BF3.SiO2 nanoparticles: A solid phase acidic catalyst for efficient one-pot Hantzsch synthesis of 1,4-dihydropyridines

Article abstract of DOI:10.3184/174751912X13542975429543

The solvent-free Hantzsch reaction between ethyl acetoacetate or 1,3-indandione, an aromatic aldehyde and ammonium acetate catalysed by BF ₃.SiO₂ nanoparticles provided an efficient one-step synthesis of 1,4-dihydropyridines in excellent yields.

Full text of DOI:10.3184/174751912X13542975429543

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 11
JANUARY, 11–13
BF3.SiO2 nanoparticles: a solid phase acidic catalyst for efficient one-pot
Hantzsch synthesis of 1,4-dihydropyridines
Bahareh Sadeghia*, Ashraf Namakkoubia and Alireza Hassanabadib
aDepartment of Chemistry, Yazd Branch, Islamic Azad University, PO Box 89195-155, Yazd, Iran
bDepartment of Chemistry, Zahedan Branch, Islamic Azad University, PO Box 98135-978, Zahedan, Iran
The solvent-free Hantzsch reaction between ethyl acetoacetate or 1,3-indandione, an aromatic aldehyde and ammo-
nium acetate catalysed by BF3.SiO2 nanoparticles provided an efficient one-step synthesis of 1,4-dihydropyridines in
excellent yields.
Keywords: BF3.SiO2 nanoparticles, ethyl acetoacetate, 1,3-indandione, ammonium acetate, 1,4-dihydropyridines, Hantzsch
reaction
Described more than a century ago by Hantzsch,1 dialkyl
1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates are the
prototypes of a classe of drugs known as the dihydropyridines
(DHP) which are vital drugs in the treatment of angina and
hypertension. Some of them such as amlodipine, felodipine,
isradipine, lacidipine, nicardipine, nifedipine, nimodipine and
nitredipine have been commercialised and it has been shown
that their mode of action is as calcium channel blockers.2 The
classical method for the synthesis of 1,4-dihydropyridines is
a one-pot condensation of an aldehyde, ethyl acetoacetate,
and ammonia either in acetic acid or in refluxing alcohol.3
However, the yields of 1,4-dihydropyridines obtained in this
way are generally low. Over the past 50 years, a number of
novel and more efficient procedures have been reported, all of
them listed and referenced by Debache and coworkers.4 These
include the use of solvent free conditions, microwave-heating,
ionic liquids, high temperatures at reflux, TMSCl–NaI, InCl3,
I2, SiO2/NaHSO4, SiO2/HClO4, Na- and Cs-Norit carbons,
tetrabutylammonium hydrogen sulfate, fermenting Baker’s
yeast, and metal triflates. Very recently, Lewis bases such as
triphenylphosphine have also been used as catalysts for the
synthesis of 1,4-dihydropyridines.4 We reporthere theHantzsch
reaction between ammonium acetate, an aromatic aldehyde
and two examples of an activated 1,3-dicarbonyl compound
using nano-BF3.SiO2 under solvent-free conditions.
synthesis of 1,4-dihydropyridine derivatives by the three-
component condensation of an aromatic aldehyde 1, a
1,3-dicarbonyl compound such as ethyl acetoacetate 2, or
indane-1,3-dione 3 and ammonium acetate occurs very rapidly
and smoothly in the presence of 0.003 g nano-BF3.SiO2 as a
catalyst (Scheme 1).
The stable catalyst is easily prepared12 and in order to opti-
mize the reaction conditions, the reaction of 4-nitrobenzalde-
hyde and ethyl acetoacetate with ammonium acetate was used
as a model reaction for 1,4-dihydropyridines synthesis. To
demonstrate the better catalytic activity of nano-BF3.SiO2,
initially, we studied the reaction with other catalysts under
solvent-free conditions during 20 min at 70 °C, and the results
are listed in Table 1.
It can be seen that nano-BF3.SiO2 is a better catalyst than
any of the others in terms of yield obtained.
To determine the optimum quantity of nano-BF3.SiO2, the
model reaction was carried out at 70 °C for 20 min using
different quantities of nano-BF3.SiO2 (Table 2). As can be seen,
BF3.SiO2 of 0.003 g gave an excellent yield (Table 2, entry 2)
and increasing the amount 5- to 10-fold hardly made any
difference.
The reaction was also examined in various solvents and
compared with solvent-free conditions (Table 3).
Different solvents clearly affected the efficiency of the
reaction, but the best results were obtained when solvent-free
conditions were used (Table 3, entry 5).
