Synthesis of β-phthalimido-alcohols via regioselective ring opening of epoxide by using reusable basic magnetic nano particles and their biological investigation

Article abstract of DOI:10.1039/c6ra07660b

In this work, tetra butyl ammonium hydroxide ([Bu₄N]OH) and magnetic nano particles (Fe₃O₄@SiO₂@CH₂)₃NH₂) were introduced as efficient catalysts for the regioselective ring openi

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Synthesis of ß-phthalimido-alcohols via regioselective ring opening of
epoxide by using reusable basic magnetic nano particles and their
biological investigation
Mohammad Ali Zolfigol,*a Ahmad Reza Moosavi-Zare,*b Mahmoud Zarei,a Abdolkarim Zare,c Ehsan
Noroozizadeh,a Roya Karamiand and Mostafa Asadbegyd
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
aliphatic and aromatic amines. Nowadays, it has been used for
the synthesis of catalysts18, complicated19 and advanced
50 materials.20 Moreover, phthalimide and its analogues have
been extensively used in medicinal chemistry owing to their
wide range of applications for designing of diverse
biologically active molecules such as anti-convulsant, anti-
inflammatory, analgesic, hypolipidimic, immunomodulatory
55 activities, antitumor drugs21 and anti HIV.22 Free radicals such
as reactive oxygen species (ROS) are formed naturally in the
body with important roles in cell signaling, however some
environmental toxins may contain free radicals or stimulate
the body’s cells to produce free radicals.23 High level of free
60 radicals are hazardous to the body and damage all major
components of cells, including nucleic acids, proteins and
plasma membrane, may play a role in the development of
cancer and other health conditions.24 A present trend in the
field of antioxidant development focuses on multipotent
65 antioxidant agents that can prevent biological substrates from
radical induced oxidative damage.25 Antioxidants may act as
free radical scavengers, reducing agents, quenchers of singlet
oxygen molecules and/or activators of antioxidative defense
enzyme systems to suppress the radical damages in biological
70 systems.26,27 Antioxidant agents such as butylated
hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)
are applied as additives in foods to prevent oxidation of lipids.
Also, BHA and BHT are restricted by legislative rules because
of doubts over their toxic and carcinogenic effects.28
75 Therefore, there is a growing request and interest for safer
antioxidants in food and pharmaceutical applications.29
Recently, phthalimide and its salts including potassium
phthalimide has been also widely used as catalyst in organic
synthetic chemistry.30 Therefore, development of eco-friendly
80 protocols using more efficient, recycle and reusable nano
magentic catalysts31 for regioselective aminolysis of epoxides
under green conditions is in more demand.32 In continuation
of our previous studies on the synthesis of nano magnetic
catalysts33 and development of task specific ionic liquids
85 (TSILs),34 nucleophilic ability of phthalimide35, and ring
opening of epoxides36, we found that desirable structural
diversity of functionalized phthalimides could be achieved via
joining all of these research areas to design a new reaction
In this work, tetra butyl ammonium hydroxide ([Bu4N]OH) and
10 magnetic nano particles (Fe3O4@SiO2@(CH2)3NH2) were
introduced as efficient catalysts for the regioselective ring
opening of epoxides including aromatic and aliphatic of epoxides
to give the corresponding ß-phthalimido-alcohols under mild
conditions. A various range of ß- phthalimido-alcohols as new
1
15 compounds were prepared and fully characterized by IR, H as
well as 13C NMR and mass spectra. Also the synthesized
compounds were studied for antioxidant properties by DPPH free
radical scavenging assay. The results indicated that studied
ß- phthalimido-alcohols derivatives have effective antioxidant
20 functions (IC50: 0.142 - 0.356 mg/mL) in compare with BHT
(IC50: 0.122 mg/mL) and ascorbic acid (IC50: 0.146 mg/mL) as
standards. This may be a new health-care food and drug
supplement for special use in the future.
