Cu-metal organic frameworks (Cu-MOF) as an environment-friendly and economical catalyst for one pot synthesis of tacrine derivatives

Article abstract of DOI:10.1039/c9ra10111j

The present work describes the catalytic activity of Cu-MOF for the one-pot synthesis of tacrine derivatives via a four-component reaction of 2-hydroxynaphthalene-1,4-dione, aldehydes, malononitrile and cycloketones in the presence of AlCl₃. The structure of the synthesized compound is confirmed by ¹H NMR, ¹³C NMR, IR, and MASS. The catalyst prepared under pressure is characterized by powder X-ray diffraction and SEM. The noteworthy advantages of this procedure include its broad substrate scope, high yields up to 93%, atom economy, using readily available starting materials and a powerful recyclable nano catalyst. Additionally, there is no need to use column chromatography for purifying products so, it has the potential for large-scale applications in pharmaceutical industries. Another advantage of this method is the ability to recycle the catalyst up to 3 times and reuse it.

Full text of DOI:10.1039/c9ra10111j

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Cu-metal organic frameworks (Cu-MOF) as an
environment-friendly and economical catalyst for
one pot synthesis of tacrine derivatives†
Cite this: RSC Adv., 2020, 10, 1995
a
a
a
*
Mohammad majid Mojtahedi
Hoda Mollabagher,
Salman Taheri,
and SeyedAmirhossein Seyedmousavib
The present work describes the catalytic activity of Cu-MOF for the one-pot synthesis of tacrine
derivatives via four-component reaction of 2-hydroxynaphthalene-1,4-dione, aldehydes,
a
malononitrile and cycloketones in the presence of AlCl3. The structure of the synthesized compound
is confirmed by 1H NMR, 13C NMR, IR, and MASS. The catalyst prepared under pressure is
characterized by powder X-ray diffraction and SEM. The noteworthy advantages of this procedure
include its broad substrate scope, high yields up to 93%, atom economy, using readily available
starting materials and a powerful recyclable nano catalyst. Additionally, there is no need to use column
chromatography for purifying products so, it has the potential for large-scale applications in
pharmaceutical industries. Another advantage of this method is the ability to recycle the catalyst up to
3 times and reuse it.
Received 3rd December 2019
Accepted 2nd January 2020
DOI: 10.1039/c9ra10111j
rsc.li/rsc-advances
transmits the message between the two nerve cells and then
decomposes with cholinesterase. In AD reducing the acetylcho-
1. Introduction
line disrupts the transmission of messages between the two nerve
cells.2 Therefore, many studies have been done to strengthen the
cholinesterase system includes acetylcholine release agents such
as 4-aminopyridine (1), and anticholinesterase drugs, such as
physostigmine (2) and acetylcholinesterase inhibitors like tacrine
(3) and 4-aminoquinoline (4).
According to the World Health Organization, over 30 million
people worldwide suffer from Alzheimer's disease (AD), and
research has shown that this number is rising substantially.1 AD
is actually a type of brain dysfunction that gradually degrades the
mental abilities of the patient and leads to memory impairment
and dementia. Acetylcholine is one of the substances that
Among the listed compounds, tacrine is one of the drugs that
boost acetylcholine by inhibiting cholinesterase enzymes3 and
is known as an important reference with amazing pharmaco-
logical properties. It was rst identied in 1993 as a drug for the
treatment of AD.4 Studying of tacrine analogues is still of
interest to researchers investigating AD. As a result, several
aChemistry and Chemical Engineering Research Center of Iran, PO Box 14115-186,
Tehran, Iran. E-mail: taheri@ccerci.ac.ir
bProcess Engineering Department, Faculty of Chemical Engineering, Tarbiat Modares
University, Tehran, Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10111j
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methods have been investigated for the synthesis of tacrine and and selectivity of one-pot reactions. The specic porous struc-
their analogues. Recently, synthesis of tacrine analogues with ture of MOF containing organic and inorganic active sites is
modern strategies including high efficiency and short time is a useful and effective alternative to heterogeneous catalysts.
a great interest of chemists and pharmacists.5,6 Synthesis of
In recent years, MOFs are highlighted due to its bicomposi-
tacrine analogues was mostly reported in the presence of tional nature contains metallic ions and organic ligands
a Lewis acid such as AlCl3,7 ZnCl2,8 BF3/Et2O,9 silica gel/p-tol- together in one complex. Organic ligands and metallic ions
uenesulfonic acid.10 Khalilzadeh and coworkers reported new could be changed to achieve different efficiencies and yields.
