Magnetically recoverable copper ferrite catalyzed cascade synthesis of 1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones under microwave irradiation and solvent-less condition

Article abstract of DOI:10.1002/aoc.6091

In recent years, magnetically active CuFe₂O₄ nanoparticles have been gaining significant interest in the field of heterogeneous catalysis as those can be easily prepared and effortlessly recovered from a reaction system. Here, we are

Full text of DOI:10.1002/aoc.6091

Received: 16 July 2020
DOI: 10.1002/aoc.6091
Revised: 22 October 2020
Accepted: 28 October 2020
F U L L P A P E R
Magnetically recoverable copper ferrite catalyzed cascade
synthesis of 1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]
pyrimidine-2,4(1H,3H)-diones under microwave irradiation
and solvent-less condition
Amar Jyoti Bhuyan1
Lakhinath Saikia1
| Pubanita Bhuyan1
| Bornali Boruah2
|
1Department of Chemistry, Rajiv Gandhi
University (A Central University),
Doimukh, India
2Department of Chemistry, Assam Down
Town University, Guwahati, India
In recent years, magnetically active CuFe2O4 nanoparticles have been gaining
significant interest in the field of heterogeneous catalysis as those can be easily
prepared and effortlessly recovered from a reaction system. Here, we are
reporting our work on cascade syntheses of 1,3-dimethyl-6-nitro-5-arylpyrido
[2,3-d]pyrimidine-2,4(1H,3H)-diones starting from 6-[(dimethylamino)
methylene-amino]-1,3-dimethyluracil, aromatic aldehydes and nitromethane
using magnetically active CuFe2O4 catalyst system under microwave irradia-
tion and solvent-less condition. The current methodology is a valued addition
to the existing procedures of 5-arylpyrido[2,3-d]pyrimidines syntheses making
best use of the diene behavior of 6-[(dimethylamino)methylene-amino]-
1,3-dimethyluracil. However, heterogeneous catalysis has been employed for
the first time to do the syntheses by carrying out [4 + 2]cycloaddition reaction
between 6-[(dimethylamino)methylene-amino]-1,3-dimethyluracil and in situ
generated 2-(2-nitrovinyl)arenes/heteroarenes. The methodology is highly
time-economic, and along with other features like easy recovery and good
reusability of the catalyst, simple operating procedure, wide substrate scope,
and good to excellent product yield, it offers the chemists a reaction protocol
worth trying for the syntheses of 1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]
pyrimidine-2,4(1H,3H)-diones. While laboratory prepared catalyst system was
characterized using FT-IR, XRD, SEM-EDX, VSM, XPS and TEM analysis, all
Correspondence
Lakhinath Saikia, Department of
Chemistry, Rajiv Gandhi University
(A Central University), Rono-Hills,
Doimukh, Arunachal Pradesh 791112,
India.
Email: lakhinath.saikia@rgu.ac.in
Funding information
Science and Engineering Research Board;
DST-INSPIRE fellowship, Grant/Award
Number: IF170498; Council of Scientific
and Industrial Research (CSIR), India,
Grant/Award Number: 02(0280)/16/EMR-
II; Department of Science and
Technology-Science and Engineering
Research Board, India, Grant/Award
Number: EMR/2016/003126
the synthesized compounds have been characterized using H and 13C NMR
1
spectroscopy and HRMS.
K E Y W O R D S
[4 + 2]cycloaddition reaction, 5-arylpyrido[2,3-d]pyrimidine, cascade synthesis, copper ferrite,
magnetic nanoparticles
Appl Organomet Chem. 2020;e6091.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
1 of 14
https://doi.org/10.1002/aoc.6091

2 of 14
BHUYAN ET AL.
1 | INTRODUCTION
multicomponent methodologies to carry out the transfor-
mation in or without presence of homogeneous
catalyst,[21–23] not a single report has been found to
employ heterogeneous catalyst system for the purpose.
In recent years, magnetically active CuFe2O4 particles
have been widely and successfully used in many cascade
synthetic processes.[48–52] We too developed a CuFe2O4
catalyzed rapid cascade synthetic methodology for 4-aryl-
1H-1,2,3-triazoles starting from aromatic aldehydes,
nitromethane, and NaN3 under microwave irradiation.[53]
In that line, we are reporting herein a CuFe2O4 catalyzed
cascade methodology for the synthesis of 1,3-dimethyl-
6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones
(4) starting from 6-[(dimethylamino)methylene-amino]-
1,3-dimethyluracil (1), aromatic aldehydes (2), and nitro-
methane (3) under microwave irradiation and solvent-
less condition. The report is indeed first of its kind to
adopt heterogeneous catalysis for cascade synthesis of
5-arylpyrido[2,3-d]pyrimidines involving [4 + 2]cycload-
dition process and is a valued addition to the existing
methodologies enabling significant minimization of time
requirement as depicted in Scheme 1.
Research works toward construction of heterocyclic
frameworks have always been constituting a pivotal area
of research, as advancement of medicinal chemistry is
considerably dependent on the development of newer
and efficient synthetic methodologies for these heterocy-
cles. Among various heterocycles, pyrido[2,3-d]pyrimi-
dine is one of the most significant entities as numerous
molecules bearing this core structure are established to
have excellent biological activities like antitumor,[1–5]
antitmicrobial,[6–11]
anti-inflammatory,[12,13]
herbicidal,[14] tyrosine kinase inhibitory activity,[15–18]
and activity against dengue virus[19]. The moiety started
gaining special attention from researchers dealing with
antibacterial studies of synthesized compounds after the
landmark publication by Stover et al. in Proceedings of
the National Academy of Sciences of the United States of
America.[20] They reported therein the screening of 1.6
million individual compounds from Pfizer compound
library for antibacterial activity and identifying three
pyrido[2,3-d]pyrimidine derivatives as potent synthetic
antibacterial. The need of developing novel and efficient
antibiotics to combat bacterial drug resistance along with
broad spectrum of biological activities associated with
pyrido[2,3-d]pyrimidine have made this unit a lucrative
target for many synthetic chemists. So a plethora of
reports have been found demonstrating efficient syn-
thetic methodologies for organic molecules containing
pyrido[2,3-d]pyrimidine core structure starting from a
diverse set of substrates employing homogenous, hetero-
geneous, and catalyst-free procedures.[21–47] Among
these, there are a good number of reports that describe
excellent use of the diene nature of 6-[(dimethylamino)
methylene-amino]-1,3-dimethyluracil (1) or related
compounds to carry out [4 + 2] cycloaddition reactions
with various electron deficient dienophiles for successful
synthesis of pyrido[2,3-d]pyrimidine derivatives.[21–28]
2 | RESULT AND DISCUSSION
2.1 | Catalyst preparation and
characterization
CuFe2O4 catalyst system used for the purpose was pre-
pared as discussed in our recent work by combined
sonochemical and co-precipitation technique.[53] Charac-
terization of the catalyst was done using electron disper-
sive X-ray (EDX) analysis, Fourier-transform-infrared
spectroscopy (FT-IR), scanning electron microscopy
(SEM), transmission electron microscopy (TEM), vibrat-
ing sample magnetometer (VSM) study, and X-ray photo-
electron spectroscopy (XPS). SEM-EDX spectrum
(Figure 1c) ascertains the elemental presence of Cu, Fe,
Although
a
few of these reports demonstrate
SCHEME 1 Comparison of reported and
present work

