Multicomponent solvent-free synthesis of benzimidazolyl imidazo[1,2-a]-pyridine under microwave irradiation

Article abstract of DOI:10.1021/co400010y

A novel one-pot, three-component reaction employing variously substituted benzimidazole-linked amino pyridines, aldehydes, and isonitriles catalyzed by scandium(III) triflate under solvent-free conditions were accomplished. This new synthetic methodology

Full text of DOI:10.1021/co400010y

Research Article
pubs.acs.org/acscombsci
Multicomponent Solvent-Free Synthesis Of Benzimidazolyl
Imidazo[1,2‑a]‑pyridine Under Microwave Irradiation
Barnali Maiti, Kaushik Chanda, Manikandan Selvaraju, Chih-Chung Tseng, and Chung-Ming Sun*
Laboratory of Combinatorial Drug Design, Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10,
Taiwan
S
* Supporting Information
ABSTRACT: A novel one-pot, three-component reaction employing variously substituted benzimidazole-linked amino
pyridines, aldehydes, and isonitriles catalyzed by scandium(III) triflate under solvent-free conditions were accomplished. This
new synthetic methodology facilitates the rapid generation of intricate molecular frameworks in three-dimensional fashion
leading to benzimidazole-imidazo[1,2-a] pyridines. This approach is envisioned as an environmentally benign process and a
simple operation to the biological interesting compounds. The present synthetic sequence permits the introduction of three
points of structural diversity to expand chemical space with high purity and excellent yields.
KEYWORDS: microwave irradiation, benzimidazole-imidazo[1,2-a]pyridines, solvent-free, bis-heterocyclic skeletons,
three-component reaction
have shown eloquent contributions in anticancer, antimicrobial,
antihelmintic (C and D) activities and against several viruses,
such as HIV, influenza, and cytomegalovirus.8 In recent years, it
has been acknowledged that the combination of two privileged
scaffolds in a single molecule potentially creates more active,
new entities with unusual bioproperties.9 In our journey to
explore new potential drug candidates, we envision that the
integration of two essential pharmacophores may provide a lead
for intangible derivation of a novel chemical skeleton for drug
discovery. Preparation methods for the two invidual skeletons
E and F are well documented,10 and in particular, the
conventional approaches toward the synthesis of the imidazo-
[1,2-a]pyridine motif, the skeleton E, can be summarized as (1)
reaction of 2-aminopyridine with aldehydes and isonitriles,11a,b
(2) reaction of alpha-haloketones with 2-aminopyridines in
presence of base,11c−e and (3) Copper-catalyzed synthesis of
imidazo[1,2-a]pyridine from 2-aminopyridines and nitroolefins
through a conjugate addition/oxidation/cyclization fashion.11f
However, most of these methods encounter limitations such
as use of solid-supported materials (e.g., expensive polymer
supported catalysts), longer reaction times, and elaborate
precursors required prior to the key transformation leading to
imidazo[1,2-a]pyridine cores. In a continuation with our on-
going research interest12 to introduce maximized diversity in
INTRODUCTION
■
In the annals of heterocyclic chemistry, discovery of new and
robust method for the synthesis of novel bis-heterocycles
for therapeutic application is an important area of research.
Because of the advances of high-throughput screening in the
pharmaceutical industry, there is an increasing demand for the
rapid breeding of novel molecular scaffolds.1 Multicomponent
reactions (MCR) have emerged as a powerful tool to construct
complex molecular architecture which involves multiple bond
formation in a single reaction step with high atom efficiency.2
Multicomponent reactions coupled with microwave irradiation
leading to accelarated synthesis of molecular libraries with
high degree of structural diversity are of both academic and
industrial significant.3 More recently, isocyanide based multi-
component reactions have been widely utilized to afford a large
number of nitrogen containing heterocyclic libraries.4 Over the
years, researchers have shown much interest in frameworks
featuring the imidazo[1,2-a]pyridine ring system and best
documented by the frequency with which the occurrence of this
previleged structure as a common skeleton in many biologically
active compounds.5 Imidazo[1,2-a]pyridine derivatives have
been found in many clinically accepted drugs, namely, zolpidem
(A) and olprinone (B), as shown in (Figure 1).6
In addition to the aforementioned drugs, the imidazo[1,2-a]-
pyridine pharmacophore also exhibits a wide range of thera-
peutic activities such as antibacterial, antiulcer, antifungal, calcium-
channel blocking and cyclin-dependent kinases (CDK) inhibition.7
More recently, compounds featuring the benzimidazole motif
Received: January 23, 2013
Revised: April 7, 2013
© XXXX American Chemical Society
A
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architechtures with multiple bond formation in a single step.