method for the preparation of tacrine analogues via applying Also, the high porosity of these structures has made them
microwave irradiation by using silica gel/p-toluenesulfonic acid a powerful nano-reactor for chemical reactions.20 According to
as a catalyst to improve reaction time.10 However, the main the above, the exibility, physical, chemical, biological proper-
problem with their work refers to microwave irradiation that ties of these compounds can be very diverse and unique.
microwave energy absorbing is possible only to a limited
Among this kind of materials copper-based MOFs used as
thickness of materials and can be changed due to material heterogeneous acid in the synthesis of the organic compound.
absorption and is not easy and precisely applicable for indus- Due to the catalytic behavior of MOFs, they have been used in
trial production.11
various reactions including the oxidation of benzoquinones,
Several reports have been made to design tacrine analogues, cyanosilylation of aldehydes, and Knoevenagel condensations.
including the replacement or hetero-annulated of the benzene Up to now most of the reported procedures for tacrine
ring with the heterocyclic systems. The presence of aromatic or synthesis go through pyranic intermediate which should be
heteroaromatic rings in the tacrine scaffolds results in addi- separated and puried for the next step of the reaction (Scheme
tional p–p interaction in the structure and have pharmaco- 1).21,22
phoric moiety that can be used for the design of new AChE
inhibitors.12
Our work has presented a novel procedure to the synthesis of
tacrine derivatives, starting from aldehyde, malononitrile, 2-
Polyfunctionalized 2-amino-3-cyano-4H-pyrans are well- hydroxynaphthalene-1,4-dione and cycloketone derivative as
known compounds that reactivity has been extensively investi- one-pot reaction without the requirement for separating the
gated and used as intermediates in the tacrine synthesis. In this pyranic intermediate. Applying the Cu-MOF as heterogeneous
¨
way, it is prepared from Friedlander annulation involving the catalyst assistances the formation of pyranic intermediates,
condensation of 2-amino-3-cyano-4H-pyrans with carbonyl followed by the addition of aluminum chloride to the
compound that contains reactive a-methylene group.7 All re- Friedlander quinoline reaction, without interfering with the two
¨
ported tacrine synthesis procedures from pyranic intermediate, catalysts in the reaction process. The presence of Cu active sites
were contained two or more steps.13
in Cu-MOF has made it a suitable candidate for the synthesis of
One-pot synthesis of materials is a simple, facile and effec- pyrene compounds. We describe convenient synthesis methods
tive method in synthetic chemistry. Minimizing the number of tacrine derivatives from the simple starting material.
steps in the synthesis procedure in order to obtain target
compounds is of great interest in the production of chemical
and pharmaceutical compounds. The requirement for the rapid 2. Experimental
and selective structure of biologically active materials for drug
2.1. Chemicals and apparatus
discovery has led to the widespread development of heteroge-
All starting materials were purchased from Sigma-Aldrich and
nous catalysis, which allows the researcher to reduce the steps
Merck companies and used without additional purication.
Reactions were monitored by aluminum TLC plate, silica gel
coated with uorescent indicator F254. Melting points were
measured using a Buchi B-545 apparatus through the capillary
of the reactions.14–17
Heterogeneous catalysts have also many other advantages
such as easily isolation from the mixture of the reaction, be
recyclable and less contamination in nal product.18 Metal
tube method and reported without any correction. IR spectra
organic frameworks (MOFs) attracted the attention of the
were recorded from KBr disks using FT-IR Bruker Vector-22
scientic community around 1990 (ref. 19) and then it has been
1
infrared spectrometer in the range of 400–4000 cmꢀ1. The H
effectively used as heterogeneous catalysis improving efficiency
NMR and 13C NMR were run on an FT-NMR Bruker
Scheme 1 Synthesis of tacrine derivatives from pyranic intermediate.
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UltraShield™ (500 MHz) in DMSO-d6 and CDCl3 as a solvent denotes the deletion of the peak associated with the DMF
and the chemical shis are expressed as d units with tetrame- methyl groups in region 2936. Remove peak in region 3486,
thylsilane (TMS) as internal standard. Mass spectra were ob- indicates a withdrawal of water and carboxylic acid present in
tained on an Agilent Technologies apparatus at ionization the cavity, aer the activation of the catalyst.
potential of 70 eV. The concentration of copper in the prepared
According to the reported literature,26 the Cu-MOF structure
catalysts was determined using inductively coupled plasma releases DMF molecules during the activation process, and has
optical emission spectroscopy by SPECTRO ARCOS ICP-OES active copper sites (Scheme 2).
spectrometer.
The powder XRD pattern of the Cu-MOF compound clearly
indicates the presence of copper in its structure and the sharp
peak appearing in less than 15 indicates a highly crystalline
structure (Fig. 2). According to the XRD spectra, the average size
of the crystals (D) was 52 nm using the Scherrer equation (1) by
replacing l as the wavelength of the X-ray beam, b1/2 as the line
broadening at half the maximum intensity and q as the Bragg's
angle.
