Bi2O3/FAp, a sustainable catalyst for synthesis of dihydro-[1,2,4]triazolo[1,5-a]pyrimidine derivatives through green strategy

Article abstract of DOI:10.1002/aoc.5590

The bismuth loaded on fluorapatite (Bi₂O₃/FAp) proved to be an excellent catalyst for the synthesis of novel dihydro-[1,2,4]triazolo[1,5-a]pyrimidine derivatives via a three-component reaction involving the mixture of 1H-1,2,4-triazo

Full text of DOI:10.1002/aoc.5590

Received: 25 November 2019
DOI: 10.1002/aoc.5590
Revised: 14 January 2020
Accepted: 27 January 2020
F U L L P A P E R
Bi O /FAp, a sustainable catalyst for synthesis of dihydro-
2
3
[
1,2,4]triazolo[1,5-a]pyrimidine derivatives through green
strategy
Nagaraju Kerru | Lalitha Gummidi | Surya Narayana Maddila |
Sandeep V.H.S. Bhaskaruni | Sreekantha B. Jonnalagadda
School of Chemistry & Physics, University
The bismuth loaded on fluorapatite (Bi O /FAp) proved to be an excellent
2 3
of KwaZulu-Natal, Westville Campus,
Chiltern Hills, Durban, 4000, South Africa
catalyst for the synthesis of novel dihydro-[1,2,4]triazolo[1,5-a]pyrimidine
derivatives via a three-component reaction involving the mixture of 1H-1,-
2,4-triazol-5-amine, ethyl cyanoacetate or ethyl acetoacetate, and different
benzaldehydes in ethanol at room temperature. The catalyst material was
characterized by X-ray diffraction, Brunauer–Emmett–Teller surface area
analysis, Fourier-transform infrared, scanning electron microscopy, energy-
dispersive X-ray spectroscopy, and transmission electron microscopy tech-
Correspondence
Sreekantha B. Jonnalagadda, School of
Chemistry & Physics, University of
KwaZulu-Natal,Durban 4000, South
Africa.
Email: jonnalagaddas@ukzn.ac.za
Funding information
University of KwaZulu-Natal, Durban,
South Africa
niques. The efficacy of Bi O /FAp as a heterogeneous catalyst was evaluated
2
3
with the loading of different wt% of bismuth on FAp. The 2.5% bismuth on
FAp performed extremely well as a catalyst with a high yield of products
(92%–96%) in a short reaction time (25–35 min). The catalyst was recovered by
simple filtration. It showed undiminished activity up to five runs. Simple
work-up, room temperature reaction, short reaction time, high yields, no
column chromatography, and good reusability of catalyst are the merits of the
proposed protocol. In addition, this process offers 100% carbon efficiency and
98% atom economy with noteworthy fiscal and environmental benefits.
K E Y W O R D S
2
Bi O
3
/FAp, dihydro-[1,2,4]triazolo-pyrimidine, ethanol medium, green methods, MCRs
1
| INTRODUCTION
reaction intermediates for refinery operations, fine
[
2]
chemicals, and for other purposes. Fluorapatite (FAp)
is a cheap and eco-friendly material with the capability
to form solid solutions and to accept varied cationic
Advances in the design of efficient reusable heteroge-
neous catalysts for organic synthesis and valued conver-
sions of target bicyclic compounds obeying green
conditions are cherished goals, with respect to the
pharmaceutical industry and production. In the past
decade, heterogeneous catalysts gained importance in
chemical science because of their high stability, activity,
selectivity, and tunable properties. Heterogeneous cata-
lysts offer a broad spectrum of applications, including
diverse sustainable methods in synthetic chemistry,
[
3]
and anionic substituents. In addition, because of the
outstanding ion exchangeability with various metal
ions, it can be used to formulate highly stable and
supported metal catalysts with vastly dispersed and tun-
[1]
[
4]
able
acid–base
properties.
Therefore,
FAp
[Ca (PO ) F ] and metal-doped/modified FAp catalysts
10
4 6 2
are becoming progressively valuable in organic synthe-
sis as catalysts, primarily owing to their high stability,
Appl Organometal Chem. 2020;e5590.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5590

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KERRU ET AL.
presence of both Lewis/Bronsted acidic and basic sites,
and easy separation from reaction mixture through sim-
In our continued efforts to develop novel and green
approaches, previously we have reported few efficient
synthetic methods involving recyclable catalysts for dif-
[5]
ple filtration.
