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P
E Cu-metal
R organic
frameworks
(Cu-MOF) as
Cite an
this:
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Adv.,
2020,
friendly and
10,
1995
economical
catalyst for
one pot
synthesis
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on 10/17/2025

tacrine
derivatives†
bution 3.0 Unported Licence

Hoda
Mollabagher, a

Receiv Salman Taheri,

ed 3rd *a Mohammad
Decem
ber majid Mojtahedi
2019 a
and
Accept
SeyedAmirhossein
ed 2nd
Seyedmousavib
Januar

y 2020 The present work describes

the catalytic activity of Cu-
DOI:
MOF for the one-pot
10.103 synthesis of tacrine
nder a derivatives via a four-
9/c9ra
component reaction of 2-
10111j hydroxynaphthalene-1,4-
rsc.li/rs
dione, aldehydes,
malononitrile and
c- cycloketones in the presence
advanc of AlCl3. The structure of the
synthesized compound is
es
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

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scope, need to use column

high chromatography for
yields purifying products so, it has
up to the potential for large-scale
93%, applications in
atom pharmaceutical industries.
econo Another advantage of this
my, method is the ability to
using recycle the catalyst up to 3
readil times and reuse it.
y
availa
ble transmits
startin the
g message
mater between
ials the two
and a nerve
power
cells and
ful
then
recycl
able
decompos
nano es with
cataly cholineste
st. rase. In
Additi AD
onally, reducing
there the
is no acetylcho-
According to the Acetylcholine is
World Health one of the
Organization, substances that
over 30 million line disrupts the
people transmission of
worldwide suffer messages
from Alzheimer's between the two
disease (AD), nerve cells.2
and research has Therefore, many
shown that this studies have
number is rising
substantially.1 AD
is actually a type
of brain
dysfunction that
gradually
degrades the
mental abilities
of the patient and been done to
leads to memory strengthen the
impairment and cholinesterase
dementia. system includes
Among the listed compounds, tacrine is one of the drugs that
boost acetylcholine by inhibiting cholinesterase enzymes3 and is
a
Chemistry and Chemical Engineering Research Center of Iran, PO Box 14115-186, Tehran,
known as an important reference with amazing pharmacological
Iran. E-mail: [email protected]
properties. It was rst identied in 1993 as a drug for the treatment of
b
Process Engineering Department, Faculty of Chemical Engineering, Tarbiat Modares
AD.4 Studying of tacrine analogues is still of interest to researchers
University, Tehran, Iran
investigating AD. As a result, several
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10111j

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acetylcholine to improve
release agents reaction time.10
such as 4- However, the
aminopyridine main problem
(1), and with their work
anticholinesteras refers to
e drugs, such as microwave
physostigmine irradiation that
(2) and microwave
acetylcholinester energy absorbing
ase inhibitors is possible only
like tacrine to a limited
(3) and 4- thickness of
aminoquinoline materials and can
(4). be changed due
methods have to material
been investigated absorption and is
for the synthesis not easy and
of tacrine and precisely
their analogues. applicable for
Recently, industrial
synthesis of production.11
tacrine analogues Several
with modern reports have been
strategies made to design
including high tacrine
efficiency and analogues,
short time is a including the
great interest of replacement or
chemists and hetero-annulated
pharmacists.5,6 of the benzene
Synthesis of ring with the
tacrine analogues heterocyclic
was mostly systems. The
reported in the presence of
presence of a aromatic or
Lewis acid such heteroaromatic
as AlCl3,7 ZnCl2,8 rings in the
BF3/Et2O,9 silica tacrine scaffolds
gel/p- results in
toluenesulfonic additional p–p
acid.10 interaction in the
Khalilzadeh and structure and
coworkers have
reported new pharmacophoric
method for the moiety that can
preparation of be used for the
tacrine analogues design of new
via applying AChE
microwave inhibitors.12
irradiation by Polyfunctiona
using silica lized 2-amino-3-
gel/p- cyano-4H-pyrans
toluenesulfonic are wellknown
acid as a catalyst compounds that