The use of microwave irradiation significantly increased the
reaction yield and shortened the reaction times.13 In this con-
text, the use of microwave irradiation under solvent-free con-
ditions stands out as an environmentally benign and powerful
tool for the rapid construction of the target molecules.
RESULTS AND DISCUSSION
■
To achieve our goal, we embarked our studies with the ester-
ification of 4-fluoro-3-nitro benzoic acid 1 under microwave
irradiation at 80 °C for 15 min to afford 4-fluoro-3-
nitrobenzoate 2 in 98% yield (Scheme 1). To introduce the
first point of diversity onto the skeleton, a variety of primary
amines were reacted with 4-fluoro-3-nitrobenzoate 2 in di-
chloromethane under reflux for 5 h to obtain intermediate 3.
We were delighted to note that the same reaction under micro-
wave irradiation at 80 °C was complete in 10 min. Subsequent
reduction of the nitro group was achieved at 90 °C for 5 min
by zinc dust and ammonium formate in methanol to furnish
o-phenylenediamines 4 in 90% yields.
The next task is to build-up the pyridinyl complexity through
an amide linkage between o-phenylenediamine derivatives 4
and 2-aminonicotinic acid 5.
Accordingly, we tested general coupling protocols such as
DCC/DMAP in CH2Cl2, EDC/HOBt/Et3N in DMF and
HBTU/HOBt/DIPEA in DMF at room temperature, under
reflux and micowave conditions. However, all such attempts
yielded no desired outcomes. When the coupling combination
was changed to DCC/HOBt and DIPEA in DMF, amide con-
jugates 6 were obtained in 25% yield. Gratifyingly, using
PyBOP/Et3N in DMF gave the satisfactory result with 90%
yield at room temperature for 24 h. The same transformation
under microwave irradiation (160 °C) was accomplished in
10 min (Scheme 1). The selective amide linkage formation with
Figure 1. Design concept of the present molecular library.
the bis-heterocycles and to develop a new strategy for the
efficient synthesis of the novel drug-like small molecules for
biological evaluation, herein, we report our recent study for
facile synthesis of benzimidazolyl-imidazo[1,2-a]pyridines.
We became interested in the possibility of using benzimidazole-
linked 2-amino pyridine as an amine fragment to react with
various aldehydes and isonitriles to afford three dimesional
Scheme 1. Microwave-Assisted Synthesis of Benzimidazole-imidazo[1,2-a]pyridine 10
B
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Table 1. Three-Component Reaction Optimization Leading to Benzimidazole-imidazo[1,2-a]pyridine 10{3,5,4}
c
reaction condition
entry
catalyst
solvent
temp (°C)
time (min)
isolated yield (%)
a
1
2
3
4
5
6
7
TFA
MeOH
MeOH
MeOH
neat
135
135
135
135
135
135
135
10
10
10
10
10
10
10
no reaction
a
a
PTSA
10
10
20
60
70
95
ZnCl2
ZnCl2
a
a
b
b
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
MeOH
PEG-200
neat
a
b
c
10 mol %. 20 mol % . Microwave-assisted reaction conditions.
the primary amine in the presence of secondary amine could be
the deactivating effect associated with the presence of ester
functionality on the benzene ring at the para position. Further,
to increase the diversity and substrate scope, the diamine 4
is attached with the aminopyridine moitey in two different posi-
tions by employing two different acids 6-aminonicotinic acid 5a
and 2-aminoisonicotinic acid 5b. Construction of benzimida-
zole fragment was achieved through an intramolecular ring
closure in the presence of TFA (10 mol %) and anhydrous
MgSO4 under microwave irradiation at 130 °C for 10 min to
afford the benzimidazole-linked aminopyridine 7 in 95% yield.