Introduction
25 Epoxides are important starting materials and useful synthetic
intermediates in organic synthesis. Also, the conversion of an
alkene to an epoxide is a part of a more extensive molecular
transformation.1 Since epoxide ring opening is usually
stereospecific, such reactions can be used to establish
30 stereochemical relationships between adjacent substituents.2
For this purpose, a wide range of mono or 1,2-disubstituted
products, have been synthesized via addition of various
nucleophiles to epoxides and different promoters and
conditions have been proposed.3 Ring opening of epoxides
35 have been carried out with various nucleophiles such as
phenols1, 4, 5 thiols and thiophenols5, 11, indoles6, 11, amines7,
sulfonamides8,
thiocyanate9,
azide10,
benzotriazole11,
alcohols11, 12, AcOH12, H2O12, cyanide10e, 13, Sulfide14 and a
good range of anions15. Almost, the above mentioned ring
40 opening of epoxides have been carried out by applying acids
or bases as catalysts in the course of reactions so that
literature surveys shows that there are a few reports for ring
opening of epoxides under neutral conditions.16
Phthalimide is a very important starting synthone in organic
45 synthetic methodology for preparing diverse functionalized
molecules.17 The most famous and oldest applications of
phthalimide is Gabriel synthesis for converting halides to
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procedure for the synthesis of ß- phthalimidoalcohols under
catalyst in which the reaction was not progressed even after
solvent-free conditions (Scheme 1). Also results indicated that 50 long reaction time (2 h). Also, the solvent-free reaction of
ß- phthalimido-alcohols derivatives studied have remarkable
phthalimide with 2-phenyl oxirane was tested using
Fe3O4@SiO2@(CH2)3NH2 at 110 °C. The best result was
given by 1 mg of catalyst after 15 minutes (Table 1, entry 7).
antioxidant functions.
5
Table 1. Effect of different amounts of the catalysts and
55 temperature on the reaction between phthalimide with 2-phenyl
oxirane.
10 Scheme 1: The reaction of phthalimide with epoxide catalyzed by
Fe3O4@SiO2@(CH2)3NH2 or [Bu4N]OH.
Amount of
Catalyst
Temp.
(°C)
Time
(min)
Yielda
(%)
Catalyst
[Bu4N]OH
[Bu4N]OH
5 mol%
80
40
22
60
91
Development of task specific catalysts and their structural
diversity could be achieved via a combination of the desired
15 structural moiety or functional group within a catalyst core.
On the other hand, development of task specific ionic liquids
(TSILs) and their structural diversity could be achieved via
designing and synthesis of novel cationic cores with suitable
anionic counterparts. By considering the above mentioned
20 synthetic strategy, in the course of our investigation we
decided to use tetra butyl ammonium hydroxide ([Bu4N]OH)
as a commercially available IL and Fe3O4@SiO2@(CH2)3NH2
as basic magnetic nano particles for the ring opening of
epoxides with phthalimide under solvent free-conditions
25 (Scheme 1).
15 mol%
110
[Bu4N]OH
10 mol%
110
35
65
[Bu4N]OH
[Bu4N]OH
20 mol%
15 mol%
0.5 mg
1 mg
3 mg
0.5 mg
1 mg
110
90
80
110
110
110
90
21
30
17
17
15
35
25
91
57
70
94
94
52
65
Fe3O4@SiO2@(CH2)3NH2
Fe3O4@SiO2@(CH2)3NH2
Fe3O4@SiO2@(CH2)3NH2
Fe3O4@SiO2@(CH2)3NH2
Fe3O4@SiO2@(CH2)3NH2
aIsolated yield.
The condensation of phthalimide (1) (1 mmol) with 2-phenyl
oxirane (1 mmol), as model reaction, was examined by some
60 various organic and inorganic bases such as LiOH, KOH,
NaOH, NaCO3, DABCO and Et3N to choose the best basic
catalyst (Table 2). As Table 2 indicates that ([Bu4N]OH) and
Fe3O4@SiO2@(CH2)3NH2 are more successful than other
bases.