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ons Attribution 3.0 Unported
reactivity has to the widespread
been extensively development of
investigated and heterogenous
used as catalysis, which
intermediates in allows the
the tacrine researcher to
synthesis. In this reduce the steps
way, it is of the
prepared from reactions.14–17
Friedl¨ander Heterogeneou
annulation s catalysts have
censed involving the also many other
condensation of advantages such
2-amino-3- as easily
cyano-4H-pyrans isolation from
with carbonyl the mixture of
compound that the reaction, be
contains reactive recyclable and
a-methylene less
group.7 All contamination in
reported tacrine nal product.18
synthesis Metal organic
procedures from frameworks
pyranic (MOFs) attracted
intermediate, the attention of
were contained
the scientic
two or more
community
steps.13
around 1990 (ref.
One-pot 19) and then it
synthesis of has been
materials is a effectively used
simple, facile and as heterogeneous
effective method catalysis
in synthetic improving
chemistry. efficiency and
Minimizing the selectivity of
number of steps one-pot
in the synthesis reactions. The
procedure in specic porous
order to obtain structure of MOF
target containing
compounds is of organic and
great interest in inorganic active
the production of sites is a useful
chemical and
and effective
pharmaceutical
alternative to
compounds. The
heterogeneous
requirement for
catalysts.
the rapid and
In recent
selective
years, MOFs are
structure of
highlighted due
biologically
to its
active materials
bicompositional
for drug
nature contains
discovery has led
metallic ions and

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organic ligands pyranic

together in one intermediate
complex. which should be
Organic ligands separated and
and metallic ions puried for the
could be changed next step of the
to achieve reaction (Scheme
different 1).21,22
efficiencies and
Our work has
yields. Also, the
presented a novel
high porosity of
procedure to the
these structures
synthesis of
has made them a
tacrine
powerful nano-
derivatives,
reactor for
starting from
chemical
aldehyde,
reactions.20
malononitrile,
According to the
2hydroxynaphtha
above, the
lene-1,4-dione
exibility, and cycloketone
physical, derivative as
chemical, one-pot reaction
biological without the
properties of requirement for
these compounds separating the
can be very pyranic
diverse and intermediate.
unique. Applying the Cu-
Among this MOF as
kind of materials heterogeneous
copper-based catalyst
MOFs used as assistances the
heterogeneous formation of
acid in the pyranic
synthesis of the intermediates,
organic followed by the
compound. Due addition of
to the catalytic aluminum
behavior of chloride to the
MOFs, they have Friedl¨ander
been used in quinoline
various reactions reaction, without
including the interfering with
oxidation of the two catalysts
benzoquinones, in the reaction
cyanosilylation process. The
of aldehydes, and presence of Cu
Knoevenagel active sites in
condensations. Cu-MOF has
Up to now made it a suitable
most of the candidate for the
reported synthesis of
procedures for pyrene
tacrine synthesis compounds. We
go through describe

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convenient NMR and 13C

synthesis NMR
methods tacrine were run
derivatives from on an
the simple FT-NMR
starting material. Bruker
UltraShield™
(500 MHz) in

2. Experi DMSO-d CDCl3 as

6 and
a
menta solvent and the
chemical shis
l are expressed as
2.1. Chemicals
d units with
and apparatus tetramethylsilane
All starting (TMS) as
materials were internal standard.
purchased from Mass spectra
Sigma-Aldrich were obtained on
and Merck an Agilent
companies and Technologies
used without apparatus at
additional ionization
purication. potential of 70
Reactions were eV. The
monitored by concentration of
aluminum TLC copper in the
plate, silica gel prepared
coated with catalysts was
uorescent determined using
indicator F254. inductively
Melting points coupled plasma
were measured optical emission
using a Buchi B- spectroscopy by
545 apparatus SPECTRO
through the ARCOS ICP-
capillary tube OES
method and spectrometer.
reported without
any correction. 2.2.
IR spectra were procedure for
recorded from the preparation
KBr disks using of compounds
FT-IR Bruker 6a–k
Vector-22
A mixture of 2-
infrared
hydroxy-1,4-
spectrometer in
naphthoquinone
the range of 400–
1 (0.174 g, 1.0
4000 cm1. The
1
mmol), aromatic
H

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Scheme 1 Synthesis of tacrine derivatives from pyranic intermediate.

