Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust Catalyst for an Array of Sustainable Multicomponent Reactions under Microwave Irradiation

Article abstract of DOI:10.1007/s10562-019-02794-8

Abstract: Herein, we are reporting a facile route to synthesize magnetically separable copper loaded L-DOPA functionalized magnetite nanoparticles (Fe₃O₄-DOPA-CuNPs), which are well characterized by FT-IR, PXRD, SEM, EDAX, HRTEM, XPS, TGA and VSM techniques. This single catalyst exhibits excellent catalytic activity towards (i) synthesis of DHPMs via Biginelli reaction (ii) synthesis of imidazoles (iii) synthesis of 2-amino-4H-chromenes (iv) 1,2,3-triazole derivatives by ‘Click reaction’ under microwave irradiation (MWI). Interestingly it can be easily recovered and reused for subsequent cycles for above mentioned four important multicomponent reactions without any significant decrease in its catalytic activity. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-019-02794-8

Catalysis Letters
https://doi.org/10.1007/s10562-019-02794-8
Synthesis of Fe3O4‑DOPA‑Cu Magnetically Separable Nanocatalyst:
A Versatile and Robust Catalyst for an Array of Sustainable
Multicomponent Reactions under Microwave Irradiation
Mitlesh Kumari1 · Yachana Jain1 · Priya Yadav1 · Harshita Laddha1 · Ragini Gupta1,2
Received: 27 February 2019 / Accepted: 21 April 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Herein, we are reporting a facile route to synthesize magnetically separable copper loaded L-DOPA functionalized magnetite
nanoparticles (Fe3O4-DOPA-CuNPs), which are well characterized by FT-IR, PXRD, SEM, EDAX, HRTEM, XPS, TGA
and VSM techniques. This single catalyst exhibits excellent catalytic activity towards (i) synthesis of DHPMs via Biginelli
reaction (ii) synthesis of imidazoles (iii) synthesis of 2-amino-4H-chromenes (iv) 1,2,3-triazole derivatives by ‘Click reac-
tion’ under microwave irradiation (MWI). Interestingly it can be easily recovered and reused for subsequent cycles for above
mentioned four important multicomponent reactions without any signifcant decrease in its catalytic activity.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-02794-8) contains
supplementary material, which is available to authorized users.
* Ragini Gupta
rgupta.chy@mnit.ac.in
1
Department of Chemistry, Malaviya National Institute
of Technology, Jaipur 302017, India
2
Materials Research Centre, Malaviya National Institute
of Technology, Jaipur 302017, India
Vol.:(0123456789)
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M. Kumari et al.
Graphical Abstract
Keywords Magnetic nanocatalyst · Multicomponent reactions · L-DOPA · Fe3O4-DOPA-Cu
introduce functional groups to the magnetic surface and
often involve the use of organosilica precursors as an organic
shell to prepare a suitable support for incorporation of difer-
ent transition metal ions [10–15]. Therefore, the preparation
of modifed MNPs via simple method and without using
organoalkoxysiloxane compounds is highly desirable from
both an environmental and economic point of view. The
chemistry of copper is extremely rich because it can easily
access Cu°, CuI, CuII, and CuIII oxidation states allowing
it to act through one electron or two electron process. This
unique characteristic of Cu based nanocatalyst have made it
suitable for many applications in nanotechnology, includ-
ing catalytic organic transformations, electrocatalysis and
photocatalysis. Because of the leaching efect and poor recy-
clability neat metal and oxide must be incorporated on some
supports [16, 17]. In this respect, we introduce a simple and
facile ultrasonication method for synthesis of highly water-
dispersible magnetic nanoparticles, end-functionalized
with non-toxic, biodegradable L-DOPA having amino and
1 Introduction
MNPs have emerged as viable alternatives to conventional
materials as robust, readily available, high surface area het-
erogeneous catalyst supports [1, 2]. Recently MNPs have
found remarkable niche in diverse areas ranging from mag-
netic resonance imaging, magnetic targeting drug delivery
to chemical catalysis, they increasingly serve as catalyst
supports or are incorporated in the hybrid nanocomposite
as sustainable catalyst for convenient separation and recy-
cling [3–5]. Bare MNPs due to their inherent instability and
hydrophobic nature results in big clusters over time in the
absence of any surface coating which reduces their surface
energy [6]. Therefore it needs to be minimized by surface
immobilization of MNPs with biocompatible and organic
and inorganic materials which protects them from being
oxidized and provides them stability against damage dur-
ing or after being used in organic transformations [7–9].
