A convenient and efficient one-pot method for the synthesis of novel acridine-calix[4]arene derivatives as new DNA binding agents via multicomponent reaction

Article abstract of DOI:10.1080/10610278.2013.832763

A new approach is applied for the synthesis of novel acridine-calix[4]arene derivatives via a multicomponent reaction. These compounds have been characterised by ¹H NMR, ¹³C NMR and HR-MS. Our binding studies between acridine-functio

Full text of DOI:10.1080/10610278.2013.832763

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A convenient and efficient one-pot method for the
synthesis of novel acridine-calix[4]arene derivatives as
new DNA binding agents via multicomponent reaction
Maryam Mirza-Aghayana, Masoud Yarmohammadia, Reza Zadmarda & Rabah Boukherroubb
a Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box
14335-186, Tehran, Iran
b Institut de Recherche Interdisciplinaire (IRI, USR 3078), Université Lille1, Parc de la Haute
Borne, 50 Avenue de Halley-BP70478, 59658 Villeneuve d'Ascq, France
Published online: 26 Sep 2013.
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To cite this article: Maryam Mirza-Aghayan, Masoud Yarmohammadi, Reza Zadmard & Rabah Boukherroub (2014) A
convenient and efficient one-pot method for the synthesis of novel acridine-calix[4]arene derivatives as new DNA binding
agents via multicomponent reaction, Supramolecular Chemistry, 26:5-6, 442-449, DOI: 10.1080/10610278.2013.832763
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Supramolecular Chemistry, 2014
Vol. 26, Nos. 5–6, 442–449, http://dx.doi.org/10.1080/10610278.2013.832763
A convenient and efficient one-pot method for the synthesis of novel acridine-calix[4]arene
derivatives as new DNA binding agents via multicomponent reaction
Maryam Mirza-Aghayana*, Masoud Yarmohammadia, Reza Zadmarda and Rabah Boukherroubb
*
b
aChemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran; Institut de Recherche
´
Interdisciplinaire (IRI, USR 3078), Universite Lille1, Parc de la Haute Borne, 50 Avenue de Halley-BP70478,
59658 Villeneuve d’Ascq, France
(Received 27 May 2013; accepted 5 August 2013)
A new approach is applied for the synthesis of novel acridine-calix[4]arene derivatives via a multicomponent reaction.
1
These compounds have been characterised by H NMR, 13C NMR and HR-MS. Our binding studies between acridine-
functionalised calix[4]arenes and calf thymus DNA (CT-DNA) via fluorescence titration show that these compounds have a
good affinity to CT-DNA.
Keywords: DNA binding agent; multicomponent reaction; fluorescence titration; acridine-calix[4]arene derivatives
Introduction
In an earlier study by some of us, we have synthesised
various types of dimeric calixarene derivatives, which can
selectively bind double-stranded (ds) DNA and RNA with
submicromolar Kf values in buffered aqueous solution
(9a). Dimeric calixarenes can replace ethidium bromide,
commonly used as intercalating agent, because of their
efficient DNA binding (8, 9).
Acridine derivatives are planar tricyclic aromatic mol-
ecules which possess the ability to intercalate tightly, but
reversibly to the helical structure of DNA (1). Acridine
derivatives are one of the oldest and most successful
classes of bioactive agents and widely utilised as
antimalarial, antiprotozoal, antibacterial and anticancer
drugs (2). Moreover, acridine and its derivatives are a well-
established class of DNA and RNA binding agents (3).
Although the intercalation of small molecules into
DNA is a very important process, the mechanistic
understanding of this process at the molecular level is
lacking (4). Two common binding modes are proposed:
intercalation or groove binding. Intercalation results from
insertion of a planar aromatic substituent between DNA
base pairs, with concomitant unwinding and lengthening
of the DNA helix. Groove binding, in contrast, does not
perturb the duplex structure to any great extent. Groove
binders are typically crescent shaped, and fit into the minor
groove with little distortion of the DNA structure (5).
Acridine and its derivatives are not toxic as com-
pared with other DNA intercalators such as ethidium
bromide (6).
Many synthetic methods for the synthesis of acridine
derivatives have been reported (10). However, these
methods are plagued by the limitation of prolonged
reaction times, poor yields and side reactions of aldehydes.
