Sequencing [3+2]-cycloaddition and multicomponent reactions: A regioselective microwave-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles using ionic liquid supported Cu(II) precatalysts in methanol

Article abstract of DOI:10.1016/j.tetlet.2020.152273

Heterocyclic compounds with two to three nitrogen atoms play a pivotal role in the normal life cycle of a cell. Further the design and synthesis of a quality heterocyclic compound library with N-atoms as new chemical probes active, is vital in drug discov

Full text of DOI:10.1016/j.tetlet.2020.152273

Journal Pre-proofs
Sequencing [3 + 2]-Cycloaddition and Multicomponent Reactions: A Regio‐
selective Microwave-assisted Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
using Ionic Liquid Supported Cu(II) Precatalysts in Methanol
Ananya Anubhav Saikia, R Nishanth Rao, Soumyadip Das, Sushovan Jena,
Sourav Rej, Barnali Maiti, Kaushik Chanda
PII:
S0040-4039(20)30740-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152273
TETL 152273
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 April 2020
15 July 2020
19 July 2020
Please cite this article as: Anubhav Saikia, A., Nishanth Rao, R., Das, S., Jena, S., Rej, S., Maiti, B., Chanda, K.,
Sequencing [3 + 2]-Cycloaddition and Multicomponent Reactions: A Regioselective Microwave-assisted
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles using Ionic Liquid Supported Cu(II) Precatalysts in Methanol,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152273
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Sequencing [3 + 2]-Cycloaddition and Multicomponent Reactions: A Regioselective
Microwave-assisted Synthesis of 1,4-Disubstituted 1,2,3-Triazoles using Ionic Liquid
Supported Cu(II) Precatalysts in Methanol
Leave this area blank for abstract info.
Ananya Anubhav Saikia, R Nishanth Rao, Soumyadip Das, Sushovan Jena, Sourav Rej, Barnali Maiti,
and Kaushik Chanda*
MeOH
R2
Cu(OIL)2
Cu(I)
N
N
Br
R1
R1
+
+
NaN3 R2
MW, 65 oC, 10 min
N
CH3
N
H3C
N
+
+
N
O
O
O
N
Cu(OIL)2
Cu
BF4
BF4
O
2.5 mol%

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Sequencing [3 + 2]-Cycloaddition and Multicomponent Reactions: A
Regioselective Microwave-assisted Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
using Ionic Liquid Supported Cu(II) Precatalysts in Methanol
Ananya Anubhav Saikia,a R Nishanth Rao,a Soumyadip Das,a Sushovan Jena,a Sourav Rej,b Barnali Maiti,a
and Kaushik Chandaa*
aDepartment of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore-632014, India
bInstitute of Bioengineering and Nanotechnology, A*STAR. 31 Biopolis Way, Singapore-138669.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Heterocyclic compounds with two to three nitrogen atoms play a pivotal role in the normal life
cycle of a cell. Further the design and synthesis of a quality heterocyclic compound library with N-
atoms as new chemical probes active, is vital in drug discovery. In this context, an efficient one-pot
multicomponent strategy for the synthesis of a mini library of 1,4-disubstituted 1,2,3-triazoles is
described. This new multicomponent one-pot method features a combination of ionic liquid
supported Cu(II) precatalysts in methanol catalyzed [3 + 2]-cycloaddition with microwave
irradiation reactions. The synthetic manipulation involved the efficient reduction of ionic liquid
supported Cu(II) catalyst by methanol followed by [3 + 2] cycloaddition with alkynes using in situ
generated azides to obtain 1,2,3-triazoles regioselectively..