At
first,
the
SEM
micrographs
of
prepared
Fe3O4@SiO2@(CH2)3NH2 as basic magnetic catalyst was
investigated to show that the particles were obtained in nano
size (Figure 1).
65 Table 2. Evaluation of various bases on the reaction between
phthalimide with 2-phenyl oxirane in comparison with
Fe3O4@SiO2@(CH2)3NH2 and [Bu4N]OH.
30
Amount of
Catalyst
(mol%)
Temp.
(°C)
Time
(min)
Yielda
(%)
Base
LiOH
KOH
15
15
120
120
110
110
0
20
NaOH
DABCO
Et3N
15
15
15
120
120
120
110
110
110
30
35
30
35
[Bu4N]OH
15
110
110
22
17
91
94
Fe3O4@SiO2@(CH2)3NH2
1 mg
Figure 1. SEM micrographs of Fe3O4@SiO2@(CH2)3NH2.
aIsolated yield.
Then, as a model reaction, the condensation of phthalimide (1)
To compare the efficiency of solution conditions versus the
70 solvent-free conditions, a mixture of phthalimide (1 mmol) and 2-
phenyl oxirane (1 mmol) in the presence of [Bu4N]OH was
heated in an oil-bath (110 °C) in various solvents for 60 min.
Low yields of the product was obtained, even after elongated
reaction times (Table 3). In the solvent-free conditions, the
75 starting materials (phthalimide and 2-phenyl oxirane) and the
catalyst formed a homogeneous system in the reaction media.
This homogeneous system was also examined using various
solvents including CHCl3, EtOH, EtOAC, CH2Cl2 and H2O.
Therefore, the catalytic activity of [Bu4N]OH decreased in the
(1 mmol) with 2-phenyl oxirane (1 mmol) was selected in the
40 presence of different amounts of the tetra butyl ammonium
hydroxide, at range of 80-110 °C under solvent-free
conditions. The results are summarized in Table 1. As it is
shown at Table 1, indicates that 15 mol% of [Bu4N]OH was
sufficient to afford the desired product in excellent yield and
45 in very short reaction time at 110 °C (Table 1, entry 2). No
improvement in the reaction results was observed by
increasing the amount of the catalyst and the temperature. The
solvent-free condensation was also tested at 110 °C without
2
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presence of these solvents. In the case of H2O as solvent,
[Bu4N]OH was soluble in water, but the starting materials were
insoluble in it. Then, the yield decreased when H2O was applied
as solvent. Therefore, the solvent-free reaction was more efficient
than solution conditions.
Table 4. The preparation of ß-phthaimidoalcohls using method A
/ B.a
Product
Time
(min)
Yieldb
(%)
M.p. °C
103-105
5
35/30
85/85c
Table 3. The effect of various solvents on the reaction of
phthalimide (1 mmol) with 2-phenyl oxirane (1 mmol) by method
A and B in comparison with solvent-free conditions.
22/19
88/90
104-106
Solvent
EtOAc
CHCl3
Temprature
reflux
Time (min)
Yielda (%) A / Bb
45 / 40
60
60
reflux
55 / 33
EtOH
CH2Cl2
H2O
H2O
-
reflux
reflux
r.t.
reflux
110 °C
60
60
120
120
22/17
40 / 54
50 / 35
0 / 0
20 / 25
91 / 94
22/17
32/25
91/94
159-161
234-238
80/82c
aIsolated yield; bIn method A, [Bu4N]OH was used as basic
10 catalyst and in method B, Fe3O4@SiO2@(CH2)3NH2 was used.
