Highly Regioselective, Acid-Catalyzed, Three-Component Cascade Reaction for the Synthesis of 2-aminopyridine-Decorated Imidazo[1,2- a]pyridine

Article abstract of DOI:10.1021/acscombsci.8b00149

A highly regioselective acid-catalyzed three-component reaction of 2-aminopyridine and 3-phenylpropiolaldehyde for the construction of imidazo[1,2-a]pyridine has been developed. This strategy provides a broad range of substrates and represents an efficien

Full text of DOI:10.1021/acscombsci.8b00149

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Letter
Highly Regioselective, Acid Catalyzed, Three-Component Cascade Reaction
for the Synthesis of 2-aminopyridine-Decorated Imidazo[1,2-a]pyridine
Qiu-Xing He, Yao-Feng Liang, Chang Xu, Xiao-Kun Yao, Hua Cao, and Hua-Gang Yao
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00149 • Publication Date (Web): 17 Jan 2019
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Highly Regioselective, Acid Catalyzed, Three-Component Cascade
Reaction for the Synthesis of 2-aminopyridine-Decorated
Imidazo[1,2-a]pyridine
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Qiu-Xing He,a, * Yao-Feng Liang,a Chang Xu,a Xiao-Kun Yao,a Hua Cao a and Hua-Gang Yao,a, *
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a School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering &
Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China
ABSTRACT: A highly regioselective acid-catalyzed three-component reaction of
2-aminopyridine and 3-phenylpropiolaldehyde for the construction of
imidazo[1,2-a]pyridine has been developed. This strategy provides a broad range of
substrates and represents an efficient approach to give various
2-aminopyridine-decorated imidazo[1,2-a]pyridine in good yields.
KEYWORDS: Pivalic acid, 2-aminopyridine, three-component reaction,
imidazo[1,2-a] pyridine
Considerable
efforts
have
been
devoted
to
developing
new
Imidazo[1,2-a]pyridine-based heterocycles compounds1-4, that is, a single
compound that displays the coexistence or synergism of two or more properties
including obvious inhibitory effects on many target enzymes5-7 and
good bioactivity in the aspect of anti-tumor8-12, anti-virus13-15, anti-bacterial16-18
anti-tuberculosis19,20 anti-inflammatory21, antiulcer22, anti-diabetic23,
,
,
antipsychotic24,25, etc. 3-Substituted imidazo[1,2-a]pyridines are of particular
interest, because of their potential applications in many commercially available
drugs such as necopidem, alpidem, saripidem, minodronic acid. The versatility
and value of these Imidazo[1,2-a]pyridine derivatives for a wide range of
applications feeds the continuous synthetic drive for novel and better synthetic
strategies, including oxidative cross-coupling, multi-component reaction26-34
.
Despite the fact that much progress has been made in the synthesis of these
derivatives, there still remains great challenges for synthetic organic chemists in
developing
3-2-aminopyridine-decorated imidazo[1,2-a]pyridines. For example, Mareev35 et
al. first reported the synthesis of 3-[2-pyridylamino(phenyl)
methyl]imidazo[1,2-a]pyridine by employing phenylpropynal and
a
facile
approach
for
the
direct
synthesis
of
2-aminopyridine (Scheme 1, a). Unfortunately, only one product has been
synthesized under their protocol. Subsequently, we disclosed an efficient one-pot
methodology for the synthesis of these compounds via AcOH catalysis (Scheme
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1, b) and a series of imidazo[1,2-α]pyridines were obtained in high to excellent
yields36. However ，there are still some limitations and inconveniences of this
protocol. The substituted pyridine-2-amine used to undergo a Michael type
addition to finish the transformation should be the same as the one reacted with
the aldehyde to form the imine intermediate during the first step of the reaction.
This seriously restricted the further application of a diversity oriented synthesis.