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aldehyde 2 (1.0 organic layer was

mmol), dried over
malononitrile 3 MgSO4. In the
(0.06 g, 1.0 end, the crude is
mmol), and crystallization by
catalytically ethyl acetate to
amount of Cu- obtain the pure
MOF (0.02 g) in product.
dry 1,2-
dichloroethane 2.3.
(DCE) (5.0 mL) of nano catalyst
was stirred under Cu-MOF
reux condition
The nano catalyst
until completion
was synthesized
reaction and
with modication
disappearance of
according to the
the starting
method
materials on TLC
described in
(EtOAc : n-
previous
hexane 1 : 1).
articles.23 0.24
Then, AlCl3
gram (1 mmol)
(0.1995 g, 1.5
of copper(II)
mmol) and
nitrate trihydrate
cycloketone 5
and 0.24 gram (1
(1.5 mmol) were
mmol) 1,4-
added into the
benzenedioic
mixture of the
acid gradually
reaction. The
dissolve in 20
mixture was
mL N,N-
continuously
dimethylformami
stirred under
de (DMF). The
argon
resulting mixture
atmosphere
was then
under reux.
transferred into a
Aer completion, 25 mL autoclave
the mixture was reactor and
centrifuged to placed under 5
isolated catalyst barr at 80 C for 4
and then the hours. Aer
solvent was
cooling to the
evaporated under
room
reduced pressure,
temperature, the
H2O and THF
precipitate was
(1 : 1) were
centrifuged and
added and the
Cu-MOF
mixture was
turquoise powder
basied with was obtained. To
10% sodium activate the
hydroxide catalyst and
solution to pH ¼ remove the DMF
8–9. Aer from the cavities,
stirring for 30 Cu-MOF was put
min, the mixture into Soxhlet
was diluted using extractor for 1
CH2Cl2 and the day with

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ons Attribution 3.0 Unported
dichloromethane from Cu-MOF
as solvent. by washing with
The point to dichloromethane.
consider is that Comparison of
the use of the diagrams (A)
subterranean and (B) denotes
radiation, as well the deletion of
as reacting in a the peak
reactor under associated with
pressure, can the DMF methyl
reduce the groups in region
censed synthesis time of 2936. Remove
MOF from 24 peak in region
hours to 4 hours, 3486, indicates a
as well as lower withdrawal of
the temperature water and
from 100 C to 80 carboxylic acid
C than that of present in the
other papers. The cavity, aer the
ICP-OES showed activation of the
the Cu content in catalyst.
Cu-BDC According to
structure was the reported
about 38.95%. literature,26 the
Cu-MOF
structure releases
3. Result DMF molecules
during the
s and activation
discus process, and has
active copper
sion sites (Scheme 2).
3.1. The powder
analysis of Cu- XRD pattern of
MOF nano the Cu-MOF
catalyst compound
FT-IR is a main clearly indicates
technique for the presence of
determination of copper in its
the functional structure and the
groups in the sharp peak
structure of appearing in less
compounds. than 15 indicates
Therefore, the a highly
study of FT-IR crystalline
spectra is an structure (Fig. 2).
accepted method According to the
among chemists XRD spectra, the
to identify average size of
materials.24,25 In the crystals (D)
Fig. 1, the FT-IR was 52 nm using
spectrum of Cu- the Scherrer
MOF shows equation (1) by
clearly the replacing l as the
removing DMF wavelength of
the X-ray beam,

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b1/2 as the line investigated to

broadening at determine the
half the optimal
maximum conditions for
intensity and q as tacrine synthesis.
the Bragg's Various solvents
angle. such as ethanol,
H2O,
0:9l
dichloromethane,
D¼
tetrachloroethyle
ne (C2Cl4) and
1,2-
dichloroethane
(EtCl2) were
screened in the
presence of the
various catalyst
SEM under an air
techniques can atmosphere. As
be used to obtain mentioned before
the surface, the most of the
shape, and reported papers
appearance of on synthesis of
particles. As it tacrine
clear in Fig. 3, derivatives from
the cubic the pyranic
CuMOF structure intermediates,
that was include two or
synthesis under more stages
pressure is which cause
welldened and unfavorable
it has good higher reaction
agreement with time and the
other published undesirable less
articles. 27 efficiency,28 it is
also clearly
visible in Table 1
3.2. (Entry 1 and 2).
Catalytic In order to
behaviors of optimize the
nano-Cu-MOF reaction
for the synthesis conditions and
tacrine increase the
derivatives yield, one step
reaction was
The investigated by
multicomponent using
reaction of triethylamine and
benzaldehyde, aluminum
malononitrile, 2- chloride which
hydroxy-1,4- does not go
naphthoquinone, further because
and of undesired
cyclohexanone interaction
under different between reagents
conditions were (Entry 3). To

