Photocatalytic regeneration of brominating agent in the visible light-mediated synthesis of imidazo[1,2-: A] pyridines

Article abstract of DOI:10.1039/c9cy00141g

A wide array of imidazo[1,2-a]pyridines are available from the coupling of 1,3-dicarbonyls with 2-aminopyridines under visible-light mediated photocatalysis. The inexpensive and commercially available fluorescein dye, erythrosine B, is employed as the pho

Full text of DOI:10.1039/c9cy00141g

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Catalysis Science & Technology
ARTICLE
Photocatalytic Regeneration of Brominating Agent in the Visible
Light-Mediated Synthesis of Imidazo[1,2-a]pyridines
Irwan Iskandar Roslan,a Kian-Hong Ng,a Stephan Jaenickea and Gaik-Khuan Chuah a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A wide array of imidazo[1,2-a]pyridines are available from the coupling of 1,3-dicarbonyls with 2-aminopyridines under
visible-light mediated photocatalysis. The inexpensive and commercially available fluorescein dye, erythrosine B, is
employed as the photoredox catalyst and KBr as halogenating agent for in situ bromination. This protocol features the use
of catalytic amounts of the halogenating agent which is regenerated by the photocatalyst under visible light irradiation.
Cyclic voltammetry studies provide supporting evidence of reductive quenching pathway. The avoidance of stoichiometric
excess of the halogen or peroxide oxidants for halide regeneration makes this protocol an environmentally-friendly
synthesis with low E-factor.
www.rsc.org/
aminopyridines,31-35 including
reactions.36-43
a
few multicomponent
Introduction
In-situ halogenation has also been used to couple 2-
aminopyridines with alkenes, alkynes and ketones.44-53 In
particular, the coupling of 2-aminopyridines with 1,3-
dicarbonyls is popular due to the ready availability of both
substrates. Early work required overstoichiometric amounts of
halogenating agents such as CBr4, CBrCl3, N-bromosuccinimide,
or PhI(OAc)2 (Scheme 1a).54-58 However, it is an environmental
as well as economical disadvantage to use the halogenating
agent in excess. To overcome this problem, Yu et al. developed
a protocol with catalytic amounts of tetra-n-butylammonium
iodide (TBAI) as the halogenating agent, and two equivalents
of tert-butylhydroperoxide (TBHP) as oxidant to regenerate the
iodide (Scheme 1b).59 This regeneration strategy using
peroxides has also been applied for in situ iodination in the
synthesis of other heterocycles.60, 61
Using excess amounts of highly reactive peroxide oxidants
is also not atom-economical and makes the reactions
unsuitable for large-scale synthesis. With these limitations in
mind, we devised a strategy to regenerate the halide using
photoredox catalysis instead. Herein, we report a visible light-
mediated synthesis of imidazo[1,2-a]pyridines with the
fluorescein dye, erythrosine B, as a photoredox catalyst and
KBr as the halogenating agent. Fluorescein dyes are frequently
used as biological stains in cellular biology. They are also
applied as dyes for inks, paints, cosmetics, papers and food.
