Fe3O4-SAHPG-Pd0 nanoparticles: A ligand-free and low Pd loading quasiheterogeneous catalyst active for mild Suzuki–Miyaura coupling and C-H activation of pyrimidine cores

Article abstract of DOI:10.1002/aoc.6020

This paper reports a green magnetic quasiheterogeneous efficient palladium catalyst in which Pd⁰ nanoparticles have been immobilized in self-assembled hyperbranched polyglycidole (SAHPG)-coated magnetic Fe₃O₄ nanoparticles (Fe₃O₄-SAHPG-Pd⁰). This catalyst has been used for effective ligandless Pd catalyzed Suzuki–Miyaura coupling reactions of different aryl halides with substituted boronic acids at room temperature and in aqueous media. Herein, SAHPG is used as support; it also acts as a reducing agent and stabilizer to promote the transformation of Pd^II to Pd⁰ nanoparticles. Also, this environmental friendly quasiheterogeneous catalyst is employed for the first time in the synthesis of new pyrimido[4,5-b]indoles via oxidative addition/C-H activation reactions on the pyrimidine rings, which were obtained with higher yield and faster than when Pd(OAc)₂ was used as the catalyst. Interestingly, the above-mentioned catalyst could be recovered in a facile manner from the reaction mixture by applying an external magnet device and recycled several times with no significant decrease in the catalytic activity.

Full text of DOI:10.1002/aoc.6020

Received: 5 May 2020
DOI: 10.1002/aoc.6020
Revised: 23 July 2020
Accepted: 30 July 2020
F U L L P A P E R
Fe3O4-SAHPG-Pd0 nanoparticles: A ligand-free and low Pd
loading quasiheterogeneous catalyst active for mild Suzuki–
Miyaura coupling and C H activation of pyrimidine cores
Hamid Azizollahi1
| Hossein Eshghi1
| José-Antonio García-López2
1Department of Chemistry, Faculty of
Science, Ferdowsi University of Mashhad,
Mashhad, 91775-1436, Iran
2Grupo de Química Organometálica,
Universidad de Murcia, Campus de
Espinardo, Murcia, 30100, Spain
This paper reports a green magnetic quasiheterogeneous efficient palladium
catalyst in which Pd0 nanoparticles have been immobilized in self-assembled
hyperbranched polyglycidole (SAHPG)-coated magnetic Fe3O4 nanoparticles
(Fe3O4-SAHPG-Pd0). This catalyst has been used for effective ligandless Pd cat-
alyzed Suzuki–Miyaura coupling reactions of different aryl halides with
substituted boronic acids at room temperature and in aqueous media. Herein,
SAHPG is used as support; it also acts as a reducing agent and stabilizer to pro-
mote the transformation of PdII to Pd0 nanoparticles. Also, this environmental
friendly quasiheterogeneous catalyst is employed for the first time in the syn-
thesis of new pyrimido[4,5-b]indoles via oxidative addition/C H activation
reactions on the pyrimidine rings, which were obtained with higher yield and
faster than when Pd(OAc)2 was used as the catalyst. Interestingly, the above-
mentioned catalyst could be recovered in a facile manner from the reaction
mixture by applying an external magnet device and recycled several times with
no significant decrease in the catalytic activity.
Correspondence
Hossein Eshghi, Department of
Chemistry, Faculty of Science, Ferdowsi
University of Mashhad, Mashhad
91775-1436, Iran.
Email: heshghi@um.ac.ir
José-Antonio García-López, Grupo de
Química Organometálica, Universidad de
Murcia, Campus de Espinardo, Murcia
30100, Spain.