Available online
Keywords:
1,2,3-triazoles
(3+2) cycloaddition
Microwave irradiation
Ionic Liquid
2009 Elsevier Ltd. All rights reserved
1. Introduction
Cu(I) based heterogeneous catalysts also used such as copper
nanocluster,9 copper(I) zeolites,10 a copper manganese spinel
To sustain drug discovery campaigns, the diversity oriented
synthesis (DOS) has become an indispensible tool for the
synthesis of nature-inspired and drug like small molecule.1
Similarly, multicomponent reactions, one of the key aspects of
DOS, allow the formation of multiple bonds at a time using more
than two reactants in a single step.2 The discovery of highly
regioselective Cu(I) catalysed (3+2) cycloadditions in 2001 by
Sharpless and his co-workers rapidly gained an important ground
in all branches of chemistry including material sciences also.3
The Cu(I) catalyzed (3+2) cycloaddition is the most widely
studied reaction among all Cu-catalyzed reactions.4 The end
product 1,4-disubstituted 1,2,3-triazole is a biologically valuable
frameworks that are found in a large number of natural products
and pharmaceutically active compounds.5 Further, 1,4-
Disubstituted 1,2,3-triazole derivatives exhibited several
biological activities such as antiviral, anticancer, anti-
inflammatory, and antibacterial activity.6 The core structure of
disubstituted triazoles has also been found in many drugs such as
ribavitrin (A), tazobactam (B), and triazole containing naamine A
and isonaamine A mimics (C, D) as shown in figure 1.7
oxide,11 Cu/C,12 and Cu2O on water.13 Further, we have
demonstrated the facet dependent catalytic potential of Cu2O
nanocrystals for the regioselective synthesis of focused 1,4-
disubstituted 1,2,3-triazoles in green media.14 Lautens and his
group reported the intramolecular Cu(I)‐catalyzed interrupted
click–acylation domino reaction.15 In 2016, Lal et al. reviewed
the use of copper nanoparticles as catalyst for the synthesis of
1,4-disubstituted 1,2,3-triazoles in water.16 Zhu and his
coworkers recently studied the use of Cu(OAc)2 as catalyst for
1,3-dipolar cycloaddition reactions with particular emphasize on
chelating ligands.17 More recently, the use of Cu(II)-tren
precatalysts and Cu(II)acetate precatalysts in methanol for the
1,3-dipolar cycloaddition reactions to afford the desired 1,2,3-
triazole evoked the special interest for Cu(II) catalysts.18 In spite
of these tremendous achievements in this field, still there is a
scope for the development of better reaction methodology in
terms of single step reactions, recyclable catalysts, atom
economy, and avoid the handling of explosive azides etc.
Task specific ionic liquids (TSILs) with functional groups
anchored to the either cation, or anion has been developed for
numerous organic transformation.19 To suite organic
transformations, many low molecular weight TSILs have been
used either as supported catalysts, reagents, or as soluble
supports.20 The whole property of an ionic liquid such as thermal
stability, vapor pressure, and the solvating ability can be altered
by fine tuning the types of cations and anions. Advantages’ lying
with ionic liquid supported catalysts is the ability to easily phase
separate from the substrate and products after completion of the
reaction simply by adding a less polar organic solvent. Finally,
the recovered ionic liquid supported catalyst can be regenerated
or reused for further organic transformation. Recently, ionic
O
N
NH2
N
R1O
N
N
O
S
O
N
R1O
H
N
N
N
HO
N
N
N
O
N
O
R2O
HO
OH
OH
O
R2O
Naamine A -triazole
conjugates (C)
Isonaamine A -triazole
conjugates (D)
B
)
Tazobactam (
A
Ribavitrin (
)
Figure 1. Biologically active triazole moieties.
In view of their wide ranging bioactivities, several synthetic
methods have been developed for the 1,3-dipolar cycloaddition to
1,2,3-triazole moieties which mainly consists of Cu(II) salts with
sodium ascorbate as reducing agent or Cu(I) salts.8 Similarly

2
Tetrahedron
liquid supported catalysts are emerged as excellent
failed to increase the product yield (Table 1, entry 6).
