Palladium functionalized phosphinite polyethyleneimine grafted magnetic silica nanoparticles as an efficient catalyst for the synthesis of isoquinolino[1,2-: B] quinazolin-8-ones

Article abstract of DOI:10.1039/c7nj04837h

In this paper, a novel methodology is introduced for the synthesis of novel 5-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one derivatives based on an efficient immobilized palladium catalyzed intramolecular carbon-carbon bond formation. The novel catalyst i

Full text of DOI:10.1039/c7nj04837h

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C7NJ04837H
Journal Name
ARTICLE
Palladium Functionalized Phosphinite Polyethyleneimine grafted
Magnetic Silica Nanoparticles as an Efficient Catalyst for the
Synthesis of Isoquinolino[1,2-b]quinazolin-8-ones
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
c
d
Saeed Bahadorikhalili , Mohammad Mahdavi , Leila Ma’mani , Abbas Shafiee , Hossein
DOI: 10.1039/x0xx00000x
,
a
,d
Mahdavi* and Tahmineh Akbarzadeh*
www.rsc.org/
In this paper, a novel methodology is introduced for the synthesis of novel 5-methyl-8H-isoquinolino[1,2-b]quinazolin-8-
one derivatives based on an efficient immobilized palladium catalyzed intramolecular carbon-carbon bond formation. The
novel catalyst is fabricated by immobilization of Pd on phosphinite polyethyleneimine functionalized Fe
3 4 2
O @SiO core-
shell nanoparticles (denoted as Pd@OPPh -PEI-mSiO NPs). In this catalyst, PEI moieties act as both water dispersant and
2
2
base in the reaction. In the key step, 3-allyl-2-(2-bromophenyl)-2,3-dihydroquinazolin-4(1H)-ones (3a-i) were synthesized
via cyclization reaction between N-allyl-2-aminobenzamides and 2-bromobenzaldehyde. The latter obtained materials
then underwent an intramolecular carbon-carbon bond formation in the presence of Pd@Ph
-methyl-13,13a-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-ones (4a-i).
2 2
PO-PEI-mSiO catalyst to give
5
effective research tools to improve novel and operative
9
Introduction
magnetically recoverable catalysts. Their widespread usage
and versatility make magnetic silica core-shell NPs excellent
and interesting supporting materials for providing new and
In the last few decades, transition metal-catalyzed carbon-
carbon bond formation has proven to be one of the most
direct and efficient methods for the preparation of complex
chemical compounds. Among different metals which are used
as catalyst, palladium is an efficient one, which has attracted
interests due to its unique properties. Palladium catalysts are
used in several organic transformations, especially in carbon-
carbon bond formation reactions. Mizoroki-Heck reaction is
an important carbon-carbon bond formation reactions, which
is catalyzed by palladium, and has intensely attracted interests
in recent years.
intramolecular carbon-carbon bond formation is a useful way
for the synthesis of complex chemical compounds such as
cyclic ketones, 11-methyl-6H-isoindolo[2,1-a]indol-6-ones,
and substituted cycloheptenone dericvatives.
Magnetic NPs have displayed high applicability in different
fields including chemistry and catalysis
9
e
improved green catalysts.
Regarding the great progress
1
which has been achieved in the field of catalytic reactions,
novel solid supported phosphine ligands have been used as a
robust supporting material for the immobilization of transition
metals and their applications as a catalyst in organic
transformations. Regarding the unique properties of
poly(ethyleneimine) (PEI) including physical and chemical
stabilities, good water solubility, and high content of functional
groups, it has attracted interest for the functionalization of
nanoparticles. Covalent functionalization of nanoparticles by
PEI has been successfully applied for directed drug delivery,
gas adsorption and separation techniques, and as a support for
2
3
4
Applying Mizoroki-Heck reaction in
5
6
1
0
7
immobilization of catalysts.
Quinazolinone derivatives are probably the most ubiquitous
nitrogen-containing heterocycles in nature and have been
referred to as privileged scaffolds in drug discovery. Their
valuable properties, such as antitumor, anticonvulsant,
and epidermal growth factor receptor
EGFR) tyrosine kinase inhibitory activities, have attracted a
8
and known as
1
1
1
2
13
1
4
anti-inflammatory,
1
5
(
great deal of attention. Also, they have been well known as
1
6
peptidomimetic scaffold. Among the various quinazolinones,
1
7
isoquinolinone derivatives widely occur in natural products,
they are also versatile building blocks for the total synthesis of
1
8
natural alkaloids. Some isoquinolinones exhibit various
biological and medicinal activities such as antihypertensive
1
9
20
activity
and act as NK3 antagonists, melatonin MT1 and
2
1
22
MT2 receptor agonists, Rho-kinase inhibitors,
and JNK
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ARTICLE
Journal Name
2
3
inhibitors.