The application of heteropolyacids as catalytic materials
is growing continuously in the catalytic field (11). In
continuation of our investigations on the synthesis of 1,4-
dihydropyridines (12) and dihydropyrimidines (13–15)
via a multicomponent reaction (MCR), herein we describe
a simple and efficient method for the preparation of
acridine-functionalised calix[4]arene derivatives 8–10
using the heteropolyacid catalyst tungstophosphoric acid
hydrate (H3[PW12O40]). In this study, we introduce an
efficient three-component reaction of amino-calix[4]
arene, dimedone and 4-bromobenzaldehyde or 3-hydro-
xybenzaldehyde that provides an easy access to acridine-
functionalised calix[4]arene derivatives. Furthermore, we
studied the interaction of the synthesised calix[4]arene
derivatives with calf thymus DNA (CT-DNA) via
fluorescence titration experiments in aqueous solution
and compared intercalation behaviour of acridine-functio-
nalised calix[4]arene derivatives 8–10.
Calixarenes are a family of synthetic macrocyclic
receptors, which can be functionalised to provide
selectivity towards targeted species. They have been
extensively used in electroanalysis (7) and because of their
dimensions exclude a potential intercalation or minor
groove insertion (8).
*Corresponding authors. Email: m.mirzaaghayan@ccerci.ac.ir; zadmard@ccerci.ac.ir
q 2013 Taylor & Francis

Supramolecular Chemistry
443
Results and discussion
and di-aminocalix[4]arenes 5 and 7 in 95% and 90% yield,
respectively (Scheme 1).
p-tert-Butylcalix[4]arene 1 (16) is readily accessible in
greater than 65% yield, which provides the starting point
for the present investigation (Scheme 1). The main
synthetic route starts from p-tert-butylcalix[4]arene 1
which is de-alkylated to give calix[4]arene 2 in 73% yield
(17). The calix[4]arene 3 is obtained in 80% yield via n-
butylation of calix[4]arene 2 with n-BuBr in the presence
of NaH in dimethylformamide (DMF) (18). The calix[4]
arenes 4 and 6 are synthesised by nitration of 3 via a
modified method (19). We have investigated different
conditions such as the concentration of nitric acid (65%)
and glacial acetic acid, time and temperature of reaction
for the synthesis of mono-nitrocalix[4]arene 4. Our results
indicated that 15 equivalents of nitric acid (65%) without
glacial acetic acid are needed for this reaction. The
reaction time was about 12 min. With this modified
method, mono-nitrocalix[4]arene 4 was isolated in 60%
yield. It should be noted that increasing the concentration
of nitric acid (65%) above 30 equiv., the reaction time or
using glacial acetic acid afforded a mixture of di-, tri- and
tetra-nitrocalix[4]arenes. Calix[4]arene 6 was obtained in
30% yield by using the same conditions by increasing the
reaction time to 23 min. Increasing the concentration of
nitric acid to 30 equiv., while reducing the reaction time to
12 min gave a similar yield. It should be noted that using
15 equiv. of nitric acid in the presence of glacial acetic acid
resulted in a mixture of mono, 1,2 alternate, 1,3 alternate,
tri- and tetra-nitrocalix[4]arene derivatives.
The MCR ofmono-aminocalix[4]arene 5 withdimedone
and 4-bromobenzaldehyde or 3-hydroxybenzaldehyde was
conducted in the presence of H3[PW12O40] as the catalyst to
yield novel acridine-calix[4]arene derivatives8 and 9 in 46%
and 50% yield, respectively (Scheme 2). To compare
the influence of the acridine-calix[4]arene structure on the
intercalation potential, we synthesised di-acridine-calix[4]
arene 10 in 40% yield, using a similar MCR, from di-amine
calix[4]arene 7 (1,3-alternate conformation) (Scheme 2).
The acridine-calix[4]arenes 8–10 were characterised on the
basisoftheirspectroscopicdatasuchas1Hand13CNMRand
ESI-HR-MS.
For comparison of binding of acridine-functionalised
calix[4]arene derivatives 8–10 with an ordinary hydroxy-
acridine derivative, we synthesised acridine 11 in 60%
yield, from the reaction of aniline with dimedone and 3-
hydroxybenzaldehyde in the presence of H3[PW12O40] as
the catalyst (Scheme 3).