BHUYAN ET AL.
3 of 14
FIGURE 1 SEM images of fresh and recovered catalysts (a and b); EDX (SEM) spectra of fresh and recovered catalysts (c and d)
and O in 12.95, 29.48, and 57.57 atomic% respectively in
the prepared sample. An absorption band at 581.10 cm−1
was observed in the FT-IR spectrum, which can be attrib-
uted to Fe O stretching vibration (Figure 2).[48] Reflec-
tion peaks at 2θ values 18.2, 29.8, 35.3, 37.2, 42.8, 52.9,
56.5, and 62.3ꢀ were observed in XRD analysis (Figure 3),
which are in good agreement with the characteristic
peaks of tetragonal CuFe2O4 with good crystallinity.[49]
From XRD data, average particle size was determined by
using Scherrer equation D = Kλ/(dCosθ) and found to be
15.09 nm (calculation is shown in supporting informa-
tion). Particle size of the nanoparticles was calculated
from TEM image (Figure 4) too and found to be in the
range of 13–18 nm, which is in good agreement with the
size calculated using Scherrer equation. Coagulation of
particles in the sample was unveiled by the TEM image
(Figure 4a), which can be attributed to the magnetic
nature of the particles. Diffraction spots were sup-
erimposed on the ring pattern (Figure 4b) in the selected
area electron diffraction (SAED) analysis, which reveals
polycrystalline nature of the material. Magnetic property
of the prepared catalyst was analyzed by vibrating sample
magnetometer under applied field of 15 kOe at room
temperature, the resulting hysteresis loop of which is
shown in Figure 5. The three important parameters,
namely coercivity, magnetization at saturation (Ms), and
retentivity (Mr) of the sample were measured as
211.24 Oe, 32.390 emu/g and 6.5982 emu/g respectively
from the hysteresis loop. The shape of the loop along
FIGURE 2 FT-IR spectra of the fresh and recovered catalyst

4 of 14
BHUYAN ET AL.
FIGURE 3 XRD spectra of fresh and
recovered catalysts
FIGURE 4 TEM and SAED images
of CuFe2O4nanoparticles
FIGURE 5 Hysteresis loop of fresh and recovered catalyst
with the value of magnetization at saturation
(32.390 emu/g) reveal the ferromagnetic property of the
material. XPS analysis was carried out to understand the
chemical composition of the prepared sample. Charge
correction of binding energies due to specimen charging
was done by setting the binding energy of C 1 s at
284.6 eV. The survey spectrum as shown in Figure 6a
clearly indicates the presence of Cu, Fe, and O in the
sample. High resolution spectrum for Cu 2p showed a
peak at 934.3 eV, which is characteristic of Cu 2p3/2 in
CuFe2O4.[54] Peaks at binding energy values 942.8 and
954.4 eV correspond to Cu 2p3/2 satellite and Cu 2p1/2
peak respectively, confirming the presence Cu2+ in the
sample (Figure 6b).[55,56] Fe 2p spectrum showed two

BHUYAN ET AL.
5 of 14
FIGURE 6 XPS spectrum of prepared CuFe2O4: Survey spectrum (a); high resolution spectrum of Cu 2p (b), Fe 2p (c) and O 1s (d)
major peaks at 711.4 and 724.7 eV, which correspond to
Synthesis System) were examined as source of energy for
performing the reactions. Table 1 clearly reveals better
outcome of the reactions under microwave irradiation
over conventional heating. Among the solvents tested,
high boiling polar solvents (DMSO and DMF) were found
more suitable than their low boiling counterpart (EtOH)
(Entries 1–14, Table 1). Solvents like CH3CN and
HOCH2CH2NH2 were found unsuitable for the purpose
(Entries 15–18, Table 1). When the reaction was carried
out in the absence of solvent using the liquid substrate,
i.e. CH3NO2 in excess, significant increase in yields were
observed (Entries 19–24, Table 1). To check the role of
CuFe2O4, the reaction was carried out in its absence
(Entries 25–26, Table 1). These reactions resulted no and
12% product formation under conventional heating and
microwave irradiation respectively and thus revealed the
worth of CuFe2O4 as catalyst in the reaction. 5% catalyst
loading was observed as optimal when the isolated yields
of the reactions carried out with different catalyst loading
were compared (Entry 20, 22 & 24, Table 1). Catalytic
effect of Cu(I) and Cu(II)-salts against CuFe2O4 were
checked by carrying out reactions in presence of 5 mol%
of Cu (NO3)2, CuCl, and CuCl2. It was observed that
Cu(II) salts display higher catalytic activity than
Fe 2p3/2 and Fe 2p respectively.[55] Two accompanying
½
satellite peaks at 711.4 and 732.8 in the spectrum indicate
the presence of Fe in Fe3+ state (Figure 6c).[55] A peak
centered at 529.8 eV was observed in the high resolution
spectrum of O 1 s, which indicates the presence of O2−
(Figure 6d).[57] Elemental quantification from the peak
area values of various peaks in the XPS spectrum showed
the presence of Cu, Fe, and O in 13.82, 28.07, and 58.1
atomic%, respectively, which confirms that the prepared
sample possesses an empirical formulae of CuFe2O4.
2.2 | Catalytic activity
To evaluate the catalytic activity of the prepared catalyst
in multicomponent synthesis of 4 starting from 1, aro-
matic aldehydes (2) and nitromethane (3), its catalytic
activity was checked by carrying out a model reaction
(Scheme 2) among 1, p-nitrobenzaldehyde (2a), and
nitromethane (3) under various reaction conditions and
the results observed are summarized in Table 1. Both
conventional and microwave heating (using a monomode
microwave synthesizer by Raga's Scientific Microwave