In order to assess the scope and the generality of the catalysts,
the condensation of phthalimide with various epoxides was tested
in the presence of 15 mol% [Bu4N]OH at 110 °C in the absence
of solvent. The results are depicted in Table 4. As it is shown in
15 Table 4, epoxide rings were utilized successfully in the reaction,
and gave the desired products in high yields and in very short
reaction times. Thus, the catalyst was general and highly
efficient. Interestingly, the condensation of phetalimide (2 eq.)
with 2-(4-(oxiran-2-yl)butyl) oxirane (1 eq.) in the presence of
20 [Bu4N]OH (30 mol%) at 110 °C under solvent-free conditions,
afforded (2.2’-(2,7- dihydroxyoctane-1,8-diyl)diisoindoline-1,3-
dione) in 90 % of yield within 25 minutes (Scheme 2).
25/21
87/90
203-205
45/40
25/21
81/84d
72/76d
173-176
132-135
30/23
35/28
80/85
86/92
125-128
121-123
25
29/21
83/89
109-112
30 Scheme 2. The condensation of phthalimide with 2-(4-(oxiran-2-
yl)butyl)oxirane.
35 aIn method A, [Bu4N]OH was used as basic catalyst and in method B,
Fe3O4@SiO2@(CH2)3NH2 was used as basic catalyst; bIsolated yield;
cThese epoxides were used 3 mmol against of 1 mmol of phthalimide;
dThese products were purified by plate chromatography.
In a plausible mechanism (Scheme 3), at first, phthalimide, as an
40 acid, reacted with Fe3O4@SiO2@(CH2)3NH2 as a basic catalyst.
The produced phthalimide anion attacked to the epoxide and
opened it. Then, (I), as an anion, reacted with
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+
Fe3O4@SiO2@(CH2)3NH3 to give the desired product and the
basic catalyst. The produced catalyst utilized the reaction to
complete it.
DPPH radical scavenging assay
The free radical scavenging activity of the compounds
synthesized in this studied were evaluated using the stable radical
The model reaction was also studied using potassium phthalimide 60 DPPH.39 Briefly, 0.3 mM DMSO solution of DPPH (1 mL) was
5
instead of phthalimide in this reaction condition. The reaction
was not carried out due to the absence of acidic hydrogen in
phthalimide anion. The ring of epoxide could be opened by
phthalimide anion, but in a reversible reaction the epoxide and
added to samples (2.5 mL) containing different synthesized
compounds. The samples were first kept in a dark place at room
temperature and their absorbance was read at 517 nm after 30
min. The antioxidant activity (AA) was determined using the
phthalimide anion were prepared again. This observation clearly 65 following formula:
10 confirmed the mechanism of the reaction.
AA % = 1- [(As – Ab)/ Ac] ×100
O
O
Blank samples contained 1 mL DMSO + 2.5 mL from various
concentrations of synthesized compounds; control sample
containing 1 mL of 0.3 mM DPPH + 2.5 mL DMSO. The optic
70 density of the samples, the control and the empty samples were
measured in comparison with DMSO. Two synthetic antioxidant,
ascorbic acid and BHT were used as standards. The discoloration
was plotted against the sample concentration in order to calculate
the IC50 value, which is the amount of sample necessary to
75 decrease the absorbance of DPPH by 50%. Experiments were
carried out triplicate.
Nano-Fe3O4@
SiO2@(CH2)3NH2
Nano-Fe3O4@
SiO2@(CH2)3NH3
NH
N
15
20
25
O
O
O
O
O
R
N
N
R
O
(I)
O
O
O
O
O
HO
R
R
Nano-Fe3O4@
Nano-Fe3O4@
N
N
SiO2@(CH2)3NH3
SiO2@(CH2)3NH2
(I)
O
O
Statistical analysis
Scheme 3: The plausible mechanism for the synthesis of ß-
phthaimidoalcohls.
Data obtained from antioxidant assay is the average of triplicate
analyses and recorded as means standard deviation. Analysis of
80 variance was performed by Excel procedures statistical analysis
was performed using student’s t-test, and p value < 0.05 was
regarded as significant.
In another study, reusability of the catalyst was tested upon the
reaction of phthalimide (1 mmol) with phenyl oxirane (1 mmol).
