An Efficient One-Pot Four-Component Synthesis of 9-Aryl-Hexahydroacridine-1,8-Dione Derivatives in the Presence of a Molecular Sieves Supported Iron Catalyst

Article abstract of DOI:10.1007/s10562-019-02845-0

Abstract: A series of 9-aryl-hexahydroacridine-1,8-diones are synthetized with good to excellent yields (50–99%) via a one-pot four-component reaction of dimedone, aromatic aldehydes and ammonium acetate in the presence of 4?? molecular sieves modified wi

Full text of DOI:10.1007/s10562-019-02845-0

Catalysis Letters
https://doi.org/10.1007/s10562-019-02845-0
An Efcient One‑Pot Four‑Component Synthesis
of 9‑Aryl‑Hexahydroacridine‑1,8‑Dione Derivatives in the Presence
of a Molecular Sieves Supported Iron Catalyst
Ágnes Magyar1 · Zoltán Hell1
Received: 12 March 2019 / Accepted: 26 May 2019
© The Author(s) 2019
Abstract
A series of 9-aryl-hexahydroacridine-1,8-diones are synthetized with good to excellent yields (50–99%) via a one-pot four-
component reaction of dimedone, aromatic aldehydes and ammonium acetate in the presence of 4 Å molecular sieves modi-
fed with iron(III) as an efcient heterogeneous catalyst, in ethanol. The process ofers the advantages of high yields, mild
reaction conditions and easy work-up procedure. The catalyst can be reused without signifcant loss of activity.
Graphic Abstract
O
R
O
Fe3+/4A
R
CHO
NH4OAc
2
EtOH, reflux
O
O
N
H
(substituted) aryl, propyl
=
R
15 examples
50-99% yield
Keywords Heterogeneous catalysis · Multicomponent reactions · 9-Aryl-hexahydro-acridine-1,8-dione · Iron · 4 Å
Molecular sieves
1 Introduction
Acridinediones are a highly important class of organic
compounds, since they possess a wide range of pharmaceu-
tical and biological activities such as a positive ionotropic
efect promoting the entry of calcium to the intracellular
space [2], anticancer activity [3], enzyme and tumour cell
inhibition [4], antimicrobial activity and cytotoxicity [5].
They have structural similarity to 1,4-dihydropyridines (1,4-
DHPs), which are well known intermediates in the synthesis
of several pharmaceuticals including those for the treatment
of hypertension and cardiovascular diseases [6]. Acridine-
1,8-diones can also be used as laser dyes with very high
lasing-efciencies [7, 8].
During the past years, multicomponent reactions (MCRs)
have emerged as valuable and efcient tools in the hands of
synthetic organic chemists, since they have several advan-
tages over the classical synthetic strategies. MCRs provide
complex organic compounds in a single step using simple
and readily available substrates without the isolation of any
intermediates under shorter reaction times, yielding less
side products with lower energy consumption and waste
production, thus leading to environmentally more friendly
processes [1].
Due to their importance, several strategies have been
developed for the synthesis of 9-aryl-acridine-1,8-diones,
including the thermal reaction of dimedone, diferent aro-
matic aldehydes and aqueous ammonia in ethanol [9], the
microwave-irradiation-aided solvent-free reaction of dime-
done and an aldehyde using alumina supported ammo-
nium acetate and catalytic N,N-dimethylformamide [10],
* Zoltán Hell
zhell@mail.bme.hu
1
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Műegyetem rkp.
3, 1111 Budapest, Hungary
Vol.:(0123456789)
1 3

Á. Magyar, Z. Hell
or ammonium bicarbonate [11], in water under microwave
irradiation [12], and in pure water without any additives
[13]. The use of ionic liquids alone [14, 15] and in the pres-
ence of CeCl3·7H2O [16] was also reported for this con-
version. Numerous protocols have been developed for the
synthesis using diferent catalysts. As homogenous catalysts,
CuSO4·5H2O [17] and ceric ammonium nitrate and PEG
[18] are described for the synthesis, and we can also fnd
examples for heterogeneous catalysts such as HY-Zeolite
[19], carbon-based solid acid (CBSA) [20], Fe3O4@SiO2@
Ni–Zn–Fe LDH [21], mesoporous silica nanoparticles
(MSNs) [22], and Fe3O4@SiO2 nanoparticles [23].
measurement, the samples were evacuated at 110 °C for
24 h.