Therefore, the development of new catalytic systems to achieve two different
2-aminopyridine reactions for the direct construction of multifunctional
imidazo[1,2-a]pyridines is still of great importance. In this context, our group
envisions to construct 2-aminopyridine-decorated imidazo[1,2-a]pyridine derivatives
via a three-component reaction of 2-aminopyridines and 3-phenylpropionaldehyde.
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Scheme 1 Syntheses of N-(imidazo[1,2-a]pyridin-3-yl(phenyl) methyl)2-aminopyridine
(a) Mareev et al. work:
Ph
H
NH2
N
CHO
N
5 mol% HCl
MeCN 25 oC
+
N
N
N
Ph
only one example
(b) Our previous work:
R1
R
N
H
CHO
N
R1
AcOH CH3CN
80 oC 8 h
+
N
N
N
NH2
R1
R
R1= Cl, CF3
(c) This work:
R
H
CHO
+
N
R2
R1
+
R2
NH2
N
R1
N
N
NH2
N
N
R
In the beginning, the model reaction of 2-amino-3-methylpyridin 1{1}
,
5-(trifluoromethyl)-2-aminopyridine 1{5} and 3-phenylpropiolaldehyde 2{1} were
conducted to determine the suitable reaction conditions37. The results are described in
Table 1. The desired product 3{1,5,1} was not obtained without any catalysts in
dioxane at room temperature (entry 1). We then attempted to increase the yield of
product 3{1,5,1} by adding variety of catalysts. Using 5 mol % PivOH in dioxane at
room temperature afforded a yield of 42% (entry 2), but the addition of benzoic acid,
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AcOH, TsOH, TFA, ZnCl2, FeCl3, FeCl2, showed that the product 3{1,5,1} was
formed in relatively lower yield or not detected (entries 3-10). It is interesting to note
that the temperature changes significantly affect the yield. The results indicated that
the reaction at 60 °C was the most suitable (entry 2, 9-13). In order to improve the
reaction efficiency, we evaluated the influence of various solvents. Among the
solvents, we were delighted to find that the product 3{1,6,1} was readily formed in 92 %
yield in CH2Cl2. Other solvents, such as DMSO, DMF, or toluene, did not lead to any
improved result (entries 14-19).
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Table 1. Optimization of the reaction conditionsa
N
CHO
Ph
NH
2 F3C
NH2
CF3
catalyst, temp
N
+
+
N
N
N
H
solvent, N2, 8 h
Ph
N
1
{1}
1
{5}
2
3
{1,5,1}
{1}
Entry
1
Catalyst
Solvent
1,4-dioxane
T (oC)
rt
Yield b (%)
N.P.
2
3
PivOH
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMSO
rt
rt
42
28
Benzoic Acid
AlCl3
4
rt
30
5
AcOH
TsOH
rt
14
6
rt
17
7
TFA
rt
14
8
ZnCl2
rt
trace
trace
N.P.
67
9
FeCl3
rt
10
11
12
13
14
15
16
17
18
19
FeCl2
rt
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
60
80
100
60
60
60
60
60
60
65
64
23
DMF
<5
CH2Cl2
92
toluene
32
DCE
56
THF
62
a Reaction conditions: 1{1} (0.5 mmol), 1{5} (0.5 mmol), 2{1} (0.6 mmol), catalyst
(5 mol %), and solvent (2 mL), carried out in a sealed tube (25 mL); b Determined
by GC analysis.
