Synthesis and Characterization of Novel Phthalimide-pyrano[3,2-c]chromene and Phthalimide-pyrano-2-one Hybrids

Article abstract of DOI:10.1002/jhet.3204

Coumarin skelton holds substantial promise for further exploration because of its immense pharmacological potential. In this pursuit, a series of phthalimide-chromen and phthalimide-pyran-2-one hybrids were synthesized in efficient yields via one-pot multicomponent reaction of aldehyde linked to phthalimide moiety, 4-hydroxy coumarin/4-hydroxy-6-methyl-2H-pyran-2-one, and malanonitrile by Knoevenagel reaction at room temperature in the presence of DABCO as catalyst. The compounds were characterized by ¹H NMR and ¹³C NMR, MS, and FTIR. All the compounds consisting of phthalimide-chromen/pyrano-2-one moieties tethered by spacers of varying lengths were evaluated for their biological activity in Ellman's assay. Most of the compounds feebly inhibited Acetylcholinesterase Enzyme and were inactive toward Butyrylcholinesterase Enzyme.

Full text of DOI:10.1002/jhet.3204

Month 2018
Synthesis and Characterization of Novel Phthalimide-pyrano[3,2-c]
chromene and Phthalimide-pyrano-2-one Hybrids
a
b,c
d
e
f
Bilqees Sameem, Mina Saeedi, Mohammad Mahdavi, Hamid Nadri, Fahimeh Vafadarnejad, and
d,f
Mohsen Amini *
a
Faculty of Pharmacy, International Campus (TUMS-IC) and Pharmaceutical Sciences Research Center, Tehran University
of Medical Sciences, Tehran, Iran
Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
b
c
Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
d
e
Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
f
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
*
E-mail: moamini@tums.ac.ir
Received October 7, 2017
DOI 10.1002/jhet.3204
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Coumarin skelton holds substantial promise for further exploration because of its immense pharmacolog-
ical potential. In this pursuit, a series of phthalimide-chromen and phthalimide-pyran-2-one hybrids were
synthesized in efficient yields via one-pot multicomponent reaction of aldehyde linked to phthalimide moi-
ety, 4-hydroxy coumarin/4-hydroxy-6-methyl-2H-pyran-2-one, and malanonitrile by Knoevenagel reaction
1
at room temperature in the presence of DABCO as catalyst. The compounds were characterized by H
1
3
NMR and C NMR, MS, and FTIR. All the compounds consisting of phthalimide-chromen/pyrano-2-one
moieties tethered by spacers of varying lengths were evaluated for their biological activity in Ellman’s assay.
Most of the compounds feebly inhibited Acetylcholinesterase Enzyme and were inactive toward Butyrylcho-
linesterase Enzyme.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
been synthesized with specific properties and applications
including layser dyes, bioactive compounds with different
biological activities, additive in food and cosmetics, and
fluorescent transthyretin folding sensors [11–15].
Coumarins are plant-derived polyphenolic compounds
belonging to the benzopyrone family. They exhibit a
wide range of pharmacotherapuetic properties and
represent one of the most versatile and applicable family
in fluorescent probes. The diverse pharmacological
properties make them useful as anti-cancer and
anti-proliferative [1], anti-inflammatory, anti-HIV agents
2], neuro-protective [3,4], anti-oxidative, antibacterial
5], antifungal [6] anticoagulants and antiplatelet [7],
vasorelaxants [8], and anti-Alzheimer agents [9].
Coumarins exhibit fascinating and
physicochemical properties, and their applications in
different area have been extensively studied. Coumarins
have high applicability in fluorescent probes of
heterogeneous environments, such as supramolecular host
cavities, micelles, polymers, and solids [10]. Several
coumarin derivatives have been designed as a new class
of far-red emitting fluorgenic agents, such as
cyanocoumarins and 7-hydroxycoumarin-hemicyanine
The physiochemical properties of coumarins devise
the extent of their biological properties. Coumarin eliciting
vast pharmacological effects has been widely explored for
the development of ligands for combating multifaceted
diseases like cancer, neurodegenerative, and metabolic
syndromes [16]. It is well established that coumarin exerts
its anti-Alzheimer activity by inhibiting acetylcholinestrase
enzyme, which remains a main target in the symptomatic
treatment of disease. Pertinently, four among the five FDA-
approved drugs for Alzheimer’s disease are cholinesterase
inhibitors (Fig. 1) [17,18]. Coumarin is a well-known
acetylcholinestrase peripheral anionic site binding moiety,
and most of the reported scaffolds are based on linking
coumarin with some catalytic binding site moiety tethered
by an appropriate spacer [19,20]. In this regard, several
coumarin-based scaffolds like emasulin [21] and AP 2238
[22] are under clinical trial (Fig. 2)
[
[
unique
hybrids [11]. Several other coumarin derivatives like
Multicomponent reactions (MCRs) occupy an important
place in organic synthesis because of the formation of
0
3-(2 -benzimidazolyl) coumarins and biscoumarins have
©
2018 Wiley Periodicals, Inc.

B. Sameem, M. Saeedi, M. Mahdavi, H. Nadri, F. Vafadarnejad, and M. Amini
Vol 000
Figure 1. Structures of AChE inhibitors used in Alzheimer’s disease. Tacrine was withdrawn because of its hepatotoxicity; however, it is used in research
and as a reference inhibitor and design of new scaffolds.