Many FAp-based heterogeneous cata-
[
27,28]
lysts have demonstrated significant catalytic activity for
the construction of C–C and C–N bond-forming organic
reactions due to the presence of both acidic and basic
ferent bioactive heterocycles.
Herein, we report the
one-pot protocol for the synthesis of novel dihydro-[1,2,4]
triazolo[1,5-a]pyrimidines by using an efficacious, recy-
clable Bi O /FAp heterogeneous catalyst in ethanol
[
6,7]
sites.
In addition, FAp has a special position in
2
3
[8]
many biomedical applications.
metal ions, bismuth (Bi ) occupies a distinct place as a
catalyst due to its vacant d-shell and Lewis acid
nature. Moreover, as it helps to stabilize the interme-
diates in reactions, it has various applications as a cata-
lyst in multicomponent condensation, oxidation, and
Among the various
medium. The reaction proceeded with excellent catalytic
activity with high yields for short reaction time
(Scheme 1). The catalyst material was fully characterized
by X-ray diffraction (XRD), scanning electron microscopy
(SEM), transmission electron microscopy (TEM),
Brunauer–Emmett–Teller (BET), and Fourier-transform
infrared (FT-IR) spectroscopic analysis.
3+
[9]
[10,11]
cycloaddition reactions.
Multicomponent reaction (MCR) is a powerful tool in
synthetic organic chemistry and drug discovery pro-
grams, as it can be utilized for the creation of libraries of
bioactive scaffolds. The development of combinatorial
synthesis by utilization of MCRs has created a sustainable
means for organic synthesis that focuses on the atom
economy and environmental safety. MCRs with ecologi-
cally benign solvents and efficient, reusable heteroge-
neous catalysts are the utmost targets for the scientific
community.
2 | EXPERIMENTAL SECTION
2.1 | General remarks
All the chemicals and reagents used for the reaction were
of analytical grade and utilized without any further puri-
fication. Bi O , Ca(NO ) ꢀ4H O, Na PO ꢀ12H O, and NaF
2
3
3 3
2
3
4
2
were purchased from Merck and Sigma-Aldrich dealers,
Durban, South Africa. For the synthesized compounds,
the structural elucidation was performed using nuclear
magnetic resonance (NMR) spectral analysis by recording
1,2,4
The dihydro- triazolo-pyrimidines are bicyclic N-
heteroarenes and these structural analogs are versatile
[
12]
synthetic building blocks in various drug molecules.
1
13
Development of methods for dihydro-[1,2,4]triazolo-
pyrimidines synthesis has received incredible attention of
synthetic chemists for their broad spectrum of biological
and pharmacological profiles, which include anticancer,
antibacterial, antiproliferative, anti-HIV, and fungicidal
the spectral values of H and C NMR spectrum (Bruker
AMX 400 MHz NMR spectrometer). Chemical shift
values are reported in δ (ppm), with tetramethylsilane as
the internal standard and dimethyl sulfoxide-d as the
6
solvent. Thin-layer chromatography (TLC)-aluminum
plates coated with silica gel (Merck Kieselgel 60 F254)
[13–18]
activities.
Most synthetic protocols involved the
MCR between active methylene substrate, aldehyde, and
various amine compounds in the presence of different
heterogeneous catalysts, bases, and solvents to synthesize
were used to confirm the completion of reaction initially.
The Bruker micro-TOF-Q II electrospray ionization (ESI)
instrument functioning at ambient temperature was used
for obtaining high-resolution mass spectrometry (HRMS)
data. The JEOL JSM-6100 microscope and JEOL JEM-
[19,20]
bioactive core moieties.
In recent years, there is con-
siderable interest toward the developing synthetic proto-
cols for new dihydropyrimidine scaffolds. Various
materials including [DABCO](SO H) (Cl) , [DABCO]
3
2
2
(
SO H) (HSO ) , [H -DABCO][ClO ] , thiamine-HCl, γ-
3
2
4 2
2
4 2
Fe O @NaHSO nanocatalyst, and Nafion-H have
2
3
4
[
21–25]
been explored as catalysts in this regard.
Recently, Sumathi and Gopal accomplished Biginelli
condensation of dihydropyrimidinone derivatives in a
one-pot approach using bismuth-substituted FAp
[
BiNaCa (PO ) F] at reflux condition. The use of hazard-
4 4 3
ous acetonitrile solvent and nonreusability of the mate-
[
26]
rial were drawbacks associated with this protocol.
