A transition metal-free cascade reaction using heterogeneous tin(IV)oxide catalyzed and iodine promoted synthesis of 3-aroylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2020.152250

The cascade synthesis of 3-aroylimidazo[1,2-a]pyridines using chalcones and 2-aminopyridine was achieved over the SnO₂/I₂ catalytic system in toluene at ambient air atmosphere. The catalyst shows high activity towards the broad subst

Full text of DOI:10.1016/j.tetlet.2020.152250

Journal Pre-proofs
A transition metal-free cascade reaction using heterogeneous tin(IV)oxide cat‐
alyzed and iodine promoted synthesis of 3-aroylimidazo[1,2-a]pyridines
Nirajkumar H. Jadhav, Sachin S. Sakate, Dnyaneshwar R. Shinde, Manohar
G. Chaskar, Ramdas A. Pawar
PII:
S0040-4039(20)30717-6
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152250
TETL 152250
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 May 2020
8 July 2020
11 July 2020
Please cite this article as: Jadhav, N.H., Sakate, S.S., Shinde, D.R., Chaskar, M.G., Pawar, R.A., A transition
metal-free cascade reaction using heterogeneous tin(IV)oxide catalyzed and iodine promoted synthesis of 3-
aroylimidazo[1,2-a]pyridines, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152250
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
©
2020 Elsevier Ltd. All rights reserved.

A Transition Metal-free Cascade Reaction Using Heterogeneous Tin(IV)oxide
Catalyzed and Iodine Promoted Synthesis of 3-Aroylimidazo[1,2-a]pyridines
a,d
b
c
Nirajkumar H. Jadhav, Sachin S. Sakate, Dnyaneshwar R. Shinde, Manohar G.
c
a,c
Chaskar, and Ramdas A. Pawar*
a) Department of Chemistry, PDEA’s Baburaoji Gholap College, Sangvi, Pune -
11027, India.
4
b) P. E. Society’s, Modern College of Arts, Science and Commerce, Shivajinagar,
Pune - 411005, India.
c) PDEA’s Prof. Ramkrishna More College, Akurdi, Pune - 411044, India.
d) Dr. D. Y. Patil School of Engineering, Lohegaon, Pune - 412105, India.
*Corresponding author:
E-mail: rapawar9@gmail.com (Dr. Ramdas A. Pawar)
Phone: 9970408113
1

Abstract:
The cascade synthesis of 3-aroylimidazo[1,2-a]pyridines using chalcones and
2
-aminopyridine was achieved over the SnO
2
2
/I catalytic system in toluene at ambient
air atmosphere. The catalyst shows high activity towards the broad substrate scope of
the various aromatic and heterocyclic chalcones with 2-aminopyridine, 4-methyl 2-
aminopyridine, and 5-methyl 2-aminopyridine in good yields during the synthesis of
3
-aroylimidazo[1,2-a]pyridines. The methodology was further extended for the one-pot
three-component synthesis of 3-aroylimidazo[1,2-a]pyridines using acetophenone,
benzaldehyde, and 2-aminopyridine derivatives. The present protocol describes the easy
purification methodology in the synthesis of 3-aroylimidazo[1,2-a]pyridines
Keywords: Acidity, 3-aroylimidazo[1,2-a]pyridines, Cascade reaction, Heterogeneous
catalyst, SnO
2 2
/I
2

Introduction
Imidazo[1,2-a]pyridines, nitrogen-fused azole heterocycles are one of the biologically
active candidates contributing to both natural products as well as synthetic organic
1
chemistry. These N-heterocyclic scaffolds are a key intermediate in the synthesis of
optoelectronics, organometallics, material science, and also in the medicinal chemistry.2
The imidazo[1,2-a]pyridine derivatives display a wide range of biological activities
such as antifungal, anthelmintic, antiviral, antiprotozoal, antiulcer, antiepileptic,
antibacterial, antituberculosis, anticancer, anti-inflammatory, anticonvulsant,
3
antipyretic, analgesic and anxioselective. In addition, they were studied as GABAA
and benzodiazepine receptor agonists, MCH1R antagonists, histamine H receptor
3
antagonists, cardiotonic agents, 5-lipoxygenase inhibitors, cyclin-dependent kinase
inhibitors, β-amyloid detecting ligands, HIF-1α prolyl hydroxylase inhibitors, and p38
4
MAP kinase inhibitors as reported in the literature. Similarly, the 2-aryl-3-
aroylimidazo[1,2-a]pyridine is one of the imidazo[1,2-a]pyridine derivatives also
possess numerous biological activities such as anticancer and calcium channel blocking
5
property. Moreover, a number of commercially available drugs such as alpidem,
zolpidem, saripidem, necopidem, olprinone, miroprofen, DS-1, zolimidine,
GSK812397, minodronic acid contains imidazo[1,2-a]pyridine motifs.
Considering the application of imidazo[1,2-a]pyridine, the continuous efforts have been
directed to develop a various synthetic methodology for the synthesis of imidazo[1,2-
6
a]pyridines. Currently, the number of reports are available for the imidazo[1,2-
a]pyridine synthesis such as condensations, multicomponent synthesis, oxidative
coupling reactions, oxidative cyclization’s, tandem reactions, amino-oxygenation
reactions, hydro-amination reactions, Vilsmmeier type cyclization’s and Groebke–
Blackburn–Bienayme (GBB) reactions using various starting materials.7
3