Fluorescence titration experiments
To further investigate the binding mode between calix[4]
arene compounds 8–10 and CT-DNA, fluorescence
titration experiments were carried out. Fluorescence
titration is widely used, because of its sensitivity and the
availability of the spectroscopic technique (21). Further-
more, this method requires micromolar concentrations
while other methods such as NMR necessitate millimolar
concentrations (22, 23).
Reduction of calix[4]arenes 4 and 6 by Raney nickel as
catalyst and hydrazine hydrate (65%) (20) afforded mono
(1) NaH, DMF
PhOH, AlCl3
toluene, r.t., 2 h
4
(2) n-BuBr, 80˚C, 24 h
4
OH
OBu
OH
1
3
2
NO2
H
H
NH2
N2H4 H2O
Raney Ni
HNO3 65% (15 equiv.)
CH2Cl2, r.t., 12 min
4
3
3
methanol
reflux, 2 h
OBu
OBu
OBu
NO2
OBu
OBu
NH2
3
4
5
N2H4 H2O
Raney Ni
HNO3 65% (15 equiv.)
CH2Cl2, r.t., 23 min
2
2
4
methanol
reflux, 2 h
OBu
OBu
OBu
OBu
OBu
3
6
7
Scheme 1. Synthetic route to calix[4]arenes 1–7.

444
M. Mirza-Aghayan et al.
OH
O
O
NH2
OBu
N
O
OH
H3[PW12O40] (6 mol%)
+
+
O
ethanol, reflux
3
3
H
OBu
O
OBu
OBu
Br
5
8
O
O
NH2
OBu
N
Br
O
H3[PW12O40] (6 mol%)
+
+
ethanol, reflux
3
3
O
OBu
OBu
OBu
H
O
5
9
Br
O
O
Br
O
NH2
OBu
N
H3[PW12O40] (10 mol%)
+
+
ethanol, reflux
O
2
2
OBu
OBu
OBu
H
O
7
10
Scheme 2. Synthetic route to acridine-calix[4]arene derivatives 8–10.
OH
O
O
O
NH2
OH
H3[PW12O40] (3 mol%)
ethanol, reflux
+
+
O
N
CHO
11
Scheme 3. MCR for synthesis of 3-hydroxy-acridine derivative 11.
The fluorescence titrations of calix[4]arene (1
£ 1026 M) 8 and 9 were carried out in Hepes-buffered
(0.05 M, pH 7.1) and NaCl (0.05 M) aqueous solutions at
208C. In the case of calix[4]arene 10, fluorescence titrations
were conducted under similar conditions, but in water:
methanol (1:5) solution. Forconvenience, CT-DNA solution
was diluted in each calix[4]arenes 8, 9 or 10 derivative
distinctly, so that there was no change in the CT-DNA
concentration throughout the entire titration. For each
compound, 1700 ml of the calix[4]arene solution
(1 £ 1026 M) was filled into cuvettes and fluorescence
intensity was measured (F0), then up to 1600 ml of CT-DNA
solution (1 £ 1027 M) was added stepwise. For each
addition, after stirring for 30 s and standing for 2 min, the
change in the emission intensity was measured (Fobs) as
shown in Figures 1, 3 and 5. According to the fluorescence
titration chart shown in Figures 1, 3 and 5, after each
addition (CT-DNA) the intensity of fluorescence emission is
decreased. The calculation of the binding constant (Kf) was
carried out using Scatchard plots (Figures 2, 4 and 6) (24).

Supramolecular Chemistry
445
Figure 4. (Colour online) Scatchard plot of 4-bromo-acridine-
calix[4]arene 9.
Figure 1. (Colour online) Decrease in the fluorescence intensity
of 3-hydroxy-acridine-calix[4]arene 8.
Figure 2. (Colour online) Scatchard plot of 3-hydroxy-acridine-
calix[4]arene 8.
Figure 5. (Colour online) Decrease in the fluorescence intensity
of di-4-bromo-acridine-calix[4]arene 10.
Figure 3. (Colour online) Decrease in the fluorescence intensity
of 4-bromo-acridine-calix[4]arene 9.
Figure 6. (Colour online) Scatchard plot of di-4-bromo-
acridine-calix[4]arene 10.