6 of 14
BHUYAN ET AL.
SCHEME 2 Model reaction for the synthesis of
1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione
TABLE 1 Optimization of reaction condition for Scheme 1a
Entry
1
Solvent
Catalyst loading [mol%]
Mode of activation
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Conventional heating
Microwave heating
Microwave heating
Microwave heating
Microwave heating
Yield [%]b
DMSO
10
20
52
18
48
15
42
2
3
5
3
4
5
6
c
d
7
—
—
8
10
18
45
18
40
—
12
—
—
—
—
30
86
20
85
12
72
—
12
60
32
65
9
DMF
10
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
EtOH
10
10
10
10
5
CH3CN
HOCH2CH2NH2
e
—
3
—
—
—
—
5f
5g
5h
aReaction condition: 1 (1 mmol); 2 (1.1 mmol); nitromethane (1.1 mmol); solvent (1 ml/mmol); 12 h (conventional heating); 5 min (microwave
heating, 420 W).
bIsolated yield of 4a.
cNo catalyst.
dNo 4a formation.
eNo solvent, CH3NO2 was used in excess (1.5 mmol).
f5 mol% of Cu (NO3)2 was used.
g5 mol% of CuCl was used.
h5 mol% of CuCl2 was used.

BHUYAN ET AL.
7 of 14
Cu(I) (Entries 27, 28, and 29, Table 1). However, in all
the cases, isolated yield of 4a were found significantly
lower than the isolated yields obtained in the presence of
CuFe2O4 as catalyst. Optimization of microwave power
employed and amount of nitromethane used were then
fine-tuned, the results of which are displayed in Table 2.
Increase in microwave power to 480 W (Entry 2, Table 2)
resulted no significant change in isolated yield of 4a,
whereas a further increase in that to 540 W (Entry
3, Table 2) caused damage to the reaction mixture
resulting lower yield of 4a. Lowering of microwave
energy (Entries 4 and 5, Table 2) led to significant
decrease in product formation. Entries 1 and 6–8 of
Table 2 demonstrate the effect of amount of nitrometh-
ane used on product formation. The use of 1.5 equivalent
of nitromethane with respect to 1 equivalent of 1 was
found sufficient to fulfill its dual role of substrate and sol-
vent (Entry 1, Table 2). Effect of the period of microwave
exposure was finally studied by carrying out the reactions
for different time intervals (Entries 1 and 9–11, Table 1)
and a reaction time of 5 min was found to be optimal. So
a microwave irradiation of 420 W for a period of 5 min
and use of 1.5 equivalents of CH3NO2 were considered
optimal for the work.
donating NMe2 group at para-position of aromatic
aldehydes are observed to result decrease in yield (4h and
4k). Although heteroaryl aldehydes also sustain the
reaction condition, yields are found to be slightly in lower
side (4f and 4l). Attempts were made to carry out
the reaction with aliphatic aldehydes (Ethanal and
n-pentanal) but went in vain.
2.3 | Reaction mechanism
To have some idea about how the reaction progresses,
some controlled experiments were carried out under our
optimized reaction condition as depicted in Scheme 3.
Initially, we carried out
a reaction between p-
nitrobenzaldehyde (2a) and nitromethane which
resulted (E)-1-nitro-4-(2-nitrovinyl)benzene (5a) in
almost quantitative yield in 2 min (Reaction 1). (E)-
1-nitro-4-(2-nitrovinyl)benzene (5a) obtained was puri-
fied by recrystallization from EtOH to exclude the excess
CH3NO2. Pure 5a obtained was then treated with 1 in a
solid phase reaction, and to our delight, the reaction
resulted
1,3-dimethyl-6-nitro-5-(4-nitrophenyl)pyrido
[2,3-d]pyrimidine-2,4(1H,3H)-dione (4a) as product in
60% yield within 3 min (Reaction 2). This observation
suggested possible involvement of 5a as intermediate in
the reaction. When the reaction was shifted from solid
phase to solution phase (using CH3NO2 as solvent), a
significant increase in product yield (90%) was observed
(Reaction 3). This can be attributed to uniform mixing
of the starting materials in solution phase. In a different
attempt, a one pot two step reaction was carried out
wherein 1 was directly added to the product mixture of
To check the generality of our developed methodol-
ogy for the synthesis of 4, a series of aromatic aldehydes
were tested and the results are summarized in Table 3.
From Table 3, it is very clear that the developed method-
ology is suitable for a wide spectrum of aromatic alde-
hydes bearing substituents of varied electronic nature at
different positions. Although a general conclusion is diffi-
cult to draw, however, the presence of electron withdraw-
ing Cl group at ortho-position and strongly electron
TABLE 2 Optimization of
microwave power and amount of
nitromethane for Scheme 1a
Entry
Equivalent of CH3NO2
Microwave power
420 W
Time (min)
Yield [%]b
1
1.5
1.5
1.5
1.5
1.5
1
5
5
85
86
45c
72
30
62
85
86
84
70
20
2
480 W
3
540 W
5
4
350 W
5
5
240 W
5
6
420 W
5
7
2
420 W
5
8
3
420 W
5
9
1.5
1.5
1.5
420 W
10
3
10
11
420 W
420 W
1
aReaction condition: 1 (1 mmol); 2 (1.1 mmol), nitromethane (1–3 mmol); CuFe2O4 (5 mol%); microwave
heating (350–540 W).
bIsolated yield of 4a.
cReaction mixture got burnt.