After the detailed literature survey of the biologically active and chemical
application of 2-aryl-3-aroylimidazo[1,2-a]pyridine, it is observed that the very few
synthetic methodologies have been reported using homogeneous and heterogeneously
catalyzed methods from 2-aminopyridine and chalcones. Further, it is also reported that
the 3-aroylimidazo[1,2-a]pyridine motifs achieved successfully using one-pot three-
component reaction of acetophenone, benzaldehyde and 2-aminopyridine via in-situ
chalcone formation.8
The homogeneously catalyzed methods have drawbacks such as the use of
stoichiometric reagents/catalysts, and critical work-up during the quenching of
9
10
11
reagents, expensive metal like ruthenium and ligand based catalysts, non-
reusability of the catalyst,9-12 which leads to environmental pollution.
Furthermore, the drawbacks associated with reported heterogeneous catalysts
during the synthesis of 2-aryl-3-aroylimidazo[1,2-a]pyridine are use of toxic
solvents like DCM/AcOH and catalyst leaching which cause loss of catalytic
activity, 13 low yields and limited substrate scope. To overcome from all these
limitations, there is a scope for the design of an efficient, recyclable, and environmental
friendly approach.
14
15
Since the last few decades, a researcher paid extensive attention to the development
of nanomaterial-based heterogeneous catalysts having a wide range of textural and
1
6
microscopic properties for their applications in organic synthetic chemistry. However,
a study revealed that SnO is one of the metal oxide NPs act as a heterogeneous catalyst
in several organic transformations to the synthesis of industrially valuable products such
as imidazoles, spirooxindoles, 2H-indazolo[2,1-β]phthalazine-triones,
polyhydroquinoline, and the styrene hydrogenation. Further, the molecular iodine (I
2
1
7
2
)
4

is cheap, low toxic, non-hazardous than the transition metal-based catalysts. Thus,
iodine is an ideal candidate as a catalyst in environment-friendly processes.18
Herein, a simple and efficient protocol of SnO
2
2
/I catalyzed 3-aroylimidazo[1,2-
a]pyridines synthesis using 2-aminopyridine and chalcones in the presence of solvent
toluene has been reported. The present protocol shows a broad substrate scope for the
aromatic and heterocyclic chalcones with various 2-aminopyridine derivatives in
moderate to good yields. Furthermore, an additional advantage is the environment-
friendly reaction work-up and easy separation as well as purification of the product.
Result and Discussion
Catalyst activity testing and optimization of the reaction conditions
The catalyst activity, catalyst concentrations, I amount, solvents screening, and
2
temperature effects were studied for the 2-aryl-3-aroylimidazo[1,2-a]pyridine synthesis
using a mixture of 2-aminopyridine (1a, 1 mmol), and 1,3-diphenyl-2-propen-1-one (2a,
1
mmol) as a model reaction and the results are presented in Table 1. No reaction was
observed when the reaction mixture was refluxed without catalyst in toluene for longer
reaction time under ambient conditions. (Table 1, Entry 1). But, when the reaction was
performed using I (0.5 equiv.), the poor yield (10%) of the desired product was
2
obtained (Table 1, Entry 2). Further, the various metal oxides as solid acid catalysts
were screened for the reaction along with the molecular iodine. The preliminary results
on the screening of various metal oxide catalysts showed that SnO was the most active
2
catalyst for the cyclization reaction and gave an 84% yield of the desired product 3a in
the short reaction of time (Table 1, Entry 3). The other solid catalysts, such as ZnO,
TiO
2
, ZrO2, and SiO
2
gave the lower yield (20-64%) of the product 3a over 18 h (Table
1
, Entries 4-7). The various solvents were optimized for the synthesis of 3-
aroylimidazo[1,2-a]pyridine such as chlorobenzene, 1,4-dioxane, THF, ethanol,
5