Not
many studies on the use of bismuth-loaded FAp as a het-
erogeneous catalyst have been reported. Therefore, there
is a void in finding of novel high-atom-economy green
methodologies.
SCHEME 1 Synthesis of dihydro-1,2,4-triazolo-pyrimidine
derivatives (4a–m). RT, room temperature

BI2O3/FAP FOR SYNTHESIS OF DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE
3 of 10
1
010 electron microscope were employed for obtaining
evaporation, which resulted in the formation of solid
products, and further recrystallized using hot ethanol to
provide the desired pure products. The structures of all
the synthesized novel derivatives were established by
spectroscopic techniques (HRMS and H and C NMR)
(Supplementary file).
SEM, energy-dispersive X-ray spectroscopy (EDX), and
TEM morphology data. XRD data associated with the
structural phases of the material were obtained using the
Bruker D8 Advance instrument (Cu-K radiation source
with a wavelength of 1.5406 Å). Materials were degassed
1
13
ꢁ
by passing nitrogen overnight at 200 C and Barrett–
Joyner–Halenda (BJH) adsorption and desorption curves
ꢁ
were obtained at −196 C. Surface area, pore size, and
3 | RESULTS AND DISCUSSION
3.1 | Characterization of the catalyst
The morphology of the as-prepared Bi O /FAp catalyst
pore volume of the material were established using a
porosity and surface area analyzer (Micromeritics Tristar-
II).
2
3
2
.2 | Bi O /FAp catalyst preparation
was established by SEM and TEM (Figure 1). Figure 1a,b
shows the SEM micrograph and mapping of the bismuth
loaded on the FAp (2.5% Bi O /FAp) catalyst. The FAp
2
3
Various weight percentages (1, 2.5, and 5 wt%) of
bismuth-loaded FAp were prepared by adopting the pro-
cedure reported previously.
dodecahydrate (Na PO ꢀ12H O; 1.5 mmol) was dissolved
2
3
particles were hexagonal and showed irregular and
lamellar arrangement with folded edges. Bismuth parti-
cles were widely dispersed on the surface of layered FAp.
EDX spectrum (Figure 1c) was used to identify the ele-
mental composition in the prepared material. The pres-
ence of Ca, P, F, and Bi elements in the resulting
material was confirmed and the result matched well with
the FAp material (Figure S1, ESI). The TEM micrograph
(Figure 1d) showed the bismuth particles to be spherical,
tightly grown, masked on the surface of FAp, and spread
throughout the FAp circumference. The average size
(diameter) of the particle was about 27 nm.
[29]
Trisodium phosphate
3
4
2
in 25 mL of deionized water in 50 mL of the beaker. To
this solution, sodium fluoride (0.5 mmol) was slowly
added under continuous stirring at room temperature
and the stirring continued for 20 min until a clear solu-
tion was obtained. Afterward, calcium nitrate
tetrahydrate (2.5 mmol) was added into this mixture and
again the mixture was stirred for 15 min. Lastly, the
required measured amount of 99.999% of powder bis-
muth oxide (0.5 mmol) was added gradually and the mix-
ꢁ
ture was further stirred for 6 h at 110 C. The resultant
Figure 2 shows the XRD spectrum of the prepared
suspensions were separated by centrifugation and
washed several times with deionized water. The obtained
2.5% Bi O /FAp and FAp catalysts, with 2θ values rang-
2
3
ꢁ
ꢁ
ing from 20 to 80 with overlying intense peaks of the
crystalline phases. The intense and sharp diffraction
ꢁ
samples were dried for 8 h in an oven at 120 C. Further-
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
more, these materials were calcinated at 350 C for 4 h
peaks detected at 2θ values of 25.8 , 30.0 , 32.3 , 34.4 ,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
under continuous airflow, to obtain the distinctive com-
position of Bi O /FAp materials.
40.3 , 47.0 , 49.9 , 50.9 , 53.4 , and 56.2 were well inde-
xed to the (002), (210), (211), (300), (310), (222), (213),
2
3
(
312), (004), and (322) plans of FAp, and well-matched
with the standard FAp pattern (JCPDS no. 15-0876). In
ꢁ ꢁ
addition, other diffraction peaks identified at 26.2 , 33.3 ,
2
.3 | General procedure for the synthesis
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
of dihydro-[1,2,4]triazolo-pyrimidine
derivatives (4a–l)
42.5 , 44.3 , 45.7 , 52.5 , and 61.9 were indexed to the
(120), (200), (122), (040), (041), (321) and (241) planes,
respectively, and assigned to Bi O (JCPDS no. 041-1449).