However most of the techniques require several steps to
1 3

Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
carboxyl groups as these are the most attractive functional
groups, which are especially suitable for the immobiliza-
tion of Cu nanoparticles. Multicomponent reactions (MCRs)
whereby three or more reactants come together in a single
vessel to create extremely ideal route for rapidly creating
a library of diverse heterocyclic scafolds. These reactions
are highly atom economic since target compound obtained
in one pot with much fewer steps containing all the atoms
which are present in the substrates [18]. The combination of
magnetic nanocatalyst and multicomponent reactions is an
attractive research area and is an ideal blend for the develop-
ment of sustainable methods in green synthetic chemistry
[19]. In view of this we have investigated the catalytic activ-
ity of the synthesized Fe3O4-DOPA-Cu nanocatalyst towards
four important multicomponent reactions: (i) ‘Biginelli reac-
tion’ for the synthesis of DHPMs derivatives (ii) synthesis
of 2,4,5 trisubstituted imidazole (iii) synthesis of 2-amino-
4H- chromene and (iv) ‘Click reaction’ for the synthesis of
1,2,3 triazole derivatives.
sustainable tools in synthetic chemistry due to its specifc
features including efcient atomic utilization, improved tem-
perature regulation, reaction homogeneity, lesser reaction
time and high product yield [45, 46]. Inspite of all these
one more factor that is tedious recoverability of the cata-
lyst particles hamper the sustainability and economics of
the nanocatalytic strategy. Therefore to address all these
issue, the development of such catalyst which will exhibit
high catalytic activity along with easy recyclability and
reusability for the synthesis of above described important
MCRs is highly needed. So in continuation of our research
endeavors towards the development of sustainable protocols
and application of nanocatalyst [47, 48], herein we report
on a highly efcient, versatile magnetically separable and
recyclable Fe3O4- DOPA-Cu catalyst towards four important
multicomponent reactions.
2 Experimental
Synthesis of DPHM and derivatives are important
because of their wide range pharmaceutical and therapeutic
applications such as calcium channel blockers, anti-infam-
matory agents, antihypertensive, anti-tumor, adrenergic
and neuropeptide antagonists [20–24] etc. Biginelli multi-
component reaction pathway is the most direct and elegant
methodology for synthesis of DHPMs. Imidazoles have
various biological applications as they are well known to
anti-infammatory, antiparasitic, antifungal, antiviral [25]. In
addition used in photography as photosensitive compounds
[26, 27], selective antagonists of the glucagon receptors
and inhibitors of the IL-1 biosynthesis [28]. They are also
the core structural skeleton in many important biological
molecules like histidine, histamine, and biotin, as well as
several drug moieties such as trifenagrel, eprosartan, and
losartan [29–31]. The 4H-chromenes are major classes of
natural oxygen-containing heterocyclic compounds, which
are extensively found in ripe fruits and vegetables. Because
of their diferent biological and pharmacological activities
such as antioxidant, antileishmanial, antibacterial, antifun-
gal, hypotensive, anticoagulant, antiviral, diuretic, antial-
lergenic, and antitumor activities [32–41], these compounds
have occupied a key place in drug research. Synthesis of
1,4-disubstituted 1,2,3-triazoles by ‘click reaction’ has
gained immense interest because it acts as scafold for large
number of biological active chemicals, pharmaceuticals,
agrochemicals, drug molecules with signifcant anti-HIV
activity, anti-microbial activity against Gram positive bac-
teria etc. [42–44]. Most of the synthetic methods are associ-
ated with one or more disadvantages such as using expensive
reagents, prolonged reaction time, low yield of products,
complex work-up procedures, formation of undesirable
side products which can be resolved by microwave-assisted
organic synthesis which is one of the most powerful and
2.1 Materials and Characterizations
All chemicals and solvents purchased are of analytical grade
and used without further purifcation. Infrared spectra were
collected on a Bruker Fourier transform infrared spectropho-
tometer (FTIR) (Alpha) with pressed KBr pellets and were
recorded in the range of 4000-400 wave number (cm−1).
The visualization of surface morphology of MNPs was done
by using a feld- emission scanning electron microscope
(FESEM; NOVA nano SEM) operated at a voltage 10 kV.
Samples were prepared by putting a little amount of fne
powdered nanoparticles on black carbon tape. Their TEM
images were recorded with a Tecnai G2 20 (FEI) S-Twin
high-resolution transmission electron microscope (HRTEM)
operating at 200 kV. Samples were prepared by drying the
droplet of dispersed solution of MNPs on a 400 mesh car-
bon coated copper grid under 100 W table lamp. Powder
X-ray difraction (XRD) pattern of the sample was obtained
with X-ray Difractometer (Panalytical X Pert Pro) using
Cu Kα radiation. X-ray photoelectron spectroscopy (XPS)
measurements recorded in ESCA+ omicron nanotechnol-
ogy oxford instrument. Thermo gravimetric analysis (TGA)
and diferential thermal analysis (DTA) was performed on a
Mettler thermal analyzer in an inert atmosphere at a heating
rate of 10 °C/min. Melting points were determined in open
glass capillaries using Gallenkamp melting point apparatus
1
and are reported uncorrected. H NMR were recorded on
a Jeol ECS 400 MHz spectrophotometer using DMSO d6
as a solvent. TMS was taken as an internal standard and
chemical shifts are reported in δ ppm. Resonance multiplici-
ties are described as s (singlet), d (doublet), t (triplet), q
(quartet) and m (multiplet). Ultrasonic bath; Elma S 70 H
with 37 kHz with an output frequency was used to carry out
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M. Kumari et al.
the sonochemical synthesis of nanoparticles and to carry
out multicomponent reactions. CEM Discover Microwave
was used to carry out all the multicomponent reactions.
