Cobalt-Catalyzed Direct Arylation of Imidazo[1,2-a]pyridine with Aryl Iodides

Article abstract of DOI:10.1002/ejoc.202000006

The Co(II)Cl₂·6H₂O catalyzed C–H activation/direct arylation of imidazo[1,2-a]pyridine with aryl/heteroaryl iodide is reported. The cost effective, ligand and additive free protocol using KOAc successfully afforded 3-arylimidazo[1,2-

Full text of DOI:10.1002/ejoc.202000006

A Journal of
Accepted Article
Title: Cobalt-catalyzed direct arylation of imidazo[1,2-a]pyridine with
aryl iodides
Authors: Dattatraya Babar and Haridas B. Rode
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000006
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000006
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10.1002/ejoc.202000006
European Journal of Organic Chemistry
FULL PAPER
Cobalt-catalyzed direct arylation of imidazo[1,2-a]pyridine with
aryl iodides
Dattatraya A. Babar,[a,b] Haridas B. Rode*[a,b]
zolimidine,[16] necopidem,[16] saripidem,[16] rifaximin[17] and
Abstract: The Co(II)Cl2.6H2O catalyzed C-H activation/direct
GSK812397.[18] Therefore, a variety of synthetic protocols have
arylation of imidazo[1,2-a]pyridine with aryl/heteroaryl iodide is
been designed for the functionalization of imidazo[1,2-
a]pyridines. Specifically, because of the electron rich nature of
C-3 position of imidazo[1,2-a]pyridine, many studies have been
reported on the development of C-3 functionalization through
formation of carbon-carbon bond, including regioselective
arylation,[19] alkenylation,[20] formylation,[21] trifluoromethylation,[22]
C-S bond formation[23] and C-X (C-halogen) bond formation
reactions.[24]
reported. The cost effective, ligand and additive free protocol using
KOAc successfully afforded 3-arylimidazo[1,2-a]pyridines in good
yields. Imidazo[1,2-a]pyridines with electron withdrawing and
electron donating substituents with various aryl iodides are well
tolerated. The reaction is performed in a Screw-top V-Vial® to
expedite the synthesis. The antibacterial 3-napthyl imidazo[1,2-
a]pyridine is smoothly prepared using this protocol.
The coupling of two different fragments through direct arylation
is an important strategy for the preparation of heteroarenes.
Such strategy, usually, avoids the prefunctinalization of starting
material and also have shown the atom economy.[25] The Pd, Rh
and Ru catalysts are often used for the direct arylation of arenes
and heteroarenes.[25] Importantly, the comparativelly inexpensive
metal catalyst such as Cu, Fe, Ni and Co-salts could be effective
for such transformation.
Introduction
Imidazo[1,2-a]pyridine is a “privileged scaffold” having broad
spectrum of biological activities. It is found in many bioactive
molecules, functional materials, agrochemicals and natural
products.[1] Specifically, substituted imidazo[1,2-a]pyridines
showed anti-inflammatory,[2] anticancer,[3] antiprotozoal,[4]
antibacterial,[5] antiulcer,[6] antiviral,[7] antifungal,[8] analgesic and
antipyretic,[9] and other biological activities.[10-12]
Figure 1. Drugs and bioactive compounds containing imidazo[1,2-a]pyridine
Recently, imidazo[1,2-a]pyridine derivative, Q203, has been
reported with antitubercular activity against multi-drug resistant
(MDR) and extensive drug resistant (XDR) tuberculosis
bacteria.[13] As shown in the figure 1, imidazo[1,2-a]pyridine
skeleton is present in various bioactive compounds and drugs i.e.