They also are novel orally active 5-HT3
Results and Discussion
To prepare the Pd catalyst based on modified magnetic NPs,
View Article Online
DOI: 10.1039/C7NJ04837H
2
4
25
antagonists, thymidylate synthase (TS) inhibitors, or applied
for the treatment of stomach tumors and diseases of human
brain cells.
shown cytotoxic activity.
Regarding our previous efforts on the synthesis of
1
7b
superparamagnetic Fe
3 4
O NPs were initially synthesized and
Isoquinolino[1,2-b]quinazolin-8-ones derivatives
2
7c
1
7f
characterized according to our previous reported methods.
Afterwards, to improve their stability and biocompatibility, the
magnetic NPs were coated with silica shell generated by
hydrolysis and condensation of TEOS to form magnetic
Fe O @SiO (mSiO ) NPs. Then mSiO was functionalized by
3 4 2 2 2
decoration of the nanoparticle surface with PEI chains via the
2
6
quinazolinone derivatives
on one hand, and extending
2
7
methodologies based on Pd catalyzed reactions, herein, we
report a promising cyclization reaction methodology via an
intramolecular Heck reaction using Pd catalyst decorated on
phosphinite polyethyleneimine modified magnetic silica NPs to
obtain novel 5-methyl-8H-isoquinolino[1,2-b]quinazolin-8-ones
covalent grafting using PEI1200–silane obtained from the
2
7d
treatment of PEI1200 and TESPIC.
onto the mSiO NPs was both for the increasing the
hydrophilicity of the catalyst, and application as a base in the
reaction. In continuation, the PEI mSiO NPs was treated with
chlorodiphenylphosphine (ClPPh ) to give the decorated
Introduction of PEI grafts
2
(
4a-i) (Scheme 1).
2
O
O
2
OH
H
phosphinite ligand on the surface of modified magnetic NPs.
Finally, PEI phosphinite moiety was applied as a dispersible
pendant for immobilizing of Pd NPs on the surface of mSiO2
NPs. Therefore, as synthesized PEI-OPPh
with Pd(OAc)2 to provide Pd@Ph PO-PEI-mSiO as the
R
R
O
R
NH2
O
H N
1
2
Br
N
or
R
H
EtOH, reflux
K CO , 12 h
reaction conditions
NH2
2 2
-mSiO was reacted
O
2
3
2
2
2
N
H
O
N
designed catalyst (Scheme 2). It is noticeable that the
phosphinite group present in the structure of the catalyst acts
as an efficient complexing agent for Pd(II). The structure of
Pd@Ph PO-PEI-mSiO was characterized by diverse techniques
1'
O
N
O
Pd@Ph PO-PEI-mSiO2
N
2
R
R
o
2
2
H O/PEG, 110 C
2
N
H
including high resolution transmission electron microscopy
HRTEM), vibrating sample magnetometer (VSM), thermal
gravimetric analysis (TGA), Fourier transform infrared
spectroscopy (FT-IR), N adsorption–desorption analysis, and
R
R
3
4
(
Br
Scheme 1 Synthesis of 5-methyl-13,13a-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-
one derivatives (4a-i)
2
inductively couple plasma-atomic emission spectrometry (ICP-
AES) analysis.
TEOS
NH 4OH
Fe2+
Fe3+
+
Fe3O4@SiO2
O
H
N
H
N
NH 2
H
N
N
n
H
H
N
O
O
EtOH/H 2O
Si
N
H
N
H
n
O
Pyridine, Ar
O C N
TESPIC
Si
pH = 4
O
+
O
O
N
NH 2
PEI-Silane
2
H N
NH 2
PEI
O
O
H
N
H
N
i) ClCH CH OH, CH Cl , ref, 24h
2 2 2 2
ii) Et3N, ClPPh2, CH 2Cl2
iii) Pd(OAc)2, CH2Cl2, 24h, rt, Ar
O
O
Si
H
H
H
N
O
O
Si
N
O
O
N
H
PPh2
n
N
H
O
n-1
O
O
O
Pd
H
N
H
N
O
Si
H
H
N
O
N
H
H
N
PPh2
n
O
O
Si
O
N
H
n-1
O
[
PEI-Fe3O4@SiO2]
Pd@OPPh 2-PEI-mSiO2 NP
H
N
H
N
NH 2
H
N
N
n
H
H2N
N
H
PEI
n
N
NH 2
H2N
NH 2
Scheme 2 The synthesis of Pd@OPPh
2
-PEI-mSiO
2
2
| J. Name., 2012, 00, 1-3
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For studying the structural morphology and core-shell
structure of the Pd@Ph PO-PEI-mSiO , SEM and HRTEM
images were applied. The TEM images of Pd@PEI-OPPh -mSiO
2
2
2
2
can be seen in Fig. 1a and 1b. In the HRTEM image, the
superparamagnetic Iron oxide nanoparticles can be seen as
dark spots encapsulated by more bright silica shell. The more
bright regions which are capsulated SPIONs are correlated to
2
SiO coating and the organic functionalization. The particles
showed narrow dispersity with particles size between 20-25
nm. The core-shell structure can clearly be seen in the images.
