Facile and direct halogenation of 1,2,3-triazoles promoted by a KX-oxone system under transition metal free conditions

Article abstract of DOI:10.1039/d0nj05170e

A convenient and efficient oxidative halogenation of 4-aryl 1,2,3-triazoles is realized at ambient temperature under transition metal free conditions. In this methodology, halogenation is achieved by using readily available potassium halides (KBr, KCl, and KI) with oxone as an oxidant under mild reaction conditions and halogenated products are obtained in good to excellent yields. In addition, the synthesized halogenated triazoles are applied for the synthesis of functionalized molecules.

Full text of DOI:10.1039/d0nj05170e

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Facile and direct halogenation of 1,2,3-triazoles
promoted by a KX–oxone system under transition
metal free conditions†
Cite this: New J. Chem., 2021,
45, 3969
Vishakha Rai,
Ganesh Shivayogappa Sorabad
and
Mahagundappa Rachappa Maddani
*
A convenient and efficient oxidative halogenation of 4-aryl 1,2,3-triazoles is realized at ambient
temperature under transition metal free conditions. In this methodology, halogenation is achieved by
using readily available potassium halides (KBr, KCl, and KI) with oxone as an oxidant under mild reaction
conditions and halogenated products are obtained in good to excellent yields. In addition, the
synthesized halogenated triazoles are applied for the synthesis of functionalized molecules.
Received 20th October 2020,
Accepted 27th January 2021
DOI: 10.1039/d0nj05170e
rsc.li/njc
Nevertheless, the metal mediated Huisgen cycloaddition
reaction has also contributed to the synthesis of halo triazoles
Introduction
Metal mediated reactions are usually not preferred because the (Scheme 1). For instance, the Fokin and Hein group12 reported
contamination of metals is a serious issue in pharmaceutical the CuI catalysed selective synthesis of 5-iodo-1,4,5-
and related industries. Owing to the increased emergence of trisubstituted-1,2,3-triazoles by using iodoalkynes and organic
atom economy and user-friendly strategies, a variety of metal azides. The Kuang13 group also observed the formation of
free synthetic methods have been developed for the construction bromo triazole when bromo alkyne was made to react with
of C–C and C–hetero bonds via cross coupling reactions. Among sodium azide in DMSO with Pd (PPh3)4 at 120 1C for 12 h
them, the C–H bond functionalization in heterocyclic systems is during the controlled experiments of their study. Similarly,
fundamentally challenging in modern organic synthesis and is Vidal14 and G. Zhang15 research groups independently demon-
of paramount importance owing to the presence of heterocyclic strated a multi component reaction for the synthesis of 5-halo-
scaffolds in a variety of medicinally and biologically active 1,2,3-triazoles from alkynes and azides in the presence of
molecules.1 Interestingly, 1,2,3-triazoles and their derivatives copper halides with different bases and additives. Despite these
are associated with unique chemical and structural properties. remarkable advances in metal mediated reactions, generally
These heterocycles have been extensively investigated and have applicable methods for the metal free synthesis of halo sub-
found applications in biological science,2 pharmaceuticals,3 stituted 1,2,3-triazoles are still desirable.
agrochemicals, materials science4 and so on.5 Among the various
derivatives, 5-halo-1,2,3-triazoles are considered as valuable
structural units6 for further chemical transformations7 and
biological activities.8 Owing to the ever-increasing importance
of 5-halo-1,2,3-triazole compounds, various approaches for
their synthesis have been developed in the recent years.9
Unfortunately, direct halogenation on the 1,2,3-triazole ring
achieved limited success using reactive halogenating agents.10
We found only one report from the L. L. Kong11 group
on the direct halogenation of 1,2,3-triazoles by reacting with
N-halosuccinimides for long reaction time (Scheme 1).
Department of Chemistry, Mangalore University, Mangalagangothri 574199,
Mangalore, Karnataka, India. E-mail: mahagundappa@gmail.com,
mahagundappa@mangaloreuniversity.ac.in
† Electronic supplementary information (ESI) available: Experimental section, 1
H
and 13C-NMR spectral data, and copies of NMR spectra. See DOI: 10.1039/
d0nj05170e
Scheme 1 Synthesis of halogenated 1,2,3-triazoles.