2.2. General procedure for the preparation of compounds
6a–k
A mixture of 2-hydroxy-1,4-naphthoquinone 1 (0.174 g, 1.0
mmol), aromatic aldehyde 2 (1.0 mmol), malononitrile 3 (0.06 g,
1.0 mmol), and catalytically amount of Cu-MOF (0.02 g) in dry
1,2-dichloroethane (DCE) (5.0 mL) was stirred under reux
condition until completion reaction and disappearance of the
starting materials on TLC (EtOAc : n-hexane 1 : 1). Then, AlCl3
(0.1995 g, 1.5 mmol) and cycloketone 5 (1.5 mmol) were added
into the mixture of the reaction. The mixture was continuously
stirred under argon atmosphere under reux. Aer completion,
the mixture was centrifuged to isolated catalyst and then the
solvent was evaporated under reduced pressure, H2O and THF
(1 : 1) were added and the mixture was basied with 10%
sodium hydroxide solution to pH ¼ 8–9. Aer stirring for
30 min, the mixture was diluted using CH2Cl2 and the organic
layer was dried over MgSO4. In the end, the crude is crystalli-
zation by ethyl acetate to obtain the pure product.
0:9l
D ¼
(1)
b1=2 cos q
SEM techniques can be used to obtain the surface, shape,
and appearance of particles. As it clear in Fig. 3, the cubic Cu-
MOF structure that was synthesis under pressure is well-
dened and it has good agreement with other published
articles.27
3.2. Catalytic behaviors of nano-Cu-MOF for the synthesis
tacrine derivatives
The multicomponent reaction of benzaldehyde, malononitrile,
2-hydroxy-1,4-naphthoquinone, and cyclohexanone under
different conditions were investigated to determine the optimal
conditions for tacrine synthesis. Various solvents such as
ethanol, H2O, dichloromethane, tetrachloroethylene (C2Cl4)
and 1,2-dichloroethane (EtCl2) were screened in the presence of
the various catalyst under an air atmosphere. As mentioned
before the most of the reported papers on synthesis of tacrine
derivatives from the pyranic intermediates, include two or more
stages which cause unfavorable higher reaction time and the
undesirable less efficiency,28 it is also clearly visible in Table 1
(Entry 1 and 2).
2.3. Preparation of nano catalyst Cu-MOF
The nano catalyst was synthesized with modication according
to the method described in previous articles.23 0.24 gram (1
mmol) of copper(II) nitrate trihydrate and 0.24 gram (1 mmol)
1,4-benzenedioic acid gradually dissolve in 20 mL N,N-dime-
thylformamide (DMF). The resulting mixture was then trans-
ferred into a 25 mL autoclave reactor and placed under 5 barr at
ꢁ
80 C for 4 hours. Aer cooling to the room temperature, the
precipitate was centrifuged and Cu-MOF turquoise powder was
obtained. To activate the catalyst and remove the DMF from the
cavities, Cu-MOF was put into Soxhlet extractor for 1 day with
dichloromethane as solvent.
In order to optimize the reaction conditions and increase the
yield, one step reaction was investigated by using triethylamine
and aluminum chloride which does not go further because of
undesired interaction between reagents (Entry 3). To overcome
this problem, we have used a heterogeneous catalyst, MOF nano
catalyst, in dichloroethane as solvent. Our research has revealed
that 4 mg catalyst per mmol of reagent has the best efficiency.
The optimum condition was achieved by the domino reaction
benzaldehyde, malononitrile, 2-hydroxy-1,4-naphthoquinone
and cyclohexanone in presence of 4 mg per mmol of Cu-MOF
and 1.2 mmol of aluminum chloride.
The point to consider is that the use of subterranean radia-
tion, as well as reacting in a reactor under pressure, can reduce
the synthesis time of MOF from 24 hours ꢁto 4 hours, as well as
ꢁ
lower the temperature from 100 C to 80 C than that of other
papers. The ICP-OES showed the Cu content in Cu-BDC struc-
ture was about 38.95%.