In SEM images, the spherical morphologies of the
nanoparticles can clearly be observed.
The magnetic behavior of mSiO NPs before and after post
2
modifications, the magnetic hysteresis was assessed by VSM in
an applied magnetic field at r.t, with the field sweeping from
−
8000 to +8000 Oe. The superparamagnetic nature of mSiO
and Pd@Ph PO-PEI-mSiO has been shown by their S-type
magnetization hysteresis loop (Fig. 2a). As illustrated in Fig. 2b,
the images of aqueous solutions of Pd@Ph PO-PEI-mSiO with
2
2
2
2
2
and without external magnet firmly have demonstrated the
sufficient magnetization for the magnetically separation.
TG analysis was applied to reveal the thermal stability and also
to determine the amount of loaded PEI phosphinite on the
surface of mSiO
Pd@Ph PO-PEI-mSiO
and shows no significant weight lose less than 300 °C. The TG
curve of Ph PO-PEI-mSiO and Pd@PEI-OPPh -mSiO show a
2
NPs (Fig. 3). TGA curves confirm that
2
2
catalyst is thermally stable (up to 300°C)
2
2
2
2
sharp decrease in weight was observed at 300 °C – 700 °C.
Regarding the weight loss on TGA curves, the amount of
−1
loaded PEI phosphinite moiety determined 1.9 mmol IL g .
In addition, the presence of PEI-phosphinite on the surface of
magnetic nanoparticles was proved by TG analysis. We note
that, the TG curve of mSiO
2
has no weight loss after 300 °C, but
PO-PEI-mSiO sharp
for Ph PO-PEI-mSiO and Pd@Ph
2
2
2
2
a
decrease in weight was observed at 300 °C – 700 °C, which can
be attributed to the decomposition of the organic moieties
grafted onto the surface of mSiO (Fig. 3).
2
The surface area of the synthesized NPs was determined by
Brunauer–Emmett–Teller (BET) theory. The large surface area
2
of mSiO magnetic nanoparticles was related to the small
particle size of this material as could be observed in TEM
images. Moreover, the content of the Pd in the catalyst was
investigated by ICP-AES. the Pd content of the obtained
-1
catalyst was 0.82 mmol.g in the Pd@Ph
catalyst using ICP-AES.
2 2
PO-PEI-mSiO
2 2
Figure 1 (a) HRTEM, (b) SEM and (c) TEM images of Pd@PEI-OPPh -mSiO
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Figure2 (a) VSM diagram of mSiO
2
and Pd@Ph
2
PO-PEI-mSiO
2
; and (b) high water
dispersion and facile magnetic separation of Pd@Ph
2
PO-PEI-mSiO
2
2 2 2 2
Figure 4 FTIR spectra for (a) mSiO , (b) PEI-mSiO , and (c) Pd@Ph PO-PEI-mSiO .
The activity of the catalyst was subsequently investigated upon
characterization in the intramolecular Heck reaction. The
reaction was studied for finding the optimized conditions.
Blank runs with provided the lack of catalytic activity in the
presence of mSiO or Ph PO-PEI-mSiO NPs as catalyst. The
2 2 2
performance of the reaction showed to be independent to in
the presence of a base beside the catalyst. Therefore a series
of bases including NaOH, KOH, K CO , pyridine and NEt were
2 3 3
screened. The great advantage of pendant PEI groups is their
role as base in the reaction (Table 1, Entry 1). In addition the
catalytic activity of the Pd@Ph
with non-immobilized palladium catalyst (Table 1, Entries 7-
4). For this purpose, palladium acetate (Table 1, Entries 7-10)
2 2
PO-PEI-mSiO was compared
1
and palladium chloride (Table 1, Entries 11-14) were used as
catalyst for the synthesis of the desired products. As can be
seen, the desired products have been obtained when non-
immobilized palladium salts are applied as catalyst in a very
lower yields.
2 2 2 2 2
Figure 3. TG analysis of mSiO , Ph PO-PEI-mSiO , and Pd@Ph PO-PEI-mSiO catalyst
Then the effect of the amount of the catalyst on the reaction
was investigated and different quantities of catalyst ranging
from 0.001 to 0.050 g were tested. The best results were
observed when 0.015 g of the catalyst (0.82 mmol of Pd in
each gram of the catalyst) has been applied, while using more
quantities of the catalyst did not improve the reaction
performance. we note that in the absence of the catalyst, no
product was formed, which proves that, the presence of the
catalyst is necessary for the reaction. However, the
performance of the reaction was investigated in the presence
2
FT-IR spectra of mSiO NPs showed characterization peaks for
Fe–O–Fe, Si–O–Si and O–H groups (Fig. 4a), which indicates the
presence of iron oxide and silica phases. As shown in Fig 4b,
after the reaction between PEI1200–silane and mSiO
2
, the
resultant PEI mSiO did not show any vibration at 2000–2500
2
-1
cm which confirmed the absence of the isocyanate group.
