I2-promoted direct one-pot synthesis of 2-aryl-3-(pyridine-2- ylamino)imidazo[1,2-a]pyridines from aromatic ketones and 2-aminopyridines

Article abstract of DOI:10.1016/j.tetlet.2012.12.072

An I₂-promoted one-pot protocol was proposed for the synthesis of 2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines from aromatic ketones and 2-aminopyridines. The present reaction proceeded well in the presence of I₂ in DMSO, and it avoided the requirement of any metal, base, and ligand.

Full text of DOI:10.1016/j.tetlet.2012.12.072

Accepted Manuscript
I2-promoted direct one-pot synthesis of 2-aryl-3-(pyridine-2-ylamino)imida‐
zo[1,2-a]pyridines from aromatic ketones and 2-aminopyridines
Zhuan Fei, Yan-ping Zhu, Mei-cai Liu, Feng-cheng Jia, An-xin Wu
PII:
S0040-4039(12)02225-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.12.072
TETL 42320
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 November 2012
11 December 2012
18 December 2012
Please cite this article as: Fei, Z., Zhu, Y-p., Liu, M-c., Jia, F-c., Wu, A-x., I2-promoted direct one-pot synthesis of
2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines from aromatic ketones and 2-aminopyridines, Tetrahedron
Letters (2012), doi: http://dx.doi.org/10.1016/j.tetlet.2012.12.072
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I2-promoted direct one-pot synthesis of 2-
aryl-3-(pyridine-2-ylamino)imidazo[1,2-
a]pyridines from aromatic ketones and 2-
aminopyridines
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Zhuan Fei, Yan-ping Zhu*, Mei-cai Liu, Feng-cheng Jia, An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, China

1
Tetrahedron Letters
journal homepage: www.elsevier.com
I2-promoted direct one-pot synthesis of 2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-
a]pyridines from aromatic ketones and 2-aminopyridines
Zhuan Fei, Yan-ping Zhu, Mei-cai Liu, Feng-cheng Jia, An-xin Wu
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An I2-promoted one-pot protocol was proposed for the synthesis of 2-aryl-3-(pyridine-2-
ylamino)imidazo[1,2-a]pyridines from aromatic ketones and 2-aminopyridines. The present
reaction proceeded well in the presence of I2 in DMSO, and it avoided the requirement of any
metal, base, and ligand.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
aromatic ketones
one-pot
imidazo[1,2-a]pyridines
heterocyclization
Imidazo[1,2-a]pyridines have attracted much attention since
the beginning of the last century. Due to their important
biological activity, they have, in recent years, been broadly
investigated and utilized in the pharmaceutical industry. They
also be used in bioimaging probes, and molecular recognition
because of their structural characters.1 In addition, the
imidazo[1,2-a]pyridine scaffolds have been found to be the core
structure of many natural products and drugs such as zolpidem,
alpidem, zolimidine, saripidem, necopidem, olprinone, and DS-1
(Scheme 1).2
Scheme 2. The methods for the synthesis of imidazo[1,2-
a]pyridines.
Scheme 1. The drugs containing imidazo[1,2-a]pyridine unit.
Consequently, many synthetic methods have been reported for
the synthesis of imidazo[1,2-a]pyridines (Scheme 2).3 In recent
times, some novel synthetic approaches have been proposed to
access imidazo[1,2-a]pyridines. For example, an efficient method
involving condensation of aldehydes, 2-aminopyridines, and
isonitriles or alkynes in one-pot has been established.4 Metals
catalyzed C-H activation or coupling methods have also been
developed.5 Moreover, transition-metal free domino protocols
were also proposed by some research groups.6–9 Despite these
achievements, the development of further diverse methods to
construct various imidazo[1,2-a]pyridines is still desirable. In
addition,
the
molecules
of
2-aryl-3-(pyridine-2-
ylamino)imidazo[1,2-a]pyridines are rarely reported in literature.
In our previous studies, we found that I2 could promote
quantitative conversion of aryl methyl ketones to aryloxoethanals
in DMSO.10 The aryloxoethanals generated in situ were easily
captured by 2-aminopyridines to afford imidazo[1,2-a]pyridines.
———
 Corresponding author. Tel./fax: +86 027 6786 7773; e-mail: chwuax@mail.ccnu.edu.cn (A. X. Wu); chemzyp@gmail.com (Y. P. Zhu)

