Novel synthesis of 1,5-disubstituted-1,2,3-triazolines catalysed by Zepto magnetic microspheres under the influence of a rotating magnetic field

Article abstract of DOI:10.1139/cjc-2018-0349

The novel reactor has been designed to perform chemical reactions under the influence of a magnetic field generated by alternating magnetic poles as a function of time. The system was successfully employed to synthesize a series of 1,5-disubstituted-1,2,3-triazolines via the regioselective [3 + 2] cycloaddition reactions between alkyl/aryl azides and nitroolefins catalysed by Zepto (para magnetic ultra-blue carboxy functionalized) microspheres (bead diameter 2.5 μm). All of the reactions went smoothly without any adverse effect on nitro, cyano, thienyl, hydroxy, halogens, and ether functions at 25 ± 2 °C and afforded 82%-99% pure products at a magnetic field of 18.99 mT and an exposure time of 180-240 min. The influence of the magnetic force exerted on the magnetic materials was found to enhance the catalytic activity of microspheres. The catalyst could easily be separated by simple centrifugation, which could be reused for at least 15 runs with no loss in activity.

Full text of DOI:10.1139/cjc-2018-0349

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Novel synthesis of 1,5-disubstituted-1,2,3-triazolines catalysed by ZeptoTM
magnetic microspheres under the influence of rotating magnetic field
Priyanka Sharma, Srinivasu V. Vallabhapurapu, Wei H. Ho, Nanjundaswamy M. Hemmaragala*
Department of Physics, College of Science, Engineering and Technology, University of South Africa,
Johannesburg-1709, South Africa
Priyanka Sharma,
E-mail: rupriyanka@gmail.com
Srinivasu V. Vallabhapurapu,
E-mail: vallavs@unisa.ac.za / vvsrinivasu@hotmail.com
Wei H. Ho
E-mail: howh@unisa.ac.za
Nanjundaswamy M. Hemmaragala
E-mail: nswamyorg@gmail.com

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Abstract:
The novel reactor has been designed to perform chemical reactions under the influence of magnetic
field generated by alternating magnetic poles as a function of time and successfully employed the
system to synthesize a series of 1,5-disubstituted-1,2,3-triazolines via the regioselective [3+2]
cycloaddition reactions between alkyl/aryl azides and nitroolefins catalysed by ZeptoTM (para
magnetic ultra-blue carboxy functionalized) microspheres (bead diameter 2.5 m). All the
reactions went smoothly without any adverse effect on nitro, cyano, thienyl, hydroxy, halogens
and ether functions at 252°C, to afford 82-99% pure products at magnetic field and exposure time
of 18.99 mT and 180-240 min. The influence of magnetic force exerted on the magnetic materials
was found to enhance the catalytic activity of microspheres. The catalyst could easily be separated
by simple centrifugation which could be reused for atleast 15 runs with no loss in activity.
Keywords: 1,2,3- Triazolines, magnetic field, Novel reactor, magnetic microspheres