Results and discussion
In summary, using the nano-BF3.SiO2 (0.003 g) under
solvent-free conditions at 70 °C for 20 min are the optimal
reaction conditions for the synthesis of 1,4-dihydropyridines.
In continution of our investigations of the application of solid
acids in organic synthesis5–11 we have found that the Hantzsch
Scheme 1 Synthesis of 1,4-dihydropyridines by condensation of ethyl acetoacetate or 1,3-indandione with an aromatic
aldehyde and ammonium acetate using nano-BF3.SiO2 as catalyst
* Correspondent. E-mail: bsadeghia@gmail.com

12 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Reaction between 4-nitrobenzaldehyde, ethyl aceto-
acetate and ammonium acetate using different catalysts under
solvent-free conditions for 20 min at 70 °C
Table 5 Reaction between 1,3-indandione (2 mmol), aromatic
aldehydes (1 mmol) and ammonium acetate (1 mmol) catalysed
by nano-BF3.SiO2 (0.003 g) for 20 min at 70 °C
Entry
Catalyst
Yield/%a
Entry
Ar
Product
Yield/%a
1
2
3
4
5
6
FeCl3.6H2O
RuCl3
40
32
37
55
20
93
1
2
3
4
5
6
C6H5
4-NO2-C6H4
4-Br-C6H4
5a
5b
5c
5d
5e
5f
85
90
91
92
88
90
InBr3
PPh3
None
Nano-BF3.SiO2
2-Cl-C6H4
2-MeO-C6H4
3-MeO-2-OH-C6H3
a Isolated yield.
a Isolated yield.
Table 2 Optimisation of the amount of nano-BF3.SiO2 on the
synthesis of 4e for 20 min at 70 °C
compound 5a also supported the suggested structure. Com-
pounds 5b–f showed similar spectral data to those of 5a and
were assigned similar structures.
Entry
Catalyst
Yield/%a
In summary, we have shown that nano-BF3.SiO2 has advan-
tages in the preparation of 1,4-dihydropyridines such as shorter
reaction times, simple work-up, and much improved yields.
Moreover, the solid phase acidic catalyst was re-usable for a
number of times without appreciable loss of activity. The
present method, which does not involve any hazardous organic
solvent, can be classified as green chemistry.
1
2
3
4
0.001
0.003
0.015
0.03
74
93
95
95
a Isolated yield.
Table 3 Solvent effect on the synthesis of 4e catalysed by
nano-BF3.SiO2 for 20 min at 70 oC
Experimental
IR spectra were recorded on a Shimadzu IR-470 spectrometer in KBr
discs. The NMR spectra were obtained on a Bruker Avance DRX-400
FT spectrometer (1 H NMR at 400 Hz, 13C NMR at 100 Hz) using
CDCl3 as solvent with TMS as internal standard.
Melting points were determined with an Electrothermal 9100 appa-
ratus. Elemental analyses were performed at the analytical laboratory
of Science and Researchs Unite of Islamic Azad University. Mass
spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. The chemicals used
in this work were purchased from Fluka (Buchs, Switzerland) and
were used without further purification. Nano-BF3.SiO2 was prepared
as previously described.12
Entry
Solvent
Yield/%a
1
2
3
4
5
CHCl3
EtOH
EtOAC
H2O
60
80
20
50
93
Solvent-free
a Isolated yield.
To study the scope of the reaction, a series of aromatic alde-
hydes 1 were investigated. The results for ethyl acetoacetate 2
and 2,3-indandione 3 are shown in Tables 4 and 5. In all cases,
aromatic aldehydes substituted with either electron-donating
or electron-withdrawing groups underwent the reaction
smoothly and gave the products in excellent yields.
The compounds 4a–f were characterised by their elemental
analyses and by their 1H NMR and IR spectral data which were
compared with literature data.4,13–15
Compounds 4g, 4h and 5a–f were new and their structures
were deduced by elemental and spectral analysis, the former
two compounds by comparison with data for 4a–f. The mass
spectrum of compound 5a showed the molecular ion peak at
General procedure
A mixture of ethyl acetoacetate or 1,3-indandione (2 mmol), aromatic
aldehyde (1 mmol), ammonium acetate (1 mmol), and nano-BF3.SiO2
(0.003 g) was placed in a round bottom flask. The materials were
mixed and heated at 70 ºC for 20 min. The progress of the reaction
was followed by TLC (n-hexane:ethylacetate). After the completion
of the reaction, the mixture was filtered to remove the catalyst. Evapo-
ration of the solvent gave the crude product which was recrystallised
from hot ethanol to obtain the pure compound.