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Fascinatingly, the HX–oxidant system has drawn special (Table 1, entries 1 and 2). Similar reactions using PhI(OAc)2
attention in recent years as an inexpensive, non-metallic, and and K2S2O8 as oxidants furnished product 2a in good yields
readily available system for oxidative halogenation reactions. (Table 1, entries 3 and 4). To our delight, the use of oxone as an
Oxidative halogenation is well known for its high fidelity as a oxidant under similar reaction conditions was fruitful and
potential alternative tool for hazardous molecular halogens, furnished the desired product 2a in an excellent yield (96%
providing experimental simplicity and good selectivity for Table 1, entry 5). Thus, we then continued exploring the solvent
various organic transformations. Despite several oxidants16 medium using oxone as an oxidant. Accordingly, subsequent
being reported for the oxidation of halide ions, there is still a reactions using aq. DMSO and aq. MeOH as solvents led to the
need for developing much safer and greener approaches in the formation of product 2a in moderate yields (Table 1, entries 6
field of heterocyclic systems. Although, 5-halo triazoles are and 7). In a similar way, the relatively non-polar solvents such
synthesized via metal mediated azide alkyne cycloaddition as toluene, hexane, dichloroethane and tetrahydrofuran in
reactions, a more atom-economical and practically viable aqueous medium were not successful and produced the corres-
approach is, however, represented by oxidative halogenation ponding brominated product 2a in moderate yields (Table 1,
to triazoles under metal free conditions. In continuation of entries 8–11). Interestingly, water as solvent underwent bromi-
our strategies for developing C–H functionalizations17 on nation under reflux conditions and gave the corresponding
electron rich systems, herein, we disclosed a general, rapid, brominated product 2a in 78% yield (Table 1, entry 12). Based
and operationally simple oxidative halogenation to obtain on the above reactions, aq. acetonitrile as solvent medium at
differently substituted triazoles. The process is promoted by a ambient temperature appeared to be the best. We then con-
KX–oxone system under ambient conditions.
tinued to investigate other halide sources for the present
halogenation reaction. The halide sources such as LiBr, NaBr
and TBAB were not efficient and led to the formation of 2a in
moderate to low yields (Table 1, entries 13–15).
Results and discussion
Furthermore, when the halide source was changed from
metal salts to aq. hydrobromic acid, we found that the desired
product was obtained in low yield (Table 1, entry 16). Addition-
ally, we found the decrease in yield of 2a when the quantity of
KBr is increased (Table 1, entries 17 and 18). After screening of
several oxidizing agents and solvents, we found that the best
reaction conditions are substrate 1a with KBr (1.1 equiv.) and
oxone (1.1 equiv.) in acetonitrile:H2O for 2 h at room tempera-
ture. Having these optimized reaction conditions in hand, we
continued to explore the substrate scope and their results are
tabulated in Table 2. The cumene substituted triazole gave the
corresponding brominated product 2b in excellent yield. Tria-
zoles bearing halogens furnished the corresponding bromi-
nated products 2c, 2d, 2e and 2f under optimized conditions
in very good yields. Triazoles containing electron withdrawing
groups like –NO2 and –CN underwent smooth conversion to
afford the desired products 2g, 2h and 2i in good yields. The
naphthyl substituted triazole also afforded product 2j in 88%
yield. Thiophene substituted triazole also afforded the corres-
ponding brominated product 2k in very good yield (91%) under
the present reaction conditions. Interestingly, triazoles with
methyl and benzyl substituents on N also furnished the desired
brominated products 2l and 2m in 74% and 72% yield,
respectively.
Similarly, triazoles with ketone and ester functional groups
were also brominated successfully to afford the corresponding
products 2n and 2o in moderate yields. Unfortunately, the
hydroxy methyl substituted triazole under optimised conditions
did not produce the corresponding brominated product 2p and
the starting material was isolated unaffected.
Encouraged by the above results of bromination, we then
changed our attention towards investigating the substrate
scope for chlorination reactions using potassium chloride
(KCl) as a chlorinating agent under optimal reaction conditions.
The initial survey of experiments was directed towards finding
the optimized reaction conditions, which included a broad
array of oxidants and solvents as shown in Table 1.
In the beginning, the halogenation of 4-phenyl-1,2,3-triazole
1a was carried out using KBr with several oxidants in aq.
acetonitrile. The reactions of 1a and KBr with aq. H2O2 and
aq. TBHP at ambient temperature for 2 h gave the expected
product 5-bromo-4-phenyl-1H-1,2,3-triazole 2a in low yields
Table 1 Optimization of reaction conditionsa
Entry Solvent : H2O (1 : 1) Oxidant (1.1 eq.) MX (1.1 eq.) Yieldb (%)
1
2
3
4
5
6
7
8
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
DMSO : H2O
MeOH : H2O
Toluene : H2O
Hexane : H2O
DCE : H2O
H2O2
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
25
32
82
69
96
45
32
65
50
45
58
78
65
32
28
45
Aq. TBHP
PhI(OAc)2
K2S2O8
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
9
10
11
12
13
14
15
16
17
18
THF : H2O
H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
MeCN : H2O
LiBr
NaBr
TBAB
Aq. HBr
KBr (1.5 eq.) 86
KBr (2.0 eq.) 20
a
All reactions were carried out by using triazole 1a (1 equiv.), MX
(1.1 equiv.) with oxidant (1.1 equiv.) in solvent : H2O (2 mL) for 2 h at
b
room temperature. Isolated yields based on triazole 1a.