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Introduction
1,2,3-Triazole scaffold has become a treasury of bioactive compounds and therefore, chemists and
biochemists have been engaged in the derivatisation of the moiety and screening them for further
exploration1.1,2,3-triazoles are the best amide surrogates in bioactive compounds due to their
strong dipole moments2. They also serve as a linker and exhibit bio-isosteric effects on peptide
linkage, imidazole ring, aromatic ring and double bonds3. These motifs are effective in the
formation of hydrogen bonds and dipole-dipole interactions facilitating the binding capacity of the
drug molecules with the target virus4. Due to these facts, 1,2,3-Triazolesarewell-known to possess
a broad spectrum of bio-activities like antifungal5, antiviral against orthopoxviruses and severe
acute respiratory syndrome6, antibacterial7 and anticancer activities [8]. Peng and co-workers have
recently synthesized 3-arylethylnyltriazolyl ribonucleosides and reported the tolyl derivative to
have potent anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaca-29. Very
recently Phokodylo et al have conjugated oxadiazoles and thiazole with 1,2,3-triazole and
demonstrated these compounds to be active against melanoma, colon and breast cancer10.
Furthermore, 1,2,3-Triazoles have drawn interest of synthetic chemists for their precursors in the
construction of novel bio-molecules11. In the year 1961, Rolf Huisgen was successful in an attempt
for the synthesis by 1,3- dipolar cycloaddition reaction of organic azides with alkynes which
afforded both the isomers such as 1,4-disubstituted and 1,5- disubstituted 1,2,3-triazoles and
couldn’t be separated12. Later developments to modify Huisgen’s reaction to achieve regio-
selective syntheses, number of methodologies have been established for 1,4- disubstituted-1,2,3-
triazoles13-15 and 1,5-disubstituted 1,2,3-triazoles16-22. Compared to 1,4- disubstituted-1,2,3-
triazoles, 1,5- disubstituted-1,2,3-triazoles have shown multiple biological activities. For example,
uracil and tert-amide derivatives of 1,5-isomer showed Human dUTPase Inhibitory activity23, the
nucleoside
derivative
shown
non-nucleoside
reverse
transcriptase
inhibitor
tertbutyldimethylsilylspiroaminooxathioledioxide (TSAO)24, antimicrobial and anti-cancer
activity by carboxyamidotriazole (CAI)9. The potential drugs based on 1,5-disubstituted 1,2,3-
triazoles are presented in figure 1.

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Therefore, it is worth to synthesize 1,5-isomer but obtaining 1,5-isomer is still a challenge. There
have been continued efforts in achieving regio-specific 1,5- disubstituted-1,2,3-triazoles25. Typical
routes include the use of in situ generated sodium, lithium, tin, germanium or magnesium
acetylides17,26. These reactions involve the use of large excess of strong bases and thus produce
undesirable chemical waste. There are also the reports which use highly expensive ruthenium and
other noble metal complexes26c which are either difficult to obtain in ordinary laboratories or which
is economically unviable and the use of Raney Nickel which is air sensitive and the reaction need
to be run under extensive care and precautions and the procedure can never be used to for the
production in multi-gram scale26b. Other procedures require harsh conditions and elevated
temperatures using oil bath26f and too much time consuming and cumbersome work-up
procedures25a, 27,28. On the other hand, owing to its wide spectrum of diverse applications, magnetic
field (MF) is playing major roles in current science and technology29. MF has been utilized in the
areas of therapeutic and diagnostic medicine, environmental management and industries over the
years30. Addressing environmental issues including water treatment using magnetic technique has
also received substantial consideration in recent times31,32. Very recently, Junka et. al have
reported in nature science, the application of rotating magnetic fields to increase the activity of
antimicrobials against wound biofilm pathogens33.
Experimental
Materials
ZeptoTM carboxy functionalized polystyrene magnetic fluorescent ultra-blue microspheres with
emission at 450 nm (lot number 2457883_M1) was obtained from cytodiagnostics, Nitroolefins
were synthesized according to a previous procedure35. All the solvents were of analytical grade
and used without further purification. Thin layer chromatography was run on pre-coated silica gel
on aluminium plates obtained from Whatmann Inc. All the reactions were performed at 20 ºC.
Büchi B-540 apparatus was used to obtain the melting points of all solid compounds. Bruker. 1H
13
NMR and C NMR spectra were recorded on Bruker Avance 400 and 100 MHz spectrometer
respectively, chemical shifts were reported in (ppm) with TMS as internal standard. Elemental
analyses were performed on Perkin Elmer – 2004. Quantity of all products reported are purified
ones by column chromatography using 70–230 mesh silica gel.
Magnetic Reactor