The purity of all the compounds was checked by TLC using
silica gel as adsorbent and solvents of increasing polarity as
mobile phase.
of water/ethanol (1:1) with “snap-on” cap with a pressure
sensor and a magnetic stirrer. The reaction tube was placed
inside the cavity of a CEM Discover focused microwave
synthesis system, operated at 80 °C, 100 Watts and 10–60
psi for 10-15 min. The reaction progress was monitored by
thin layer chromatography (TLC, eluent: petroleum ether:
ethyl acetate: 8: 2). After the completion of the reaction, the
nano magnetite based catalyst was separated by using an
external magnet and the reaction product was then poured
into crushed ice. The obtained solid product was separated
by simple fltration, washed with EtOH and dried and recrys-
tallized from ethanol to aford pure product.
2.2 Preparation of Fe3O4‑ DOPA‑Cu Nanocatalyst
The magnetite nanoparticles were synthesized by chemi-
cal co-precipitation method similar to previously reported
method with slight modifcation [49]. In a 250 ml round
bottom fask 16 mmol of FeCl3.6H2O (4.32 g) and 8 mmol
of FeCl2.4H2O (1.59 g) were taken in 50 mL of deionised
(DI) water and ultrasonicated for 15 min at room temper-
ature (25 °C). Then slowly the temperature was raised to
60 °C and maintained for further 30 min. After that 50 mL
of 1 M NaOH solution was added dropwise at the same tem-
perature till the pH of the solution became 10-11. It was
further sonicated for another 30 min. The resulting black
dispersion was then allowed to remain undisturbed for one
night and the desired nanoparticles were separated by using
an external magnet then washed thoroughly with deionised
water (5 × 100 mL) followed by acetone, (2 × 50 mL) and
fnally dried in a vacuum oven for 6 h at 60 °C. In order
to graft L-DOPA over Fe3O4- nanoparticles, the mixture
of Fe3O4 (0.2 g) and L-DOPA (0.1 g) was ultrasonicated
in deionized water (10 mL) at 80 °C for 2 h. Black pre-
cipitate of Fe3O4-DOPA was separated magnetically,
washed with deionized water (3×20 mL) and dried under
vacuum. Finally, for immobilization of Cu nanoparticles
onto Fe3O4-DOPA, the aqueous solution of CuCl2·2H2O
(0.01 g, 3 mL) was added into the dispersed solution of
Fe3O4-DOPA (0.1 g) in MeOH/H2O (1:1, 10 mL), and the
reaction mixture was ultrasonicated at room temperature for
0.5 h. Hydrazine hydrate was added till the pH of the solu-
tion became 9 followed by addition of NaBH4 (0.01 g) into
the reaction mixture which was further sonicated for 2 h.
Fe3O4-DOPA-CuNPs so prepared was separated magneti-
cally and washed successively with ethanol (2×20 mL) and
water (2 × 20 mL). Finally, it was dried under vacuum at
room temperature to get Fe3O4-DOPA-Cu nanoparticles as
dark black powder.
2.4 General Procedure for the Synthesis
of 2,4,5‑trisubstituted Imidazoles Under
Microwave Irradiation by Fe3O4‑DOPA‑Cu
Nanocatalyst (8a‑e)
Fe3O4–DOPA–Cu (30 mg) as an efcient magnetic nano-
catalyst was added to a mixture of benzil (1 mmol), aromatic
aldehyde (1 mmol), NH4OAc (4 mmol) in a sealed pressure
regulated 10 mL pressurized vial with a pressure sensor and
a magnetic stirrer containing 5 mL of ethanol. The reaction
tube was placed inside the cavity of a CEM Discover focused
microwave synthesis system, operated at 80 °C, 100 Watts
and 10–60 psi for 15–18 min. After the TLC (eluent: petro-
leum ether:ethyl acetate:7:3) indicates the disappearance of
starting materials, the reaction was cooled to room tempera-
ture. The resultant solid was dissolved in acetone and the
magnetic nanocatalyst was separated using an external mag-
net. The mixture was concentrated on a rotary evaporator
under reduced pressure and the solid product obtained was
washed with water and recrystallized from acetone–water
9:1 (v/v) to aford the pure 2,4,5-trisubstituted imidazole
derivatives.
