K2S2O8-Mediated halogenation of 2-arylimidazo[1,2-a]pyridines using sodium halides as the halogen sources

Article abstract of DOI:10.1016/j.tetlet.2019.03.008

A convenient halogenation of 2-arylimidazo[1,2-a]pyridines using sodium chloride/bromide/iodide as the halogen sources in the presence of K₂S₂O₈ as an easy-to-handle oxidizing agent was developed. The present work offers a

Full text of DOI:10.1016/j.tetlet.2019.03.008

Accepted Manuscript
K2S2O8-Mediated halogenation of 2-arylimidazo[1,2-a]pyridines using sodium
halides as the halogen sources
Praewpan Katrun, Chutima Kuhakarn
PII:
S0040-4039(19)30209-6
https://doi.org/10.1016/j.tetlet.2019.03.008
TETL 50649
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
14 January 2019
26 February 2019
3 March 2019
Please cite this article as: Katrun, P., Kuhakarn, C., K2S2O8-Mediated halogenation of 2-arylimidazo[1,2-a]pyridines
using sodium halides as the halogen sources, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.03.008
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K2S2O8-Mediated halogenation of 2-
arylimidazo[1,2-a]pyridines using sodium
halides as the halogen sources
Praewpan Katrun a* Chutima Kuhakarnb
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1
Tetrahedron Letters
K2S2O8-Mediated halogenation of 2-arylimidazo[1,2-a]pyridines using sodium
halides as the halogen sources
Praewpan Katrun a and Chutima Kuhakarnb
aNatural Products Research Unit, Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Khon Kaen
University, Khon Kaen 40002, Thailand
bDepartment of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok
10400, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
convenient
halogenation
of
2-arylimidazo[1,2-a]pyridines
using
sodium
chloride/bromide/iodide as the halogen sources in the presence of K2S2O8 as an easy-to-handle
oxidizing agent was developed. The present work offers an efficient and rapid access to 3-
chloro-, 3-bromo- and 3-iodo-2-arylimidazo[1,2-a]pyridines which can be readily converted to
C3-substituted imidazo[1,2-a]pyridines by cross-coupling reactions.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Bromination
Potassium persulfate
Imidazo[1,2-a]pyridine
Nitrogen-heterocycle
———
 Corresponding author. Tel.: +66-43-202376 (to 136); fax: +66-43-202376; e-mail: praewka@kku.ac.th