The key and final step in the present investigation is to accom-
plish the three component Groebke−Blackburn−Bienayme
reaction14 involving benzimidazole linked aminopyridine, aldehyde
and isonitrile to afford the target molecules. 4-Nitrobenzaldehyde
and cyclopentyl isonitrile were chosen as the reactive com-
ponents to optimize the reaction conditions (results sum-
marized in Table 1). Initially protic acids (TFA and p-TSA) and
Lewis acid ZnCl2 were tried as a catalyst to perform the task.
However all these catalysts failed to deliver the desired product
with significant yield. To our delight, 60% yield was achieved in
the presence of a catalytic amount of Sc(OTf)3 in methanol,
whereas no reaction was observed without Sc(OTf)3. Further
improvement was achieved under solvent-free condition with
an isolated yield of 83% for 10 min and no improvement was
observed with increasing reaction time.
Having obtained satisfactory results, a variety of aldehydes
were employed under this optimized condition. A significant
electronic effect of the sustituents on the reactivity was ob-
served. The results showed that aldehydes containing electron-
withdrawing substituents tend to react much faster than
electron-rich and neutral aldehydes but all reactants were
consumed within 10 min. Moreover, aliphatic aldehydes are
inert under these conditions and no reaction occurred even
under forcing conditions. We infer the observed reactivity was
from the facile imine-formation of the electron-deficient
aldehydes with intermediate 7 under Sc(OTf)3 catalysis and
the sequential addition of isocyanides onto the in situ formed
iminium ion was also considered more rapid than that of electron-
rich substrates.
Encouraged by these observations, we next turned our
attention to delineate the substrate scope of this three-
component reaction for the rapid access of substituted
benzimdazole-imidazo[1,2-a]pyridines 10 (Table 2). The
three component coupling of substituted benzimidazole-2-
aminopyridines 7, aldehydes 8, and isonitriles 9 afforded a
library of benzimidazole-imidazo[1,2-a]pyridines 10 in ex-
cellent yields by a simple one pot operation. On this basis, a
plausible reaction mechanism of the three component coupling
transformation is proposed (Scheme 2).
Benzimidazole-linked amino pyridine 7 condensed effectively
with Lewis acid activated aldehyde 8 to give imine intermediate
a, which subsequently underwent nucleophilic addition fol-
lowed by 5-exodig cylization with isonitrile to give the imidazo-
[1,2-a]pyridine intermediate b. Upon rearomatization, the
intermediate b furished the final compound benzimidazole-
imidazo[1,2-a]pyridine 10 (Scheme 2). The structure of the
obtained benzimidazole-imidazo[1,2-a]-pyridine was assigned
unambiguously by a single X-ray crystallographic study15
(Figure 2).
́
Thus the present methedology generates three different
benzimidazole-imidazo[1,2-a]pyridine scaffolds where benzimi-
dazole and imidazolopyridine linked each other with three different
combinations to broaden the scope of this molecular library.
CONCLUSION
■
In summary, we have successfully developed a multi-
component coupling method using Groebke−Blackburn−
Bienayme reaction as a key transformation to synthesize
́
biologically interesting benzimidazole-imidazo[1,2-a]pyridines
under solvent-free conditions. The use of microwave irradia-
tion in the entire synthetic sequence facilitated the trans-
formation with high efficiency at each step. In addition, this
one-pot novel reaction which integrated two different
pharmacophores into one framework may lead to new
hybrid molecules with interesting biological profiles. To the
best of our knowledge, the present new approach is the first
successful systemic synthesis of the titled bis-heterocyclic
compounds.