8 of 14
BHUYAN ET AL.
TABLE 3 Substrate study of aromatic aldehydes in synthesis of 1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones
Note: Stoichiometry of reaction: 1 (1 mmol); 2 (1.1 mmol); 3 (1.5 mmol); CuFe2O4 (5 mol%). Figures in parenthesis describe isolated yields.
2a and CH3NO2 (3) of the first step, and the reaction
mixture obtained was exposed to MWI (420 W) for
3 min (Reaction 4). This resulted to a final product (4a)
in 80% yield, which is in good agreement with the earlier
observations and to the fact that the reaction proceeds
via initial formation of 5a, which then reacts with the
third reaction partner, i.e. 1 to furnish the final product
(4a) in a cascade manner. Reaction 1 and Reaction 3
were checked in absence of CuFe2O4 too as in Reaction
5 and Reaction 6, which resulted their corresponding
products in 20% and 45% yields. These results clearly
reveal active participation of CuFe2O4 as catalyst in both
the steps of the developed cascade process. Reaction of
1 with 2a resulted a stable bisuracil derivative (6) as
product (Reaction 7)[58] ruling out the initial reaction
between those two in the developed reaction protocol.
Further mechanistic studies were not carried out;
however, a plausible sequence of reactions for the
overall cascade synthetic process is depicted in Scheme 4
based on the observations of the controlled experiments.
(E)-1-nitro-4-(2-nitrovinyl)benzene (5a) formed initially
is assumed to undergo Diels-Alder cycloaddition with
1 in a cascade process to result the fused bicyclic
product (7a), which eliminates one molecule of Me2NH,
followed by aerial aromatization to generate the final
product (4a).

BHUYAN ET AL.
9 of 14
SCHEME 3 Controlled experiments for
Scheme 1
A hot filtration test was conducted to investigate the
heterogeneous nature of the catalyst. For this, the
reaction was stopped halfway (2 min) under an otherwise
optimized reaction condition (reaction condition of
Table 3). The catalyst particles were first removed from
the hot reaction mixture using a bar magnet and then the
reaction mixture was exposed to the reaction condition
again for 3 min. Reaction did not proceed after the
removal of the catalyst, which reveals the heterogeneous
nature of the catalyst. However, AAS analysis of the final
reaction mixture detected very small amount of Cu and
Fe (4 and 2 ppm, respectively) in it. These two results led
us to have the opinion that a very small amount of the
magnetically active CuFe2O4 catalyst underwent some
changes under the reaction condition to produce some
SCHEME 4 Plausible sequence of reactions for cascade
synthesis of4a

10 of 14
BHUYAN ET AL.
substances, which were both magnetically as well as
catalytically inactive.
shifting of the Fe O stretching band to lower wave num-
ber was observed in the IR spectrum (Figure 2) of the
recovered catalyst (576.25 cm−1). VSM study revealed
that there was no loss in magnetic property of the catalyst
during the catalytic process as the coercivity, magnetiza-
tion at saturation (Ms), and retentivity (Mr) value of the
recovered catalyst sample were found as 259.01 Oe,
34.641 emu/g, and 9.1327 emu/g, respectively (Figure 5).
2.4 | Reusability of the catalyst
To check the reusability of the catalyst, a reaction was
carried out in gram scale taking 1 (2.1 g, 10 mmol),
p-nitrobenzaldehyde (1.66 g, 11 mmol), nitromethane
(915 mg, 15 mmol), and CuFe2O4 (430.5 mg, 1.8 mmol)
under MWI (420 W) at 120ꢀC. After 5 min, the reaction
was stopped, allowed to cool, and recovered the catalyst
using a bar magnet. The recovered catalyst was washed
thrice with ethanol followed by water and then dried in a
hot air oven at 80ꢀC (12 h). Recovered catalyst obtained
was used for the subsequent batch of reactions and the
product yield obtained are summarized in Figure 7. A
slight decrease in activity of the catalyst was observed in
every subsequent batch of reactions up to the fourth run
of reusing the catalyst, beyond which reusability was not
continued. It was observed that while carrying out the
hot filtration test, a small fraction of the catalyst might
undergo some changes under the reaction condition
to produce catalytically and magnetically inactive sub-
stances. So slightly reduced amounts of the catalyst were
recovered in every subsequent batches of reactions,
which can attribute slight decreases in isolated yields of
the product in subsequent batches of reaction. The recov-
ered catalyst after fourth run was subjected to SEM-EDX,
IR, XRD, and VSM analyses. Although SEM image and
XRD data (Figure 1a,b and Figure 3) revealed minor
changes in morphology and crystallinity of the catalyst
material, SEM-EDX analysis (Figure 1d) ascertained
presence of Cu, Fe, and O in the sample. Only a slight
3 | EXPERIMENTAL
Chemicals needed were of analytical reagent grade
(AR grade) and were used as purchased without further
purification. Reactions were carried out using Raga's Sci-
entific Microwave Synthesis System (Model: RG34L). IR
spectra were recorded as KBr pallets with a Nicolet iS5
FT-IR spectrophotometer with frequencies expressed in
1
wave numbers (cm−1). H and 13C NMR spectra were
recorded with a JNM ECS 400 MHz NMR spectropho-
tometer (JEOL) using tetramethylsilane (TMS) as the
internal standard. Chemical shift values are expressed in
ppm. Reactions were monitored by thin-layer chromatog-
raphy using aluminum sheets with silica gel60F254
(Merck). Ethyl acetate and hexane mixtures at different
ratio were used as the mobile phase for separation of the
reaction mixture. UV light was used as visualizer. Mass
spectrometric analysis were performed using an Agilent
Technologies 6520 Accurate-Mass Q-TOF LC mass
spectrometer.
3.1 | Preparation of CuFe2O4
nanoparticles
CuFe2O4 catalyst was prepared following a procedure as
describe in our recent work.53 Specifically, to a solution
.
of Fe (NO3)2 9H2O (3.34 g, 8.2 mmol) and Cu
.
(NO3)2 3H2O (1 g, 4.1 mmol) in 75 ml of distilled water,
3 g (75 mmol) of NaOH dissolved in 15 ml of water was
added from a dropping funnel at room temperature over
a period of 10 min. The reaction mixture was then
exposed to ultrasonic irradiation in an ultra-sonication
bath preheated at 90ꢀC with occasional stirring. After
2 h, it was cooled to room temperature, and the CuFe2O4
particles obtained were collected by ultracentrifuge
technique, washed with water till complete removal of
NaOH, and then kept in an oven for overnight (12 h) at
80ꢀC. The material obtained was grounded in a mortar-
pestle, kept in a furnace at 700ꢀC for 5 h, and then
allowed to cool to room temperature inside the furnace
which finally furnished 780 mg of magnetically active
CuFe2O4 nanoparticles.
FIGURE 7 Reusability of CuFe2O4in synthesizing4a