Thus, they are abundant, commercially available and
inexpensive. Eosin Y (EY) in particular has been employed for a
wide spectrum of organic reactions.62-64 Erythrosine B and its
acidic derivative tetraiodofluorescein on the other hand are
Electrophilic activation by in-situ halogenation is an attractive
strategy to employ as a great variety of readily available
starting materials can be used, thereby saving costs and time
needed to prepare the required halogenated substrates. In
recent years, in-situ halogenation has attracted significant
attention in the synthesis of nitrogen-containing heterocyclic
ring systems. Electrophilic activation of carbon by in-situ
halogenation facilitates nucleophilic attack by nitrogen,
thereby allowing the rapid and selective formation of C-N
bonds. This synthetic strategy has allowed for the efficient
5
preparation of indoles,1-3 pyrazoles,4,
imidazoles,6-8
indolizines,9 pyrroles,10-12 quinolones,13-15 and other nitrogen
containing heterocycles.16-19
Imidazo[1,2-a]pyridines
are
nitrogen-containing
heterocycles that are ubiquitous in pharmaceuticals and
21
biologically active molecules.20,
Compounds with the
imidazo[1,2-a]pyridine motif have been used as organic
functional materials and as ligands in organometallic
chemistry.22-26 Thus, efficient synthetic methodologies for
imidazo[1,2-a]pyridines remain an interest to synthetic
chemists. Imidazo[1,2-a]pyridines are traditionally constructed
via a condensation reaction between 2-aminopyridines and α-
halo ketones.27-30 Over the years, alkynyl(phenyl) iodonium
salts, nitroolefins, α-diazoketones, arylglyoxal hydrates and 1-
bromo-2-phenylacetylenes were also paired with 2-
a. Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543. http://Fax: (+65)67791691; phone: (+65)65162839; e-mail:
chmcgk@nus.edu.sg.
less explored. They are currently employed in cyclization
66
reactions,65,
photoinitiated radical polymerization,67
† Footnotes relating to the title and/or authors should appear here.
photodehydrogenation,68 and as sensitizers for cis/trans
isomerization of alkenes.69, 70 The ability to regenerate the
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 | 1
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1) Previous work using stoichiometric amounts of halogenating agents.54 - 58
R1
Table 1. Optimization of parametersa
View Article Online
DOI: 10.1039/C9CY00141G
R2
O
O
R1
N
R2
R2
R2
R3
CBrCl3/CBr4/NBS/PIDA
R2
R1 = Br, R2 & R3 = H (Eosin Y)
R2
X = C, N or O
X
+
N
R1 = I, R2 & R3 = H (Tetraiodofluorescein)
R1 = I, R2 = Cl, R3= H (Rose Bengal Free Acid)
R1 = Br, R2 = H, R3= Na (Na2-eosin Y)
R1 = I, R2 = H, R3= Na (Erythrosin B)
R1 = I, R2 = Cl, R3= Na (Rose Bengal)
N
NH2
CO2R3
X
R3
R1
R3O
R1
O
2) Previous work using catalytic amounts of halogenating agent.59
TBAI (10 mol % )
O
O
R1
O
O
R1
R1
R1
N
BF3.OEt2 (20 mol %)
2 equiv. TBHP
R3
R2
R2
X
+
N
photocatalyst (5 mol %)
N
O
O
halogenating agent (20 mol %)
N
NH2
X = C or O
+
X
R3
OMe
N
MeCN, rt
air (O2), 24 h
O
N
NH2
OMe
3) Current work using catalytic amounts of halogenating agent.
O
1a
2a
3a
R1
Entry
Photocatalyst
Hal.
Agent
Yield 3a
(%)[b]
N
O
O
R1
erythrosine B (5 mol %)
KBr (10 mol %)
R2
R3
N
R2
X = C, N or O
X
+
1
2
3
4
5
6
Eosin Y
Rose Bengal Free Acid
Phloxine B
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KI
12
35
39
60
89
81
0
N
NH2
X
R3
O
Scheme 1. Previous and current work on imidazopyridines using in situ
halogenation strategies. Abbr. PIDA: (diacetoxyiodo)benzene; NBS: N-
bromosuccinimide; TBAI: tetra n-butyl ammonium iodide; TBHP: tert-butyl
hydroperoxide.
Na2-eosin Y
Erythrosine B
Rose Bengal
—
7
8c
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
Erythrosine B
0
reduced erythrosine B by molecular oxygen is an important feature
of our protocol as it results in a closed catalytic cycle. Aerobic
oxidative coupling reactions have received increasing attention
recently.71-76 In these reactions, molecular oxygen is employed as
an oxidizing agent77, 78 or as part of the desired product itself.79-81
9d
53
69
85
n.d.