Email: joangalo@um.es
Funding information
Fundación Séneca Región de Murcia,
Grant/Award Number: 19890/GERM/15;
MICINN, Grant/Award Number:
PGC2018-100719-B-I00; Research Council
of Ferdowsi University of Mashhad,
Grant/Award Number: 3/41215
K E Y W O R D S
cross-coupling reaction, hyperbranched polyglycidole, palladium nanoparticles, pyrimido[4,5-b]
indoles, quasiheterogeneous catalyst
1 | INTRODUCTION
not sufficient stability during separation and recovery
steps. To overcome this problem, immobilization
Cross-coupling reactions catalyzed by transition metals
are one of the most efficient and direct strategies to form
carbon–carbon bonds.[1–4] Among various transition-
metal catalysts, palladium nanoparticles (NPs) occupy a
privileged position to achieve this goal.[5] The key of the
versatility and high activity of palladium NPs in cross-
coupling reactions relies on the large surface-to-volume
ratio of the NPs compared with the bulk phase, but such
feature can also make them quickly aggregated to large
particles in certain conditions.[6–8] Therefore, they have
of palladium particles on
a
heterogeneous and
quasiheterogeneous support seems to be an efficient way,
especially in the chemical industry.[9] A broad range of
supports such as polymers,[10] silica,[11] zeolites,[12]
carbon nanotubes,[13,14] and graphene oxide[15] have been
explored so far to avoid these problems. Nowadays,
hyperbranched polymers have attracted significant
attention as catalyst support because of their ability to sta-
bilize NPs.[16–18] Among them, hyperbranched
polyglycidole (HPG) has emerged as a great support due to
This paper is dedicated to Prof. Mehdi Bakavoli who passed away recently.
Appl Organomet Chem. 2020;e6020.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6020

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AZIZOLLAHI ET AL.
its characteristics: (i) it possess multiple anchoring sites,
(ii) it acts as a reducing agent for metal ions to generate
metal NPs via oxidation of the terminal hydroxyl groups
and ether moieties,[19–21] (iii) it has a stabilizer action due
to dendritic structure, and (iv) can be easily prepared
through a single step cationic ring-opening polymerization
reaction,[22] avoiding the harsh conditions generally
required for the synthesis of dendrimers.[23–25]
nontoxic and eco-friendly species to facilitate their sepa-
ration and recycling (Fe3O4-SAHPG-Pd0). Our interest in
using SAHPG to synthesize a new palladium catalyst sys-
tem is based on two phenomenal properties of HPG: (i) it
can encapsulate the Pd NPs controlling their size and
uniform distribution,[34] and (ii) SAHPG can generate
and stabilize Pd0 NPs arising from Pd2+ without the use
of an external reducing agent through the coordination
of free hydroxyl groups and ether moieties with the metal
ions, while most polymers require a proper agent to
reduce metal ions.[18,19,21]
In particular, self-assembly of hyperbranched poly-
mers gives them unique properties in comparison to those
developed from linear polymers, for example, facile func-
tionalization, morphology varieties, unusual mechanical
properties, and excellent template ability.[26,27] Through
the self-assembly process, hyperbranched polymers form
an organized structure via local van der Waals, Coulomb,
or hydrophobic interaction and π–π stacking.[28] Up to
now, there is no report on the self-assembly of the HPG for
catalytic applications and most of the reports focused on
the modification and self-assembly of other
hyperbranched polymers in order to diversify their func-
tional groups[20] and/or improve their solubility.[16–18]
An interesting feature of heterogeneous catalyst relies
on the possibility of their recovery and reutilization. Regard-
ing this aspect, the introduction of magnetic NPs (MNPs)
such as Fe3O4 has proven a useful strategy to make hetero-
geneous catalyst easily recoverable through the application
of an external magnet.[29–33] This strategy has been applied
in the production of a range of heterogeneous transition-
metal catalyst applied in cross-coupling reactions.[8]
2 | RESULTS AND DISCUSSION
2.1 | Catalyst preparation
HPG with a variety of molecular weight were synthesized
via cationic ring-opening multibranching polymerization
reaction.[19,20] In order to be benefitted from the unique
characteristics of the self-assembled polymer, part of the
terminal hydroxyl groups of HPG were reacted with ben-
zoyl chloride to obtain benzoyl-HPG in first place,
because the terminal hydrophilic OH groups in HPG do
not allow to carry out a correct self-assembly process dur-
ing the coating process of Fe3O4 in a polar solvent. The
presence of aromatic groups in related polymeric mate-
rials is known to contribute to the self-assembly process
through π–π interactions,[35–39] improving also the stabil-
ity of the micellar structure (Scheme 1).
Herein, we report a straightforward approach to
combine supporting property of self-assembled
hyperbranched polyglycidole (SAHPG) for effective
reduction and stabilization of palladium NPs in aqueous
media, including the magnetic properties of Fe3O4 as
There are two pathways for the synthesis of Fe3O4-
SAHPG, either separate synthesis of SAHPG and Fe3O4,
then dispersing Fe3O4 NPs on the SAHPG (route a,
Fe3O4-SAHPG1, Scheme 2), or the synthesis Fe3O4 in situ
SCHEME 1 Synthetic route to self-
assembled hyperbranched polyglycidole
(SAHPG)

AZIZOLLAHI ET AL.