1H and 13C NMR spectra were made on BRUKER
Avance-500 instrument using TMS as an internal standard
in CDCl3. All compounds and solvents were purchased from
Merck Hungary Ltd.
2.1 Preparation of the Catalyst
Four Angstrom molecular sieves (4A) were impregnated
with FeCl3×6H2O as follows: 1 mmol of the metal salt was
dissolved in 100 ml of deionised water and stirred with 1 g
4A at room temperature for 24 h. The solid was fltered,
washed with deionised water and with acetone, then dried
in an oven at 150 °C for 1 h. Samples were heated at 120 °C
for 1 h before the reaction.
Although the reported methods have their own advan-
tages and limitations, a simple, easily accessible and reusa-
ble heterogeneous catalyst may have a synthetic importance.
The main research profle of our group is to elaborate
new heterogeneous catalytic methods for the preparation
of organic compounds in the presence of supported metal
catalysts. Several metals have been used successfully in dif-
ferent organic syntheses, such as palladium [24–27], nickel
[28], copper [29–32], titanium [33, 34], lanthanum [35, 36]
and zinc [37] on diferent supports (Mg:La 3:1 mixed oxide,
4 Å molecular sieves). In this paper we present a simple
method for the one-pot four-component synthesis of 9-aryl-
acridine-1,8-dione derivatives from dimedone, aldehydes
and ammonium acetate in the presence of a slightly basic, 4
Å molecular sieves-supported iron catalyst (Fe3+/4A).
2.2 Determination of the pH of the Catalyst
The catalyst (1 g) was stirred in 30 mL deionised water under
continuous measuring of the pH. The values were accepted
after reaching a constant value at least during 10 min.
2.3 Typical Reaction Conditions
2.3.1 General Procedure for the One‑Pot Synthesis
of Acridinedione Derivatives
A typical reaction was carried out in a 10 mL fask. Dime-
done (2 mmol), aldehyde (1 mmol), ammonium acetate
(3 mmol), Fe3+/4A (0.1 g) and ethanol (3 mL) were stirred
at refux temperature for 14 h. The progression of the reac-
tion was monitored by TLC. After completion, the solid
was fltered, and washed with ethanol, then the fltrate was
evaporated. The residue was extracted with dichloromethane
and 0.25 M NaOH solution. The organic phase was dried
over anhydrous sodium sulphate, fltered and the solvent was
evaporated. The product was subjected to 1H and 13C NMR
spectroscopy.
2 Experimental
Morphology of the catalyst samples was investigated by a
JEOL 6380LVa (JEOL, Tokyo, Japan) type scanning elec-
tron microscope and elemental mapping was also accom-
plished using the energy-dispersive X-ray detector of the
equipment. Each specimen was fxed by conductive double-
sided carbon adhesive tape and sputtered by gold (using a
JEOL 1200 instrument). Applied accelerating voltage and
working distance were between 15 and 30 kV and 10 and
12 mm, respectively. In the case of the comparison of the
fresh and the used catalysts, the samples were examined
without sputtering with gold and were not fxed on a carbon
tape.
All products have satisfactory spectral data (1H and 13
C
NMR). The spectral data of the known compounds were
identical with those reported in the literature.
The nitrogen adsorption/desorption isotherms were meas-
ured at − 196 °C with a computer-controlled Nova 200e
(Quantachrome) instrument. The apparent surface area
(SBET) was calculated using the Brunauer–Emmett–Teller
(BET) model. The total pore volume (Vt) was derived
from the amount of vapour adsorbed at p/p0 → 1, assum-
ing that the pores were already flled with liquid adsorb-
ate. The micropore volume (W0) was derived from the
Dubinin–Radushkevich (DR) plot. Prior to the adsorption
2.3.2 Characterisation of the Products
9-Phenyl-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacrid-
ine-1,8-dione, 4a yellow solid. 1H NMR (500 MHz, CDCl3)
δ (ppm): 0.95 (s, 6H); 1.06 (s, 6H); 2.13-2.30 (m, 8H); 5.09
(s, 1H); 7.06 (t, J = 7.5 Hz, 1H); 7.19 (t, J = 7.5 Hz, 2H);
7.34 (d, J=7.0 Hz, 2H); 7.96 (s, 1H). 13C NMR (125 MHz,
CDCl3) δ (ppm): 27.17, 29.63, 32.67, 33.71, 40.77, 50.97,
113.31, 126.04, 128.01, 146.70, 149.22, 195.94. Anal.