10
67
73
91
0
73
89
93
0
10e
11f
12
13
14
15
16
17
18g
19h
20i
21h,j
22h,k
23h,l
24h,m
25h,n
KCl
TBAB
NaBr
CsBr
—
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
Results and Discussions
Optimization studies
We began our optimization studies by reacting 1 mmol of methyl
isobutyrylacetate 1a with 1.2 mol of 2-amino-3-methylpyridine 2a
for 24 h using 5 mol % of eosin Y and 20 mol % of KBr in acetonitrile
at room temperature. The system was open to air and a 15 W
compact fluorescent lamp (CFL) was used as the visible light source
(Table 1). 3a was obtained in a poor yield of 12 % (Table 1, entry 1).
Slightly higher yields were obtained with tetraiodofluorescein, rose
Bengal free acid and phloxin B (Table 1, entries 2-3). The disodium
salt of eosin Y and rose Bengal performed significantly better with
moderate to good yields, respectively, while erythrosine B gave the
best result with 89 % yield (Table 1, entries 4-6). Product 3a was not
formed in the absence of photocatalyst or when the reaction was
carried out in the dark, confirming the photocatalytic nature of the
reaction (Table 1, entries, 7 and 8). Next, the amount of erythrosine
B was varied from 1 to 10 mol % (Table 1, entries 9-11). While 10
mol % gave similar results to that of 5 mol % photocatalyst, there
were significant drops in yields when 1 and 2 mol % of erythrosine B
were used instead. Other alkali halide salts were also screened
during the optimization process. Reaction with KI was messy with
many unidentifiable side products whereas that with KCl proceeded
sluggishly (Table 1, entries 12-13). On the other hand, tetra n-butyl
ammonium bromide (TBAB) and NaBr gave moderate yields of 3a
(Table 1, entries 14-15). CsBr gave comparable yields to KBr (Table
1, entry 16). In the absence of KBr, product 3a was not formed,
suggesting that the reaction proceeded via in situ bromination of
0
0
83
91
aReaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), halogenating agent (20 mol %),
photocatalyst (5 mol %), solvent (10 mL), 24 h, rt in open air and under irradiation of 15
W compact fluorescence lamp (CFL). bIsolated yield. cReaction performed in the dark.
d,e,f1, 2 and 10 mol % photocatalyst. g,h,i5, 10 and 40 mol % of KBr used. jUnder argon. k1
equiv. of 2,2,6,6-tetramethylpiperidin-1-yl oxyl (TEMPO) added. l1 equiv. of
hydroquinone added. m1 equiv. of 2,3-dimethyl-2-butene added. nScale-up to 10 mmol
w.r.t 1a. Abbr. n.d: not determined. TBAB: n-tetrabutyl ammonium bromide.
the β-ketoester moiety (Table 1, entry 17). The amount of KBr was
varied from 5 to 40 mol % (Table 1, entries 18 to 20). Gratifyingly,
the amount of KBr could be reduced to 10 mol % without a
significant drop in yield of 3a (Table 1, entries 5 and 19). However,
when only 5 mol % of KBr were used, the yield decreased to 73 %.
Hence, 10 mol % KBr was optimum. This is a first example involving
the use of a catalytic amount of halogenating agent which is
regenerated by the photocatalyst. Hence, the protocol benefits
from reduced waste which translates to a smaller E-factor (mass of
waste to mass of product). A scaled-up synthesis also produced
2 | J. Name., 2012, 00, 1-3
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ARTICLE
excellent yields of 3a, 91 %, highlighting the potential of this Table 2. Scope of reaction.a
View Article Online
DOI: 10.1039/C9CY00141G
protocol for large scale synthesis (Table 1, entry 25).