446
M. Mirza-Aghayan et al.
Table 1. Association constants between CT-DNA and acridine-
calix[4]arene derivatives 8–10 and 3-hydroxy-acridine 11.
12 base pair: 50-GTG ACG AAC CTC-30
50-GAG CTT GGT AAC-30
Crothers (25) previously reported that in intercalation
process, each intercalator occupied at least 4 base pairs as
the rule of nearest neighbour-exclusion. According to this
rule, a 3:1 ratio was expected for 3-hydroxy-acridine 11
and ds-DNA, but the plot showed at least a 9:1 ratio
between them. We also carried out a Job plot for 4-bromo-
acridine-calix[4]arene 9 with ds-DNA to investigate the
acridine-calix[4]arene stoichiometry with ds-DNA. Our
result suggested a 2:1 ratio of acridine-calix[4]arene 9 and
ds-DNA (Figure 7).
Entry
Receptor
Guest
Kf (M21
)
1
2
3
4
3-Hydroxy-acridine-calix[4]arene 8
4-Bromo-acridine-calix[4]arene 9
CT-DNA 3.75 £ 106
CT-DNA 2.18 £ 107
Di-4-bromo-acridine-calix[4]arene 10 CT-DNA 6.36 £ 107
3-Hydroxy-acridine 11
CT-DNA 1.34 £ 108
Equations (1) and (2)were used to fit data to Scatchard plots.
The results of binding constants are summarised in Table 1,
and calculations and complete data are given in supplemen-
tary data.
These results indicate that there is another interaction for
3-hydroxy-acridine 11 with ds-DNA. We assume that in the
solution, the aggregation process of this compound is
responsible for decreasing the intensity of the fluorescence.
While in the case of 4-bromo-acridine-calix[4]arene 9, just
the interaction with ds-DNA is responsible of complexation,
not aggregation or something else.
½Mꢀtotal
1
½Lꢀtotal
¼
þ
;
ð1Þ
ð2Þ
f
ðN·Kf ð1 2 fÞÞ
N
F0 2 Fobs
f ¼
;
F0 2 Fmax
According to recent reports, DNA recognition
efficiency of major groove binders can also be quanti-
tatively characterised by ethidium bromide displacement
assays (26). Hence, we carried out an ethidium bromide
displacement assay for 3-hydroxy-calix[4]arene 8 and
4-bromo-acridine-calix[4]arene 9. Unfortunately, as the
binding constant of ethidium bromide for CT-DNA is
107 M21, our results show that these compounds cannot
displace ethidium bromide.
where [M]total is the total volume of DNA after each
addition, N is the number of binding sites per DNA
molecule, Kf is the constant of complexation and [L]total is
the total volume of ligand. Conversion to a linear plot using
the term f, corresponding to the fraction of ligand bound
during titration, was calculated using Equation (2). In this
equation, F0 is the fluorescence intensity of free ligand, Fobs
is the fluorescence intensity after each addition and Fmax is
the fluorescence intensity when all possible ligand is bound
to CT-DNA.
In conclusion, we present an easy synthetic method of
non-charged and large amphiphilic molecules, which
selectively bind CT-DNA and ds-DNA with submicro-
molar Kf values in buffered aqueous solution.
The association constants obtained for 3-hydroxy-
acridine-calix[4]arene 8 and 3-hydroxy-acridine 11,
according to decreasing emission intensity (Figure 1)
and Scatchard plot (Figure 2), are equal to 3.75 £ 106 and
1.34 £ 108 M21, respectively (Table 1).
Experimental
Materials
4-Bromo-acridine-calix[4]arene 9 has a strong emis-
sion (Figure 3) that was noticeably quenched during the
titration process which yielded Scatchard plot in Figure 4
with an association constant of 2.18 £ 107 M21 (Table 1).
The influence of the number of binding sites on
acridine-calix[4]arene in complexing with CT-DNA was
investigated using the di-4-bromo-acridine-calix[4]arene
10 by measuring the changes in fluorescence intensity
during titration with CT-DNA (Figure 5). 4-Bromo-di-
acridine-calix[4]arene 10 Scatchard plot (Figure 6)
allowed to determine an association constant of 6.36
£ 107 M21 (Table 1).