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The experimental setup is made up of a 1.1 kW three-phase induction motor having a stator
winding of internal thickness and height of 14.39 X 160 mm, a rotor modified to hold an open-top
toroidal cleaning chamber made from perspex plastic (internal, external and height diameters of
66 x 100 x 25 mm), a 10 A variable power source used as an AC power supply to the three-phase
induction motor and a 220 V, 34 W fan mounted on a retort stand to maintain a uniform
temperature within the system. Rotating magnetic field generated in the air-gap by the stator
windings was measured using a digital gaussmeter (GM07/GM08 model), with a maximum
magnetic field of 26.94 mT generated. The graphics representation of the magnetic reactor used to
generate the magnetic field experimental setup is shown in figure 2.
Results and Discussion
As part of our ongoing project, we were demonstrating enzymatic catalysis under the influence of
rotating magnetic field. The reaction mixture was static as the enzymes couldn’t be moved around
and to achieve the movement, enzymes were conjugated with carboxy functionalized polystyrene
magnetic microspheres and brought the reaction mixture to stirring. When the control experiments
were run, to our surprise, there was catalytic influence even without enzymes but with carboxy
functionalized polystyrene magnetic microspheres. There were reports in the literature that,
magnetic field can improve the catalytic activity thereby facilitating organic and biochemical
reactions34. Surprised by these observations, in continuation of our interest in exploring catalyzing
organic [3+2] cycloaddition reaction, we wanted to utilize this system for the [3+2] cycloaddition
reaction. 150 mg of (2-nitroethenyl)benzene (1.0 mmol) is taken into the reactor, 5 mL of DMF
and 155 mg of phenyl azide (1.3 equiv.) were charged and 50 L ZeptoTM magnetic ultra-blue
carboxyl microspheres were added. The system was exposed to the magnetic field and reaction
was monitored by TLC. After 6 hours, the disappearance of starting material (2-
Nitroethenyl)benzene was observed on thin-layer chromatography. The reaction mixture was
transferred to a test tube, centrifuged to separate the catalyst, the solvent was evaporated off under
reduced pressure to get the crude product which was purified by column chromatography over
silica gel using [ethyl acetate: hexane (1.5: 8.5)] as an eluent to afford 170 mg (85% yield) of pure
1,5-diphenyl-1H-1,2,3-triazole as white solid which melted at 113−114 °C (lit. 113−114 °C); 1H
NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.47−7.41 (m, 3H), 7.40−7.32 (m, 5H), 7.24−7.21 (m,

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2H) ppm; 13C NMR (100 MHz, CDCl3) δ 137.7, 136.6, 133.4, 129.4, 129.2, 128.9, 128.6, 126.8,
125.2 ppm. Further to standardize the reaction, (2-nitroethenyl)benzene with phenyl azide was
carried out with various amounts of catalyst under varied time of magnetic exposure and the results
are presented in table 1. It is very clear from table 1 that, 1 mM of (2-nitroethenyl)benzene, the
catalyst required to afford the maximum yield (94%) is 250 L of carboxy functionalized
polystyrene magnetic microspheres and the maximum exposure time of magnetic field required is
180 minutes. To check with various other solvents, the reactions have been tried with EtOH,
MeOH, 50% aqueous MeOH, THF, 50% aqueous THF, CHCl3, CCl4, CH3NO2, DMF and
acetonitrile have been studied and among all, DMF emerged as the best solvent in terms of shorter
reaction time and best yields and the next best solvent was DMSO which are presented in table 2.
Encouraged by this result we wanted to investigate the reaction with other substituted nitroolefins
such as phenyl and thio-nitroolefins with phenyl/benzyl azides for the suitability. The approach
was successful, and the reactions afforded the expected 1,5-disubstituted-1,2,3-triazoles as
products in high to excellent yields as shown in scheme 1 and the results are summarized in table
3. It is to be noted that, reaction of 4-nitro(2-nitroethenyl)benzene with benzyl azide gave the
corresponding triazoline [1-Benzyl-5-(4-nitrophenyl)-1H-1,2,3-triazole, 3g] in highest yield,
almost quantitative, 99% whereas the reaction of 4-cyzno(2-nitroethenyl)benzene with benzyl
azide gave the corresponding triazoline [4-(1-Benzyl-1H-1,2,3-triazol-5-yl)Benzonitrile, 3j] in
lowest yield, 60% with this system.
Control Experiment
The control experiments were run, firstly in the absence of magnetic field, but only using the
catalyst ZeptoTM magnetic ultra-blue carboxyl microspheres under same reaction conditions, but
using stirrer; secondly, under the magnetic field with no catalyst. There was no reaction even after
8 hours, in the latter case whereas trace products have seen on TLC in former case clearly
indicating magnetic field is influencing the catalytic activity of ZeptoTM magnetic ultra-blue
carboxyl microspheres to have catalytic activity which is catalyzing the [3+2] cycloaddition
reaction of nitroolefins and azides to afford 1,5-disubstituted-1,2,3-triazolines. The control
experiments were also carried to know the effect of rotation frequency for the reaction under the
magnetic field, but we couldn’t observe any difference with the rate of the reaction at varied
rotation frequencies under the magnetic field strength 18.99 T. Further, the combined effect of