2.5 General Procedure for the Synthesis
of 2‑amino‑3‑cyano‑4H‑Chromenes Under
Microwave Irradiation by Fe3O4‑DOPA‑Cu
Nanocatalyst
An equimolar mixture of resorcinol (1 mmol), malon-
onitrile (1 mmol) and aromatic aldehyde (1 mmol) was
placed in a sealed pressure regulated 10 mL pressurized
vial containing ethanol (5 mL) and Fe3O4–PEG–Cu nano-
catalyst (45 mg) with “snap-on” cap with a pressure sen-
sor and a magnetic stirrer. The reaction tube was placed
inside the cavity of a CEM Discover focused microwave
synthesis system, operated at 60 °C, 100 Watts and 10–60
psi for 5–10 min. After completion of the reaction (TLC,
eluent: petroleum ether:ethyl acetate:7:3), the mixture was
poured into ice cold water. The resulting precipitate was
2.3 General Procedure for the Synthesis
of Dihydropyrimidinones via Biginelli
Condensation Under Microwave Irradiation
by Fe3O4‑DOPA‑Cu Nanocatalyst (4a‑e)
25 mg of Fe3O4-DOPA-Cu nanocatalyst was added to a
homogeneous mixture of aromatic aldehyde (1 mmol),
ethylacetoacetate (1 mmol) urea (1.2 mmol) in a sealed
pressure regulated 10 mL pressurized vial containing 5 ml
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Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
fltered, dried and recrystallized from ethanol to aford pure
Firstly Fe3O4 nanoparticles were prepared by the co-pre-
2-amino-4H-chromenes.
cipitation method and were reacted with L-3,4 dihydroxy-
phenylalanine (L-DOPA) in water to yield the Fe3O4-DOPA
and these obtained nanoparticles were further metallated
with copper chloride in the presence of aqueous NaBH4
solution to obtained the fnal copper decorated L-DOPA
functionalized magnetic nanoparticles. The synthesized
catalyst was characterized by various techniques such as
FTIR, SEM–EDS, HRTEM, XPS, VSM, PXRD and TGA.
FTIR is one of the best technique to characterize the func-
tionalization and modifcation of magnetite nanoparticles.
The FTIR spectra of the magnetite, L-DOPA, Fe3O4-DOPA
and Fe3O4-DOPA-Cu nanocomposites were recorded to
2.6 General procedure for synthesis of triazole
via in situ generation of alkyl azide
under microwave irradiation by Fe3O4‑DOPA‑Cu
nanocatalyst
Alkyl halides (1.2 mmol), NaN3 (1.5 mmol), alkyne
(1.0 mmol) and Fe3O4–DOPA–Cu nanocatalyst (100 mg) in
a sealed pressure regulation 10 mL pressurized vial contain-
ing 5 mL of water with “snap-on” cap with a pressure sensor
and a magnetic stirrer. The reaction tube was placed inside
the cavity of a CEM Discover focused microwave synthesis
system, operated at 120 °C, 100 Watts and 10–60 psi for
10–12 min. After completion of the reaction, the catalyst
was easily removed from reaction mixture using an external
magnet. After separation of catalyst the solid product was
fltered of or extracted with ethyl acetate and recrystallized
or purifed by column chromatography.
3 Results and Discussion
3.1 Characterization of the Fe3O4‑DOPA‑Cu
nanocatalyst
In the present protocol, we have synthesized an efcient and
magnetically recoverable catalyst, Fe3O4-DOPA-CuNPs
and the process of its preparation has been schematically
described in Scheme 1.
Fig. 1 FTIR spectra of a Fe3O4 b L-DOPA c Fe3O4-DOPA d
Fe3O4-DOPA-CuNPs
Scheme 1 Schematic representation of the synthesis of Fe3O4-DOPA-Cu nanocatalyst
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M. Kumari et al.
confrm the modifcation of the magnetite surface with the
L-DOPA and metal ion. (Figure 1a–d). The IR spectrum
of Fe3O4 shows a broad band at 578 cm−1 due to the Fe–O
stretching vibrational mode [50], Fig. 1a. The IR spectra of
L-DOPA show a peak at 1656 cm−1 due to C = O stretch-
ing of carboxylic acid. The IR bands appearing at about
3408 cm−1 and 679 cm−1 correspond to the N–H stretch-
ing and bending vibration mode of L-DOPA as shown in
Fig. 1b. Fe3O4-DOPA shows IR peak at 3402, 3206, 3071,
2919, 2840, 1651, 1465, 1405, 1274, 561 cm−1. It has
been observed that the stretching vibrational mode of the
C–H of CH2 group of L-DOPA appeared at 2919 cm−1 and
2840 cm−1 while the bending vibrational mode appeared
at 1465 cm−1 [51]. Moreover, IR peaks at 1651 cm−1 and
1405 cm−1 could be ascribed to the carboxylate group of
L-DOPA whereas the IR peak at 1274 cm−1 to the C-O
stretching vibrational mode of the carboxylate group [50].
These results show that a large number of L-DOPA mol-
ecules are grafted over the Fe3O4 support. In terms of
Fe3O4-DOPA-Cu (Fig. 1d), all the peaks become broaden
and appears as band, and one of the noticeable change was a
red shift of the band at 1651 cm−1 was observed (1651 cm−1
to 1617 cm−1), which was probably characteristic of the
asymmetrical fuctuations of the carbonyl group after inter-
action with the metal ion [52]. Overall, the IR results sug-
gested that Cu was successfully immobilized onto the sur-
face of Fe3O4-DOPA nanoparticles.
assessment of the difractograms of nanoparticles, the very
distinguishable FCC peaks of the magnetite crystal were
not changed, which means that these particles have phase
stability, but there is a slight decrease in the intensity with
broadening of the corresponding peak. The signals of Cu
metal were not detected in XRD, indicating that Cu species
is highly dispersed on ferrites.