All reagents were purchased at highest commercial grade
and used as supplied. All solvents were distilled. Reactions
According to the fluorescence titration of acridine-
calix[4]arenes 8–10 and 3-hydroxy-acridine 11, we
observed a high-binding constant for 3-hydroxy-acridine
11 (Table 1) that seems an unusual amount for a small and
a non-ionic molecule; therefore, we carried out a Job plot
to investigate the stoichiometry of this compound with ds-
DNA with the following sequence:
Figure 7. (Colour online) Job plot of 4-bromo-acridine-calix[4]
arene 9 with 12 base-pair DNA.

Supramolecular Chemistry
447
1
were monitored by thin-layer chromatography (TLC) with
Merck silica gel 60 F254 plates. Silica gel 60 for flash
chromatography (particle size 230–400 mesh) was
supplied by Merck, Darmstadt, Germany.
dried to obtain a white powder in 95% yield. H NMR
(CDCl3, 80 MHz): d ¼ 1.16 (t, J ¼ 6.8 Hz, 12H, CH3),
1.32–1.80 (m, 8H, CH2), 1.80–2.40 (m, 8H, CH2), 3.00–
3.60 (m, 4H, ArCH2Ar and NH2), 3.70–4.30 (m, 8H,
4OCH2), 4.56 (d, J ¼ 6.4 Hz, 2H, ArCH2Ar), 4.65 (d,
J ¼ 6.4 Hz, 2H, ArCH2Ar), 6.08 (s, 2H, HAryl), 6.49–7.00
(s, 9H, HAryl).
Instrumentation
Melting points were determined in evacuated capillaries
with a Buchi B-545 apparatus. Mass spectra were obtained
on a FISONS GC 8000/TRIO 1000 under 70 eV. 1H or 13
C
5,11-Dinitro-26,27,28,29-tetrabutyloxy calix[4]arene 6
NMR spectra were recorded on a Bruker 80, 250, 300
and 500 or 300 and 500 MHz, respectively, in CDCl3 or
deuterated dimethyl sulfoxide (DMSO-d6)/CDCl3 using
tetramethylsilane as internal standard. HR-MS was
recorded with a Qstar ESI-q-TOF mass spectrometer
(Applied Biosystems, Darmstadt, Germany). Fluorescence
spectra were recorded using a Jasco FP-6500 device.
Calix[4]arenes 1–3 were synthesised according to the
literature methods (16–18).
To a solution of 3 (0.50 g, 0.77 mmol) in CH2Cl2 (30 ml)
was added 15 equivalents of 65% nitric acid (0.75 ml,
11.55 mmol) at once at room temperature under mild
stirring. The reaction was stopped after 23 min by adding
25 ml of water. The solution was decanted and the organic
layer was washed with water (3 £ 25 ml), saturated
Na2CO3 (3 £ 10 ml) and water (3 £ 25 ml) again, the
solvent was dried over Na2SO4 and evaporated. The
product was isolated as white crystals by crystallisation
in dichloromethane:methanol (3:2) in 30% yield. M.p.:
182–1878C; 1H NMR (CDCl3, 80 MHz): d ¼ 0.92
(t, J ¼ 2.4 Hz, 12H, 4CH3), 1.1–1.6 (m, 8H, 4CH2),
1.6–2.06 (m, 8H, 4CH2), 3.16 (d, J ¼ 6.8 Hz, 4H,
2ArCH2Ar), 3.68–4.1 (m, 8H, 4OCH2), 4.41
(d, J ¼ 6.8 Hz, 4H, 2ArCH2Ar), 6.65 (s, 6H, HAryl), 7.36
(s, 4H, HAryl); MS (E.I.) (70 eV): m/z % 739 (2) [M]þ, 681
(3), 625 (5), 119 (11), 57 (87).
5-Nitro-26,27,28,29-tetrabutoxy calix[4]arene 4
To a solution of calix[4]arene 3 (0.50 g, 0.77 mmol) in
CH2Cl2 (30 ml) was added 15 equiv. of 65% nitric acid
(0.75 ml, 11.55 mmol) in one portion at room temperature.