Subsequently, we tried with MeOH as solvent at refluxing
temperature for 4 hours which dramatically increases the reaction
yield upto 80% (Table 1, entry 7). The above results indicate that
the MeOH is the most effective solvent for this cycloaddition
reaction.
heterogeneous catalysts to promote the sustainable development
in organic synthesis. In past, we have demonstrated the synthesis
of unique heterocyclic scaffolds using task specific ionic liquids
(TSILs) as soluble support under microwave heating.21 The use
of microwave (MW) technology in chemical synthesis is greatly
established which offers simple, clean, fast, efficient, and
economic features for the synthesis of a large number of organic
molecules compared to the conventional heating system.22 The
use of microwaves greatly reduced the reaction time in minutes
compared to hours in conventional heating conditions. As part of
our ongoing programme on the diversity-oriented synthesis of
bioactive heterocycles,23 we to report herein, a regioselective
microwave-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
using ionic liquid supported Cu(II) precatalysts in methanol by
sequencing 1,3-dipolar cycloaddition and multicomponent
reactions. The synthetic manipulation involves the reduction of
ionic liquid supported Cu(II) catalyst in methanol followed by
microwave-assisted 1,3-dipolar cycloaddition of in situ generated
organic azide with alkynes in excellent yields.
Table 1. Optimization of 1,3-dipolar cycloaddition reaction
between benzyl azide and phenyl acetylene catalyzed by ionic
liquid supported Cu(II) catalyst 4.a
CH3
H3C
N
N
+
+
N
O
O
O
N
N
N
Cu
BF4
N
BF4
O
N3
+
4
Reaction conditions
5a
entry
6a
7a
c
Y
ield%
solvent
temperature
80 o
reflux
80 o
time
4h
1
2
Neat
0%
0%
C
CH3CN
4 h
3
4
5
6
DMSO
EtOH
4 h
4 h
4 h
4 h
0%
C
reflux
45%
40%
35%
2. Results and Discussion
80oC
reflux
H2O-IPA
H2O
At the onset of our study, the recyclable ionic liquid supported
copper (II) catalyst 4 was synthesized in aqueous solutions in
three steps starting from 1-methyl imidazole 1 and 2-chloro
acetic acid 2 as depicted in scheme 1 using microwave
irradiation.
7
8
MeOH
MeOH
MeOH
MeOH
refux
4 h
80%
95%
MWb, 65 o
MWb, 65 o
MWb, 50 o
C
C
C
8 min
25 min
10 min
85%d
50%
9
1. Neat, MW, 80 o
OH
C
O
CH3
H3C
N
N
+
Cu(OAc)2
+
N
15 min
N
N
OH
O
O
O
N
10
Cl
+
N
N
H2O, 100 oC,
MW, 20 min
2. NaBF4, CH3CN
80 oC, 10 h
Cu
-
BF4
O
BF4
BF4
O
a reaction was performed using 5a (1 mmol), 6a (1.1 mmol), 4 (2.5 mol%),
b Microwave reactions were carried out in Microwave Model No. CATA R (Catalyst systems, Pune)
using power 280 watt, c Yield of the isolated product, d reaction was repeated with 2 mol%.
1
2
3
4
Scheme 1. Three step synthesis of ionic liquid supported Cu(II)
catalyst 4 in aqueous medium
To enhance the reaction efficiency, the same reaction was
performed under microwave irradiation. The reaction that was
performed in MeOH solution at 65 C under microwave heating
The synthetic strategy towards the synthesis of ionic liquid
support
3
equipped with carboxyl group linker, 1-(1-
tetrafluoroborate
o
carboxymethyl)-3-methylimidazolium
took 8 minutes for completion with 95% yield of product 7a
(Table 1, entry 8). It is interesting to observe that the yield of the
product 7a did not increase with decreasing the catalyst loading up
to 2 mol% under microwave irradiation which took 25 minutes for
completion (Table 1, entry 9). However, the reaction did not go to
([Carbmmim][BF4]) was prepared in two steps under microwave
irradiation. The first step involved the reaction of N-methyl
imidazole 1 with 2-chloroacetic acid 2 in neat condition under
microwave irradiation at 80 oC for 15 minutes followed by anion
exchange reaction with NaBF4 resulted the ionic liquid support 3.