1 3

An Efcient One‑Pot Four‑Component Synthesis of 9‑Aryl‑Hexahydroacridine‑1,8‑Dione…
Calcd. for C23H27NO2: C 79.08, H 7.74, N 4.01%, found: C
79.12, H 7.79, N 3.98%.
6.91 (t, J = 8.0 Hz, 1H); 6.97 (t, J = 7.5 Hz, 2H); 7.08 (d,
J=7.5 Hz, 1H); 8.39 (s, 1H). 13C NMR (125 MHz, CDCl3)
δ (ppm): 19.34, 26.39, 28.92, 31.89, 40.05, 50.30, 113.92,
125.01, 127.58, 128.96, 129.02, 129.06, 135.56, 146.09,
148.14, 195.07. Anal. Calcd. for C24H29NO2: C 79.34, H
7.99, N 3.86%, found: C 79.37, H 8.04, N 3.81%.
9-(3-Bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4b yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.97 (s, 6H); 1.08 (s, 6H); 2.13-
2.38 (m, 8H); 5.02 (s, 1H); 7.05 (t, J = 8.0 Hz, 1H); 7.17
(d, J=8.0 Hz, 1H); 7.32 (d, J=6.0 Hz, 1H); 7.40 (s, 1H);
8.16 (s, 1H). 13C NMR (125 MHz, CDCl3) δ (ppm): 26.96,
29.29, 32.35, 39.91, 40.55, 50.54, 112.37, 121.74, 126.95,
128.59, 129.16, 130.66, 148.59, 195.00. Anal. Calcd. for
C23H26BrNO2: C 64.49, H 6.07, N 3.27%, found: C 64.52,
H 6.12, N 3.25%.
9-(3-Methylphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4h yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.06 (s, 6H);
2.10-2.32 (m, 11H); 5.01 (s, 1H); 6.85 (d, J = 7.0 Hz, 1H);
7.03-7.09 (m, 2H); 7.14 (s, 1H); 8.40 (s, 1H). 13C NMR
(125 MHz, CDCl3) δ (ppm): 21.56, 27.05, 29.57, 32.50,
40.57, 50.88, 112.98, 125.01, 126.55, 127.68, 128.92,
136.94, 146.78, 149.11, 149.17, 195.56. Anal. Calcd. for
C24H29NO2: C 79.34, H 7.99, N 3.86%, found: C 79.35, H
8.02, N 3.83%.
9-(4-Bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4c yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.07 (s, 6H); 2.12-
2.32 (m, 8H); 5.03 (s, 1H); 7.22 (d, J=8.5 Hz, 2H); 7.29 (d,
J=8.5 Hz, 2H); 8.45 (s, 1H). 13C NMR (125 MHz, CDCl3)
δ (ppm): 27.17, 29.65, 32.63, 40.67, 50.90, 112.70, 119.65,
129.99, 130.97, 145.99, 149.44, 195.79. Anal. Calcd. for
C23H26BrNO2: C 64.49, H 6.07, N 3.27%, found: C 64.54,
H 6.09, N 3.29%.
9-(4-Methylphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4i yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.05 (s, 6H);
2.12-2.28 (m, 11H); 5.06 (s, 1H); 6.99 (d, J = 8.0 Hz, 2H);
7.22 (d, J=8.0 Hz, 2H); 8.50 (s, 1H). 13C NMR (125 MHz,
CDCl3) δ (ppm): 21.09, 27.08, 29.55, 32.55, 40.51, 50.99,
113.09, 127.88, 128.67, 135.14, 143.86, 149.79, 196.13.
Anal. Calcd. for C24H29NO2: C 79.34, H 7.99, N 3.86%,
found: C 79.38, H 8.05, N 3.86%.
9-(2-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4d yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.07 (s, 6H); 2.02-
2.39 (m, 8H); 5.25 (s, 1H); 6.98 (t, J=8.0 Hz, 1H); 7.09 (t,
J=7.5 Hz, 1H); 7.18 (d, J=7.5 Hz, 1H); 7.39 (d, J=8.0 Hz,
1H); 8.84 (s, 1H). 13C NMR (125 MHz, CDCl3) δ (ppm):
26.86, 29.34, 32.08, 39.91, 40.31, 50.60, 111.60, 125.89,
126.64, 129.19, 131.91, 132.86, 143.82, 149.38, 194.87.