Diethyl-4-)4-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4g): Yellow oil; IR (νmax, cm−1): 3480 (NH), 2250
(C=N), 1692 (C=O) 1H NMR: δ 1.22 (6H, t, 3JHH = 7 Hz, 2 × CH2CH3),
2.35 (6H, s, 2 × CH3), 4.03–4.15 (4H, m, 2 × OCH2), 5.04 (1H, s, CH),
5.08 (1H, br. s, NH), 7.39 (2H, d, 3JHH = 7 Hz, aromatic), 7.52 (2H, d,
3JHH = 7 Hz, aromatic) ppm; 13C NMR: δ 14.2, 19.5, 40.2, 59.9, 103.2,
109.7, 119.3, 128.8, 131.8, 144.6, 153.4 and 167.1 ppm; MS (m/z, %):
354 (M+, 10). Anal Calcd for C20H22N2O4: C, 67.81; H, 6.21; N, 7.91.
Found: C, 67.69; H, 6.26; N, 7.84%.
1
361. The H NMR spectrum of compound 5a exhibited a
methine proton at 4.27 ppm and a NH proton at 9.06 ppm
which disappears after addition of D2O. There are multiplets
between 7.25 and 7.88 ppm which are due to aromatic protons.
The 13C NMR spectrum of compound 5a showed 14 signals in
agreement with the proposed structure. The IR spectrum of
Table 4 Reaction between ethyl acetoacetate (2 mmol), aromatic aldehydes (1 mmol) and ammonium acetate (1 mmol) catalysed
by nano-BF3.SiO2 (0.003 g) for 20 min at 70 °C
Entry
Ar
Product
Yield/%a
M.p./°C
Found
Reported
1
2
3
4
5
6
7
8
C6H5
4a
4b
4c
4d
4e
4f
91
90
90
88
93
92
82
80
157–159
169–171
160–162
226–228
131–132
161–163
Oil
158–160 (Ref. 14)
169–170 (Ref. 13)
161–163 (Ref. 14)
227–228 (Ref. 15)
129–130 (Ref. 15)
162–164 (Ref. 4)
–
2-NO2-C6H4
4-MeO-C6H4
4-OH-C6H4
4-NO2-C6H4
2-Br-C6H4
4-NC-C6H4
4-Cl-3-NO2-C6H3
4g
4h
Oil
–
a Isolated yield.

JOURNAL OF CHEMICAL RESEARCH 2013 13
Diethyl-4-)3-nitro-4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyri-
136.7, 140.3, 157.6, 195.8 ppm; MS (m/z, %): 391 (M+, 4). Anal Calcd
for C26H17NO3: C, 79.78; H, 4.37; N, 3.57. Found: C, 79.81; H, 4.41;
N, 3.46%.
dine-3,5-dicarboxylate (4h): Yellow oil; IR (νmax, cm−1): 3380 (NH),
1
3
1693 (C=O), 1535 and 1364 (NO2). H NMR: δ 1.20 (6H, t, JHH
=
7 Hz, 2 × CH2CH3), 2.32 (6H, s, 2 × CH3), 4.02–4.17 (4H, m, 2 ×
OCH2), 4.96 (1H, s, CH), 5.53 (1H, br. s, NH), 7.72–8.35 (3H, m,
aromatic) ppm; 13C NMR: δ 14.2, 19.6, 39.9, 59.6, 99.3, 104.2, 127.4,
130.0, 140.6, 143.6, 145.1, 150.0 and 167.7 ppm; MS (m/z, %): 408
(M+, 7). Anal Calcd for C19H21ClN2O6: C, 55.81; H, 5.17; N, 6.85.
Found: C, 55.86; H, 5.19; N, 6.76%.
11-Phenyl-5,11-dihydro-diindeno[1,2-b:2′,1′-e]pyridine-10,12-
dione (5a): White powder, m.p. 207–209 °C; IR (νmax, cm−1): 3453
(NH), 1696 (C=O); 1H NMR: δ 4.27 (1H, s, CH), 7.25–7.88 (13H, m,
aromatic), 9.06 (1H, br. s, NH) ppm; 13C NMR: δ 40.2, 91.1, 118.4,
126.2, 127.5, 129.1, 129.7, 130.8, 138.3, 140.5, 140.6, 141.05, 151.1,
190.9 ppm; MS (m/z, %): 361 (M+, 11). Anal Calcd for C25H15NO2: C,
83. 1; H, 4.15; N, 3.87. Found: C, 83.6; H, 4.22; N, 3.79%.
