A new In-SiO2 composite catalyst in the solvent-free multicomponent synthesis of Ca2+ channel blockers nifedipine and nemadipine B

Article abstract of DOI:10.1039/c2nj40060j

An In-SiO₂ composite was prepared by the sol-gel method and was applied as a heterogeneous Lewis acid catalyst in the multicomponent Hantzsch synthesis of symmetrical and non-symmetrical 1,4-DHPs. The Ca²⁺ channel blockers nifedipine and nemadipine B were synthesized in a single step through a solvent-free protocol. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2012.

Full text of DOI:10.1039/c2nj40060j

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PAPER
A new In–SiO2 composite catalyst in the solvent-free multicomponent
synthesis of Ca2+ channel blockers nifedipine and nemadipine Bw
Ricardo F. Affeldt,a Edilson V. Benvenuttib and Dennis Russowsky*a
Received (in Gainesville, FL, USA) 26th January 2012, Accepted 11th April 2012
DOI: 10.1039/c2nj40060j
An In–SiO2 composite was prepared by the sol–gel method and was applied as a heterogeneous
Lewis acid catalyst in the multicomponent Hantzsch synthesis of symmetrical and non-symmetrical
1,4-DHPs. The Ca2+ channel blockers nifedipine and nemadipine B were synthesized in a single
step through a solvent-free protocol.
The first synthesis of these molecules was carried out by
Arthur Rudolf Hantzsch, in 1882, through a multicomponent
1. Introduction
The diversity and complexity of organic molecules represent
reaction between 2 equivalents of a b-ketoester (9), aldehydes
(10), and NH4OAc (11) in the presence of hydrochloric acid as
catalyst. This protocol has been widely used until now due
one of the main goals in modern synthetic organic chemistry as
well as the central objective to be pursued in the construction of
new libraries of bioactive compounds.1 1,4-Dihydropyridines
to its simple one-pot process, bringing an economical and
environmental benefit (Scheme 1).12
Multicomponent reactions (MCRs) can be defined as those
(DHPs) are an important and privileged class of heterocyclic
scaffolds of low molecular weight in medicinal chemistry,
providing important ligands for biological receptors.2 These
where three or more reagents are combined in the same
compounds, although described for the first time more than a
reaction flask to give a new product which contains portions
of all the components.13 These reactions have been currently
century ago, have recently been recognized as vital drugs in the
treatment of angina pectoris, blood pressure and hypertension.
applied in diverse synthetic processes mainly to those directed
to the synthesis of biological active heterocyclic compounds.14
Furthermore, many syntheses of dihydropyridines have been
widely used in the synthesis of alkaloids and related nitrogen
heterocycle containing compounds.3 Many DHPs are already
Hantzsch multicomponent reaction is frequently associated
On the other hand, the use of Brønsted acid catalysis in the
commercial products such as: amlodipine (1), felodipine (2),
p-TSA has been reported as an efficient catalyst.15 Alter-
isradipine (3), lacidipine (4), nicardipine (5), nitrendipine (6),
nifedipine (7) and nemadipine B (8), and nemadipine B exhibits
widely employed as Lewis acid catalysts16 to produce the
potent calcium channel blocking activities (Fig. 1).
1,4-dihydropyrimidines.17 Additionally, a plethora of different
These molecules have therapeutic success due to the effective
binding to the active site of the receptors of calcium channels,
with low yields and decomposition of the reagents, although
natively, metal halides as well as metal triflates have been
promoters and reaction conditions were investigated: ionic
liquids,18 fluorous phase,19 aqueous phase,20 microwave21 and
regulating the transport of calcium ions through the biological
ultrasound22 energies, organocatalyzed reactions,23 hetero-
membranes, providing a relaxation effect on the contractions of
the cardiac muscle.4 Their pharmacological properties include
polyacids,24 industrial fly ashes,25 metal oxides,26 CAN,27
neuro- and radio protective effects,5,6 noncompetitive inhibition
TMSI,28 iodine,29 Ph3P,30 bakers’ yeast,31 transition metal
of topoisomerases,7 anticancer activity,8 and HIV protease
complexes,32 among others have allowed us to access the
inhibition,9 among others. Due to the particular molecular
dihydropyridines. Zeolites,33 silica-based catalysts34 or solvent-
free conditions35 have also emerged as important environ-
structure, certain Hantzsch dihydropyridines are considered as
mimics of the biological redox system NAD/NADH+ and have
mentally benign synthetic methods.
emerged as hydrogen transfer agents in biomimetic reductions10
We have focused our research interest in the development of
new methodologies and catalysts addressed to the synthesis of
and also as photoactive compounds.11
nitrogen containing small molecules.36 In an earlier work, we
a
´
´
ˆ
´
Laboratorio de Sınteses Organicas, Instituto de Quımica,
Universidade Federal do Rio Grande do Sul, Av. Bento Gonc¸alves
9500, 91501-970, Porto Alegre, RS, Brazil.
have reported the synthesis of the Cu–SiO2 composite and its
successful application in the multicomponent Biginelli reaction37
which revealed a promising antiproliferative activity against
many cancer and glioma cell lines.38
E-mail: dennis@iq.ufrgs.br
b
´
´
´
´
Laboratorio de Solidos e Superfıcies, Instituto de Quımica,
Universidade Federal do Rio Grande do Sul, Av. Bento Gonc¸alves
9500, 91501-970, Porto Alegre, RS, Brazil
In connection with our ongoing research, we describe here
the preparation of a new indium–silica composite (In–SiO2)
and its application in the multicomponent Hantzsch reactions.
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2nj40060j
c
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Fig. 1 Some bioactive dihydropyridines.
Scheme 1 Multicomponent Hantzsch synthesis of 1,4-dihydropyridines.
This new heterogeneous Lewis acid catalyst was success-
fully employed in the one-pot preparation of a series of
1,4-dihydropyridines and polyhydroquinolines, including the
synthesis of the calcium channel blockers nifedipine (7) and
nemadipine B (8).