Figure 2. Related coumarin-based and phthalimide-based scaffolds as cholinesterase inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]
carbon–carbon and carbon–heteroatom bond involving one
pot, simple procedures, low cost, time and energy saving,
and less environmental hazards. Pyrano[3,2-c] chromens
being an imperative class of heterocycles have previously
been synthesized from 4-hydroxy coumarin, malanonitrile,
and aromatic aldehydes in the presence of different
catalysts. In continuation of our interest in the development
of coumarin-based scaffolds in the spotlight of previously
mentioned facts and MCRs [4], we herein report the
DABO-catalyzed Knoevenagel reaction followed by
cyclization that produced novel phthalimide-pyrano[3,2-c]
chromene and phthalimide-pyrano-2-one hybrids bearing
different linker lengths (Fig. 3) with this aim that they could
have some chemical and biological interest (Scheme 1).
of 4.1–4.4 ppm corresponding to the chiral proton
(CH). Further evidence was gained from their mass
spectra that displayed characteristic mass fragments and
abundant peaks.
Phthalimide (1) (20 mmol) was dispersed in a solution
of KOH in EtOH. The solution was refluxed for 7 h,
reaction progress was monitored by TLC, and the
solution was concentrated under vacuum. The obtained
solid was washed with little amount of cold ethanol,
dried to afford 2a. In the next step, dibromomethane 2b
(9 mmol) was added to a solution of 2a (3 mmol) in
6 mL of DMF and left to stir for 9 h at 85°C. The
reaction mixture was poured in ice-cold water, and the
precipitate formed was filtered, dried, and crystallized in
ethanol to afford 3. Compounds 3a, 3b (10 mmol), and
aldehydes 4 (10 mmol) were mixed in dry acetone and left
to stir under reflux temperature for 22–24 h (compounds
RESULTS AND DISCUSSION
3
a (n = 3) and 3b (n = 4) are commercially available). The
Chemistry. In continuation of our work based on the
synthesis and evaluation of coumarin-based scaffolds
4,23,24], we synthesized phthalimide-pyrano[3,2-c]
chromene and phthalimide-pyrano-2-one hybrids and
evaluated them for their biological activity. The
synthesis pathway for preparation of compounds 7 and
was illustrated in Scheme 1. The structure of the
target compounds was confirmed by the spectral data.
reaction progress was monitored by TLC, and then the
mixture was concentrated under vacuum. The obtained
solid was washed with water, dried and crystallized in
appropriate solvent to furnish pure compound 5. Finally,
the desired compounds 7 and 8 were prepared via one-pot
MCR by stirring the intermediate (5) (2 mmol) with
malanonitrile (6) (2 mmol), or with 4-hydroxy
coumarin/6-methyl, 4-hydroxy-2-one-pyrone (2 mmol) in
ethanol in the presence of catalytic amount of DABCO
overnight at ambient temperature, respectively. The
reaction progress was monitored by TLC, and the
[
8
The IR showed the appearance of characteristic NH
2
ꢀ
1
band around 3193–3367 cm
and CN 2105–
ꢀ
1 1
2
295 cm . H NMR spectra showed a peak at a range
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Characterization of Novel Phthalimide-pyrano
Figure 3. Design strategy of coumarin/pyranone- phthalimide hybrids. [Color figure can be viewed at wileyonlinelibrary.com]
2 3
Scheme 1. Reagents and conditions: (a) KOH, EtOH, reflux; (b) DMF, 85°C, 9 h; (c) K CO , acetone, reflux, 22–24 h; (d) 4-hydroxy coumarin, DABCO,
EtOH, rt, 24 h; (e) 4-hydroxy-6-methyl-2H-pyran-2-one, DABCO, EtOH, rt.
precipitate formed was filtered off and washed with EtOH to
afford pure compound in 85–95% yields.
replacement of chromene moiety with pyran-2-one did
not display any significant effect on the activity of
compounds either on AChE or BuChE. The changing in
spacer length changed the percentage of inhibition AChE
at 70 μM significantly, as optimum distance between
phthalimide and O-phenyl ring is provided with three
methylene groups. However, these changes in spacer
length for inhibition of BuChE did not display important
role. The positive effects of spacer length in increasing
Biological assay.
