Efficient sonochemical synthesis of alkyl 4-aryl-6-chloro-5-formyl-2- methyl-1,4-dihydropyridine-3-carboxylate derivatives

Article abstract of DOI:10.1016/j.ultsonch.2011.07.003

A facile, efficient and environment-friendly protocol for the synthesis of 6-chloro-5-formyl-1,4-dihydropyridine derivatives has been developed by the convenient ultrasound-mediated reaction of 2(1H)pyridone derivatives with the Vilsmeier-Haack reagent. T

Full text of DOI:10.1016/j.ultsonch.2011.07.003

Ultrasonics Sonochemistry 19 (2012) 221–226
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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Short Communication
Efficient sonochemical synthesis of alkyl 4-aryl-6-chloro-5-formyl-2-methyl-
1,4-dihydropyridine-3-carboxylate derivatives
Enrique Ruiz a, Hortensia Rodríguez a, Julieta Coro a, Vladimir Niebla a, Alfredo Rodríguez a,
b,
Roberto Martínez-Alvarez b, Hector Novoa de Armas c, Margarita Suárez a, , Nazario Martín
⇑
⇑
a Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400-Ciudad Habana, Cuba
b Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid, Spain
c Pharmaceutical Sciences Department, Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, efficient and environment-friendly protocol for the synthesis of 6-chloro-5-formyl-1,4-dihydro-
pyridine derivatives has been developed by the convenient ultrasound-mediated reaction of 2(1H)pyri-
done derivatives with the Vilsmeier–Haack reagent. This method provides several advantages over
current reaction methodologies including a simpler work-up procedure, shorter reaction times and
higher yields.
Received 21 April 2011
Received in revised form 7 July 2011
Accepted 7 July 2011
Available online 22 July 2011
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Ultrasound irradiation
Sonochemistry
1,4-Dihydropyridine derivatives
Vilsmeier–Haack reaction
1. Introduction
As part of our program aimed at synthesize 1,4-dihydropyri-
dines endowed with different groups on the carbons of the hetero-
The exploration of privileged structures in drug discovery is a
rapidly emerging topic in medicinal chemistry [1]. These structures
represent a class of molecules capable of binding to multiple recep-
tors with high affinity. The development of these molecules should
allow the medicinal chemist to rapidly discover biologically active
compounds across a broad range of therapeutic areas on a reason-
able time scale [2].
In this sense, 1,4-dihydropyridines are very attractive targets
due to their wide range of biological activities [3]. Perhaps the best
known pharmacological class of 1,4-dihydropyridines are those
acting as calcium channel blockers. These compounds are routinely
used in the treatment of a variety of cardiovascular disorders, such
as hypertension, cardiac arrhythmias or angina [4].
It is well known that the Vilsmeier–Haack reaction is a mild
method for the introduction of a formyl group in various activated
aromatic and heteroaromatic compounds [5]. It can be carried out
on methylene-active compounds leading mainly to the formation
of b-halo-carboxaldehyde derivatives, which are useful precursors
in the construction of different heterocyclic compounds by means
of further chemical transformations [6].
cyclic ring, we have previously reported the synthesis of 6-chloro-
5-formyl-2-methyl-3-alkoxycarboxyl-1,4-dihydropyridines which
were obtained from the corresponding 4-aryl 3,4-dihydropyridone
using the Vilsmeier–Haack reagent [7].
In our case, 6-chloro-5-formyl-1,4-dihydropyridines proved to
be an excellent building block for further transformations into
other heterocycle-fused 1,4-dihydropyridines such as pyrazol-
o[3,4-b]pyridines [7], 4,7-dihydrothieno[2,3-b]pyridines [8] and
2-iminodihydropyrido[3,2-e][1,3]thiazines [9]. Furthermore, we
have carried out the synthesis of novel fulleropyrrolidines bearing
biologically active the preparation of 1,4-DHPs covalently con-
nected to the fullerene core, from the corresponding 6-chloro-5-
formyl-1,4-dihydropyridines [10] and the preparation of 1,4-
dihydropyridines endowed with a methylenethiocarbazide group
on C5 of the heterocyclic ring [11].
The traditional method for 6-chloro-5-formyl-1,4-dihydropyri-
dine synthesis entails the reaction of the corresponding 2(1H)pyri-
done with the Vilsmeier–Haack reagent (POCl3, DMF) in dry
chloroform under nitrogen atmosphere at room temperature [7].
