Efficient synthesis of polyhydroquinolines via the Hantzsch reaction using iron loaded mesoporous materials

Article abstract of DOI:10.1002/cjoc.201090341

A simple and convenient protocol is described for the preparation of polyhydroquinolines via one-pot, multi component reaction of an aromatic aldehyde, ethylacetoacetate, ammonium acetate and dimedone using iron loaded mesoporous materials as an efficient

Full text of DOI:10.1002/cjoc.201090341

FULL PAPER
Efficient Synthesis of Polyhydroquinolines via the Hantzsch
Reaction Using Iron Loaded Mesoporous Materials
Heravi, Majid M.*
Hosseini, Mariam
Oskooie, Hossein A.
Baghernejad, Bita
Farzaneh, F.
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
A simple and convenient protocol is described for the preparation of polyhydroquinolines via one-pot, multi
component reaction of an aromatic aldehyde, ethylacetoacetate, ammonium acetate and dimedone using iron loaded
mesoporous materials as an efficient catalyst in good yields.
Keywords mesoporous materials, quinolines, one-pot, multi component, Fe/Al-MCM-41
Introduction
to further explore its catalytic activity towards the syn-
thesis of 1,4-dihydropyridines via four component reac-
tion of an aromatic aldehyde, ethyl-acetoacetate, am-
monium acetate and dimedone in good yields (Scheme
Quinolines having a 1,4-dihydropyridine nucleus are
very important compounds because of their pharmacol-
ogical properties. Cardiovascular agents such as
nifedipine, nicardipine, amlodipine and other related
derivatives are dihydropyridyl compounds, which are
1
).
Scheme 1
1
effective for the treatment of hypertension. 4-Aryl-1,4-
dihydropyridines are analogues of NADH (nicotinamide
adenine dinucleotide) coenzymes, which have been ex-
plored for their calcium channel activity and the het-
erocyclic rings are found in a variety of bioactive com-
pounds such as bronchodilators, geroprotective, and
2
heptaprotective agents. Extensive studies indicate that
these compounds exhibit different medical functions,
acting as neuroprotectants, platelet antiaggregators,
3
cerebral antiischemic agents, and chemosensitisers. For
these reasons, polyhydroquinoline compounds not only
have attracted the attention of chemists to synthesize but
also represent an interesting research challenge. Nu-
merous methods have been reported for the synthesis of
polyhydroquinoline derivatives, because of the biologi-
Experimental
All products are known compounds and were char-
acterized by m.p., IR, H NMR and GC/MS. Melting
4
,5
1
cal importance associated with these compounds.
However, these methods suffer from drawbacks such as
a long reaction time, an excess of organic solvent, lower
yields, and harsh refluxing conditions. Consequently,
there is a need to develop new methods to synthesis of
these compounds. Multicomponent reactions (MCRs)
offer a unique way to generate efficiently libraries of
complex molecules with high degree of diversity.
Among them, the Ugi four component reaction
points were measured using the capillary tube method
with an electrothermal 9200 apparatus. H NMR spectra
1
were recorded on a Bruker AQS AVANCE-300 MHz
spectrometer using TMS as an internal standard (CDCl3
solution). IR spectra were recorded from KBr disk on
the FT-IR Bruker Tensor 27. GC/MS spectra were re-
corded on an Agilent Technologies 6890 network GC
system and an Agilent 5973 network mass selective de-
tector. Thin layer chromatography (TLC) on
commercial aluminum-backed plates of silica gel, 60
F254 was used to monitor the progress of reactions. All
products were characterized by spectra and physical
data.
(Ugi-4CR) is without doubt one of the most powerful
transformations that has been extensively investigated
6
for the past twenty years. As part of our ongoing inter-
est in the mesoporous materials catalyzed reactions for
various organic transformations, we had the opportunity
*
E-mail: mmh1331@yahoo.com; Tel.: 0098-21-88041347; Fax: 0098-21-88047861
Received February 4, 2010; revised April 15, 2010; accepted May 26, 2010.
Chin. J. Chem. 2010, 28, 2045— 2048
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Chen et al.
FULL PAPER
Catalyst preparation