The activity against Acetyl-
cholinesterase Enzyme (AChE) and Butyrylcholinesterase
Enzyme (BuChE) was determined in spectrophotometric
Elman’s assay. Donepezil was used as reference drug.
The enzyme inhibitory activity of all the compounds is
summarized in Table 1. Interestingly, change substitution
on the phenyl ring-linking phthalimide and coumarin and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Sameem, M. Saeedi, M. Mahdavi, H. Nadri, F. Vafadarnejad, and M. Amini
Vol 000
Table 1
AChE and BuChE inhibitory activity of compounds 7 and 8.
Entry
Product 7/8
R
n
% of inhibition of AChE at 70 μM
% of inhibition of BuChE at 70 μM
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
H
H
H
4
1
3
1
1
3
4
4
1
3
1
1
3
4
36
55
69
31
53
67
37
31
45
65
32
42
61
30
100
<10
16
18
<10
13
19
17
<10
16
19
<10
14
3,5-OCH
3
3-OCH
3-OCH
3-OCH
H
3
3
3
H
H
10
1
1
3,5-OCH
3
12
13
14
3-OCH
3-OCH
3-OCH
3
3
3
16
<10
100
8g
Donepezil
the activity for both series 7 and 8 and also for phenyl (7a–
c and 8a–c) or substituted-phenyl group (7d–g and 8d–g)
were observed. All synthesized compound did not inhibit
BuChE significantly at concentration of 70 μM.
was monitored by TLC. The mixture was concentrated
under reduced pressure, and the solid material was
washed with little amount of cold ethanol, dried to afford
2a. In the next step, dibromomethane (9 mmol) was
added to a solution of 2a (3 mmol) in 6 mL of DMF and
left to stir for 9 h at 85°C. The reaction mixture was
poured in ice-cold water, and the precipitate formed was
filtered, dried, and crystalized in ethanol to afford 3b.
Compounds 3 (10 mmol) and aldehyde 4 (10 mmol) were
mixed in dry acetone and left to stir under reflux
condition for 24 h (compounds 3a, n = 4, and 3c, n = 3,
are commercially available). The reaction progress was
monitored by TLC, and after completion, the mixture was
concentrated under reduced pressure. The obtained solid
material was washed with water, dried, and crystalized in
appropriate to furnish pure compound 5. Finally, the
desired compounds 7 and 8 were prepared via one-pot
MCR by stirring the intermediate 5 (2 mmol) with
malononitrile (6) (2 mmol) or with 4-hydroxy coumarin/6-
methyl, 4-hydroxy-2-one-pyrone (2 mmol) in ethanol in the
presence of catalytic amount of DABCO overnight in
ambient temperature, respectively. The reaction progress
was monitored by TLC, and precipitate was filtered off and
washed with ethanol. The solid material was crystalized in
EXPERIMENTAL
General.
All commercially available materials and
reagents were purchased from Merck and Aldrich and
were used without further purification. Thin-layer
chromatography was performed using silica gel 250
micron and F254 plates. Melting points were obtained
using Koftler hot stage apparatus. The IR spectra were
recorded on Nicolet FT magna 550 spectrograph (KBr
1
13
pellets). H NMR and C NMR spectra were recorded
on Bruker spectrometer at 500 and 125 MHz,
respectively. The chemical shifts and coupling constants
(
(
J) are expressed in parts per millennium (ppm) and hertz
Hz), respectively. Mass spectra were acquired on an
Agilent Technology (HP) mass spectrometer operating at
an ionization potential of 70 eV. Elemental analyses were
carried out with a Perkin Elmer Model 240-C apparatus.
Elemental analyses were within ±0.4% of theoretical
values for C, H, and N.
ethanol to afford pure compound in 85–95% yield.
2-Amino-4-(4-(4-(1,3-dioxoisoindolin-2-yl)butoxy)phenyl)-5-
oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (7a).
General procedure for the synthesis of compounds 7a–g
and 8a–g. The target compounds 7 and 8 were prepared
as illustrated in Scheme 1. Phthalimide (1) (20 mmol)
was dispersed in a solution of KOH in ethanol. The
solution was refluxed for 7 h, and the reaction progress
White solid; yield 92.5%; mp = 223–225°C; IR (KBr)
ꢀ
1
1
cm : 3425, 3327, 2195, 1777, 1723. H NMR
(500 MHz, DMSO-d6): 7.89–7.81 (m, 5H, Ha–d, and H ),
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Characterization of Novel Phthalimide-pyrano
+
7
.70 (t, J = 7.7 Hz, 1H, H ), 7.43–7.49 (m, 2H, H ,
104.5, 103.8, 67.7, 57.7, 55.7, 37.1. MS (m/z, %): [M ;
551 (1%)], 160 (100), 133 (14), 104 (17), 77 (22). Anal.