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Scheme 2 Synthesis of Imidazoles using different 2-aminopyridine and alkynal
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CHO
R1
R
NH2
NH2
N
R2
PivOH
R1
N
R2
+
+
N
N
N
℃
CH2Cl2, 60 ,N2, 8 h
H
R
N
9
1
1
2
3
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CF3
Ph
CF3
CF3
CF3
N
N
N
N
Ph
Ph
Ph
NH
NH
NH
NH
N
N
N
N
N
N
N
N
3
{3,5,1} 82%
3
{4,5,1} 77%
Cl
3
{1,5,1} 92%
3
{2,5,1} 83%
NO2
Cl
CF3
N
N
N
N
Ph
Ph
Ph
Ph
I
NH
NH
NH
NH
I
I
N
N
N
N
N
N
N
N
3
3
{3,7,1} 70%
3
{9,7,1} 81%
{5,5,1} 79%
3
{1,10,1} 88%
I
Br
CF3
N
N
N
N
Ph
Ph
Ph
Ph
NH
NH
NH
NH
I
Br
N
N
N
N
N
N
N
N
F3C
3
3
{9,9,1} 75%
3
{5,5,1} 90%
{1,1,1} 82%
3
{8,8,1} 82%
CF3
N
N
N
N
Ph
Ph
Ph
NH
NH
NH
NH
N
N
N
N
N
N
N
N
3
{1,5,2} 63%
3
3
{4,4,1} 68%
{2,2,1} 71%
3
{3,3,1} 63%
CF3
CF3
CF3
N
N
N
NH
NH
NH
N
N
N
N
N
N
3
{1,5,3} 66%
3
3
{2,5,4} 70%
{1,5,4} 65%
a Isolated yields.
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Table 2. Structural diversity of 2-aminopyridine 1 and alkynal 2
5
6
1
pyridin-2-amines
7
8
9
NH2
N
NH2
NH2
NH2 F3C
NH2
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N
N
N
N
N
{2}
{1}
{3}
{5}
{4}
NH2
NH2
NH2
I
NH2
I
NH2
N
N
N
N
O2N
Cl
Br
Cl
{9}
{6}
{8}
{10}
{7}
2
Alkynal
CHO
CHO
CHO
CHO
{4}
{3}
{1}
{2}
Under the optimized reaction conditions, we examined a series of amino pyridines
and alkynals to probe the scope of this PivOH-catalyzed, three-component
transformation. The structural diversity of the starting materials are summarized in
Table 2. To our delight, a wide range substituted groups of aminopyridines all gave
the corresponding imidazo[1,2-a]pyridine with great efficiency. The results are shown
in Scheme 2. It was pleasing to find that methyl-substituted and iodized
pyridine-2-amine successfully reacted with 1{5} and 2{1} under the optimized
conditions to generate the corresponding product 3{1,5,1},
{4,5,1}, {5,5,1} with good yield of 79-92%. 5-NO2 and 5-I or 5-methyl and 5-Cl
monosubstituted aminopyridine also give the corresponding product 3{9,7,1} or
{3,7,1} in 81% or 70% yields, respectively. Additionally, the pyridine-2-amine
3{2,5,1}, 3{3,5,1},
3
3
3
substituted both with 5-Cl and 3-I reacted with 1{1} and 2{1} under the same
conditions to generate the product 3{1,10,1} with yield of 88%. It is no surprise that
the electron-withdrawing groups (4-CF3, 5-Br, 5-I) on the pyridine ring exhibit a
beneficial effect for the improvement of yield and the desired product 3{5,5,1},
3
{8,8,1}, 3{9,9,1} were obtained with the yield of 75-90%. With a electron donating
group on the pyridine ring such as 3-methyl, 4-methyl, 5-methyl and 6-methyl,
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reacted with 2{1} stably to afford the expected products 3{1,1,1}, 3{2,2,1}, 3{3,3,1},
5
6
7
8
3
{4,4,1} in good isolated yield. Subsequently, a variety of alkyls were also tested as
the substrate with various substituted 2-aminopyridines. For instance,
3-(p-tolyl)propiolaldehyde 2{2} and 3-(3,5-dimethylphenyl)propiolaldehyde 2{3}
reacted with 1{1} and 1{5} afforded products 3{1,5,2}, 3{1,5,3} in good yields. Then,
when oct-2-ynal 2{4} was tested as substrate, the corresponding product 3{1,5,4},
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3
{2,5,4} was also isolated. These results clearly show that this scheme is general and
suitable for the reaction of various substituted 2-aminopyridines and various alkynals.
The molecular structure of product 3{1,5,1} was determined by X-ray crystallography
(Figure S1).