by TLC. After completion of the reaction, chloroform (5
mL) was added and the filtrate was concentrated in
vaccuo and the residue was recrystallized from ethanol
to give pure product.
Al-MCM-41 (Si/Al＝100, 50 and 25) samples were
synthesized hydrothermally using a gel composition of
SiO
2
∶xAl
2
O
3
∶0.2CTAB∶0.89H
2
SO
4
∶120H
2
O (x
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
varies with Si/Al ratio). Sodium metasilicate and alu-
minium sulphate were used as the sources for silicon
and aluminium, respectively. Cetyl trimethyl ammo-
nium bromide (CTAB) was used as the structure direct-
ing agent. In a typical synthesis, 10.6 g of sodium
metasilicate in water was combined with appropriate
amount of aluminium sulphate in distilled water and the
pH of the solution was adjusted to 10.5 with constant
stirring to form a gel. After 30 min, an aqueous solution
of CTAB was added to it and the mixture was stirred for
1
4
-phenylquinoline-3-carboxylate (5a): H NMR δ: 0.91
(
(
1
4
s, 3H), 1.02 (s, 3H), 1.34 (t, J＝6.9 Hz, 3H), 2.2—2.35
m, 7H), 3.97 (q, J＝6.9 Hz, 2H), 5.02 (s, 1H), 5.87 (s,
H), 7.21—7.45 (m, 5H).
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
1
-p-tolylquinoline-3-carboxylate (5b): H NMR δ: 0.92
(
s, 3H), 1.04 (s, 3H), 1.28 (t, J ＝ 7.2 Hz, 3H),
2
2
4
.11—2.39 (m, 7H), 2.39 (s, 3H), 4.07 (q, J＝7.2 Hz,
H), 4.69 (s, 1H), 5.54 (s, 1H, NH), 7.03—7.45 (m,
H).
1
h at room temperature. The suspension was then trans-
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
ferred into a 300 mL stainless steel autoclave, sealed
and heated in a hot air oven at 160 ℃ for 48 h. After
cooling to room temperature, the product formed was
filtered, washed with deionised water and dried.
Fe/Al-MCM-41 were synthesised by adopting the same
procedure in which ferric nitrate was used as the source
for iron. The dried materials were calcined at 550 ℃
for 1 h in nitrogen atmosphere and 5 h in air in order to
maintain the crystallinity. The calcined materials were
converted into H-form by repeated ion-exchange with
1
4
-methoxyphenylquinoline-3-carboxylate (5c): H NMR
δ: 0.89 (s, 3H), 1.06 (s, 3H), 1.29 (t, J＝7.2 Hz, 3H),
2
2
4
.01—2.42 (m, 7H), 3.31 (s, 3H), 4.09 (q, J＝7.2 Hz,
H), 4.67 (s, 1H), 5.44 (s, 1H, NH), 7.09—7.51 (m,
H).
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
1
4
0
2
1
-chlorophenylquinoline-3-carboxylate (5d): H NMR δ:
.99 (s, 3H), 1.12 (s, 3H), 1.36 (t, J＝6.8 Hz, 3H),
.11—2.49 (m, 7H), 4.11 (q, J＝6.8 Hz, 2H), 4.86 (s,
H), 5.66 (s, 1H, NH), 7.14—7.64 (m, 4H).
－
1
4
aqueous 1 mol•L NH Cl solution followed by calcina-
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
tion at 550 ℃ for 5—6 h. SEM image of Al-MCM-41
1
4-hydroxyphenylquinoline-3-carboxylate (5f): H NMR
and Fe/Al-MCM-41 are illustrated in Figure 1.
δ: 0.94 (s, 3H), 1.08 (s, 3H), 1.22 (t, J＝7.1 Hz, 3H),
2
1
4
.08—2.34 (m, 7H), 4.03 (q, J＝7.1 Hz, 2H), 4.97 (s,
H), 5.56 (s, 1H, NH), 5.98 (s, 1H, OH), 7.11—7.42 (m,
H).
Ethyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-
1
4
1
2
1
-(2-furyl)quinoline-3-carboxylate (5i): H NMR δ:
.02 (s, 3H), 1.18 (s, 3H), 1.26 (t, J＝6.8 Hz, 3H),
.19—2.38 (m, 7H), 4.13 (q, J＝6.8 Hz, 2H), 4.88 (s,
H), 5.78 (s, 1H, NH), 6.08 (m, 1H), 6.29 (m, 1H), 7.05
(
m, 1H).
Catalyst reusability
The catalyst was separated from the reaction using
simple filtration technique, washed with acetone, air
dried and used for subsequent runs of the reaction proc-
ess. In Table 1, the comparison of efficiency of
Fe/Al-MCM-41 in synthesis of 5a after five times re-
covery is reported. As it is shown in Table 1, this cata-
lyst can be used efficiently after reusing.
Table 1 Reuse of Fe/Al-MCM-41 for the synthesis of 5a
Figure 1 SEM pictures of (a) Al-MCM-41 and (b) Fe-Al-
MCM-41 catalysts.
a
Entry
Time/min
Yield /%
1
30
30
30
30
30
95
93
92
90
90
Typical experimental procedure for the synthesis of
Hantzsch polyhydroquinoline derivatives
2
3
A mixture of aldehyde 1 (1 mmol), ethylacetoacetate
4
5
(
(
1.0 mmol), dimedone (1 mmol), ammonium acetate
1.5 mmol) and catalyst (1 mol%) was stirred at room
a
Isolated yields.
temperature. The progress of the reaction was monitored
2
046
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Chin. J. Chem. 2010, 28, 2045— 2048