2. Results and discussion
2.1. Synthesis and characterization of the In–SiO2 xerogel
composite
Scheme 2 Synthesis of the In–SiO2 composite by the sol–gel method.
Attempts to apply the Cu–SiO2 composite as a heterogeneous
Lewis acid catalyst in the multicomponent Hantzsch synthesis
did not lead to the formation of 1,4-dihydropyridines, even
after a week at room temperature. We observed an intense
dark-blue color when Cu–SiO2 (a pale green solid) was added
to the reaction mixture which was assigned to a possible
formation of an ammonia–copper stable complex, poisoning
the catalyst and stopping the course of the reaction.
gram of silica composite, respectively. The N2 adsorption–
desorption isotherms of the In–SiO2 composite are shown in
Fig. 2, together with the HK (Horvath–Kawazoe) pore size
distribution curve.40 A type I isotherm, typical of microporous
material, with a predominant pore diameter near 1 nm was
observed.41 The preference for the HK instead of the usual
BJH method for pore size distribution analysis was made
considering that the HK method is more appropriate for
microporous materials (smaller than 2 nm of diameter), while
the BJH can be only successfully applied to mesoporous
materials (with pore sizes between 2 and 50 nm of diameters).
From the BET multipoint method, a specific surface area of
578 Æ 20 m2 gÀ1 was obtained.
Taking into account our interest to explore the ability of
indium(III) compounds as Lewis acid catalysts,39 we decided to
synthesize a new In–SiO2 composite based on the sol–gel
method. For instance, we used a similar protocol described
previously to prepare the Cu–SiO2 composite (Scheme 2).
The In–SiO2 composite material prepared was characterized
by EDS (Energy Dispersive Spectroscopy) and XRF (X-Ray
Fluorescence Spectroscopy) elemental analyses. The experi-
mental values were 0.94 mmol and 0.88 mmol of indium per
Typical SEM images are shown in Fig. 3. It is possible to
observe a homogeneous and compact surface, without the
presence of macroporous materials (larger than 50 nm of
diameter). Therefore, from these analyses, we can infer that
c
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Scheme 3 Synthesis of dihydropyridine 12a under different conditions.
Table 1 Synthesis of 12a under different reaction conditions
Entry Catalyst Loading
Solvent Cond. T/h Yield (%)
Fig. 2 N2 adsorption–desorption isotherms of the In–SiO2 compo-
1
2
3
4
5
6
7
8
—
SiO2
—
EtOH
EtOH
EtOH
MeOH
iPrOH
DCM
THF
RT
RT
RT
RT
RT
RT
RT
120
—
site; inset: Horvath–Kawazoe pore size distribution curve.
100 mga
120 35
120 40
120 45
120 50
120 30
120 50
120 50
48 65
5
5
5
5
In–SiO2 2 mol%b
In–SiO2 2 mol%b
In–SiO2 2 mol%b
In–SiO2 2 mol%b
In–SiO2 2 mol%b
In–SiO2 2 mol%b
CH3CN RT
9
In–SiO2 10 mol%c iPrOH
In–SiO2 10 mol%c iPrOH
In–SiO2 10 mol%c EtOH
In–SiO2 10 mol%c MeOH
RT
10
11
12
13
14
15
Reflux
Reflux
Reflux
88
87
79
75
In–SiO2 10 mol%c CH3CN Reflux
InCl3
InCl3
10 mol%c CH3CN RT
10 mol%c EtOH
RT
144 58
96 60
a
b
Pure silica-gel. 22.2 mg of catalyst considering 0.90 mmol of
c
indium per gram of the material composite. 111.1 mg of catalyst
considering 0.90 mmol of indium per gram of the material composite.
desired product (entry 2). When the In–SiO2 composite (22.2
mg of silica composite, 2 mol% of indium) was used, a small
increase in the yield was observed (entry 3).
Fig. 3 SEM (Scanning Electron Microscopy) image of the In–SiO2
composite, obtained with 50 000Â of magnification.
We analyzed the performance of this reaction carried out in
protic solvents (MeOH and iPrOH) and polar aprotic solvents
(DCM, THF and CH3CN). Unfortunately, no significant improve-
ments (50% yield) were observed (entries 4–8, respectively).
We then decided to increase the catalyst load to 10 mol% of
indium (111.1 mg of the silica composite) in the reaction
performed in iPrOH at room temperature. After 48 h, the
reaction was stopped and the product was isolated in 65%
yield (entry 9). The increase of catalyst load allowed a
significant reduction in the reaction time.
the indium was incorporated into the silica matrix forming the
In–SiO2 composite. The composite is microporous presenting
high surface area and unimodal pore size distribution with a
maximum near to 1 nm, characteristics that allow this material
to be applied as a catalyst.
The synthesis was repeated twice, under the same conditions,
and all analyses produced essentially the same results, showing
the consistency and reproducibility of the method. With the
composite material in hand, we performed a set of experiments
to evaluate the efficiency of the In–SiO2 composite as a
heterogeneous Lewis acid catalyst.
Next, we performed the reaction under reflux conditions.
The reactions were monitored by TLC and after 5 h 12a was
isolated in 88%, 87%, 79% and 75% yields (entries 10–13,
respectively). The reactions carried out in iPrOH or EtOH
afforded better yields than those employing MeOH or
CH3CN. At this point, special attention was dedicated to the
use of alcoholic solvents due to their relative low toxicity and
environmental compatibility. We found that the crude product
was cleaner in iPrOH than EtOH, which was therefore elected
as the best solvent. Additionally, to compare the efficiency of
In–SiO2 we performed two experiments using 10 mol% InCl3
at room temperature. The reaction performed in CH3CN
afforded compound 12a in 58% yield after 144 hours, while
the reaction in EtOH afforded the product in 60% yield after
96 hours (entries 13 and 15, respectively).