Calcd for C H N O : C, 65.49; H, 3.84; N, 7.62.
3
2
and H ), 7.33 (s, 2H, NH ), 7.15 (d, J = 8.5 Hz, 2H,
H3,5-phenyl), 6.84 (d, J = 8.0 Hz, 2H, H2,6-phenyl), 4.38
4
2
30
21 3 8
(
s, 1H,CH), 3.94 (t, J = 6.0 Hz, 2H, CH ), 3.62 (t,
Found: C, 65.40; H, 4.03; N, 7.39.
2
13
2
-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)-3-
methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile (7e). 84%;
J = 6.5 Hz, 2H, CH ), 1.71–1.73 (m, 4H, 2 × CH ).
NMR (125 MHz, DMSO-d6): 167.8, 159.3, 157.8, 157.6,
1
1
5
C
2
2
White
solid;
yield
53.0, 152.0, 135.2, 134.2, 132.7, 131.5, 128.6, 124.5,
23.0, 122.3, 119.1, 116.4, 114.3, 112.9, 104.2, 66.8,
ꢀ
1
mp = 261–262°C; IR (KBr): cm 3373, 3202, 2944,
1
+
2195, 1777, 1731. H NMR (500 MHz, DMSO-d6):
8.2, 37.1, 36.1, 26.1, 24.6. MS (m/z, %): [M ; 533
7
.83–7.87 (m, 5H, Ha–d, and H ), 7.70 (t, J = 8.0 Hz, 1H,
1
(3%)], 160 (100), 202 (76), 130 (29), 77 (16). Anal.
H ), 7.44–7.49 (m, 2H, H , and H ), 7.33 (s, 2H, NH ),
3
2
4
2
Calcd for C H N O : C, 69.79; H, 4.35; N, 7.88.
Found: C, 69.43; H, 4.39; N, 7.65.
31 23 3 6
7
.07 (d, J = 8.0 Hz, 1H, H -phenyl), 6.91 (s, 1H,
5
H -phenyl), 6.75 (d, J = 8.0 Hz, 1H, H -phenyl), 5.49 (s,
2
-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)phenyl)-5-
2
6
1
3
2
H, CH ), 4.44 (s, 1H, CH), 3.68 (s, 3H, OCH ).
C
oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (7b).
2
3
NMR (125 MHz, DMSO-d ): 166.7, 159.4, 157.9, 153.2,
152.1, 149.8, 144.6, 138.5, 134.9, 132.7, 131.2, 124.5,
White solid; yield 84%; mp = 242–244°C; IR (KBr)
6
ꢀ
1
1
cm : 3419, 3327, 2283, 1789, 1729. H NMR
500 MHz, DMSO-d6): 7.89–7.95 (m, 5H, Ha–d, and H1),
.69 (t, J = 7.5 Hz, 1H, H ), 7.43–7.49 (m, 2H, H ,
1
6
23.5, 122.4, 119.6, 119.1, 117.5, 116.4, 112.3, 103.8,
6.6, 57.9, 55.6, 36.5. MS (m/z, %): [M ; 521 (1%)],
(
+
7
3
2
and H ), 7.35 (s, 2H, NH ), 7.23 (d, J = 8.0 Hz, 2H,
160 (100), 133 (8), 103 (11). Anal. Calcd for
C H N O : C, 66.79; H, 3.67; N, 8.06. Found: C,
4
2
H3,5-phenyl), 7.06 (d, J = 8.0 Hz, 2H, H2,6- phenyl), 5.55
29 19 3 7
1
3
6
6.51; H, 3.70; N, 7.95.
(
s, 2H, CH ), 4.43 (s, 1H, CH). C NMR (125 MHz,
2
2
-Amino-4-(4-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-3-
DMSO-d6): 166.8, 159.4, 157.9, 155.2, 153.1, 152.0,
36.7, 134.9, 132.7, 131.1, 128.8, 124.5, 123.7, 122.4,
methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile (7f). White solid; yield 88%; mp = 237–
1
1
19.1, 116.4, 115.4, 112.9, 104.0, 65.2, 58.1, 55.9, 36.1,
ꢀ
1
2
1
5
7
6
H
38°C; IR (KBr): cm 3376, 3196, 2941, 2198, 1734,
+
1
9
8.4. MS (m/z, %): [M ; 491 (5%)], 120 (100), 162 (99),
2 (77). Anal. Calcd for C H N O : C, 68.43; H, 3.49;
1
775. H NMR (500 MHz, DMSO-d6): 7.79–7.85 (m,
H, Ha–d, and H ), 7.70 (t, J = 7.5 Hz, 1H, H ), 7.44–
.49 (m, 2H, H , and H ), 7.29 (s, 2H, NH ), 6.78–
.84 (m, 2H, H , and H -phenyl), 6.70 (d, J = 2.0 Hz,
2
8 17 3 6
1
3
N, 8.55. Found: C, 68.63; H, 3.39; N, 8.65.