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Table 2 Substrate scope on bromination of 1,2,3-triazolesa
Table 3 Substrate scope on chlorination and iodination of aryl-1,2,3-
triazolea
a
All reactions were carried out by using triazole 1a (1 equiv. 0.44 mmol),
KX (1.1 equiv.) and oxone (1.1 equiv.) in aq. acetonitrile (1 : 1, 2 mL) at
room temperature for 2 h.
a
All reactions were carried out by using triazole 1a (1 equiv.), KBr
(1.1 equiv.) with oxone (1.1 equiv.) in aq. acetonitrile (1 : 1, 2 mL) for 2 h
at room temperature. NR = no reaction.
Chlorination of aryl triazoles was also successful and the corres-
ponding results are shown in Table 3.
The reactions of phenyl and cumene substituted triazoles Scheme 2 Gram scale experiment.
with potassium chloride under optimal reaction conditions
gave chlorinated products 3a and 3b in good yields. Halogen
substituted aryl triazole derivatives furnished the corres-
To demonstrate the synthetic applications of the synthe-
ponding products 3c, 3d, 3e, 3f and 3g in good yields. Similarly, sized products, a few transformations were carried out. When
triazoles bearing methyl and benzyl substituents on N also compound 2d was treated with phenacyl bromide using potas-
produced the desired products 3h and 3i in good yields under sium carbonate in DMF at room temperature, the corres-
optimized reaction conditions. In addition to the above, iodi- ponding product 4a was obtained in 88% yield. Similarly, 2a
nated triazoles 3j and 3k were also synthesized in good yields was made to couple with DMF under the oxidative C–H
under the optimised reaction conditions.
functionalization strategy using Cu(OAc)2 and K2S2O8 at
To check the performance of present halogenation on a 100 1C. This reaction produced the desired product 5a in 76%
large scale, we carried out the reactions in a 2.0 g scale as yield. Furthermore, 3a was also subjected to reaction with
shown in Scheme 2. Accordingly, both bromination and 2-bromo ethyl propionate in the presence of potassium carbo-
chlorination reactions proceeded well furnishing the desired nate in DMF at room temperature to furnish the desired
halogenated products in very good yields. Thus, these reactions product 6a in 92% yield (Scheme 3).
indicate the practical applications of the present method on a
large scale.
To understand the mechanism of the reaction, we performed
controlled experiments as shown in Scheme 4.
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proceed and the starting material was isolated unaffected. This
reaction indicates that an oxidizing agent is necessary for
the present halogenation reaction. Thus, based on the above
controlled experiments and literature precedence,18 we believe
that the combination of KX and oxone results in the formation
of an electrophilic X+ species which further takes part in
the reaction to furnish the desired halogenated substituted
triazoles as shown in Scheme 5.
Conclusions
A mild and convenient method for the oxidative halogenation
of aryl-1,2,3-triazoles under transition metal free conditions is
developed. The success of this method lies in the use of readily
available and inexpensive KX (potassium halides) as a halide
source and oxone as an oxidant. The present method furnished
a variety of halogenated aryl-1,2,3-triazole derivatives in a
short reaction time in very good yields. The present reaction
represents considerable advancement over previously reported
halogenation of aryl-1,2,3-triazoles and is a straightforward
approach for halogenation without the use of toxic molecular
halogens. We demonstrated successfully the practical feasibility
of the present strategy by scaling up the reaction quantity.
Furthermore, the synthesized products are transformed into
functionalised molecules in good yields.
Scheme 3 Transformations of halogenated triazoles.
Scheme 4 Controlled experiment.
The bromination reaction was carried out in the presence
a radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) in order to check the possibility of the radical
mechanism. However, this reaction displayed almost no effect
and the corresponding halogenated product was obtained in
very good yields. Thus, these experiments suggest that the
Conflicts of interest
of
There are no conflicts to declare.
Acknowledgements
present oxidative halogenation might not be proceeding The authors thank DST-INSPIRE (DST/INSPIRE Fellowship/
through the radical mechanism. In addition, as expected the 2017/IF70456), New Delhi, India, for financial support.
present halogenation in the absence of an oxidant did not
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