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overcome this 6a. The IR

problem, we spectra of 6a
have used a exhibited nmax at
heterogeneous 1631 cm1 for the
catalyst, MOF carbonyl function
nano catalyst, in and 3372 cm 1
dichloroethane as and 3452 cm1 for
solvent. Our NH2. The 1H
research has NMR spectra of
revealed that 4 6a showed the
mg catalyst per proton attached
mmol of reagent to spiro carbon
has the best and proton
efficiency. The attached to the
optimum nitrogen were
condition was resonated as a
achieved by the singlet at d 5.26
domino reaction and 4.20
benzaldehyde, respectively. The
malononitrile, 2- 1H-decoupled
hydroxy-1,4- 13
C NMR
naphthoquinone spectrum of 6a
and showed 26
cyclohexanone in distinct
presence of 4 mg resonances in
per mmol of Cu- agreement with
MOF and 1.2 the proposed
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structure 6a,
aluminum carbonyl groups
Creative Commons
chloride.Attribution 3.0carbon
Unported
displayed
The elemental 13C resonance
analyses, 1H, 13C signal at d 182.2
NMR, FT-IR and 176.7 ppm,
spectra and MS respectively.
of the product Aer the

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Fig. 1 FT-IR spectra of Cu-MOF (A) after activation, (B) before activation that present omitting DMF.
clearly indicated optimization of
the formation of reaction

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conditions, it was change in its

generalized by catalytic
different types of properties was
aromatic observed. As
aldehydes and shown in Fig. 4,
cycloketones. the efficiency of
The domino one- the fresh catalyst
pot synthesis of and the catalyst
tacrine used have no
derivatives was main different.
achieved from Also, FT-IR
the reaction of spectra of the
various aromatic fresh and recycle
aldehydes, Cu-MOF catalyst
malononitrile, are in good
and 2-hydroxy- agreement with
1,4- each other (Fig.
naphthoquinone S2†).
in the presence of No leached
Cu-MOF nano copper was
catalyst followed found in the
by the increase of solution.
various ketones However, the
and aluminum effect of the
chloride in short homogeneous
reaction time catalyst was
with high yield investigated by
as shown in species leached
Table 2. from the catalyst
One aer hot
advantage of ltration, and as
using shown in Fig.
heterogeneous
S1,† it presented
catalysts
negligible
compared to
activity in the
homogeneous
ltered solution.
catalysts is their
Representativ
ability to be
e spectral
recycled and
data
reused in
14-Amino-13-
chemical
reactions, which phenyl-2,3,4,13-
has attracted tetrahydro-1H-
particular benzo[6,7]chrom
attention.
eno[2,3-
b]quinoline-7,12-
3.3. Reusability of
nano catalyst dione (6a). Yield
93 (%); yellow
The ability to the
recovery of Cu- solid; mp ¼ 290–
MOF catalyst 293 dec C; IR
was measured by
(KBr): 3464,
using aer 5
times and no 3376 (NH 2),

signicant 1631, 1595

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(C]O) cm1. 1
H 4.94; N, 6.86.
NMR (500 MHz,
CDCl3) d¼ 8.44–
7.83 (m, 2H),
7.78–7.57 (m,
2H), 7.54–7.15
(m, 5H), 5.24 (s,
1H), 4.19 (s, 2H,
NH2), 2.87–2.80
(m, 2H), 2.45–
2.23 (m, 2H),
1.92–1.77 (m,
13 Found: C, 76.50;
4H) ppm; C