BHUYAN ET AL.
11 of 14
3.2 | Representative procedure for the
synthesis of 5-arylpyrido[2,3-d]pyrimidine
3.63 (s, 3H), 3.16 (s, 3H); 13C NMR (400 MHz, DMSO):
δ = 159.0, 157.7, 152.8, 150.5, 147.4, 146.6, 143.7, 128.7,
123.3, 114.8, 108.4, 30.4, 28.4. HRMS (ESI-TOF) m/z:
[M + H]+. Calcd for C15H12N4O5 329.0808; found
329.0807.
1 (210.2 mg, 1 mmol), p-nitrobenzaldehyde aldehyde
(166.2 mg, 1.1 mmol), CH3NO2 (91.6 mg, 1.5 mmol), and
CuFe2O4 (43.05 mg, 0.18 mmol, 5 mol%) were taken in a
25 ml round bottomed flask and uniformly mixed under
stirring. The reaction mixture obtained was then exposed
to microwave irradiation (420 W) for 5 min. CuFe2O4
particles were then recovered using a bar magnet. The
residue was dissolved in ethyl acetate (5 ml) and washed
with water (5 ml) and brine (5 ml). The organic layer was
then dried over anhydrous Na2SO4. The crude product
was obtained by evaporating the ethyl acetate and then
purified by column chromatography using silica gel
(100–200 mesh) as adsorbent and ethyl acetate-hexane
as eluent.
3.3.4 | 5-(4-Chlorophenyl)-1,3-dimethyl-
6-nitropyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (4d)
1H NMR (400 MHz, DMSO): δ = 9.32 (s, 1H), 7.49
(d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 3.65 (s, 3H),
3.15 (s, 3H); 13C NMR (400 MHz, DMSO): δ = 159.0,
153.1, 150.4, 148.3, 145.5, 142.2, 133.0, 132.5, 129.1, 127.9,
108.3, 30.3, 28.4. HRMS (ESI-TOF) m/z: [M + H]+. Calcd
for C15H11ClN4O4 347.0469; found 347.0468.
3.3 | Spectral data of synthesized
compounds
3.3.5 | 1,3-Dimethyl-6-nitro-
5-(2-nitrophenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4e)
3.3.1 | 1,3-Dimethyl-6-nitro-
5-(4-nitrophenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4a)
1H NMR (400 MHz, DMSO): δ = 9.49 (s, 1H), 8.40
(d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.4 Hz, 1H), 7.75
(t, J = 8.4 Hz, 1H), 7.30 (d, J = 6.4 Hz, 1H), 3.67 (s, 3H),
3.11 (s, 3H), 13C NMR (400 MHz, DMSO): δ = 159.4, 153.5,
150.3, 150.0, 146.6, 146.1, 139.7, 134.9, 130.8, 130.0, 128.5,
124.3, 107.5, 30.4, 28.5. HRMS (ESI-TOF) m/z: [M + H]+.
Calcd for C15H11N5O6 358.0709; found 358.0708.
1H NMR (400 MHz, DMSO): δ = 9.32(s, 1H), 7.49 (d,
J = 8.8 Hz, 2H), 7.25 (d, J = 4.8 Hz, 2H), 3.64 (s, 3H), 3.15
(s, 3H); 13C NMR (400 MHz, DMSO): δ = 159.1, 153.2,
150.5, 148.4, 145.5, 142.2, 133.0, 132.5, 108.3, 39.5, 30.4,
28.5. HRMS (ESI-TOF) m/z: [M + H]+. Calcd for
C15H11N5O6 358.0709; found 358.0708.
3.3.6 | 5-(Furan-2-yl)-1,3-dimethyl-
6-nitropyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (4f)
3.3.2 | 5-(4-Methoxyphenyl)-
1,3-dimethyl-6-nitropyrido[2,3-d]
pyrimidine-2,4(1H,3H)-dione (4b)
1H NMR (400 MHz, DMSO): δ = 9.28 (s, 1H), 7.89
(s, 1H), 6.73 (d, J = 3.2 Hz, 1H), 6.64 (q, J = 5.2 Hz, 1H),
3.61 (s, 3H), 3.22 (s, 3H), 13C NMR (400 MHz, DMSO):
δ = 158.7, 153.4, 150.5, 148.5, 145.1, 142.6, 142.1,134.7,
113.2, 111.8, 108.2, 30.4, 28.5. HRMS (ESI-TOF) m/z:
[M + H]+. Calcd for C13H10N4O5 303.0651; found
303.0652.
1H NMR (400 MHz, DMSO): δ = 9.23 (s, 1H), 7.13
(d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 3.81 (s, 3H),
3.63 (s, 3H), 3.16 (s, 3H); 13C NMR (400 MHz, DMSO):
δ = 159.3, 159.0, 152.9, 150.4, 147.6, 146.4, 143.4, 128.8,
125.0, 113.3, 108.4, 55.1, 30.3, 28.3. HRMS (ESI-TOF)
m/z: [M + H]+. Calcd for C16H14N4O5 343.0964; found
343.0965.
3.3.7 | 1,3-Dimethyl-6-nitro-
5-phenylpyrido[2,3-d]pyrimidine-2,4
(1H,3H)-dione (4g)
3.3.3 | 5-(4-Hydroxyphenyl)-1,3-dimethyl-
6-nitropyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (4c)
1H NMR (400 MHz, DMSO): δ = 9.27(s, 1H), 7.41
(d, J = 8.0 Hz, 3H), 7.20 (d, J = 8.0 Hz, 2H), 3.64 (s, 3H),
3.14 (s, 3H), 13C NMR (400 MHz, DMSO): δ = 159.0,
153.1, 150.5, 148.0, 146.5, 142.9, 133.3, 128.4, 127.8, 127.2,
1H NMR (400 MHz, DMSO): δ = 9.67 (s, 1H), 9.20
(s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H),