R3
N
R3
R1
O
O
erythrosine B (5 mol %)
KBr (10 mol %)
R2
+
N
R1
X
Scope of Reaction
R2
MeCN, rt,
air (O2), 24 h
N
NH2
X = C, N or O
Using the optimized conditions, a wide array of β-ketoesters with
various alkyl or aryl substituents at the keto moiety were screened
for their suitability in this reaction. With a methyl substituent, the
reaction proceeded with a moderate yield of 72 % whereas ethyl, n-
propyl and tert-butyl substituted building blocks fared significantly
better (Table 2, 3b-3e). A cyclopropyl ring or the trifluoromethyl
group were also well tolerated (Table 2, 3f-3g). Phenyl groups were
less suitable as the reaction proceeded with low yield (Table 2, 3h).
Phenyl groups carrying the electron withdrawing NO2 group were
less tolerated compared to electron donating methoxy group (Table
2, 3i and 3j). Various acetoacetates were also screened for the
reaction, including ethyl, isopropyl, tert-butyl, isopentyl, 2-
methoxyethyl and allyl derivatives, proceeding with moderate to
good yields of 72 % to 82 % (Table 2, 3k-3p). Gratifyingly, with N,N-
diethylacetoacetamide and acetylacetone, the reaction proceeded
smoothly to form the corresponding products 3q and 3r.
O
3
1
2
N
N
N
N
N
N
O
O
O
O
O
O
89 % 3a
81 % 3c
72 % 3b
N
N
N
N
N
N
O
O
O
O
O
O
79% 3e
82 % 3f
85 % 3d
NO2
N
N
N
N
CF3
N
N
O
O
O
O
O
O
We also tested the reaction with a variety of 2-aminopyridine
derivatives. 2-Aminopyridines with 4-methyl and 5-methyl
substituents were well tolerated under the optimized conditions
whereas only traces of product were observed with the 6-methyl
derivative (Table 2, 3s-3u). Chloro- and bromo-substituted 2-
aminopyridines as well as 2-aminopyridines without any
substituents were also suitable substrates for the reaction (Table 2,
3v-3x). Only trace amounts of 3y was observed when 2-
aminopyridine with the electron withdrawing NO2 group was used,
with majority of the aminopyridine moiety not converted whereas a
moderate yield of 59 % of 3z was obtained in the case of an
electron donating methoxy group.
80 % 3g
39 % 3h
31 % 3i
O
N
N
N
N
N
N
O
O
O
O
O
O
65 % 3j
77 % 3l
72 % 3k
N
N
N
N
O
O
O
O
82 % 3n
75 % 3m
N
N
N
N
N
Mechanistic studies
N
N
O
To obtain some insight into the photocatalytic nature of the
reaction, an experiment was conducted under argon. No formation
of 3a was observed, implying that O2 is necessary (Table 1, entry
O
O
O
O
O
74 % 3o
79 % 3p
85 % 3q
21). When
1 equivalent of the radical scavengers 2,2,6,6-
N
N
N
tetramethylpiperidin-1-yl oxyl (TEMPO) and hydroquinone were
added to two separate reaction mixtures, production of 3a was
suppressed, suggesting that free radicals are involved (Table 1,
entries 22-23). However, the singlet O2 scavenger 2,3-dimethyl-2-
butane did not interfere with the reaction, and 3a was obtained in
83 % yield (Table 1, entry 24). This supports the hypothesis that the
reaction involves triplet O2 rather than singlet O2,82 and that the
photocatalytic step is the generation of Br˙ radicals.
N
N
N
O
O
O
O
82 % 3s
N
O
80 % 3t
89 % 3r
N
N
N
N
N
N
O
O
Cl
O
O
O
To better understand the role of the photoredox catalyst
trace 3u
69 % 3v
80 % 3w
erythrosine
B in the reaction, cyclic voltammetry (CV) was
N
N
N
N
N
N
conducted to obtain the reduction potentials in the ground and the
various excited states (Figure S1, supporting information). Four
different samples of 1 mM erythrosine B in acetonitrile were
subjected to visible light irradiation for 0 to 4 h. A standard three-
electrode system was used with a glassy carbon working electrode
and Ag/AgCl as the reference. Without irradiation, the CV of
erythrosine B shows a peak at -1.05 V which is due to the reduction
O
O
O
O
O2N
Br
O
O
O
72 % 3x
59 % 3z
trace 3y
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), erythrosine B (5 mol %), KBr (10
mol %), MeCN (10 mL), 24 h, rt in open air and under irradiation of 15 W compact
fluorescence lamp (CFL).