3. Results and discussion
3.1. Structural analysis of Cu-MOF nano catalyst
FT-IR is a main technique for determination of the functional
The elemental analyses, 1H, 13C NMR, FT-IR spectra and MS
groups in the structure of compounds. Therefore, the study of of the product clearly indicated the formation of 6a. The IR
FT-IR spectra is an accepted method among chemists to identify spectra of 6a exhibited nmax at 1631 cmꢀ1 for the carbonyl
materials.24,25 In Fig. 1, the FT-IR spectrum of Cu-MOF shows function and 3372 cm ꢀ1 and 3452 cmꢀ1 for NH2. The 1H NMR
clearly the removing DMF from Cu-MOF by washing with spectra of 6a showed the proton attached to spiro carbon and
dichloromethane. Comparison of the diagrams (A) and (B) proton attached to the nitrogen were resonated as a singlet at
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Fig. 1 FT-IR spectra of Cu-MOF (A) after activation, (B) before activation that present omitting DMF.
d 5.26 and 4.20 respectively. The 1H-decoupled 13C NMR spec-
Also, FT-IR spectra of the fresh and recycle Cu-MOF catalyst
trum of 6a showed 26 distinct resonances in agreement with the are in good agreement with each other (Fig. S2†).
proposed structure 6a, carbonyl groups carbon displayed 13C
resonance signal at d 182.2 and 176.7 ppm, respectively.
No leached copper was found in the solution. However, the
effect of the homogeneous catalyst was investigated by species
Aer the optimization of reaction conditions, it was gener- leached from the catalyst aer hot ltration, and as shown in
alized by different types of aromatic aldehydes and cyclo- Fig. S1,† it presented negligible activity in the ltered solution.
ketones. The domino one-pot synthesis of tacrine derivatives
was achieved from the reaction of various aromatic aldehydes,
Representative spectral data
14-Amino-13-phenyl-2,3,4,13-tetrahydro-1H-benzo[6,7]chro-
malononitrile, and 2-hydroxy-1,4-naphthoquinone in the pres- meno[2,3-b]quinoline-7,12-dione (6a). Yield 93 (%); yellow solid;
ꢁ
ence of Cu-MOF nano catalyst followed by the increase of mp ¼ 290–293 dec C; IR (KBr): 3464, 3376 (NH2), 1631, 1595
various ketones and aluminum chloride in short reaction time (C]O) cmꢀ1. 1H NMR (500 MHz, CDCl3) d ¼ 8.44–7.83 (m, 2H),
with high yield as shown in Table 2.
7.78–7.57 (m, 2H), 7.54–7.15 (m, 5H), 5.24 (s, 1H), 4.19 (s, 2H,
One advantage of using heterogeneous catalysts compared to NH2), 2.87–2.80 (m, 2H), 2.45–2.23 (m, 2H), 1.92–1.77 (m,
homogeneous catalysts is their ability to be recycled and reused 4H) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 182.2, 176.7, 154.0,
in chemical reactions, which has attracted particular attention. 152.8, 149.7, 149.2, 140.6, 133.0, 132.4, 130.7, 129.8 (2C), 127.9
(2C), 126.6, 125.4, 125.2, 121.5, 113.6, 97.6, 54.2, 34.9, 31.4, 21.9,
21.5, 21.2 ppm; MS (70 eV) m/z 408 [M+], 331, 105, 77; anal. calcd
for C26H20N2O3: C, 76.46; H, 4.94; N, 6.86. Found: C, 76.50; H,
3.3. Reusability of nano catalyst
The ability to the recovery of Cu-MOF catalyst was measured by
4.83; N, 6.91.
using aer 5 times and no signicant change in its catalytic
properties was observed. As shown in Fig. 4, the efficiency of the
fresh catalyst and the catalyst used have no main different.
14-Amino-13-(4-chlorophenyl)-2,3,4,13-tetrahydro-1H-benzo
[6,7]chromeno[2,3-b]quinoline-7,12-dione (6b). Yield 91 (%);
Scheme 2 Synthesis and activation of Cu-MOF.
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Fig. 2 pXRD pattern of Cu-MOF.