12 of 14
BHUYAN ET AL.
108.2, 30.1, 28.2. HRMS (ESI-TOF) m/z: [M + H]+. Calcd
for C15H12N4O4 313.0859; found 313.0858.
3.3.12 | 1,3-Dimethyl-6-nitro-5-(pyridin-
2-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (4l)
3.3.8 | 5-(2-Chlorophenyl)-1,3-dimethyl-
6-nitropyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (4h)
1H NMR (400 MHz, DMSO): δ = 9.32 (s, 1H), 8.49
(d, J = 4.8 Hz, 1H), 7.85 (t, J = 7.6/9.2 Hz, 1H), 7.43
(t, J = 7.6 Hz, 2H), 3.62 (s, 3H), 3.11 (s, 3H); 13C
NMR (400 MHz, DMSO): δ = 159.86, 154.17, 153.43,
151.48, 150.28, 149.22, 145.97, 141.48, 136.98, 124.60,
124.13, 108.46, 31.18, 29.21. HRMS (ESI-TOF) m/z:
[M + H]+. Calcd for C14H11N5O4 314.0381; found
314.0380.
1H NMR (400 MHz, DMSO): δ = 9.42 (s, 1H), 7.53
(d, J = 8 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz,
1H), 7.20 (d, J = 7.2, 1H), 3.66 (s, 3H), 3.16 (s, 3H); 13C
NMR (400 MHz, DMSO): δ = 158.8, 153.4, 150.4, 149.3,
144.0, 141.3, 133.0, 131.2, 130.0, 128.6, 128.3, 127.0, 108.2,
30.4, 28.4. HRMS (ESI-TOF) m/z: [M + H]+. Calcd for
C15H11ClN4O4 347.0469; found 347.0468.
4 | CONCLUSIONS
In conclusion, we have developed an efficient methodol-
ogy for the synthesis of 1,3-dimethyl-6-nitro-5-arylpyrido
3.3.9 | 1,3-Dimethyl-6-nitro-
5-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4i)
[2,3-d]pyrimidine-2,4(1H,3H)-diones
starting
from
6-[(dimethylamino)methylene-amino]-1,3-dimethyluracil,
aromatic aldehydes, and nitromethane under microwave
irradiation in solvent less condition. A salient feature of
the current methodology is its cascade nature, which
makes it step-economic avoiding isolation of the inter-
mediate. The methodology demonstrates the first use of
heterogeneous catalyst (CuFe2O4) in multicomponent
synthesis of 5-arylpyrido[2,3-d]pyrimidine involving
6-[(dimethylamino)methylene-amino]-1,3-dimethyluracil
as one of the substrates. It enjoys the advantage of
being significantly time economic over other existing
procedures. Easy recovery and good reusability of the
catalyst, simple operating procedure, wide substrate
scope, good to excellent product yield, and so forth
ensure it to be a methodology to go for the synthesis of
1,3-dimethyl-6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4
(1H,3H)-diones.
1H NMR (400 MHz, DMSO): δ = 9.42 (s, 1H), 8.32–8.20
(m, 2H), 7.77–7.71 (m, 2H), 3.67 (s, 3H), 3.14 (s, 3H), 13C
NMR (400 MHz, DMSO): δ = 159.2, 153.4, 150.5, 149.2,
147.3, 144.5, 141.4, 135.9, 134.0, 129.6, 123.1, 122.3, 108.5,
30.4, 28.4. HRMS (ESI-TOF) m/z: [M + H]+. Calcd for
C15H11N5O6 358.0709; found 358.0708.
3.3.10 | 1,3-Dimethyl-5-(naphthalen-
1-yl)-6-nitropyrido[2,3-d]pyrimidine-2,4
(1H,3H)-dione (4j)
1H NMR (400 MHz, DMSO): δ = 9.40(s, 1H), 7.98 (t, 2H),
7.51 (t, 2H), 7.41–7.35 (m, 2H), 7.23 (d, 1H), 3.69 (s, 3H),
3.05 (s, 3H); 13C NMR (400 MHz, DMSO): δ = 158.8,
153.5, 150.7, 148.8, 145.6, 143.0, 132.6, 131.2, 128.6, 128.3,
126.5, 126.1, 125.3, 125.0, 124.1, 109.4, 30.4, 28.3. HRMS
FUNDING
(ESI-TOF)
m/z:
[M
+
H]+.
Calcd
for
P. B. and L. S. are indebted to the Department of Science
and Technology-Science and Engineering Research
Board, India, for financial support to the project
(EMR/2016/003126). L. S. is also grateful to Council of
Scientific and Industrial Research (CSIR), India for finan-
cial support through project (02(0280)/16/EMR-II).
A. J. B. is a receiver of DST-INSPIRE fellowship
(IF170498) and is grateful to DST for the same.
C19H14N4O4363.1015; found 363.1016.
3.3.11 | 5-(4-(Dimethylamino)phenyl)-
1,3-dimethyl-6-nitropyrido[2,3-d]
pyrimidine-2,4(1H,3H)-dione (4k)
1H NMR (400 MHz, DMSO): δ = 9.15 (s, 1H), 7.01
(d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.62 (s, 3H),
3.16 (s, 3H), 2.97 (s, 6H); 13C NMR (400 MHz, DMSO):
δ = 159.13, 152.97, 150.60, 147.17, 146.82, 143.83, 128.61,
119.57, 111.14, 108.31, 30.62, 29.01, 28.28. HRMS
(ESI-TOF) m/z: [M + H]+. Calcd for C17H17N5O4
356.1281; found 356.1282.
ACKNOWLEDGMENTS
Authors acknowledge MHR research group of the
Department of Chemistry, Rajiv Gandhi University for
giving access to the ultrasonicator. Analytical
support from SAIC, Tezpur University is gratefully
acknowledged.