Anal. Calcd. for C23H26ClNO2: C 72.06, H 6.79, N 3.66%,
found: C 72.11, H 6.82, N 3.61%.
9-(2-Methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4k yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.90 (s, 6H); 1.04 (s, 6H);
2.02-2.33 (m, 8H); 3.78 (s, 3H); 5.16 (s, 1H); 6.75-6.80
(m, 2H); 7.03 (t, J = 7.5 Hz, 1H); 7.37 (d, J = 7.0 Hz,
1H); 8.62 (s, 1H). 13C NMR (125 MHz, CDCl3) δ (ppm):
26.44, 29.67, 32.28, 50.89, 55.19, 110.66, 111.37, 119.76,
126.86, 131.57, 133.94, 149.62, 157.63, 195.21. Anal.
Calcd. for C24H29NO3: C 75.99, H 7.65, N 3.69%, found:
C 76.03, H 7.68, N 3.64%.
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4e yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.07 (s, 6H); 2.17-
2.29 (m, 8H); 5.07 (s, 1H); 7.16 (d, J=8.5 Hz, 2H); 7.29 (d,
J=8.5 Hz, 2H); 8.49 (s, 1H). 13C NMR (125 MHz, CDCl3)
δ (ppm): 27.17, 29.69, 32.72, 40.70, 50.98, 112.85, 128.19,
129.57, 131.65, 145.39, 149.79, 196.16. Anal. Calcd. for
C23H26ClNO2: C 72.06, H 6.79, N 3.66%, found: C 72.09,
H 6.80, N 3.63%.
9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4l yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.06 (s, 6H);
2.12-2.28 (m, 8H); 3.67 (s, 3H); 5.04 (s, 1H); 6.71 (d,
J = 8.5 Hz, 2H); 7.24 (d, J= 8.5 Hz, 2H); 7.92 (s, 1H). 13
C
9-(2-Fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
NMR (125 MHz, CDCl3) δ (ppm): 27.11, 29.57, 32.59,
40.66, 50.89, 55.01, 113.29, 113.39, 128.93, 139.18,
148.96, 157.64, 195.99. Anal. Calcd. for C24H29NO3: C
75.99, H 7.65, N 3.69%, found: C 76.05, H 7.71, N 3.65%.
9-(2-Nitrophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4f yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.94 (s, 6H); 1.05 (s, 6H);
2.10-2.30 (m, 8H); 5.24 (s, 1H); 6.89 (t, J = 9.5 Hz, 1H);
6.99-7.08 (m, 2H); 7.45 (t, J = 7.5 Hz, 1H); 8.01 (s, 1H).
13C NMR (125 MHz, CDCl3) δ (ppm): 26.91, 29.64, 32.59,
40.69, 50.92, 111.77, 115.20, 123.56, 127.64, 131.69,
133.04, 149.71, 195.81. Anal. Calcd. for C23H26FNO2: C
75.20, H 7.08, N 3.81%, found: C 75.25, H 7.11, N 3.75%.
9-(2-Methylphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
hexahydroacridine-1,8-dione, 4g yellow solid. 1H
NMR (500 MHz, CDCl3) δ (ppm): 0.92 (s, 6H); 1.06
(s, 6H); 2.05-2.37 (m, 8H); 2.84 (s, 3H); 5.06 (s, 1H);
1
hexahydroacridine-1,8-dione, 4m yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.92 (s, 6H); 1.03 (s, 6H);
2.07–2.32 (m, 8H); 5.30 (s, 1H); 7.19 (t, J = 8.5 Hz, 1H);
7.45–7.50 (m, 2H); 7.71 (d, J = 8.0 Hz, 1H); 8.20 (s, 1H).
13C NMR (125 MHz, CDCl3) δ (ppm): 27.27, 29.17,
32.35, 40.55, 50.66, 112.15, 123.89, 126.31, 130.82,
130.84, 131.98, 141.27, 149.71, 195.17. Anal. Calcd. for
1 3

Á. Magyar, Z. Hell
C23H26N2O4: C 70.05, H 6.60, N 7.11%, found: C 70.11,
H 6.65, N 7.05%.