2
4
2
2
-Amino-4-(4-(3-(1,3-dioxoisoindolin-2-yl)propoxy)phenyl)-
-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile
7c).
5
5
6
(
(
(
White solid; yield 83%; mp = 223–226°C; IR
KBr): cm 3351, 3193, 2204, 1763, 1735. H NMR
500 MHz, DMSO-d6): 7.79–7.83 (m, 5H, Ha–d, and
-phenyl), 4.38 (s, 1H, CH), 3.96 (t, J = 6.0 Hz, 2H,
2
ꢀ
1
1
CH ), 3.75 (t, J = 6.5 Hz, 2H, CH ), 3.55 (s, 3H,
2
2
13
OCH ), 2.04 (d, J = 6.5 Hz, 2H, CH ). C NMR
3
2
H1), 7.70 (dt, J = 8.5, and 1.5 Hz, 1H, H ), 7.43–7.49
(125 MHz, DMSO-d
): 167.8, 159.5, 157.9, 153.1,
6
3
1
1
52.0, 148.7, 147.1, 135.9, 134.1, 132.7, 131.7, 124.5,
22.8, 122.4, 119.5, 119.1, 116.5, 113.3, 112.9, 111.9,
(
m, 2H, H , and H ), 7.32 (s, 2H, NH ), 7.13 (d,
2 4 2
J = 8.5 Hz, 2H, H3,5-phenyl), 6.75 (d, J = 8.5 Hz, 2H,
H2,6- phenyl), 4.37 (s, 1H, CH), 3.97 (t, J = 6.0 Hz, 2H,
CH ), 3.74 (t, J = 6.5 Hz, 2H, CH ), 2.01–2.06 (m, 2H,
+
04.1, 66.5, 55.5, 36.4, 35.2, 27.7. MS (m/z, %): [M
49; (1%)], 188 (100), 160 (60), 130 (15), 66 (10).
Anal. Calcd for C H N O : C, 67.75; H, 4.22; N,
5
2
2
13
CH2). C NMR (125 MHz, DMSO-d ): 167.8, 159.5,
31 23 3 7
6
1
1
1
57.9, 157.5, 153.1, 152.1, 135.3, 134.2, 132.8, 131.7,
28.6, 124.6, 122.9, 122.4, 119.2, 116.5, 114.3, 112.9,
04.3, 65.5, 36.1, 34.9, 27.6. MS (m/z, %): [M ; 519
7.65. Found: C, 67.69; H, 4.29; N, 7.54.
2
-Amino-4-(4-(4-(1,3-dioxoisoindolin-2-yl)butoxy)-3-
+
methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile (7g). White solid; yield 81%; mp = 184–
(
(
2%)], 160 (100), 188 (100), 130 (35), 265 (25), 104
11), 77 (7). Anal. Calcd for C H N O : C, 69.36; H,
ꢀ
1
1
1
86°C; IR (KBr): cm 3403, 3327, 2934, 2201, 1761,
3
0
21
3
6
1
718. H NMR (500 MHz, DMSO-d6): 7.81–7.86 (m,
4
.07; N, 8.09. Found: C, 69.53; H, 4.19; N, 7.88.
2
5
H, Ha–d, and H ), 7.70 (t, J = 8.5 Hz, 1H, H ), 7.44–
1
3
-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)-3,5-
dimethoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile (7d).
2
1
5
7
7
.50 (m, 2H, H , and H ), 7.31 (s, 2H, NH ), 6.83–
2 4 2
White solid; yield 85%; mp = 250–
6.86 (m, 2H, H , and H -phenyl), 6.70 (d, J = 1.5 Hz,
5 6
H -phenyl), 4.3 (s, 1H, CH), 3.92 (t, J = 6.0 Hz, 2H,
2
ꢀ
1
53°C; IR (KBr): cm 3391, 3315, 2928, 2198, 1778,
1
726. H NMR (500 MHz, DMSO-d6): 7.89–7.95 (m,
CH
CH
2
), 3.70 (s, 3H, OCH
), 1.71–1.75 (m, 4H, 2× CH
): 167.9, 159.5, 157.8, 153.1,
3
), 3.63 (t, J = 6.5 Hz, 2H,
13
H, Ha–d, and H ), 7.69 (t, J = 7.5 Hz, 1H, H ), 7.44–
2
2
).