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SCHEME 2 Schematic representation of
Fe3O4-SAHPG-Pd0
on the aqueous solution of SAHPG (route b, Fe3O4-
SAHPG2, Scheme 2). In the reports published so
far,[18,21,40] functionalized Fe3O4 NPs have been used as a
core and polymerization has been carried out in the sur-
face of MNPs. Probably in such polymer support cases,
immobilization of Fe3O4 cannot occur uniformly because
the support is not able to prevent the aggregation of
MNPs. However, in situ generation of Fe3O4 in an aque-
ous solution of SAHPG under stirring conditions enabled
us to get Fe3O4-SAHPG2, where the magnetic Fe3O4 NPs
are nicely dispersed into the polymeric material. Hence,
this method avoided any undesired aggregation. Fe3O4-
SAHPG2 was used as catalyst support to prepare the
Fe3O4-SAHPG-Pd0 by post-synthesis reaction of
Pd(OAc)2 with the support. Finally, the prepared catalyst
was separated from the mixture by an external magnet
and dried up in vacuum at 50ꢀC for 6 h. The ICP-OES
analysis of the catalyst showed a 16.8 weight% of Pd.
In many cases reported so far,[41–44] after coating
Fe3O4 particles with various polymers, they need to be
modified with different groups to improve the solubility
of the catalyst in a polar solvent (e.g., water, ethanol, and
dimethylformamide); however, SAHPG on the Fe3O4-
SAHPG2-Pd0 does not need any further modification to
have a good solubility in these solvents. In contrast to the
difficulties in separation and recovery of homogeneous
catalysts,[7,11,13,45] the Fe3O4-SAHPG2-Pd0 catalyst can be
separated easily by an external magnetic field and
recycled several times with no noticeable loss in the
activity (see below). The new catalyst was characterized
by various techniques, such as Fourier-transform infrared
(FT-IR), scanning electron microscopy (SEM), transmis-
sion electron microscopy (TEM), dynamic light scattering
(DLS), vibrating sample magnetometer (VSM), ther-
mogravimetric analysis (TGA), X-ray diffraction (XRD),
and X-ray photoelectron spectroscopy (XPS).
FIGURE 1 Fourier-transform infrared (FT-IR) spectra of
(a) Fe3O4, (b) hyperbranched polyglycidole (HPG), (c) self-
assembled hyperbranched polyglycidole (SAHPG),
(d) Fe3O4-SAHPG, and (e) Fe3O4-SAHPG2-Pd0
bond. In the spectrum of the HPG, Figure 1b, the broad
band at 3377 cm−1 was attributed to a hydroxyl group.
To further verify the structural features including size
distribution and surface morphology of Fe3O4-SAHPG2-
Pd0 NPs, TEM and particle size histogram (DLS) were
used (Figure 2). As can be seen in Figure 2a, the synthe-
sized Fe3O4-SAHPG2-Pd0 revealed rounded magnetic
nanoparticles distributed uniformly into the polymeric
structure as a composite material which is probably aris-
ing from the great template ability of SAHPG. The Fe3O4
MNPs are characterized by a diameter of 20 nm as con-
firmed by TEM analysis (Figure 2b). We observed that
when the route a (Scheme 2) was followed for the synthe-
sis of Fe3O4-SAHPG1, as can be seen in (Figure 2c,d), the
Fe3O4 NPs were aggregated, which was probably due to
the low dispersity of MNPs into the SAHPG polymer
structure. While in the route b a very good dispersion of
magnetite NPs in the HPG and a nearly uniform distribu-
tion of particle size was observed (Figure 2a). So the in
situ method (Scheme 2, route b) was selected as the main
To confirm the synthesis of the catalyst, FT-IR spectra
of (a) Fe3O4, (b) HPG, (c) self-assembled HPG (SAHPG),
(d) Fe3O4-SAHPG2, and (e) Fe3O4-SAHPG2-Pd0 were car-
ried out (Figure 1). As shown in Figure 1a, the FT-IR
spectrum of Fe3O4 MNPs shows a broad band at
578 cm−1 corresponding to the stretching of the Fe O

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AZIZOLLAHI ET AL.