alpidem,[14] zolpidem,[14] olprinone,[15] minodronic acid,[15]
Figure 2. Synthetic routes to prepare 3-arylimidazo[1,2-a]pyridine by direct
arylation of imidazo[1,2-a]pyridine
Mr. Dattatraya A. Babar, Dr. Haridas B. Rode
In the past few years, much progreses has been made in the
[a]
[b]
Department of Organic Synthesis and Process Chemistry, CSIR-
Indian Institute of Chemical Technology, Tarnaka, Hyderabad-
500007, India
synthesis
of
C-3
aryl/heteroaryl
imidazo[1,2-a]pyridine
derivatives by direct C-H arylation employing transition metals
such as Pd, Rh, Ru and Cu-catalyst (Figure 2).[19] Of note, there
is no report on cobalt catalyzed direct arylation of the
imidazo[1,2-a]pyridine. Cobalt has been widely used in C-H
bond functionalization reactions[26] whereas its application in
E-mail: haridas.rode@iict.res.in
Academy of Scientific and Innovative Research (AcSIR), CSIR-
HRDC Campus, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh-
201001, India
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000006
European Journal of Organic Chemistry
FULL PAPER
direct arylation of heteroarenes is scarce.[26h] As part of our
ongoing interest in development of convergent synthetic
methods for the versatile 3-arylimidazo[1,2-a]pyridines,[19g, 27] we
anticipated the use of earth abundant metal catalyst for the
synthesis of arylated imidazo[1,2-a]pyridines. This could be
realized by replacing expensive and precious catalysts such as
Ru, Rh, Pd with cobalt salt. Herein, we report the CoCl2.6H2O
catalyzed C-3 arylation of imidazo[1,2-a]pyrididnes with
aryl/heteroaryl iodides.
CoCl2.6H2O
(10 mol%)
KOAc
13
14
15
16
17
18
DMF
DMF
DMF
DMF
DMF
DMF
150
150
150
150
150
150
38%
10%
90%
22%
86%
81%
(2 equiv.)
CoCl2.6H2O
(5 mol%)
KOAc
(2 equiv.)
CoCl2.6H2O
(30 mol%)
KOAc
(2 equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
(1 equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
Results and Discussion
(3 equiv.)
We started initial experiment by employing imidazo[1,2-
a]pyridine (1a) and iodobenzene (2a) with 20 mol% CoCl2.6H2O
and 2 equivalent of Cs2CO3 in DMF at 150 °C in a Screw-top V-
Vial®. The desired 3-arylated product 3a was observed in 10%
yield after 24 h (Entry 1). Inspired from this result, we next
screened different bases like K2CO3, LiOAc, NaHCO3 and KOAc
(Entry 2-5). The results obtained from above experiments
showed that KOAc is a suitable base for this transformation
(Entry 5).
CoCl2.6H2O (20
mol%)
KOAc
(5
equiv.)
Reaction conditions: 1a (0.05 g, 1 equiv.), 2a (1.5 equiv.), KOAc, Cobalt salt
in various solvents (2 mL) at 90-150 °C for 24 h in a 5 mL capacity Screw-top
V-Vial®. NR indicate no reaction. [a]Isolated yields are shown.
Next, reactions were carried out with different cobalt salts
including CoBr2 and Co(OAc)2.4H2O (Entry 6-7). Unfortunately,
these reactions did not show any increment in the yield of 3a.
This indicates CoCl2.6H2O was a suitable catalyst for this
transformation. Further, the reaction was studied in different
Table 1. Optimization of reaction condition
organic
and
non-organic
solvents,
such
as
N,N-
dimethylacetamide (DMA), 1,4-dioxane, 1,2-dichloroethane
(DCE), EtOH and H2O. The reaction could be conducted in DMA
but yield of 3a was lower than that of DMF condition (Entry 8).
The other solvents did not show any improvement in the yields
of 3a (Entry 9-12). Further, the variation in amount of catalyst
required for the reaction was studied using different amounts of
CoCl2.6H2O i.e. 10 mol% and 5 mol% which gave 3a in 38% and
10%, respectively (Entry 13, 14). By increasing the catalyst to 30
mol%, no improvement in the yield of 3a was observed (Entry
15). The equivalence of base also varied to observe its effect on
reaction product. The reduced amount of base to 1 equivalent
decreased yield of 3a to 22% (Entry 16). The increased amount
of base to 3 and 5 equivalents afforded 3a in 86% and 81%,
respectively (Entry 17-18). This indicated that 2 equivalent of
KOAc is optimal amount of base to carry out this reaction.
Hence, 20 mol% CoCl2.6H2O, 2 equivalent of KOAc and DMF as
a solvent at 150 oC in screw capped closed reaction vial was
identified as optimal reaction condition for this transformation
(Entry 5, table 1).
