TFA-catalysed tandem double cyclisation: A one-pot, metal-free routes for novel indolo-imidazo[1,2-a]pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151317

A transition-metal free, one-pot tandem synthetic routes for novel indole and imidazo[1,2-a]pyridine derivative hybrids have been established. An efficient three-component reaction was designed with incorporation of two sequential Groebke–Blackburn–Bienay

Full text of DOI:10.1016/j.tetlet.2019.151317

Journal Pre-proofs
TFA-catalysed tandem double cyclisation: A one-pot, metal-free routes for nov-
el indolo-imidazo[1,2-a]pyridine derivatives
Asha Ganesher, Gautam Panda
PII:
S0040-4039(19)31101-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151317
TETL 151317
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Tetrahedron Letters
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24 August 2019
18 October 2019
23 October 2019
Please cite this article as: Ganesher, A., Panda, G., TFA-catalysed tandem double cyclisation: A one-pot, metal-free
routes for novel indolo-imidazo[1,2-a]pyridine derivatives, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151317
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TFA-catalysed tandem double cyclisation: A one-pot, metal-free routes for novel indolo-
imidazo[1,2-a]pyridine derivatives
Asha Ganesher and Gautam Panda*
Lab No. CSS 106, Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Sitapur Road, Jankipuram Extension, Lucknow-226031, UP, India
E-mail: gautam.panda@gmail.com; gautam_panda@cdri.res.in
Phone: 915222772450, ext 4659; Fax: 915222771941
Abstract: A transition-metal free, one-pot tandem synthetic routes for novel indole and imidazo[1,2-
a]pyridine derivative hybrids have been established. An efficient three-component reaction was designed
with incorporation of two sequential Groebke–Blackburn–Bienayme (GBB) and cyclization reaction in
one-pot under mild acidic condition. The salient feature of this protocol is atom economy, good yield and
operational simplicity. A molecular prospective library of 32 compounds was synthesized by utilizing the
various substituted aryl aldehydes and 2-aminopyridine.
Keywords: tandem double cyclisation, one-pot, metal-free, indoloimidazo[1,2-a]pyridines
Introduction
Heterocyclic architectures are the promising scaffolds in various bioactive natural products
including marketed pharmaceuticals, agrochemicals, dyes, and many other application-oriented
materials.1 Over the past decade, there has been growing interest in the synthesis and studies of properties
of heteroaromatic compounds specially the construction of fused N-heterocyclic scaffolds due to their
presence in drugs and functional materials.2 Among them, imidazopyridine and related diversity has been
reported for a wide range of biological profiles including diabetes, cancers, microbial infection etc and
thus imidazo[1,2]pyridine is often considered a privileged scaffold that can be combined with other
fragments and lead to complex polyheterocyclic molecules which can serve as novel therapeutics in drug
discovery studies.3 During the past few years, hybrid drugs have generated much attention. The objective
of developing new potent small molecules is to furnish new therapeutic heterocyclic hybrid molecules
where two or more bioactive heterocyclic scaffolds are embedded in a single molecule to exert multiple
or combined biological activities.4,5,6 Kamal et al. have reported the synthesis of imidazopyridine-
oxindole and pyrazole-oxindole conjugates which exhibit excellent antiproliferative activity.7,8 The

Imidazo[1,2]pyridines and indoles are two “privileged” heterocyclic scaffolds commonly used in various
small-molecule drug discovery programs.9,10,11 Recent studies from many groups have shown the
presence of these scaffolds in the therapeutics of many of the most common diseases, including diabetes,
cancers, microbial infection etc. Fig.1 shows some examples of compounds containing either
imidazo[1,2]pyridine or indole as their basic core structure; these compounds have been reported to
exhibit a wide range of physical, chemical and biological properties.
Several synthetic approaches to access functionalized imidazo[1,2]pyridine derivatives have been
widely reported by using condensation, tandem reaction, multicomponent strategy, intramolecular C–H
amination, oxidative coupling.12 In contrast, the synthesis of indole has been reported by using metal-free
C−H amination,13 coupling/cyclization under aerobic conditions,14 from 2-aminobenzyl phosphonium
salts,15 synthesis from anilines and ketones,16 ruthenium catalyzed heterocyclizations17. But, there are no
literature precedents for the synthesis of their hybrid imidazo[1,2]pyridine-indole frameworks. In recent
years, multicomponent reactions (MCRs) followed by post synthetic transformations have emerged as the
most powerful approaches for diversity-oriented synthesis of polyheterocyclic scaffolds having novel
biological properties. Multicomponent reactions (MCRs) provide the tandem performance of multiple
reactions in one pot, high atom, structural and bond-forming economy, convergent synthesis, and the
probability of furnishing maximum chemical diversity elements in one chemical reaction.18 Recently,
people are exploring a Ugi-variant Groebke–Blackburn–Bienayme (GBB)19 tandem reactions to further
extend the structural diversity of Ugi products. The GBB reaction is a three component processes (3 CR)
which involve an aldehyde, an amine and an isocyanide and delivers libraries of bioactive compounds in a
highly effective fashion. These types of tandem reactions are highly efficient and atom-economical as
isolation of intermediates is not required. It is interesting to note that only simple isocyanides have been
successfully employed as starting materials for GBB reactions, whereas the reactivity of convertible
isocyanides remain largely unexplored. Encouraged by the skeletal diversity of N-rich heterocyclic
compounds, we report our efforts toward the synthesis of novel indolo-imidazo[1,2-a]pyridine analogues
in one pot via double cyclisation approach. To the best of our knowledge, this is first report to synthesize
novel indolo-imidazo[1,2-a]pyridine analogues by utilising GBB-3CR followed by cyclisation under
acidic medium.