However, due to the long reaction time (18 h) this classic thermal
reaction presents some disadvantages. Thus, the development of a
more efficient method for the synthesis of 6-chloro-5-formyl-1,4-
dihydropyridine is highly desirable.
⇑
Corresponding authors.
E-mail addresses: msuarez@fq.uh.cu (M. Suárez), nazmar@quim.ucm.es
Ultrasounds, an efficient and virtually innocuous means of acti-
vation in synthetic chemistry, have been employed for decades with
(N. Martín).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.07.003

222
E. Ruiz et al. / Ultrasonics Sonochemistry 19 (2012) 221–226
varied success [12]. This high-energy input enhances not only mech-
anism effects in heterogeneous processes, but it is also known to in-
duce new reactivity leading to the formation of unexpected
chemical species. The remarkable phenomenon of cavitation makes
sonochemistry unique. The effects of ultrasoundobserved duringor-
ganic reactions are due to cavitation, a physical process that creates,
enlarges, and implodes gaseous and vaporous cavities in an irradi-
ated liquid. Cavitation induces very high local temperatures and
pressures inside the bubbles, leading to turbulent flow of the liquid
and enhanced mass transfer. When compared with conventional
methods, ultrasound-accelerated chemical reactions could be car-
ried out under ultrasound irradiation to give higher yields in shorter
reaction times and milder conditions [13].
Ali and coworkers have reported on the cyclization and formy-
lation of acetanilides with Vilsmeier–Haack reagent under ultra-
sound irradiation conditions to afford the corresponding 2-
chloro-3-formylquinolines in good yields, using an ultrasonic bath
for 60 min at 40 °C. They also observed a similar tendency in the
case of the formylation of aromatic hydrocarbons where the de-
sired formylated product was obtained in good to excellent yields
under ultrasonic irradiation. In both cases the yields were signifi-
cantly lower under thermal conditions [14].
2.2. General procedure
Synthesis of alkyl 4-aryl-6-chloro-5-formyl-2-methyl-1,4-dihy-
dropyridine-3 carboxylates (2) under ultrasound irradiation.
To the Vilsmeier–Haack reagent prepared from a mixture of
POCl3 1.1 mL (12.2 mmol) and 1.4 mL (18.2 mmol) of DMF at
5 °C, 7 mmol of the alkyl 4-aryl-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyridine-5-carboxylate (1) in 15 mL of dry chloroform was
added. The mixture was sonicated at 30 °C with a sonic horn or
in an ultrasonic cleaner. The reaction was monitored by TLC (chlo-
roform:hexane:ethyl acetate, 5:4:3). After the completion of the
reaction an aqueous sodium acetate solution was added (12 g in
21 mL of water) and sonicated for 10 min. The product was ex-
tracted twice from water with dichloromethane. The organic
phases were collected and dried under MgSO4. The organic solvent
was removed in vacuo and the solid residue was washed twice
with small portions of cold ether to afford 2. All experiments per-
formed in this work were repeated three times. The yield reported
represents the average of the values obtained for each reaction. The
identity of the products was confirmed by comparing their melting
points and NMR data with those reported in the literature
[7,18b,23] (see Supporting Information).
Ultrasound irradiation has also been successfully used in the
synthesis and chemical modification of a variety of 1,4-dihydro-
pyridines [15].
3. Results and discussion
We have very recently developed an efficient procedure for the
synthesis of 3,4-dihydropyridone derivatives under ultrasonic irra-
diation at room temperature [16], improving the yields and short-
ening the reaction times compared with the previous conventional
methods [17]. These 3,4-dihydro-2-oxopyridines are important
key intermediates for the preparation of o-chloroformyl 1,4-
dihydropyridines.
As a part of our studies aimed at synthesizing 1,4-dihydropyri-
dine derivatives [18] as well as the use of non-conventional tech-
niques in the synthesis of this class of compounds, [19] we
describe here in a novel procedure for the preparation of 6-
chloro-3-formyl-1,4-dihydropyridine derivatives under mild ultra-
sound irradiation.
Compounds 2 were obtained as we previously reported [7] from
the corresponding methyl 2-oxo-1,2,3,4-tetrahydropyridine-5-car-
boxylate (1) via Vilsmeier–Haack chloroformylation by conven-
tional methods. Even though this procedure allows the
preparation of the desired 6-chloro-5-formyl-1,4-dihydropyridines
2 in a straightforward fashion, it demands long reaction times, and
the usual product purification procedures such as recrystallization
or column chromatography require large volumes of organic sol-
vent. In order to achieve milder reaction conditions, lower temper-
atures as well as speeding up the reaction, in this work we have
developed the synthesis of compounds 2, under heterogeneous
conditions and ultrasound irradiation.