FIGURE 2 Transmission electron microscopy (TEM) image of (a) Fe3O4-SAHPG2-Pd0, (b) particle size histogram of Fe3O4 NPs,
(c) TEM image of Fe3O4-SAHPG1, and (d) scanning electron microscopy (SEM) image of Fe3O4-SAHPG1
procedure for the synthesis of final catalyst Fe3O4-
SAHPG2.
To investigate magnetic properties of Fe3O4 and
Fe3O4-SAHPG2-Pd0 NPs, vibrating sample magnetometer
(VSM) was used. As illustrated in Figure 3, super-
paramagnetic behavior was confirmed for the obtained
NPs which were seized from the Fe3O4 core. The magne-
tization saturation (MS) value of Fe3O4 and Fe3O4-
SAHPG2-Pd0 NPs was equal to 57 and 39 emu g−1
,
respectively. Comparing with Fe3O4 MNPs, the MS value
of Fe3O4-SAHPG-Pd0 NPs was lower, which occurred
upon dispersion of Fe3O4 MNPs in the SAHPG support.
However, the magnetic property was high enough to
recycle from the crude by the application of an external
magnetic field.
In order to get more information on the crystallo-
graphic structure, chemical composition, and physical
properties of Fe3O4, Fe3O4-SAHPG, and Fe3O4-SAHPG2-
Pd0, XRD technique was used (Figure 4). As shown in
Figure 4a, the Fe3O4 NPs were characterized by the dif-
fraction peaks located approximately at 2θ = 30.2ꢀ (220),
35.6ꢀ (311), 43.1ꢀ (400), 53.2ꢀ (422), 57.1ꢀ (511), and 62.8ꢀ
(440) which can be attributed to the cubic structure of
FIGURE 3 Magnetization hysteresis loops at room
temperature (vibrating sample magnetometer [VSM])
Fe3O4 MNPs.[5] In Figure 4c, after grafting the Fe3O4-
SAHPG with Pd NPs, the appearance of three new peaks
at 2θ = 40.1ꢀ (111), 46.5ꢀ (200), and 68.0ꢀ (220) are
imputed to the face-centered cubic system Pd0. The

AZIZOLLAHI ET AL.
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336.4 and 341.9 eV corresponded to the oxidized Pd2+
(3d5/2 and 3d3/2, respectively) which are in agreement
with the values reported in the literature.[23–25] Measur-
ing out the area under the peaks shows that the percent-
age of the Pd0 and Pd2+ are 81.31 and 18.68, respectively
(Figure 5).
To prove the efficiency of the Fe3O4-SAHPG2-Pd0
nanocatalyst, the coupling of iodobenzene with phe-
nylboronic acid was selected as a standard model reac-
tion for Suzuki–Miyaura cross-coupling. An initial
reaction of 1a with 2a in the presence of our catalyst
(1 mol% of Pd regarding the substrate) and 1.5 equiv. of
K2CO3 in H2O at room temperature gave almost full con-
version of the starting materials, affording the biaryl
product 3a.
In order to optimize the reaction conditions, we tested
several parameters affecting the result of the reaction,
such as temperature, base, and catalyst loading (see
Table S1). Because Fe3O4-SAHPG2-Pd0 nanocatalyst has
good solubility in water and also it is stable under aerobic
conditions, we focused our initial investigation on the
effect of various types of base, temperature, and palla-
dium amount on the standard model reaction in aqueous
media and the presence of air. The results of the model
reaction indicated that the use of K2CO3 as a base and an
amount of Fe3O4-SAHPG2-Pd0 equivalent to 0.1 mol% of
Pd NPs provided the coupling product in more than 99%
yield at room temperature after 30 min. No significant
difference was observed in the yield of the reaction when
the temperature was risen up to 80ꢀC. Using other bases
such as Et3N and NaOAc led to lower yield of 3a, so
K2CO3 was selected as the base. Next, we tested the
amount of catalyst and observed that lower loading of
Fe3O4-SAHPG2-Pd0 were not effective. Upon establishing
the optimized conditions to obtain biaryl products, we
proceeded to study the scope of the reaction. We found
that aryl iodides and bromides 1 bearing both electron-
donating/electron-withdrawing groups gave excellent
yields of biaryls 3 (Scheme 3). Also, we were interested in
investigating the behavior of Fe3O4-SAHPG2-Pd0 in the
Suzuki–Miyaura cross-coupling reaction of substituted
aryl chlorides and arylboronic acids.