Fig. 1 Imidazo[1,2]pyridine and indole containing some drugs and bio-active agents and designed indolo-
imidazopyridine hybrid prototype.
Results and Discussion
The synthesis was started from the commercially available substituted aromatic aldehydes,
substituted 2-amino pyridine and isocyanide. The beauty of our reaction is diverse use of convertible
isocyanide. A new and promising convertible isocyanide, 1-isocyano2-(2,2-dimethoxyethyl)-benzene (3)
has been introduced, by the Wessjohann and Kobayashi groups.20,21,22,23,24 It is stable, easily accessible,
versatile, and reacts specifically, as proven elegantly in the total synthesis of (-)-Dysibetaine.25 Earlier
people have used this type of convertible isocyanide in Ugi MCR.26 In our work, we first time introduced
this novel convertible isocyanide also called indole–isonitrile (3) in GBB MCR to synthesize the designed
3-(1H-indol-1-yl)-2-phenylimidazo [1,2-a]pyridine derivatives because this isocyanide is capable of being
further deprotected and eventually cyclized to deliver the intended scaffolds.
Scheme-1: (a) TFA (20 mol%), 1,4-dioxane, 110 °C, 2-3 h, 60-70% yield.

We have synthesised indolo-imidazopyridine derivatives containing halogens such as fluoro, chloro,
bromo, trifluoromethane etc at the para position based on their role in introducing metabolic stability in
molecules in medicinal chemistry. The synthesis was achieved by utilizing the Groebke, Blackburn,
Bienayme multicomponent technique which involved the reaction of 2-aminopyridines, substituted
benzaldehydes and isocyanides in the presence of acid. In a typical simple reaction condition, 2-
aminopyridine, substituted benzaldehyde and isocyanide in 1,4-dioxane in a vial was treated with 20
mol% TFA under argon flush and sealed with a teflon cap and was allowed to stir at 110 °C for 2 h. After
completion of the reaction, solvent was evaporated and standard workup was done. Purification by
column chomatography over silica gel delivered the final compounds in good to excellent yields. To
optimize the conditions, the reaction was initially done with 2-aminopyridine 1a, 4-fluorobenzaldehyde
2a and isocyanide 3 in 1,4-dioxane at 110 °C for 8 h in the absence of any catalyst. In this case, the
desired product was not observed and the reaction was stopped at the intermediate stage (Table 1, entry
1) which was isolated and later reacted with acid to furnish the desired product 5a. Encouraged by the
preliminary result, we thought of directly synthesizing the final product 5a in one pot without isolating
the intermediate 4a. So, various reaction conditions were investigated and the results are summarized in
Table 1.
Table 1. Optimization of reaction conditionsa