On the basis of the above results, a plausible mechanism for this transformation is
described in Scheme 3. Initially, PivOH promotes dehydration of 2{1} by 1{1} to
afford intermediate imine A, which then cyclizes to intermediate B via an
intramolecular nucleophilic attack on the triple bond by the lone electron pair of the
nitrogen atom on the pyridine ring. Intermediate B then is converted to Intermediate C
via nuclephilic attack of 1{5} on its exocyclic double bond. Subsequent proton loss
finally affords product 3{1,5,1}.
Scheme 3
Possible mechanism
Ph
Ph
CHO
NH2
H
N
N
PivOH
+
N
N
N
- H2O
Ph
1
2
B
{1}
{1}
A
NH2
N
F3C
1
{5}
- H+
Ph
Ph
N
N
N
N
N
N
CF3
CF3
H2
H
N
N
3
C
{1,5,1}
In summary, we have developed an efficient and general PivOH-catalyzed
approach to prepare imidazole derivatives. This three-component reaction of
2-aminopyridines and ynals has been demonstrated by the preparation of a broad
range of functionalized imidazoles in moderate to good yields. This transformation
provides a convenient route for the formation of C–N bonds to prepare
amino-modified imidazo[1,2-a]pyridines.
ASSOCIATED CONTENT
Supporting Information
Details of experimental and analytical procedures, along with spectroscopic data for
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synthesized compounds. Crystallographic data for 3{1,5,1} (CCDC 1868963).
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AUTHOR INFORMATION
Corresponding Author
9
*E-mail: hgyao@gdpu.edu.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was financially supported by the National Natural Science Foundation of
China (21301035).
REFERENCES
(1) Delgado, O.; Delgado, F.; Vega, J. A.; Trabanco, A. A. N-bridged 5,6-bicyclic Pyridines: Recent Applications
in Central Nervous System Disorders. Eur. J. Med. Chem. 2015, 97, 719-731.
(2) Hulme, C.; Lee, Y.-S. Emerging Approaches for the Syntheses of Bicyclic Imidazo[1,2-x]-heterocycles. Mol.
Diversity 2008, 12 (1), 1-15.
(3) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. Synthesis of Imidazo[1,2-a]pyridine C-Nucleosides with
an Unexpected Site of Ribosylation. J. Org. Chem. 1997, 62 (11), 3453-3459.
(4) Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. Structural Requirements for Eszopiclone and
Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABAA) Receptor Are Different. J. Med. Chem. 2008, 51
(22), 7243-7252.
(5) Stec, M. M.; Andrews, K. L.; Bo, Y.; Caenepeel, S.; Liao, H.; McCarter, J.; Mullady, E. L.; San Miguel, T.;
Subramanian, R.; Tamayo, N.; Whittington, D. A.; Wang, L.; Wu, T.; Zalameda, L. P.; Zhang, N.; Hughes, P. E.;
Norman, M. H. The imidazo[1,2-a]pyridine Ring System as a Scaffold for Potent Dual Phosphoinositide-3-kinase
(PI3K)/mammalian target of Rapamycin (mTOR) Inhibitors. Bioorg. Med. Chem. Lett. 2015, 25 (19), 4136-4142.
(6) Ducray, R.; Simpson, I.; Jung, F. H.; Nissink, J. W. M.; Kenny, P. W.; Fitzek, M.; Walker, G. E.; Ward, L. T.;
Hudson, K. Discovery of Novel Imidazo[1,2-a]pyridines as Inhibitors of the Insulin-like Growth Factor-1 Receptor
Tyrosine Kinase. Bioorg. Med. Chem. Lett. 2011, 21 (16), 4698-4701.
(7) Han, W.; Menezes, D. L.; Xu, Y.; Knapp, M. S.; Elling, R.; Burger, M. T.; Ni, Z.-J.; Smith, A.; Lan, J.;
Williams, T. E.; Verhagen, J.; Huh, K.; Merritt, H.; Chan, J.; Kaufman, S.; Voliva, C. F.; Pecchi, S. Discovery of
Imidazo[1,2-a]-pyridine Inhibitors of Pan-PI3 Kinases that are Efficacious in a Mouse Xenograft Model. Bioorg.