dichloromethane, and DMF but these were not as effective as toluene (Table 1, Entries
and 8-13). A series of reactions were also studied with varying concentrations of
SnO and I to determine the most optimal reaction conditions in the tandem cyclization,
and the highest yield was obtained with 10 mol% of SnO and 0.5 equivalents of I in
3
2
2
2
2
toluene (Table 1, Entries 3 and 14-18). Moreover, the reaction which was performed at
room temperature could not furnish the desired product even though in long reaction
time (Table 1, Entry 19). The best yield of the product 3a (84%) was obtained from the
reaction of 1a (1 mmol), 2a (1 mmol), SnO (10 mol %) and molecular iodine (0.5
2
mmol), in toluene (6 mL) refluxing for 12 h in ambient conditions.
Table 1 Catalyst screening and optimization of the reaction conditions.
Catalyst (mol
I
2
Temp
( C)
Time
(h)
Yield
(%)
Entry
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhCl
O
%
)
(Equiv.)
1
2
3
4
5
6
7
8
9
Nil
Nil
Nil
110
110
110
110
110
110
110
130
100
24
24
12
18
18
18
18
12
12
Nil
10
84
52
64
45
15
76
24
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
SnO
TiO
ZrO
2
(10)
2
(10)
(10)
2
ZnO (10)
SiO
2
(10)
(10)
(10)
SnO
SnO
2
2
1,4-dioxane
6

1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
SnO
SnO
SnO
SnO
SnO
2
2
2
2
2
(10)
(10)
(10)
(10)
(15)
0.5
0.5
THF
65
80
12
12
12
12
12
18
24
12
12
24
10
18
15
54
84
52
Nil
65
84
Nil
EtOH
0.5
DCM
40
0.5
DMF
150
110
110
110
110
110
RT
0.5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
SnO
2
(5)
0.5
SnO
SnO
SnO
SnO
2
(10)
(10)
(10)
(10)
Nil
0.25
0.75
0.5
2
2
2
Reaction conditions: 2-aminopyridine (1a, 1 mmol), and 1,3-diphenyl-2-propen-1-one
2a, 1 mmol), amount of SnO and I , solvent, time specified as given, isolated yields*.
(
2
2
Substrate scope
Using the optimized reaction conditions, this cyclization reaction was successfully
carried out using the SnO /I catalytic system with different substituted chalcones
2
2
exerting electronic effects with 2-aminopyridine derivatives to give the 2-aryl-3-
aroylimidazo[1,2-a]pyridines in moderate to good yields (51-84%) (Table 2). Initially,
2
-aminopyridine reacted smoothly with various substituted chalcones under optimized
reaction conditions. Chalcone derivatives bearing substituents like fluoro, nitro, methyl
and trifluoromethyl group present at the ortho, meta and para positions on both 2-aryl as
well as 3-aroyl rings are well tolerated and yields the desired products (55-84%) (Table
2
, Entries 3a-3i). Furthermore, the electronic effects, both electron-withdrawing and
electron-rich substituents groups on chalcones show similar reactivity patterns and
afforded good yields. Moreover, hetero-aryl chalcone like 2-thienyl reacted smoothly
7

Table 2 Substrate scope for the synthesis of 2-aryl-3-aroylimidazo[1,2-a]pyridines.
Reaction conditions: 2-aminopyridine derivatives (1a-d) (1 mmol), chalcones (2a-k) (1
O
mmol), SnO
2
(10 mol %), I
2
(0.5 equiv.), toluene (6 mL), 110 C, air, Isolated yields*.
8

with 2-aminopyridine to the desired products in a 59-64% yield (Table 2, Entries 3j
and 3k). Further, the different substituted 2-aminopyridines were investigated to
produce desired products with good yields. 2-amino-4-methylpyridine as well as 2-
amino-5-methylpyridine also reacted efficiently with chalcones bearing halogen,
electron-donating and electron-withdrawing group and hetero-aroyl chalcones (Table 2,
Entries 3l and 3u) to give corresponding products in 51-77% yields. Whereas the 2-
amino-3-nitro-5-chloro-pyridine on reaction with chalcone (2a) gives traces of the
corresponding product (3v) due to the strong deactivating -R and -I effect of -nitro as
well as -Cl group on the 2-aminopyridine. In the present work, synthesis of fluorine and
fluorine-containing substituents were focused due to the vast scope in the drug industry
1
9
because of the 20-30% drug contain organo-fluorine compounds. The above substrate
scope study reveals that the SnO /I catalytic system demonstrated better catalytic
2
2
activity in the synthesis of 2-aryl-3-aroylimidazo[1,2-a]pyridines using a wide range of
the chalcones and 2-aminopyridine.
One-pot synthesis of 3-aroylimidazo[1,2-a]pyridines
From the point of view of minimizing the number of steps and achieving the atom
economy, the synthesis of 3-aroylimidazo[1,2-a]pyridines was planned as a one-pot
three-component tandem-cyclization reaction using acetophenone (1 mmol),
benzaldehyde (1.2 mmol) and 2-aminopyridine (1 mmol) using the same SnO
/I
2 2
catalyst which yields 3-aroylimidazo[1,2-a]pyridines in 55–76% yields without using
any additives (Scheme 1).
9

