Metal-free, base catalyzed oxidative amination and denitration reaction: Regioselective synthesis of 3-arylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2018.08.024

A metal-free, regioselective strategy for the synthesis of 3-arylimidazo[1,2-a]pyridines from β-nitrostyrenes and 2-aminopyridines using triethylamine as the catalyst and H₂O₂ (30% aq.) as the oxidant is reported. The use of an inexp

Full text of DOI:10.1016/j.tetlet.2018.08.024

Accepted Manuscript
Metal-free, base catalyzed oxidative amination and denitration reaction: regio-
selective synthesis of 3-arylimidazo[1,2-a]pyridines
Elango Sankari Devi, Anitha Alanthadka, Subbiah Nagarajan, Vellaisamy
Sridharan, Chockalingam Uma Maheswari
PII:
S0040-4039(18)31006-2
https://doi.org/10.1016/j.tetlet.2018.08.024
TETL 50199
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
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3 August 2018
13 August 2018
Please cite this article as: Devi, E.S., Alanthadka, A., Nagarajan, S., Sridharan, V., Maheswari, C.U., Metal-free,
base catalyzed oxidative amination and denitration reaction: regioselective synthesis of 3-arylimidazo[1,2-
a]pyridines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.024
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Metal-free, base catalyzed oxidative
amination and denitration reaction:
regioselective synthesis of 3-arylimidazo[1,2-
a]pyridines
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Elango Sankari Devi,a Anitha Alanthadka,a Subbiah Nagarajan,a,b Vellaisamy Sridharana,c and Chockalingam
Uma Maheswari*a

1
Tetrahedron Letters
Metal-free, base catalyzed oxidative amination and denitration reaction:
regioselective synthesis of 3-arylimidazo[1,2-a]pyridines
Elango Sankari Devi,a Anitha Alanthadka,a Subbiah Nagarajan,a,b Vellaisamy Sridharana,c and
Chockalingam Uma Maheswari*a
a
Organic Synthesis Group, Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, India. Fax:
(+91)-4362-264111. e-mail: umamaheswaric@scbt.sastra.edu, uma.cchem@gmail.com
b Department of Chemistry, National Institute of Technology, Warangal, Warangal-506 004,Telangana State, India
c
Department of Chemistry and Chemical Sciences, Central University of Jammu, Temporary Academic Block, Sainik Colony Sector E Extension, Jammu-
180011, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free, regioselective strategy for the synthesis of 3-arylimidazo[1,2-a]pyridines from β-
nitrostyrenes and 2-aminopyridines using triethylamine as the catalyst and H2O2 (30% aq.) as
the oxidant is reported. The use of an inexpensive base and facile reaction conditions make this
strategy a practical alternative for the synthesis of 3-arylimidazo[1,2-a]pyridines.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridines
β-nitrostyrenes
2-aminopyridines
Oxidation
Base catalysis
Nitrogen-bridgehead fused heterocycles containing an
imidazole ring are common structural moiety in
Most of these strategies focus on the synthesis of 2-aryl
substituted imidazo[1,2-a]pyridines and approaches for the
preparation of its regioisomer, i.e. 3-aryl substituted imidazo[1,2-
a]pyridines, are rather limited.
Various transition metal-catalyzed strategies for the
preparation of 3-arylimidazo[1,2-a]pyridines have been
reported.8 Conversely, there are few reports on the metal-free
synthesis of 3-arylimidazo[1,2-a]pyridines.9 However, these
strategies involve either pre-functionalization of the starting
materials, employ high temperatures, or require stoichiometric
reagents and fluorous solvents as a reaction medium.