Med. Chem. Lett. 2016, 26 (3), 742-746.
(8) Dam, J.; Ismail, Z.; Kurebwa, T.; Gangat, N.; Harmse, L.; Marques, H. M.; Lemmerer, A.; Bode, M. L.; de
Koning, C. B. Synthesis of Copper and Zinc 2-(pyridin-2-yl)imidazo[1,2-a]pyridine Complexes and Their
Potential Anticancer Activity. Eur. J. Med. Chem. 2017, 126, 353-368.
(9) Gladysz, R.; Adriaenssens, Y.; De Winter, H.; Joossens, J.; Lambeir, A.-M.; Augustyns, K.; Van der Veken,
P. Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an
Imidazo[1,2-a]pyridine Scaffold. J. Med. Chem. 2015, 58 (23), 9238-9257.
(10) Jarak, I.; Kralj, M.; Suman, L.; Pavlovic, G.; Dogan, J.; Piantanida, I.; Zinic, M.; Pavelic, K.;
Karminski-Zamola,
G.
Novel
Cyano-
and
N-Isopropylamidino-Substituted
Derivatives
of
Benzo[b]thiophene-2-carboxanilides and Benzo[b]thieno[2,3-c]quinolones: Synthesis, Photochemical Synthesis,
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Crystal Structure Determination, and Antitumor Evaluation. 2. J. Med. Chem. 2005, 48 (7), 2346-2360.
(11) Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic, M.; Suman, L.; Pavelic, K.; Karminski-Zamola, G. Novel
Cyano- and Amidino-Substituted Derivatives of Styryl-2-Benzimidazoles and Benzimidazo[1,2-a]quinolines.
Synthesis, Photochemical Synthesis, DNA Binding, and Antitumor Evaluation, Part 3. J. Med. Chem. 2007, 50
(23), 5696-5711.
(12) Dahan-Farkas, N.; Langley, C.; Rousseau, A. L.; Yadav, D. B.; Davids, H.; de Koning, C. B. 6-Substituted
Imidazo[1,2-a]pyridines: Synthesis and Biological Activity Against Colon Cancer Cell Lines HT-29 and Caco-2.
Eur. J. Med. Chem. 2011, 46 (9), 4573-4583.
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(13) Enguehard-Gueiffier, C.; Musiu, S.; Henry, N.; Veron, J.-B.; Mavel, S.; Neyts, J.; Leyssen, P.; Paeshuyse, J.;
Gueiffier, A. 3-Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines and Analogues, Novel Flaviviridae
Inhibitors. Eur. J. Med. Chem. 2013, 64, 448-463.
(14) Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.; Townsend, L. B. Synthesis and Antiviral Activity of
Novel Erythrofuranosyl Imidazo[1,2-a]pyridine C-Nucleosides Constructed via Palladium Coupling of
Iodoimidazo[1,2-a]pyridines and Dihydrofuran. J. Med. Chem. 2003, 46 (8), 1449-1455.
(15) Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.; Kerbal,
A.; Essassi, E. M. Synthesis of Acyclo-C-nucleosides in the Imidazo[1,2-a]-pyridine and Pyrimidine Series as
Antiviral Agents. J. Med. Chem. 1996, 39 (14), 2856-2859.
(16) Oezdemir, A.; Turan-Zitouni, G.; Kaplancikli, Z. A.; Iscan, G.; Khan, S.; Demirci, F. Synthesis and the
Selective Antifungal Activity of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine Derivatives. Eur. J. Med. Chem. 2010,
45 (5), 2080-2084.
(17) Al-Tel, T. H.; Al-Qawasmeh, R. A.; Zaarour, R. Design, Synthesis and in Vitro Antimicrobial Evaluation of
Novel Imidazo[1,2-a]pyridine and Imidazo[2,1-b][1,3]benzothiazole Motifs. Eur. J. Med. Chem. 2011, 46 (5),
1874-1881.