FIGURE 4 X-ray diffraction (XRD) patterns of (a) Fe3O4,
(b) Fe3O4-SAHPG2, and (c) Fe3O4-SAHPG2-Pd0
observation of additional crystalline phase of Fe3O4 and
Fe3O4-HPG in the XRD pattern of Fe3O4-SAHPG2-Pd0 is
a proof for embedding Fe3O4 NPs in the SAHPG. The
chemical modification makes the peaks intensity
decrease.
To investigate the coordination state of the embedded
palladium enclosed by Fe3O4-SAHPG, XPS analysis was
accomplished. As can be seen in Figure 5, two bands cen-
tered at the binding energies 335.3 and 340.7 eV are
attributed to Pd0 (3d5/2 and 3d3/2, respectively), which
indicate that the Pd NPs are present in the
nanocomposite structure of Fe3O4-SAHPG2-Pd as metal-
lic state. The difference between observed and standard
binding energy of Pd0 is due to the higher density around
the palladium species on the catalyst. The fitted peaks at
We observed a reasonable yield for the cross-coupling
process at room temperature (Scheme 3) for aryl chlo-
rides, although the reaction required slightly longer time
than aryl iodides and aryl bromides, in comparison with
reported works.[46,47]
The catalyst could be easily removed from the reac-
tion mixture and reused with no significant loss of activ-
ity for seven cycles (Tables 1 and S2).
In order to determine the catalytically active species
in the Suzuki cross-coupling reaction, we performed a
poisoning test. After 8 min of starting the reaction of
FIGURE 5 X-ray photoelectron spectroscopy (XPS) analysis

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AZIZOLLAHI ET AL.
SCHEME 3 Scope of the
Suzuki–Miyaura cross-coupling
TABLE 1 Recycling of Pd catalyst in the Suzuki–Miyaura cross-coupling reaction under the optimized reaction conditions
Entry
Cycle
1st
Time (min)
30
Isolated yield (%)
>99
TONa
>999.9
TOF (h−1 b
)
1
>1999.8
>1999.8
2
2nd
3rd
4th
30
>99
>999.9
>999.9
3
30
>99
>1999.8
4c
5c
6c
7c
30/35
30/40
30/45
30/60
98/>99
98/>99
95/>99
92/>99
980/>999.9
980/>999.9
950/>999.9
920/>999.9
1960/>1714.8
1960/>1499.8
1900/>1333.2
1840/>999.9
5th
6th
7th
Note: Reaction conditions: Fe3O4-SAHPG2-Pd0 (0.1 mol% Pd), iodobenzene (1 mmol), phenylboronic acid (1.1 mmol), 1.5 equiv. base, 3-ml
solvent.
aTON = mmol of products/mmol of catalyst.
bTOF = TON/time.
cIn the second columns, second numbers are related to isolated yield after 35, 40, 45, and 60 min.
1-iodo-4-methylbenzene 1ab and phenylboronic acid 2aa
(Scheme 4), one drop of mercury was added to the crude.
We observed that the reaction completely halted (see
Figures S9 and S10) These results show most likely palla-
dium(0) species arising from palladium acetate are the
catalytically active species in this reaction.
Fe3O4-SAHPG-Pd0, generating the organometallic inter-
mediate II. Next, transmetallation of intermediate II with
aryl boronic acid in the presence of K2CO3 can lead to
the intermediate III. Finally, reductive elimination of
biaryl compound restores the Pd(0), completing the cata-
lytic cycle.
The mechanism of Suzuki–Miyaura coupling is
shown in the Scheme 5. The first step is the oxidative
addition of the aryl halide to Pd(0), arising from the
To indicate the efficiency of our catalyst, the catalytic
activity of Fe3O4-SAHPG2-Pd0 was compared with that of
some previously reported for the Suzuki–Miyaura cross-

AZIZOLLAHI ET AL.
7 of 11
SCHEME 4 Mercury-amalgamation test
Entries 1–6), or high temperatures (Table 2, Entries 1–8)
are avoided. Furthermore, some of these methods may
present disadvantages for the recovery and reusability of
the catalyst (Table 2, Entry 8).