BHUYAN ET AL.
13 of 14
Fry, W. D. Klohs, A. M. Doherty, Bioorg. Med. Chem. Lett.
1997, 7, 2415.
AUTHOR CONTRIBUTIONS
Amar Bhuyan: Methodology. Pubanita Bhuyan:
Conceptualization. Dr. Bornali Boruah: Resources.
LAKHINATH SAIKIA: Conceptualization; resources;
supervision.
[18] M. T. El Sayed, H. A. R. Hussein, N. M. Elebiary, G. S. Hassan,
S. M. Elmessery, A. R. Elsheakh, M. Nayel, H. A. Abdel-Aziz,
Bioorg. Chem. 2018, 78, 312.
[19] V. Nair, G. Chi, Q. Shu, J. Julander, D. F. Smee, Bioorg. Med.
Chem. Lett. 2009, 19, 1425.
ORCID
[20] J. R. Miller, S. Dunham, I. Mochalkin, C. Banotai, M.
Bowman, S. Buist, B. Dunkle, D. Hanna, H. J. Harwood, M. D.
Huband, A. Karnovsky, M. Kuhn, C. Limberakis, J. Y. Liu, S.
Mehrens, W. T. Mueller, L. Narasimhan, A. Ogden, J. Ohren,
J. V. N. V. Prasad, J. A. Shelly, L. Skerlos, M. Sulavik, V. H.
Thomas, S. VanderRoest, L. Wang, Z. Wang, A. Whitton, T.
Zhu, C. K. Stover, PNAS 2009, 106, 1737.
Amar Jyoti Bhuyan https://orcid.org/0000-0002-4963-
4974
Pubanita Bhuyan https://orcid.org/0000-0003-3131-
4611
Bornali Boruah https://orcid.org/0000-0001-8790-662X
Lakhinath Saikia https://orcid.org/0000-0003-0252-
2120
[21] M. M. Sarmah, D. Prajapati, RSC Adv. 2014, 4, 22955.
[22] S. Das, A. J. Thakur, T. Medhi, B. Das, RSC Adv. 2013, 3, 3407.
[23] R. Sarma, K. J. Borah, Y. Dommaraju, D. Prajapati, Mol. Diver-
sity 2011, 15, 697.
REFERENCES
[1] C. Kurumurthy, P. Sambasiva Rao, B. Veera swamy, G.
Santhosh kumar, P. Shanthan Rao, B. Narsaiah, L. R.
Velatooru, R. Pamanji, J. Venkateswara Rao, Eur. J. Med.
Chem. 2011, 46, 3462.
[2] M. M. Gineinah, M. N. A. Nasr, S. M. I. Badr, W. M.
El-Husseiny, Med. Chem. Res. 2013, 22, 3943.
[3] A. Gangjee, O. Adair, S. F. Queener, J. Med. Chem. 1999, 42,
2447.
[4] H. B. El-Nassan, Eur. J. Med. Chem. 2011, 46, 2031.
[5] O. A. Abdelaziz, W. M. El Husseiny, K. B. Selim, H. M. Eisa,
Bioorg. Chem. 2019, 90, 103076.
[24] D. Prajapati, M. Sarmah, W. Hu, Synlett 2013, 24, 471.
[25] D. Prajapati, M. Gohain, B. J. Gogoi, J. S. Sandhu, Synlett
2004, 1179. https://doi.org/10.1055/s-2004-825601
[26] P. Saikia, A. J. Thakur, D. Prajapati, J. S. Sandhu, Indian
J. Chem. 2002, 41B, 804.
[27] A. J. Thakur, P. Saikia, D. Prajapati, J. S. Sandhu, Synlett 2001,
8, 1299.
[28] E. B. Walsh, Z. Nai-Jue, G. Fang, H. Wamhoff, Tetrahedron
Lett. 1988, 29, 4401.
[29] M. Daraie, M. M. Heravi, M. Mirzaei, N. Lotfian, Appl.
Organomet. Chem. 2019, 33, e5058.
[6] S. Ravi Kanth, G. Venkat Reddy, K. Hara Kishore, P.
Shanthan Rao, B. Narsaiah, U. Surya Narayana Murthy, Eur.
J. Med. Chem. 2006, 41, 1011.
[7] B. Lakshmi Narayana, A. Raghu Ram Rao, P. Shanthan Rao,
Eur. J. Med. Chem. 2009, 44, 1369.
[8] A. Bazgir, M. M. Khanaposhtani, A. A. Soorki, Bioorg. Med.
Chem. Lett. 2008, 18, 5800.
[9] M. Fares, S. R. Abd El Hadi, R. A. Eladwy, A. A. Shoun, M. M.
Abdel-Aziz, W. M. Eldehna, H. A. Abdel-Aziz, P. A. Keller,
Org. Biomol. Chem. 2018, 16, 3389.
[30] B. Mirhosseini-Eshkevari, M. A. Ghasemzadeh, M.
Esnaashari, Appl. Organomet. Chem. 2019, 33, e5027.
[31] J. Safari, M. Tavakoli, M. A. Ghasemzadeh, J. Organomet.
Chem. 2019, 880, 75.
[32] N. Jamasbi, M. Irankhah-Khanghah, F. Shirini, H. Tajik,
M. S. N. Langarudi, New J. Chem. 2018, 42, 9016.
[33] F. Zhang, C. Li, X. Liang, Green Chem. 2018, 20, 2057.
[34] S. Moradi, M. A. Zolfigol, M. Zarei, D. A. Alonso, A.
Khoshnood, A. Tajally, Appl. Organomet. Chem. 2018,
32, e4043.
[10] J. Matsumoto, S. Minami, J. Med. Chem. 1975, 18, 74.
[11] B. Veeraswamy, D. Madhu, G. Jitender Dev, Y.
Poornachandra, G. Shravan Kumar, C. Ganesh Kumar, B.
Narsaiah, Bioorg. Med. Chem. Lett. 2018, 28, 1670.
[12] H. Huang, D. A. Hutta, J. M. Rinker, H. Hu, W. H. Parsons,
C. Schubert, R. L. DesJarlais, C. S. Crysler, M. A.
Chaikin, R. R. Donatelli, Y. Chen, D. Cheng, Z. Zhou, E.
Yurkow, C. L. Manthey, M. R. Player, J. Med. Chem. 2009,
52, 1081.
[13] A.-R. B. A. El-Gazzar, H. N. Hafez, Bioorg. Med. Chem. Lett.
2009, 19, 3392.
[14] D.-W. Wang, Q. Li, K. Wen, I. Ismail, D.-D. Liu, C.-W. Niu, X.
Wen, G.-F. Yang, Z. Xi, J. Agric. Food Chem. 2017, 65, 5278.
[15] J. F. Dorsey, R. Jove, A. J. Kraker, J. Wu, Cancer Res. 2000,
60, 3127.
[35] M. Mohsenimehr, M. Mamaghani, F. Shirini, M. Sheykhan,
F. A. Moghaddam, Chin. Chem. Lett. 2014, 25, 1387.
[36] S. P. Satasia, P. N. Kalaria, D. K. Raval, Org. Biomol. Chem.
2014, 12, 1751.
[37] F. Nemati, R. Saeedirad, Chin. Chem. Lett. 2013, 24, 370.
[38] S. Abdolmohammadi, M. Afsharpour, Chin. Chem. Lett. 2012,
23, 257.
[39] K. Nurjamal, G. Brahmachari, ChemistrySelect 2019, 4, 2363.
[40] R. Aryan, H. Beyzaei, M. Nojavan, F. Pirani, H. Samareh
Delarami, M. Sanchooli, Mol. Diversity 2019, 23, 93.
[41] P. Acosta, B. Insuasty, R. Abonia, M. Gutierrez, J. Quiroga,
Mol. Diversity 2017, 21, 943.
[42] O. G. Jolodar, F. Shirini, M. Seddighi, Chin. J. Catal. 2017, 38,
1245.
[43] A. Upadhyay, L. K. Sharma, V. K. Singh, R. K. P. Singh,
Tetrahedron Lett. 2016, 57, 5599.
[44] S. Singh, M. Saquib, M. Singh, J. Tiwari, F. Tufail, J. Singh, J.
Singh, New J. Chem. 2016, 40, 63.
[45] F. Belhadj, Z. Kibou, N. Cheikh, N. Choukchou-Braham, D.
Villemin, Tetrahedron Lett. 2015, 56, 5999.
[16] N. Kammasud, C. Boonyarat, K. Sanphanya, M. Utsintong, S.
Tsunoda, H. Sakurai, I. Saiki, I. André, D. S. Grierson, O.
Vajragupta, Bioorg. Med. Chem. Lett. 2009, 19, 745.
[17] C. J. C. Connolly, J. M. Hamby, M. C. Schroeder, M. Barvian,
G. H. Lu, R. L. Panek, A. Amar, C. Shen, A. J. Kraker, D. W.