yellow solid; mp ¼ 290–291 dec ꢁC; IR (KBr): 3463, and 3376
(NH2), 1631, 1595 (C]O) cmꢀ1; 1H NMR (500 MHz, CDCl3) d ¼
8.15 (dd, J ¼ 4.0, 5.0 Hz, 1H), 7.98 (dd, J ¼ 4.0, 5.0 Hz, 1H), 7.70
(d, J ¼ 5.0 Hz, 1H), 7.69 (d, J ¼ 5.0 Hz, 1H), 7.38 (d, J ¼ 8.5 Hz,
2H), 7.23 (d, J ¼ 8.5 Hz, 2H), 5.27 (s, 1H), 4.31 (s, 2H, NH2), 2.82–
2.81 (m, 2H), 2.42–2.38 (m, 2H), 1.88–1.81 (m, 4H) ppm; 13C
NMR (125 MHz, CDCl3) d ¼ 182.3, 176.8, 154.2, 152.7, 149.8,
149.4, 139.2, 133.2, 132.6, 132.5, 130.6, 129.8, 129.2, 128.1,
125.6, 125.3, 121.2, 113.8, 97.0, 34.3, 31.5, 22.0, 21.5, 21.2 ppm;
MS (70 eV) m/z 442 [M+], 331, 105, 77; anal. calcd for
14-Amino-13-(thiophen-2-yl)-2,3,4,13-tetrahydro-1H-benzo[6,7]
chromeno[2,3-b]quinoline-7,12-dione (6e). Yield 55 (%); brown
solid; mp ¼ 269–271 dec ꢁC; IR (KBr) ¼ 3472, 3378 (NH2), 1734,
1678, 1635, 1594 cmꢀ1. 1H NMR (500 MHz, DMSO-d6) d ¼ 8.11–
8.04 (m, 1H), 8.03–7.97 (m, 1H), 7.92–7.66 (m, 2H), 7.27 (d, J ¼
5 Hz, 1H), 7.0 (d, J ¼ 3.5 Hz, 1H), 6.86 (dd, J ¼ 5.1, 3.6 Hz, 1H),
6.03 (s, 2H, NH2), 5.84 (s, 1H), 2.61 (d, J ¼ 5.5 Hz, 2H), 2.46–2.13
(m, 2H), 1.34–0.97 (m, 2H) ppm; 13C NMR (125 MHz, DMSO-d6)
d ¼ 182.0, 177.3, 152.7, 152.4, 151.2, 149.7, 145.5, 134.0, 133.4,
130.6, 130.0, 126.0, 125.5, 125.5, 125.3, 124.5, 121.8, 113.2, 96.7,
31.4, 28.4, 22.5, 21.7, 21.4 ppm; MS (70 eV) m/z 414 [M+], 331,
105, 77; anal. calcd for C24H18N2O3S: C, 69.55; H, 4.38; N, 6.76;
S, 7.74. Found: C, 69.50; H, 4.32; N, 6.84; S, 7.79.
13-Amino-12-(p-tolyl)-1,2,3,12-tetrahydrobenzo[6,7]chromeno
[2,3-b]cyclopenta[e]pyridine-6,11-dione (6f). Yield 92 (%); yellow
solid; mp ¼ 300–302 dec ꢁC; IR (KBr) ¼ 3445, 3355 (NH2), 1731,
1644, 1582 cmꢀ1. 1H NMR (500 MHz, CDCl3) d ¼ 8.27–7.92 (m,
2H), 7.76–7.59 (m, 2H), 7.34 (d, J ¼ 8.0 Hz, 2H), 7.11 (d, J ¼
7.8 Hz, 2H), 5.25 (s, 1H), 4.18 (s, 2H, NH2), 2.96 (hept, J ¼ 8.2,
C
26H19ClN2O3: C, 70.51; H, 4.32; N, 6.33. Found: 70.43; H,
4.45; N, 6.38.
14-Amino-13-(3-methoxyphenyl)-2,3,4,13-tetrahydro-1H-benzo
[6,7]chromeno[2,3-b]quinoline-7,12-dione (6c). Yield 89 (%);
yellow solid; mp ¼ 270–271 dec ꢁC; IR (KBr): 3472, 3375
1
(NH2),1682, 1634, 1594 cmꢀ1. H NMR (500 MHz, CDCl3) d ¼
8.17 (dd, J ¼ 5.8, 3.3 Hz, 1H), 8.03 (dt, J ¼ 7.3, 3.8 Hz, 1H), 7.70
(dt, J ¼ 7.1, 3.6 Hz, 2H), 7.23 (t, J ¼ 7.9 Hz, 2H), 7.07 (d, J ¼
7.6 Hz, 1H), 6.99 (t, J ¼ 2.2 Hz, 1H), 6.76 (dd, J ¼ 8.3, 2.6 Hz, 1H),
5.23 (s, 1H), 4.21 (s, 2H, NH2), 3.76 (s, 3H, OMe), 2.84 (s, 2H),
2.49–2.20 (m, 2H), 1.86 (s, 4H); 13C NMR (125 MHz, CDCl3) d ¼
182.2, 161.2, 159.0, 154.2, 152.6, 149.8, 142.3, 133.0, 132.5,
130.7, 129.9, 128.9, 125.5, 125.3 (2C), 120.3 (2C), 114.0, 113.9,
113.66, 111.7, 54.2, 35.0, 31.4, 21.9, 21.4, 21.2 ppm; MS (70 eV)
m/z 438 [M+], 331, 92, 77; anal. calcd for C27H22N2O4: C, 73.96;
H, 5.06; N, 6.39. Found: C, 73.89; H, 5.15; N, 6.33.