In order to determine the heterogeneity nature of the
Fe3O4-SAHPG2-Pd0 catalyst system, the hot filtration test
was performed. The reaction of 1-iodo-4-methylbenzene
with phenylboronic acid under the optimized reaction
conditions was selected as a model reaction. After
10 min, the catalyst was separated by an external mag-
netic field (49% 1H-NMR yield, Figures S11 and S12), and
the reaction was allowed to continue without the catalyst
1
for 1 h. The crude H-NMR showed no further progress
in the coupling reaction even after an extended time,
which indicated that no significant leaching of palladium
NPs took place during the catalytic reaction (see
Figures S11 and S12). This result demonstrated the
heterogeneous nature of our catalyst. The ICP-OES
analysis of the filtrate showed that there is no leaching of
the palladium after 10 min. In the course of our investi-
gations devoted to the synthesis of new heterocyclic
compounds with interesting pharmacological properties,
we were interested in the examination of the ability of
the Fe3O4-SAHPG2-Pd0 catalyst to accomplish oxidative
addition/C H activation reactions on N-(2-iodophenyl)-
N-substituted pyrimidine-4-amine substrates, in order to
achieve the synthesis of new derivatives of the
9-substituted-9H-pyrimido[4,5-b]indole core. There are
various synthetic routes to prepare pyrimido[4,5-b]indole
SCHEME 5 Mechanistic pathway for Suzuki–Miyaura cross-
coupling
coupling of aryl halides with phenylboronic acid
(Table 2). Although all of the listed catalysts can achieve
the desired product in good to excellent yield, our catalyst
can perform the Suzuki coupling under greener and
milder reaction conditions. Compared with previously
reported supported Pd catalyst employed for the Suzuki
coupling reaction (Table 2), the use of hazardous solvents
(Table 2, Entries 4–6), longer reaction time (Table 2,
TABLE 2 Comparison of various catalysts in the Suzuki–Miyaura cross-coupling of 4-halobenzenes with phenylboronic acid
Temp
(ꢀC)
Time
(h)
Entry Catalyst
x
Solvent
Base
Yield (%)
97/82/–
Ref.
1
2
MOP-Pd
I/Br/Cl H2O: EtOH
I/Br/Cl H2O: EtOH
K3PO4
80
3
Wu et al.[48]
Akbarzadeh et al.[49]
CNT–Fe3O4–PTh–Cu
K2CO3 80
1/1.1/4
90/85/55
(I)
3
4
MP-TPy/Pd
I/Br/Cl H2O: EtOH
K2CO3 80
K2CO3 90
2/4/10
98/95/92
Targhan et al.[50]
Han et al.[51]
Pd@TMC-Bpy COF
I/Br/Cl Ethyl
lactate
−/1.5/−
−/95/−
5
6
7
8
GO/NiTAPP
Pdnp-2
I/Br/Cl Dioxane
I/Br/Cl DMF
I/Br/Cl H2O
K3PO4
80
1/1/2.5
4/−/−
95/92/60
94/−/−
−/95/−
−/−/87
Keyhaniyan et al.[52]
Dutta and Sarkar[53]
Paul et al.[54]
K2CO3 110
Pd-γ-Fe2O3
NaOH
K3PO4
80
−/0.5/−
−/−/2
NiCl2(PPh3)2/PPh3
I/Br/Cl Toluene
100
Inada and
Miyaura[55]
9
Fe3O4-SAHPG2-Pd0
I/Br/Cl H2O
K2CO3 r.t.
0.5/0.5/1
>99/
Present work
>99/85

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AZIZOLLAHI ET AL.
rings reported in the literature, for instance, (a) ring clo-
sure of 2,3-functionalized indoles with CN moieties such
as formamide or cyanamide[56]; (b) reaction of ben-
zylidenindolenine borate derivatives with amidines, thio-
Likely in our catalyst, the oxidative addition of Pd in
the carbon–halogen bond and/or C H activation on the
C5 of pyrimidine are much faster than in the case when
Pd(OAc)2 is used as the metal source. According to the
1H-NMR of the crude mixture, Fe3O4-SAHPG2-Pd0 can
perform this reaction without any side reaction such as
homocoupling, which occur in higher extension with
Pd(OAc)2.