a
pharmacologically significant molecules and possess several
biological activities on a wide range of targets. Among them,
imidazo[1,2-a]pyridine is one of the most common and possesses
remarkable biological properties.1 The imidazo[1,2-a]pyridine
moiety is found in several natural products and commercially
marketed drugs such as zolpidem,2a olprinone,2b zolimidine2c and
saripidem.2d Due to their biological importance, numerous
synthetic approaches have been developed to gain access to
substituted imidazo[1,2-a]pyridines.3
The oxidative amination between 2-aminopyridines and β-
nitrostyrenes has proven to be an elegant strategy for the
synthesis of imidazo[1,2-a]pyridines (Scheme 1). 2-
Aminopyridine undergoes initial nucleophilic addition in two
ways which controls the regioselectivity of the product: through
the exocyclic amino group leading to 2-arylimidazo[1,2-
a]pyridines (Scheme 1a),10 and 3-nitro-2-arylimidazo[1,2-
a]pyridines (Scheme 1b)11 or rarely through the endocyclic
pyridinium nitrogen to give 2-nitro-3-arylimidazo[1,2-
a]pyridines (Scheme 1c, 1d).12
However, to the best of our knowledge, the synthesis of 2-
unsubstituted-3-arylimidazo[1,2-a]pyridines
from
2-
aminopyridines with β-nitrostyrene under metal-free condition
has not been reported. Recently, we reported the metal-free
oxidative amidation of aldehydes with aminopyridines employing
H2O2 (30% aq.) as the oxidant.13 In this context, herein we
present a facile metal-free, base-catalyzed construction of 3-
Figure 1. Structures of selected bioactive 3-arylimidazo[1,2-a]pyridines

2
arylimidazo[1,2-a]pyridines from β-nitrostyrene and 2-
amination (Table 2). Initially, various β-nitrostyrenes were
aminopyridine employing H2O2 (30% aq.) as the oxidant.
reacted with 2-aminopyridine and the reaction was found to be
tolerant of the electronic nature of the (E)-(2-nitrovinyl)benzenes
since both electron-donating and withdrawing substituted
compounds performed well, to deliver the corresponding 3-
arylimidazo[1,2-a]pyridines in good to excellent yields (3a–e).
However, the strongly electron withdrawing –NO2 substituent in
(E)-(2-nitrovinyl)benzene furnished the desired product in lower
yield (3f). The steric factor had a minimal effect on this
transformation, as 2-substituted (E)-(2-nitrovinyl)benzene gave
the corresponding products in good yields (3g–i). In addition,
with (E)-2-(2-nitrovinyl)naphthalene as the β-nitrostyrene
variant, the corresponding product was obtained in good yield
(3j). The expected product (3k) was obtained in trace amounts
employing (E)-5-(2-nitrovinyl)benzo[d][1,3]dioxole as the
nitroalkene
variant
and
instead
N-(pyridine-2-
yl)benzo[d][1,3]dioxole-5-carboxamide was obtained. In the case
of (E)-(2-nitroprop-1-en-1-yl) benzene, the desired product 2-
methyl-3-phenylimidazo[1,2-a]pyridine (3l) was obtained along
with its regioisomer, 3-methyl-2-phenylimidazo[1,2-a]pyridine
(3l’) in almost equal amounts (Scheme 2).
Table 1. Optimization for the base-catalyzed construction of 3-
arylimidazo[1,2-a]pyridines a
Scheme 1. Synthesis of imidazopyridines from β-nitrostyrenes and 2-
aminopyridine.
In order to identify suitable reaction conditions for the
preparation of 3-arylimidazo[1,2-a]pyridines, initial optimization
Entry
Solvent
Base
Oxidant
Yield
(%)b
52
45
62
23
83
76
61
studies
were
carried
out
using
(E)-1-methyl-4-(2-
nitrovinyl)benzene and 2-aminopyridine as the model substrates
at room temperature (Table 1). The reaction product was
1
2
3
4
5
6
7
8
9
CH3CN
DMF
H2O
EtOH
DCM
DCE
THF
Toluene
PhCl
DCB
CH2Cl2
CH2Cl2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
TBHP
Various
peroxides
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
compared
with
2-arylimidazo[1,2-a]pyridines
and
3-
arylimidazo[1,2-a]pyridines from the literature in order to
unambiguously confirm the formation of 3-arylimidazo[1,2-
a]pyridines by 1H and 13C NMR.9d To begin our study, the
reaction was performed in the presence of Et3N as the base and
H2O2 (30% aq.) as the oxidant in CH3CN. This led to the desired
product in 52% yield (Entry 1). Several polar solvents were
screened and the yield was found to be highest with CH2Cl2 as
the solvent (Entries 2-7). The yield of the desired product did not
improve when the reaction was performed in non-polar solvents
such as toluene, chlorobenzene and dichlorobenzene (Entries 8-
10). We then shifted our focus to identifying the best oxidant for
this reaction. When the reaction was performed with tert-butyl
hydroperoxide (TBHP), the yield of the desired product
decreased considerably to 42% (Entry 11) and other organic
peroxides such as di-tert-butyl benzoyl peroxide (DTBP),
dicumyl peroxide (DCP), benzoyl peroxide (BPO) or tert-
butylperoxybenzoate (TBPB) did not afford the desired product
(Entry 12). After identifying the best oxidant for this reaction, we
screened various bases and it was found that organic bases
worked well compared to inorganic bases and the yield was
found to be optimum with Et3N (Entries 5, 13-17). When the
amount of oxidant was reduced to 2 equivalents, the product
yield decreased considerably and an increase in the amount of
oxidant did not increase the yield of the desired product (Entries
5, 18, 19). There was no significant increase in the yield when
0.2 equivalents of Et3N was used (Entry 20) and under neat
conditions the yield of the desired product decreased significantly
(Entry 21). Thus, we arrived at the optimized reaction conditions:
Et3N (10 mol%) as the base and H2O2 (3.0 equiv.) as the oxidant
in CH2Cl2 at room temperature.