2
3
A mixture of 1H-1,2,4-triazol-5-amine (1, 1 mmol), vari-
Bi O /FAp was appropriately paired with the FAp mate-
2 3
ous chosen benzaldehydes (2,
cyanoacetate (3, 1 mmol), and 30 mg of 2.5% Bi O /FAp
1
mmol), ethyl
rial. The XRD data indicated the high degree of crystal-
linity of bismuth loaded onto FAp (Bi O /FAp).
2
3
2 3
heterogeneous catalyst in absolute ethanol (5 mL) was
mixed in a round-bottomed flask. The reaction mixture
was continuously stirred for 25–35 min at room tempera-
ture. TLC was used for screening the reaction comple-
tion. After completion of the reaction, the catalyst
material was retrieved from the reaction mixture by cen-
trifugation and filtration. The retrieved dried catalyst was
recycled for subsequent runs. The filtrate was concen-
trated under reduced vacuum pressure by rotatory
Figure
3
illustrates the nitrogen adsorption–
desorption isotherms of the Bi O /FAp composite, as
2
3
obtained based on the BET analysis. The catalyst material
showed stepwise adsorption and desorption hysteresis
and was categorized as having the Type IV isotherm lying
in the P/P range from 0.05 to 1.0. The BET surface area,
pore size, and pore volume were 54.1240 m /g,
0
2
3
197.075 Å, and 0.331 cm /g respectively. The inset in
Figure 3 validates the prepared catalyst as a mesoporous

4
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KERRU ET AL.
FIGURE 1 (a) Scanning electron microscopy (SEM) micrograph, (b) SEM mapping, (c) energy-dispersive X-ray spectroscopy spectrum,
and (d) transmission electron microscopy micrograph of the 2.5% Bi
2
O
3
/FAp catalyst. FAp, fluorapatite
material. Greater specific surface area with 2.5% Bi O /
FAp may have contributed to the higher catalytic activity
observed, in the form of more active sites available for
the reacting substrates and intermediates on the catalyst
surface.
2
3
Figure 4 presents the infrared spectra of the catalyst
with the major characteristic absorption bands displayed
−
1
at 1023, 599, and 564 cm , which can be attributed to
the stretching and bending absorbance of phosphate
3
− [29]
groups (PO4 ).
A prominent absorption band was
−
1
observed at 1023 cm , which was associated with the
3−
stretching vibration of P–O linkages of the PO
group.
4
The absorption band at 599 and 564 cm− can be assigned
to the triply degenerated bending asymmetric modes of
the O–P–O bonds. In addition, the absorption peak
1
2
−
corresponding to the carbonate group (CO ) was
3
−1
observed at 1450 cm . These findings confirm that cal-
cium phosphate and carbonate ions are present in the
material.
Figure 5 illustrates the pyridine-adsorbed IR spec-
trum, which was used for identifying the kind of acidic
sites on the surface of bismuth loaded on FAp. The stron-
gest absorption band at 1431 cm− was assigned to Lewis
acidic sites on the Bi O /FAp catalyst, whereas the small
1
2 3
FIGURE 2 Powder X-ray diffractogram pattern of 2.5% Bi O /
FAp and FAp materials. FAp, fluorapatite
2
3
absorption frequency at 1480 cm− agrees to pyridine
1

BI2O3/FAP FOR SYNTHESIS OF DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE
5 of 10
FIGURE 3
2
N adsorption–desorption
isotherm of the 2.5% Bi
fluorapatite
2 3
O /FAp catalyst. FAp,
adsorbed onto both Lewis and Brønsted acid sites, and
involving 1H-1,2,4-triazol-5-amine (1), 4-methoxy benzal-
dehyde (2a), and ethyl cyanoacetate (3) as reactants
(Scheme 1). Various acid, base, and metal oxide catalysts
(30 mg per 1 mmol of aldehyde) were examined for the
model reaction in ethanol medium, and the results are
illustrated in Table 1. First, the reaction was carried out
in the absence of the catalyst, during when the reaction
progressed with trace and only low yields of desired prod-
uct (4a) were obtained even after 24 h at both room tem-
perature and under reflux condition (Table 1, Entries
−
1
the weak band at 1559 cm corresponds to an apparent
[30]
Brønsted acidic site.
Thus, the synthesized material
was composed of strong Lewis acidic and weak Brønsted
acidic sites. The catalyzed reaction can be assumed to
occur as a result of the many Lewis acid sites on the
Bi O /FAp catalyst surface.
