropyl dihydropyridine as the
major product. On the other hand, dealkylated
pyridine was isolated from the oxidation of 4-propyl or
4-phenyl dihydropyridines in substantial yield that this
On the other hand, the synthesis of heteroaromatics
by oxidative dehydrogenation is of fundamental impor-
tance in organic chemistry. These ubiquitous features
always encourage synthetic chemist to explore improved
protocols for the synthesis as well as the oxidation of
1,4-dihydropyridines. Oxidation of 1,4-dihydropyridines
is one of the possible ways for the synthesis of the cor-
responding pyridines. Aromatization of 1,4-dihydropyri-
dines has received considerable attention because of the
fact that 1,4-dihydropyridine-based calcium channel
blockers are oxidatively converted to pyridine deriva-
tives by the action of cytochrome P-450 in the liver
[9,10]. In addition, the corresponding pyridine deriva-
tives show antihypoxic and anti-ischemic activities and
are used in the treatment of atherosclerosis [11]. Addi-
tionally, dihydropyridines are often produced in a syn-
thetic sequence and have to be oxidized to pyridines
[12]. Numerous reagents and procedures have been rec-
ommended for this purpose, such as pyridinium chloro-
chromate (PCC) [13], N2O4 complex of 18-crown-6
C
V
2009 HeteroCorporation

932
M. Nasr-Esfahani, B. Karami, and M. Behzadi
Vol 46
Scheme 1
dines were prepared on a 50-mmol scale, and the results
were comparable with the small-scale experiments.
According to the literature, the thermal decomposition
of NH4ClO3 begins at 50ꢀC, which possibly includes
equilibrium formation of ammonia and chloric acid
according to Scheme 2 [28]. This process is probably
accelerated by water formed in reaction. Thus, formed
ammonia acts as a nitrogen nucleophile in Hantzsch di-
hydropyridine synthesis while chloric acid as an actual
oxidant. However, it cannot be excluded that the prod-
uct, substituted pyridine, is formed by the oxidation of
intermediates different than 1,4-dihydropyridines.
observation contrasts with the presented results in the
second report [23], such as they do not mention the
presence of this case of pyridine in the final mixtures.
In the Vilsmeier–Haack reaction progress, Jutz et al.
[24] have demonstrated that the cyclization of the inter-
mediate iminium salts formed by the multiple iminoal-
kylations of certain alkenes, in the presence of ammo-
nium acetate, leads to the formation of substituted pyri-
dines and naphthyridines. Thomas and Asokan [25]
envisaged that a similar ammonium acetate-induced cy-
clization of the intermediates formed by the treatment of
Based on the evidences from the reaction and previ-
ous suggestions on such a system as shown in Scheme
1, our rationalization about the proposed mechanism
includes thermal decomposition of ammonium chlorate
to NH3 and HClO3 that these lead to Hantzsch dihydro-
pyridine synthesis and its oxidation of the products with
chloric acid to corresponding pyridines.
a-hydroxyketenedithioacetals would afford
method for the synthesis of substituted pyridines with
a useful
moderate yields.
In this research, we report that the ammonium chlo-
rate can be used as both ammonia and oxidizing agent
source for the direct synthesis and oxidation of Hantzsch
1,4-dihydropyridines to pyridines.
CONCLUSIONS
In conclusion, we have developed a simple and effi-
cient synthetic protocol for the synthesis of a wide vari-
ety of Hantzsch pyridine derivatives under solvent-free
conditions. Mild reaction conditions, cost efficiency,
simplicity in operation, and large-scale applicability are
some significant features of this protocol.
RESULTS AND DISCUSSION
As a part of our current studies on multicomponent
reaction (MCR) involving synthesis of dihydropyrimidi-
nones [26] and our interest in the chemistry of dihydro-
pyridines [18], we have investigated the one-pot synthe-
sis of pyridine derivatives (Scheme 1).
EXPERIMENTAL
All chemicals were purchased from Merck, Fluka, and
Sigma-Aldrich chemical companies. The reactions were moni-
tored by TLC. The products were isolated and identified by
comparison of their physical and spectral data with authentic
samples. IR spectra were recorded on FTIR JASCO-680. The
1H NMR spectra were obtained on a Bru¨ker-instrument DPX-
300 MHz and melting points determined on a Barnstead Ele-
ctrothermal (BI 9300) apparatus.