Furthermore, the chemical composition of the
Fe3O4-DOPA-Cu nanocomposite was determined by energy
X-ray spectroscopy (SEM–EDX). The presence of C, N, O,
Fe and copper centers in the nanocomposite was confrmed
by elemental mapping images (Fig. 3). The result showed
uniform distribution of Cu nanoparticles over the structure
of the L-DOPA supported magnetite nanoparticles. The
percentage of each element present in nanocatalyst were
obtained from energy dispersive X-ray spectrum and the
results obtained were in good agreement with the proposed
catalyst composition (Fig. 4).
TEM image of the Fe3O4-DOPA-Cu nanocatalyst shows
a somewhat spherical morphology, with some cubic par-
tials, and an average size range of 8–20 nm with a mean
particle size of 12 nm. The HRTEM image in Fig. 5b shows
the characteristic lattice fringes of Fe3O4 nanoparticles
with the d-spacing of 0.233 nm corresponds to the [311]
plane of Fe3O4 [53]. Additional HRTEM image (Fig h) of
Fe3O4-DOPA-Cu showed the lattice fringes with an inter-
planar spacing of approximately 0.216 nm corresponding
to the [111] lattice plane of metallic Cu [54]. Figure 5i
showed selected area electron difraction pattern of the
Fe3O4-DOPA-Cu nanocatalyst which revealed its polycrys-
talline nature.
The crystalline structure of Fe3O4 and
Fe3O4-DOPA-CuNPs were analyzed by powder X-ray dif-
fraction (XRD). As displayed in Fig. 2a, b, according to the
JCPDS card no. 19-0629, all the samples show difraction
peaks at around 30.4°, 35.5°, 43.3°, 53.4°, 57.2° and 62.8°
which can be assigned to difraction of Fe3O4 crystal with
an inverse spinal structure from the (220), (311), (400),
(422), (511), and (440) faces of the crystals, respectively. On
In order to provide further evidence of the formation of
Cu+2 complex over the iron oxide core and to determine
the oxidation state of copper, the XPS resolution spectros-
copy have been investigated. For a better understanding of
Fig. 2 XRD of a Fe3O4 b Fe3O4-DOPA-CuNPs
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Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
Fig. 3 EDS elemental mapping
of the Fe3O4-DOPA-CuNPs
the oxidation state of copper, the binding energy obtained
from the catalyst was compared with the Cu + 2 2p3/2 and
2p1/2 peak positions. The binding energies of the main peaks
magnetic so that it can be easily separated from the reaction
mixture by using an external magnet. The thermal stabil-
ity of the synthesized nanocatalyst was also investigated by
performing thermogravimetric analysis. The major weight
loss was observed after 350 due to the decomposition of
chemisorbed material i.e. L-DOPA. This confrms that ther-
mal stability of the synthesized catalyst maintained at higher
temperature.
were about 935.6 eV and 955.5 eV due to Cu 2p3/2 and 2p1/2
,
respectively [55]. Two other peaks were also obtained at
944.5 eV and 963.8 eV that attributed to the Cu 2p3/2 and
2p1/2 satellite peaks (Fig. 6b). Since all these lie within the
given literature, it can be concluded that the oxidation state
of copper in the catalyst is +2.
Another important parameter for the practical appli-
cations of nanoparticles is revealed from the VSM curve
shown in Fig. 7a. The hysteresis loops of powdered material
showed almost negligible magnetic hysteresis, with both the
magnetization and demagnetization curves passing through
the origin, which clearly indicates the supermagnetic nature
of the materials. This also means that the magnetic material
can only be aligned under an applied magnetic feld, but it
will not retain any residual magnetism upon removal of the
feld. Thus, Fe3O4-DOPA-Cu nanoparticles are sufciently
3.2 Catalytic Activity
3.2.1 Catalytic Studies for the Synthesis
of Dihydropyrimidinone (4a‑e)
After characterization and demonstration of the structure
and morphology of nanocatalyst, we examined its efciency
in the synthesis of 3,4-DHP derivatives under microwave
irradiation. Initially, the reaction of benzaldehyde (1 mmol),
ethyl acetoacetate (1 mmol) and urea (1.2 mmol) was taken
1 3

M. Kumari et al.
Fig. 4 EDS spectrum of
Fe3O4-DOPA-CuNPs
as a model reaction. The efect of solvent on reaction was
examined along with catalyst amounts. Based on the results
as shown in Fig. S2, 25 mg of Fe3O4-DOPA-Cu was con-
sidered as the optimum amount of catalyst and EtOH/H2O
as best suitable solvent. After the optimization of solvent
and catalyst amount, we further examined the efects of the
microwave power and temperature on the yield of the reac-
tion. From obtained results depicted in Fig. S1, optimized
power of microwave oven was 100 W at 80 °C. When the
reaction has been carried out without using any catalyst it
showed less yields in optimum time and after increasing
time it gives quantitative yield. A comparative study with
other synthetic method like conventional and ultrasonica-
tion has also been carried out, resulting best yield obtained
by microwave irradiation in least reaction time (Fig. S3).