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magnetic field and viscosity of the reaction mass have also been studied for any possible effect on
the rate of reaction, but there was no significant contribution of viscosity of the reaction mixture.
The plausible mechanism for the catalysis of carboxy functionalized Zepto magnetic microspheres
for the 3+2 cycloaddition reaction is presented in below scheme 2.
Recycling the catalyst
On completion of the reaction, the reaction mixture along with solvent was taken into the test tube
(15 mL capacity) and centrifuged, the liquid was decanted off and the catalyst (ZeptoTM carboxy
functionalized polystyrene magnetic fluorescent ultra-blue microspheres) stuck to the bottom of
the test tube was added 5 mL of acetonitrile, heated to 40C on a steam bath and centrifuged, the
process was repeated twice and the recovered catalyst was utilized for fifteen subsequent reactions
without any loss in catalytic activity.
General Procedure for the synthesis of 1,5-disubstituted-1,2,3-triazoles under the influence
of rotating magnetic field
In to the reactor, a mixture of (2-nitroethenyl)benzene (1.0 mmol), DMF (5 mL) and phenyl/benzyl
azide (1.3 equiv.)and ZeptoTM carboxy functionalized polystyrene magnetic fluorescent
ultra-blue microspheres (250 L) were added. The reaction mixture was exposed to magnetic
field at 20 °C. After completion of the reaction, the reaction mixture was transferred to a test tube,
centrifuged to recover the catalyst. The filtrate was evaporated to dryness under vacuum to afford
the crude which was purified by column chromatography using (1.5:8.5 :: ethyl acetate: hexane)
as an eluent to afford pure 1,5-diphenyl-1H-1,2,3-triazole.
Conclusions
In summary, we have demonstrated the use of magnetic field in catalysing the 3+2 cyclo-addition
of nitroolefins and azides to obtain a variety of 1,5-disubstituted-1,2,3-triazoles utilising carboxy
functionalized magnetic microspheres as catalyst. The process is advantageous over the previous
reports in terms reaction time, yields, no generation of undesired intermediates as the reactions
were carried out at ambient temperature and the catalyst used is not complex material which would
not generate any other inorganic complex which can easily separate by simple centrifugation which
could be reused for the next subsequent reactions which makes the process neat and environmental
friendly.

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Supplementary data
Supplementary data are available with the article through the journal website.
Acknowledgements
The authors are thankful to the University of South Africa for the financial support and Mr. Joseph
A. Walker for his assistance in terms of experimental facility at Resolution circle, Johannesburg
throughout the project.
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TABLES
Table 1. Standardization of the reaction of (2-nitroethenyl)benzene(1.0 mM) with phenyl
azide(1.3 equiv.) with various amounts of catalyst ZeptoTM magnetic ultra-blue carboxyl
microspheres and varied time of magnetic exposure at 20 °C using DMF as solvent
Entry
Catalyst (L)
Magnetic exposure (min)
Yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
0
5
240
240
240
240
240
240
240
240
240
240
240
240
180
180
180
180
180
180
180
No reaction
Trace
5
10
15
20
25
30
35
40
45
50
55
60
75
100
125
200
250
300
8
14
20
26
35
52
66
83
85
85
85
90
93
94
94
94
s