General procedure for the preparation of the Hantzsch
pyridines. All reactions were carried out in a 25-mL round
bottomed flask equipped with a magnetic stirring bar. A mix-
ture of aldehyde (2 mmol), b-dicarbonyl (4 mmol), and ammo-
nium chlorate (3 mmol) was heated at 80ꢀC. After completion
of the reaction, as monitored by TLC, the mixture was
extracted with CH2Cl2 (3 ꢁ 5 mL). The solvent was evapo-
rated off, and the crude product was purified by silica gel plate
or silica gel column (eluent: n-hexane–EtOAc). The products
were characterized by IR, 1H NMR, and via comparison of
their melting points with the reported ones.
The synthetic method for the preparation of substi-
tuted pyridine derivatives (4) was relatively easy and
simple, and the compounds could be obtained in one
step. The optimized reaction conditions were subse-
quently applied to the reaction between various aliphatic
or aromatic aldehydes and b-dicarbonyls in the presence
of ammonium chlorate in solvent-free conditions at
80ꢀC. In all cases, the desired pyridine derivatives were
obtained in high to excellent yields. Both electron-rich
and electron-deficient aromatic aldehydes as well as het-
erocyclic ones worked well. Aliphatic aldehydes
afforded equally good results. Many of the pharmaco-
logically significant substitution patterns can be intro-
duced with good efficiency (Table 1).
In a typical procedure, 2 mmol of aldehyde, 4 mmol
of b-dicarbonyl, and 3 mmol of ammonium chlorate
were mixed in solvent-free conditions at 80ꢀC for 40–
300 min. After work-up, the corresponding pyridines
were isolated with excellent yields (4a–4s). One advant-
age of this method is its large-scale applicability. Pyri-
Spectral and physical data for selected compounds
Diethyl 4-(2,4-dichlorophenyl)-2,6-dimethyl-3,5-pyridinedicar-
boxylate (4i). mp: 58–60ꢀC, Rf (n-hehaxe/EtOAc, 5:1) ¼ 0.55.
IR (KBr): t (cmꢂ1) ¼ 2982, 2905, 1720, 1585, 1472, 1412,
1375, 1264, 1242, 1143, 1105, 1051, 837, 758; 1H NMR
(CDCl3): d (ppm) ¼ 1.05 (t, 6H), 2.11 (s, 6H), 3.89 (q, 4H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 A Simple, Efficient, One-Pot Three-Component Domino Synthesis of Hantzsch
Pyridines Under Solvent-Free Condition
933
Table 1
The one-pot synthesis of pyridine derivatives.a
Entry products
R1
R2
Products
Time (min)
70
Yieldsb (%)
90
mp (ꢀC)
3
CH
4a
OEt
Oily [27b]
4b
4c
4d
(CH3)2CH
CH3(CH2)2
C6H5
OEt
OEt
OEt
75
60
50
95
90
94
70–72 [27e]
Oily [27a]
62–63 [27b]
4e
4-NO2AC6H4
OEt
75
89
113–115 [27b]
4f
2-NO2AC6H4
C6H5ACHCH3
OEt
OEt
180
80
94
95
75–76 [27f]
70–72 [27d]
4g
4h
4-CH3OAC6H4
OEt
OEt
40
94
49–50 [27a]
4i
4j
2,4-(Cl)2AC6H3
130
85
91
96
62–64
2-Furyl
OEt
39–41 [27c]
4k
4l
H
OMe
200
200
92
97
100–102 [27h]
90–93 [27g]
4-NO2AC6H4
OMe
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

934
M. Nasr-Esfahani, B. Karami, and M. Behzadi
Vol 46
Table 1
(Continued)
Entry products
R1
R2
Products
Time (min)
180
Yieldsb (%)
85
mp (ꢀC)
4m
4n
4o
CH3(CH2)2
OMe
Oily [27h]
125–127 [27i]
163–164 [27i]
3-NO2-C6H4
Me
Me
300
200
92
87
4-CH3O-C6H4
4p
4q
4r
4-Cl-C6H4
2-Br-C6H4
2-OH-C6H4
Me
Me
Me
250
160
130
80
89
90
174–176 [27i]
190–192
140–142
a Characterized by spectral analysis and comparison with these reported in the literature [27].
b Isolated yields.
6.91 (q, 1H), 7.06–7.13 (m, 2H). Anal. Calcd. for
C19H19Cl2NO4: C, 57.59; H, 4.83; N, 3.53; found: C, 57.5; H,
4.7; N 3.4.
Acknowledgment. The authors thank the Yasouj University for
partial support of this work.
3,5-Diacetyl-4-(2-bromophenyl)-2,6-dimethylpyridine (4q). mp:
190–192ꢀC, Rf (CCl4/EtOAc, 5:1) ¼ 0.57. IR (KBr): t (cmꢂ1
)
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¼ 2975, 2900, 1695, 1620, 1456, 1405, 1378, 1260, 1225,
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