C
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Table 2. Substrate Scope of the Reaction and Physical Properties of Compound 10
a
b
c
entry
product
yield (%)
LRMS
H-bond donor
H-bond acceptor
clogP
1
10{1,1,1}
10{1,2,1}
10{1,3,1}
10{1,1,2}
10{1,4,2}
10{1,5,1}
10{2,5,2}
10{2,1,2}
10{2,4,2}
10{3,3,1}
10{3,4,3}
10{3,5,4}
10{3,5,3}
10{3,3,3}
10{3,1,5}
10{4,4,5}
10{5,6,3}
10{5,7,3}
10{5,6,1}
10{5,9,1}
72
83
89
80
84
86
82
90
87
81
83
83
80
77
82
86
85
78
87
88
538
583
556
512
556
583
593
548
592
540
574
553
575
548
481
537
567
559
559
575
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
8
10
8
7.83
7.59
7.98
7.04
7.08
7.59
9.27
9.52
9.55
9.34
8.65
8.39
8.37
8.77
8.01
8.04
8.47
8.26
9.05
8.57
2
3
4
8
5
8
6
8
7
9
8
7
9
9
10
11
12
13
14
15
16
17
18
19
20
7
9
9
9
7
7
9
5
5
5
6
D
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Table 2. continued
a
b
c
entry
product
yield (%)
LRMS
H-bond donor
H-bond acceptor
clogP
21
22
23
24
25
26
10{5,4,3}
10{6,1,3}
10{6,9,3}
10{6,8,3}
10{6,6,1}
10{6,10,1}
90
85
90
77
81
83
597
555
585
545
561
1
1
1
1
1
2
7
5
6
5
5
6
8.01
9.06
9.07
8.44
10.14
9.17
563
a
b
c
Isolated yields. LRMS was recorded by ESI ionization method. Estimated clogP by ChemBioOffice 2010.
Scheme 2. Proposed Reaction Mechanism for the Formation of 10
Figure 2. ORTEP diagram of compound 10{1,3,1} (Table 2, entry 3).
to obtain 6{3}. After completion of the reaction, the by-
products were filtered through filter paper. The reaction
mixture was partitioned by sodium bicarbonate solution and
ethyl acetate to remove the undesired impurities and dried to
give methyl 3-(2-aminonicotinamido)-4-(butylamino)benzoate
6{3}. To a solution of methyl 3-(2-aminonicotinamido)-4-
(butylamino)benzoate 6{3} (1.10 g, 3.22 mmol, 1.0 equiv) in
1,2-dichloroethane (3.0 mL), trifluoroacetic acid (2.5 mL), and
MgSO4 (400 mg) was added, and the mixture was subsequently
heated with stirring in a 10 mL microwave process sealed vial at
130 °C for 10 min. After completion of the reaction, MgSO4
EXPERIMENTAL PROCEDURES
■
Synthesis of Key Intermediate (7). Compound 4{3} was
prepared using our earlier reported procedure. To a solution
of 2-aminonicotinic acid 5 (869 mg, 6.30 mmol, 2.0 equiv)
in N,N′-dimethylformamide (DMF/Et3N) (3:7) was added
PyBOP (3.28 g, 6.30 mmol, 2.0 equiv) in a sequential order.
The resulting slurry was stirred for 5 min at room tempera-
ture and then added 3-amino-4-(butylamino)benzoate 4{3}
(700 mg, 3.15 mmol, 1.0 equiv) in N,N′-dimethylformamide
(5 mL). The reaction mixture was subsequently heated with
stirring in a 10 mL microwave process vial for 10 min at 160 °C
E
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was removed by filtration and the reaction mixture was
partitioned by water and ethyl acetate (100 mL) to obtain
methyl 2-(2-aminopyridin-3-yl)-1-butyl-1H-benzo[d]imidazole-
5-carboxylate 7{3} with high purity.
ACKNOWLEDGMENTS
■
The authors thank the authorities of the National Chiao Tung
University for providing the laboratory facilities.
Representative Example for Synthesis of Methyl 1-Butyl-2-
(3-(cyclopentylamino)-2(4-nitrophenyl)imidazo[1,2-a]-
pyridin-8-yl)-1H-benzo[d]imidazole-5-carboxylate 10{3,5,4}.