To achieve suitable conditions for the synthesis of compounds
2, different reaction conditions have been investigated in the reac-
tion of the corresponding 3,4-dihydro-2-pyridones 1 with the Vils-
meier–Haack reagent. (See Scheme 1).
2. Methods
To determine the effect of ultrasound on this reaction, the
experiments were carried out under the same conditions used in
the conventional experiments [7]. Therefore, they were carried
out using anhydrous chloroform as solvent.
To determine the influence of the source of ultrasonic irradia-
tion on the development of the process, we carried out and moni-
tored the reactions using an ultrasonic cleaner and a sonic horn.
First, we developed the synthesis using an ultrasonic cleaner; the
reaction flask was located in the cleaner bath, where the surface
of reactants is slightly lower than the level of the water.
2.1. Apparatus and analysis
Reagents and solvents were purchased from Fluka or Aldrich.
Melting points were determined in capillary tubes in an Electro-
thermal C14500 apparatus and are uncorrected. The progress of
the reaction and the purity of compounds were monitored by
TLC analytical silica gel plates (Merck 60 F250). The NMR spectra
were recorded on a Bruker Avance-300 instrument. 1H and 13C
were recorded in DMSO-d6 at 300 MHz and 75 MHz and are refer-
enced to 2.50 and 39.5 ppm for DMSO, respectively. Chemical
shifts are given as d values and J values are given in Hz. The ultra-
sonic irradiation experiments were carried out in: (a) a sonochem-
ical apparatus SONIPRED-150. The frequency can be tuned
between 17 and 35 kHz and the power can be varied up to a max-
imum output of 350 W. The reactions were carried out in an open
double walled glass tube (diameter: 30 mm; thickness: 1 mm; vol-
ume: 50 mL) at 30 °C. The temperature was controlled by a Buchi
B-491 water bath at 30 1 °C; (b) a Shanghai Branson-CQX ultra-
sonic cleaner with a frequency of 25 kHz and a nominal power
250 W. The reaction flask was located in the water bath of the
ultrasonic cleaner, and the temperature of the water bath was con-
trolled at 30 °C. The reaction temperature was controlled by addi-
tion or removal of water from ultrasonic bath. The reactions were
performed in open vessels.
Scheme 1. Synthesis of 6-chloro-5-formyl-1,4-dihydropyridines (2a–l) under
ultrasound irradiation.

E. Ruiz et al. / Ultrasonics Sonochemistry 19 (2012) 221–226
223
Table 1
Table 2
Synthesis under heterogeneous conditions of 6-chloro-5-formyl-1,4-dihydropyridines
Synthesis under heterogeneous conditions of 6-chloro-5-formyl-1,4-dihydropyridines
(2a–e) and ultrasound irradiation (25 kHz) at 30 °C.
(2a–e) and ultrasound irradiation at 30 °C for 15 min. using a sonic horn.
Product
X
R
Bath cleaner
Sonic horn
Product
X
R
35 kHz
25 kHz
18 kHz
Yield (%)
Yield (%)
Yield (%)
Time (min) Yield (%) Time (min) Yield (%)
2a
2b
2c
2d
2e
H
–CH3
–CH3
–CH3
–CH3
–CH3
68
70
74
74
78
75
80
80
87
85
83
85
86
95
92
2a
2b
2c
2d
2e
H
–CH3 40
75
76
78
80
80
18
15
15
15
18
78
80
80
87
82
2-NO2
3-NO2
4-NO2
2-Cl
2-NO2 –CH3 30
3-NO2 –CH3 30
4-NO2 –CH3 30
2-Cl
–CH3 40
Observation of the surface of the reaction solution during vertical
adjustment of vessel depth will show the optimum position by
the point at which maximum surface disturbance occurs. The reac-
tion temperature was controlled by addition or removal of water
from ultrasonic bath. The chloroformylation methodology involved
the interaction of the halomethylenium salt, formed in situ from
POCl3 and DMF at 5 °C, with alkyl 4-aryl-6-methyl-2-oxo-1,3,3,4-
tetrahydropyridine-5-carboxylate 1 in dry chloroform. Further
irradiation at 25 kHz of the reaction mixture in an ultrasonic bath
at 30 °C for 30–40 min and subsequent hydrolysis with aqueous
solution of sodium acetate, afforded the desired 6-chloro-5-formyl
1,4-DHP derivative 2 in good yields. (See Table 1).
