Visible light-mediated photocatalytic bromination of 2-arylimidazo[1,2-a]pyridines using CBr4 as bromine source

Article abstract of DOI:10.1080/00397911.2019.1691738

The photocatalytic bromination of 2-arylimidazo[1,2-a]pyridines is described in this paper. This reaction uses the readily accessible and shelf-stable CBr₄ as a bromine source. This photocatalytic system is shown to serve as a convenient and pr

Full text of DOI:10.1080/00397911.2019.1691738

Synthetic Communications
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Visible light-mediated photocatalytic bromination
of 2-arylimidazo[1,2-a]pyridines using CBr4 as
bromine source
Ju Hui Lee, Hye Im Jung & Dae Young Kim
To cite this article: Ju Hui Lee, Hye Im Jung & Dae Young Kim (2019): Visible light-mediated
photocatalytic bromination of 2-arylimidazo[1,2-a]pyridines using CBr4 as bromine source, Synthetic
Communications, DOI: 10.1080/00397911.2019.1691738
To link to this article: https://doi.org/10.1080/00397911.2019.1691738
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https://doi.org/10.1080/00397911.2019.1691738
Visible light-mediated photocatalytic bromination of
2-arylimidazo[1,2-a]pyridines using CBr4 as bromine source
Ju Hui Lee, Hye Im Jung, and Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam, 31538, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 14 October 2019
The photocatalytic bromination of 2-arylimidazo[1,2-a]pyridines is
described in this paper. This reaction uses the readily accessible and
shelf-stable CBr4 as a bromine source. This photocatalytic system is
shown to serve as a convenient and practical synthetic protocol for
the preparation of 2-aryl-3-bromoimidazo[1,2-a]pyridines.
KEYWORDS
Bromination; photoredox
reaction; 2-arylimidazo[1,2-
a]pyridines; 3-
bromoimidazo[1,2-
a]pyridines
GRAPHICAL ABSTRACT
Introduction
The imidazo[1,2–a]pyridine scaffold is found as a privileged core in a wide variety of
biologically active compounds.[1] These derivatives exhibit a broad range of pharmaceut-
ical activities, such as antibacterial,[2] antifungal,[3] anti-inflammatory,[4] antitumor,[5]
and antiviral.[6] In recognition of these pharmaceutical properties of C-3 substituted
imidazo[1,2–a]pyridines, a number of C-3 functionalization methods have been devel-
oped over the last decade.[7] Among C-3 substituted imidazo[1,2-a]pyridine derivatives,
3-bromoimidazo[1,2-a]pyridines have attracted substantial attention for use as common
intermediates enabling the displacement of bromide at C-3 position.[8] The
3-Bromination of imidazo[1,2-a]pyridines with various halogen sources is a typical pro-
cedure used for the synthesis of 3-bromo-imidazo[1,2-a]pyridine derivatives.[9–12]
Various C-3 bromination methods have been developed to date, with most of them
including the bromination of 2-aryl imidazo[1,2-a]pyridines with CuBr2, N-bromosucci-
nimide,[9] and NaBrO2 (Scheme 1(1)).[10] In recent years, several groups have reported
on the bromination of 2-arylimidazo[1,2-a]pyridines with alkali and ammonium
bromides in the presence of various oxidizing agents (Scheme 1(2)).[11] Very recently,
Lei and coworkers reported on the electrochemical bromination of 2-
CONTACT Dae Young Kim
dyoung@sch.ac.kr
Department of Chemistry, Soonchunhyang University,
Soonchunhyang-Ro 22, Asan, Chungnam, 31538, Republic of Korea.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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J. LEE ET AL.
Scheme 1. Bromination of 2-arylimidazo[1,2-a]pyridines
arylimidazo[1,2-a]pyridines with carbon tetrabromide (Scheme 1(3)).[12] Despite the
above advancements, more efficient and mild approaches for the bromination of 2-aryli-
midazo[1,2-a]pyridines are still desired. Photocatalysis reactions have emerged as an
efficient protocol to introduce functional groups to organic molecules due to their
environmental friendliness and potential application in industry.[13] To our knowledge,
no studies have reported on the photocatalytic bromination of 2-arylimidazo[1,2-a]pyri-
dines. Thus, we envisioned the bromination of 2-arylimidazo[1,2-a]pyridines to 2-aryl-
3-bromo-imidazo[1,2-a]pyridines by visible light-mediated photoredox bromination
with carbon tetrabromide as the bromine source (Scheme 1(4)).
Results and discussion
In connection with our ongoing research program investigating the C-H bond function-
alization via redox reactions, of alkene derivatives,[14] we recently reported on the visible
light-mediated photoredox functionalization of alkenes and aromatics.[15] Herein, we
present the visible light-mediated photocatalytic bromination of 2-arylimi-
dazo[1,2-a]pyridines.
To determine the optimized reaction conditions for the photocatalytic bromination
of 2-arylimidazo[1,2-a]pyridines, we examined the reaction of 2-phenylimidazo[1,2-
a]pyridine (1a) with carbon tetrabromide (2) in DMSO in the presence of photoca-
talyst (2 mol%) with blue LEDs (5 W, kmax ¼ 455 nm). We conducted this reaction
with several different metal photocatalysts and organic dyes (Table 1, entries 1–9).