REFERENCES
■
(1) (a) Zhang, J.; Yang, P. L.; Gray, N. S. Targeting cancer with small
molecule kinase inhibitors. Nat. Rev. Cancer 2009, 9, 28−39.
(b) Brown, C. J.; Lain, S.; Verma, C. S.; Fersht, A. R.; Lane, D. P.
Awakening guardian angels: drugging the p53 pathway. Nat. Rev.
Cancer 2009, 9, 862−873.
(2) (a) Ganem, B. Strategies for innovation in multicomponent
reaction design. Acc. Chem. Res. 2009, 42, 463−472. (b) Estev
Villacampa, M.; Menendez, J. C. Multicomponent reactions for the
synthesis of pyrroles. Chem. Soc. Rev. 2010, 39, 4402−4421.
(c) Isambert, N.; Duque, M. M. S.; Plaquevent, J. C.; Genisson, Y.;
́
ez, V.;
́
́
Rodriguez, J.; Constantieux, T. Multicomponent reactions and ionic
liquids: a perfect synergy for eco-compatible heterocyclic synthesis.
Chem. Soc. Rev. 2011, 40, 1347−1357.
(3) (a) Mossetti, R.; Pirali, T.; Saggiorato, D.; Tron, G. C. Imides:
Forgotten players in the Ugi reaction. One-pot multicomponent
synthesis of quinazolinones. Chem. Commun. 2011, 47, 6966−6968.
(b) Cerulli, V.; Banfi, L.; Basso, A.; Rocca, V.; Riva, R. Diversity
oriented and chemoenzymatic synthesis of densely functionalized
pyrrolidines through a highly diastereoselective Ugi multicomponent
reaction. Org. Biomol. Chem. 2012, 10, 1255−1274.
To a 10 mL microwave process vial methyl 2-(2-aminopyridin-
3-yl)-1-butyl-1H-benzo[d]imidazole-5-carboxylate 7{3} (100 mg,
0.30 mmol, 1.0 equiv), 4-nitrobenzaldehyde 8{5}(68 mg, 0.45
mmol, 1.5 equiv), cyclopentyl isocyanide 9{4} (43 mg, 0.45
mmol, 1.5 equiv), and scandium triflate (3 mg, 0.006 mmol)
was added. The microwave vial was sealed and irradiated at
135 °C for 5 to 10 min in neat condition. After completion of
the reaction, reaction mixture was diluted with dichloromethane
(15 mL) and washed by 1% HCl solution. The dichloromethane
was evaporated. The slurry was loaded on silica gel column and
eluted with a mixture of ethyl acetate and hexane (1:1) to get the
(4) (a) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. New entry to
convertible isocyanides for the Ugi reaction and its application to the
stereocontrolled formal total synthesis of the proteasome inhibitor
́
omuralide. Org. Lett. 2007, 9, 3631−3634. (b) Cheron, N.; Ramozzi,
R.; Kaïm, L. E.; Grimaud, L.; Fleurat-Lessard, P. Challenging 50 years
of established views on Ugi reaction: A theoretical approach. J. Org.
Chem. 2012, 77, 1361−1366.
1
title compounds 10{3,5,4} in 83% yield. H NMR (300 MHz,
CDCl3): δ 8.60 (s, 1H), 8.36 (d, J = 8.7 Hz, 2H), 8.27 (d, J = 8.7
Hz, 2H), 8.20 (d, J = 6.9 Hz, 1H), 8.12 (dd, J = 7.3, 1.2 Hz, 1H),
7.58 (dd, J = 6.9, 1.5 Hz, 2H), 6.80 (t, J = 6.9 Hz, 1H), 4.48 (t,
J = 7.4 Hz, 2H), 4.00 (s, 3H), 3.73 (m, 2H), 1.83−1.76 (m, 6H),
1.73−1.62 (m, 4H), 1.13 (sext, J = 7.4 Hz, 2H), 0.69 (t, J = 7.4
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.1, 152.0, 147.1,
143.5, 141.2, 139.6, 135.5, 128.7, 128.5, 127.9, 127.0, 124.9,
124.8, 124.7, 127.2, 122.8, 120.8, 112.1, 110.6, 59.8, 52.6, 45.7,
34.1, 32.0, 24.1, 20.3, 13.8. MS (ESI) m/z: 553 (MH+). HRMS
(ESI, m/z) calcd for C31H33N6O4: m/z 553.2563; found
553.2566 (M + H). IR (cm−1, KBr): 3421, 3245, 2967, 1712,
1440, 1214.
(5) (a) Parenty, A. D. C.; Song, Y. F.; Richmond, C. J.; Cronin, L. A
general and efficient five-step one-pot procedure leading to nitrogen-
bridgehead heterocycles containing an imidazole ring. Org. Lett. 2007,
9, 2253−2256. (b) Kercher, T.; Rao, C.; Bencsik, J. R.; Josey, J. A.
Diversification of the three-component coupling of 2-aminohetero-
cycles, aldehydes, and isonitriles: Efficient parallel synthesis of a
diverse and druglike library of imidazo- and tetrahydroimidazo[1,2-a]
heterocycles. J. Comb. Chem. 2007, 9, 1177−1187. (c) Linton, A.;
Kang, P.; Ornelas, M.; Kephart, S.; Hu, Q.; Pairish, M.; Jiang, Y.; Guo,
C. Systematic structure modifications of imidazo[1,2-a]pyrimidine to
reduce metabolism mediated by aldehyde oxidase (AO). J. Med. Chem.
2011, 54, 7705−7712.
(6) (a) Ueda, T.; Mizusgige, K.; Yukiiri, K.; Takahashi, T.; Kohno, M.
Improvement of cerebral blood flow by olprinone, a phosphodiester-
ase-3 inhibitor, in mild heart failure. Cerebrovasc. Dis. 2003, 16, 396−
401. (b) Harrison, T. S.; Keating, G. M. Zolpidem: A review of its use
in the management of insomnia. CNS Drugs 2005, 19, 65−89.
(7) (a) Koubachi, J.; Kazzouli, S. E.; Berteina-Raboin, S.; Mouaddib,
A.; Guillaumet, G. Synthesis of polysubstituted imidazo[1,2-a]-
pyridines via microwave-assisted one-pot cyclization/Suzuki cou-
pling/palladium-catalyzed heteroarylation. J. Org. Chem. 2007, 72,
7650−7655. (b) Kianmehr, E.; Ghanbari, M.; Niri, M. N.; Faramarzi,
R. Novel one-pot three-component reaction for the synthesis of [2-
(alkylsulfanyl)imidazo[1,2-a]pyridin-3-yl](aryl)methanone. J. Comb.
Chem. 2010, 12, 41−44.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H and 13C NMR, LRMS, HRMS, FT-IR)
of essential intermediates, compound 10, and X-ray data of
compound 10{1,3,1}. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
(8) (a) Morningstar, M. L.; Roth, T.; Farnsworth, D. W.; Kroeger-
Smith, M.; Watson, K.; Buckheit, R. W.; Das, K.; Zhang, W.; Arnold,
E.; Julias, J. G.; Hughes, S. H.; Michejda, C. J. Synthesis, biological
activity, and crystal structure of potent nonnucleoside inhibitors of
HIV-1 reverse transcriptase that retain activity against mutant forms of
the enzyme. J. Med. Chem. 2007, 50, 4003−4015. (b) Sørensen, U. S.;
Trøbæk, D.; Christophersen, P.; Hougaard, C.; Jensen, M. L.; Nielsen,
E.; Peters, D.; Teuber, L. Synthesis and structure−activity relationship
studies of 2-(N-substituted)-aminobenzimidazoles as potent negative
gating modulators of small conductance Ca2+-activated K+ channels. J.
Med. Chem. 2008, 51, 7625−7634. (c) Peddibhotla, S.; Shi, R.; Khan,
*E-mail: cmsun@mail.nctu.edu.tw.