Scheme 1 One-pot synthesis of 3-aroylimidazo[1,2-a]pyridines from ketone,
aldehyde and 2-aminopyridine
Plausible reaction mechanism
The plausible reaction mechanism for the synthesis of imidazo[1,2-a]pyridines using
chalcone and 2-aminopyridine through cyclization, represented in scheme 2, the
mechanism for the reaction is assumed to be the same as previously reported.8, 11
Initially, the chalcone gets activated by SnO
aminopyridine to activated chalcone takes place to form an enolate A, next the key
intermediate B (4a) is formed with the release of catalyst SnO . Then B reacts with I to
2
, and then Michael addition of 2-
2
2
produce intermediate C, followed by subsequently intra-molecular cyclization to form
intermediate D, which leads to product 2-aryl-3-aroylimidazo[1,2-a]pyridines 3a under
aerobic conditions.
10

Scheme 2 plausible mechanism 3-aroylimidazo[1,2-a]pyridines synthesis using
chalcone and 2-aminopyridine promoted by SnO /I catalytic system.
2
2
Catalyst recycles study
Figure 1 Recyclability study of SnO
The recycle study of the SnO NPs was studied for the reaction between chalcone and
-aminopyridine under the optimized reaction conditions up to ten cycles (Figure 1).
After completion of the reaction, the reaction mixture was centrifuged. Then, the upper
2
for tandem cyclization reaction.
2
2
11

solvent layer was separated and then the catalyst was washed with toluene for 2 to 3
times. The recycled catalyst was further used for the reaction along with the addition of
0
.5 equivalents Iodine. The experimental results revealed that the catalytic activity of
SnO NPs displayed only a marginal decrease in yield (84 to75%) after ten catalytic
cycles. The XRD pattern of the recycled SnO catalyst was studied after the ten
2
2
catalytic cycles (Figure 2), and was found to be indistinguishable from those of
the fresh catalyst. This observation recommends the high chemical stability of the
catalyst.
Figure 2 XRD spectra of fresh and recovered SnO catalyst.
2
Conclusion
Cascade synthesis of 3-aroylimidazo[1,2-a]pyridines was achieved successfully from
chalcones and 2-aminopyridine using the SnO /I catalytic system in toluene at ambient
conditions. SnO catalyzed in situ Michael addition of chalcone and 2-aminopyridine,
2
2
2
followed by the addition of I2, catalyzed intramolecular oxidative C-N bond formation.
The efficiency of this tandem cyclization protocol was established by a broad substrate
scope involving various 2-aminopyridine with aromatic and heterocyclic chalcones to
give good yields (51-84%) of 3-aroylimidazo[1,2-a]pyridines. Under similar reaction
12

conditions, One-pot three-component synthesis of 3-aroylimidazo[1,2-a]pyridines was
achieved successfully using acetophenone, benzaldehyde, and 2-aminopyridine
derivatives. Further, the SnO NPs recycled several times without losing their activities
2
and stability of the catalyst was studied by XRD of fresh and reused catalyst.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors thank the Research Center, Baburaoji Gholap College, Sangvi, Pune for
support. We are also thankful to the Central Instrumental Facility (CIF) Savitribai Phule
Pune, University, Pune for analytical support.
References
[
[
1] C. Enguehard-Gueiffier, A. Gueiffier, Mini-Rev. Med. Chem. 7(9) (2007) 888–899.
2] a) A. Douhal, Ber. Bunsenges. Physi. Chem. 102(3) (1998) 448–451; b) J. Wan, C.
J. Zheng, M. K. Fung, X. K. Liu, C. S. Lee, X. H. Zhang, J. Mater. Chem. 22(10)
(2012) 4502–4510; c) G. Song, Y. Zhang, X. Li, Organometallics 27(8) (2008)
1
936–1943.
[
[
3] K. Pericherla, P. Kaswan, K. Pandey, A. Kumar, Synthesis 47(07) (2015) 887–912.
4] G. K. Reen, A. Kumar, P. Sharma, Beilstein J. Org. Chem. 15(1) (2019) 1612–
1
704.
[
5] a) Y.-S. Tung, M. S. Coumar, Y.-S. Wu, H. Y. Shiao, J. Y. Chang, J. P. Liou, P.
Shukla, C.-W.Chang, C.-Y. Chang, C. C. Kuo, T. K. Yeh, C.-Y. Lin, J. S. Wu, S.
Y. Wu, C. C. Liao, H. P. Hsieh, J. Med. Chem. 54 (2011) 3076–3080; b) P. J.
Sanfilippo, M. Urbanski, J. B. Press, B. Dubinsky, J. B. Moore Jr., J. Med. Chem.
3
1 (1988) 2221–2227.
13