Page 12 of 18
12
Table 2. Standardization of the reaction of (2-nitroethenyl)benzene(1.0 mM) with phenyl
azide(1.3 equiv.) employing ZeptoTM magnetic ultra-blue carboxyl microspheres with various
solvents.
Entry
Solvent
Reaction time (h)
Yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Hexane
Ethylene glycol
MeOH
50% aq MeOH
EtOH
50% aq EtOH
THF
50% aq THF
DMSO
DMF
CHCl3
CCl4
4
4
4
4
4
4
4
4
4
3
4
4
4
4
No reaction
No reaction
12
Trace
9
Trace
18
15
85
94
37
42
32
45
CH3CN
CH3NO2
Table 3: Synthesis of 1,5-disubstituted-1,2,3-triazoles by the reaction of nitroolefins(1.0 mM) and
(1.3 equiv.) catalyzed by ZeptoTM magnetic ultra-blue carboxyl microspheres (250 L) under the
influence of rotating magnetic field using DMF as solvent.
Entry R1
R2
Reaction time (min)
Yield (%)
94
88
93
87
82
92
99
96
98
60
92
95
82
88
a
b
c
d
e
f
H
4-NO2
4-Br
4-OCH3
Thiophene
H
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
180
210
210
210
180
240
210
210
210
210
240
240
240
240
g
h
i
4-NO2
2-NO2
2-Cl
j
4-CN
k
l
m
n
4-CH3
4-OCH3
4-OH
Thiophene

Page 13 of 18
13
Captions to the figures
Figure 1.
Potential applications based on 1,5-disubstituted-1,2,3-triazoles
Figure 2.
Graphical representation of the magnetic reactor used to generate the magnetic field
Scheme 1.
Cycloaddition reaction between nitrolefins and aryl/alkyl azides under the influence of magnetic
field catalysed by magnetic microspheres

Page 14 of 18
14
Scheme 2.
Plausible mechanism for the 3+2 cycloaddition nitrolefins and azides catalysed by carboxy
functionalized magnetic microspheres

Page 15 of 18
1
H
N
O
O
Cl
O
CH
HO
3
N
H N
O
F
N
2
N
N
Cl
Cl
N
O
N
H N
2
N
Active anticancer drug
Potent Human DuTpase inhibitor
IC50 = 0.067 micromoles
Carboxyamidotriazole (CAI)
O
OTBS
O
N
N
S
O
O
N
O
N
N
TBSO
O
NH2
N
NH
H CO
Non nucleoside reverse transcriptase inhibitor
TSAO
3
N
N
O
N
H CO
3
NH
2
O C H
N
3
O C H
Potent Human DuTpase inhibitor
IC50 = 1.3 micromoles
3
Tubulin polymerization inhibitor
S
C
S
C
H
3
H
NH
3
N
N
N
N
O2N
N
O
O
C
H
3
H C
3
N
N
High active on Leukemia & Melanoma
Potent HIV1 Vif antagonist

Page 16 of 18
1
STATIC COILS
GLASS REACTOR
REACTANTS
INDUCTION MOTOR
FIELD DIRECTION

Page 17 of 18
1
O
O
O
O
H
H
O
O
O
Polystyrene
H
NO
2
Magnetic core (Iron)
O
O
H
N
N
O
O
O
O
H
R1
N
O
H
H
+
1
R
2
ZeptoTM polystyrene magnetic microspheres
Magnetic field of 18.99 mT
-
N
+
N
R1
DMF, 20 oC, 180-240 min
N
82-99%
3a - 3n
2
R
2
R1= H, CH 3, OCH 3, OH, NO 2, CN, Cl, Br, Thiophene;
R2 = phenyl / benzyl group

Page 18 of 18
1
N
N
N
O
R
Carboxy functionalized
Magnetic microspheres
2
O
H
.
HNO2
O
N
+
-
O
O
N
O
+
-
R
O
2
O
N
O
H
.
+
N
N
N
O.
.
R
N
2
O
+
-
N
N
O
O
H
.
+
N
R
O
.
.
2
O
N
N
N
O
N
O
H
.
+
O
.
.
R
N
2
+
N
N