2.2. The Hantzsch multicomponent reaction in solvent media
In a first set of experiments, we tried to establish the effect of
the catalyst load, the nature of the solvent, the optimum
reaction time and temperature. As a model reaction we have
employed ethyl acetoacetate (9a, 2 mmol), benzaldehyde
(10a, 1 mmol), and NH4OAc (11, 2 mmol) (Scheme 3). The
results are shown in Table 1.
In the absence of any catalyst, the reaction performed in
ethanol did not proceed, even after 120 h at room temperature
(Table 1, entry 1). The use of pure silica gel (100 mg),
employed as a standard condition, afforded poor yield of the
c
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Scheme 4 Synthesis of 1,4-dihydropyridines 12b–m.
Table 2 Synthesis of 1,4-DHPs 12b–m via In–SiO2 catalyst in iPrOH
acids that can cause corrosion, safety, manipulation and pollu-
tion problems. These acids can be replaced advantageously by
solid, recyclable acids such as clays and silica matrices. The
enhancement in the kinetics of the reaction can result from the
increasing concentrations of reactants when a diluting agent
such as a solvent is avoided. As the concentrations of reactive
species are optimal, reactivity is increased and, generally, mild
reaction conditions are required. In several cases, difficult
reactions using solvents are easily achieved under solvent-free
conditions. Another unquestionable advantage lies in the fact
that higher temperatures, when compared to classical conditions,
can be used without the limitation imposed by solvent boiling
points.44 These prompted us to investigate the use of the new
In–SiO2 composite as a catalyst under solvent-free conditions
in the multicomponent Hantzsch synthesis of 1,4-dihydro-
pyridines (Scheme 5).
Dicarbonyl
Aldehyde
R1
R2
Ar
Entry
1,4-DHP Yield (%)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me 4-N,N(Me)2–C6H4 12b
80
84
81
82
80
86
87
90
83
85
73
78
Me 4-NO2–C6H4
Me 4-MeO–C6H4
Me 3,4-(MeO)2–C6H3
Me 1-Naphthyl
Me 4-CN–C6H4
Me 2-Thienyl
12c
12d
12e
12f
12g
12h
12i
Me 3-Thienyl
9
Me 2-Pyridinyl
Me 2-NO2–C6H4
Me 2,3-(Cl)2–C6H3
12j
12k
12l
10
11
12
Et
4-NO2–C6H4
12m
Once the best conditions were established, we extended this
protocol to a series of different aromatic aldehydes 10b–l,
including the reactions with b-ketoesters 3b and c (Scheme 4).
The results are shown in Table 2.
In a first attempt, ketoester 9a (2 mmol), benzaldehyde (10a,
1 mmol), and ammonium acetate (11b, 2 mmol) were charged in
a reaction flask, followed by the addition of 10 mol% (106 mg)
of In–SiO2 composite. All reagents were mixed with the aid of a
stirring bar and the flask was immersed in an oil bath previously
heated at 50 1C and kept over 30 min. After this time, the crude
mixture was diluted with CH2Cl2 and filtered to separate the
solid catalyst. The filtrate was evaporated and the crude mixture
was purified by column chromatography to afford the
1,4-dihydropyridine 12a in 60% yield (see Table 3, entry 1).
Next, the amount of reagents and catalyst were kept
unchanged and the temperature of the oil bath was raised to
100 1C. After 30 min, the crude reaction mixture was isolated
and purified by column chromatography. Compound 12a was
obtained in 75% yield, evidencing the effect of temperature on
the reactivity (entry 2). These new reaction conditions were
extended to the reactions with aldehydes 10b–k to afford
the corresponding dihydropyridines 12a–j in 50–90% yields
(entries 3–11, respectively).
The 1,4-dihydropyridines 12b–k were obtained in up to 80%
yield, despite the electron-release or electron-withdrawing
character of the substituents in the aromatic ring of 10b–k
(entries 1–10, respectively). The exceptions were the reactions
performed with aldehyde 10l and 1,3-dicarbonyl 9b (73%,
entry 11) and the reaction of aldehyde 10a with 1,3-dicarbonyl
9c (78%, entry 12), where the yields were slightly inferior.
2.3. The Hantzsch multicomponent reaction under solvent-free
conditions
Despite the success of organic reactions carried out in solvent
media, the reactions performed under environmentally benign
solvents42 or solvent-free conditions43 have increased the
interest due to the claim for the development of new synthetic
protocols with less environmental impact. Therefore, the waste
prevention and environmental protection are major goals in an
overcrowded world of increasing demands. These approaches
can also enable experiments to be run without strong mineral
Due to the success of the composite In–SiO2 as a hetero-
geneous Lewis acid catalyst in the multicomponent Hantzsch
Scheme 5 Solvent-free multicomponent Hantzsch reaction catalyzed by the In–SiO2 composite.
c
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Table 3 Solvent-free synthesis of 1,4-dihydropyridinesa
glycogen phosphorylase inhibitors.46 Due to this fact, recent
investigations have focused on the synthesis of bicyclical
Hantzsch derivatives which are able to act as new lipid
modulating agents addressed to the treatment of type-2
diabetes.47 Therefore, this prompts us to apply the developed
methodology in a tetra component non-symmetrical Hantzsch
reaction. For these investigations we carried out the reaction
under the same reaction conditions described above for
symmetrical 1,4-dihydropyridines using the aldehydes 10a,d–f,m,
dimedone (13) and ethyl acetoacetate (3b) as the 1,3-dicarbonyl
compounds and ammonium acetate (11) (Scheme 6). The results
are shown in Table 4.