9-(3-Nitrophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4m yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.95 (s, 6H); 1.09 (s, 6H); 2.11-
2.43 (m, 8H); 5.15 (s, 1H); 7.37 (t, J=7.5 Hz, 1H); 7.80 (d,
J=7.5 Hz, 1H); 7.92 (d, J=7.5 Hz, 1H); 8.11 (s, 1H); 8.66
(s, 1H). 13C NMR (125 MHz, CDCl3) δ (ppm): 27.03, 29.47,
32.50, 40.54, 50.65, 111.95, 120.82, 122.57, 128.50, 134.96,
149.65, 195.31. Anal. Calcd. for C23H26N2O4: C 70.05, H
6.60, N 7.11%, found: C 70.09, H 6.67, N 7.06%.
9-(4-Nitrophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
1
hexahydroacridine-1,8-dione, 4n yellow solid. H NMR
(500 MHz, CDCl3) δ (ppm): 0.94 (s, 6H); 1.08 (s, 6H);
2.11–2.42 (m, 8H); 5.14 (s, 1H); 7.51 (d, J=8.0 Hz, 2H);
8.06 (d, J=8.0 Hz, 2H); 11.91 (s, 1H). 13C NMR (125 MHz,
CDCl3) δ (ppm): 27.08, 29.51, 32.47, 34.49, 50.68, 111.57,
123.02, 129.04,145.82, 149.82, 154.66, 195.09. Anal. Calcd.
for C23H26N2O4: C 70.05, H 6.60, N 7.11%, found: C 70.12,
H 6.65, N 7.04%.
Fig. 1 SEM image of the catalyst
Table 1 The reaction of dimedone, 4-chlorobenzaldehyde and ammo-
nium acetate in the presence of La3+/4A
9-Propyl-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacri-
dine-1,8-dione, 4o yellow solid. 1H NMR (500 MHz, CDCl3)
δ (ppm): 0.79 (s, 3H); 1.08 (s, 12H); 1.21–1.29 (m, 2H); 2.18
(s, 4H); 2.31 (s, 4H); 3.27 (s, 2H); 3.93 (s, 1H); 8.72 (s, 1H).
13C NMR (125 MHz, CDCl3) δ (ppm): 14.75, 18.92, 27.31,
30.03, 32.56, 37.97, 40.87, 51.32, 66.10, 112.29, 150.59,
196.06. Anal. Calcd. for C20H29NO2: C 76.19, H 9.21, N
4.44%, found: C 76.25, H 9.27, N 4.43%.
Entry
Ammonium acetate (mmol)
Yield (%)a
1
2
3
1.5
2
3
67
70
78
3 Results and Discussion
We investigated the structure of the Fe3+/4A catalyst by
scanning electron microscopy (SEM). During the impreg-
nation procedure the molecular sieves support preserved its
characteristic cuboctahedron shape as can be seen on Fig. 1.
The average particle size ranged from 6 to 8 μm, and the
particles are well defned both in shape and size. The iron is
evenly distributed on the surface of the support, EDS meas-
urement showed 5.14 w/w% iron on the surface. The iron
content of the catalyst determined by ICP-OES is concordant
with the theoretical value (5.3 w/w%), thus it can be con-
cluded that the metal is mainly situated on the surface of the
support. The nitrogen adsorption/desorption measurements
showed a considerable decrease in the surface of the sup-
port as well, the specifc surface of 4A dropped from 800 to
106.065 m2/g. The total pore volume of the molecular sieves
altered from 0.3 to 0.11 cm3/g, the micropore volume was
0.022 cm3/g. The catalysts pH value is 8.42, so it is in the
slightly basic region.
Reaction conditions: 2 mmol dimedone, 1 mmol 4-chlorobenzalde-
hyde, 1.5-3 mmol ammonium acetate, 0.1 g catalyst, 3 mL EtOH,
refux, 14 h
aIsolated yield
acridinediones are structurally similar to 1,4-DHPs, frst we
tested our La3+/4A catalyst in the synthesis of 9-aryl-acrid-
ine-1,8-dione derivatives. As a model reaction, we investi-
gated the reaction of dimedone, 4-chlorobenzaldehyde and
ammonium acetate applying the previously elaborated reac-
tion conditions. With the use of 1.5 mmol ammonium ace-
tate, the yield of the desired product was only 67%, hence we
attempted to increase the yield of the product applying excess
of ammonium acetate. The results are summarised in Table 1.