46
65
71
10
11
42
NRc
12
13
14
15
16
17
18
19
20
21
CH2Cl2 Morpholine
69
71
54
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
--
Piperidine
K2CO3
Cs2CO3
t-BuOK
Et3N
52
61
62d
79e
78f
34
Et3N
Et3N
Et3N
a
Reagents and condition: 4-methyl-β-nitrostyrene (1.2 mmol), 2-
aminopyridine (1.0 mmol), base (10 mol%), oxidant (3.0 mmol), solvent (2
mL), rt.
b Isolated yield.
c DTBP, DCP, BPO, TBPB.
d Oxidant (2.0 mmol).
e Oxidant (4.0 mmol).
f Et3N (20 mol%).
With the optimized results in hand, structurally diverse β-
nitrostyrenes and 2-aminopyridines were employed to investigate
the scope and limitations of this base catalyzed oxidative

3
Scheme 2. Reaction of (E)-(2-nitroprop-1-en-1-yl) benzene with 2-
aminopyridine.
Table 2. Scope of β-nitrostyrenes and aminopyridines for the construction of 3-arylimidazo[1,2-a]pyridines.a,b
a Reagents and conditions: 1 (1.2 mmol), 2 (1.0 mmol), Et3N (10 mol%), H2O2 (3.0 equiv.), CH2Cl2 (2 mL), rt.14
b Isolated yields..
Next, we explored the scope and limitation of the process
with substituted 2-aminopyridines. Methyl groups at different
positions reacted well with (E)-(2-nitrovinyl)benzene to afford
the corresponding products in good yields (3m–o). The scope of
the reaction was further extended by varying both the substituent
Scheme 3. Reaction of 2-aminopyridines with β-halo and β-cyano styrenes.
on the 2-aminopyridines and (E)-(2-nitrovinyl)benzene which
gave corresponding products in good yields (3p–t). When 2-
amino thiazole was used as the amine variant, the corresponding
product was obtained in lower yield (3u). When the reaction was
performed with 2-aminopyrazine as the amine variant, Michael
adduct (3v) was observed along with trace amounts of the
expected product. The reaction failed completely when less
nucleophilic 2-aminopyridines were employed as the amine
variant. When 5-chloro and 5-bromopyrin-2-amine were treated
with β-nitrostyrene, only the corresponding Michael adduct was
observed under the optimized reaction conditions (3w, x). The
reaction of 5-nitropyridin-2-amine and ethyl 2-aminonicotinate
with β-nitrostyrene failed to yield the corresponding 3-
arylimidazo[1,2-a]pyridine (see ESI). When the reaction was
performed with other β-substituted olefins such as
In order to propose a plausible mechanism for this base-
catalyzed coupling, we carried out several experiments
employing (E)-(2-nitrovinyl)benzene and 2-aminopyridine as the
model substrates (Table 3). In the absence of both base and
oxidant, ~10% of Michael adduct (3a’) was observed (Entry 1).
When the reaction was carried out only with base, Michael
adduct (3a’) along with unreacted starting materials was
observed (Entry 2). Similarly, when the reaction was carried out
only with oxidant, trace amounts of the expected product was
detected along with 3a’ (Entry 3). These experiments emphasize
the role of the oxidant as well as the base for this oxidative
amination. Under the optimized conditions, in situ generated
Michael adduct 3a’ gave the desired 3-arylimidazo[1,2-
a]pyridine in good yield (Entry 4). This suggests that 3a’ acts as
an intermediate for this oxidative amination.
cinnamonitrile,
(E)-(2-chlorovinyl)benzene
and
(E)-(2-
bromovinyl)benzene, the reaction failed completely (Scheme 3).
This suggest that the highly electron withdrawing β-nitrostyrenes
are ideal substrates for this oxidative cyclization.