C
NMR
1
3
.48 (m, 2H, H , and H ), 7.29 (s, 2H, NH ), 6.45 (s, 2H,
(125 MHz, DMSO-d
6
2
4
2
H2,6-phenyl), 5.36 (s, 2H, CH ), 4.42 (s, 1H,CH), 3.50 (s,
152.1, 148.8, 147.3, 135.9, 134.3, 132.7, 131.6, 124.5,
122.9, 122.4, 119.6, 119.2, 116.5, 113.4, 112.9, 112.0,
104.1, 67.8, 55.6, 37.1, 36.4, 26.2, 24.7. MS (m/z, %):
2
13
6
1
1
H, 2 × OCH3). C NMR (125 MHz, DMSO-d ): 166.8,
59.5, 158.1, 153.5, 153.0, 152.2, 140.0, 135.0, 133.6,
33.0, 131.2, 124.5, 123.3, 123.0, 119.0, 116.5, 113.0,
6
+
[M ; 563 (1%)], 160 (100), 202 (48), 120 (16), 92 (9).
Journal of Heterocyclic Chemistry
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B. Sameem, M. Saeedi, M. Mahdavi, H. Nadri, F. Vafadarnejad, and M. Amini
Vol 000
Anal. Calcd for C H N O : C, 68.20; H, 4.47; N, 7.46.
Found: C, 67.97; H, 4.51; N, 7.61.
CH), 4.24 (s, 1H, CH), 3.49 (s, 6H, 2 × OCH ), 2.23 (s,
3
3H, CH ). C NMR (125 MHz, DMSO-d ): 166.7, 162.7,
3 6
32
25
3
7
13
2
-Amino-4-(4-(4-(1,3-dioxoisoindolin-2-yl)butoxy)phenyl)-7-
methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile
8a).
(
(
161.2, 158.1, 152.7, 140.3, 134.7, 131.3, 123.3, 118.9,
104.3, 100.4, 97.8, 67.7, 55.6, 36.3, 19.2. MS (m/z, %):
+
(
White solid; yield 90%; mp = 215–216°C; IR
[
M ; 515 (1%)], 160 (100), 133 (6), 104 (6), 77 (7.5).
ꢀ
1
1
KBr): cm 3406, 3327, 2195, 1720, 1765. H NMR
500 MHz, DMSO-d6): 7.87–.81 (m, 4H, Ha–d), 7.10–
.05 (m, 4H, NH , and H3,5-phenyl), 6.82 (d, 2H,
J = 8.5 Hz, H2,6-phenyl), 6.23 (s, 1H, H ), 4.20 (s, 1H,
CH), 3.95 (t, J = 6.0 Hz, 2H, CH2), 3.63 g (t, J = 6.5 Hz,
H, CH ), 2.21 (s, 3H, CH ), 1.74–1.72 (m, 4H,
× CH2). C NMR (125 MHz, DMSO-d ): 167.8,
62.5, 161.1, 157.9, 157.7, 157.5, 135.5, 134.2, 131.5,
28.4, 122.8, 119.2, 114.2, 100.9, 7.8, 66.8, 58.2, 37.1,
5.4, 26.1, 24.6, 19.2. MS (m/z, %): [M ; 497 (6%)], 160
Anal. Calcd for C H N O : C, 62.91; H, 4.11; N, 8.15.
27 21 3 8
Found: C, 62.82; H, 3.96; N, 8.24.
7
2-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)-3-
methoxyphenyl)-7-methyl-5-oxo-4,4a,5,8a-
tetrahydropyrano[4,3-b]pyran-3-carbonitrile (8e).
2
1
White
ꢀ
1
solid; yield 82%; mp = 240–243°C; IR (KBr): cm
2
2
1
1
3
2 3
1
13
3
214, 3029, 2105, 1734, 1768. H NMR (500 MHz,
6
DMSO-d6): 7.95–7.89 (m, 4H, Ha–d), 7.13 (s, 2H, NH2),
7
.05 (d, J = 8.5 Hz, 1H, H -phenyl), 6.82 (s, 1H,
5
+
H -phenyl), 6.65 (d, J = 8.5 Hz, H -phenyl), 6.25 (s, 1H,
2
6
H ), 5.48 (s, 2H, CH ), 4.25 (s, 1H, CH), 3.66 (s, 3H,
(
100), 229 (24), 202 (22), 130 (9), 104 (11), 66 (13).
Anal. Calcd for C H N O : C, 67.60; H, 4.66; N, 8.45.