(18) Sun, X.-Y.; Wu, R.; Wen, X.; Guo, L.; Zhou, C.-P.; Li, J.; Quan, Z.-S.; Bao, J. Synthesis and Evaluation of
Antibacterial Activity of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline Derivatives. Eur. J. Med. Chem. 2013,
60, 451-455.
(19) Kang, S.; Kim, R. Y.; Seo, M. J.; Lee, S.; Kim, Y. M.; Seo, M.; Seo, J. J.; Ko, Y.; Choi, I.; Jang, J.; Nam, J.;
Park, S.; Kang, H.; Kim, H. J.; Kim, J.; Ahn, S.; Pethe, K.; Nam, K.; No, Z.; Kim, J. Lead Optimization of a Novel
Series of Imidazo[1,2-a]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and
Extensively-Drug-Resistant Anti-tuberculosis Agent. J. Med. Chem. 2014, 57 (12), 5293-5305.
(20) Moraski, G. C.; Markley, L. D.; Hipskind, P. A.; Boshoff, H.; Cho, S.; Franzblau, S. G.; Miller, M. J. Advent
of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis
Activity. ACS Med. Chem. Lett. 2011, 2 (6), 466-470.
(21) Hamdouchi, C.; De Blas, J.; Del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L.
2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a Novel Class of
Inhibitors of Human Rhinovirus: Stereospecific Synthesis and Antiviral Activity. J. Med. Chem. 1999, 42 (1),
50-59.
(22) Kaminski, J. J.; Doweyko, A. M. Antiulcer Agents. 6. Analysis of the in Vitro Biochemical and in Vivo
Gastric Antisecretory Activity of Substituted Imidazo[1,2-a]pyridines and Related Analogs Using Comparative
Molecular Field Analysis and Hypothetical Active Site Lattice Methodologies. J. Med. Chem. 1997, 40 (4),
427-436.
(23) Liang, G.-B.; Qian, X.; Feng, D.; Biftu, T.; Eiermann, G.; He, H.; Leiting, B.; Lyons, K.; Petrov, A.;
Sinha-Roy, R.; Zhang, B.; Wu, J.; Zhang, X.; Thornberry, N. A.; Weber, A. E. Optimization of 1,4-diazepan-2-one
Containing Dipeptidyl Peptidase IV Inhibitors for the Treatment of type 2 Diabetes. Bioorg. Med. Chem. Lett.
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2007, 17 (7), 1903-1907.
(24) Ulloora, S.; Shabaraya, R.; Adhikari, A. V. Facile Synthesis of New Imidazo[1,2-a]pyridines Carrying
1,2,3-triazoles via Click Chemistry and Their Antiepileptic studies. Bioorg. Med. Chem. Lett. 2013, 23 (11),
3368-3372.
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(25) Nikalje, A. P. G.; Shaikh, A. N.; Shaikh, S. I.; Kalam Khan, F. A.; Sangshetti, J. N.; Shinde, D. B.
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Microwave
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thiazolidin-3ylamino)ethyl)benzamide Derivatives as Anticonvulsant Agents. Bioorg. Med. Chem. Lett. 2014, 24
(24), 5558-5562.
(26) Rassokhina, I. V.; Shirinian, V. Z.; Zavarzin, I. V.; Gevorgyan, V.; Volkova, Y. A. Copper(II)-Mediated
Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade Aminomethylation/Cycloisomerization of Alkynes. J.
Org. Chem. 2015, 80 (21), 11212-11218.
(27) Meng, X.; Wang, Y.; Yu, C.; Zhao, P., Heterogeneously Copper-catalyzed Oxidative Aynthesis of
imidazo[1,2-a]pyridines Using 2-aminopyridines and Ketones Under Ligand- and Additive-free Conditions. RSC
Adv. 2014, 4 (52), 27301-27307.
(28) Santra, S.; Mitra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Iron(III)-catalyzed Three-component Domino
Strategy for the Synthesis of Imidazo[1,2-a]pyridines. Tetrahedron Lett. 2014, 55 (37), 5151-5155.
