Direct one-pot synthesis of zolimidine pharmaceutical drug and imidazo[1,2-a]pyridine derivatives via I2/CuO-promoted tandem strategy

Article abstract of DOI:10.1016/j.cclet.2014.12.016

An efficient one-pot synthetic protocol was developed for the synthesis of imidazo[1,2-a]pyridines from easily available starting materials: Aromatic ketones, α,β-unsaturated ketones, β-keto esters and 2-aminopyridines. The present reaction proceeded well in MeOH under the media of I₂/CuO. By using this method, the marketed drug zolimidine could be prepared easily with 95% yield. All these target products were characterized by NMR, HRMS and IR spectra. Furthermore, the target compound 3fa was determined by X-ray crystallographic analysis.

Full text of DOI:10.1016/j.cclet.2014.12.016

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CCLET-3185; No. of Pages 4
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Direct one-pot synthesis of zolimidine pharmaceutical drug
and imidazo[1,2-a]pyridine derivatives via I2/CuO-promoted
tandem strategy
*
Qun Cai, Mei-Cai Liu, Bi-Ming Mao, Xuan Xie, Feng-Cheng Jia, Yan-Ping Zhu, An-Xin Wu
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient one-pot synthetic protocol was developed for the synthesis of imidazo[1,2-a]pyridines from
easily available starting materials: Aromatic ketones, -unsaturated ketones, -keto esters and 2-
Received 4 November 2014
Received in revised form 22 November 2014
Accepted 3 December 2014
Available online xxx
a,
b
b
aminopyridines. The present reaction proceeded well in MeOH under the media of I2/CuO. By using this
method, the marketed drug zolimidine could be prepared easily with 95% yield. All these target products
were characterized by NMR, HRMS and IR spectra. Furthermore, the target compound 3fa was
determined by X-ray crystallographic analysis.
Keywords:
ß 2014 An-Xin Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of
Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
2-Aminopyridines
Aromatic ketones
Imidazo[1,2-a]pyridines
Zolimidine
One-pot
1. Introduction
several domino protocols have also been proposed for preparation
of imidazo[1,2-a]pyridines, which avoided the requirement of any
Imidazo[1,2-a]pyridines are very important heterocycles which
have been found to be the core scaffold of many natural products
anddrugs(Scheme1). Theyhavereceivedconsiderableinterestfrom
the pharmaceutical industry because of their important biological
activities and interesting therapeutic properties [1], including
antibacterial [2a], antifungal [2b,2c], antiviral [2d,2f], antiulcer
[2g], and anti-inflammatory behavior [2h]. Moreover, they can also
be used in material science and molecular recognition [3].
transition-metal [9,10].
In our previous studies, we found that aryl methyl ketones
could be quantitatively converted to aryloxoethanals in I2/DMSO
system. The aryloxoethanals generated in situ were easily captured
by 2-aminopyridines to afford 2,3-disubstituted imidazo[1,2-
a]pyridines [10]. Based on these results, this work developed an
I2/CuO-promoted one-pot protocol for the synthesis 2-substituted
imidazo[1,2-a]pyridines via 2-aminopyridines capturing
a-iodo
By now, many synthetic methods for the construction of
imidazo[1,2-a]pyridines have been reported. In general, the
common strategies were the cyclocondensations of 2-aminopyr-
acetophenones generated in situ from aryl methyl ketones in
MeOH (Scheme 2).
idines with
a-halocarbonyl compounds [4], 1,3-dicarbonyl com-
2. Experimental
pounds [5], nitroolefins or alkynes [6]. Besides, the condensation of
2-aminopyridines, aldehydes and isonitriles or alkynes in one-pot
was also an efficient method for the synthesis of imidazo[1,2-
a]pyridines [7]. Some other novel synthetic approaches have been
established in recent years. For example, the transition-metal
catalyzed C–H activation or coupling methods have been
demonstrated by some research groups recently [8]. Furthermore,
All aryl methyl ketones, b-ketone esters, 2-aminopyridines, and
other reagents were obtained from commercial suppliers and used
without further purification. TLC analysis was performed using
pre-coated glass plates. Column chromatography was performed
using silica gel (200–300 mesh).
IR spectra were recorded on a Perkin-Elmer PE-983 infrared
spectrometer as KBr pellets with absorption in cmÀ1 1H NMR
.
spectra were recorded on a Varian Mercury 400 or 600 MHz
spectrometer. Chemical shifts are reported in ppm, relative to the
internal standard of tetramethylsilane (TMS). HRMS were obtained
*
Corresponding author.
E-mail address: chwuax@mail.ccnu.edu.cn (A.-X. Wu).
http://dx.doi.org/10.1016/j.cclet.2014.12.016
1001-8417/ß 2014 An-Xin Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All
rights reserved.
Please cite this article in press as: Q. Cai, et al., Direct one-pot synthesis of zolimidine pharmaceutical drug and imidazo[1,2-a]pyridine
derivatives via I2/CuO-promoted tandem strategy, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2014.12.016