4
Table 3. Control experiments.a
Youji Huaxue, 2009, 29, 1708-1718; (d) Enguehard-Gueiffier, C.;
Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888-899; (e) Bartholini,
G.; L. E. R. S. Monogr, Ser. 1993, 8, 1; (f) Abignente, E. Actual.
Chim. Ther. 1991, 18, 193-214.
2. (a) Langer, S. Z.; Arbilla, S.; Benavides, J.; Scatton, B. Adv. Biochem.
Psychopharmacol. 1990, 46, 61-72; (b) Harrison, T. S.; Keating, G.
M. CNS Drugs, 2005, 19, 65-89; (c) Mizushige, K.; Ueda, T.; Yukiiri,
K.; Suzuki, H. Cardiovasc. Drug Rev. 2002, 20, 163-174; (d) Ueda,
T.; Mizusgige, K.; Yukiiri, K.; Takahashi, T.; Kohno, M.
Cerebrovasc Dis. 2003, 16, 396-401.
Entry
Solvent
Oxidant
Base
Yield (%)
3a 3a’
~10%
-
-
NRb
-
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
Et3N
-
56
36
3. (a) Katritzky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem. 2003, 68, 4935-
3
4c
H2O2
H2O2
Trace
73
4937; (b) Chernyak, N.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010
,
Et3N
Trace
49, 2743-2746; (c) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A.
Chem. Commun. 2015, 51, 1555-1575.
a
Reagents and conditions: 1a (1.2 mmol), 2a (1.0 mmol), Et3N (10 mol %),
H2O2 (3.0 equiv.), CH2Cl2 (2 mL), rt.
4. Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre, S.; Hallett,
b
No reaction.
D.; Merchant, K. J.; Thomas, S. R. Bioorg. Med. Chem. Lett. 2006
16, 1518-1522.
,
c Reaction performed with in situ generated Michael adduct 3a’
5. Fradley, R. L.; Guscott, M. R.; Bull, S.; Hallett, D. J.; Goodacre, S.
C.; Wafford, K. A.; Garrett, E. M.; Newman, R. J.; O’Meara, G. F.;
Whiting, P. J.; Rosahl, T. W.; Dawson, G. R.; Reynolds, D. S.; Atack,
J. R. J. Psycopharm. 2007, 21, 384-391.
6. Farag, A. M.; Mayhoub, A. S.; Barakat, S. E.; Bayomi, A. H. Bioorg.
Med. Chem. 2008, 16, 4569-4578.
7. Buckley, G. M.; Ceska, T. A.; Fraser, J. L.; Gowers, L.; Groom, C.
R.; Higueruelo, A. P.; Jenkins, K.; Mack, S. R.; Morgan, T.; Parry, D.
M.; Pitt, W. R.; Rausch, O.; Richard, M. D.; Sabina, V. Bioorg. Med.
Chem. Lett. 2008, 18, 3291-3295.
8. (a) Enguehard, C.; Renou, J.-L.; Collot, V.; Hervet, M.; Rault, S.;
Gueiffier, A. J. Org. Chem. 2000, 65, 6572-6575; (b) Nandi, D.;
Jhou, Y.-M.; Lee, J.-Y.; Kuo, B.-C.; Liu, C.-Y.; Huang, P.-W.; Lee,
H. M. J. Org. Chem. 2012, 77, 9384-9390; (c) Palani, T.; Park, K.;
Kumar, M. R.; Jung, H. M.; Lee, S. Eur. J. Org. Chem. 2012, 5038-
5047; (d) Zeng, J.; Tan, Y. J.; Leow, M. L.; Liu, X.-W. Org. Lett.
2012, 14, 4386-4389; (e) Cao, H.; Zhan, H.; Lin, Y.; Lin, X.; Du, Z.;
Jiang, H. Org. Lett. 2012, 14, 1688-1691. (f) Gao, Y.; Yin, M.; Wu,
W.; Huang, H.; Jiang, H. Adv. Synth. Catal. 2013, 355, 2263-2273;
(g) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun.
2015, 51, 1555-1575.
Based on the above observations, we propose a mechanism as
shown in Scheme 3. Initially, 1a reacts with 2a in the presence of
base to give intermediate 3a’’ through intermolecular Michael
addition. The formation of tautomer 3a’ was confirmed by
control experiments and was successfully isolated. Intermediate
3a’’ undergoes base-catalyzed intramolecular cyclization to
generate intermediate I, which on further oxidation, generates the
final product 3a with the removal of nitroxyl (HNO) and
water.10,15 Nitroxyl may be converted to nitrous or nitric acid
under the oxidative conditions.