(29) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.; Han, J.; Lei, A. Heteroaromatic Imidazo[1,2-a]pyridines Synthesis
from C-H/N-H oxidative Cross-coupling/cyclization. Chem. Commun. (Cambridge, U. K.) 2012, 48 (90),
11073-11075.
(30) Kaswan, P.; Pericherla, K.; Rajnikant; Kumar, A., Synthesis of 3-aroylimidazo[1,2-a]pyridines via CuCl2
catalyzed tandem dual carbon-nitrogen bonding. Tetrahedron 2014, 70 (45), 8539-8544.
(31) Guchhait, S. K.; Chandgude, A. L.; Priyadarshani, G., CuSO4-Glucose for in Situ Generation of Controlled
Cu(I)-Cu(II) Bicatalysts: Multicomponent Reaction of Heterocyclic Azine and Aldehyde with Alkyne, and
Cycloisomerization toward Synthesis of N-Fused Imidazoles. J. Org. Chem. 2012, 77 (9), 4438-4444.
(32) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A., Synthesis of Imidazo[1,2-a]pyridines: a Decade Update.
Chem. Commun. (Cambridge, U. K.) 2015, 51 (9), 1555-1575.
(33) Samanta, S.; Hajra, A., Regioselective Synthesis of Unsymmetrical Biheteroaryls via Copper(II)-catalyzed
Cascade Annulation. Chem. Commun. (Cambridge, U. K.) 2018, 54 (27), 3379-3382.
(34) Samanta, S.; Hajra, A., Ruthenium-catalyzed Tandem Annulation/arylation for the Synthesis of
Unsymmetrical Bis(heteroaryl)methanes. Org. Biomol. Chem. 2018, 16 (37), 7012-7016.
(35) Mareev, A. V.; Medvedeva, A. S.; Mitroshina, I. V.; Afonin, A. V.; Ushakov, I. A.; Romanenko, G. V.;
Tret'yakov, E. V. Self-assembling 3-[2-pyridylamino(phenyl)methyl]imidazo[1,2-a]pyridine from Phenylpropynal
and 2-aminopyridine. Russ. J. Org. Chem. 2008, 44 (11), 1718-1720.
(36) Cao, H.; Liu, X.; Zhao, L.; Cen, J.; Lin, J.; Zhu, Q.; Fu, M. One-Pot Regiospecific Synthesis of
Imidazo[1,2-a|pyridines: A Novel, Metal-Free, Three-Component Reaction for the Formation of C-N, C-O, and
C-S Bonds. Org. Lett. 2014, 16 (1), 146-149.
(37) Synthesis of 3{1,5,1} according to the following procedure: A 25 mL sealed tube was charged with a stirring
bar, and added 3-methylpyridin-2-amine 1{1} (0.081g, 1.0 equiv), 4-(trifluoromethyl)pyridin-2-amine 1{5}
(0.054g, 1 equiv), 3-phenylpropiolaldehyde 2{1} (0.078g, 1.2 equiv), PivOH (0.005g, 5% equiv), CH2Cl2 (2 mL).
The reaction was carried out at 60 OC stirring for 8 h and monitored by TLC. The reaction mixture was then
diluted with EtOAc and water, extracted with EtOAc. The organic layers were washed with brine and dried over
MgSO4, evaporated under reduced pressure. The crude mixture was purified by Thin layer chromatography silica
gel plate (eluted with petroleum ether : ethyl acetate = 2 : 1) to give 3{1,5,1} in 92% yield (175.8 mg).
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A highly regioselective acid-catalyzed three-component reaction of 2-aminopyridine and 3-
phenylpropiolaldehyde for the construction of imidazo[1,2-a]pyridine has been developed. This strategy
provides a broad range of substrates and represents an efficient approach to give various 2-aminopyridine-
decorated imidazo[1,2-a]pyridine in good yields.
285x41mm (72 x 72 DPI)
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