2
Tetrahedron Letters
Based on these results, we aimed to investigate if it would be
possible to develop an I2 promoted one-pot protocol to synthesis
of imidazo[1,2-a]pyridines via sp3 C-H bonds functioalization
from aromatic ketones (Scheme 2).
With this idea in mind, we selected acetophenone (1a) and 2-
aminopyridine (2a) as a model reaction (Table 1). The reaction of
acetophenone (1a) and 2-aminopyridine (2a) with I2, CuO at 80-
100 ℃ could not perform to give the desired product (entries 1–
3). It was found, however, the desired product was obtained in
68% yield when acetophenone 1a and I2 were heated at 100 ℃
for 1–2 h, with the subsequent addition of 2a for another 2 h
(entry 4). The yield was up to 73% when the does of I2 was
increased to 150-200 mol % (entries 5–6). To our delight, the
reaction still performed well with only 150 mol % of I2 (entry 7).
However, no desired product was obtained in the absence of I2 or
I2/CuO (entries 8–9). Further elevation or reduction of
temperature could not enhance the yield (entries 10–11). After
several experimental optimization processes, we found that a
mixture of 1a (1.0 mmol) and I2 (1.5 mmol) in DMSO was
heated to 100 ℃ for 1-2 h. Addition of 2a (2.0 mmol) to this
and heating to 100 ℃ for 1 h produced product 3a in 75%
isolated yield.
Table 1. Optimization of the reaction conditions
I2
CuO
Yield
(%) c
Entry
Temp. (℃)
(mmol)
(mmol)
1a
2a
1.1
1.1
1.1
1.1
1.5
2.0
1.5
-
1.1
1.1
1.1
1.1
1.1
1.1
-
n.r.
n.r.
n.r.
68
80
a Reaction conditions: A mixture of 1 (1.0 mmol) and I2 (1.5 mmol) in DMSO
(3–5 mL) was heated at 100 ℃ for 1–6 h, and then for an additional 1–2 h
after addition of 2 (2.0 mmol). b Isolated yield.
90
3a
100
100
100
100
100
100
100
110
80
4b
With the optimal reaction conditions established, the scope of
the present transformation was investigated in DMSO.15 As
summarized in Table 2, various aromatic ketones were found to
participate in this reaction. The electronic and steric nature of
aromatic methyl ketones had little influence on the reaction
efficiency, and all the corresponding products were obtained in
moderate to good yields (52–78%; Table 2). For example,
various aromatic ketones bearing electron-rich (3b–3d) and
electron-deficient (3e–3h) substituents on the aryl ring could
perform smoothly to give the corresponding products in generally
good yields (60–78%). In addition, the scope of the substrates
was further extended to various heteroaryl methyl ketones, such
as 2-acethyl furan, -thiophen, -benzofuran. To our delight, the
corresponding products 3i–3k were furnished in 65–73% yields.
Meanwhile, steric hindrance substrate 1-naphthyl methyl ketone
1l was also tolerant to this reaction to afford the desired product
3l in 62% yield. The substrate bearing a phenolic hydroxy group
(OH) could be used and was successfully converted to the
corresponding product 3m in 52% yield. Subsequently, the
substituted 2-aminopyridines 2b, 2c, 2d, 2e, 2f, and 2-
aminepyrimidin 2g were also employed. 2b-2e could perform to
afford the corresponding products 3n-3q in 35-52% yields.
However, 2f and 2g were not suitable for the reaction and no
desired products were observed. The target compound 3j was
further determined by X-ray crystallographic analysis (Figure 1).
5b
73
6b
72
7b
75
8b
1.1
-
n.r.
n.r.
69
9b
-
10b
11b
1.5
1.5
-
-
60
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), I2, and CuO were
b
heated in DMSO (3–5 mL). 1a (1.0 mmol), I2, and/or CuO were
heated for 1–2 h in DMSO (3–5 mL), and then added 2a (2.0 mmol) for
another 1 h. c Isolated yield. n.r. = no reaction.
Table 2 The scope of ketones and 2-aminopyridinesa, b