Meanwhile, the successful immobilization of PEI phosphinite
on the surface of mSiO
2 2 2
in PEI-OPPh -mSiO catalyst was
-1
confirmed by additional peaks observed at 1677 cm and 1491
-1
cm which could be assigned to C=O bonds (Fig. 4c).
We expected that the immobilization of PEI pincer-like
phosphinite pendant on the surface of magnetic NPs provides
a good distribution of catalytically active Pd species on the
support and accordingly it stabilizes the Pd NPs during the
chemical reaction, and also prevents the aggregation of Pd
NPs. Therefore, PEI plays multiple role in giving more
hydrophilic character to the catalyst and acting as base during
the reaction.
of PEI-mSiO
in this case, no product could be formed. This observation
proves that, PEI-mSiO without palladium nanoparticles do not
2
nanoparticles without any palladium loading. Also
2
show any catalytic activity in this reaction.
For comparing the catalytic activity of Pd@Ph PO-PEI-mSiO
2 2
with other palladium catalysts, the reaction was performed in
Pd(OAc) , PdCl and Pd-PVP catalyst (Table 1, Entries 7-18).
2
2
4d,4e
As can be seen in Table 1, the desired product is obtained
in all cases. But the isolated yields were lower than
2 2
Pd@Ph PO-PEI-mSiO catalyzed reactions.
4
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[
a]
[a]
Table 1 Effect of different based on the reaction time and the isolated yield
Table 2 Effect of different solvents on the reaction time and the yieldView Article Online
DOI: 10.1039/C7NJ04837H
Entry
Base
---
DIPEA
KOH
Catalyst (g)
Pd@Ph PO-PEI-mSiO
Time (h)
24
36
36
48
48
48
48
48
48
48
48
48
48
36
36
36
Yield (%)
[
b]
Entry
Solvent
H O
DMF
Time (h)
47
36
36
24
48
48
48
Isolated Yield (%)
1
2
3
4
5
6
7
8
9
2
2
83
62
58
67
75
71
66
71
64
59
56
75
72
71
67
69
66
2
1
2
3
4
5
6
7
41
56
62
83
48
55
41
Pd@Ph
Pd@Ph
Pd@Ph
Pd@Ph
Pd@Ph
2
2
2
2
2
PO-PEI-mSiO
2
PO-PEI-mSiO
PO-PEI-mSiO
PO-PEI-mSiO
PO-PEI-mSiO
2
DMSO
K
2
CO
pyridine
NEt
3
2
2
2
2
[b]
PEG/H O
EtOH
3
[c]
CH
CH
2
Cl
CN
2
NaOH
pyridine
DIPEA
Pd(OAc)
2
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
[
a]
Reaction conditions: 3 (1 mmol), solvent (5 mL), and catalyst (0.015 g) at 110°C;
50:50 (v/v) mixture
[b]
1
1
1
1
1
1
1
1
0
2
3
4
5
6
7
8
K
2
CO
3
[
c]
NaOH
pyridine
DIPEA
PdCl
2
solvents with different polarities. The results show that, a 50:50
PdCl
PdCl
Pd-PVP
2
2
(
2
v/v) mixture of H O/PEG600. Finally, performing the reaction in
[d]
different temperature conditions proved 110°C as the best one
for yielding the desired product.
K
2
CO
3
NaOH
pyridine
DIPEA
Pd-PVP
Pd-PVP
Pd-PVP
Having the optimized conditions in hand, the scope of the Pd
catalyzed intramolecular cyclization reactions of 3-allyl-2-(2-
bromophenyl)-2,3-dihydroquinazolin-4(1H)-ones (3a-i) was
36
[
a]
[b]
Reaction conditions: 3 (1 mmol), H2O:PEG (5 mL), and base (1.5 eq) at 110°C;
investigated. As shown in Table 3, Pd@Ph
successfully catalyzes the reaction to give the desired products.
The corresponding 5-methyl-13,13a-dihydro-8H-
2 2
PO-PEI-mSiO
[c]
Pd@Ph2PO-PEI-mSiO2 catalyst (0.82 mmol of Pd in each gram of the catalyst);
Pd(OAc)2 or PdCl2 (5 mol %), PPh3 (10 mol%), PEG (5 mL), and base (1.5 eq) at 110
[d]
°
C; Pd-PVP (5 mol%), H2O:PEG (5 mL), and base (1.5 eq) at 110 °C.
isoquinolino[1,2-b]quinazolin-8-one derivatives (4a-i) were
obtained in moderate to good yields for various examined
substrates at 110 °C. As illustrated, a wide range of
isoquinazolinone can be efficiently produced with this catalytic
system. All substrates possessing electron-rich as well as
electron-poor substituents underwent intramolecular cyclization
Afterwards, the performance of the reaction was studied in
different solvents. As can be seen in table 2, the synthesis of 5-
methyl-13,13a-dihydro -8H-isoquinolino[1,2-b]quinazolin-8-one
derivatives was performed in different protic and aprotic
catalyzed by Pd@Ph
heteroatoms were also performed the reaction (Table 3, 4e and
f). It was noteworthy that the hetero-atoms could be tolerated
under identical conditions with good yields.