Compounds 5i–5l bearing different secondary amines
can be synthesized through either the substitution reac-
tion of various secondary amines on the C2 of pyrimidine
followed by the oxidative addition/C H activation reac-
tions or initial oxidative addition/C H activation and
subsequent reaction with the secondary amines
(Scheme 6). A plausible mechanism to explain the forma-
tion of compounds 5 is depicted in Scheme 7. The initial
oxidative addition of compound 4 leads to intermediate
A, which undergoes C H activation reaction affording
intermediate B. Next, a reductive elimination takes place
in intermediate B leading to synthesis pyrimido[4,5-b]
indoles and regeneration of active catalytic species Pd0
for the next run.
urea, and guanidines[57]; (c) azidouraciles cyclization[58]
;
and (d) the reaction of glycine ethyl ester with
2,4,6-trichloropyrimidine. The downsides of these
methods are low to medium yielding rates, volatile sol-
vent usage, and the need of additional steps to get the
desired products. Moreover, a palladium-catalyzed reac-
tion in pyrimidine systems has been reported.[59] It
involved the intramolecular arylation of pyridine ring
where oxidative addition occurs on the C5 position of
pyrimidine, followed by C H activation on the aryl ring,
giving rise the pyrimido[4,5-b]indole scaffold. In spite of
the availability of these synthetic methods, a general
route which incorporates a different range of substitution
patterns is highly desirable.
We tested an initial reaction of the compound 4a in
the presence of 10 mol% of Pd(OAc)2, 20 mol% of PPh3,
and 1.5 equiv. of K2CO3 in toluene at 80ꢀC to investigate
the feasibility of this reaction. We observed that the intra-
molecular cyclization was complete after 8 h to afford the
compound 5a in 63% 1H-NMR yield. The screening of the
amount of Pd(OAc)2/PPh3 (Tables 3 and S3) indicated
that 10 mol% of catalyst loading could perform the intra-
molecular coupling reaction in moderate yield and the
efficiency did not change with higher loading amounts of
catalyst. To evaluate the applicability of Fe3O4-SAHPG2-
Pd0 as a catalyst to synthesize pyrimido[4,5-b]indole
rings, the same experiment was repeated with Fe3O4-
SAHPG2-Pd0 (1 mol% of Pd regarding the substrate)
3 | EXPERIMENTAL
3.1 | Synthesis of Fe3O4-SAHPG-Pd0
Magnetic hyperbranched polyglycidole (Fe3O4-SAHPG)
(0.5 g) was added to a suspension of Pd(OAc)2 (0.5 g,
2.2 mmol) in water (40 ml). The mixture was stirred over-
night at room temperature overnight. The resulting solid
was isolated by separation from the reaction mixture with
an external magnet device, washed with water, and then
dried at room temperature to give Fe3O4-SAHPG-Pd0
1
obtaining compound 5a (91% H-NMR yield) in milder
conditions and shorter time in comparison with
Pd(OAc)2/PPh3 as palladium source.
TABLE 3 Optimization studies and screening the amount of the catalyst to synthesis pyrimido[4,5-b]indole
Entry
Catalyst system
Pd(OAc)2/P(Ph)3
Pd(OAc)2/P(Ph)3
Pd(OAc)2/P(Ph)3
Pd(OAc)2/P(Ph)3
Fe3O4-SAHPG2-Pd0
Fe3O4-SAHPG2-Pd0
Fe3O4-SAHPG2-Pd0
Fe3O4-SAHPG2-Pd0
Fe3O4-SAHPG2-Pd0
Fe3O4-SAHPG2-Pd0
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Acetonitrile
DMF
Catalyst amount (mol% Pd)
Yield (%)
1
2
2
20
45
63
65
66
91
91
92
89
56
5
3
10
20
0.5
1
4
5
6
7
2
8
5
9
1
10
1
Note: Reaction conditions: N-methyl-N-phenylpyrimidin-4-amine (1 mmol), 1.2 equiv. k2CO3, 3-ml solvent, 60ꢀC, 2 h.

AZIZOLLAHI ET AL.
9 of 11
SCHEME 6 Scope of the pyrimido[4,5-b]indoles
the Supporting Information for more detailed
information.