14 of 14
BHUYAN ET AL.
[46] M. Jatczak, K. Muylaert, L. M. De Coen, J. Keemink, B.
Wuyts, P. Augustijns, C. V. Stevens, Bioorg. Med. Chem. 2014,
22, 3947.
[58] S. Das, S. J. Kalita, P. Bharali, B. K. Konwar, B. Das, A. J.
Thakur, ACS Sustainable Chem. Eng. 2013, 1, 1530.
[47] A. Gangjee, O. A. Namjoshi, S. Raghavan, S. F. Queener, R. L.
Kisliuk, V. Cody, J. Med. Chem. 2013, 56, 4422.
[48] S. Paul, G. Pal, A. R. Das, RSC Adv. 2013, 3, 8637.
[49] A. S. Kumar, M. A. Reddy, M. Knorn, O. Reiser, B. Sreedhar,
Eur. J. Org. Chem. 2013, 2013, 4674.
[50] K. B. Rasal, G. D. Yadav, Catal. Today 2018, 309, 51.
[51] B. Sreedhar, A. S. Kumar, D. Yada, Tetrahedron Lett. 2011, 52,
3565.
[52] A. Dandia, A. K. Jain, S. Sharma, RSC Adv. 2013, 3, 2924.
[53] P. Bhuyan, P. Bhorali, I. Islam, A. J. Bhuyan, L. Saikia, Tetra-
hedron Lett. 2018, 59, 1587.
[54] I. Nedkov, R. E. Vandenberghe, T. Marinova, P. Thailhades, T.
Merodiiska, I. Avramova, Appl. Surf. Sci. 2006, 253, 2589.
[55] Y. Zhao, G. He, W. Dai, H. Chen, Ind. Eng. Chem. 2014, 53,
12566.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Bhuyan AJ, Bhuyan P,
Boruah B, Saikia L. Magnetically recoverable
copper ferrite catalyzed cascade synthesis of 1,3-
dimethyl-6-nitro-5-arylpyrido[2,3-d]pyrimidine-2,4
(1H,3H)-diones under microwave irradiation and
solvent-less condition. Appl Organomet Chem.
2020;e6091. https://doi.org/10.1002/aoc.6091
[56] S. Vepřek, D. L. Cocke, S. Kehl, H. R. Oswald, J. Catal. 1986,
100, 250.
[57] M. Zhu, D. Meng, C. Wang, G. Diao, ACS Appl. Mater. Inter-
faces 2013, 5, 6030.