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2
Q. Cai et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
yields of the desired product were increased when acetophenone
(1a), I2 and CuO were refluxed in methanol or ethanol for 1–2.5 h,
withthe subsequent additionof 2a foranother 2 h (entries 9 and 10).
Next, the equiv. of I2 and CuO was also optimized. Further elevating
the amounts of I2 or CuO did not increase the yield obviously (entries
11 and 12). Above all, the optimal reaction condition turned out to
be acetophenone 1a (1.0 mmol), I2 (1.1 mmol) and CuO (1.1 mmol)
refluxedinMeOHfor1–2.5 h, then2-aminopyridine(2a)(1.0 mmol)
was added at reflux for another 2 h.
With suitable reaction conditions established, the generality of
the reaction was explored (Table 2). The substrates with the
electron-donating substituents on the benzene ring gave good
yields, such as 4-Me, 4-OMe, 2,4-(OMe)2 and 2,6-O(CH2)2O groups
(80%–86%, 3ba–3ea). The electron-withdrawing substituent
groups, such as 4-Cl, 4-Br, 3,4-Cl2, 3-NO2 attached to the benzene
ring shown a slight decrease in yields (70%–76%, 3fa–3ia). It should
be noted that the substrate with a sensitive hydroxy group (4-OH)
in the phenyl group presented a moderate yield of 3ja (65%).
Meanwhile, steric hindrance substrates 2-naphthyl methyl ketone
and 1-naphthyl methyl ketone were also tolerant to this reaction to
afford the desired products 3ka–3la in 79%–80% yields. Encour-
aged by the results obtained with aryl methyl ketones, we turned
our attention to the heteroaryl ketones. The heterocycles,
including thiophenyl and benzofuryl, did not affect the overall
efficiency, and the corresponding products 3ma–3oa were
furnished in 69%–75% yields. The unsaturated methyl ketones
Scheme 1. The drugs containing imidazo[1,2-a]pyridine unit.
on a Bruker Apex-Ultra 7.0T FTMS equipped with an electrospray
source (ESI) or atmospheric-pressure chemical ionization (APCI).
Melting points were determined using XT-4 apparatus and not
corrected.
The synthetic route of the target products was outlined in
Scheme 2. Finely powdered CuO (88 mg, 1.1 mmol) and I2 (279 mg,
1.1 mmol) were added to a solution of acetophenone 1a (120 mg,
1 mmol) in anhydrous MeOH (20 mL). The mixture was refluxed
for 1–10 h. When disappearance of the reactant (monitored by
TLC), then added 2-aminopyridine 2a (94 mg, 1.0 mmol) at reflux
for another 2 h. After the reaction completed, the mixture was
filtered and the solvent was removed under reduced pressure. The
residue was poured into 10% Na2S2O3 solution (50 mL), the
mixture was extracted with EtOAc (3Â 50 mL), and the organic
layer was dried (Na2SO4). Removal of the solvent and purification
of the residue by column chromatography gave the desired
product 3aa as yellow solid 159.1 mg (yield 82%).
and
b-ketone esters were also tested under the standard
conditions. When unsaturated methyl ketones were selected as
substrates, the corresponding products 3pa–3qa were obtained in
55%–58% yields. Moreover,
b-ketone esters were also tolerant to
the reaction to yield the corresponding products 3ra–3ta in
moderate to good yields (55%–73%). Furthermore, the product 3fa
was further determined by X-ray crystallographic analysis (Fig. 1).
To further expand the substrate scope, the substrates 2-
aminopyridines were investigated. To our satisfaction, both
electron-donating and electron-withdrawing groups attached to
2-aminopyridines were all suitable for this protocol, and provided
the corresponding products (3ab–3ae) in 62%–78% yields. To our
delight, 2-aminopyrimidine was also tolerant to the reaction to
afford the corresponding product 3af in 88% yield.
Zolimidine 3ua, which was the marketed antiulcer drug, could
be synthesized in this concise route. As shown in Table 2, by
utilizing 1-(4-(methylsulfonyl)phenyl)ethanone and 2-aminopyr-
idine under I2/CuO-mediated conditions, the cyclization product
3ua could be generated smoothly in 95% yield.
3. Results and discussion
We firstly selected acetophenone (1a) and 2-aminopyridine (2a)
as model substrates to optimize the reaction conditions (Table 1).
Several solvents were firstly examined. The reaction could not
perform to give the desired product in acetonitrile, tetrahydrofuran,
toluene, chloroform, and isopropanol (entries 1, 2, 4, 5, and 8).
However, the desired product was obtained in 30% yield when
acetophenone (1a), 2-aminopyridine (2a), I2 and CuOwere heated in
DMF at 100 8C for 1–2 h (entry 3). When the reaction was performed
in methanol or ethanol, the target product could be obtained in 40%
and 35% yields, respectively (entries 6 and 7). To our delight, the
Scheme 2. Synthesis of imidazo[1,2-a]pyridines.
Please cite this article in press as: Q. Cai, et al., Direct one-pot synthesis of zolimidine pharmaceutical drug and imidazo[1,2-a]pyridine
derivatives via I2/CuO-promoted tandem strategy, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2014.12.016