Found: C, 67.49; H, 4.75; N, 8.31.
1
2
13
OCH ), 2.22 (s, 3H, CH ). C NMR (125 MHz, DMSO-
3
3
28 23 3 6
d6): 166.7, 162.7, 161.2, 160.2, 158.1, 157.9, 149.8,
1
44.5, 138.8, 134.9, 131.2, 123.5, 119.3, 119.1, 117.5,
2
-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)phenyl)-7-
methyl-5-oxo-4,4a,5,8a-tetrahydropyrano[4,3-b]pyran-3-
carbonitrile (8b).
112.2, 100.6, 97.8, 66.6, 55.5, 35.7, 19.2. MS (m/z, %):
+
White solid; yield 87%; mp = 249–
[M ; 485 (2%)], 160 (100), 104 (18), 66 (31). Anal.
ꢀ
1
2
51°C; IR (KBr): cm 3400, 3199, 2201, 1720, 1775.
H NMR (500 MHz, DMSO-d6): 7.96–7.88 (m, 4H,
Ha–d), 7.14 (d, J = 8.5 Hz, 2H, H3,5-phenyl), 7.08 (s, 2H,
Calcd for C H N O : C, 64.33; H, 3.95; N, 8.66.
26 19 3 7
1
Found: C, 64.52; H, 3.96; N, 8.54.
2-Amino-4-(4-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-3-
methoxyphenyl)-7-methyl-5-oxo-4,4a,5,8a-
tetrahydropyrano[4,3-b]pyran-3-carbonitrile (8f).
NH ), 7.04 (d, J = 8.5 Hz, 2H, H2,6-phenyl), 6.23 (s, 1H,
2
White
H ), 5.55 (s, 2H, CH ), 4.24 (s, 1H, CH), 2.21 (s, 3H,
1
2
ꢀ
1
13
solid; yield 89%; mp = 210–213°C; IR (KBr): cm
CH3). C NMR (125 MHz, DMSO-d ): 167.8, 162.6,
61.2, 157.9, 157.8, 155.2, 137.0, 134.9, 131.1, 128.6,
23.6, 119.1, 115.3, 100.8, 97.8, 65.2, 35.4, 19.2. MS
m/z, %): [M ; 455 (8%)], 160 (100), 66 (9), 229 (4),
04 (3). Anal. Calcd for C H N O : C, 65.93; H, 3.76;
N, 9.23. Found: C, 65.81; H, 3.61; N, 9.32.
6
1
3
391, 3193, 2204, 1723, 1776. H NMR (500 MHz,
1
1
(
DMSO-d6): 7.86–7.80 (m, 4H, Ha–d), 7.09 (s, 2H,
NH ), 6.84 (d, J = 8.0 Hz, 1H, H -phenyl), 6.73 (s,
+
2
5
1
H, H -phenyl), 6.64 (d, J = 8.0 Hz, 1H, H -phenyl),
2 6
1
25 17 3 6
6
.24 (s, 1H, H ), 4.21(s, 1H, CH), 3.97 (t, J = 6.5 Hz,
1
2
H, CH ), 3.76 (t, J = 6.5 Hz, 2H, CH ), 3.55 (s, 3H,
2
-Amino-4-(4-(3-(1,3-dioxoisoindolin-2-yl)propoxy)phenyl)-
-methyl-5-oxo-4,4a,5,8a-tetrahydropyrano[4,3-b]pyran-3-
carbonitrile (8c).
2
2
7
OCH
3
), 2.22 (s, 3H, CH
3
), 2.08–2.01 (m, 4H, 2× CH ).
2
13
White
solid;
yield
84%;
C NMR (125 MHz, DMSO-d ): 167.8, 162.6, 161.2,
6
ꢀ
1
mp = 225–227°C; IR (KBr): cm 3403, 3324, 2198,
718, 1779. H NMR (500 MHz, DMSO-d6): 7.86–7.81
m, 4H, Ha–d), 7.09 (s, 2H, NH ), 7.05 (d, J = 9.0 Hz,
158.0, 157.8, 148.6, 147.0, 136.3, 134.1, 131.7, 122.8,
119.3, 119.2, 113.3, 111.8, 100.8, 97.8, 66.5, 58.1,
1
1
+
(
55.4, 35.7, 35.2, 27.7, 19.2. MS (m/z, %): [M ; 513
2
H3,5-phenyl), 6.75 (d, J = 9.0 Hz, 2H, H2,6-phenyl), 6.24
s, 1H, H ), 4.19 (s, 1H, CH), 3.98 (t, J = 6.0 Hz, 2H,
(3%)], 188 (100), 160 (100), 130 (31), 66 (25). Anal.