2
Tetrahedron
Among various types of nitrogen-containing organic
molecules, imidazo[1,2-a]pyridine is an important structural
scaffold commonly found in biologically active natural products
and pharmaceutical molecules. Compounds bearing imidazo[1,2-
a]pyridine core were shown to exhibit a variety of biological
activities and pharmacological effects such as antibacterial,1
antiviral,2 antitumor3 and anti-inflammatory4 activities.
Imidazo[1,2-a]pyridine-containing molecules also act as GABA
and benzodiazepine receptor agonists, GnRH antagonist and
cardiotonic agents.5 Therefore, imidazo[1,2-a]pyridine scaffold
was found in many commercially available drugs such as
Zolpiden, Zolimidine, Saripidem, Alpidem, Necopidem,
Miroprofen, Olprione and GSK812397 as shown in Figure 1.6
Scheme 1. The halogenation of imidazo[1,2-a]pyridines scaffold.
and K2S2O8 (1.5 equiv.) in solvent (3 mL) and the reactions were
carried out at either at 80 C or at refluxing temperature for 1.5 h.
Pleasingly, the reaction performed in a mixture of EtOH:H2O
(2:1 v/v) gave the corresponding 3-bromo-2-phenylimidazo[1,2-
a]pyridine (2a) in 80% yield (Table 1, entry 1). Next, a few
choices of combination of organic solvents (THF, 1,4-dioxane
and 1,2-dichloroethane) with water in a ratio of 2:1 v/v were
screened (Table 1, entries 2−5). Compound 2a was obtained in
highest yield (85% yield) when the reaction was carried out in
MeCN:H2O (2:1 v/v). Unfortunately, the reaction poorly
proceeded when it was carried out in water solely leading to 2a in
40% yield (Table 1, entry 6). Attempts to increase the water to
MeCN ratio by employing 1:2 v/v MeCN:H2O as the solvent
gave unsatisfactory result; 2a was isolated in 32% yield with
recovery of compound 1 (44% yield) (Table 1, entry 7). Next, the
reaction temperature was briefly investigated. Although the
Figure 1. Selected examples of drugs bearing an imidazo[1,2-
a]pyridine scaffold.
Accordingly, there has been of great interest in the
development of synthetic methods for the construction and
functionalization of the imidazo[1,2-a]pyridine core.7
Halogenated arenes are important synthetic intermediates and
building blocks in organic transformation through cross-coupling
reactions. Thus, halogenated imidazo[1,2-a]pyridines have been
widely employed as versatile synthetic intermediates8 which
could be readily converted to highly complex compounds.9 In the
past decades, there have been a number of studies towards the
development of synthetic methodologies for the construction of a
core structure of imidazo[1,2-a]pyridines 1. On the other hand,
fewer works have addressed general methods to access C2- or
o
reaction carried out at 100 C did not provide a better yield, the
reaction performed at room temperature gave poorer results
(Table 1, entries 8 and 9). After the solvent was identified
(MeCN/H2O, 2:1 v/v), we then examined the effect of a
stoichiometry of NaBr and K2S2O8 (Table 1, entries 10−16).
While increasing the amount of NaBr employed (from 4 equiv. to
5 equiv.) did not significantly enhance the yield of 2a, lowering
the amount of NaBr (from 4 to 3 and 2 equiv.) significantly
decreased the yield of 2a (Table 1, entries 10−12). The
stoichiometry of K2S2O8 employed also displayed similar
scenario to those of the NaBr (Table 1, entries 13−15). It is worth
to emphasize that the desired product 2a was not observed when
the reaction was carried out in the absence of K2S2O8 (Table 1,
entry 16). Finally, after screening of other bromide sources, it
was found that n-Bu4NBr and Et4NBr gave 2a in poorer yields
while KBr gave comparable results to those obtained when NaBr
was employed as a halogen source (Table 1, entries 17−19).
Based on the results shown in Table 1, the optimum reaction
conditions were chosen as the following: imidazo[1,2-a]pyridine
1 (0.5 mmol), NaBr (4.0 equiv.) and K2S2O8 (1.5 equiv.) in
MeCN:H2O (2:1 v/v, 3 mL) at 80 C for 1.5 h (Table 1, entry 5).
C3-halogenated
bromoimidazo[1,2-a]pyridines 2 were readily prepared by
treatment of C2-substituted [1,2-a]pyridines with N-
imidazo[1,2-a]pyridines.10-17
2-Aryl-3-
1
bromosuccinimide (NBS) (Scheme 1a).16 A facile transition-
metal-free regioselective halogenation of imidazo[1,2-a]pyridines
1 using sodium chlorite/bromite as the halogen sources yielded
the corresponding C3-halogenated derivatives 2 (Scheme 1b).17
Although the previous works disclosed for the synthesis of C3-
halogenated imidazo[1,2-a]pyridines are useful, it is still
desirable, in the perspective view of the development of new
synthetic methodology, to develop alternative and general
procedure to access halogenated imidazo[1,2-a]pyridines under
simple and convenient reaction conditions. Herein, the present
work described our findings on halogenation of imidazo[1,2-
a]pyridines 1 employing readily available and inexpensive
sodium halides as halogen sources in the presence of easy-to-
handle K2S2O8 as an oxidizing agent under mild conditions and
short reaction time.
We began our study employing 2-phenylimidazo[1,2-
a]pyridine (1a) and sodium bromide (NaBr) as the model
substrates to screen for optimum reaction conditions. A variety of
reaction parameters including solvent, reaction temperature,
bromide source and reagent stoichiometry were screened and the
results are summarized in Table 1. First, the effect of solvents
was primarily evaluated. The reactions were screened employing
2-phenylimidazo[1,2-a]pyridine (1a, 0.5 mmol), NaBr (4 equiv.)