Synthesis
Scheme 2Open Access and activation
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onCu-MOF.
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NMR (125 MHz, H,
CDCl3) ¼ Commons
Creative
d 4.83; N,Attribution
6.91. 3.0 Unported
182.2, 176.7, 14-Amino-13-
(4-
154.0, 152.8,
chlorophenyl)
149.7, 149.2, -2,3,4,13-
140.6, 133.0, tetrahydro-
132.4, 130.7, 1H-benzo
[6,7]chromeno[2,
129.8 (2C), 127.9
3-b]quinoline-
(2C), 126.6, 7,12-dione
125.4, 125.2, Yield
121.5, 113.6, (%);
This article is licensed
Fig. 2 pXRD pattern
97.6, 54.2, 34.9,
of Cu-MOF.
31.4, 21.9, 21.5,
21.2 ppm; MS
(70 eV) m/z 408 yellow solid; mp
+
[M ], 331, 105, ¼ 290–291 dec
77; anal. calcd
C; IR (KBr):
for C26H20N2O3:
3463, and 3376
C, 76.46; H,

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(NH2), 1631, MS (70 eV)

m/z 442
1595 (C]O) cm1;
[M+], 331,
1
H NMR (500 105, 77;
anal.calcd
MHz, CDCl3) d¼
for
8.15 (dd, J ¼ 4.0, C26H19ClN2O3: C,
5.0 Hz, 1H), 7.98 70.51; H, 4.32;
N, 6.33. Found:
(dd, J ¼ 4.0, 5.0 70.43; H,
Hz, 1H), 7.70 (d, 4.45; N, 6.38.
14-Amino-13-
J ¼ 5.0 Hz, 1H),
(3-
7.69 (d, J ¼ 5.0
methoxyphenyl)-
Hz, 1H), 7.38 (d,
2,3,4,13-
J ¼ 8.5 Hz, 2H), tetrahydro-1H-
7.23 (d, J ¼ 8.5 benzo
Hz, 2H), 5.27 (s, [6,7]chromeno[2,
1H), 4.31 (s, 2H, 3-b]quinoline-
NH2), 2.82– 2.81 7,12-dione (6c).

(m, 2H), 2.42– Yield 89 (%);

2.38 (m, 2H), yellow solid; mp

¼ 270–271 dec
1.88–1.81 (m,
13 C; IR (KBr):
4H) ppm; C
3472, 3375
NMR (125 MHz,
(NH2),1682,
CDCl3) d ¼
1634, 1594 cm1.
182.3, 176.8, 1
H NMR (500
154.2, 152.7,
MHz, CDCl3) d
149.8, 149.4,
¼ 8.17 (dd, J ¼
139.2, 133.2,
5.8, 3.3 Hz, 1H),
132.6, 132.5,
8.03 (dt, J ¼ 7.3,
130.6, 129.8,
3.8 Hz, 1H), 7.70
129.2, 128.1,
(dt, J ¼ 7.1, 3.6
125.6, 125.3, Hz, 2H), 7.23 (t,
121.2, 113.8, J ¼ 7.9 Hz, 2H),
97.0, 34.3, 31.5, 7.07 (d, J ¼
22.0, 21.5, 21.2
7.6 Hz, 1H), 6.99
ppm; (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),

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3.76 (s, 3H, CDCl3) d ¼ 8.39–

OMe), 2.84 (s, 7.94 (m, 2H),
2H),
2.49–2.20 (m, 7.81–7.54 (m,
2H), 1.86 (s, 2H), 7.41–7.30
13
4H); C NMR (m, 2H), 7.11 (d,
(125 MHz,
J ¼ 7.9 Hz, 2H),
CDCl3) d¼
5.25 (s, 1H), 4.20
182.2, 161.2,
159.0, 154.2, (s, 2H, NH2),