Subsequently, the next step involved the reaction of ionic liquid
support 3 with Cu(OAc)2 in water medium under microwave
irradiation for 20 min to obtain the ionic liquid supported copper
(II) catalyst 4 as light blue powder in 95% yield. The catalyst 4
o
completion on lowering the reaction temperature at 50 C (Table
1, entry 10). The results clearly established the role of MeOH as
reducing agent for the reduction of ionic liquid supported Cu(II)
catalyst to Cu(I) precatalyst as the reaction did not yield any
Glaser reaction product, 1,4-diphenylbuta-1,3-diyne. To fully
consolidate our result that the MeOH acts as a reducing agents for
the in situ conversion of Cu(II) to Cu(I) during the course of the
1,3-dipolar cycloaddition reaction for, we have performed the X-
ray photoelectron spectroscopic (XPS) analysis of ionic liquid
supported Cu(II) catalyst before and isolated intermediate. In
figure 2a, the ionic liquid supported Cu(II) catalyst 4 displayed
peaks at 934.2 eV, and 953.7 eV attributed for the Cu2+ 2p1/2 and
Cu2+ 2p3/2 state respectively.24 We isolated the intermediate catalyst
during the course of the reaction and carried out the XPS analysis
which is shown in the figure 2b. In figure 2b, we observed small
peaks at 931.4 and 951.4 eV which correspond to the Cu+ 2p1/2 and
Cu+ 2p3/2 state respectively. This observation confirms the
generation of Cu(I) state from methanol mediated in-situ reduction
of Cu(II) state which is the active catalyst for click reaction.
1
was subsequently characterized by H, 13C NMR, MS, IR and
atomic absorption spectroscopic measurement with an attached
ionic liquid (IL-tag). The quantitative catalyst formation was
depicted in each step on ionic liquid support (See supporting
information). As a model reaction, we attempted the reaction of
benzyl azide 5a with phenyl acetylene 6a in the presence of ionic
liquid supported Cu(II) catalyst 4. To optimize the conditions, the
above reaction was performed using a 2.5 mol% of ionic liquid
supported Cu(II) catalyst 4 without using any solvent at 80 °C for
4 hours. No desired triazole product 7a was obtained under this
reaction condition (Table 1, entry 1). The reaction was further
tried in polar aprotic solvents such as CH3CN and DMSO. In
both cases, no required product was obtained (Table 1, entry, 2,
3). Therefore, the reaction was further conducted in refluxing
EtOH solvent. Interestingly, the product 7a was obtained in
moderate yield (45%, Table 1, entry 4). Inspired by this result,
we tested the efficacy of this cycloaddition reaction with solvent
such as H2O-IPA (Table 1, entry 5) which failed to increase the
yield to an appreciable extent. Even the use of H2O as solvent

3
Table 2. Substrate scope for the synthesis of 1,4-disubstitited
1,2,3-triazoles.a,b
CH3
H3C
N
N
+
+
N
O
O
O
N
Cu
BF4
BF4
O
4
R2
2.5 mol%
N
N
Br
R1
R1
+
+
NaN3 R2
MeOH, MW, 65 oC, 8-10 min
N
8
6
7
N
N
N
N
N
N
N
N
N
CH3
7a, 95%
7b, 94%
7c, 91%
N
N
N
N
N
N
N
N
N
O2N
O2N
CH3
Figure 2. High resolution XPS spectra of Cu 2p in ionic liquid
F
7d, 93%
7e, 89%
7f, 88%
supported Cu(II) catalyst before and after the reaction.