2
3
3.2 | Catalytic activity
1
and 2). Further, this synthetic protocol was performed
Initially, we focused on identifying a suitable catalyst for
the model multicomponent condensation reaction
using various organic and inorganic basic catalysts such
as CS CO , K CO , NaOH, Et N, pyridine, and DABCO,
2
3
2
3
3
FIGURE 4 Fourier-transform infrared spectrum of the 2.5%
2 3
FIGURE 5 Pyridine infrared spectrum of the 2.5% Bi O /FAp
Bi
2
O
3
/FAp catalyst. FAp, fluorapatite
catalyst. FAp, fluorapatite

6
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KERRU ET AL.
TABLE 1 Screening of catalysts for the synthesis of
dihydropyrimidine 4a
Entry 19). FAp exhibits an amphoteric feature having
a
2+
both Lewis acid and basic sites, with the Ca account-
−
−
able for the acidic sites, and F and P–O being liable for
the basic sites.
Time
%
Yield
[
31]
b
This combination allows effective con-
Entry Catalyst
Conditions
(h)
versions, which explains the superior catalytic perfor-
mance of FA. We further examined the efficacy of a
1
–
Room
temperature
24
Trace
modified FAp catalyst system (Bi O /FAp) with different
(
RT)
2 3
weight percentages. The reaction was conducted with 1%
bismuth loaded on an FAp catalyst. The reaction
proceeded well with less reaction time (30 min), and pro-
duced the desired product in a good yield of 87%
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
–
Reflux
RT
24
17
22
18
39
19
19
22
29
32
41
46
38
44
51
66
CS
2
CO
3
10
K
2
CO
3
RT
8.0
6.0
10
NaOH
RT
(
Table 1, Entry 20). The increase in weight% of bismuth
on FAp from 1% to 2.5%, accordingly increased the yield
96%) of the product (Table 1, Entry 21). With further
Triethylamine RT
(
Pyridine
DABCO
AcOH
p-TSA
HCl
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
9.0
8.0
7.0
10.0
12.0
4.5
5.0
7.5
3.0
2.5
2.5
2.5
1.0
increase in bismuth loading to 5%, the reaction proceeded
smoothly, but with reduced yield (92%; Table 1, Entry
22). The obtained yield was lower than that with 2.5% of
0
1
2
3
4
5
6
7
8
9
the catalyst. These differences in the catalytic efficiency
of 1, 2.5, and 5 wt% of Bi O /FAp may be attributed to
2
3
HClO
SO
SiO
ZnO
4
–SiO
2
the distribution of active ions on the surface of
supporting material, which influences the availability of
active sites that accelerate the reaction and allows suc-
cessful transformation. Many of the chemical reactions
occur on the surface of the catalyst materials, and there-
fore, the nature, size, and distribution of particles on the
catalyst surface have a distinct impact on their catalytic
activity. In most cases, atoms on the particle surface act
as Lewis acid centers, where the chemical reaction could
H
2
4
–SiO
2
2
2
Bi
Bi
Bi
2
2
2
O
3
3
3
c
O
O
69
d
71
Fluorapatite
FAp)
1% Bi
FAp
69
87
96
92
[
32,33]
(
be catalytically activated.
At 1% loading, the reac-
20
21
22
2
O
3
/
RT
RT
RT
0.50
tion time was longer due to the inadequate active sites
present on the surface of the material, whereas at 5%
loading, bismuth particles were highly agglomerated on
2.5% Bi
FAp
2
O
3
/
0.50
0.50
[
27]
the surface of FAp.
This is because at these loading
5% Bi
2
O
3
/
rates several bismuth particles covered the active sites on
the surface of the support material; eventually, the num-
ber of active sites available for the reaction to proceed is
reduced. However, 2.5% loading of the Bi O /FAp cata-
FAp
a
Reaction conditions: amine (1) (1 mmol), 4-methoxy benzaldehyde (2a)
1 mmol), ethyl cyanoacetate (3) (1 mmol), catalyst (30 mg per 1 mmol
(
2
3
aldehyde), and solvent (5 mL).
lyst system demonstrated greater catalytic activity for the
dihydropyrimidine derivatives, compared with 1% and
5% loading of Bi O /FAp. This may be due to the wide
b
Isolated yields.
c
0.75 mg of Bi
2
O
3
.
d
2
3
1.5 mg of Bi
2
O
3
.