152.6, 149.8, 2.97 (h, J ¼ 9.2

142.3, 133.0, Hz, 2H), 2.79–
132.5, 130.7,
2.50 (m, 2H),
129.9, 128.9,
2.28 (s, 3H, Me),
125.5, 125.3
(2C), 120.3 (2C), 2.21–2.09 (m,
114.0, 113.9, 2H), 2.07 (s,
113.66, 111.7, 1H), 1.28 (t, J ¼
54.2, 35.0, 31.4,
7.2 Hz, 1H) ppm;
21.9, 21.4, 21.2 13
C NMR (125
ppm; MS (70
eV) m/z 438 MHz, CDCl3) d
+
[M ], 331, 92, ¼ 182.4,
77; anal. calcd 177.0, 162.0,
for C27H22N2O4: 155.0, 149.2,
C, 73.96; H, 147.8, 137.9,
136.5, 133.0,
5.06; N, 6.39.
132.5, 130.7,
Found: C, 73.89;
129.8, 128.6
H, 5.15; N, 6.33. (2C), 127.7 (2C),
14-Amino-13- 125.5, 125.3,
(p-tolyl)- 121.6, 118.3,
98.2, 33.3, 33.2,
2,3,4,13-
26.0, 21.2, 20.0,
tetrahydro-1H- 13.1 ppm; MS
benzo[6,7]chrom (70 eV) m/z 442
eno[2,3- [M+], 331, 105,
b]quinoline-7,12- 91; anal. calcd
for C27H22N2O3:
dione (6d). Yield
C, 76.76; H,
90 (%); yellow 5.25; N, 6.63.
solid; mp ¼ 242– Found: C, 76.70;
245 dec C; IR H, 5.19; N, 6.70.
(KBr) ¼ 3472, 14-Amino-13-
(thiophen-2-yl)-
3375 (NH2),
2,3,4,13-
1734, 1635, 1594
tetrahydro-1H-
cm1. 1
H NMR benzo[6,7]
(500 MHz, chromeno[2,3-
b]quinoline-7,12-

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dione (6e). Yield eV) m/z 414

55 (%); brown [M+], 331,
solid; mp ¼ 269–
105, 77; anal.
271 dec C; IR
calcd for
(KBr) ¼ 3472,
C24H18N2O3S: C,
3378 (NH2), 69.55; H, 4.38;
1734, 1678, N, 6.76; S, 7.74.
1635, 1594 cm1. Found: C, 69.50;
1
H NMR (500 H, 4.32; N, 6.84;
MHz, DMSO-d6) S, 7.79.
d¼ 8.11– 13-Amino-12-
(p-tolyl)-
8.04 (m, 1H), 1,2,3,12-
8.03–7.97 (m, tetrahydrobenzo
[6,7]chromeno
1H), 7.92–7.66 [2,3-
(m, 2H), 7.27 (d, b]cyclopenta[e]p
J ¼ 5 Hz, 1H), yridine-6,11-
7.0 (d, J ¼ 3.5 dione (6f). Yield
Hz, 1H), 6.86 92 (%); yellow
(dd, J ¼ 5.1, 3.6 solid; mp ¼ 300–
Hz, 1H), 6.03 (s, 302 dec C; IR
2H, NH2), 5.84
(KBr) ¼ 3445,
(s, 1H), 2.61 (d, J
3355 (NH2),
¼ 5.5 Hz, 2H),
1731, 1644, 1582
2.46–2.13 (m, cm1. 1
H NMR
2H), 1.34–0.97 (500 MHz,
(m, 2H) ppm; 13C
CDCl3) d¼ 8.27–
NMR (125 MHz,
7.92 (m, 2H),
DMSO-d6) d¼
7.76–7.59 (m,
182.0, 177.3,
2H), 7.34 (d, J ¼
152.7, 152.4,
8.0 Hz, 2H), 7.11
151.2, 149.7,
(d, J ¼ 7.8 Hz,
145.5, 134.0,
2H), 5.25 (s,
133.4, 130.6,
1H), 4.18 (s, 2H,
130.0, 126.0,
NH2), 2.96 (hept,
125.5, 125.5,
J ¼ 8.2,
125.3, 124.5,
121.8, 113.2,
96.7, 31.4, 28.4,
22.5, 21.7, 21.4
ppm; MS (70

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Fig. 3
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

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H, 4.82; N, 6.92. 113.6, 97.7, 34.5,