Since the yields were not satisfactory, we investigated the
model reaction applying other molecular sieves supported
metal catalysts. The results are shown in Table 2.
The best result was obtained with Fe3+/4A, the desired
product was formed with complete conversion (99% iso-
lated yield, Table 2, entry 7). In the case of the Cu2+/4A
catalyst, the metal dissolved into the reaction mixture from
Recently, we reported the efcient synthesis of polyhy-
droquinolines via Hantzsch reaction in the presence of a
molecular sieves supported lanthanum catalyst [36]. As
1 3

An Efcient One‑Pot Four‑Component Synthesis of 9‑Aryl‑Hexahydroacridine‑1,8‑Dione…
Table 2 The reaction of dimedone, 4-chlorobenzaldehyde and ammo-
nium acetate in the presence of diferent molecular sieves supported
metal catalysts
Table 3 The synthesis of acridinedione derivatives in the presence of
Fe3+/4A
Entry
R
Product
Yield (%)a
1
2
3
4
5
6
7
8
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
91
84
89
76
99
98
99
96
99
99
98
58
79
70
50
Entry
Catalyst
Yield (%)a
3-BrC6H4
4-BrC6H4
2-ClC6H4
4-ClC6H4
2-FC6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-OCH3C6H4
4-OCH3C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
CH3(CH2)2
2-furyl
b
1
2
3
4
5
6
7
4A
–
La3+/4A
Cu2+/4A
Ti4+/4A
Zn2+/4A
Zr4+/4A
Fe3+/4A
78
c
–
96
93
92
99
9
10
11
12
13
14
15
16
17
Reaction conditions: 2 mmol dimedone, 1 mmol 4-chlorobenzalde-
hyde, 3 mmol ammonium acetate, 0.1 g catalyst, 3 mL EtOH, refux,
14 h
aIsolated yield
bUnidentifable and inseparable side products were also obtained
cThe product was contaminated by copper
b
–
b
2-thienyl
–
the surface of the support probably because of a complex
formation between copper and ammonium acetate, thus con-
taminated the product. Titanium, zinc and zirconium were
less active; while in their 1H NMR spectra small impurities
could be detected.
Reaction conditions: 2 mmol dimedone, 1 mmol aldehyde, 3 mmol
ammonium acetate, 0.1 g catalyst, 3 mL EtOH, refux, 14 h
aIsolated yield
bComplex reaction mixture was formed
Based on the reaction conditions elaborated, a wide
range of aromatic aldehydes were reacted with dimedone
and ammonium acetate in the Fe3+/4A catalysed one-pot
synthesis of 9-aryl-acridine-1,8-diones. The results are sum-
marized in Table 3.
Fig. 2 The structure of 4l′
NO2
OH
O
Benzaldehyde and other substituted aromatic aldehydes
containing electron-withdrawing or electron-donating
groups were tested in the reaction and gave the desired prod-
uct in good to excellent yields. There was no signifcant sub-
stituent efect observed; only the nitro-derivatives (Table 3,
entries 12–14) showed slightly weaker reactivity. In the case
of the 2-nitro-derivate, another product could be isolated
from the reaction mixture, which, based on the NMR spec-
tra, proved to be the enol form of the desired product. The
structure of this enol form can be seen on Fig. 2. This form
might be stabilized by the H-bond formation between the
hydroxyl and the nitro groups.
N
4l'
the condensation reaction, but in these cases complex reac-
tion mixtures were formed.