Efficient Synthesis of Polyhydroquinolines via the Hantzsch Reaction
Results and discussion
pleted after 30 min. A variety of aldehydes were sub-
mitted to this reaction condition and the desired prod-
ucts were obtained in good to excellent yields (Table 2).
It is evident that both electron rich and electron defi-
cient aldehydes reacted smoothly with ethylacetoacetate
to produce high yields of products. In this work, we
present the results of the synthesis of 1,4-dihydropy-
ridines over bimetallic (Fe and Al) substituted MCM-41
in comparison to Al-MCM-41 and MCM-41. The effect
of Fe loading on MCM-41 for the synthesis of 5a is
shown in Table 3. It is obvious that the best yield was
achieved with Fe/Al-MCM-41. The reaction proceeds
very cleanly at room temprature and free of side prod-
ucts. In the absence of the catalyst, the reaction did not
complete even after 24 h.
The synthesis of M41S family of siliceous solids
with sharply distributed pore diameter in the range of
2
0—100 Å have achieved the main goals in heteroge-
neous catalysis over the past two decades since it pos-
sessed the crystallinity and well-defined structure of
7
,8
zeolites in the mesoporous range. The size of the
hexagonally arranged pores can be varied by changing
the surfactant chain length. These materials allow the
conversion of organics which are too large to be proc-
essed in the pores of microporous molecular sieves.
Pure siliceous materials have electrically neutral
frameworks and consequently no Brønsted acidity.
Much effort has been devoted to the introduction of tri-
valent metal atoms into the siliceous walls of MCM-41.
The incorporation of trivalent atoms (Al, Fe) into the
walls of MCM-41 creates Brønsted acid sites and allows
the preparation of materials with various acidity, which
Table 3 Catalytic activities of mesoporous materials for the
synthesis of 5a
a
9
,10
Entry
Catalyst
MCM-41
Time/min
Yield /%
possess different catalytic and adsorptive properties.
Iron loaded MCM-41 materials are remarkable for their
molecular and electronic diversity and have quite sig-
nificance in many areas e.g. catalysis, medicine, mate-
rial science etc. These iron loaded MCM-41 materials
have received much attention because of their redox
1
50
40
30
89
89
95
2
Al-MCM-41
3
Fe/Al-MCM-41
a
Isolated yields.
1
1-13
properties and unusual activity in organic reactions
which is higher compared to conventional mineral ac-
Conclusion
1
4
15
ids, Lewis acids. The use of iron loaded mesoporous
materials as catalyst can also eliminate the hurdles like
pore size constraint, recyclability, thermal and hydro-
thermal stability posed by other support materials.
In conclusion, we have developed a simple and effi-
cient method for the synthesis of polyhydroquinoline
derivatives via Hantzsch condensation using Fe/Al-
MCM-41 as a catalyst and therefore Fe/Al-MCM-41
could be a convenient substitute for hazardous
In an initial endeavor, 1 equiv. each of benzaldehyde,
dimedone, ethyl acetoacetate, and ammonium acetate
under solvent-free condition at room temperature af-
forded the desired quinolines (5a) in 95% yield (Entry 1,
Table 2). We performed the effect of various solvents
on the synthesis of 5a. This reaction was carried out in
various solvents such as water, chloroform, ethanol,
Friedel-Crafts catalysts like FeCl
3 3
and AlCl . The
Fe/Al-MCM-41 catalysts are recyclable, heterogeneous,
environmentally benign solid acid catalysts possessing
desirable properties such as high thermal and hydro-
thermal stability which are the prerequisite in the area of
green chemistry. The mildness of the conversion, ex-
perimental simplicity, compatibility with various func-
tional groups, efficient yields, short reaction times, and
the easy workup procedure, makes this procedure at-
tractive to synthesize a variety of these derivatives.
2 2
CH Cl and solvent-free. The best results in terms of
yield and time were obtained under solvent-free condi-
tion. In each reaction, the yield is a function of the reac-
tion time and the best time for all reactions was com-
Table 2 Fe/Al-MCM-41 catalyzed synthesis of polyhydroqui-
nolines
Acknowledgements
Time/
min
m.p./℃
The authors are thankful from Alzahra Research
Council for the partial financial support. We thank Prof.
F. Farzaneh for the catalyst.
a
Entry
Ar
Product
Yield /%
Observed Reported
1
6
7
6
6
7
6
8
9
0
1
2
3
4
5
6
7
8
Ph
4-Me-Ph
5a
5b
30
30
30
30
30
30
30
30
30
211 209— 210
263 261— 262
245 243— 245
231 230— 232
179 177— 178
239 237— 238
255 253— 255
242 240— 242
248 245— 247
95
91
92
94
91
90
92
93
92
1
1
1
1
1
1
1
2
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Chin. J. Chem. 2010, 28, 2045— 2048
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2047

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