13-Amino-14- 31.4, 21.9, 21.5,
(p-tolyl)-
21.2, 20.0, 13.1
8,9,10,11,12,14-
hexahydrobenzo[ ppm; MS (70 eV)
6,7] m/z 436 [M+],
chromeno[2,3- 421, 345, 91;
b]cyclohepta[e]p
anal. calcd for
yridine-5,15-
dione (6g). Yield C28H24N2O3: C,
50 (%); brownish 77.04; H, 5.54;
solid; mp ¼ 263– N, 6.42. Found:
266 dec C; IR C, 77.02; H,
(KBr) ¼ 3465,
5.59; N, 6.49.
3378 (NH2), 14-Amino-13-
(2-
1641, 1599 cm1. chlorophenyl)
1
H NMR (500 -2,3,4,13-
tetrahydro-
MHz, CDCl3) d 1H-benzo
[6,7]chromeno[2,
¼ 8.14 (s, 1H),
3-b]quinoline-
7.99 (s, 1H), 7.67
7,12-dione (6h).
(s, 2H), 7.33 (d, J
Yield 70 (%);
¼ 7.9 Hz, 2H),
yellow solid; mp
7.0 (d, J ¼ 8.5
¼ 274–277 dec
Hz, 2H), 5.21 (s, C; IR (KBr) ¼
1H), 4.25 (s, 2H, 3451, 3383
NH2), 2.81 (s, (NH2), 1636,
1 1
2H), 2.30–2.12 1597 cm . H

(m, 4H), 1.9–1.4 NMR (500 MHz,

CDCl3) d¼ 8.26–
(m, 5H), 1.26 (d,
8.09 (m, 1H),
J ¼ 7.8 Hz, 2H)
8.09–7.92 (m,
ppm;
1H), 7.79–7.61
13
C NMR (125 (m, 2H), 7.44–
MHz, CDCl3) d¼ 7.32 (m, 1H),
182.4, 176.8,
7.15 (tt, J ¼ 7.4,
161.6, 158.7, 5.4 Hz, 2H), 5.63
153.8, 149.8, (s, 1H), 4.54 (s,
137.8, 136.4, 2H, NH2), 2.96–
133.0, 132.4, 70.48; H, 4.31;
N, 6.40.
130.7, 129.8,
14-Amino-13-
128.6 (2C), 127.7 phenyl-4,13-
(2C), 125.5, dihydro-1H,3H-
125.2, 121.6,

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benzo[6,7]chro 122.7, 111.8,

meno 32.6, 30.4, 23.0,
[2,3-
22.6 ppm; MS
b]thiopyrano[3,4
(70 eV) m/z 426
-e]pyridine-7,12-
[M+], 349, 315,
dione (6i). Yield
303; anal. calcd
82 (%); yellow
for C25H18N2O3S:
solid; mp ¼ 270–
C, 70.41; H,
273 dec C; IR
4.25; N, 6.57; S,
(KBr) ¼ 3451, 7.52.
3376 (NH2), Found: C, 70.40;
1657, 1595 cm1. H, 4.23; N, 6.63;
1
H NMR (500 S, 7.61.
14-Amino-13-
MHz, DMSO-d6)
(4-nitrophenyl)-
d ¼ 8.07–8.00
4,13-dihydro-
(m, 1H), 7.93 (d,
1H,3H-
J ¼ 4.8 Hz, 1H),
benzo[6,7]
7.85–7.77 (m,
chromeno[2,3-
2H), 7.57–7.46
b]thiopyrano[3,4-
(m, 2H), 7.30– e]pyridine-7,12-
6.9 (m, 5H), 5.54
dione (6j). Yield
(s, 1H), 3.64–
78 (%); yellow
3.53 (m, 1H),
solid; mp ¼ 284–
3.40 (d, J ¼ 16.2
286 dec C; IR
Hz, 1H), 3.00 (q,
(KBr) ¼ 3490,
J ¼ 6.2 Hz, 2H),
3360 (NH2),
2.88 (d, J ¼ 6.1 1637, 1592 cm1.
13
Hz, 2H) ppm; C 1
H NMR (500
NMR (125 MHz, MHz, DMSO-d6)
DMSO-d6) d¼ d¼ 8.10 (d, J ¼
181.7, 176.1, 8.3 Hz, 2H),
152.9, 150.7,
8.08–8.02 (m,
148.6, 148.3,
1H), 7.96–7.90
148.3, 140.8,
(m, 1H), 7.86–
134.1, 133.7,
7.79 (m, 2H),
130.3, 129.9,
7.77 (d, J ¼ 8.2
128.2 (2C), Hz, 2H), 6.19 (s,
128.1, 127.8 2H, NH2), 5.69
(2C), 126.7, (s,