2 2
PO-PEI-mSiO . Starting materials containing
4
2 2
Table 3 The synthesis of 5-methyl-13,13a-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one derivatives using Pd@Ph PO-PEI-mSiO catalyst
The reaction conditions: 3 (1 mmol), Pd@PEI-OPPh2-mSiO2 (0.015 g, 0.82 mmol of Pd in each gram of the catalyst) and H2O/PEG600 50:50 v/v (5 mL) at 110°C.
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(
0.505 g,
5
mmol) were added to
a
solution of
Cl . The
chlorodiphenylphosphine (1.1 g, 5 mmol) in dry CH
2
2
mixture was stirred under argon atmosphere for 12 h at room
temperature. Then the solid residue separated by a magnet,
washed with CH
to give Ph PO-PEI-mSiO
Preparation of Pd@Ph PO-PEI-mSiO
2 2
Cl and dried in a vacuum oven at 50 °C for 12 h
2
2
.
2
2
catalyst
To a mixture of Ph PO-PEI-mSiO
2
2
2 2
(1 g) in 50 ml dry CH Cl ,
palladium acetate (2 mmol) was added and stirred at room
temperature under argon atmosphere for 24 h. The obtained
solid was magnetically separated and washed with CH
2
Cl (2×10
2
ml) and Et O (2×10 ml). Ph PO-PEI-mSiO catalyst was obtained
2 2 2
as a dark brown powder after drying under vacuum for 12 h.
General procedure for the preparation of N-allyl-2-
aminobenzamide (2) from isatoic anhydrides
Isatoic anhydride (5 mmol) was poured in water (100 ml) and
allylamine (6 mmol) was added dropwise during 30 min. The
mixture was stirred overnight at room temperature. N-allyl-2-
aminobenzamide product was formed as cream colored
precipitates. The product was filtrated and washed 3 times with
cold water and dried at room temperature. Typical yield for the
products were above 95%.
2 2
Figure 5 Reusability of Pd@Ph PO-PEI-mSiO in the synthesis of triazolylquinazolinone
after 10 runs
An advantage of current catalyst is its high reusability. The
recycling of Pd@Ph PO-PEI-mSiO catalyst tested in 10
sequential reactions for the preparation reaction of 5-methyl-
H-isoquinolino[1,2-b]quinazolin-8-one. The results are
presented in Figure 5. It is obvious in Figure 5 that, no significant
2
2
General procedure for the preparation of N-allyl-2-
aminobenzamide (2) from anthranilic acid
8
th
loss in the catalyst activity can be observed after 10 run. It can Anthranilic acid (1 mmol) was dissolved in dry dichloromethane.
be due to the high stability of the catalyst, and low leaching of To this, Hydroxybenzotriazole (1.1 mmol) and allyl amine (1
copper, which makes the structure of Pd@Ph
catalyst stable during the reaction.
2
PO-PEI-mSiO
2
mmol) was added. Following this, 1 equivalent of diisopropyl
carbadiimide was added to the mixture and the reaction was
mixed overnight. Upon completion of the reaction, the isopropyl
urea was filtrated away and dichloromethane layer was washed
with saturated sodium bicarbonate solution and then with 2M
HCl. The organic layer was dried over anhydrous sodium sulfate
and the solvent was then removed under reducer pressure.
Typical yield for the products were above 80%.
Experimental Section
Preparation of PEI Functionalized-Fe O @SiO
3 4 2
PEI1200–silane was synthesized via the hydrogen-transfer
nucleophilic addition reaction between PEI (MW = 1200) and the
General procedure for the synthesis of 3-allyl-2-(2-
isocyanate group of 3-(triethoxysilyl) propyl isocyanate (TESPIC). bromophenyl)-2,3-dihydroquinazolin-4(1H)-one derivatives (3)
2
7d
First 0.01 mol of dried PEI1200 was dissolved into 50 mL of dry
N-allyl-2-aminobenzamide
(3.0
mmol)
3
and
2-
pyridine with vigorous stirring under argon atmosphere for 6 h
at 70 °C, and then, 0.01 mol of TESPIC was added. After more 24
h stirring of the reactioin mixture, the solvent was removed by
vacuum evaporation and the residue was washed three times
with n-hexane. The obtained white PEI1200–silane was filtered at
bromobenzaldehyde (3 mmol) and K
2
CO (1.1 eqivalent) was
dissolved in ethanol (20 ml) in a round flask equipped with
condenser, heater and magnetic stirrer. The reaction mixture
was refluxed for 24 h, while the reaction progress monitored by
TLC. After completion of the reaction, the solvent was
evaporated under reduced pressure and the product was
recrystallized in ethanol to obtain pure product.
0
°C and then dried at room temperature in vacuum.