The solution turned to dark purple immediately and then to
dark green when the reaction was finished by adding 25 ml
water after 12 min. The organic layer was separated
and washed with water (3 £ 15 ml), saturated Na2CO3
(3 £ 10 ml) and water again (3 £ 15 ml), then dried over
Na2SO4, and the solvent was evaporated. The product was
isolated as yellow crystals by crystallisation in dichlor-
5,11-Diamine-26,27,28,29-tetrabutyloxy calix[4]arene 7
To a mixture of 6 (0.50 g, 0.67 mmol) in methanol (50 ml)
was added 0.1 g Raney nickel and the mixture was refluxed
for 30 min, then hydrazine hydrate 60% (4 ml, 0.08 mmol)
was added dropwise. The reaction was completed after 2 h.
The mixture was filtered on a sintered funnel and the
solution was washed with water (3 £ 20 ml) and dried to
1
omethane:methanol (3:2) in 60% yield. M.p.: 1558C; H
NMR (CDCl3, 80 MHz): d ¼ 0.91 (t, J ¼ 6.4 Hz, 12H,
4CH3), 1.10–1.51 (m, 8H, 4CH2), 1.51–2.00 (m, 8H,
4CH2), 3.08 (d, J ¼ 13.6 Hz, 2H, ArCH2Ar), 3.12 (d,
J ¼ 13.6 Hz, 2H, ArCH2Ar), 3.6–4.10 (m, 8H, 4OCH2),
4.35 (d, J ¼ 13.6 Hz, 2H, ArCH2Ar), 4.40 (d, J ¼ 13.6 Hz,
2H, ArCH2Ar), 6.16 (s, 3H, HAryl), 6.52–7.00 (m, 6H,
1
obtain a white powder in 95% yield. H NMR: (CDCl3,
500 MHz) d ¼ 0.99–1.05 (m, 10H, CH3 and CH2), 1.38–
1.49 (m, 4H, CH2), 1.50–1.53 (m, 4H, CH2), 1.86–1.93
(m, 10H, CH2 and CH3) 3.08 (d, J ¼ 10.0 Hz, 4H,
ArCH2Ar), 3.7 (t, J ¼ 10.0 Hz, 4H, OCH2), 3.9 (t,
J ¼ 10.0 Hz, 4H, OCH2), 4.3 (d, J ¼ 15.0 Hz, 4H,
ArCH2Ar), 5.9 (s, 4H, HAryl), 6.71–6.83 (m, 2H, HAryl),
6.85 (d, J ¼ 10.0 Hz, 4H, HAryl).
H
Aryl), 7.05 (s, 2H, HAryl); MS (E.I.) (70 eV): m/z (%) 694
(3) [M þ 1]þ, 693 (5) [M]þ, 664 (2), 636 (3), 580 (10),
524 (7), 468 (6), 149 (10), 119 (22), 57 (87), 29 (100); anal.
calcd for C44H55NO6 C, 76.16; H, 7.99; N, 2.02%. Found:
C, 76.28; H, 8.07; N, 1.93%.
5-Amino-26,27,28,29-tetrabutyloxy calix[4]arene 5
3-Hydroxy-acridine-calix[4]arene 8
To a mixture of calix[4]arene 4 (0.50 g, 0.72 mmol) in
methanol (50 ml) was added 0.10 g Raney nickel and the
mixture was refluxed for 30 min, then hydrazine hydrate
60% (2 ml, 0.04 mmol) was added dropwise. After
completion of the reaction (2 h) as indicated by TLC, the
solvent was evaporated and the residue was dissolved in
dichloromethane, then washed with water (3 £ 20 ml) and
To a mixture of calix[4]arene 5 (0.48 g, 0.72 mmol) in dry
ethanol (5 ml) and H3[PW12O40] (0.12 g, 6 mol%) was
added the first portion of dimedone (0.10 g, 0.72 mmol).