Entry
1
Acid
-
Solvent
Temp.
(°C)
110
Time (h) Yield % Yield %
(4a)b
70
(5a)b
-
1,4-dioxane
8
2
3
4
5
ZnCl2 (20 mol%)
Sc(OTf)3 (5 mol%)
AcOH (200 mol%)
1,4-dioxane
MeOH:DCM
MeOH
110
RT
60
4
60
50
60
60
10
8
15
5
24
24
12
4N HCl (dioxane 20 mol%)
1,4-dioxane
RT
6
4N HCl (dioxane 20 mol%)
1,4-dioxane
110
4
40
40
7
8
9
10
11
12
TFA (20 mol %)
TFA (20 mol %)
TFA (20 mol %)
TFA (40 mol %)
TFA (20 mol %)
TFA (40 mol %)
1,4-dioxane
1,4-dioxane
EtOH
RT
110
75
75
60
12
2
24
24
24
24
70
-
50
30
50
30
10
70
20
45
20
40
EtOH
MeOH
MeOH
60
aReaction conditions: 1a (0.6 mmol), 2a (0.6 mmol), 3a (0.6 mmol), catalyst, solvent (2 ml,
sealed tube) according to the described conditions. The vial was flushed with argon and sealed
with a teflon cap and was allowed to stir for required time. bIsolated Yields.
The results revealed that the nature of acid had a significant effect on the outcome of the
reaction. In the absence of acid, only intermediate 4a was obtained (Table 1, entry 1). The
employment of Lewis acids was less effective and only trace amount of the target product was
formed (Table 1, entries 2−3). Among various Brønsted acids, TFA gave the best result with
70% yield (Table 1, entries 4−12). After screening different amount of TFA with various
solvents, we found that 20 mol% of TFA in 1,4-dioxane was the most suitable (Table 1, entries
7-12). Varying the reaction temperature from room temperature to 110 °C indicated that 110 °C
was optimal for this reaction (Table 1, entries 7, 8). We further investigated the influence of
solvents, namely, MeOH, EtOH, but the yield of the desired product was not improved (Table 1,
entries 9-12). Finally, the optimal conditions were determined as 1a (1 equiv), 2a (1 equiv), 3 (1

equiv) and TFA (20 mol%) in 1,4-dioxane at 110 °C for 2 h (Table 1, entry 8). With the
optimized reaction conditions in hand, the scope to generate various functionalized 3-(1H-indol-
1-yl)-2-phenylimidazo [1,2-a]pyridine derivatives was explored. As shown in Table 2, various
starting materials were successfully transformed into corresponding products via double
cyclisation in one step in 60-70% yields with only one purification, indicating wide functional
group tolerability with either electron donating or electron withdrawing substituents. The present
protocol is broadly applicable and accommodates a variety of substitution patterns. A small
library of 32 derivatives was prepared using the optimized synthetic protocol.
Table 2. Substrate scope

Based on our experimental results and literature reports, we proposed a possible
mechanism for the formation of 3-(1H-indol-1-yl)-2-phenylimidazo [1,2-a]pyridine as shown in
Figure 2. Firstly, the imine intermediate was generated by the reaction of amino-pyridine (1)
with benzaldehyde (2), which after formal [4+1] cycloaddition reaction with isocyanide (3)
forms cyclic intermediate C which subsequently forms an oxonium ion because of the acidic
conditions employed. The intermediate C was then undergoes [1,3-H] shift to afford the
intermediate D which has one nucleophilic center and can attack to the positive carbon and
provides the cyclized intermediate E. The intermediate E afforded the desired product 5 in good
yield with removal of methanol.

Figure 2: Plausible reaction mechanism or the synthesis of 3-(1H-indol-1-yl)-2-phenylimidazo
[1,2-a]pyridine.
Conclusion
In this work, we introduced the convertible isocyanide (3) in GBB thee component
reactions which furnished a library of biologically valuable poly-heterocyclic compounds using
one-pot, tandem GBBR/post cyclisation protocol. To our knowledge, this is the first report for
the construction of indolo-imidazopyridine hybrids. This methodology is highly efficient and
straight forward towards the preparation of diverse indolo-imidazopyridine analogues. The
salient feature of our protocol is high atom-economy, operational simplicity, easy work-up, and
easily available precursors. These indolo-imidazopyridine hybrids are expected to possess
enhanced biological activity as two pharmacophores are embedded in a single molecule.
Synthesis of chemical library based on this pharmacophore as possible Mycobacterial
Tuberculosis ATP synthase inhibitor is currently underway.
Acknowledgements
Asha Ganesher gratefully acknowledges financial support by the CSIR, New Delhi for
Senior Research Fellowship. We also sincerely thank Mrs. Surabhi Jain for some initial
preliminary experiment of this manuscript and SAIF division, CDRI for providing analytical

data. Funding from Ministry of Earth Sciences (MoES), New Delhi in the form of a project
(MoES/09-DS/3/2015/PC-IV dated 27/01/2016) is highly acknowledged. This has CDRI
communication no
Supporting Information
1
13
Experimental procedures, compound characterization data, and H and C NMR spectra
of the synthesized compounds.
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 Highlights
Transition-metal free
 One-pot tandem synthetic routes
 Atom economy, good yield and operational simplicity.