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84
-
of EB to EB•-.83, Upon visible light irradiation, another peak at C which loses a proton to HO2 , resulting in the desiVrieedw Aprtrioclde uOcntlin3e
DOI: 10.1039/C9CY00141G
-1.87 V was observed which became more pronounced with and regenerating the second bromide ion in the process together
63, 90
increasing irradiation time. This value corresponds to the energy of with H2O2.
the triplet state of erythrosine B which is formed by intersystem as no H2O2 could be detected by NMR90 or KI/starch paper.66, 82
crossing from the singlet. The energy involved in the deactivation of
H2O2 likely decomposed immediately to H2O and O2
the excited 3EB* to EB•- is calculated to be 0.82 eV (Figure S2,
supporting information). Similar values have been found for
erythrosine B85, 86 and its derivatives eosin Y and rose Bengal.86-89
With 1 mM KBr in acetonitrile, the electrochemical oxidation of Br-
to Br• occurs at 0.89 V vs Ag/AgCl.87, 88 This potential matches well
with the value of 0.82 V obtained for the reduction of EB to EB•-
anion radical. These results provide an insight into the role of the
phototocatalyst EB in the formation of Br• from Br-. This agrees with
the work of Najmar and Mac who reported the reductive quenching
of fluorescein dyes using KBr.89
Conclusions
In summary, we have developed
a green synthetic
methodology for the construction of imidazo[1,2-a]pyridines
by coupling of 2-aminopyridines and 1,3-dicarbonyls using
visible light-mediated photoredox catalysis. This protocol
requires only catalytic amounts of photocatalyst erythrosine B
and the halogenating agent KBr, reducing its E-factor and
making it extremely environmentally friendly. The bromide
anion is regenerated in the reaction, without the need for
overstoichiometric amounts of chemicals for regeneration
such as peroxide oxidants. Cyclic voltammetry studies was
conducted to give further evidence of the reductive quenching
mechanism in the reaction. The protocol also has a wide scope
of reaction and proceeds under ambient reaction conditions.
Proposed Mechanism
The proposed mechanism for the synthesis of imidazo[1,2-
a]pyridines using photoredox catalysis is shown in Figure 1. The
reductive quenching cycle starts with visible light irradiation to
promote the photoredox catalyst, erythrosine B (EB), to its excited
state (EB*). Single electron transfer (SET) from the bromide ion to
EB* generates a Br• radical and the radical anion EB•–. Aerobic
oxygen regenerates the photocatalyst in a dark reaction, hence
Experimental
General information
completing the reductive quenching cycle by generating
a
Thin layer chromatography (TLC) was performed using TLC silica gel
60 F254 glass plates and silica gel 60 (230 – 400 mesh) was used for
superoxide radical anion O2
.
•- 63, 90 Simultaneously, the condensation
1
column chromatography. H NMR and 13C NMR were measured in
reaction between 1,3-dicarbonyl 1 and 2-aminopyridine 2 affords
enamine A and its corresponding tautomer A’. This is followed by
the addition of Br• and proton abstraction by O2•-, forming the α-
bromo intermediate B and regenerating a Br- in the process.