The reaction mixture was heated at 808C for 8 h. Then, 3-
hydroxybenzaldehyde (0.88 g, 0.72 mmol) and the second
portion of dimedone (0.10 g, 0.72 mmol) were added to
this mixture. The reaction mixture was heated at 808C for

448
M. Mirza-Aghayan et al.
16 h. After completion of the reaction, the crude product
was purified by column chromatography with hexane:ethyl
acetate (8:3) as eluent and crystallised in dichloromethane:
Di-4-bromo-acridine-calix[4]arene 10
To a solution of calix[4]arene 7 (0.20 g, 0.29 mmol) in dry
ethanol (5 ml), H3[PW12O40] (0.08 g, 10 mol%) was added
the first portion of dimedone (0.82 g, 0.58 mmol). The
reaction mixture was heated at 808C for 8 h. Then, 4-
bromobenzaldehyde (0.10 g, 0.58 mmol) and the second
portion of dimedone (0.82 g, 0.58 mmol) were added to
this mixture. The resulting mixture was heated at 808C for
16 h. After completion of the reaction, the crude product
was purified by column chromatography with hexane:ethyl
acetate (8:3) as eluent and crystallised in dichloromethane:
methanol (2:1) to give 10 in 40% yield. 1H NMR (CDCl3,
500 MHz) d ¼ 0.89 (s, 6H, 2CH3), 0.91 (s, 6H, 2CH3),
0.95–1.20 (m, 24H, 8CH3), 1.43–1.48 (m, 4H, 2CH2),
1.66–1.72 (m, 4H, 2CH2), 1.91–1.95 (m, 4H, 2CH2),
1.99–2.06 (m, 8H, 4CH2), 2.13–2.19 (m, 4H, 2CH2),
2.21–2.28 (m, 8H, 4CH2), 3.28 (t, J ¼ 14.0 Hz, 2H, CH2),
3.78 (t, J ¼ 6.1 Hz, 2H, OCH2), 4.28 (t, J ¼ 8.2 Hz, 2H,
OCH2), 4.60 (d, J ¼ 13.0 Hz, 2H, CH2), 5.27 (s, 2H, CH),
6.23 (m, 6H, HAryl), 7.03 (d, J ¼ 21.3 Hz, 4H, HAryl), 7.37
(d, J ¼ 8.5 Hz, 4H, HAryl), 7.41 (d, J ¼ 8.5 Hz, 4H, HAryl);
13C NMR (CDCl3, 300 MHz): 13.99, 14.18, 18.99, 19.69,
26.58, 26.69, 29.66, 29.73, 29.90, 30.62, 30.74, 32.27,
32.44, 32.55, 32.70, 41.83, 42.54, 49.94, 50.20, 75.26,
75.52, 113.66, 114.27, 119.72, 121.65, 127.39, 127.49,
129.23, 129.75, 130.23, 131.10, 132.42, 132.57, 132.63,
138.64, 139.03, 145.41, 150.12, 150.22, 155.36, 158.33,
195.54, 195.70; HR-MS (ESI): m/z [M]þ calcd for
C90H104Br2N2O8: 1498.6159; found: 1498.9059.
1
methanol (2:1) to give 8 in 50% yield. H NMR (CDCl3,
300 MHz): d ¼ 0.92 (s, 6H, 2CH3), 0.97–1.11 (m, 18H,
4CH3 and 2CH3), 1.26 1.5 (m, 4H, 2CH2), 1.57–1.78 (m,
4H, 2CH2), 1.83–2.15 (m, 12H, 6CH2), 2.18–2.34 (m, 5H,
2CH2 and OH), 3.21 (t, J ¼ 13.5 Hz, 4H, 2ArCH2Ar),
3.66–3.84 (m, 4H, OCH2), 4.11 (t, J ¼ 7.5 Hz, 2H,
OCH2), 4.24 (t, J ¼ 7.5 Hz, 2H, OCH2), 4.47 (d,
J ¼ 3.2 Hz, 2H, ArCH2Ar), 4.57 (d, J ¼ 3.2 Hz, 2H,
ArCH2Ar), 5.31 (s, 1H, CH), 6.10–6.31 (m, 6H, HAryl),
6.62 (dd, J ¼ 3 and 9 Hz, 1H, HAryl), 6.88–7.26 (m, 4H,
NH2 and HAryl), 7.08–7.31 (m, 4H, HAryl); 13C NMR
(CDCl3, 300 MHz): d ¼ 13.97, 14.14, 14.18, 19.01, 19.64,
26.78, 29.76, 30.73, 30.91, 31.93, 32.28, 32.36, 32,53,
32.71, 41.80, 42.47, 49.99, 74.74, 75.12, 75.54, 113.13,
114.05, 114.55, 116.12, 118.78, 121.87, 121.96, 125.24,
127.90, 128.17, 128.94, 129.02, 129.22, 130.09, 131.89,
131.89, 133.74, 136.91, 138.53, 139.05, 147.72, 150.49,
150.60, 155.22, 156.05, 157.72, 158.43, 196.21; HR-MS
(ESI): m/z [M]þ calcd for C67H81NO7: 1011.6013; found:
1011.4021.