3
Table 1. Optimization reaction condition for the synthesis of 3-
bromo-2-phenylimidazo[1,2-a]pyridine (2a)a
corresponding products 2i−2q in high to excellent yield
(62−96% yields). Unfortunately, 2-methylimidazo[1,2-a]pyridine
(1r) was not a good substrate; only trace amount of 2r was
observed (TLC monitoring). To expand the utility of the present
methodology, we then explored the iodination and chlorination of
2-phenylimidazo[1,2-a]pyridine (1a). Gratifyingly, under similar
reaction conditions when NaI or NaCl were employed in placed
of NaBr, 3-iodo-2-phenylimidazo[1,2-a]pyridine (3a) and 3-
chloro-2-phenylimidazo[1,2-a]pyridine (4a) were obtained in
67% and 31% yields, respectively. To further enhance iodination
and chlorination efficiency, optimization of the reaction
conditions was revisited. After extensive screening, the optimal
conditions for iodination were to expose 1 with NaI (5 equiv),
K2S2O8 (2 equiv) in MeCN:H2O (2:1 v/v, 3 mL) at 60 C (Scheme
3), leading to the iodinated products 3 in moderate to good yields
(58−80% yields). Unfortunately, attempts toward the chlorination
by employing either excess amount of K2S2O8 or NaCl (saturated
NaCl 1 mL in place of H2O)18 were not satisfactory. Finally, it is
worth to note that scaling up experiments (5 mmol scale) for the
bromination reaction of 1a was also investigated under the
optimized conditions leading to the product 2a in similar
efficiency (84% yield) (Scheme 4).
Yield
(%)b
Temp.
K2S2O8
(eq)
Time
(h)
Entry
Br (eq)
Solvent
(oC)
1a
-
2a
80
78
1
2
3
NaBr (4)
NaBr (4)
1.5
1.5
EtOH:H2O (2:1)
THF:H2O (2:1)
80
80
1.5
1.5
-
1,4-dioxane:H2O
(2:1)
NaBr (4)
1.5
80
1.5
-
61
4
NaBr (4)
NaBr (4)
NaBr (4)
NaBr (4)
NaBr (4)
NaBr (4)
NaBr (5)
NaBr (3)
NaBr (2)
NaBr (4)
NaBr (4)
NaBr (4)
NaBr (4)
KBr (4)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.1
0.6
-
DCE:H2O (2:1)
MeCN:H2O (2:1)
H2O
80
80
80
80
100
rtc
1.5
1.5
3
-
55
85
40
32
74
31
88
77
60
80
75
49
-
5
-
6
-
7
MeCN:H2O (1:2)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
MeCN:H2O (2:1)
1.5
1.5
18
44
-
8
9
36
-
10
11
12
13
14
15
16
17
18
19
80
80
80
80
80
80
80
80
80
80
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
-
-
-
-
27
98
-
1.5
1.5
1.5
84
78
70
Bu4NBr (4)
Et4NBr (4)
-
-
aReaction conditions: 1a (0.5 mmol), Br- suorces and K2S2O8 in solvent (3
mL) at following temperature for 1.5 h.
bIsolated yield after column chromatography on SiO2.
c30-35 oC.
Having established the optimized conditions to access to 3-
bromo-2-phenylimidazo[1,2-a]pyridine (2a) employing
a
combination of NaBr and K2S2O8 in aqueous acetonitrile, we next
explored the scope and generality of the present reaction and the
results are summarized in Scheme 2. First, compounds 1 with
various substituents (R1) on the pyridine ring of 2-
phenylimidazo[1,2-a]pyridines were evaluated. Compound 1
containing electron-donating groups (5-Me, 6-Me, 7-Me and 8-
Me) gave the corresponding products 2b−2e in moderate to good
yields (44−86% yields). It is evident that the steric effect arising
from the location of the methyl group at C5 deteriorated the
yield; 2b was obtained in low yield (44% yield). The bromination
reaction of compound 1 bearing electron-withdrawing groups (6-
Cl, 6-Br and 6-CN) on the pyridine ring proceed smoothly and
delivered the corresponding products 2f−2h in moderate to good
yields (58−85% yields). Next, 2-arylimidazo[1,2-a]pyridines
bearing a series of electronically different groups (R2, including
4-Me, 4-tBu, 4-Ph, 4-OMe, 4-Cl, 4-Br, 4-CN, 4-NO2 and 3-NO2)
on the C2-phenyl ring were well tolerated and yielded the
Scheme 2. Halogenation of imidazo[1,2-a]pyridines 1. Reaction
conditions: 1 (0.5 mmol), NaBr (4 equiv.) and K2S2O8 (1.5 equiv.)
in MeCN:H2O (2:1 v/v, 3 mL), at 80 C for 1.5 h. In parentheses:
isolated yield after column chromatography (SiO2). aNaI was
employed in placed of NaBr. bNaCl was employed in placed of
NaBr.