We propose a plausible mechanism for the synthesis
of 9-aryl-acridine-1,8-dione derivatives involving a Kno-
evenagel condensation, a Michael addition, and an intra-
molecular ring closure in the presence of a 4Å molecular
sieves-supported iron catalyst (Scheme 1). The mechanism
is similar to the one described by Dam et al. [23]. We have
identifed two intermediates, thus the Knoevenagel interme-
diate (D) could be detected in the GC–MS and NMR spectra
when the reaction was interrupted before completion. When
the reaction was carried out in the absence of ammonium
As an example for aliphatic aldehydes, we examined the
reaction of butyraldehyde (Table 3, entry 15), that gave the
desired product with moderate yield, no secondary product
was observed. We also investigated the applicability of het-
eroaryl aldehydes (furfural, thiophene-2-carbaldehyde) in
1 3

Á. Magyar, Z. Hell
3+Fe
O
Fe3+
O
Fe3+
H
H
O
O
O
R
H
O
OH
H
O
2
R
R
O
O
O
Fe3+
C
1
A
B
H
O
Fe3+
O
R
O
O
- H2O
- H2O
O
R
NH4OAc
NH3 + AcOH
O
O
O
3
D
E
O
R
O
O
R
O
H
- H2O
N
H
O
NH2
F
4
Scheme 1 Proposed mechanism of the reaction
acetate, intermediate E could be isolated. The role of the iron
might be to facilitate the reaction steps through the coordina-
tion of the heteroatoms in the transition states.
the conversion necessarily increases further, otherwise the
reaction stops without the catalyst. We carried out the hot
fltration test in the reaction of dimedone, 4-chlorobenzal-
dehyde and ammonium acetate. After 5 h the catalyst was
fltered, the fltrate was divided into two fractions, one was
worked up, and the other was reacted further for the rest of
the reaction time. After 14 h, the latter one was worked up as
well. The two fractions were subjected to 1H NMR spectros-
copy. There was no diference between the two spectra, thus
the leaching of the metal was not observable.
The workup of the reaction mixtures was rather simple;
at the end of the reaction the catalyst was fltered out and
washed with ethanol. The fltrate was evaporated, and the
crude product obtained was extracted with DCM and 0.25 M
NaOH solution. The organic phase was dried over anhydrous
sodium sulphate, fltered and the solvent was evaporated.
The reusability of the catalysts was examined in the reac-
tion of dimedone, 4-chlorobenzaldehyde and ammonium ace-
tate. After 14 h refux, the reaction mixture was worked up as
described above, then the catalyst was heated at ca. 150 °C
for 1 h. The catalyst was reused in two more runs without the
signifcant loss of its activity. The yields in the 1st, 2nd and
3rd runs were 99, 98 and 98%, respectively. These results
clearly demonstrate the reusability of the Fe3+/4A catalyst.
The use of a heterogeneous catalyst often induces a dis-
pute over whether the reaction takes place on the solid sur-
face of the catalyst or in the liquid phase through the leaching
of the metal. To determine the heterogeneous or homogene-
ous nature of the reaction, we used the hot fltration test. The
reaction is interrupted; the catalyst is fltered out, than the
fltrate is reacted further. In case of the leaching of the metal,
In order to evaluate the efciency of our catalyst with
respect to the previously reported catalysts for the prepara-
tion of acridinedione derivatives, we compared our results
with the methods reported in the literature for this synthe-
sis. The comparison is shown in Table 4. In contrast to the
homogeneous catalysts, e.g. CuSO4·5H2O and CAN, a het-
erogeneous catalyst has several advantages; it can be easily
separated from the reaction mixture thus the product is not
contaminated by the catalyst. Although solvent-free methods
have been described, during the isolation and purifcation
of the products, solvents had to be applied and the prepara-
tion of the catalysts have often been a complex procedure
consisting of several steps (e.g. CBSA, Fe3O4@SiO2@
Ni–Zn–Fe LDH, MSNs, Fe3O4@SiO2 nanoparticles). As it
1 3

An Efcient One‑Pot Four‑Component Synthesis of 9‑Aryl‑Hexahydroacridine‑1,8‑Dione…
Table 4 Comparison of
Catalyst
Solvent
Temperature (°C)
Yield (%)
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slightly basic conditions. The desired products were formed
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Acknowledgments Open access funding provided by Budapest Uni-
versity of Technology and Economics (BME). Á. M. is grateful to the
József Varga Foundation for the fnancial support.
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Compliance with Ethical Standards
20. Davoodnia A, Khojastehnezhad A, Tavakoli-Hoseini N (2011) Bull
Korean Chem Soc 32:2243–2248
Conflict of interest The authors declare that they have no confict of
interest.
21. Gilanizadeh M, Zeynizadeh B (2019) Polycycl Aromat Comp. https
://doi.org/10.1080/10406638.2019.1567560
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creativeco
mmons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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