and uniform dispersion of bismuth particles on the sur-
face of layered FAp and more available active sites all
over the FAp lattice (Figure 1). Evidently, metal-modified
FAp often possesses improved tunable properties (stabil-
but again only low yield of the corresponding product
4a) was achieved (Table 1, Entries 3–8). Consequently,
(
[
3,26]
the reaction was performed in the presence of different
Brønsted acid catalysts; however, again, only lower yields
were obtained (Table 1, Entries 9–13). Then, the reaction
was performed using various metal oxides (Table 1,
Entries 14–16), with Bi O giving a better yield (66%). In
ity and acidity) than its non-modified form
; thus, the
Lewis acid nature of the highly efficient metal oxide
(Bi O ) loaded on the surface of supporting material
2
3
(FAp) plays a vital role in organic synthesis.
Solvent plays a significant role in this condensed reac-
tion and this could be attributed to the variation in the
insolubility of the substrates and capability of solvents to
swell the catalyst, thereby influencing its activity. A vari-
2
3
subsequent steps, the effect of increasing the amount of
Bi O was examined, but this did not increase the yield of
2
3
the product (Table 1, Entries 17 and 18). FAp also pro-
vided a satisfactory yield of the desired product (Table 1,
ety of polar-protic (MeOH, EtOH and H O), polar-aprotic
2

BI2O3/FAP FOR SYNTHESIS OF DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE
7 of 10
(
CH CN, THF, and DMF), and non-polar (toluene) sol-
of the vital criteria indicating catalyst efficiency. After
completion of the reaction, the catalyst was separated
from the reaction mixture by centrifugation and filtra-
tion. The acquired catalyst was further washed with ethyl
3
vents were examined (Table 2, Entries 2–8), among
which ethanol was found to be the superior medium for
the reaction, which facilitated highest product yield. In
addition, the model reaction was carried out under a
catalyst-free condition in DMF solvent at 130 C, for
which no such improvement of the yield was noticed
ꢁ
acetate and desiccated in a heating oven for 2 h at 120 C
ꢁ
under vacuum. The recovered catalyst was reused for the
next cycle of reaction performed under similar conditions
(Figure 6). The recovered catalyst performed effectively
up to the fifth cycle with similar efficacy in the MCR.
Subsequently, a hot filtration analysis was executed to
study the heterogeneity of 2.5% of the Bi O /FAp catalyst
(Table 2, Entry 9). Under the solvent-free condition, no
yield of product was noticed even after 24 h (Table 2,
Entry 1). As ethanol is a green solvent, it is of significance
from an eco-point of view. To optimize the required
quantity of 2.5% Bi O /FAp, the reaction was studied by
2
3
for the synthesis of compound 4a. After 15 min of reac-
2
3
using 10, 20, 30, and 40 mg of the catalyst. The use of
tion time, the Bi O /FAp catalyst was removed from the
2
3
1
9
0 mg of catalyst gave 73% yield in 60 min, 20 mg gave
1% yield in 40 min, 30 mg of catalyst offered 96% yield
reaction mixture and the reaction in the left-over filtrate
was continued under stirring and the same reaction con-
ditions for up to 60 min. No substantial improvement in
the yield of the product was observed in this reaction
(Figure 7). These findings show that the Bi O /FAp mate-
rial was stable and no leaching of metal content from the
catalyst material occurred at the chosen reaction condi-
tions. In addition, the EDX spectrum and TEM image of
the recycled catalyst after the fifth run showed no signifi-
cant changes in the elemental composition and morphol-
ogy as compared with the fresh catalyst (Figure S2, ESI).
The characterization data confirmed that there is no such
erosion of the active material from the support, and the
material proved to be of highly robust heterogeneous
nature, preserving its crystal structure even after
repeated use.
in 30 min, whereas with 40 mg of catalyst, the yield and
reaction time remained unaltered (Table 3, Entries 1–4).
Thus, 30 mg of catalyst was considered the optimum
amount for the chosen reaction conditions.