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3
Table 1
Optimization of the reaction conditions.
.
Entry
I2 (mmol)
CuO (mmol)
Solvent
Yield (%)b
1
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
MeCN
THF
n.r.
n.r.
30
3
DMF/100 8C
Toluene
CHCl3
Fig. 1. The X-ray crystal structure of compound 3fa.
4
n.r.
n.r.
40
5
6
MeOH
EtOH
afford product 3aa in 92% yield in MeOH at reflux conditions.
Meanwhile, -ketone ester 1r could also be transformed to
7
35
8
n-PrOH
MeOH
EtOH
n.r.
82
b
9a
10a
11a
12a
intermediate 4r in 78% yield under I2/CuO-mediated conditions
(Scheme 3b). Intermediate 4r could also react with 2a to furnish
product 3ra in 90% yield in MeOH at reflux for 2 h.
79
MeOH
MeOH
82
1.1
81
Based on the above results, a possible mechanism of the
present reaction was proposed as follows using acetophenone
(1a) and 2-aminopyridine (2a) as an example (Scheme 4). Initially,
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), I2, and CuO were heated in one
pot for 1–12 h.
a
1a (1.0 mmol), I2, and CuO were reflux for 1–2.5 h. Subsequently, 2a was added
(1.0 mmol) to this reaction mixture, until the disappearance of 2a, monitored by
the acetophenone 1a was converted to intermediate a-iodo
TLC. It was a two-step process.
acetophenone 1aa in the media of I2 and CuO [11]. The in situ
generated intermediate 1aa underwent an intermolecular
nucleophilic substitute with 2-aminopyridine 2a to obtain
intermediate D, which was followed by isomerization to furnish
intermediate E. Finally, intermediate E further underwent an
intramolecular cyclization to afford the desired product 3aa. In
the whole process, CuO plays multiple roles. It not only acts as
the oxidizing agent or catalyst to convert molecular iodine into
the reacting iodonium ion (I+) species, but also act as a weak
base to neutralize hydrogen iodide, and reoxidize iodide ion (IÀ)
into molecular iodine (I2), which forms together with insoluble
copper(I) oxide and water [11a].
b
Isolated yield. n.r. = no reaction.
To gain some insight into the mechanism of the reaction process,
some control experiments were also performed (Scheme 3). It was
found that acetophenone 1a could be converted into a-iodo ketone
1aa in 95% yield under I2/CuO-mediated conditions (Scheme 3a)
[11a]. 1aa with 2-aminopyridine 2a could perform smoothly to
Table 2
The scope of ketones and 2-aminopyridines.
.
Entry R1
R2
R3
X
Product Yield (%)a
1
2
C6H5
H
–
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
3aa
3ba
3ca
3da
3ea
3fa
82
85
86
80
84
76
72
70
70
65
80
79
75
73
69
55
58
65
73
55
68
62
78
76
88
95
4-Me–C6H4
4-OMe–C6H4
2,4-OMe2–C6H3
2,6-O(CH2)2O–C6H3
4-Cl–C6H4
H
–
3
H
–
4
H
–
5
H
–
6
H
–
7
4-Br–C6H4
H
–
3ga
3ha
3ia
8
3,4-Cl2–C6H3
3-NO2–C6H4
4-OH–C6H4
2-Naphthyl
1-Naphthyl
2-Thiophenyl
3-Thiophenyl
2-Benzofuryl
C6H5CH5CH
3,4-OMe2–C6H3CH5CH
C6H5
H
–
9
H
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26b
H
–
3ja
Scheme 3. The control experiments.
H
–
3ka
3la
H
–
H
–
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
3ab
3ac
3ad
3ae
3af
H
–
H
–
H
–
H
–
CO2Et
CO2Et
CO2Et
H
–
3,4-OMe2–C6H3
4-NO2–C6H4
C6H5
–
–
5-Br
3,5-Br2
6-Me
4-Me
–
C6H5
H
C6H5
H
C6H5
H
C6H5
H
4-CH3SO2–C6H4
H
–
3ua
Reaction conditions: 1 (1.0 mmol), I2 (1.1 mmol), and CuO (1.1 mmol) were reflux
in MeOH (3 mL) for 1–10 h, and then added 2 (1.0 mmol) until the disappearance
of 2, monitored by TLC.
a
Isolated yield.
b
Reaction conditions: 1u (1.0 mmol), I2 (1.1 mmol), and CuO (1.1 mmol) at reflux
in MeOH (3 mL) for 12 h, and then added 2a (1.0 mmol) for another 2 h.
Scheme 4. The plausible mechanism of the present reaction.
Please cite this article in press as: Q. Cai, et al., Direct one-pot synthesis of zolimidine pharmaceutical drug and imidazo[1,2-a]pyridine
derivatives via I2/CuO-promoted tandem strategy, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2014.12.016

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In conclusion, an I2/CuO-promoted one-pot tandem strategy
has been proposed for the synthesis of imidazo[1,2-a]pyridine
derivatives. It is notable that the present reaction has a broad scope
of substrates, including aryl methyl ketones, heteroaryl ketones,
[5] (a) X. Wang, L. Ma, W. Yu, Synthesis of imidazo[1,2-a]pyridines by the bis(ace-
tyloxy)(phenyl)-l3-iodane-mediated oxidative coupling of 2-aminopyridines
with b-keto esters and 1,3-diones, Synthesis (2011) 2445–2453;
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a,b-unsaturated methyl ketones, b-ketone esters, and substituted
2-aminopyridines. Owing to the generality of the reaction, this
protocol should be of great utility in medical chemistry and organic
methodology. Further investigations into the scope of this reaction
and its applications are ongoing in our laboratory.
Acknowledgments
(b) J. Zeng, Y.J. Tan, M.L. Leow, X.W. Liu, Copper(II)/iron(III) co-catalyzed inter-
molecular diamination of alkynes: facile synthesis of imidazopyridines, Org. Lett.
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(c) C.L. Zong, R.S. Zeng, J.P. Zou, One-pot copper nanoparticle-catalyzed synthesis
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We would like to thank the National Natural Science Founda-
tion of China (Nos. 21032001 and 21272085) for their generous
financial support. We acknowlege the excellent doctorial disserta-
tion cultivation grant from Central China Normal University
Wuhan, China (No. 2013YBYB63). We also thank Dr. Chuanqi Zhou,
Hebei University, for analytical support.
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Please cite this article in press as: Q. Cai, et al., Direct one-pot synthesis of zolimidine pharmaceutical drug and imidazo[1,2-a]pyridine
derivatives via I2/CuO-promoted tandem strategy, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2014.12.016