30 The reaction mixture was extracted by warm ethanol to separate
from the catalyst. Afterward, the reused catalyst was used for
another reaction. We observed that the catalytic activity of the
catalyst was restored within the limits of the experimental errors
for four successive runs.
Conclusions
In summary, we have introduced tetrabutyl ammonium hydroxide
85 [Bu4N]OH, as homogeneous catalyst, for the synthesis of ß-
phthalimido-alcohls under green media. Also, basic magnetic
nano particles, (Fe3O4@SiO2@(CH2)3NH2), as heterogeneous
catalyst, was employed in this transformation. The promising
points for the presented methodology are efficiency, generality,
90 high yield, relatively short reaction time, low cost, cleaner
reaction profile, ease work-up and finally compliance with the
green chemistry protocols. Results from present study clearly
demonstrated that all ß-phthalimido-alcohols derivatives exhibit
antioxidant properties that might be helpful in preventing the
95 progress of various diseases and development of novel
therapeutic agents. Of course, other effects of newly synthesized
compounds in this research must be studied under in vivo
condition.
35 Antioxidant activity
Antioxidant properties, especially radical scavenging activities,
are very important due to the deleterious role of free radicals in
foods and biological systems.37 Free radical scavenging activity
of the synthesized compounds (C1-C9) assayed by 2,2-Diphenyl-
40 1-picrylhydrazyl radical (DPPH) and comparison with ascorbic
acid and BHT as a standard. Assessment of antioxidant activity
showed that all compounds have effective free radical scavenging
activity but in average function, compounds not showed different
remarkable in amount of scavenging activity (62.92% - 73.71%),
45 (Table 5). The higher antioxidant activity is reflected in a lower
IC50 value (mg/mL). The effectiveness of antioxidants as DPPH
radical scavengers ranged based on the IC50 value in the
following descending order: BHT > C3 = C6 ≥ ascorbic acid ≥ C2
≥ C7 ≥ C1 > C5 ≥ C8 > C9 > C4 (Table 5). The above results
50 indicate that the synthesized compounds may be used in the
treatment of diseases caused by free radicals. Further studies are
needed to evaluate the in vivo potential of these compounds in
animal models.
100 Acknowledgements
We thank Bu-Ali Sina University and Iran National Science
Foundation (INSF) (The Grant of Allameh Tabataba'i's Award,
Grant Number BN093) for financial support to our research
group.
55
105
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Table 5. Comparison of DPPH radical scavenging activity of
ß- phthalimide alcohols derivatives and ascorbic acid as a
standard.
35
Concentration (mg/mL)
Compounds
0.2
0.4
0.6
0.8
1
Average
66.42
66.92
73.05
62.92
71.02
73.71
71.22
62.88
62.25
61.50
76.88
76.88
IC50
59.16 2.7a 67.35 1.5b
65.21 2.1a 66.55 2.2a
70.56 3.3a 71.23 2.3a
48.33 1.8a 56.14 1.2b
55.45 2.6a 67.45 2.7b
70.24 1.3a 71.27 2.1a
61.56 2.8a 65.23 1.9a
55.32 3.1a 62.15 2.7b
50.62 1.2a 53.21 1.6a
58.21 2.2a 57.36 3.1a
68.74 2.7a 76.16 3.4b
82.24 0.8a 87.65 1.1b
66.26 1.3b
64.23 2.4a
70.00 2.5a
67.35 2.4c
72.25 1.2c
75.16 1.8a
73.54 2.7b
64.15 3.1b
61.41 2.3b
58.41 1.9a
78.85 1.4b
89.26 1.6b
68.18 2.6b 71.14 3.3b
69.17 1.2b 69.46 1.6b
75.13 1.1b 78.32 2.4b
69.17 2.2c 73.61 1.5c
78.26 3.2c 81.51 1.3d
73.24 2.6a 78.65 3.3b
76.34 3.2b 76.43 2.5b
64.58 2.6b 68.21 2.4b
69.74 2.5c 76.25 1.1d
64.21 1.4b 69.33 2.6b
80.41 2.2b 80.24 1.6b
88.12 2.7b 92.37 1.4b
0.169cd
0.153c
0.142b
0.356f
1
2
3
4
0.180d
40
5
0.142b
0.162c
0.181d
0.197e
0.172d
0.146b
6
7
8
9
10
Ascorbic acid
BHT
0.122a
45
5
Experiment was performed in triplicate and expressed
as mean SD. Values along column with different
superscripts are significantly different (P<0.05).