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3
Table 1. Reaction condition optimizationa.
Entry
Photocatalyst
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
[Ru(bpy)3](PF6)2
[Ru(bpy)3Cl2]ꢀ6H2O
[Ru(phen)3Cl2]ꢀH2O
fac-Ir(ppy)3
Ir(ppy)2(dtbbpy)PF6
Na2 EosinY
Eosin Y
Rose Bengal
Rhodamine B
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
MeCN
MeOH
THF
DCM
DCE
PhMe
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
18
16
16
16
7
66
75
69
73
84
trace
23
33
43
81
63
trace
49
20
6
3
12
64
16
20
18
18
18
18
17
18
17
17
17
18
18
18
18
7
9
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
22h
23i
24j
25k
66
56
84
71
trace
trace
79
12
15
15
15
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
aReaction conditions: 2-phenylimidazo[1,2-a]pyridine (1a, 0.1 mmol), carbon tetrabromide (2, 0.2 mmol), photocatalyst
c
(2 mol%) in solvent (1.0 mL), blue LEDs, room temperature under N2. bIsolated yields. Red LEDs instead of blue LEDs.
f
dWhite LEDs LEDs instead of blue LEDs. eGreen LEDs LEDs instead of blue LEDs. 1 mol% photocatalyst loading. g1.5
equiv. of carbon tetrabromide was used. h1.2 equiv. of carbon tetrabromide was used. iWithout photocatalyst.
k
jReaction performed in the dark. 3 equiv of TEMPO was added.
By screening photocatalysts, Ir(ppy)2(dtbbpy)PF6 was found to be the best photocata-
lyst for this bromination (84% yield, Table 1, entry 5). Various commonly used
solvents were examined: DMSO, DMF, acetonitrile, methanol, THF, dichloromethane,
1,2-dichloroethane, and toluene (entries 5 and 10–16). The results showed that the reac-
tion gave the highest yield in DMSO (entry 5). Furthermore, a lower yield was obtained
when the visible light sources were switched to red, white, and green LEDs (Table 1,
entries 17–19). Reducing the photocatalyst (Ir(ppy)2(dtbbpy)PF6) loading to 1 mol %
slightly decreased the yield of 3-bromo-2-phenylimidazo[1,2-a]pyridines (3a, Table 1,
entry 20). The optimal amount of carbon tetrabromide (2) was determined after the
parallel reactions, and 1.5 equiv of 2 was considered to be suitable for this reaction
(entries 5 and 21–22). Finally, the controlled experiments demonstrated the critical roles
of the photocatalyst and visible light in this bromination (Table 1, entries 23–24).
With the optimal reaction conditions determined, we investigated the substrate scope of
imidazopyridines (Table 2). We initially examined the bromination of 2-phenylimidazo[1,2-
a]pyridines 1 bearing various substituents on the pyridine ring with carbon tetrabromide (2)
under the optimized conditions. 2-Phenylimidazo[1,2-a]pyridines 1 with electron-donating

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J. LEE ET AL.
Table 2. Substrate scopea,b
.
aReaction conditions: imidazo[1,2-a]pyridine
Ir(ppy)2(dtbbpy)PF6 (2 mol%) in DMSO (1.0 mL) blue LEDs, room temperature under N2.
Isolated yield.
1 (0.1 mmol), carbon tetrabromide (2, 0.15 mmol),
b
groups such as 6-methyl, 7-methyl, and 8-methyl substituents on the pyridine ring provided
the corresponding 3-brominated products 3b, 3e, and 3f in moderate-to-high yields
(66–78%). The bromination of 2-phenylimidazo[1,2-a]pyridines 1 having electron-with-
drawing groups such as 6-fluoro, 6-bromo, and 8-bromo substituents on the pyridine ring
also respectively delivered the desired 3-brominated products 3c, 3d, and 3g in moderate-to-