14-Amino-13-(p-tolyl)-2,3,4,13-tetrahydro-1H-benzo[6,7]chro-
meno[2,3-b]quinoline-7,12-dione (6d). Yield 90 (%); yellow solid;
mp ¼ 242–245 dec ꢁC; IR (KBr) ¼ 3472, 3375 (NH2), 1734, 1635,
1
1594 cmꢀ1. H NMR (500 MHz, CDCl3) d ¼ 8.39–7.94 (m, 2H),
7.81–7.54 (m, 2H), 7.41–7.30 (m, 2H), 7.11 (d, J ¼ 7.9 Hz, 2H),
5.25 (s, 1H), 4.20 (s, 2H, NH2), 2.97 (h, J ¼ 9.2 Hz, 2H), 2.79–2.50
(m, 2H), 2.28 (s, 3H, Me), 2.21–2.09 (m, 2H), 2.07 (s, 1H), 1.28 (t,
J ¼ 7.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 182.4,
177.0, 162.0, 155.0, 149.2, 147.8, 137.9, 136.5, 133.0, 132.5,
130.7, 129.8, 128.6 (2C), 127.7 (2C), 125.5, 125.3, 121.6, 118.3,
98.2, 33.3, 33.2, 26.0, 21.2, 20.0, 13.1 ppm; MS (70 eV) m/z 442
[M+], 331, 105, 91; anal. calcd for C27H22N2O3: C, 76.76; H,
5.25; N, 6.63. Found: C, 76.70; H, 5.19; N, 6.70.
Fig. 3 SEM image of cubic structure of Cu-MOF.
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Table 1 One-pot domino reaction between 2-hydroxy-1,4-naphthoquinone (1 mmol), benzaldehyde (1 mmol), malononitrile (1 mmol) and
cyclohexanone (1 mmol) under various conditions
Entry
Solvent (conditions)a
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
EtOH (reux)
H2O (reux)
EtOH (reux)
EtOH (reux)
EtOH (reux)
EtOH (reux)
EtCl2 (reux)
CH2Cl2 (reux)
C2Cl4 (reux)
CH2Cl2 (US)c
EtCl2 (reux)
ꢀ(120 ꢁC)
NEt3 (5 mol%)/AlCl3 (2 step)
NEt3 (5 mol%) AlCl3 (2 step)
NEt3 (5 mol%) AlCl3
Ni-MOF (3 mg)/AlCl3
Al-MOF
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
Cu-MOF (3 mg)/AlCl3
CuAl-MOF
12
24
24
12
12
24
5
67
Trace
—
30
20
50
88
40
—
Trace
30
Trace
40
93
93
5
9
24
12
30
20
12
5
10
11
12
13
14
15
16
EtOH (reux)
EtCl2 (reux)
EtCl2 (reux)
EtCl2 (reux)
Cu-MOF (4 mg)/AlCl3
Cu-MOF (5 mg)/AlCl3
Cu-MOF (2 mg)/AlCl3
5
5
73
a
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), 2-hydroxy-1,4-naphthoquinone (1 mmol) and cyclohexanone (1.2 mmol).
Isolated yields. c Ultrasound at 80% amplitude and was sonicated for 10 min.
b
7.3 Hz, 2H), 2.81–2.48 (m, 2H), 2.28 (s, 3H), 2.07 (s, 1H), 1.28 (t, J 2.61 (m, 2H), 2.45–2.14 (m, 2H), 1.88–1.65 (m, 4H) ppm; 13C
¼ 7.1 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 182.4, 162.0, NMR (125 MHz, CDCl3) d ¼ 182.1, 176.8, 153.8, 152.4, 150.1,
155.0, 149.1, 147.8, 137.9, 136.4, 133.0, 132.5, 130.7, 129.8, 149.8, 138.9, 133.2, 132.5, 130.4, 130.5, 130.2, 129.8, 128.5,
128.7, 127.7, 125.5, 125.2, 121.5, 118.2, 98.1, 34.5, 33.2, 26.1, 127.8, 127.0, 125.6, 125.3, 121.4, 113.3, 97.1, 31.7, 31.3, 22.0,
21.2, 20.0, 13.1 ppm; MS (70 eV) m/z 408 [M+], 317, 91, 77; anal. 21.4, 21.2 ppm; MS (70 eV) m/z 442 [M+], 407, 331, 105; anal.
calcd for C26H20N2O3: C, 76.46; H, 4.94; N, 6.86. Found: C, 76.50; calcd for C26H19ClN2O3: C, 70.51; H, 4.32; N, 6.33. Found: C,
H, 4.82; N, 6.92.
70.48; H, 4.31; N, 6.40.