Regarding to the obtained desired reaction conditions, we
developed the present method for the reaction between
benzaldehyde derivatives, ethyl acetoacetate and urea in
the presence of optimum amount of catalyst. As shown in
Table 1, products have high to excellent yields both in case
of aldehydes bearing electron donating and electron with-
drawing groups obtained in shorter reaction time. Products
were characterized using physical and spectroscopic meth-
ods such as melting point, 1HNMR technique. A proposed
mechanism for the formation of dihydropyrimidines has
been given in Scheme S1 based on the mechanism suggested
by Kappe [56]. Initially the catalyst activated the carbonyl
group of aldehyde followed by condensation by urea forming
the intermediate A. The role of nanocatalyst is to increase
the electrophilicity of carbonyl carbons of both aldehyde and
ethylacetoacetate. The formation of enol structure favored
by catalyst can be explained via HSAB theory. Here Cu+2
in the nanocatalyst act as harder acid due to the high charge
density that is 6.2×102 nm−3 and the presence of low energy
d-orbitals that can be used to hold the free electrons of the
oxygen atom of ethylacetoacetate which can act as a base or
nucleophile for chemical reactions. After that B intermedi-
ate was formed by nucleophilic addition of enol form of
β-dicarbonyl to the intermediate A. Finally cyclization to
the C intermediate subsequently proceeds by elimination of
water to aford fnal product [57].
3.2.2 Catalytic Studies for the Synthesis of 2,4,5
Trisubstituted Imidazoles (8a‑e)
To optimize the reaction conditions for the synthesis of
2,4,5 trisubstituted imidazoles, the reaction of benzaldehyde
(1 mmol), benzil (1 mmol) and ammonium acetate (4 mmol)
was used as a model reaction. Reactions were performed
by varying microwave power and temperature, and the best
optimum conditions obtained were 80 °C, 100 W. Further
solvent optimization also carried out and the best suitable
solvent observed was ethanol (Fig. S5 and S6). Optimiza-
tion for catalyst loading has been also carried out revealed
that the optimum amount of catalyst was 30 mg. The reac-
tion showed less yields in optimum time when it has been
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Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
Fig. 5 a TEM image of Fe3O4 b HRTEM image of Fe3O4 c TEM image of Fe3O4 –DOPA d HRTEM image of Fe3O4 e, f and g TEM image of
Fe3O4- DOPA-CuNPs h HRTEM image of Fe3O4- DOPA-CuNPs i SAED pattern of the of Fe3O4-DOPA-CuNPs
Fig. 6 X-ray photoelectron spectra of Fe3O4-DOPA-CuNPs showing Cu 2p3/2 and Cu 2p1/2 binding energies
1 3

M. Kumari et al.
Fig. 7 a Room temperature magnetization curves of Fe3O4-DOPA-Cu b TGA of (i) Fe3O4 (ii) Fe3O4-DOPA-CuNPs
carried out without using any catalyst and after increasing
time it gives quantitative yield. A comparative study has
been carried out for various synthetic methods and micro-
wave irradiation opted out as best method (Fig. S7). After
optimizing the reaction conditions, in order to explore the
scope and generality of this protocol, various aldehydes were
used as substrate for the synthesis of 2,4,5 trisubstituted imi-
dazoles. The results are shown in Table 2 and indicated that
the reactions are equally facile with both electron withdraw-
ing and electron donating groups present on the aromatic
aldehydes, resulting in high yields of the corresponding
imidazoles. Products were characterized using physical and
spectroscopic methods such as melting point, 1HNMR tech-
nique. The plausible mechanism for the synthesis of 2,4,5
trisubstituted imidazoles with the nanocatalyst shown in
Scheme S2. Ammonium acetate is the source of ammonia
molecule. At frst the catalyst facilitates the formation of
diamine intermediate (A) by increasing the electrophilicity
of the carbonyl group of the aldehyde. Intermediate (A),
undergo condensation with benzil to form intermediate (B)
which further undergo condensation leading to intermediate
(C) which rearranges via a [1, 5] sigmatropic shift to give the
corresponding tri-substituted imidazole [58].
any catalyst also and it gives quantitative yield after increas-
ing time but showed less yields in optimum time. For this
reaction also a comparative study has been carried out for
various synthetic methods and microwave irradiation opted
out as best method (Fig. S11). After optimizing the reaction
conditions, various aldehydes were used as substrate for the
synthesis of 2-amino-4H-chromene. As shown in Table 3
aldehydes bearing either electron-withdrawing or electron
donating groups showed equally well in the reaction and all
2-amino-4H-chromenes were prepared in high yields. Prod-
ucts were characterized using physical and spectroscopic
1
methods such as melting point, HNMR technique. The
plausible reaction mechanism for the synthesis of 2-amino
4H-chromene derivatives in the presence of nanocatalyst is
shown in Scheme S3. Firstly, catalyst binds with the oxygen
of the carbonyl group makes the alpha hydrogen very acidic,
thereby involving the Knoevenagel condensation reaction
between aromatic aldehyde and malononitrile. In the sec-
ond step, Knoevenagel product was reacted in a Michael
addition with resorcinol to produce desired product after
rearomatization and intramolecular cyclization with the help
of nanocatalyst [59].