125.5, 125.4,
Table 2 One-pot, four-component
synthesis of new tacrine derivatives in the

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ons Attribution 3.0 Unported
presence of Cu-MOF and AlCl3 in 1,2-
dichloroethane under reflux conditions

Entry Aldehyde Cycloketone Yield (%) Time (h) Product Mp ( C)

195
6a

censed 291
6b

389
6c

490
6d

555
6e

692
6f

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7
50
6g

870
6h

982
6i

1078
6j

11
90
6k

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eV m/z 471M+], 349, 315, 303; anal. calcd
2 H1 N3O5S: cists and chemists and biologically active tacrine
that3.68;
63.6; H, 3.63; N, 8.91; S, 6.80. Found: C, 63.60; H, wereN,synthesized over several stages can be easily
S, sized without the need to separate intermediates and
them View Article Online
(6k) Yiel
RSC Advances Paper
2
11
6
Co f icts of
8.01m, ), –7.91m, 1H), 7.85
J ¼4. Hz, 2H), 7.55
J There are noicts to

14-Amino-13-
(4-chlorophenyl)-
4,13-dihydro-
1H,3H-benzo[6,7]
chromeno[2,3-
b]thiopyrano[3,4-
e]pyridine-7,12-
dione
9
0

(
%
)
;

y
e
l
l
o
w

s
o
l
i
d
;

m
p

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5
0

2
5
3

d
e
c

C
;

I
R

(
K
B
r
)

3
4
5
0
,

3
3
4
5

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(
N
H

)
,

1
6
6
5
,

1
5
9
5

c
m

N
M
R

(
5
0
0

M
H
z

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D
M
S
O
-
d

8
.
1
3

¼ 8.1 Hz, 2H), (2C), 125.5,

125.4, 122.0,
7.32 (d, J ¼ 8.1 112.0, 97.5, 32.1,
Hz, 2H), 7.09 (s, 30.5, 23.1, 22.6
ppm; MS (70
2H, NH2), 5.59 eV) m/z 460
(s, 1H), 3.60 (d, J [M+], 349, 315,
303; anal. calcd
¼ 16.3 Hz, 1H), for
C25H17ClN2O3S:
3.40 (d, J ¼ 16.2 C, 65.15; H,
Hz, 1H), 3.08– 3.72; 6.08; S,
6.96. Found: C,
2.81 (m, 4H) 65.10; H, 3.83;
13 6.18; S, 6.90.
ppm; C NMR

(125 MHz,

CDCl3) d ¼ 4. Concl
182.8, 176.5, usion
In conclusion, we
152.9, 150.7,
have effectively
148.8, 139.7,
developed and
134.1, 133.6,
expanded simple
131.4, 130.5,
and
130.2 (2C),
straightforward
130.0, 127.7

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procedure for article also

one-pot synthesis express their
of tacrine gratitude and
derivatives. One- appreciation for
pot, domino the efforts made
four-component by Tarbiat
reaction of Modares
aldehydes, University in
malononitrile, 2- catalyst
hydroxy-1,4- synthesis.
naphthoquinone,
and cycloketones
was carried out References
in the presence 1 P. L.
of Cu-MOF and
Valenzuela,
aluminum
J. S.
chloride. Without
Morales, C.
the requirement
to isolate the Fiuza-
pyranic Luces, P. de
intermediate and la Villa, A.
in a single Santos-
container, the Lozano and
reaction was A. Lucia, J.
conducted under Am. Med.
reux to give the Dir. Assoc.,
desired products 2019, 20,
in high yields. 101–102.
Prominent
2 S.
features of the
Shimohama
current
and J.
procedure
Kawamata,
include a step-
in Nicotinic
economic
Acetylcholi
increasing yield,
ne Receptor
economic
Signaling in
feasibility,
Neuroprotec
capability of
tion,
recycling the
Springer,
catalyst and
Singapore,
covering a broad
2018, pp.
substrate
137–158.
Acknowled 3 H. Cavdar,
M. Senturk,
gements M. Guney,
We would like to S. Durdagi,
thank the G. Kayik, C.
Research T. Supuran
Council at and D.
CCERCI Ekinci, J.
Foundation for Enzyme
the nancial Inhib. Med.
support of this Chem.,
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