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Scheme 2. Gram-scale synthesis of 3a.
Figure 1. Plausible reaction pathway.
high yields (64–76%). Moreover, 2-arylimidazo[1,2-a]pyridines bearing various substituents
such as p-methyl, p-methoxy, p-fluoro, p-bromo, and m-methyl groups of the C-2 aryl ring
underwent facile transformation to give the corresponding 3-brominated products 3h–3l in
moderate-to-high yields (65–83%). Notably, the naphthyl- and heteroaryl-substituted cyclo-
butanols 1m and 1n provided the brominated products with moderate yields (58–66%,
Table 2, for 3m and 3n). Unfortunately, the bromination of 2-alkyl substituted imidazo[1,2-
a]pyridine, 2-methylimidazo[1,2-a]pyridine, gave the corresponding 3-bromo-2-methylimi-
dazo[1,2-a]pyridine (3p) with low yield (8%).
To demonstrate the practicality and synthetic utility of the visible light-mediated
photocatalytic bromination of imidazopyridines investigated here, the gram-scale reac-
tion was conducted under the optimized reaction conditions. As shown in Scheme 2,
the reaction of 2-phenylimidazo[1,2-a]pyridine (1a) with carbon tetrabromide under the
optimized conditions (2) afforded the desired 3-bromo-2-phenylimidazo[1,2-a]pyridines
(3a) with 83% yield.
After gaining insight into the mechanism, some controlled experiments were con-
ducted. In these experiments, the absence of the photocatalyst (Ir(ppy)2(dtbbpy)PF6) or
dark condition suppressed the reaction. These reaction factors play an important role in
this bromination reaction (Table 1, entries 23–24). In the presence of 3 equiv of 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO), a high yield of desired product 3a was
obtained (Table 1, entry 25). Therefore, the possibility of a radical pathway was
neglected. Based on the preliminary experimental results obtained here as well as the
related literature, we propose the plausible reaction pathway shown in Figure 1.[12,16]

6
J. LEE ET AL.
Irradiation of the photocatalyst Ir(III) with visible light leads to the excited-state
ꢁ
ꢁ
Ir(III) . The initial reduction of carbon tetrabromide (2) by Ir(III) via a single-electron
transfer process should generate bromide ion (Brꢂ) and tribromomethyl radical. This
bromide ion is then oxidized by Ir(IV) to afford the molecular bromine. The reaction
of imidazopyridines with Br2 affords the corresponding 3-bromoimidazo[1,2-a]pyri-
dines 3.
Conclusion
In conclusion, we have described a practical synthetic method that can be used to
synthesize 3-bromoimidazo[1,2-a]pyridines by employing carbon tetrabromide under
photoredox conditions. This protocol is environmentally friendly because it uses
inexpensive and easily handled carbon tetrabromide as the molecular bromine source
and visible light as the source of energy. This reaction represents a convenient and
mild method for the preparation of 3-bromo-2-arylimidazo[1,2-a]pyridine derivatives.
Experimental
General procedure for the photocatalytic bromination of 2-arylimidazo
[1,2-a]pyridines
An oven-dried flask was equipped with a magnetic stir bar, 2-arylimidazo[1,2-a]pyri-
dines 1 (0.1 mmol), carbon tetrabromide (2, 49.7 mg, 0.15 mmol), Ir(ppy)2(dtbbpy)PF6
(1.8 mg, 0.002 mmol), and DMSO (1 mL) under N2 atmosphere. The reaction mixture
was then stirred for 7–21 h under irradiation using 5 W blue LEDs (kmax ¼ 455 nm).
Upon completion of the reaction, the mixture was concentrated in vacuum and purified
by chromatography on silica gel (ethyl acetate:n-hexane ¼ 1:5) to afford 3-bromo-2-ary-
limidazo[1,2-a]pyridines 3.
Yield: 84%; white solid; mp 63–65 ꢃC; 1H NMR (400 MHz, CDCl3): d 8.19 (d,
J ¼ 6.8 Hz, 1 H), 8.13 (d, J ¼ 7.2 Hz, 2 H), 7.66 (d, J ¼ 9.2 Hz, 1 H), 7.49 (t, J ¼ 7.6 Hz,
2 H), 7.40 (t, J ¼ 7.4 Hz, 1 H), 7.32–7.26 (m, 1 H), 6.95 (td, J ¼ 6.9 Hz, 1.1 Hz, 1 H); 13C
NMR (100 MHz, CDCl3): d 145.4, 142.6, 132.8, 128.5, 128.3, 127.9, 125.2, 124.0, 117.6,
113.1, 91.8; HRMS (ESI) calcd for C13H10BrN2 [M þ H]þ 273.0027; found 273.0031.
Funding
This research was supported by Soonchunhyang University Research Fund and Basic Science
Research Program through the National Research Foundation of Korea [NRF-
2019R1F1A1059821].
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