Furthermore, we assessed the suitability of the
recycled 2.5% of Bi O /FAp catalyst as recyclability is one
2
3
2
3
a
TABLE 2 Effect of solvents on yield and reaction time
Time
Entry Medium
(min)
1440
40
%Yield
b
1
2
3
4
5
6
7
No solvent
MeOH
–
82
96
31
48
50
68
EtOH
30
Toluene
300
240
120
360
The efficiency of the prepared Bi O /FAp material in
2
3
Tetrahydrofuran
the current study was compared with the literature
reported catalysts, in terms of the reaction conditions,
time, and yields. The results are summarized in Table 4
CH
Dimethylformamide
DMF)
3
CN
(
8
9
Water
DMF
90
30
53
c
51
a
Reaction conditions: amine (1) (1 mmol), 4-methoxy benzaldehyde (2a)
(
1 mmol), ethyl cyanoacetate (3) (1 mmol), 2.5% Bi
2
O
3
/fluorapatite (30 mg),
and solvent (5 mL) at room temperature.
b
No reaction observed.
c
ꢁ
Reaction was carried out under catalyst-free conditions at 130
C
TABLE 3 Optimization of 2.5% Bi
quantity and reaction time
2
O
3
/fluorapatite catalyst
a
Entry
Catalyst/mg
Time/min
Yield%
73
1
2
3
4
10
20
30
40
60
40
30
30
91
96
96
2 3
FIGURE 6 Recycling experiment of 2.5% Bi O /FAp catalyst
for synthesis of dihydro-[1,2,4]triazolo[1,5-a]pyrimidine. FAp,
fluorapatite
a
Reaction conditions: amine (1) (1 mmol), 4-methoxy benzaldehyde (2a)
1 mmol), ethyl cyanoacetate (3) (1 mmol), and ethanol (5 mL) at room
temperature.
(

8
of 10
KERRU ET AL.
and the described catalyst gave higher yields with shorter
reaction time at room temperature. Therefore, bismuth
loaded on FAp is an adequate catalyst with high effi-
ciency for the synthesis of dihydro-[1,2,4]triazolo-
pyrimidine derivatives in comparison with catalysts
reported in the literature.
Having the optimized the reaction conditions, we
generalized the applicability of this procedure for the syn-
thesis of a series of 13 dihydropyrimidine derivatives
(4a–m) starting from 1H-1,2,4-triazol-5-amine (1), differ-
ent benzaldehydes (2a–l), and ethyl cyanoacetate or ethyl
acetoacetate (3) in ethanol using 2.5% of Bi O /FAp cata-
2
3
lyst at room temperature (Table 5). Of the 13 derivatives,
2 were novel, with the remaining one being a known
compound. All the reactions carried out gave high yields
92%–96%) of functionalized dihydropyrimidine deriva-
tives within a short reaction time (25–35 min). The
different electron-donating and electron-withdrawing
1
(
FIGURE 7 Hot filtration test results of the 2.5% Bi
catalyst for the synthesis of 4a. FAp, fluorapatite
2 3
O /FAp
2 3
TABLE 4 Comparison of efficacy of Bi O /fluorapatite with other reported catalysts for the synthesis of dihydropyrimidine derivatives
[
Ref]
Catalyst
Solvent
Solvent free
Conditions
Time/min
75–180
25–60
% Yield
ꢁ
[21]
[22]
DABCO-IL
DABCO-IL
Thiamine-HCl
100 C
75–90
78–95
81–96
85–96
86–94
37–90
6.0–82
ꢁ
H
2
2
O
O
75 C
[
23]
H
Reflux
180–360
10–40
ꢁ
[24]
[25]
γ-Fe
Nafion-H
BiNaCa (PO
Catalyst free
2
O
3
@NaHSO
4
Solvent free
PEG-400
100 C
ꢁ
50 C
30–50
[
26]
4
4
)
3
F
Acetonitrile
Dimethylformamide
EtOH
Reflux
90–420
15–20
ꢁ
[14]
130–160 C
2
.5% Bi
2
O
3
/fluorapatite
Room temperature
25–35
92–96 [This work]
a
TABLE 5 Dihydro-[1,2,4]triazolo-pyrimidine derivatives obtained using 2.5% Bi
2
O
3
/fluorapatite catalyst
b
ꢁ
Entry
R
X
Compound
Time/min
% Yield
96
Melting point ( C)
1
2
3
4
5
6
7
8
9
4-OCH
3,4-OCH
4-N(CH
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
COCH
4a
4b
4c
4d
4e
4f
30
28
35
26
28
35
25
35
30
30
35
26
30
186–188
192–194
179–181
202–204
184–186
212–214
204–206
209–211
186–188
201–203
194–196
182–184
3
95
3
)
2
92
3-OH,4-OCH
3,4-Di-OH
3-Indolyl
3
93
94
94
2,4,6-Tri-OCH
2-OCH
2-NO
3
4g
4h
4i
92
3
96
2
94
10
11
12
13
4-OH,3-OCH
3
4j
92
4-Cl
4k
4l
94
4-Br
95
[25]
4-OCH
3
3
4m
93
178–180
a
Reaction conditions: amine (1) (1 mmol), different substituted benzaldehydes (2a–l) (1 mmol), ethyl cyanoacetate (3) (1 mmol), 2.5% Bi
30 mg), and ethanol (5 mL) at room temperature.