Dicarbonyl
R1
Aldehyde
Ar
Entry
1,4-DHP
Yield (%)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
C6H5
C6H5
12a
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
7
60
75
50
78
62
69
84
71
90
85
70
85
75
4-N,N-(Me)2–C6H4
4-NO2–C6H4
4-MeO–C6H4
3,4-(MeO)2–C6H3
1-Naphthyl
4-CN–C6H4
2-Thienyl
9
10
11
12
13
3-Thienyl
2-Pyridinyl
2-NO2–C6H4
2,3-(Cl)2–C6H3
All reagents were mixed in a reaction flask which was
immersed in an oil bath previously heated at 100 1C and kept
at this temperature for 30 minutes. The crude mixture was
then diluted with ethyl acetate and filtered to separate the solid
catalyst. The filtrate was evaporated and the crude mixture
was purified by column chromatography to afford 1,4-dihydro-
pyridine 14 in reasonable to good yields. The yields of products
were quite similar to those obtained for the symmetrical
dihydropyridines. The yields of products derived from
aromatic aldehydes 10d,e,m with electron-releasing substitu-
ents (Table 4, entries 2, 3 and 5, respectively) were superior
compared to non-substituted aromatic aldehydes 10a,f
(entries 1 and 4, respectively) or with an electron-withdrawing
nitro group at the para position (entry 6).
8
a
Reaction carried out at 50 1C.
synthesis of 1,4-dihydropyridines under solvent-free conditions,
we decided to apply this methodology to the synthesis of
nifedipine (7, see Fig. 1), a notorious calcium channel blocker
widely used for angina pectoris treatment and blood pressure
control. 2-Nitrobenzaldehyde (10k, 1 mmol) was reacted
with methyl acetoacetate (9b, 2 mmol), ammonium acetate
(11b, 2 mmol) and In–SiO2 composite (10 mol%, 106 mg) over
30 minutes at 100 1C. After separation of the composite
catalyst, the crude mixture was purified by chromatography
to afford nifedipine (7) in 85% yield in a single step (Table 3,
entry 12). Nemadipine B (8, see Fig. 1) was recently employed
by Kwok and Ricker as a specific protein inhibitor which
induces phenotypic variations in Caenorhabditis elegans worms,
showing marked defects in their morphology.45 Therefore, we
decided to perform its synthesis in a one-pot reaction. A similar
procedure was also applied successfully in the reaction of
ethyl acetoacetate (9a), 2,3-dichlorobenzaldehyde (10l), which
afforded nemadipine B, isolated in 75% yield, after purification
by column chromatography in a single step (entry 13).
2.5. A tentative mechanistic pathway for the multicomponent
Hantzsch reaction
During the course of the reaction of 1,3-dicarbonyl compound
9a, aldehyde 10b and NH4OAc (11), the TLC analysis revealed
the formation of two new different spots (ca. 2 hours). We
stopped the reaction and the crude mixture was fractioned by
column chromatography. The 1H NMR and 13C NMR spectro-
scopic analyses of the less polar product (major) allowed us to
suggest the structure of an a,b-unsaturated compound 15
which was isolated as a mixture of E and Z isomers. The
spectral data of the more polar product (minor) were compatible
with the structure of the 1,4-dihydropyridine 12b (Scheme 7).
With compound 15 (mixture of E and Z) in hand, we
performed the reaction with 1 equivalent of ethyl acetoacetate
(9a) and 2 equivalents of NH4OAc (11), under the same
previous conditions. After 3 hours of reflux in isopropanol,
we stopped the reaction and the dihydropyridine 12b was
isolated in 60% yield after purification by column chromato-
graphy (Scheme 7). This possible mechanistic pathway is in
accordance with previously suggested mechanistic pathways in
2.4. Multicomponent synthesis of polyhydroquinolines under
solvent-free conditions
Polyhydroquinolines are the unsymmetrical derivatives of
1,4-dihydropyridines and many methodologies are reported
for their synthesis. Among various biologically active 1,4-
dihydropyridines, the prominent biological activities are asso-
ciated with calcium channel blockers (for the treatment of
cardiovascular diseases) and hypertension. However, some
previous reports indicated that 1,4-DHPs derivatives may act
as a lead compound in the antidiabetic drug discovery, such as
Scheme 6 Solvent-free multicomponent synthesis of polyhydroquinolines.
c
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Table 4 Solvent-free synthesis of polyhydroquinolines
4. Experimental methods
Aldehyde
Ar
4.1. General remarks
Entry
Dihydropyridine
Yield (%)
All reagents and solvents were purchased from commercial
suppliers and used without further purification except hexane,
which was distilled prior to use. The 1H and 13C NMR spectra
were recorded in CDCl3 on a Varian VNMRS spectrometer at
300 MHz and 75 MHz, respectively. The chemical shifts (d) are
reported in parts per million (ppm) relative to TMS (0.00 ppm)
1
2
3
4
5
6
C6H5
14a
14b
14c
14d
14e
14f
69
75
84
65
86
62
4-MeO–C6H4
3,4-(MeO)2–C6H3
1-Naphthyl
2,3,4-(MeO)3–C6H2
3-NO2–C6H4
1
for H NMR and to the central line of CDCl3 (77.0 ppm) for
the literature.48 Although we were not able to isolate the
enamine compound 16, its formation from an amine and
1,3-dicarbonyl compound is widely reported in the literature.49
The subsequent Michael-type addition of 16 to 15 would
afford the open-chain adduct 17. To complete the process,
an intra-molecular cyclization would lead to the formation of
1,4-dihydropyridine nucleus 12. Therefore, the formation of
intermediate 16 can be suggested as being part of a second
process occurring concomitantly with the formation of
compound 15 in this multicomponent reaction (Scheme 8).
13C NMR. Coupling constants J are reported in hertz (Hz).
The following abbreviations are used for the multiplicities: s,
singlet; d, doublet; dd, double-doublet; t, triplet; q, quartet;
m, multiplet; br, broad. IR spectra were recorded on a
FTIR-Varian 640-IR spectrometer. Melting points were
measured on an Olympus BX41 microscope equipped with a
Mettler-Toledo FP82HT hot stage (Mettler-Toledo FP90
controller) and are uncorrected. Reactions were monitored
using thin layer chromatography (TLC) carried out on Merck
silica gel 60 F254 pre-coated aluminum plates. The visualiza-
tion was achieved under UV light (254 nm) or staining with I2.
Chromatographic separations were achieved on silica gel
columns (70–230 mesh, Aldrich) using a gradient of hexanes–
ethyl acetate as eluent.