N
N
N
N
N
N
N
N
N
After the successful synthesis of 1,4-disubstituited 1,2,3-triazole
derivatives, we aimed to develop a one-pot multi-component
synthetic strategy from commercially available benzyl bromide,
NaN3, and alkynes. Because of the highly explosive nature of
benzyl azide, it is always important to develop the one-pot
methodology without isolating and handling of this potentially
harmful chemical. We have decided to carry out a one-pot two-
step process for the regioselective synthesis of 1,4-disubstituted
1,2,3-triazoles 7 from substituted benzyl bromide 8, NaN3 and
alkynes 6 in scheme 2. Initially, substituted benzyl bromide first
reacts with NaN3 in methanol solution at room temperature for
10-15 minutes to convert into an azide, The in-situ generated
azide further reacts with a terminal alkyne in the presence of 2.5
mol% of ionic liquid supported Cu(II) catalyst 4 at optimized
reaction condition for 8-10 minutes to generate the corresponding
1,4-disubstituted 1,2,3-triazole regioselectively.26
NC
O2N
O2N
F
7g, 85%
7h, 85%
7i, 89%
N
N
N
N
N
N
N
N
N
NC
NC
NC
F
CH3
7j, 90%
7k, 90%
7l, 87%
N
N
H3C
N
7m, 85%
a
8
6
4
reaction was performed using (1 mmol), NaN3 (1.1 mmol), (1.1 mmol), (2.5 mol%),
b
Yield of the isolated product,
A
plausible mechanistic pathway for this 1,3-dipolar
CH3
H3C
N
N
cycloaddition reaction is outlined in figure 3. The first step
involves the formation of in-situ azides from the reaction of
organic halides and NaN3 in methanol. The second step was the
addition of Cu(II) catalyst and reduced to Cu(I) species by
methanol followed by the addition of alkynes formed the five-
membered copper metallacycle A. Subsequent protonolysis of
intermediate A generates the 1,4-disubstituted 1,2,3-triazole
product and arial oxidation to Cu(II) species again formed
completes the catalytic cycle.
+
+
N
O
O
O
N
Cu
BF4
BF4
O
R2
4
N
N
2.5 mol%
Br
R1
R1
N
+
NaN3
+
R2
MeOH, MW, 65 oC, 8-10 min
8
6
7
Scheme 2. One-pot multicomponent strategy for the
regioselective synthesis of 1,4-disubstututed 1,2,3-triazoles.
After completion of the reaction, the reaction mixtures were
precipitated with cold ether and filtered through fritted funnel to
obtain the ionic liquid supported Cu(II) catalyst 4 followed by
washing and solvent evaporation. Finally the crude products were
purified by column chromatography followed by spectroscopic
characterization using 1HNMR, 13C NMR, and mass
spectroscopy (MS).
CH3
H3C
N
N
+
+
N
O
O
O
N
Cu
BF4
BF4
O
4
MeOH
Cu(I)
(O)
N
N
R2
N
R1
H
R1
6
With a set of optimized multicomponent reaction conditions in
hand, we examined the substrate scope with respect to various
benzyl bromide and alkynes derivatives, and the results are
reported in the table 2. Initially, we examined the effect of benzyl
bromides or substituted benzyl bromides containing electron
withdrawing groups reacted slowly to obtain corresponding
triazoles in good yields. Subsequently, the substituted benzyl
bromide with electron donating group reacted nicely to obtain the
corresponding triazole in good yield. Further, it has been
observed that aromatic alkynes containing electron-withdrawing
group such as F substituents have no effect on the outcome of the
reaction.
7
N
N
R2
N
R1
Cu
A
R1
R2
Cu
N
N
N
5
+
R2 Br
NaN3
R2
8
N
N N
R1
Cu
Figure 3. Plausible mechanism for the ionic liquid supported
Cu(II) catalyzed 1,3-dipolar cycloaddition reaction.

4
Tetrahedron
The recyclability of the ionic liquid supported Cu(II) catalyst 4
5. References and notes
was also examined. After finishing one run of reaction, another
cycle of the reaction was carried out using the same catalyst 4. It
has been observed that the ionic liquid supported Cu(II) catalyst 4
is effective and recyclable catalyst for the 1,3-dipolar
cycloaddition reaction leading to the regioselective synthesis of
1,4-disubstituted 1,2,3-triazole 7a with excellent yields of 75-80%
after third cycle of reaction.
1. (a) Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136,
14629. (b) Koh, M.; Park, J.; Koo, J. Y.; Lim, D.; Cha, M. Y.; Jo,
A.; Choi, J. H.; Park, S. B. Angew. Chem., Int. Ed. 2014, 53,
5102. (c) Kuruvilla, F. G.; Shamji, A. F.; Sternson, S. M.;
Hergenrother, P. J.; Schreiber, S. L. Nature 2002, 416, 653.
2. (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(b) Zhu, J.; Bienaymé, H., Eds. Multicomponent Reactions;
Wiley-VCH: Weinheim, Germany, 2005.
3. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Tornøe, C. W. Christensen, C.;
Meldal, M. J. Org. Chem., 2012, 67, 3057.
4. (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51. (b) Meldal, M.; Tornøe, C. W. Chem. Rev.
2008, 108, 2952. (c) Amblard, F.; Cho, J. H.; Schinazi, R. F.
Chem. Rev. 2009, 109, 4207. (d) Berg, R.; Straub, B. F. Beilstein
J. Org. Chem. 2013, 9, 2715. (e) Haldón, E.; Nicasio, M. C.;
Pérez, P. J. Org. Biomol. Chem. 2015, 13, 9528.
After successfully conducted the regioselective syntheses of
1,4-disubstituted 1,2,3-triazoles, we plan to extend our
methodology for the synthesis of rufinamide 9 as antiepileptic
drug, through this multi-component synthetic strategy. The
previous synthetic methodologies involved for the synthesis of
this drug molecule via multistep procedures, and its synthesis
requires the use of a high temperature (135 ºC) and long reaction
times typically more than 24 hour.25 The synthetic conditions are
tedious and involved the use of explosive azides.
CH3
H3C
N
N
+
+
N
O
O
O
N
N
F
F
N
Cu
N
5. (a) Bonandi, E.; Christodoulou, M. S.; Fumagalli, G.;
Perdicchia, D.; Rastelli, G.; Passarella, D. Drug Discov. Today
2017, 22, 1572. (b) Bunders, C.; Cavanagh, J.; Melander, C. Org.
Biomol. Chem. 2011, 9, 5476. (c) Minvielle, M. J.; Bunders, C.
A.; Melander, C. MedChemComm 2013, 4, 916. (d) Ballard, T.
E.; Richards, J. J.; Wolfe, A. L.; Melander, C. Chem. Eur. J.
2008, 14, 10745.
BF4
BF4
2.5 mol%
MeOH, reflux,3h
O
O
Br
NH2
4
F
NaN3
+
+
NH2
O
F
8e
6e
9
Rufinamide , 87%
Scheme 3. One-pot multicomponent synthesis of rufinamide
using ionic liquid supported Cu(II) catalyst.
6. (a) Kant, R.; Singh, V.; Nath, G.; Awasthi, S. K. Eur. J. Med.
Chem. 2016, 124, 218. (b) Yadav, P.; Lal, K.; Kumar, A.; Guru,
S. K.; Jaglan, S.; Bhushan, Sh. Eur. J. Med. Chem. 2017, 126,
944. (c) Darandale, S. N.; Mulla, N. A.; Pansare, D. N.;
Sangshetti, J. N.; Shinde, D. B. Eur. J. Med. Chem. 2013, 65,
527.
7. (a) Paeshuyse, J.; Dallmeier, K.; Neyts, J. Curr Opin Virol.
2011, 1, 590. (b) Yang, Y.; Rasmussen, B. A.; Shlaes, D. M.
Pharmacol. Ther. 1999, 83, 141. (c) Linares, D.; Bottzeck, O.;
Pereira, O.; Praud-Tabaries, A.; Blache, Y. Bioorg. Med. Chem.
Lett., 2011, 21, 6751.
We decided that rufinamide 9 could be synthesized through a
multi-component reaction by employing 2,6-difluorobenzyl
bromide 8e, NaN3, and propiolamide 6e as shown in scheme 3 in
the presence of ionic liquid supported Cu(II) 4 as the catalysts.
Interestingly, the product yield of designed rufinamide 9 was
obtained in 87% yield in 3h at refluxing methanol solution. The
synthesis demonstrated the huge advantage of using ionic liquid
supported Cu(II) catalyst for the synthesis of this drug molecule.
3. Conclusions
In summary, we have developed a versatile synthetic strategy
for 1,4-disubstuituted 1,2,3-triazole derivatives through an ionic
liquid supported Cu(II) catalyst precatalyst in methanol under
microwave irradiation. Further, the catalyst is thermally stable,
green, easy to prepare, and devoid of any drawback normally
associated with homogeneous catalysts. The key features of the
present protocol was the in-situ reduction of ionic liquid
supported Cu(II) catalyst to Cu(I) followed by the formation of
1,2,3-triazole moieties in one-pot multicomponent pathway. The
synthetic manipulation demonstrates the sufficient substrate
scope, high yields and environmentally benign conditions.