2 3
O /fluorapatite
(
b
Isolated yields.

BI2O3/FAP FOR SYNTHESIS OF DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE
9 of 10
SCHEME 2 Proposed mechanism of
dihydro-1,2,4-triazolo-pyrimidine derivatives
(
4a–m)
substituents on the aromatic phenyl ring did not show a
marginal influence on the overall yields of the products.
Both the active methylene compounds, ethyl
cyanoacetate and ethyl acetoacetate, were well-tolerated
and both reactions offered high conversions in the MCR.
The newly synthesized analogs were characterized by
the formation of Knoevenagel condensation compound
(I) from the condensation of aldehyde (2a) and ethyl
cyanoacetate (3). It is likely that in this reaction the alde-
hyde was adsorbed on the acidic sites of the catalyst to
stimulate its C=O group. Simultaneously, the Lewis or
Brønsted basic sites of the Bi O /FAp catalyst coordinat-
2
3
1
13
spectroscopic techniques, HRMS, H and C NMR analy-
ing with 1H-1,2,4-triazol-5-amine (1) facilitated the gen-
eration of the other intermediate, the deprotonated
1,2,4-triazole-5-amine (II), which undergoes a Michael-
type addition with Knoevenagel product (I) to give a
transient intermediate (III). Finally, the intermediate
(III), through consequent intramolecular cyclization and
ring closure, results in the formation of the desired
dihydro-[1,2,4]triazolo-pyrimidine derivative (4a). The
alternative iminium ion mechanism 2a ! ia ! iia does
not constitute a major pathway. The proposed mecha-
nism involving the Knoevenagel condensation and for-
mation of intermediate is consistent with the reported
sis (Supplementary file). For instance, compound 4a dis-
1
played five sets of singlets in H NMR: a characteristic
singlet was observed at δ 5.22 ppm for one proton of the
dihydropyrimidine moiety and the other four singlets
appeared at
δ 3.86, 6.45, 8.30, and 8.58 ppm,
corresponding to the OCH , NH, CH, and NH groups,
3
2
respectively. In addition, one triplet (1.29 ppm) and one
quartet (4.29 ppm) appeared due to the –COOCH CH3
2
group, respectively. Two doublets were found at δ 8.08
and 7.14 ppm due to the four protons of the methoxy-
substituted phenyl ring. The farthest downfield peak that
appeared at δ 163.52 ppm belongs to the carbonyl carbon
[
34]
literature.
Therefore, Bi O /FAp is an efficient catalyst
2 3
13
of the ester moiety of 4a in C NMR. In HRMS analysis,
the molecular-ion peak was detected at m/z = 338.1082.
A suitable mechanistic pathway for the three-
component condensation reaction for the construction of
dihydropyrimidines (Scheme 2) is described. To investi-
gate the nature of reaction intermediates, the reaction
mixture was analyzed after 15 min of reaction time by
LC–MS (Figure S3, ESI). Based on the presence of
alkene (I) iminium ion (2a) intermediates in the reaction
mixture and the final reaction product, a probable mech-
anism is proposed. The key step in this sequence involved
in value-added organic conversions and this is probably
due to its surface acidity and basicity. The synergetic
effects of this complex enable smooth reaction.
4 | CONCLUSIONS
We reported the synthesis and characterization of a
Bi O /FAp composite as a reusable heterogeneous cata-
2
3
lyst for the synthesis of a series of biologically significant
1,2,4-triazole-fused dihydropyrimidine bicyclic systems in

10 of 10
KERRU ET AL.
an ethanol medium at room temperature. The 2.5%
Bi O /FAp composite exhibited excellent performance as
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2 novel dihydro-[1,2,4]triazolo[1,5-a]pyrimidine deriva-
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2
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2 3
Easily recovery of catalyst, reusability, short reaction
time, excellent yields, mild conditions, and no hazardous
solvents or column chromatography are the advantages
of this method.
[
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ACKNOWLEDGMENTS
The authors thank the University of KwaZulu-Natal,
Durban, South Africa, for financial support and research
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