3.2.4 Catalytic Studies for Synthesis of 1,4 Disubstituted
1,2,3‑Triazole (12a‑d)
3.2.3 Catalytic Studies for Synthesis of 2‑Amino‑4H‑
Chromenes (12a‑e)
After preparing the catalyst, we examined its ability to pro-
mote the formation of the organic azide in situ, and subse-
quent 1,3-dipolar cycloaddition with the alkyne. We defned
various parameters of analysis in order to optimize the reac-
tion conditions. As can be seen from the Fig. S13 and S14
the infuence of temperature, microwave power, solvent and
catalyst loading were analysed. For the initial studies, we
selected the reaction of benzyl bromide (1.2 mmol), sodium
azide (1.5 mmol) and phenyl acetylene (1 mmol) as a model
Now to optimize the reaction conditions for the synthesis
of 2-amino-4H-chromene, the reaction of benzaldehyde
(1 mmol), malononitrile (1 mmol) and resorcinol (1 mmol)
was used as a model reaction. Reactions were performed
at diferent microwave power, temperatures, solvents, and
catalyst loading resulting that the best condition were 60 °C,
100 W, 45 mg of the catalyst and ethanol as a solvent (Fig.
S9, S10). The reaction has been carried out without using
1 3

Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
Table 1 Fe3O4-DOPA-Cu catalyzed synthesis of 3,4 dihydropyrimidinones by Biginelli reaction
R
H
O
C
O
O
O
e
-
-
u
s
m
NP 25
,
g
)
F
D
PA
MW
:
3O4
O
C
,
(
Et
NH
O
Et
O
100W 80 o
5
L H Et H 1 1
H2N
NH2
m
C
2O/
O
,
,
,
(
)
N
H
O
R
O
a-e
4
a-e
2
3
1
Entry
4a
Product
Time (min)
bYield %
O
10
95
Et
Et
NH
O
N
H
O
l
C
O
12
93
4b
4c
NH
O
N
H
O
N
O2
O
05
15
96
92
Et
NH
O
N
O
H
H
O
O
4d
Et
NH
O
N
H
O
N
O2
O
H
O
O
12
90
Et
NH
4e
N
O
H
Reaction conditions: benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.2 mmol) in the presence of 25 mg of Fe3O4-DOPA-CuNPs in
5 ml EtOH/H2O, 100 W and 80 °C)
aIsolated yield
1 3

M. Kumari et al.
Table 2 Fe3O4-DOPA-Cu catalyzed synthesis of 2,4,5 trisubstituted imidazole
H
C O
Ph
H
N
O
Ph
Ph
O
R
e
-
- u
PA
s
m
F
D
NP 30
3O4
O
C
g
(
)
MW 100W 80 o
5
L Et H
O
+H N
H
C
3
m
C
,
,
,
O
4
O
N
Ph
R
a-e
8
7
5
a-e
6
Entry
8a
Product
N
Time (min)
Yield %
H
Ph
15
95
N
Ph
H
Ph
N
18
16
12
15
92
90
96
96
8b
8c
8d
8e
l
C
N
Ph
Ph
H
N
H
O
N
Ph
H
Ph
N
N
O2
N
Ph
H
O
H
N
Ph
N
Ph
N
O2
Reaction conditions: benzaldehyde (1 mmol), benzil (1 mmol), ammonium acetate (4 mmol) in the presence of 30 mg of Fe3O4-DOPA-CuNPs
in 5 ml EtOH at 100 W and 80 °C)
aIsolated yield
reaction to yield the 1,2,3-triazole. It was observed that the
optimum condition for the synthesis of triazole achieved
were 100 W, 120 °C, 100 mg of the nanocatalyst and water
as a solvent. In case of triazole synthesis, when the reaction
was carried out without catalyst 1:1 of 1,4 and 1,5 cyclic
adducts were obtained. The cycloaddition of alkyne and
azide become region-selective and a very selective forma-
tion of 1,4 adduct in quantitative yield was observed with
the help of Fe3O4–DOPA–Cu nanocatalyst. After inde-
pendent optimization of the reaction conditions the same
model reaction has been carried out under diferent syn-
thetic methods like conventional heating, ultrasonication
and microwave irradiation and results revealed that the best
yield was obtained by microwave irradiation in less reac-
tion time (Fig. S15). Further we extended these optimized
conditions for diferent benzyl halides and terminal alkynes
to check the versatility of the protocols and results obtained
were mentioned in Table 4. Products were characterized
using physical and spectroscopic methods such as melting
point, 1HNMR technique. Mechanism of copper catalysed
synthesis of 1,2,3-triazoles has been recently been reviewed
by Fokin who proposed a revisited mechanism whereby a
σ-bound Cu(I)-acetylide bearing a π complexed copper
atom reacts with an organoazide forming a bridging dicop-
per µ-acetylide intermediate [60–64]. Based upon their stud-
ies we proposed following mechanism for the formation of
1,2,3-triazoles (Scheme S4).