Further, the use of microwave irradiation in the present synthetic
sequence demonstrated the dramatic reduction of reaction times
in minutes with excellent yields and high selectivity. This
synthetic methodology can open up avenues for further
development of various diverse heterocycles catalyzed by ionic
liquid supported Cu(II) catalyst. Finally, the current synthetic
protocol useful for the one-pot synthesis of an antiepileptic drug
rufinamide in good yield.
8. (a) Meldal, M.; Tornøe, C. W. J. Org. Chem., 2002, 67, 3057.
(b) Rostovsev, V. V.; Fokin, V. V.; Green, L. G.; Sharpless, K.
B. Angew Chem. Int. Ed., 2002, 41, 2596. (c) Ackermann, L.;
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4. Acknowledgements
The authors thank the Chancellor and Vice Chancellor of VIT
University for providing opportunity to carry out this study.
Further the authors wish to thank the management of this
university for providing seed money as research grant. R
Nishanth Rao thanks for ICMR-SRF ship. Kaushik Chanda
thanks ICMR-Govt of India for funding through Grant no
45/03/2019-BIO/BMS.
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26. General procedure for the synthesis of 1-benzyl-4-phenyl-
1H-1,2,3-triazole (7a): In a round bottomed flask, a mixture of
benzyl bromide 8a (0.050 g, 0.29 mmol, 1.0 equiv) and NaN3
(0.021 g, 0.32 mmol, 1.1 equiv) in 5 mL of mthanol. After the
mixture was stirred for 10 min at room temperature, 2.5 mol% of
ionic liquid supported Cu(II) catalyst 4 was added followed by
phenyl acetylene 6a (0.033 g, 0.32 mmol, 1.1 equiv) was added
into the solution. The reaction mixture was irradiated under
microwave heating at 280 watt for 8 min at 65 ºC. The progress
of the reaction was monitored by TLC. After completion of the
reaction, the mixture was precipitated with cold ether, filtered
through a fritted funnel to remove the catalyst. The combined
filtrate was removed under reduced pressure followed by the
aqueous workup. The combined organic layer was dried over
anhydrous MgSO4. The combined filtrate was subjected to
evaporation followed by column chromatography to obtain the
pure compound 1-benzyl-4-phenyl-1H-1,2,3-triazole 7a as the
product.
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19, 199. (b) Padmaja, R. D.; Devi C. V.; Mukku, N.; Chanda, K.;
Maiti, B. ACS Omega, 2018, 3, 4583. (c) Rao, R. N.; Balamurali,
M. M.; Maiti, B.; Thakuria, R.; Chanda, K. ACS Comb. Sci.
2018, 20, 164-171. (c) Panchagam, R. L.; Manickam, V.;
Chanda, K. ChemMedChem, 2019, 14, 262. (d) Padmaja, R. D.;
Balamurali, M. M.; Chanda, K. J. Org. Chem. 2019, 84, 11382.
Supplementary Material
Experimental procedures, compound characterization data and
copies of NMR spectra for all products are included in
Supplementary data. Supplementary data associated with this
article can be found in the online version.
(e) Rao, R. N.; Chanda, K. Bioorg. Chem. 2020, 99, 103801.
Click here to remove instruction text...
MeOH
R2
Cu(OIL)2
Cu(I)
N
N
Br
R1
R1
+
+
NaN3 R2
MW, 65 oC, 10 min
N
CH3
N
H3C
N
+
+
N
O
O
O
N
Cu(OIL)2
Cu
BF4
BF4
O
2.5 mol%
Highlights
 One-pot multicomponent reaction
 In-situ reduction of Cu2+to Cu+ and
confirmed by XPS analysis
 Recyclability and microwave assisted
synthesis
 Application
for
the
synthesis
of
Antiepileptic drug rufinamide