Experimental
General
procedure
for
the
synthesis
of
ß-phthaimidoalcohls using Nano Fe3O4@NH2
10 All chemicals were purchased from Merck or Fluke Chemical
Companies. Magnetic nanoparticles were prepared according the
previous literature.38 Progress of the reactions was monitored by
50 A mixture of Phthalimide (0.147 g, 1 mmol), epoxide (1 mmol),
and nano Fe3O4@SiO2@(CH2)3NH2 (1 mg) in a 10 mL round-
bottomed flask connected to a reflux condenser, was stirred in an
oil-bath (110°C). After completion of the reaction, as monitored
by TLC, the reaction mixture was cooled to room temperature,
55 extracted with Ethanol separate the catalyst. The product was
recrystallized in ethanol to afford the pure product which required
no further purification.
1
TLC using silica gel SIL G/UV 254 plates. The H NMR (400 or
300 MHz) and 13C NMR (100 or 75 MHz) were run on a Bruker
15 Avance DPX-250 FT-NMR spectrometer (δ in ppm).
Microanalyses were performed on Perkin-Elmer 240-B
microanalyses. Melting points were recorded on a Büchi B-545
apparatus in open capillary tubes.
20 General procedure for the synthesis of ß-phthaimidoalcohls
using [Bu4N]OH
Notes and references
a
Depatment of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina
60 University, Hamedan 6517838683, Tel: +988138282807, Fax:
+988138380709 Iran. E-Mail: zolfi@basu.ac.ir & mzolfigol@yahoo.com
b Sayyed Jamaleddin Asadabadi University, Asadabad, 6541835583, Iran.
E-mail addresses: moosavizare@yahoo.com,
cDepartmentof Chemistry, Payame Noor University, Iran
65 dDepartment of Biology, Faculty of Science, Bu-Ali Sina University,
65175/4161, Hamedan, Iran. E-Mail: R_karamian@basu.ac.ir
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
A mixture of phthalimide (0.147 g, 1 mmol), epoxide (1 mmol),
and [Bu4N]OH (0.15 mol%) in a 10 mL round-bottomed flask,
connected to a reflux condenser, was stirred in an oil-bath at
25 110°C. After completion of the reaction, as monitored by TLC,
the reaction mixture was cooled to room temperature, extracted
with CHCl3 (10 mL) and H2O (10 mL) to separate the catalyst.
The product was recrystallized in CHCl3 to afford the pure
product, which required no further purification.
70 ‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
30
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DOI: 10.1039/C6RA07660B
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DOI: 10.1039/C6RA07660B
Synthesis of ß-phthalimido-alcohols via regioselective ring opening of epoxide
by using reusable basic magnetic nano particles and their biological
investigation
Mohammad Ali Zolfigol,* Ahmad Reza Moosavi-Zare,* Mahmoud Zarei, Abdolkarim Zare,
Ehsan Noroozizadeh, Roya Karamian and Mostafa Asadbegy
Tetra butyl ammonium hydroxide ([Bu4N]OH) and magnetic nano particles
(Fe3O4@SiO2@(CH2)3NH2) were introduced for the regioselective ring opening of epoxides
including aromatic and aliphatic of epoxides to give the corresponding ß-phthalimido-alcohols.
The products were studied for antioxidant properties by DPPH free radical scavenging assay.