13-Amino-14-(p-tolyl)-8,9,10,11,12,14-hexahydrobenzo[6,7]
14-Amino-13-phenyl-4,13-dihydro-1H,3H-benzo[6,7]chromeno
chromeno[2,3-b]cyclohepta[e]pyridine-5,15-dione (6g). Yield 50 [2,3-b]thiopyrano[3,4-e]pyridine-7,12-dione (6i). Yield 82 (%);
(%); brownish solid; mp ¼ 263–266 dec ꢁC; IR (KBr) ¼ 3465, yellow solid; mp ¼ 270–273 dec ꢁC; IR (KBr) ¼ 3451, 3376 (NH2),
1
1
3378 (NH2), 1641, 1599 cmꢀ1. H NMR (500 MHz, CDCl3) d ¼ 1657, 1595 cmꢀ1. H NMR (500 MHz, DMSO-d6) d ¼ 8.07–8.00
8.14 (s, 1H), 7.99 (s, 1H), 7.67 (s, 2H), 7.33 (d, J ¼ 7.9 Hz, 2H), 7.0 (m, 1H), 7.93 (d, J ¼ 4.8 Hz, 1H), 7.85–7.77 (m, 2H), 7.57–7.46
(d, J ¼ 8.5 Hz, 2H), 5.21 (s, 1H), 4.25 (s, 2H, NH2), 2.81 (s, 2H), (m, 2H), 7.30–6.9 (m, 5H), 5.54 (s, 1H), 3.64–3.53 (m, 1H), 3.40
2.30–2.12 (m, 4H), 1.9–1.4 (m, 5H), 1.26 (d, J ¼ 7.8 Hz, 2H) ppm; (d, J ¼ 16.2 Hz, 1H), 3.00 (q, J ¼ 6.2 Hz, 2H), 2.88 (d, J ¼ 6.1 Hz,
13C NMR (125 MHz, CDCl3) d ¼ 182.4, 176.8, 161.6, 158.7, 153.8, 2H) ppm; 13C NMR (125 MHz, DMSO-d6) d ¼ 181.7, 176.1, 152.9,
149.8, 137.8, 136.4, 133.0, 132.4, 130.7, 129.8, 128.6 (2C), 127.7 150.7, 148.6, 148.3, 148.3, 140.8, 134.1, 133.7, 130.3, 129.9, 128.2
(2C), 125.5, 125.2, 121.6, 113.6, 97.7, 34.5, 31.4, 21.9, 21.5, 21.2, (2C), 128.1, 127.8 (2C), 126.7, 125.5, 125.4, 122.7, 111.8, 32.6,
20.0, 13.1 ppm; MS (70 eV) m/z 436 [M+], 421, 345, 91; anal. calcd 30.4, 23.0, 22.6 ppm; MS (70 eV) m/z 426 [M+], 349, 315, 303;
for C28H24N2O3: C, 77.04; H, 5.54; N, 6.42. Found: C, 77.02; H, anal. calcd for C25H18N2O3S: C, 70.41; H, 4.25; N, 6.57; S, 7.52.
5.59; N, 6.49.
Found: C, 70.40; H, 4.23; N, 6.63; S, 7.61.
14-Amino-13-(2-chlorophenyl)-2,3,4,13-tetrahydro-1H-benzo
14-Amino-13-(4-nitrophenyl)-4,13-dihydro-1H,3H-benzo[6,7]
[6,7]chromeno[2,3-b]quinoline-7,12-dione (6h). Yield 70 (%); chromeno[2,3-b]thiopyrano[3,4-e]pyridine-7,12-dione (6j). Yield 78
ꢁ
yellow solid; mp ¼ 274–277 dec ꢁC; IR (KBr) ¼ 3451, 3383 (NH2), (%); yellow solid; mp ¼ 284–286 dec C; IR (KBr) ¼ 3490, 3360
1636, 1597 cmꢀ1. 1H NMR (500 MHz, CDCl3) d ¼ 8.26–8.09 (m, (NH2), 1637, 1592 cmꢀ1. 1H NMR (500 MHz, DMSO-d6) d ¼ 8.10
1H), 8.09–7.92 (m, 1H), 7.79–7.61 (m, 2H), 7.44–7.32 (m, 1H), (d, J ¼ 8.3 Hz, 2H), 8.08–8.02 (m, 1H), 7.96–7.90 (m, 1H), 7.86–
7.15 (tt, J ¼ 7.4, 5.4 Hz, 2H), 5.63 (s, 1H), 4.54 (s, 2H, NH2), 2.96– 7.79 (m, 2H), 7.77 (d, J ¼ 8.2 Hz, 2H), 6.19 (s, 2H, NH2), 5.69 (s,
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Table 2 One-pot, four-component synthesis of new tacrine derivatives in the presence of Cu-MOF and AlCl3 in 1,2-dichloroethane under reflux
conditions
Entry
1
Aldehyde
Cycloketone
Yield (%)
95
Time (h)
5
Product
Mp (ꢁC)
6a
Dec: 290–293
2
3
4
5
6
91
89
90
55
92
3.25
6b
6c
6d
6e
6f
Dec: 290–291
Dec: 270–271
Dec: 242–245
Dec: 269–271
Dec: 300–302
3
3.35
6
2.5
7
50
4.5
6g
Dec: 263–266
8
9
70
82
3.5
4
6h
6i
Dec: 274–277
Dec: 270–273
10
11
78
90
5
6j
Dec: 284–286
Dec: 250–253
4.5
6k
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Fig. 4 The recycling of Cu-MOF as catalysts using a model reaction of 2-hydroxynaphthalene-1,4-dione, benzaldehyde, malononitrile following
by adding cyclohexanone and AlCl3.