4
Tetrahedron
Scheme 5. Synthetic applications of 3-haloimidazo[1,2-
a]pyridine
To help to better understand the reaction mechanism, some
control experiments were carried out. The reactions of 2-
phenylimidazo[1,2-a]pyridine (1a) with NaBr/K2S2O8 were
carried out under standard reaction conditions but in the presence
of
radical
inhibitors
including
2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and hydroquinone (Scheme 6). From
the experimental results, it was clearly showed that the reaction
was suppressed by both radical scavengers. Thus, there should be
radical species involved in the present transformation.
Scheme 3. Iodination of imidazo[1,2-a]pyridines 1. Reaction
conditions: 1 (0.5 mmol), NaI (5 equiv.) and K2S2O8 (2.0 equiv.) in
MeCN:H2O (2:1 v/v, 3 mL), at 60 C. In parentheses: isolated yield
after column chromatography (SiO2) and reaction time
Scheme 6. Control experiments
Scheme 4. Gram scale synthesis of 3-bromoimidazo[1,2-a]pyridine
(2a)
On the basis of the control experiments in Scheme 6 and the
previously reports concerning oxidative halogenation,17,18,20 we
proposed possible reaction mechanism for this transformation as
shown in Scheme 7. Initially, decomposition of K2S2O8 generates
sulfate radical anion which then oxidizes bromide ion to bromine
radical or molecular bromine. Then, bromine radical
regioselectively added to the C3 of imidazo[1,2-a]pyridine 1 to
produce benzylic radical intermediate A. Subsequently, the
oxidation of intermediate A by sulfate radical anion takes place
to provide benzylic cation intermediate B. Finally, intermediate B
undergoes deprotonation to give the observed product 2.
Synthetic applications of 2a and 3a were conducted
employing Pd-catalyzed cross-coupling reactions (Scheme 5).
Sonogashira coupling reactions of 2a and 3a with phenyl
acetylene readily proceeded and gave the product 5a in 57%
yield (from 2a) and 88% yield (from 3a). Suzuki-Miyaura
reaction of 2a also worked well providing the corresponding
product 6a in excellent yield (90% yield). The Heck reaction of
3-bromo-2-phenylimidazo[1,2-a]pyridine (2a) with methyl
acrylate afforded the product 7a (89% yield) which can be further
reduced to give compound 8a in 58% yield. Compound 8a is an
intermediate for the synthesis of selective melatonin receptor
ligands.19
Scheme 7. Possible reaction mechanism
In conclusion, we have described a facile and convenient
method to synthesize 3-chloro-, 3-bromo- or 3-iodo-2-
arylimidazo[1,2-a]pyridines
by
using
sodium
chloride/bromide/iodide as the halogen source in the presence of
K2S2O8 as an easy-to-handle oxidizing agent under convenient
reaction conditions and short reaction time. Additionally, the
reaction can be scaled up to 5 mmol scale and the prepared
halogenated products can be converted to more complex
imidazo[1,2-a]pyridine compounds through cross-coupling
reactions.

5
8. For the selected example, see: (a) Gudmundsson, K. S.; Drach, J. C.;
Acknowledgments
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We thank the Natural Products Research Unit, Department of
Chemistry and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Khon Kaen University and the Center for
Innovation in Chemistry (PERCH-CIC), Mahidol University for
financial support.
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21. General procedure for the synthesis of 3-haloimidazo[1,2-a]pyridines 2:
Potassium persulfate (K2S2O8) (202.7 mg, 0.75 mmol) was added to a
suspension of imidazo[1,2-a]pyridines 1 (0.5 mmol) and sodium bromide
(205.8 mg, 2.0 mmol) in acetonitrile/H2O (2:1 v/v, 3 mL), and the
reaction mixture was stirred at 80 C for 1.5 h. After completion of the
reaction, the reaction mixture was quenched by the addition of sat. aq
Na2S2O3 (5 mL). Further stirring was followed by extraction with EtOAc
(2 × 20 mL). The combined organic extracts were washed with H2O (20
mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated
(aspirator). The residue was purified by column chromatography using
EtOAc/hexanes as eluent to afford the corresponding product. 3-Bromo-
2-phenylimidazo[1,2-a]pyridine
(2a):
Prepared
from
2-
phenylimidazo[1,2-a]pyridine (1a) (97.1 mg, 0.5 mmol), K2S2O8 (202.7
mg, 0.75 mmol) and NaBr (205.8 mg, 2.0 mmol). Colorless solid; yield:
116.1 mg (85%); mp 62.0−64.0 °C (lit.10 63−64.5 °C); Rf = 0.50 (30%
EtOAc in hexanes). IR (neat): 2918, 1628, 1491, 1466, 1440, 1343, 980,
1
748, 690 cm-1. H NMR (400 MHz, CDCl3):  = 8.19 (d, J = 7.0 Hz, 1
H), 8.15 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 9.1 Hz, 1 H), 7.51 (t, J = 7.6
Hz, 2 H), 7.41 (t, J = 7.4 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 6.94 (t, J =
6.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 145.5 (C), 142.7 (C),
132.9 (C), 128.6 (2×CH), 128.4 (CH), 128.0 (2×CH), 125.2 (CH), 124.1
(CH), 117.7 (CH), 113.2 (CH), 91.8 (C). HRMS (ESI-TOF): m/z [M +
H]+ calcd for C13H10BrN2: 273.0027; found: 273.0020.

6
Tetrahedron
Supplementary Material
Highlight
Supplementary material that may be helpful in the review



Convenient procedure for halogenation of 2-arylimidazo[1,2-
a]pyridines.
Rapid preparation of 3-halo-2-arylimidazo[1,2-a]pyridines in
a short reaction time.
K2S2O8 as an easy-to-handle oxidizing agent.
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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