The optimized reaction condition was used to generate 3-
arylimidazo[1,2-a]pyridines by employing different aryl iodides
(2a-2r) with imidazo[1,2-a]pyridine (1a). The electron releasing
substituents such as -CH3, -OCH3 containing iodobenzenes
showed greater reactivity in this protocol affording moderate to
excellent yields of 3a-3h (Scheme 1). The electron withdrawing
substituents (-F, -Cl, -CN, -CF3, and -NO2) on iodobenzenes also
furnished desired products (3i-3o) in moderate to good yields. In
brief, the 4-flouroiodobenzene and 4-chloroiodobenzene reacted
with 1a to afford 3i and 3j in 77% and 72%, respectively. The
1,2,5-trichloro-3-iodobenzene also produced corresponding
derivative 3k in 66% yield. The 3-iodobenzonitrile coupled with
1a and produced 3l in 74% yield. The electron withdrawing
group such as -CF3 and -NO2 also afforded required products
(3m, 3n and 3o) with moderate to good yield. The -NH2 and -OH
substituted iodobenzenes didn’t afford 3p and 3q. Importantly,
the heterocyclic 2-iodothiophene successfully provided bi-
heterocyclic compound 3r with 56% yield. The scope of the
reaction was extended using diphenyliodonium triflate as
Catalyst
(mol%)
Base
Temp.
(oC)
Yield[a]
(%)
Entry
Solvent
(equiv.)
CoCl2.6H2O
(20 mol%)
Cs2CO3
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
Dioxane
DCE
EtOH
H2O
150
150
150
150
150
150
150
150
110
150
90
10%
40%
65%
44%
92%
52%
10%
79%
NR
(2 equiv.)
CoCl2.6H2O
(20 mol%)
K2CO3
2
(2 equiv.)
CoCl2.6H2O
(20 mol%)
LiOAc
3
(2 equiv.)
CoCl2.6H2O
(20 mol%)
NaHCO3
(2 equiv.)
4
CoCl2.6H2O
(20 mol%)
KOAc
5
(2 equiv.)
CoBr2
KOAc
6
(20 mol%)
(2 equiv.)
Co(OAc)2.4H2O
(20 mol%)
KOAc
7
(2 equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
8
(2 Equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
9
(2 equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
10
11
12
NR
(2 Equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
Traces
NR
(2 equiv.)
CoCl2.6H2O
(20 mol%)
KOAc
100
(2 equiv.)
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10.1002/ejoc.202000006
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Scope of imidazo[1,2-a]pyridines
electrophile in the arylation reaction. In this case, the reaction of
diphenyliodonium triflate and 1a afforded product 3a though in
low yield (Scheme 1). In general, this study indicates that the
reaction is well tolerated for both i.e. electron donating and
electron withdrawing aryl iodides.
Scheme 1. Scope of aryl iodides
R
I
CoCl2.6H2O, KOAc
DMF, 150 °C, 24 h
N
N
+
N
N
R
1a
2a-2r
3a-3r
H3C
CH3
H3C
CH3
H3C
N
N
N
N
N
N
N
N
N
N
3a (92%)
(46%)b
3c (74%)
OCH3
N
3b (87%)
3d (79%)
OCH3
3e (82%)
F
Cl
N
N
N
N
N
N
N
N
N
3f (82%)
3g (80%)
3h (78%)
3i (77%)
3j (72%)
CF3
NO2
Cl
F3C
Cl
Cl
CN
N
N
N
N
N
N
N
N
N
N
3k (66%)
3m (64%)
3n (68%)
3o (42%)
3l (74%)
Scheme 2. Reagents and condition: 1b-1f (0.05 g, 1 equiv.), 2 (1.5 equiv.),
KOAc (2 equiv.), 20 mol% CoCl2.6H2O, 2 mL DMF at 150 °C for 24 h in a 5 mL
Screw-top V-Vial®. Yields are based on the recovered starting material.
NH2
OH
S
N
N
N
N
The practical applicability of this protocol was studied using a
gram scale synthesis of 3a from 1a. In this case, compound 3a
was obtained in 81% yield (Scheme 3).
N
N
3r (56%)
3p (00%)
3q (00%)
Scheme 1. Reagents and condition: 1a (0.05 g, 1 equiv.), 2a-2r (1.5 equiv.),
KOAc (2 equiv.), 20 mol% CoCl2.6H2O, 2 mL DMF at 150 °C for 24 h in a 5 mL
I
[b]
CoCl2.6H2O (20 mol%)
KOAc (2 equiv.)
Screw-top V-Vial®. Isolated yields are shown.
used as aryl source.