(
Calcd for C H N O : C, 65.49; H, 4.51; N, 8.18.
1
28 23 3 7
CH ), 3.75 (t, J = 6.5 Hz, 2H, CH ), 2.21 (s, 3H, CH ),
Found: C, 65.29; H, 4.27; N, 8.29.
2
2
3
1
3
2.05 (t, J = 6.5 Hz, 2H, CH2). C NMR (125 MHz,
2-Amino-4-(4-(4-(1,3-dioxoisoindolin-2-yl)butoxy)-3-
methoxyphenyl)-7-methyl-5-oxo-4,4a,5,8a-
tetrahydropyrano[4,3-b]pyran-3-carbonitrile (8g).
DMSO-d ): 167.8, 162.6, 161.2, 157.9, 157.8, 157.4,
6
White
1
6
35.6, 134.2, 131.7, 128.4, 122.9, 119.2, 114.2, 97.8,
5.4, 58.2, 35.4, 34.9, 27.6, 19.2. MS (m/z, %): [M ; 483
ꢀ
1
+
solid; yield 87%; mp = 223–224°C; IR (KBr): cm
1
3
367, 3193, 2947, 2201, 1776, 1725.
H NMR
(4%)], 188 (100), 160 (86), 229 (3.5), 130 (6), 77 (3).
(500 MHz, DMSO-d6): 7.85–7.82 (m, 4H, Ha–d), 7.06 (s,
Anal. Calcd for C H N O : C, 67.07; H, 4.38; N, 8.69.
27 21 3 6
2
1
6
H, NH ), 6.87 (d, J = 8.0 Hz, 1H, H -phenyl), 6.77 (s,
Found: C, 67.21; H, 4.57; N, 8.55.
2
5
H, H -phenyl), 6.65 (d, J = 8.0 Hz, 1H, H -phenyl),
2
6
2
-Amino-4-(4-((1,3-dioxoisoindolin-2-yl)methoxy)-3,5-
.23 (s, 1H, H ), 4.22 (s, 1H, CH), 3.93 (t, J = 6.1 Hz,
dimethoxyphenyl)-7-methyl-5-oxo-4,4a,5,8a-
1
tetrahydropyrano[4,3-b]pyran-3-carbonitrile (8d).
White
2H, CH
CH ), 2.21 (s, 3H, CH
C NMR (125 MHz, DMSO-d
6
2
), 3.71 (s, 3H, OCH
), 1.75–1.72 (m, 4H, 2× CH
): 167.8, 162.6, 161.3,
3
), 3.64 (t, J = 6.1 Hz, 2H,
ꢀ
1
solid; yield 83%; mp = 253–254°C; IR (KBr): cm
2
3
).
2
1
13
3
452, 3327, 2938, 2189, 1780, 1727. H NMR (500 MHz,
DMSO-d6): 7.92–7.86 (m, 4H, Ha–d), 7.13 (s, 2H, NH2),
.37 (s, 2H, H2,6-phenyl), 6.24 (s, 1H, H ), 5.35 (s, 1H,
158.0, 157.8, 148.7, 147.1, 136.2, 134.2, 131.5, 122.8,
119.4, 119.2, 113.4, 111.9, 100.8, 97.8, 67.8, 58.1, 55.6,
6
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Characterization of Novel Phthalimide-pyrano
+
3
1
7.1, 35.6, 26.2, 24.7, 19.2. MS (m/z, %): [M ; 527 (3%)],
the introduction of an additional methoxy group
mounted on inactivity.
60 (100), 202 (89), 130 (28), 102 (10), 77 (15). Anal.
Calcd for C H N O : C, 66.03; H, 4.78; N, 7.97.
29 25 3 7
Found: C, 66.12; H, 4.90; N, 7.97.
Acknowledgments. This work was financially supported by
Research Council of Tehran University of Medical Sciences,
International Campus (TUMS-IC), vide grant no. 93-01-103-
Cholinesterase inhibition assay. Electric eel (Torpedo
californica), AChE (type VI-S), Butyrylcholinesterase
Enzyme (BChE) (E.C.3.1.1.8, from equine serum),
acetylthiocholine iodide, butyrylthiocholine iodide, 5,5-
di thio bis[2-nitrobenzoic acid] (DTNB), and donepezil
hydrochloride were purchased from Sigma–Aldrich
2
5020. Late Prof. Abbas Shafiee is highly acknowledged for
providing me insight and all over support in this work.
(Steinheim, Germany). Compounds stock solutions were
REFERENCES AND NOTES
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the synthesized compounds was determined by the
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dide as substrate in 24-well plates. The solutions
consisted of 2 mL of phosphate buffer, 65 mL of DTNB,
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2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet