Iodine–ammonium acetate promoted reaction between 2-aminopyridine and aryl methyl ketones: a novel approach towards the synthesis of 2-arylimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2016.08.058

I₂–NH₄OAc was found to be an efficient system for the metal-free synthesis of diversely substituted imidazo[1,2-a]pyridines 3a–r from 2-aminopyridine 1 and aryl methyl ketones 2a–r in one pot. 2-Arylimidazo[1,2-a]pyridines 3a–r were

Full text of DOI:10.1016/j.tetlet.2016.08.058

Accepted Manuscript
Iodine-ammonium acetate promoted reaction between 2-aminopyridine and aryl
methyl ketones: a novel approach towards the synthesis of 2-arylimidazo[1,2-
a]pyridines
Dilpreet Kour, Rajni Khajuria, Kamal K. Kapoor
PII:
S0040-4039(16)31085-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.058
TETL 48029
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2016
16 August 2016
18 August 2016
Please cite this article as: Kour, D., Khajuria, R., Kapoor, K.K., Iodine-ammonium acetate promoted reaction
between 2-aminopyridine and aryl methyl ketones: a novel approach towards the synthesis of 2-arylimidazo[1,2-
a]pyridines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.058
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Graphical Abstract
Iodine-ammonium acetate promoted
reaction between 2-aminopyridine and aryl
methyl ketones: a novel approach towards
the synthesis of 2-arylimidazo[1,2-
a]pyridines
Leave this area blank for abstract info.
Dilpreet Kour, Rajni Khajuria and Kamal K. Kapoor*
[Type text]

1
Tetrahedron Letters
Iodine-ammonium acetate promoted reaction between 2-aminopyridine and aryl
methyl ketones: a novel approach towards the synthesis of 2-arylimidazo[1,2-
a]pyridines
Dilpreet Kour, Rajni Khajuria and Kamal K. Kapoor
Department of Chemistry, University of Jammu, Jammu-180 006, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
I2-NH4OAc was found to be an efficient system for the metal-free synthesis of diversely
substituted imidazo[1,2-a]pyridines 3a-r from 2-aminopyridine 1 and aryl methyl ketones 2a-r
in one pot. 2-Arylimidazo[1,2-a]pyridines 3a-r were obtained in good to excellent yields via in
situ generation of an Ortoleva-King intermediate (pyridinium iodide), followed by NH4OAc-
assisted cyclization.
Available online
Keywords:
Intramolecular cyclization
Ortoleva-King intermediate
2-Aminopyridine
2009 Elsevier Ltd. All rights reserved.
Aryl methyl ketones
NH4OAc
2-Arylimidazo[1,2-a]pyridines
Imidazo[1,2-a]pyridines are indispensable biologically active
nitrogen containing heterocyclic scaffolds and exhibit a wide
range of biological activities.1 These are broadly investigated in
materials science and organometallics.2 Imidazo[1,2-a]pyridines
are recognized as a ‘privileged scaffold’ because these have got
the significant importance in pharmaceutical industry owing to
their interesting biological activities such as anti-cancer,3 anti-
viral,4 anti-inflammatory,5 analgesic, anti-pyretic,6 anti-ulcer7 and
anti-bacterial.8 Prospective radio ligands for positron emission
tomography (PET) for β-amyloid in Alzheimer’s disease based
on imidazo[1,2-a] derivatives have been widely reported.9 They
also act as GABA and benzodiazepine receptor agonists10 and
cardiotonic agents.11 These structures are also found in clinical
drugs such as alpidem,12 zolpidem,10 olprinone,13 zolimidine6 and
anti-HIV drug (GSK812397),14 etc (Figure 1). Furthermore, 2-(2-
hydroxy phenyl)imidazo[1,2-a]pyridines exhibit excellent
excited state intramolecular proton transfer (ESIPT)15 thereby
embracing significance in the field of optoelectronics. Prevalence
of these skeletons in biologically active compounds continues to
give chemists a momentum to develop novel methods for their
synthesis.
α-haloketones,16e nitroalkenes,16f α-diazoketones,16g alkynes
derivatives16h etc followed by cyclization via exocyclic amino
group generates a variety of imidazo[1,2-a]pyridines. These
reactions occur in the presence of various Bronsted or Lewis
acids,17,18 metal catalysts (Cu,19 Fe,20 Zn,21) and a carbocatalyst
graphene oxide.22 Few literature reports are available for the
synthesis of 2-arylimidazo[1,2-a]pyridines from 2-aminopyridine
and aryl methyl ketones via in situ generation of pyridinium
iodide, first reported by Ortoleva23 and King.24 One of these
reports has explored the I2 catalysed Ortoleva-King reaction in
combination with a strong base NaOH25 for the intramolecular
cyclization of pyridinium iodide to access o-hydroxy substituted
2-arylimidazo[1,2-a]pyridines with a limited substrate scope
while the other reports make use of copper containing catalytic
systems such as CuI/In(CF3SO3)326 and I2/CuO.19d These methods
are suitable for a variety of substrates but suffer from one or
more disadvantages such as high cost, long reaction time, inert
and anhydrous conditions, low yields, tedious workup and
product purification procedures. In view of these drawbacks and
our quest to develop efficient and milder methods,27 we
contemplated the replacement of the stronger base NaOH with
milder NH4OAc in the Stasyuk’s protocol.25
Owing to the attractive properties of imidazo[1,2-a]pyridines,
various methods to synthesize this core have been developed and
reviewed.16a-c Initial coupling reaction of endocyclic nitrogen of
2-aminopyridine with various reagents such as acetophenones,16d
Ammonium acetate is known to be a mild base for effective
Knoevenagel condensation28 and has also been demonstrated as
an important source of ammonia in the synthesis of various
heterocyclic scaffolds.29 Further, iodine-catalysed reactions are
———
 Corresponding author. Tel.: +91-191-2453969;
fax: +91-191-2450014/2431365; e-mail: kamalkka@gmail.com

2
Tetrahedron
Figure 1. Bioactive drugs containing imidazo[1,2-a]pyridine
nucleus.
One-pot reaction is much desired by the chemists because it
found to be highly efficient alternatives in C-N bond formation
as compared to transition metal-catalysed reactions and therefore
have attracted great interest of synthetic chemists. Iodine is
inexpensive, readily available,30 environmentally-benign as
compared to transition metal catalysts31 and operates under mild
conditions.32 Further, most iodine catalysed reactions involve
domino reaction sequences33 forming several bonds in a single
operation thereby imparting molecular diversity and complexity
among the compounds synthesized. Some of the well-known
reactions include one-pot synthesis of 2-acylbenzothiazoles via
iodine promoted domino oxidative cyclization,34 one-pot
synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-
a]quinoxaline derivatives via sp3 and sp2 C-H dehydrogenative
coupling,35 divergent synthesis of benzimidazoles, dihydro-2H-
benzo[e][1,2,4]thiadiazines,36 oxidative esterification of o-
alkynylaldehydes,37 one-pot synthesis of 2-aryl-3-(pyridine-2-
ylamino)imidazo[1,2-a] pyridines from alkylaryl ketones and 2-
aminopyridines.38
saves time and resources by eliminating the separation processes
for purification of the chemical intermediates and also improves
the overall yield. We wished to develop one-pot method for the
synthesis of 2-arylimidazo[1,2-a]pyridines by the condensation
of 2-aminopyridine with various arylmethyl ketones using
Ortoleva-King conditions followed by intramolecular cyclization
with NH4OAc.
The preliminary investigation was performed using 2-
aminopyridine 1 and acetophenone 2a as the model substrates.
The initial reaction between 2-aminopyridine 1 (1.2 mmol),
acetophenone 2a (1.0 mmol), I2 (1.0 mmol) and NH4OAc (2.0
mmol) in CHCl3 at room temperature for 1 h led to the formation
of the desired product 2-phenylimidazo[1,2-a]pyridine39 3a in
85% yield (Scheme 1).
Scheme 1. Synthesis of 2-phenylimidazo[1,2-a]pyridine 3a
During this study, a comparison between the literature
methods (entries 1-6)19c-d, 25,26,39,40 and present work (entries 7-10)
was made and it became evident from the Table 1 that our
reaction conditions (entry 7) were milder with better or
comparable yields. Different ratios of iodine and ammonium
acetate to effect this reaction (entries 7-10) revealed the optimum
requirement as the usage of 1 and 2 equivalents of I2 and
NH4OAc with respect to ketone (entry 7, 85% yield).
Table 1. Comparison of model reaction with literature reports.a
Entry
Catalyst
Ligand (10 mol%)
Additive
Solvent
Oxidant
Temp (ºC)/ Time (h)
Yield (%)b
1
Cu(OAc)2.H2O
(0.1 equiv)
1,10-phenanthroline
ZnI2
Dichlorobenzene
O2
120/24
8439
(0.1 equiv)
(1atm)
2
CuI
-
-
-
-
1,4-dioxane
Neat
-
100/14
40/24
7119c
7040
8126
(0.2 equiv)
3c
4d
CuI
BF3.Et2O
O2
(0.2 equiv)
(0.1 equiv)
(1atm)
CuI
In(CF3SO3)3
(0.01 equiv)
NMP
O2
100/30
(0.05 equiv)
(1atm)
5
Iodine
-
-
-
aq. NaOH
(45%)
-
-
-
-
100-110/
reflux/12
r.t./1
5525
8219d
85
(1.2 equiv)
6e
7
Iodine
CuO
MeOH
CHCl3
(1.1 equiv)
(1.1 equiv)
Iodine
NH4OAc
(1.0 equiv)
(2.0 equiv)
8
Iodine
-
-
-
NH4OAc
CHCl3
CHCl3
-
-
r.t./1
r.t./1
r.t./1
80
82
63
(2.0 equiv)
(2.0 equiv)
9
Iodine
NH4OAc
(1.0 equiv)
(3.0 equiv)
10
Iodine
NH4OAc
CHCl3
-
(0.5 equiv)
(1.0 equiv)
b
c
aReaction Conditions: 1 (1.2 equiv), 2a (1.0 equiv), at a given temperature and time; Isolated yields; 2a (3.0 equiv) was used; d2a (2.0 equiv) was used;
e1 (1.0 equiv) was used.
[Type text]

3
Replacement of NH4OAc with NH4OH, NH4HCO3,
NH4H2PO4, (NH4OOCH)2, NH4(OOCH), (NH4)2CO3, NH4Cl,
NH4NO3, NH4SCN, Et3N or DMAP as well as CHCl3 with
CH3CN, 1,2-DCE, DMF, EtOH, n-BuOH or toluene did not
prove beneficial toward product yield.
(entries 3a-m) in good to excellent yields (63-85%). Further, to
establish the generality of the reaction, furan-2-yl/thiophen-2-yl
methyl ketones were investigated and smooth formation of the
corresponding furan-2-yl/thiophen-2-yl substituted imidazo[1,2-
a]pyridines (entries 3n-o) was observed with good yields (77-
79%). The construction of imidazo[1,2-a]pyridines bearing bi-
cyclic substitutions (entries 3p-q) was also achieved under these
optimized conditions. Interestingly, 3-acetyl-2H-chromen-2-one
led to the formation of 3-(imidazo[1,2-a]pyridin-2-yl)-2H-
chromen-2-one, a hybrid of imidazo[1,2-a]pyridine and coumarin
(entry 3q, 80% yield). The 2-aminopyridine with a methyl group
in the 3-position smoothly underwent the reaction, and product
(entry 3r) was obtained in an appreciable 82% yield.
Under the optimized conditions, diversely substituted aryl
methyl ketones were investigated41 and the results are
summarized in Table 2. It was also noticed that for some
sterically hindered and electron rich substrates (entries 2i, 2n-q),
better yields were obtained under reflux. Aryl methyl ketones
bearing electron donating (Me, OMe), electron withdrawing
groups (F, Cl, NO2) as well as disubstitution in the phenyl ring
generated the corresponding 2-arylimidazo[1,2-a]pyridines
Table 2. I2–NH4OAc promoted synthesis of 2-arylimidazo[1,2-a]pyridines 3a-r
In line with the mechanism proposed by Zhang et al.,42 following mechanism is proposed for the synthesis of 2-arylimidazo[1,2-
a]pyridines 3a-r as illustrated in Scheme 2.
Scheme 2. Plausible mechanism for the formation of 2-arylimidazo[1,2-a]pyridines 3a-r with I2-NH4OAc.