11-(2-Hydroxy-3-methoxyphenyl)-5,11-dihydro-diindeno[1,2-b:
2′,1′-e]pyridine-10,12-dione (5f): White powder, m.p. 160–162; IR
(νmax, cm−1): 3475 and 3065 (NH, OH), 1706 (C=O). 1H NMR: δ 1.39
(1H, br. s, OH), 3.39 (1H, s, OCH3), 4.36 (1H, s, CH), 6.72-7.76 (11H,
m, aromatic), 9.01 (1H, br. s, NH) ppm; 13C NMR: δ 40.3, 50.4, 118.1,
119.1, 120.0, 122.1, 122.1, 128.6, 131.5, 131.6,131.7, 135.1, 136.2,
136.1, 140.6, 166.9, 200.4 ppm; MS (m/z, %): 407 (M+, 8). Anal Calcd
for C26H17NO4: C, 76.64; H, 4.2; N, 3.43. Found: C, 79.57; H, 4.17; N,
3.52%.
We gratefully acknowledge financial support from the Research
Council of the IslamicAzad University ofYazd and The Islamic
Azad University of Zahedan of Iran.
11-(4-Nitrophenyl)-5,11-dihydro-diindeno[1,2-b:2′,1′-e]pyridine-
10,12-dione (5b): White powder, m.p. 192–194 °C; IR (νmax, cm−1):
3455 (NH), 1708 (C=O), 1558 and 1343 (NO2); 1H NMR: δ 4.22 (1H,
Received 5 October 2012; accepted 30 October 2012
Paper 1201557 doi: 10.3184/174751912X13542975429543
Published online: 15 January 2013
s, CH), 7.23–7.82 (12H, m, aromatic), 9.01 (1H, br. s, NH) ppm; 13
C
NMR: δ 41.3, 91.2, 118.1, 124.4, 129.4, 129.9, 130.9, 138.5, 140.6,
140.8, 141.1, 147.8, 151.3, 191.1 ppm; MS (m/z, %): 406 (M+, 5).
Anal Calcd for C25H14N2O4: C, 73.89; H, 3.47; N, 6.89. Found: C,
73.78; H, 3.53; N, 6.72%.
References
1
A. Hantzsch, Ber., 1881, 14, 1637.
11-(4-Bromophenyl)-5,11-dihydro-diindeno[1,2-b:2′,1′-e]pyri-
2
B.G. Katzung, Basic and clinical pharmacology 1998, Appleton & Lange,
dine-10,12-dione (5c): White powder, m.p. 120–122 °C; IR (νmax
,
Stamford, CT.
cm−1): 3405 (NH), 1697 (C=O). H NMR: δ 3.42 (1H, s, CH), 7.02–
7.79 (12H, m, aromatic), 8.75 (1H, br. s, NH) ppm; 13C NMR: δ 43.5,
91.6, 121.4, 122.9, 123.1, 128.8, 129.6, 130.9, 131.2, 132.4, 135.1,
136.4, 136.7, 196.4 ppm; MS (m/z, %): 440 (M+, 8). Anal Calcd for
C25H14BrNO2: C, 68.19; H, 3.2; N, 3.18. Found: C, 68.23; H, 3.27; N,
3.07%.
1
3
4
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6
11-(2-chlorophenyl)-5,11-dihydro-diindeno[1,2-b:2′,1′-e]pyridine-
10,12-dione (5d): White powder, m.p. 109-111; IR (νmax, cm−1): 3450
(NH), 1699 (C=O). 1H NMR: δ 3.67 (1H, s, CH), 7.08-7.68 (12H, m,
aromatic), 8.70 (1H, br. s, NH) ppm; 13C NMR: δ 41.6, 91.7, 122.1,
125.9, 127.8, 129.8, 130.7, 131.5, 132.7, 133.4, 135.2, 136.5, 136.8,
140.1, 142.2, 196.2 ppm; MS (m/z, %): 395 (M+, 7). Anal Calcd for
C25H14ClNO2: C, 75.85; H, 3.56; N, 3.53. Found: C, 75.79; H, 3.62; N,
3.49%.
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11-(2-Methoxyphenyl)-5,11-dihydro-diindeno[1,2-b:2′,1′-e]pyri-
dine-10,12-dione (5e): White powder, m.p. 144–146; IR (νmax, cm−1):
1
3490 (NH), 1725 (C=O). H NMR: δ 3.86 (1H, s, CH), 7.12–8.24
14 J.J. Eynde, F. Delfosse, A. Mayence and Y.V. Haverbeke, Tetrahedron,
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