9. (a) Wu, Z.; Pan Y.; Zhou, X. Synthesis, 2011, 2255-2260; (b)
Bangade, V. M.; Reddy, B. C.; Thakur, P. B.; Babu, B. M.; Meshram,
H. M. Tetrahedron Lett. 2013, 54, - ; (c) Egner, .;
Gerbling, K. .; oyer, G. -A.; Kr ger, G.; Wegner, P. Pestic. Sci.
1996, 47, 145-158; (d) Dixon, L. I.; Carroll, M. A.; Gregson, T. J.;
Ellames, G. J.; Harrington, R. W.; Clegg, W. Org. Biomol. Chem.
2013, 11, 5877-5884; (e) S. K. Lee and J. K. Park, J. Org. Chem.
2015, 80, 3723-3729.
Scheme 2. Plausible reaction mechanism.
In conclusion, a facile protocol was developed for the
regioselective synthesis of 3-arylimidazo[1,2-a]pyridines in the
presence of an inexpensive base (Et3N), and H2O2 (30% aq.) at
room temperature from readily available starting materials. The
scope of the reaction included several substituted β-nitrostyrenes
and 2- aminopyridines to furnish a wide variety of 3-
arylimidazo[1,2-a]pyridine in moderate to good yield.
10. Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Adv. Synth. Catal.
2013, 355, 1065-1070.
11. (a) Jagadhane, P. B.; Telvekar, V. N.; Synlett. 2014, 25, 2636-2638;
(b) Tachikawa, Y.; Nagasawa, Y.; Furuhashi, S.; Cui, L.; Yamaguchi,
E.; Tada, N.; Miura, T.; Itoh, A. RSC Adv. 2015, 5, 9591-9593.
12. (a) Monir, K.; Bagdi, A. K.; Ghosh, M.; Hajra, A. Org. Lett. 2014, 16,
4630-4633; (b) Ha, P. T. M.; Lieu, T. N.; Doan, S. H.; Phan, T. T. B.;
Nguyen, T. T.; Truong, T.; Phan, N. T. S. RSC Adv. 2017, 7, 23073-
23082; (c) Yadav, S.; Srivastava, M.; Rai, P.; Tripathi, B. P.; Mishra,
A.; Singh, J.; Singh, J. New J. Chem. 2016, 40, 9694-9701.
13. Devi, E. S.; Alanthadka, A.; Tamilselvi, A.; Nagarajan, S.; Sridharan,
V.; Maheswari, C. U. Org. Biomol. Chem. 2016, 14, 8228-8231.
14. General procedure for the synthesis of substituted 3-
Acknowledgements
Financial support from Dept. of Science and technology, DST,
New Delhi for the award of Extramural research grant (no.
EMR/2016/002485/OC) is gratefully acknowledged.
arylimidazo[1,2-a]pyridines: To a mixture of the β-nitrostyrene
(0.195g, 1.2 mmol) and 2-aminopyridine (0.0941g, 1.0 mmol) in
CH2Cl2 (2.0 mL), Et3N (10 mol%) and aq. H2O2 (3.0 equiv.) was
added and stirred at room temperature for 6 h. The reaction progress
was monitored by Thin Layer Chromatography (TLC) and after
reaction completion, the mixture was extracted with water. The
organic layer was washed with a brine solution and dried over
anhydrous Na2SO4. Removal of the solvent under vacuum afforded
the crude product, which was purified by column chromatography
using a hexane/ethyl acetate mixture.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.xx.xxx.
References
1. Couty, F.; Evano, G. in Comprehensive Heterocyclic Chemistry III,
ed. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J.
K. Elsevier, Oxford, 2008, vol. 11, p. 409-499; (b) Liu, J.; Chen, Q.
Huaxue Jinzhan, 2010, 22, 631-638; (c) Zhou, J.; Liu, J.; Chen, Q.
15. Gattu, R.; Bhattacharjee, S.; Mahato, K.; Khan, A.T. Org. Biomol.
Chem. 2018, 16, 3760-3770.

5
 First metal free system for synthesis of 3-
phenylimidazo[1,2-a]pyridine
 Can be performed at room temperature,
unlike other reported strategies
 Inexpensive base – Et3N and H2O2 (30%
aq.) as oxidant were used
 Substrate scope includes substituted β-
nitrostyrenes and 2-aminopyridines