Then a solution of 0.1 g of PEI1200–silane in 30 mL of EtOH was
added drop-wise to a vigorous stirring solution of 25 mg of
General procedure for Pd@Ph
2
PO-PEI-mSiO
2
catalyzed
Fe O @SiO nanoparticles, which was prepared according to the
3 4 2
8d
intramolecular coupling of 3-allyl-2-(2-bromophenyl)-2,3-
2
reported procedure, in 30 mL EtOH/H O (1:2) and HCl (pH = 4).
After vigorous stirring for 24 h, the solution was filtered off and dihydroquinazolin-4(1H)-one derivatives to 5-methyl-8H-
washed thoroughly. The white residue was dried at 100 °C in isoquinolino[1,2-b]quinazolin-8-ones
vacuum for 12 h to obtain PEI-mSiO
Preparation of ethanol modified PEI-Fe
-chloroethanol (0.4 g, 5 mmol) was poured to a mixture of PEI- equivalent) and Pd@Ph
mSiO
(2 g) in 50 ml toluene and the mixture was stirred at 90 °C mixture was stirred at 90°C. TLC monitoring showed the reaction
overnight. Then the solid residue was magnetically separated, completion after 48 h. After completion of the reaction, the
washed with toluene and Et
O, and dried in a vacuum oven at 50 mixture was cooled to the room temperature and was poured
C for 24 h. The dried magnetic solid (2 g) and triethylamine into water (10 ml) and the product was extracted with ethyl
2
.
In a 1:1 mixture of H
,3-dihydroquinazolin-4(1H)-one (1 mmol), sodium acetate (1.2
PO-PEI-mSiO (0.015 g) was added. The
2
O:PEG600 (2 ml), 3-allyl-2-(2-bromophenyl)-
3 4 2
O @SiO
2
2
2
2
2
2
°
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 6
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Page 7 of 9
Pl eNa es we dJ oo u nr no at l ao df j Cu hs te mm i as tr rgy ins
Journal Name
acetate. The organic phase was dried over Na
ARTICLE
4
SO . Then the 5-methyl-8H-pyrido[2',3':4,5]pyrimido[2,1-a]isoquinoVliienw-A8r-toicnleeO(n4linf)e
2
combined organic phase was evaporated and the products were
purified by column chromatography on silica gel using a mixture
of n-hexane:ethyl acetate (5:1) as eluent. The recovered catalyst
was rinsed with water and EtOH, and finally dried at r.t. and
used without any pretreatment for the next run. The recycling
test of the catalyst was performed in the reaction between
bromobenzene and n-butyl acrylate according to the above
procedure.
Yield: 75%; white crystals; mp 155-15
O: C: 73.55, H: 4.24, N: 16.08, O: 6.12, Found: C: 73.14,
D
8
O
°
I
C
:
;
10.
A
10
n
3
a
9
l
/
.
C7
C
N
a
J
l
0
cd483
for
7
H
16 11 3
C H N
-
1 1
H: 4.55, N: 16.27, O: 5.92; IR (KBr): υ = 1676, 1606 cm ; H NMR
DMSO-d , 500 MHz): δ = 2.51 (3H, s), 6.98 (1H, d, J = 8 Hz), 7.26-
.28 (2H, m), 7.50 (1H, s), 7.60 (1H, t, J = 8 Hz), 7.71 (1H, d, J = 8
Hz), 7.88 (1H, t, J = 8 Hz), 8.21 (1H, d, J = 8 Hz) ppm; C NMR
DMSO-d , 125 MHz): δ = 20.9, 117.4, 118.8, 120.3, 126.4, 127.3,
28.2, 128.3, 129.8, 131.8, 133.7, 134.6, 134.7, 135.5, 146.8,
(
7
6
1
3
(
1
6
+
Spectral
dihydroquinazolin-4(1H)-one derivatives
-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (4a)
Yield: 83%; white crystals; mp 202-205°C (Lit. 203-205°C );
Anal. Calcd for C17 O: C: 78.44, H: 4.65, N: 10.76, O: 6.15,
Found: C: 78.28, H: 4.81, N: 10.89, O: 6.02; IR (KBr): υ = 1676,
data
of
3-allyl-2-(2-bromophenyl)-2,3- 154.9, 161.3 ppm; MS (70 eV): m/z = 261 (M ).