3. Conclusions
We have prepared a new indium–SiO2 composite through the
sol–gel method which was successfully applied as a hetero-
geneous Lewis acid catalyst in the synthesis of a series of
1,4-dihydropyridines and polyhydroquinolines in good yields.
Additionally, the calcium channel blockers nifedipine and
nemadipine B were synthesized in a single step in 85% and
75% yield, respectively. The use of multicomponent synthesis
allied with the development of a greener solvent-free protocol
with the recoverable heterogeneous catalyst makes this
methodology a superior approach for the preparation of small
molecules of biological interest.
4.2. Synthesis of composite In–SiO2 by the sol–gel method
In a beaker flask, adapted with a magnetic stirrer, 5 mL of
ethanol, 2 mL of deionized H2O and 3 drops of conc. HCl
were placed. Next, 1.43 g (6.43 mmol) of InCl3 was added in
one portion. The mixture was vigorously stirred until total
dissolution (ca. 15 min). To this clean homogeneous solution
was added 5.56 mL (25 mmol) of TEOS in one time in a
continuous flow. This new mixture remained under vigorous
stirring for additional 15 minutes. The magnetic stirrer bar was
Scheme 7 Isolation of a,b-unsaturated compound 5-E,Z as intermediate.
Scheme 8 Tentative mechanistic pathway to dihydropyridine formation.
c
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removed and the flask was covered with a clock glass
and leaved in rest until the formation of a glass material
(ca. 5 days). Then, the glass material was pulverized in a
mortar and the white solid was subjected to the thermal
treatment at 120 1C for 24 hours. After this time, the material
was washed with 20 mL of ethanol followed by 20 mL of
deionized H2O. The material was subjected again to the
thermal treatment at 100 1C for additional 24 hours.
1 mmol of aldehyde followed by the addition of 2 mmol of
NH4OAc. The heterogeneous catalyst In–SiO2 (10 mol%,
111.1 mg) was added in a single portion and no solvent was
used. The reaction was carried out in a 100 1C oil bath until
consumption of the reagents (ca. 30 minutes) indicated by
TLC. The mixture was dissolved in ethyl acetate and the
catalyst was filtered off. The solvent was evaporated and
the crude product was purified by column chromatography
(hexane–ethyl acetate).
4.2.1. Characterization of metal–silica composites. The N2
adsorption–desorption isotherms of the In–SiO2 composite
were determined at the liquid nitrogen boiling point, using a
Tristar II Krypton 3020 Micromeritics equipment. The samples
were previously degassed at 120 1C under vacuum, for 4 h. The
specific surface area was determined by the BET (Brunauer,
Emmett and Teller) multipoint technique41 and the pore size
distribution was obtained by using the Horvath–Kawazoe
method.40 Scanning electron microscopy (SEM) images with
magnification from 1000 to 50 000Â were obtained for the
In–SiO2 composite, which was dispersed on a double faced
conducting tape on an aluminum support and coated with a
thin film of carbon using a Baltec SCD 050 Sputter Coater
apparatus. The micrograph was obtained using a Jeol
Scanning Electron Microscope, model JSM 5800, connected
to a secondary electron detector and an X-ray energy disper-
sive spectrometer (EDS). X-ray fluorescence analysis of the
In–SiO2 composite was performed using H3BO3 as support,
using a Rigaku RIX 2000 equipment.
4.3.3.2. Synthesis of polyhydroquinolines 14a–f. In a 25 mL
round-bottom flask were added 1 mmol of methyl acetoacetate
(9b), 1 mmol of 5,5-dimethyl cyclohexane-1,3-dione (13),
10 mol% (111.1 mg) of the In–SiO2 composite catalyst, 2 mmol
of NH4OAc, followed by the addition of 1 mmol of the
aldehyde. The mixture was heated at 100 1C in an oil bath
for 30 minutes. The crude mixture was dissolved in ethyl
acetate and the catalyst was filtered off. The solvent was
evaporated and the crude product was purified by column
chromatography (hexane–ethyl acetate).
4.4. Spectroscopic data of compounds 7, 8, 12a–m and 14a–f
4.4.1. Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-
3,5-dicarboxylate (12a). Solid, mp 158–160 1C.35 1H NMR
(300 MHz, CDCl3): d = 1.22 (t, J = 17.05, 6H); 2.33 (s, 6H);
4.04–4.13 (m, 4H); 4.99 (s, 1H); 5.64 (br s, 1H); 7.12–7.30
(m, 5H). 13C NMR (75 MHz, CDCl3): d = 14.2; 19.6; 39.6;
59.7; 104.2; 126.1; 127.8; 128.0; 143.8; 147.7; 167.6. IR (KBr,
n = cmÀ1) 3342, 3060, 2982, 1687, 1652, 1488, 1211, 703.
4.3. General procedure for synthesis of dihydropyridines and
polyhydroquinolines
4.4.2. Diethyl 2,6-dimethyl-4-(4-dimethylaminophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (12b). Solid, mp 158–162 1C.48
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.2 Hz, 6H);
2.26 (s, 6H); 2.86 (s, 6H); 4.04–4.13 (m, 4H); 4.89 (s, 1H); 6.43
(br s, 1H); 6.60 (d, J = 8.7 Hz, 2H); 7.15 (d, J = 8.7 Hz, 2H).
13C NMR (75 MHz, CDCl3): d = 14.1; 19.1; 38.2; 40.6; 59.4;
103.8; 112.2; 128.4; 136.6; 142.9; 148.8; 167.9. IR (KBr,
n = cmÀ1) 3354, 3095, 2976, 1693, 1652, 1488, 1212.
4.3.1. General procedure for the reactions catalyzed by
InCl3 performed in solvent phase. In a 25 mL round-bottom
flask were added 2 mmol of the b-ketoester, 1 mmol of the
aldehyde followed by the addition of 2 mmol of NH4OAc. The
InCl3 (10 mol%) catalyst was added in a single portion and
2.5 mL of the solvent was added. The reaction was carried out
under reflux conditions until consumption of the reagents,
indicated by TLC. The solvent was evaporated and the crude
product was dissolved in ethyl acetate, washed with water and
the organic layer separated and dried. After the filtration and
evaporation of the solvent, the crude product was purified by
column chromatography (hexane–ethyl acetate).