3.2.5 Recyclability and Leaching Aspect
of the Fe3O4‑DOPA‑Cu Nanocatalyst
The reusability of the nanocatalyst was also examined and
it is an important advantage of magnetic nanocatalyst that
being magnetically separable from the reaction mixture, eas-
ily recovered by using an external magnet and can be reused
for subsequent cycles. After every reaction they were washed
1 3

Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
Table 3 Fe3O4-DOPA-Cu catalyzed synthesis of 2-amino-4H-chromenes
R
H
C
O
H
O
H
O
N
C
e
-
-
u s
m
NP 45
C
(
N
C
F
D
PA
3O4
MW 100W 60 o
5
C
,
O
g
)
m
L Et
H
O
,
,
N
C
H
O
NH2
O
R
a-e
12
a-e
11
9
10
Entry
12a
Product
Time (min)
bYield %
08
95
N
C
H
NH2
O
O
O
O
C
l
10
05
94
98
12b
12c
N
C
H
H
H
NH2
O
N
O2
N
C
NH2
O
O
H
08
10
92
92
12d
12e
N
C
NH2
O
O
N
O2
N
H
O
C
H
O
NH2
O
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), resorcinol (1 mmol) in the presence of 45 mg of Fe3O4-DOPA-CuNPs in
5 ml EtOH at 100 W and 60 °C)
aIsolated yield
with hot ethanol, air-dried and used directly for next round
of reactions. The nanocatalyst was found to exhibit good
catalytic activity for up to fve reaction cycles for Biginelli
reaction and triazole synthesis and up to six runs for imida-
zole and chromene synthesis.
The leaching aspect of any copper after recycling was
examined by determining the metal content of reaction
solution using AAS (atomic absorption spectroscopy) and
sample digestions were carried out in a microwave oven
at 500 W for 10 min with 5 mL aqua regia. It was found
1 3

M. Kumari et al.
Table 4 Fe3O4-DOPA-Cu catalyzed synthesis of 1,2,3- triazoles by Click reaction
N
N
e
-
-
u
PA
C
s
m
NP 100
,
g
)
F
D
O
3O4
(
r
B
a
Ph
Ph'
N N3
MW 100W 120 o
5
Ph
N
m
L H
2O
C
,
,
,
Ph'
13
15
a
-
16
d
14
Entry
Product
N
Time (min)
bYield %
N
N
10
96
16a
N
N
H
3C
N
12
12
10
98
95
94
16b
N
N
16c
16d
N
N
O2
N
N
H
3C
N
N
O2
Reaction conditions: benzyl bromide (1.2 mmol), sodium azide (1.5 mmol), phenyl acetylene (1 mmol) in presence of 100 mg of
Fe3O4-DOPA-CuNPs in 5 ml H2O at 120 °C)
aIsolated yield
that the concentration of copper in the reused catalyst was
reduced to 1.34 wt % for Biginelli reaction and 1.89 wt %
for triazole synthesis after 5th run, 2.65 wt % for imida-
zole synthesis and 2.39 wt % for chromene synthesis after
6th run. The small amount of copper leaching might be
due to some changes that occurred on the surface of the
magnetic catalyst. Major weight loss of catalyst at high
temperature and a small amount of leaching also proves
that the catalyst is highly stable at high temperature also.
A comparative study of the reported methods in the
literature to synthesize all the above described multicom-
ponent reactions to show the efficiency of the catalyst. It
is clear from the Tables S1-S4 given in the supplementary
information that Fe3O4-DOPA-Cu is an efficient and envi-
ronmentally benign nanocatalyst which could be used in
the synthesis of an array of the above discussed important
multicomponent reactions.
4 Conclusion
The synthesized catalyst (Fe3O4-DOPA-Cu) exhibits high
catalytic activity towards (i) synthesis of DHPMs via Bigi-
nelli reaction (ii) synthesis of imidazoles (iii) synthesis of
2-amino-4H-chromenes (iv) 1,2,3-triazole derivatives by
‘Click reaction’ under microwave irradiation (MWI). The
advantage of this catalyst are easy to prepare, inexpensive,
and ofers easy magnetic separation and reusability. More-
over the mild reaction conditions, operational simplicity,
giving the desired product in high yields, easy work-up
are the key advantages of this protocol. To the best of
our knowledge, this is the frst time one single catalyst
is reported which shows its high activity for these four
important multicomponent reactions and this fact makes
it attractive.
1 3

Synthesis of Fe3O4-DOPA-Cu Magnetically Separable Nanocatalyst: A Versatile and Robust…
29. Koike H, Konse T, Sada T, Ikeda T, Hyogo A, Hinman D, Saito
Acknowledgements Authors are thankful to Materials Research Cen-
tre, MNIT Jaipur for providing spectral analysis facilities. M. Kumari
acknowledge to Department of Science and technology (DST), India,
for providing JRF under INSPIRE fellowship scheme (IF140506). One
of the author Y. Jain is grateful to MNIT Jaipur for proving fnancial
assistance. Other authors P. Yadav and H. Laddha are thankful to CSIR
for providing JRF.
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1 3