5-methyl-2-nitro-8H-benzo[g]isoquinolino[1,2-b]quinazolin-8-one
4g)
Yield: 84%; white crystals; mp 187-189°C; Anal. Calcd for
: C: 70.98, H: 3.69, N: 11.83, O: 13.51, Found: C:
(
5
1
7f
21 13 3 3
C H N O
12 2
H N
-1
7
0.32, H: 3.45, N: 12.01, O: 13.23; IR (KBr): υ = 1679, 1590 cm ;
1
-
1 1
H NMR (DMSO-d
t, J = 8.5 Hz), 7.32 (1H, t, 8.5 Hz), 7.56 (1H, d, 6 Hz), 7.66 (1H, s),
.76 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 6
Hz), 8.01 (1H, d, J = 8.5 Hz), 8.11 (1H, s), 8.42 (1H, s), 8.73 (1H, s)
6
, 500 MHz): δ = 2.00 (3H, d, 1.2 Hz), 7.26 (1H,
1
6
590 cm ; H NMR (DMSO-d , 500 MHz): δ = 2.00 (3H, d, J = 1.5
Hz), 7.28-7.31 (3H, m), 7.35-7.38 (2H, m), 7.48-7.50 (1H, m), 7.69
1
3
7
(
1H, q, J = 8.5 Hz), 7.82 (1H, d, J = 8.5 Hz), 8.01 (1H, s) ppm; C
NMR (DMSO-d
6
, 125 MHz): δ = 23.1, 112.6, 117.3, 117.4, 121.6,
1
3
ppm; C NMR (DMSO-d
6
, 125 MHz): δ = 45.6, 115.1, 115.9,
16.3, 116.5, 117.3, 118.2, 118.4, 119.7, 122.3, 123.4, 125.3,
27.3, 129.0, 129.4, 141.1, 142.6, 149.7, 150.5, 160.2 ppm; MS
(70 eV): m/z = 355 (M ).
-methyl-8H-benzo[g]isoquinolino[1,2-b]quinazolin-8-one (4h)
Yield: 80%; white crystals; mp 179-181°C; Anal. Calcd for
O: C: 81.27, H: 4.55, N: 9.03, O: 5.16, Found: C: 81.55, H:
1
25.3, 127.1, 128.3, 129.4, 130.8, 132.5, 133.2, 138.0, 138.3,
+
1
1
1
46.5, 156.7, 161.0 ppm; MS (70 eV): m/z = 261 (M ).
-methyl-2-nitro-8H-isoquinolino[1,2-b]quinazolin-8-one (4b)
5
+
1
7f
Yield: 87%; white crystals; mp 222-224°C (Lit. 224-226°C );
Anal. Calcd for C17 : C: 66.88, H: 3.63, N: 13.76, O: 15.72,
Found: C: 67.12, H: 3.47, N: 13.57, O: 15.93; IR (KBr): υ = 1671,
5
11 3 3
H N O
-
1 1
21 14 2
C H N
1
(
597 cm ; H NMR (DMSO-d
1H, s), 6.87 (1H, d, J = 8 Hz), 7.00 (1H, d, J = 7 Hz), 7.10-7.12 (1H,
m), 7.15-7.20 (2H, m), 7.68 (1H, d, J = 1.5 Hz), 8.13 (1H, d, J = 7
6
, 500 MHz): δ = 1.92 (3H, s), 6.82
-
1
1
4
.77, N: 9.52, O: 5.95; IR (KBr): υ = 1675, 1588 cm ; H NMR
DMSO-d , 500 MHz): δ = 2.02 (3H, d, J = 1 Hz), 7.14-7.22 (2H,
m), 7.32-7.37 (2H, m), 7.41-7.49 (2H, m), 7.60-7.69 (2H, m), 7.91
(
6
1
3
Hz) ppm; C NMR (DMSO-d
6
, 125 MHz): δ = 21.6, 114.4, 115.6,
16.6, 116.9, 118.7, 121.9, 126.0, 126.2, 127.3, 129.3, 133.0,
33.3, 139.2, 146.5, 154.5, 162.3 ppm; MS (70 eV): m/z = 305
1
3
(
1H, d, J = 7 Hz), 8.27 (1H, s), 8.24 (1H, s) ppm; C NMR (DMSO-
1
1
(
1
d
1
1
6
, 125 MHz): δ = 15.8, 109.1, 117.5, 120.1, 120.4, 121.5, 123.7,
+
24.8, 125.2, 126.8, 128.1, 128.9, 129.6, 130.7, 132.9, 136.4,
M ).
0-chloro-5-methyl-2-nitro-8H-isoquinolino[1,2-b]quinazolin-8-
one (4c)
Yield: 85%; white crystals; mp 277-280°C (Lit. 279-281°C );
36.8, 143.5, 147.1, 153.7, 162.5 ppm; MS (70 eV): m/z = 310
+
(
M ).