4.4.3. Diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (12c). Solid, mp 118–127 1C.49
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.2 Hz, 6H);
2.35 (s, 6H); 4.08–4.10 (m, 4H); 5.09 (s, 1H); 5.90 (br s, 1H);
7.45 (d, J = 9.0 Hz, 2H); 8.08 (d, J = 9.0 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d = 14.2; 19.5; 40.1; 59.9; 103.0; 123.2;
128.9; 144.8; 146.2; 155.1; 167.1. IR (KBr, n = cmÀ1) 3319,
3102, 2978, 1704, 1651, 1519, 1488, 1348, 1212.
4.3.2. General procedure for the reactions catalyzed by
In–SiO2 performed in solvent phase. In a 25 mL round-bottom
flask were added 2 mmol of the b-ketoester, 1 mmol of the
aldehyde followed by the addition of 2 mmol of NH4OAc. The
heterogeneous catalyst In–SiO2 (10 mol%, 111.1 mg) was added
in a single portion and 2.5 mL of solvent was added. The reaction
was carried out under reflux conditions until consumption of the
reagents, indicated by TLC. The heterogeneous catalyst was
recovered from the reaction media by a simple filtration. The
solvent was evaporated affording a crude solid product, which
was purified by column chromatography (hexane–ethyl acetate).
4.4.4. Diethyl
2,6-dimethyl-4-(4-methoxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (12d). Solid, mp 148–153 1C.50
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.2 Hz, 6H);
2.31 (s, 6H); 3.75 (s, 3H); 4.07–4.10 (m, 4H); 4.92 (s, 1H); 5.73
(br s, 1H); 6.74 (d, J = 7.5 Hz, 2H); 7.19 (d, J = 7.8 Hz, 2H).
13C NMR (75 MHz, CDCl3): d = 14.2; 19.6; 38.7; 55.1; 59.7;
104.3; 113.1; 128.9; 140.3; 143.5; 157.8; 167.7. IR (KBr, n = cmÀ1
)
3342, 3096, 2984, 1690, 1651, 1490, 1211.
4.3.3. General procedure for the reactions catalyzed by
In–SiO2 performed under solvent-free conditions
4.4.5. Diethyl 2,6-dimethyl-4-(3,4-dimethoxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (12e). Solid, mp 137–145 1C.50
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 6H);
2.33 (s, 6H); 3.82 (s, 3H); 3.84 (s, 3H); 4.09–4.122 (m, 4H);
4.3.3.1. Synthesis of dihydropyridines 7, 8 and 12a–m. In a
25 mL round-bottom flask were added 2 mmol of b-ketoester,
c
1508 New J. Chem., 2012, 36, 1502–1511
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4.94 (s, 1H); 5.81 (br s, 1H); 6.74–6.99 (m, 3H). 13C NMR
(75 MHz, CDCl3): d = 14.4; 19.5; 38.9; 55.7; 59.7; 104.1;
110.7; 111.6; 119.7; 140.7; 143.7; 147.2; 148.0; 167.7. IR (KBr,
n = cmÀ1) 3343, 3096, 2982, 1686, 1651, 1483, 1208.
103.8; 123.9; 126.9; 131.3; 132.7; 142.6; 144.6; 147.7; 167.2. IR
(KBr, n = cmÀ1) 3320, 2991, 2541, 1720, 1637, 1552, 1255, 759.
4.4.12. Dimethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (12l). Solid, mp 176–179 1C.52
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3H); 3.61 (s, 3H);
5.45 (s, 1H); 5.89 (br s, 1H); 7.07 (t, J = 8.3 Hz, 1H); 7.23–7.31
(m, 2H). 13C NMR (75 MHz, CDCl3): d = 19.3; 38.3; 50.9;
103.5; 127.1; 128.0; 128.2; 129.4; 132.7; 144.4; 148.2; 167.8. IR
(KBr, n = cmÀ1): 3335, 3115, 2949, 1686, 1508, 1215, 736.
4.4.6. Diethyl 2,6-dimethyl-4-(1-naphthyl)-1,4-dihydropyridine-
3,5-dicarboxylate (12f). Solid, mp 197–200 1C.4 1H NMR
(300 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 6H); 2.33
(s, 6H); 4.09–4.22 (m, 4H); 5.34 (s, 1H); 5.98 (br s, 1H);
6.78–6.85 (m, 2H); 7.05 (d, J = 2.4 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d = 14.3; 19.4; 34.3; 59.9; 103.4; 123.0;
123.1; 126.3; 144.5; 151.5; 167.3. IR (KBr, n = cmÀ1) 3373,
3098, 2985, 1679, 1630, 1483, 1200, 793.
4.4.13. Dimethyl 2,6-diethyl-4-(4-nitrophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (12m). Solid, mp 196–198 1C.48
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.5 Hz, 6H);
2.65 (dq, J = 15.0 Hz and J = 7.5 Hz, 2H); 2.88 (dq, J = 15.0
Hz and J = 7.5 Hz, 2H); 3.65 (s, 1H); 5.11 (s, 1H); 5.95
(br s, 1H); 7.76 (d, J = 8.7 Hz, 2H); 8.10 (d, J = 9.0 Hz, 2H).
13C NMR (75 MHz, CDCl3): d = 12.7; 26.0; 39.7; 51.1; 102.0;
4.4.7. Diethyl 4-(4-cyanophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (12g). Solid, mp 197–199 1C.50
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.2 Hz, 6H);
2.35 (s, 6H); 4.05–4.13 (m, 4H); 5.03 (s, 1H); 6.00 (br s, 1H);
7.39 (d, J = 8.4 Hz, 2H); 7.51 (d, J = 8.1 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d = 14.2; 19.5; 40.4; 59.9; 103.1; 109.6;
123.4; 128.4; 146.3; 150.7; 154.9; 167.0. IR (KBr, n = cmÀ1
)
3345, 3081, 2950, 1713, 1683, 1636, 1520, 1205.