4-Bromo-acridine-calix[4]arene 9
To a solution of calix[4]arene 5 (0.48 g, 0.72 mmol) in dry
ethanol (5 ml) and H3[PW12O40] (0.12 g, 6 mol%) was
added the first portion of dimedone (0.10 g, 0.72 mmol).
The reaction mixture was heated at 808C for 8 h. Then
(0.13 g, 0.72 mmol) of 4-bromobenzaldehyde and the
second portion of dimedone (0.10 g, 0.72 mmol) were
added to this mixture. The resulting mixture was heated at
808C for 16 h. After completion of the reaction, the crude
product was purified by column chromatography with
hexane:ethyl acetate (8:3) as eluent and crystallised in
dichloromethane:methanol (2:1) to give 9 in 46% yield. 1H
NMR (CDCl3, 250 MHz): d ¼ 0.87 (s, 6H, 2CH3), 0.96–
1.08 (m, 18H, 4CH3 and 2CH3), 1.21–1.47 (m, 4H, 2CH2),
1.51–1.73 (m, 4H, 2CH2), 1.8–2.17 (m, 12H, 4CH2 and
2CH2), 2.19–2.31 (m, 4H, 2CH2), 3.14–3.3 (m, 4H,
2ArCH2Ar), 3.64–3.83 (m, 4H, 2OCH2), 4.07 (t,
J ¼ 7.5 Hz, 2H, OCH2), 4.21 (t, J ¼ 17.5 Hz, 2H,
OCH2), 4.44 (d, J ¼ 12.5 Hz, 2H, ArCH2Ar), 4.55 (d,
J ¼ 12.5 Hz, 2H, ArCH2Ar), 5.24 (s, 1H, CH), 6.07–6.28
(m, 6H, HAryl), 6.91–7.00 (m, 3H, HAryl), 7.14 (d,
J ¼ 7.5 Hz, 2H, HAryl), 7.32–7.43 (m, 4H, HAryl); 13C
NMR (CDCl3, 300 MHz): d ¼ 13.98, 14.15, 14.19, 19.02,
19.66, 26.69, 29.84, 30.74, 30.93, 31.95, 32.30, 32.54,
32,68, 41.79, 42.47 50.17, 74.77, 75.15, 113.66, 114.16,
119.67, 121.87, 122.00, 126.67, 127.98, 128.97, 129.76,
130.06, 131.09, 131.75, 132.28, 133.84, 136.89, 138.89,
139.12, 145.49, 150.33, 155.25, 157.72, 158.52, 195.70;
HR-MS (ESI): m/z [M]þ calcd for C67H80BrNO6:
1073.5169; found: 1073.5066.
9-(3-Hydroxyphenyl)-3,3,6,6-tetramethyl-10-phenyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 11
To a solution of aniline (0.13 g, 1.4 mmol) in 5 mL ethanol
was added dimedone (0.14 g, 1 mmol) and heteropolyacid
(HPA) (3%mol). The mixture was refluxed and the reaction
was followed by TLC until the dimedone was entirely
consumed. After 4 h, the second part of dimedone (0.14 g,
1 mmol) and 3-hydroxybenzaldehyde (0.12 g, 1 mmol)
were added to the mixture. The reaction was refluxed for
4 h. The reaction was stopped by adding crushed ice to the
mixture, filtered through sintered funnel and the residue
was dissolved in warm ethanol. Then, the solvent was
evaporated and the crude was crystallised in ethanol to give
the product in 80% yield. M.p.: 2508C. 1H NMR (DMSO-
d6/CDCl3, 80 MHz): d ¼ 0.78 (d, J ¼ 11.2 Hz, 12H,
2CH3), 1.72–2.29 (m, 8H, 4CH2), 5.01 (s, 1H, CH),
6.42–7.71 (m, 9H, HAryl). MS (E.I.) (70 eV): m/z 441 (3)
[M]þ, 348 (100), 272 (28), 93 (70), 77 (43).
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