1
1-chloro-5-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (4i)
Yield: 76%; white crystals; mp 183-185 °C; Anal. Calcd for
O: C: 69.28, H: 3.76, N: 9.50, O: 5.43, Found: C: 69.14,
1
7f
Anal. Calcd for C17
H
10ClN
3
O
3
: C: 60.10, H: 2.97, N: 12.37, O:
17 2
C H11ClN
1
1
(
4.13, Found: C: 60.24, H: 2.75, N: 12.22, O: 14.35; IR (KBr): υ =
-1 1
-
1
1
H: 3.95, N: 9.77, O: 5.70; IR (KBr): υ = 1673, 1561 cm ; H NMR
6
601, 1583, 1527 cm ; H NMR (DMSO-d , 500 MHz): δ = 1.99
(
DMSO-d
6
, 500 MHz): δ = 1.99 (3H, s), 6.72 (1H, d, J = 8 Hz), 7.00
3H, s), 7.22 (1H, s), 7.35 (1H, d, J = 8 Hz), 7.51 (1H, s), 7.65 (1H,
(
1H, s), 7.21-7.35 (3H, m), 7.39 (1H, d, J = 7 Hz), 7.68 (1H, d, J = 8
d, J = 8 Hz), 7.97 (1H, d, J = 8 Hz), 8.33 (1H, d, J = 8 Hz), 8.54 (1H,
13
1
3
Hz), 8.04 (1H, s) ppm; C NMR (DMSO-d
6
, 125 MHz): δ = 23.1,
s) ppm; C NMR (DMSO-d
6
, 125 MHz): δ = 18.3, 119.5, 121.9,
26.2, 127.0, 127.8, 128.1, 128.3, 128.4, 129.6, 129.7, 134.8,
36.3, 137.4, 145.9, 146.5, 160.3 ppm; MS (70 eV): m/z = 339
1
1
12.9, 117.3, 117.5, 122.0, 127.6, 128.9, 129.9, 131.2, 135.1,
1
1
35.6, 139.8, 140.1, 149.7, 150.0, 158.5, 161.4 ppm; MS (70 eV):
+
+
m/z = 294 (M ).
(
M ).
1
0-chloro-5-methyl-8H-isoquinolino[1,2-b]quinazolin-8-one (4d)
Yield: 78%; white crystals; mp 216-218°C (Lit. 217-219°C );
Anal. Calcd for C17 O: C: 69.28, H: 3.76, N: 9.59, O: 5.43,
1
7f
Conclusions
H
11ClN
2
Found: C: 69.54, H: 3.58, N: 9.81, O: 5.13; IR (KBr): υ = 1676, In summary, we have introduced an unprecedented Pd catalyzed
-
1
1
1
594cm ; H NMR (DMSO-d
1H, d, J = 9 Hz), 7.04 (1H, s), 7.29-7.36 (2H, m), 7.47 (1H, d, J = 7 construction of fused tetracyclic heteroarenes. A novel and
Hz), 7.51 (1H, d, J = 9 Hz), 7.66-7.68 (2H, m), 8.16 (1H, s) ppm; efficient Pd-containing PEI phosphinite modified magnetite core-
6
, 500 MHz): δ = 1.93 (3H, s), 6.99 intramolecular cyclization of quinazolones for the facile
(
1
3
C NMR (DMSO-d
6
, 125 MHz): δ = 19.2, 107.7, 113.5, 117.3, shell, Pd@Ph PO-PEI-mSiO , has been developed as highly active
2
2
1
1
5
17.5, 127.2, 128.4, 129.4, 132.6, 133.3, 136.3, 138.0, 139.2, and
stable
Pd@Ph PO-PEI-mSiO
for
intramolecular
2
2
+
43.2, 145.5 157.1, 166.8 ppm; MS (70 eV): m/z = 294 (M ).
coupling/cyclization reactions. The PEI functionality showed
-methyl-2-nitro-8H-pyrido[2',3':4,5]pyrimido[2,1-a]isoquinolin-8- good performance for raising water compatibility and acted as
the base in reaction. The results show that all the reaction of
different substrate containing a broad substrate scope have
been proceeded well under mild conditions to give the desired
products in good to high yields. The salient features of the
proposed method include high efficiency, generality and
simplicity which lead to high yields, a cleaner reaction profile
and easy recyclability of the highly stable heterogeneous catalyst
by a simple magnet separation.
one (4e)
Yield: 81%; white crystals; mp 177-179°C; Anal. Calcd for
C H N O : C: 62.74, H: 3.29, N: 18.29, O: 15.67, Found: C:
16 10 4 3
-1
6
2.97, H: 3.44, N: 18.04, O: 15.53; IR (KBr): υ = 1685, 1582 cm ;
1
H NMR (DMSO-d
6
, 500 MHz): δ = 1.99 (3H, s), 7.95 (1H, s), 8.13-
8
.19 (2H, m), 8.31-8.42 (2H, m), 7.58 (1H, t, J = 6 Hz), 8.92 (1H, s)
1
3
ppm; C NMR (DMSO-d
6
, 125 MHz): δ = 20.3, 127.4, 128.1,
128.9, 130.2, 130.4, 130.5, 131.0, 131.1, 132.7, 134.7, 135.1,
1
+
37.6, 146.7, 153.5, 161.3 ppm; MS (70 eV): m/z = 306 (M ).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Pl eNa es we dJ oo u nr no at l ao df j Cu hs te mm i as tr rgy ins
Page 8 of 9
ARTICLE
Journal Name
1
6 K. W. Fowler, D. Huang, E. A. Kesicki, H. C. OoiV,ieAw.AOrticlilveeOrn,linFe.
Notes and references
Ruan, J. Treiberg, K. D. Puri, US Patent RE44599, 2013.
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DOI: 10.1039/C7NJ04837H
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