119.3; 128.8; 131.8; 144.6; 153.1; 167.1. IR (KBr, n = cmÀ1
)
4.4.14. Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (nifedipine, 7). Solid, mp 157–161 1C.4
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 6H); 3.59 (s, 6H);
5.72 (s, 1H); 6.04 (br s, 1H); 7.22–7.28 (m, 1H); 7.43–7.53
(m, 2H); 7.68 (dd, J = 8.1 Hz and J = 0.9 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d = 19.4; 34.4; 60.0; 103.5; 123.8; 127.0;
3344, 3091, 2981, 2228, 1682, 1489, 1214.
4.4.8. Diethyl 2,6-dimethyl-4-(2-thiophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (12h). Solid, mp 164–168 1C.35
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.2 Hz, 6H);
2.35 (s, 6H); 4.05–4.13 (m, 4H); 5.03 (s, 1H); 6.00 (br s, 1H);
6.80–6.79 (m, 1H); 6.84 (dd, J = 4.2 Hz and J = 3.3 Hz, 1H);
7.05 (dd, J = 5.1 Hz and J = 1.2 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d = 14.3; 19.4; 34.3; 59.9; 103.4; 123.0;
123.1; 126.3; 144.5; 151.5; 167.3. IR (KBr, n = cmÀ1) 3345,
3098, 2979, 1692, 1658, 1486, 1211, 722.
131.0; 132.7; 142.1; 145.0; 147.8; 167.6. IR (KBr, n = cmÀ1
)
3332, 3101, 2953, 1689, 1529, 1497, 1432, 1350, 1227.
4.4.15. Dimethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (nemadipine B, 8). Viscous
oil. 1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3H); 3.61
(s, 3H); 5.45 (s, 1H); 5.89 (br s, 1H); 7.07 (t, J = 8.3 Hz, 1H);
7.23–7.31 (m, 2H). 13C NMR (75 MHz, CDCl3): d = 19.3;
38.3; 50.9; 103.5; 127.1; 128.0; 128.2; 129.4; 132.7; 144.4; 148.2;
167.8. IR (KBr, n = cmÀ1): 3331, 2946, 1704, 1681, 1501,
1428, 1310, 1285, 1215.
4.4.9. Diethyl 2,6-dimethyl-4-(3-thiophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (12i). Solid, mp 159–164 1C.51
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 6H);
2.34 (s, 6H); 4.08–4.24 (m, 4H); 5.16 (s, 1H); 5.85 (br s, 1H);
6.94 (dd, J = 3.0 Hz and J = 1.2 Hz, 1H); 7.00 (dd, J =
4.8 Hz and J = 1.2 Hz, 1H); 7.14 (dd, J = 4.8 Hz and J = 3.0 Hz,
1H). 13C NMR (75 MHz, CDCl3): d = 14.3; 19.5; 34.6; 59.8;
103.5; 120.3; 124.5; 127.6; 144.3; 147.8; 167.7. IR (KBr,
n = cmÀ1) 3345, 3096, 2980, 1695, 1651, 1489, 1208, 776.
4.4.16. Methyl 2-methyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydro-
quinoline-3-carboxylate (14a). Solid, mp 210–212 1C.53
1H-NMR (CDCl3, 300 MHz): d = 0.93 (s, 3H); 1.07 (s, 3H);
2.22–2.34 (m, 4H); 2.38 (s, 3H); 3.61 (s, 3H); 5.06 (s, 1H); 6.22
(br s, 1H); 7.10–7.30 (m, 5H). 13C-NMR (CDCl3, 75 MHz):
d = 19.5; 27.1; 29.5; 32.7; 36.3; 41.0; 50.6; 51.1; 105.8; 112.1;
126.1; 127.8; 128.0; 143.8; 146.7; 148.7; 167.8; 195.6. IR (KBr,
n = cmÀ1): 3280, 3205, 3080, 2963, 2953, 1707, 1607, 1489.
4.4.10. Diethyl 2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (12j). Solid, mp 192–195 1C.4 1H NMR
(300 MHz, CDCl3): d = 1.19 (t, J = 7.05 Hz, 6H); 2.23
(s, 6H); 4.02–4.09 (m, 4H); 5.19 (s, 1H); 7.15 (dt, J = 4.8 Hz
and J = 0.9 Hz, 1H); 7.41 (d, J = 7.8 Hz, 1H); 7.59
(dt, J = 7.8 Hz and J = 1.8 Hz, 1H); 8.5 (dd, J = 4.8 Hz and
J = 0.9 Hz, 1H); 9.23 (br s, 1H). 13C NMR (75 MHz, CDCl3):
d = 14.2; 18.5; 42.8; 59.4; 101.5; 121.8; 124.5; 135.6; 146.6;
148.0; 165.2; 167.7. IR (KBr, n = cmÀ1) 3176, 3059, 2814,
1690, 1507, 1305, 1211, 1115, 755.
4.4.17. Methyl 2-methyl-4-(4-methoxyphenyl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (14b). Solid, mp 253–255 1C.53
1H-NMR (CDCl3, 300 MHz) d = 0.93 (s, 3H); 1.07 (s, 3H);
2.18–2.37 (m, 4H); 2.38 (s, 3H); 3.61 (s, 3H); 3.74 (s, 3H); 5.00
(s, 1H); 5.94 (br s, 1H); 6.74 (d, J = 8.7 Hz, 2H); 7.20 (d, J =
8.7 Hz, 2H). 13C-NMR (CDCl3, 75 MHz) d = 19.5; 27.1; 29.4;
32.7; 35.3; 41.1; 50.6; 51.0; 55.1; 105.9; 112.4; 113.3; 128.8;
139.3; 143.4; 147.7; 157.7; 167.9; 195.6. IR (KBr, n = cmÀ1):
3188, 3071, 2954, 1704, 1600, 1496, 1379, 1255, 1214.