[
6] a) Z. Chen, B. Liu, P. Liang, Z. Yang, M. Ye, Tetrahedron Lett. 59(7) (2018) 667–
70; b) L. Hariss, K. B. Hadir, M. El-Masri, T. Roisnel, R. Grée, A.
6
Hachem, Beilstein J. Org. Chem. 13(1) (2017) 2115–2121; c) O. Gomez, H.
Salgado-Zamor, A. Reyes, M. E. Campos, Heterocycl. Commun. 16(2-3) (2010)
9
9–104.
7] A. K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun. 51(9) (2015) 1555–
575.
8] P. Kaswan, K. Pericherla, H. K. Saini, A. Kumar, RSC advances 5(5) (2015) 3670–
677.
9] M.-M. Xing, M. Xin, C. Shen, J.-R. Gao, J.-H. Jia, Y.-J. Li, Tetrahedron 72 (2016)
201–4204.
[
[
[
[
[
1
3
4
10] P. S. Ramya, S. Angapelly, C. S. Digwal, U. Yadav, B. N. Babu, A. Kamal, J.
Saudi Chem. Soc. 22(1) (2018) 90–100.
11] K. Monir, A. K. Bagdi, S. Mishra, A. Majee, A. Hajra, Adv. Synth. Catal. 356
(2014) 1105–1112.
[
[
12] P. Kaswan, K. Pericherla, A. Kumar, Tetrahedron 70(45) (2014) 8539–8544.
13] X. Meng, J. Zhang, B. Chen, Z. Jing, P. Zhao, Catal. Sci. Technol. 6 (2016) 890–
8
96.
[
[
[
14] O. T. Nguyen, P. T. Ha, H. V. Dang, Y. H. Vo, T. T. Nguyen, N. T. Le, N. T. Phan,
RSC adv. 9(10) (2019) 5501–5511.
15] F. Nemati, M. Kaveh, A. Elhampour, M. S. Mirhosseyni, Natl. Acad. Sci. Lett.
4
2(6) (2019) 479–484.
16] a) Q. Zhang, H.-Y. Wang, X. Jia, B. Liu, Y. Yang, Nanoscale 5 (2013) 7175−7183;
b) J. Védrine, Catalysts 7(11) (2017) 341.
14

[
17] a) N. S. Fallah, M. Mokhtary, J. Taibah Uni. Sci. 9(4) (2015) 531−537; b) L.
Moradi, Z. Ataei, Z. Zahraei, J. Iran. Chem. Soc. 16(6) (2019) 1273−1281; c) C. S.
Maheswari, C. Shanmugapriya, K. Revathy, A. Lalitha, J. Nanostruct. Chem. 7(3)
(2017) 283−291; d) S. M. Vahdat, F. Chekin, M. Hatami, M. Khavarpour, S.
Baghery, Z. Roshan-Kouhi, Chinese J. Catal. 34(4) (2013) 758−763; e) R. Adnan,
N. A. Razana, I. A. Rahman, M.A. Farrukh, J. Chinese Chem. Soc. 57(2) (2010)
2
22−229.
[
[
18] a) P. Finkbeiner, B. J. Nachtsheim, Synthesis 45(08) (2013) 979–999; b) D. Liu, A.
Lei, Chem. Asian J. 10(4) (2015) 806–823.
19] J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S.
Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 114(4) (2013) 2432–2506.
15

16

Highlights


The SnO
2
/I
2
system investigated in the synthesis of 3-aroylimidazo[1,2-
a]pyridines
The Py-FTIR of the SnO
2
shows both the Lewis and Brønsted types of acidic
sites


One-pot three-component synthesis of 3-aroylimidazo[1,2-a]pyridines
The SnO NPs recycled successfully and showed high chemical stability
2
17