Diphenyliodonium triflate
N
N
DMF (10 mL)
150 C, 36 h
N
N
Further, the reaction scope was studied by using various
substituted imidazo[1,2-a]pyridines (Scheme 2). The electron
donating group i.e. -CH3 at 6 or 7 or 8 position of imidazo[1,2-
a]pyridines with various aryl iodides furnished the arylated
products (4a-4h) in good yields. The 6-chloro imidazo[1,2-
a]pyridine furnished 4i and 4j in moderate to good yields. Next,
the reactions between 2-phenyl substituted imidazo[1,2-
a]pyridines and different iodobenzenes were studied. It afforded
corresponding 2,3-diphenylimidazo[1,2-a]pyridine derivatives 4k-
4q in good yields regardless of the substitution pattern. Of note,
the 3-napthyl imidazo[1,2-a]pyridine (4h) was successfully
prepared using this protocol. This compound was synthesized
and tested against Staphylococcus aureus with minimum
inhibitory concentration (MIC) of 25 µM in our earlier work.[27b]
Staphylococcus aureus is one of the member of ESKAPE
pathogens which are priority pathogens declared by WHO that
pose high risk to humans.[28]
1a (1 g)
2a
3a (1.33 g)
Scheme 3. Gram scale experiment
The detail understanding of mechanistic aspects of cobalt
catalysed direct arylation of arenes/heteroarenes is not clear.
Sames et al reported the direct arylation of azole with
iodobenzene and provided few thoughts on the arylation
process.[26h] The cobalt (II) catalysed cross-coupling reaction of
alkyl chloride with heteroaryl substituted arenes indicate the
involvement of single electron transfer (SET) type processes.[29a]
Similarly, in the alkylation of aromatic imines with alkyl halides
suggested the SET to alkyl halide from a cobalt species.[29b]
Based on this information, a plausible mechanism for the
arylation of imidazo[1,2-a]pyridine with aryl iodide is proposed
(Figure 3). Initially, the homolysis of aryl iodide in the presence
of a cobalt species generates aryl radical which then forms an
aryl-cobalt complex II. Next, the oxidative addition of
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10.1002/ejoc.202000006
European Journal of Organic Chemistry
FULL PAPER
imidazo[1,2-a]pyridine on aryl-cobalt complex produce species
III. Finally, the reductive elimination will afford the 3-
arylimidazo[1,2-a]pyridine along with generation of cobalt(II)
species.
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Figure 3. Plausible mechanism of the arylation of imidazo[1,2-a]pyridine with
aryl iodides
Conclusions
In summary, by taking advantage of the inexpensive, earth
abundant cobalt, we developed a ligand/additive free practical
protocol for the direct C-3 arylation of imidazo[1,2-a]pyridines
using aryl/heteroaryl iodides. This protocol features broad
substrate scope with moderate to excellent yields, thus
rendering it
a
highly versatile, atom economical and
straightforward alternative to the available methods for the
synthesis of 3-aryl imidazo[1,2-a]pyridines.
Acknowledgements
[12] a) C. E. McKenna, B. A. Kashemirov, K. M. Błazewska, I. M. Favier,
C. A. Stewart, J. Rojas, M. W. Lundy, F. H. Ebetino, R. A. Baron, J.
E. Dunford, M. L. Kirsten, M. C. Seabra, J. L. Bala, M. S. Marma,
M. J. Rogers, F. P. Coxon, J. Med. Chem. 2010, 53, 3454-3464; b)
A. Kaźmierczak, D. Kusy, S. P. Niinivehmas, J. Gmach, L.
Joachimiak, O. T. Pentikainen, E. G. Darmach, K. Blazewska, J.
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Aamir, A. V. Adhikari, Bioorg. Med. Chem. Lett. 2013, 23, 1502-
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H.B.R. thanks the Department of Science and Technology (DST), Government
of India for financial support through GAP0584 grant. D.A.B. thanks the
Council of Scientific and Industrial Research (CSIR), Government of India, for
senior research fellowship. We thank Director, CSIR-IICT (Ms. No.
IICT/Pubs./2019/428) for providing all the required facilities to carry out the
work.
Keywords:
Imidazo[1,2-a]pyridine, C-H activation, privileged scaffold,
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arylation, heterocyclic compounds, transition metals.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000006
European Journal of Organic Chemistry
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A practical protocol for the C-3 arylation of imidazo[1,2-a]pyridines with aryl/heteroaryl iodides using Co(II)Cl2.6H2O is reported. The
reaction can be performed in a Screw-top V-Vial® to expedite the synthesis.
This article is protected by copyright. All rights reserved.