4.4.11. Diethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (12k). Solid, mp 120–125 1C.51
1H NMR (300 MHz, CDCl3): d = 1.16 (t, 7.2 Hz, 6H); 2.32
(s, 6H); 3.94–4.09 (m, 4H); 5.85 (s, 1H); 7.22–7.27 (m, 1H);
7.46 (dt, J = 7.8 Hz and J = 0.9 Hz, 1H); 7.54 (dd, J = 7.8 Hz
and J = 1.5 Hz, 1H); 7.73 (dd, J = 8.1 Hz and J = 1.2 Hz,
1H). 13C NMR (75 MHz, CDCl3): d = 14.1; 19.6; 34.6; 60.0;
4.4.18. Methyl 2-methyl-4-(3,4-dimethoxyphenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (14c). Solid, mp
1
198–200 1C. H-NMR (CDCl3, 300 MHz): d = 0.94 (s, 3H);
1.07 (s, 3H); 2.15–2.34 (m, 4H); 2.40 (s, 3H); 3.63 (s, 3H); 3.80
c
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New J. Chem., 2012, 36, 1502–1511 1509

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(s, 3H); 3.83 (s, 3H); 5.02 (s, 1H); 6.44 (br s, 1H); 6.70 (d, J =
8.1 Hz, 1H); 6.77 (d, J = 8.1 Hz, 1H); 6.92 (s, 1H). 13C-NMR
(CDCl3, 75 MHz): d = 19.4; 27.0; 29.5; 32.6; 35.6; 41.0; 50.5;
51.0; 55.7; 55.8; 105.9; 110.7; 111.6; 112.1; 119.4; 139.6; 143.6;
147.2; 148.3; 148.7; 167.9; 195.7. IR (KBr, n = cmÀ1): 3289,
3214, 3081, 2951, 1702, 1600, 1512, 1489, 1383, 1215. HRMS
(ESI, w/-H+) calculated 384.18164, found 384.18131.
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4.4.19. Methyl 2-methyl-4-(1-naphthyl)-5-oxo-1,4,5,6,7,8-
hexahydro quinoline-3-carboxylate (14d). Solid, mp 234–236 1C.54
1H-NMR (CDCl3, 300 MHz): d = 1.05 (s, 3H); 1.26
(s, 3H); 2.02–2.28 (m, 4H); 2.37 (s, 3H); 3.39 (s, 3H); 5.30
(s, 3H); 5.82 (s, 1H); 6.13 (br s, 1H); 7.20–7.45 (m, 3H); 7.56
(t, J = 7.1 Hz, 1H); 7.62 (d, J = 7.8 Hz, 1H); 7.74 (d, J =
7.5 Hz, 1H); 8.77 (d, J = 8.7 Hz, 1H). 13C-NMR (DMSO-d6,
75 MHz): d = 18.6; 26.7; 29.6; 31.8; 32.5; 50.5; 51.0; 105.9;
111.8; 125.6; 125.7; 126.1; 126.8; 127.0; 128.2; 130.8; 133.3;
144.8; 146.8; 150.2; 168.2; 195.6. IR (KBr, n = cmÀ1): 3304,
2959, 1703, 1605, 1485, 1374, 1214.
4.4.20. Methyl 2-methyl-4-(3,4,5-trimethoxyphenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (14e). Solid, mp
205–207 1C.55 1H-NMR (CDCl3, 300 MHz): d = 0.99 (s, 3H);
2.15–2.33 (m, 4H); 2.36 (s, 3H); 3.66 (s, 3H); 3.78 (s, 9H); 5.04
(s, 1H); 6.53 (s, 2H); 6.72 (s, 1H). 13C-NMR (CDCl3, 75 MHz):
d = 19.2; 26.8; 29.5; 32.5; 36.2; 40.7; 50.6; 50.9; 55.9; 60.6;
104.7; 105.4; 111.5; 136.0; 142.7; 143.9; 148.9; 152.6; 167.9;
195.8. IR (KBr, n = cmÀ1): 3276, 2960, 2933, 1701, 1604,
1485, 1376, 1222, 1124.
4.4.21. Methyl 2-methyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (14f). Solid, mp 224–227 1C.56
1H-NMR (CDCl3, 300 MHz): d = 0.93 (s, 3H); 1.09 (s, 3H);
2.13–2.43 (m, 4H); 2.40 (s, 3H); 3.62 (s, 3H); 5.17 (s, 1H); 6.51
(s, 1H); 7.38 (t, J = 7.8 Hz, 1H); 7.73 (d, J = 7.8 Hz, 1H); 7.99
(m, 1H); 8.09 (m, 1H). 13C-NMR (CDCl3, 75 MHz): d = 19.5;
27.0; 29.3; 32.7; 36.7; 40.9; 50.5; 51.2; 104.8; 111.2; 121.3;
122.6; 128.7; 134.7; 144.7; 148.3; 148.9; 164.7; 167.3; 195.5. IR
(KBr, n = cmÀ1): 3278, 3209, 3087, 2950, 1700, 1624, 1532,
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Acknowledgements
The authors acknowledge the Conselho Nacional de
Desenvolvimento Cientıfico e Tecnologico (D. R. – CNPq
Grant Universal – 484615/2007-6 and E. V. B. – CNPq Grant
475599/2009-8) and Fundacao de Amparo a Pesquisa do
Estado do Rio Grande do Sul (FAPERGS) for the financial
support. The PIBIC/CNPq-UFRGS Undergraduate Fellow-
ship Program is also acknowledged (R.F.A.). We are grateful
to Prof. Dr Marcos N. Eberlin and MSc. Clecio F. Klitzke
from the Thomson Mass Spectrometry Laboratory of Institu-
to de Quımica, UNICAMP, for the HRMS analysis and
Prof. Dr Ronaldo A. Pilli for helpful suggestions.
14 J. Zhu and H. Bienayme, in Multicomponent Reactions,
Wiley-VCH Verlag GmbH
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