CDCl3 using a Bruker Avance 500 (AV500) spectrometer with
tetramethylsilane as an internal standard. For 1H NMR spectra,
chemical shifts were reported in ppm (δ), multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet) and coupling
constant (Hz). The signals at approximately δ 1.23 (1H NMR) and δ
29.6 (13C NMR) correspond to trace amounts of long-chained alkane
impurity from technical grade hexane used in column
chromatography. Mass spectra measurements were recorded on
Bruker micrOTOFQII under electrospray ionization (ESI) mode. The
cyclic voltammograms were recorded using an Iviumstat
electrochemical interface and employing a three-electrode system
consisting of glassy carbon electrodes as working and counter
electrodes and Ag/AgCl as the reference electrode. The scan rate
was 10 mV/s and current range of 100 μA and E step of 10 mV was
employed.
•
-
Subsequently, electron transfer to HO2 forms the HO2 anion.
Intramolecular nucleophilic attack of B then gives the intermediate
Br
Br
SET
EB*
Reductive quenching
cycle
EB
O2
EB
O2
Materials
O
O
H
N
R2
The following chemicals were obtained from Alfa-Aesar,
Sigma-Aldrich, and TCI and used as received: organic dyes, KBr,
MeCN, 1,3-dicarbonyls and their derivatives, 2-aminopyridines
and their derivatives and silica gel 60 (230 – 400 mesh). A
commercially available Philips Tornado 15 W compact
fluorescent lamp (CFL) was used as the visible light source.
N
R1
R2
R1
R3
R2
X
H2O
N
X
N
1
X
R3
R3
+
R1
O
O
A'
A
Br , O2
N
NH2
2
R1
SET
-
HO2
HO2
R1
N
N
R2
R2
R2
N
R1
Typical procedure for the synthesis of imidazo[1,2-a]pyridines via
photoredox catalysis
N
N
H
Br-
X
N
X
X
R3
R3
Br
O
H2O2, Br-
-
O
R3
HO2
O
A test tube was charged with methyl isobutyrylacetate 1a (143
μL, 1.0 mmol), 2-amino-3-methylpyridine 2a (121 μL, 1.2
mmol), potassium bromide (11.9 mg, 0.1 mmol) and
erythrosine B (44 mg, 0.05 mmol) in 10 mL of MeCN. The test
3
C
B
Figure 1. Proposed mechanism.
4 | J. Name., 2012, 00, 1-3
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12.
13.
14.
15.
16.
17.
18.
19.
20.
Y. Wang, C.-M. Jiang, H.-L. Li, F.-S. He, X. Luo and W.-
tube was placed in the 8-port sample holder of the
photoreactor (Figure S3, supporting information). The reaction
mixture was stirred in open air under irradiation from the
fluorescent lamp at room temperature. After 24 h, the
reaction mixture was diluted with H2O (15 mL) and extracted
with EtOAc (3 × 15 mL). The combined organic layers were
dried with anhydrous Na2SO4. After filtration, the solvent was
removed by rotary evaporation and the residue was purified
by column chromatography (hexane/ ethyl acetate, 10:1 (v/v)
to afford 3a in 89 % yield.
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Methyl
2-isopropyl-8-methylimidazo[1,2-a]pyridine-3-
carboxylate (3a) 1H NMR (500 MHz, CDCl3) δ 9.17 (d, J = 7.0 Hz,
1H), 7.14 (d, J = 7.0 Hz, 1H), 6.85 (t, J = 7.0 Hz, 1H), 3.95 (s, 3H),
3.86-3.76 (m, 1H), 2.63 (s, 3H), 1.38 (d, J = 7.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 162.0, 161.7, 147.4, 127.0, 126.3, 125.8,
113.4, 111.4, 51.1, 28.1, 22.1, 17.0. HRMS (ESI) calcd for
C13H17N2O2 [M+H]+: 233.1285; found 233.1287.
21.
S. Muniyan, Y.-W. Chou, M. A. Ingersoll, A. Devine, M.
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Conflicts of interest
There are no conflicts of interests to declare.
22.
23.
Acknowledgements
Financial support from NUS Tier 1 Grants R-143-000-667-114
and R-143-000-A46-114 is gratefully acknowledged. I.I. Roslan
thanks Faculty of Science, NUS for the award of a RSB-funded
research fellowship.
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