3.3 | General procedure for the synthesis
of compounds 5
A Carius tube was charged with compound 4 (1 mmol),
Fe3O4-SAHPG2-Pd0 (1 mol% of Pd loading), K2CO3
(1.5 equiv.), and a magnetic stirrer. Dry toluene (3 ml)
was added, and the tube was sealed. The reaction mixture
was stirred in a preheated oil bath at 60ꢀC for 2 h. After
cooling the tube, the crude was diluted with CH2Cl2
(20 ml) and filtered through a Celite pad. The filtrate was
concentrated, and the crude was purified by column
chromatography (silica gel, n-hexane/EtOAc, gradient
from 0% to 10% EtOAc) to afford pyrimido[4,5-b]indoles
5. See the Supporting Information for more detailed
information.
SCHEME 7 Proposed mechanistic pathway for the synthesis
of pyrimido[4,5-b]indoles
(0.59 g). See the Supporting Information for more
detailed information.
3.2 | General procedure for the synthesis
of biaryl compounds
4 | CONCLUSION
Fe3O4-SAHPG-Pd0 (0.1 mol%, calculated according to the
ICP analysis) was added to a solution of aryl halide
(1 mmol) and arylboronic acid (1 mmol) in H2O (3 ml).
The resulting suspension was stirred at room temperature
for 1 h. After the reaction was completed (monitored by
TLC), the catalyst was removed from the crude by exter-
nal magnet field and washed with water (3 × 2 ml) and
chloroform (3 × 5 ml). Then, the organic phase was dried
over MgSO4 and concentrated by rotary evaporation. The
resulting crude product was purified by column chroma-
tography over silica gel to obtain the final product. See
In summary, we have introduced an eco-friendly and
magnetic quasiheterogeneous catalytic system Fe3O4-
SAHPG2-Pd0 that is very efficient for the Suzuki–Miyaura
cross-coupling reaction of aryl halides with aryl boronic
acids at room temperature and in aqueous media. The
SAHPG, prepared by ring-opening polymerization in a
one-pot process, proved to be an excellent support for the
dispersion of Fe3O4 NPs in polar solvents, as well as good
stabilizer of the Pd NPs via coordination with the termi-
nal hydroxyl groups and ether moieties present in
SAHPG. The Fe3O4-SAHPG2-Pd0 catalyst showed high

10 of 11
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ACKNOWLEDGMENTS
The authors gratefully acknowledge Research Council of
Ferdowsi University of Mashhad (Grant 3/41215),
MICINN (Grant PGC2018-100719-B-I00 with FEDER
funding), and Fundación Séneca Región de Murcia
(Grant 19890/GERM/15) for supporting this study. The
authors gratefully acknowledge Prof. Isabel Maria Saura
and Prof. Maria Teressa Chicote for their support during
the current work.
AUTHOR CONTRIBUTIONS
Hamid Azizollahi: Conceptualization; data curation;
formal analysis; investigation; methodology; validation;
visualization. Hossein Eshghi: Conceptualization; data
curation; formal analysis; funding acquisition; investiga-
tion; methodology; project administration; resources;
supervision; validation. José-Antonio García-López:
Data curation; formal analysis; investigation; methodol-
ogy; validation; visualization.
CONFLICT OF INTEREST
There are no conflicts to declare.
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article.
[28] Y. Zhou, W. Huang, J. Liu, X. Zhu, D. Yan, Adv. Mater. 2010,
22, 4567.
ORCID
[29] H. Alinezhad, M. Tarahomi, B. Maleki, A. Amiri, Appl.
Organomet. Chem. 2019, 33, e4661.
[30] M. Tarahomi, H. Alinezhad, B. Maleki, Appl. Organomet.
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[31] B. Maleki, E. Sheikh, E. R. Seresht, H. Eshghi, S. S. Ashrafi,
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Hamid Azizollahi https://orcid.org/0000-0002-3634-
2200
Hossein Eshghi https://orcid.org/0000-0002-8417-220X
José-Antonio García-López https://orcid.org/0000-0002-
8143-7081
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
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How to cite this article: Azizollahi H, Eshghi H,
García-López J-A. Fe3O4-SAHPG-Pd0
nanoparticles: A ligand-free and low Pd loading
quasiheterogeneous catalyst active for mild
Suzuki–Miyaura coupling and C H activation of
pyrimidine cores. Appl Organomet Chem. 2020;
e6020. https://doi.org/10.1002/aoc.6020