4
Tetrahedron
The first step involves the reaction of pyridine endocyclic
Catal. Sci. Technol. 2015, 5, 372; (e) Donohoe, T. J.; Kabeshov, M. A.;
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nitrogen with the α-carbon of in situ generated α-iodoketone
leading to the formation pyridinium salt A. Intramolecular
cyclisation of the imine B generated by the deprotonation of A
gives
tetrahydroimidazo[1,2-a]pyridin-2-ol C, which upon
elimination of water resulted in the formation of 2-
arylimidazo[1,2-a]pyridines 3a-r. HI produced during the
reaction is believed to be scavenged by NH3 produced from
NH4OAc.
19 (a) Yan, R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Huang, G. S.;
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In summary, we have developed an efficient, metal-free
synthesis of diversely substituted 2-arylimidazo[1,2-a]pyridines
showing versatility in terms of milder reaction conditions and
easy product purification avoiding the use of column
chromatography.
20 Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013,
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Acknowledgments
The authors are thankful to University Grants Commission
(UGC), New Delhi for funding (Project No. MRP-MAJOR-
CHEM-2013-21745). RK further acknowledges UGC, New
Delhi for Senior Research Fellowship.
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41 Procedure for the synthesis of 2-arylimidazo[1,2-a]pyridines (3a- r): A
mixture of 2-aminopyridine 1 (1.2 mmol), aryl methyl ketone 2a-r (1.0
mmol), I2 (1.0 mmol) and NH4OAc (2.0 mmol) in CHCl3 (10 mL) in a 25 mL
16 (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun. 2015,
51, 1555; (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A. Synthesis
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[Type text]

5
round-bottomed flask was stirred at room temperature until the completion of
reaction (Table 2). The reaction mixture was further diluted with 20 mL of
CHCl3, washed with saturated solution of Na2S2O3 (2×10 mL), water (1×10
mL), brine (1×10 mL) and finally dried over anhydrous Na2SO4. The solvent
was removed and the residue after recrystallisation with EtOH afforded the
desired 2-arylimidazo[1,2-a]pyridines (3a-r, 63-85%). For entries 2i and 2n-
q, reaction was performed under reflux.
42 Wang, F. –J.; Xu, H.; Xin, M.; Zhang, Z. Mol. Divers. 2016, 20, 659.

6
Tetrahedron
Iodine-ammonium acetate promoted reaction
between 2-aminopyridine and aryl methyl ketones:
a novel approach towards the synthesis of 2-
arylimidazo[1,2-a]pyridines
Dilpreet Kour, Rajni Khajuria and Kamal K. Kapoor*
Department of Chemistry, University of Jammu, Jammu-180 006, India
I2-NH4OAc was found to be an efficient system for the metal-
free synthesis of diversely substituted imidazo[1,2-a]pyridines
from 2-aminopyridine and aryl methyl ketones in one pot. 2-
Arylimidazo[1,2-a]pyridines were obtained in good to
excellent yields via in situ generation of an Ortoleva-King
intermediate (pyridinium iodide), followed by NH4OAc-
assisted cyclization.
[Type text]

7
Highlights

An expedient, metal-free, one-pot protocol for the
synthesis of diversely substituted 2-arylimidazo[1,2-
a]pyridines


Usage of milder reaction conditions
Easy product isolation without column chromatography
purification.

The synthesis of novel 3-(imidazo[1,2-a]pyridin-2-yl)-
2H-chromen-2-one 3q,
a
hybrid of imidazo[1,2-
a]pyridine and coumarin, has also been presented.