1H), 3.57 (d, J ¼ 16.3 Hz, 1H), 3.38 (d, J ¼ 16.0 Hz, 1H), 2.94 (q, J scope. The heterogeneous nanocatalyst Cu-MOF presented
¼ 6.0, 5.4 Hz, 2H), 2.85 (h, J ¼ 8.2, 7.3 Hz, 2H) ppm; 13C NMR excellent catalytic performance and can be recycled simply by
(125 MHz, DMSO-d6) d ¼ 182.0, 177.0, 152.7, 152.0, 150.7, 150.1, centrifuging; it can also recover 5 times without considerable
149.2, 145.7, 133.9, 133.4, 130.5, 130.0, 129.5 (2C), 125.5, 125.2, loss of efficiency.
122.7 (2C), 121.0, 111.9, 96.8, 33.3, 32.9, 24.0, 22.9 ppm; MS (70
We expect this method to be performed easily by pharma-
eV) m/z 471 [M+], 349, 315, 303; anal. calcd for C25H17N3O5S: C, cists and chemists and biologically active tacrine derivatives
63.69; H, 3.63; N, 8.91; S, 6.80. Found: C, 63.60; H, 3.68; N, 8.88; that were synthesized over several stages can be easily synthe-
S, 6.76.
14-Amino-13-(4-chlorophenyl)-4,13-dihydro-1H,3H-benzo[6,7]
sized without the need to separate intermediates and purify
them.
chromeno[2,3-b]thiopyrano[3,4-e]pyridine-7,12-dione (6k). Yield
90 (%); yellow solid; mp ¼ 250–253 dec ꢁC; IR (KBr) ¼ 3450, 3345
(NH2), 1665, 1595 cmꢀ1. 1H NMR (500 MHz, DMSO-d6) d ¼ 8.13–
8.01 (m, 1H), 8.00–7.91 (m, 1H), 7.85 (t, J ¼ 4.6 Hz, 2H), 7.55 (d, J
¼ 8.1 Hz, 2H), 7.32 (d, J ¼ 8.1 Hz, 2H), 7.09 (s, 2H, NH2), 5.59 (s,
1H), 3.60 (d, J ¼ 16.3 Hz, 1H), 3.40 (d, J ¼ 16.2 Hz, 1H), 3.08–2.81
(m, 4H) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 182.8, 176.5,
152.9, 150.7, 148.8, 139.7, 134.1, 133.6, 131.4, 130.5, 130.2 (2C),
130.0, 127.7 (2C), 125.5, 125.4, 122.0, 112.0, 97.5, 32.1, 30.5,
23.1, 22.6 ppm; MS (70 eV) m/z 460 [M+], 349, 315, 303; anal.
calcd for C25H17ClN2O3S: C, 65.15; H, 3.72; 6.08; S, 6.96. Found:
C, 65.10; H, 3.83; 6.18; S, 6.90.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We would like to thank the Research Council at CCERCI
Foundation for the nancial support of this work. The authors
of this article also express their gratitude and appreciation for
the efforts made by Tarbiat Modares University in catalyst
synthesis.
4. Conclusion
References
In conclusion, we have effectively developed and expanded
simple and straightforward procedure for one-pot synthesis of
tacrine derivatives. One-pot, domino four-component reaction
of aldehydes, malononitrile, 2-hydroxy-1,4-naphthoquinone,
and cycloketones was carried out in the presence of Cu-MOF
and aluminum chloride. Without the requirement to isolate
the pyranic intermediate and in a single container, the reaction
was conducted under reux to give the desired products in high
yields. Prominent features of the current procedure include
a step-economic increasing yield, economic feasibility, capa-
bility of recycling the catalyst and covering a broad substrate
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