3
(Scheme 3c). It demonstrated that the reaction did not undergo
through the intermediate 2-phenyl imidazo[1,2-a]pyridine 7.
Figure 1 The X-Ray crystal structure of compound 3j
To probe the reaction process, the reaction of 1a (0.1 mmol)
with I2 (0.15 mmol), and 2a (0.2 mmol) in DMSO-d6 was
monitored by H NMR spectroscopic analysis (Figure 2). The
Scheme 3. The controlled experiments to prove the mechanism.
1
signal at 4.6 ppm that appeared at 5-15 mins was unambiguously
assigned to the -CH2- group of α-iodo aryl methyl ketone 4 by
comparison with that of an authentic sample of 4 (Figure S2).
Meanwhile, the signals at 9.54 ppm and 5.70 ppm were assigned
to the characteristic peaks of phenylglyoxal (5) and its hemiacetal
(6), respectively.10c, 11 When the reaction was performed for 35
mins, the substrate 1a was absolutely transformed into
intermediates 5 and 6. After the addition of 2a, the characteristic
peaks of 5 and 6 disappeared immediately. The characteristic
peaks of product 3a were also clearly observed. Thus, Figure 2
indicates a high conversion of the reaction without formation of
any byproduct.
Possible mechanism for the process is illustrated in Scheme 4.
Initially, the acetophenone 1a takes place α-halogenation to
afford α-iodo ketone 4 in the media of I2 in DMSO.12
Subsequently, α-iodo ketone 4 is further oxidized by DMSO to
13
yield phenylglyoxal 5.10,
Phenylglyoxal 5 undergoes two
possible pathways to afford intermediate C.14 In pathway A, the
amino group of 2a initially attacks the aldehyde group of 5 to
obtain intermediate A, which is further attacked by the pyridine
group of another molecule of 2a to yield intermediate C. In
pathway B, the pyridine group of 2a first attacks the aldehyde
group of 5 to afford intermediate B. Then, the amino group of
another molecule of 2a undergoes condensation with B to give
intermediate C. Finally, intermediate
C experiences an
intramolecular condensation to furnish the desired product 3a.
Scheme 4 The plausible mechanism of the present reaction
In conclusion, a metal-free I2-promoted protocol was
proposed for the synthesis of 2-aryl-3-(pyridine-2-
ylamino)imidazo[1,2-a]pyridines from aromatic ketones and 2-
aminopyridines. Mechanism investigation demonstrated that the
reaction proceeded through α-iodo aryl methyl ketone and
aryloxoethanal intermediates. Unlike previous processes, the
present protocol avoids the requirement of metal, base, and
ligand. In addition, the molecules of 2-aryl-3-(pyridine-2-
ylamino)imidazo[1,2-a]pyridines are rarely reported in literature.
Further investigations into the scope of this reaction and its
applications are ongoing.
Figure 2 The reaction process of 1a (0.1 mmol), 2a (0.2 mmol)
with I2 (0.15 mmol) was monitored by H NMR spectroscopy
(400 MHz, DMSO-d6).
1
Some control experiments were conducted (Scheme 3). It was
found that phenacyl iodine 4 (1.0 mmol) reacted with 2a (2.0
mmol) in DMSO at 100 ℃ to provide product 3a in 69% yield
(Scheme 3a). The reaction of intermediate 6 (1.0 mmol) with 2a
(2.0 mmol) at 100 ℃ also proceeded smoothly to provide product
3a in good yield (86%) in DMSO (Scheme 3b). The results
suggest that phenacyl iodine 4 and phenylglyoxal 5 are proper
intermediates for production of 3a. The reaction of 2-phenyl
imidazo[1,2-a]pyridine 7 with 2a was also performed under the
standard conditions; however, no desired product was observed
Acknowledgments
We would like to thank the National Natural Science Foundation of
China (Grant 21032001 and 21272085) for their generous financial
support and the research was supported in part by the PCSIRT (No.

4
Tetrahedron Letters
submitted along with the manuscript and graphic files to the
appropriate editorial office.
IRT0953). We also thank Dr. Chuanqi Zhou, Hebei University, for
analytical support.
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15 Typical procedure for preparation of 3: A sealed tube was charged with
acetophenone 1a (120 mg, 1 mmol), iodine (380.7 mg, 1.5 mmol) and
DMSO (3 mL) at room temperature. The resulting mixture was stirred at
100 ℃. After disappearance of the reactant (monitored by TLC), 2-
aminopyridine 2a (188 mg, 2.0 mmol) was added and the mixture was
heated to 100 ℃ for 2 h. After completion of the reaction and addition of
water (50 mL), the mixture was extracted with EtOAc (3 × 50 mL). The
extract was washed with 10% aqueous Na2S2O3 solution, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (eluent:
Petr/EtOAc = 3:1) to yield the desired product 3a as a white solid (214.6
mg, 75% yield).
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