Table 3
Synthesis under heterogeneous conditions of 6-chloro-5-formyl-1,4-dihydropyridines
(2a–d) and ultrasound irradiation using a sonic horn (18 kHz) for 15 min at different
temperatures.
Product
X
R
20 °C
Yield (%)
30 °C
Yield (%)
50 °C
Yield (%)
2a
2b
2c
2d
H
–CH3
–CH3
–CH3
–CH3
76
78
78
84
83
85
90
95
15
32
30
30
2-NO2
3-NO2
4-NO2
Following the same work up the reaction was developed using a
sonic horn as source of ultrasound. In this case the reaction mix-
ture was irradiated at 25 kHz during a variable time (15–18 min)
at 30 °C. The results are shown in Table 1.
When the reaction was carried out in a cleaner bath, it compar-
atively gave slightly lower yields of products and the reaction time
was approximately duplicated to that when it was performed
using a sonic horn. Comparing these results, it is possible to assert
the advantages of using a sonic horn in comparison with the bath
cleaner as they get higher yields in lesser reaction times. This is
probably due to the fact that the ultrasound works under more fo-
cused conditions.
Nevertheless, both methodologies work better than the conven-
tional method (reaction time 18 h and slightly lower yields (75–
80%) [7]), they are more efficient, less time consuming and more
environmentally friendly, particularly when considering the basic
green chemistry concepts.
We have also determined the effect of the frequency of the
ultrasound irradiation on the reaction progress. In this case, we
carried out the reaction under the same experimental conditions,
using a sonic horn at 35 and 18 kHz. (See Table 2).
The results show that the method to obtain 6-chloro-5-formyl-
1,4-dihydropyridine derivatives (2a–l) under ultrasonic irradiation
from 3,4-dihydropyridone derivatives (1a–l) offers several signifi-
cant advantages including faster reaction rates, higher purity, and
higher yields. In comparison with conventional methods, the main
advantage of ultrasound application is the significant decrease in
the reaction times and milder experimental conditions. Thus, while
conventional method requires 18 h, ultrasonic irradiation affords
the respective products in only 15–20 min (see Table 4). These re-
sults support that the energy provided by ultrasound significantly
accelerates these reactions. The difference in yields and reaction
times may be a consequence of the specific effects of ultrasound.
In particular, to cavitation, a physical process that creates, enlarges,
and implodes gaseous and vaporous cavities in an irradiated liquid,
thus enhancing the mass transfer [13] and allowing chemical reac-
tions to occur. The creation of the so-called hot spots in the reac-
tion mixture produces intense local temperatures and high
pressures generated inside the cavitation bubble and its interfaces
when it collapses. Under these conditions, the 6-chloro-5-formyl-
1,4-dihydropyridines derivatives (2a–l) are efficiently formed in
shorter times and in better yields.
When the frequency used was 25 kHz, the reactions yields were
quite similar to those obtained when the cleaner bath was used
(Table 1). Under 35 kHz the yields decreased significantly and, at
18 kHz, they remarkably increased. These data reveal that using a
lower frequency of ultrasound irradiation results in an improved
of the yield. The reason for this experimental finding could stem
from the better cavitations produced at lower frequency irradia-
tion [12,13,20,21].
To study the effect of the temperature on this synthesis, we also
performed four experiments at 5, 20, 30 and 50 °C under optimized
ultrasonic irradiation at 18 kHz. (Table 3) We found that at 5 °C the
reaction does not occur, and at 50 °C the yield decreases signifi-
cantly, possibly due to the decomposition of the Vilsmeier-Haack
reagent. Yields at 20 °C are however, slightly lower that at 30 °C.
At this temperature the cavitation increases and enhances the
reactivity of the respective substrates.
The structures of all the synthesized compounds were corrobo-
rated by their 1H and 13C NMR spectra. The structure of 2h was fur-
ther confirmed by X-ray analysis [22]. The molecular structure of
the product 2h is shown in Fig 1a. The host molecule
(C16H15ClN2O5) crystallizes forming a tri-hemihydrate (three mole-
cules of water per two host molecules). Contrary to most 1,4-dihy-
dropyridine (1,4-DHP) rings previously studied by us [18a,c,d,23]
where this ring adopts a boat conformation with the N1 and C4
atoms defining the stern and bow positions, in this crystal struc-
ture the 1,4-DHP ring is rather flat. The average ring bond distance
is 1.413(2) Å. The conformation of 2h in the solid state shows an
ap,ap orientation of the carboxylic groups with respect to the endo-
cyclic double bonds of the 1,4-DHP ring. The nitrophenyl ring is
positioned above the concave site of the 1,4-DHP bisecting this ring
(torsion angle C3–C4–C10–C60 = 46.1(4)°). The nitro group is syn-
periplanar to the H4 atom on C4.
Thus, we have carried out a series of experiments under opti-
mized conditions, namely at 30 °C and using a sonic horn at
18 kHz, and the results are summarized in Table 4. In order to show
the advantages of the present experimental conditions, in Table 4
we have also collected the results obtained under conventional
conditions.
The crystal structure is stabilized by means of strong intermo-
lecular hydrogen bonds involving the water molecules (see Fig
1b and Table A.2 in Supporting Information). The O7 atom of one
of the water molecules is located in a special position coincidently
with a crystallographic two-fold axis. Also some weak interactions
of the type C–H. . .O and C–H..Cl are present.

224
E. Ruiz et al. / Ultrasonics Sonochemistry 19 (2012) 221–226
Table 4
Synthesis under heterogeneous conditions of 6-chloro-5-formyl-1,4-dihydropyridines (2a–l) and ultrasound irradiation at 30 °C using a sonic horn at 18 kHz.
Product
X
R
US
Conventional methoda
Yield (%)b
m.p °C (Ref)
t (min)
Yield (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH2CH3
–CH2CH3
–CH2CH3
–CH2CH3
–CH2CH3
–CH2CH3
15
15
15
15
15
20
15
15
15
15
15
20
83
85
90
95
92
80
84
85
88
94
90
78
80
80
75
85
82
74
78
80
82
85
82
72
181–182 (181–182 [7])
178–180 (179–181 [18b])
212–214 (213–214 [7])
190–192 (190–192 [18b])
196–198 (197–198 [23])
199–201 (200–201 [18b])
201–202 (200–202 [18b])
198–200 (199–201 [18b])
225–227 (224–226 [18b])
251–253 (251–253 [18b])
210–212 (210–211 [18b])
217–219 (217–219 [18b])
2-NO2
3-NO2
4-NO2
2-Cl
3-pyridyl
H
2-NO2
3-NO2
4-NO2
2-Cl
2j
2k
2 l
3-pyridyl
a
For comparison, reaction time 1080 min.
Yield of isolated and recrystallized product.
b
Fig. 1. X-ray crystallography of compound 2 h. (a) Plot showing the atomic numbering scheme. Displacement ellipsoids are drawn at 50% probability level for non-H atoms.
(b) Packing of the molecules in the unit cell showing their hydrogen bond network.
Gaussian 03 [25]. The conformers distribution was accomplished
by the Monte Carlo methods [24]; and twenty possible minimum
structures were studied which were ordered according to their
own energy values. All these molecules were re-optimized using
DFT methods [24] with functional B3LYP [26] and 6–31G(d,p) base
[26]. In all cases, each conformation converges to the same struc-
ture (see Fig 2), which is very near to those determined by X-ray
analyses. Only five of the calculated bond angles move over from
the X-ray parameters reported. The gas phase model predicts quite
well the geometrical parameters of the molecule which nicely
match with those obtained experimentally by X-ray analysis. The
structural data are collected in the Supplementary Material.
4. Conclusions
In summary, we have described an ultrasound assisted synthe-
Fig. 2. Most stable conformation for compound 2 h calculated at B3LYP/6–31G(d,p).
sis of a wide variety of 6-chloro-5-formyl-1,4-dihydropyridines
that offers several practical advantages including faster reaction
rates, higher purity, and higher yields, as well as cleaner conditions
In order to gain better understanding of the minimum energy
conformation of 2h, we performed a conformational study using
the Molecular Mechanic Force Field (MMFF) [24] methods and
the semiempirical Hamiltonian AM1 [24]. Calculations were car-
ried out using the programs package PC Spartan Pro [24] and
when compared with the conventional thermal method. Further-
more, we have determined unambiguously the X-ray structure of
compound 2h and calculated its minimum energy conformation
which compares quite well with that obtained by means of the dif-
fraction technique.

E. Ruiz et al. / Ultrasonics Sonochemistry 19 (2012) 221–226
225
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This work was supported by the MICINN of Spain (Project
CT2008-00795/BQU and Consolider-Ingenio 2010C-07-25200)
and the CAM (Project P-PPQ-000225-0505). M. Suárez is grateful
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