Funding
The authors thank the National Science Council of Taiwan for
financial assistance. This paper is particularly supported by
“Center for Bioinformatics Research of Aiming for the Top
University Program” of the National Chiao Tung University
and Ministry of Education, Taiwan.
Notes
The authors declare no competing financial interest.
F
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P.; Smith, L. H.; Mangravita-Novo, A.; Vicchiarelli, M.; Su, Y.;
Okolotowicz, K. J.; Cashman, J. R.; Reed, J. C.; Roth, G. P. Inhibition
of protein kinase C-driven nuclear factor-KB activation: Synthesis,
structure−activity relationship, and pharmacological profiling of
pathway specific benzimidazole probe molecules. J. Med. Chem.
2010, 53, 4793−4797.
component condensation. Synlett. 1998, 29, 661−663. (b) Blackburn,
C.; Guan, B.; Fleming, K.; Shiosaki, K.; Tsai, S. Parallel synthesis of 3-
aminoimidazo[1,2-a]pyridines and pyrazines by a new three-
component condensation. Tetrahedron Lett. 1998, 39, 3635−3638.
(c) Bienayme, H.; Bouzid, K. A new heterocyclic multicomponent
reaction for the combinatorial synthesis of fused 3-aminoimidazoles.
Angew. Chem., Int. Ed. 1998, 37, 2234−2237.
(15) Final product 10c was crystallized by slow evaporation of a
solution of ethyl acetate/hexane (1:1, v/v) at room temperature.
Crystal data: Empirical formula of 10c: C32H34F1N5O3. Formula
weight: 555.64. Crystal system: Monoclinic. The crystal data has been
deposited at Cambridge Crystallographic Data Centre [CCDC No.
859133]. Copies of the data can be obtained free of charge via www.
ccdc.ac.uk/conts/retrieving.html or CCDC, 12 union Road, 50
Cambridge CB2 1EZ, U.K.
(9) (a) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales, G.
A.; Thomas, C. J.; Zhang, W. Comprehensive survey of chemical
libraries for drug discovery and chemical biology: 2007. J. Comb. Chem.
̌ ́
2008, 10, 753−802. (b) Soural, M.; Bouillon, I.; Krchnak, V.
Combinatorial libraries of bis-heterocyclic compounds with skeletal
diversity. J. Comb. Chem. 2008, 10, 923−933.
(10) (a) Brasche, G.; Buchwald, S. L. CH functionalization/CN bond
formation: Copper-catalyzed synthesis of benzimidazoles from
amidines. Angew. Chem., Int. Ed. 2008, 47, 1932−1934. (b) Peng, J.;
Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, X.; Wang, Y.; Chen, C.
Copper-catalyzed intramolecular C−N bond formation: A straightfor-
ward synthesis of benzimidazole derivatives in water. J. Org. Chem.
2011, 76, 716−719. (c) Herath, A.; Dahl, R.; Cosford, N. D. P. Fully
automated continuous flow synthesis of highly functionalized
imidazo[1,2-a] heterocycles. Org. Lett. 2010, 12, 412−415. (d) Burch-
̀
ak, O. N.; Mugherli, L.; Ostuni, M.; Lacapere, J. J.; Maxim, Y.;
Balakirev, M. Y. Combinatorial discovery of fluorescent pharmaco-
phores by multicomponent reactions in droplet arrays. J. Am. Chem.
Soc. 2011, 133, 10058−10061. (e) Husinec, S.; Markovic, R.; Petkovic,
M.; Nasufovic, V.; Savic, V. A. Base-promoted cyclization of N-
propargylaminopyridines. Synthesis of imidazo[1,2-a]pyridine deriva-
tives. Org. Lett. 2011, 13, 2286−2289.
(11) (a) Schwerkoske, J.; Masquelin, T.; Perunb, T.; Hulmea, C.
Sequential Ugi/Strecker reactions via microwave assisted organic
synthesis: novel 3-center-4-component and 3-center-5-component
multicomponent reactions. Tetrahedron Lett. 2006, 47, 2989−2991.
(b) DiMauro, E. F.; Kennedy, J. M. Rapid synthesis of 3-amino-
imidazopyridines by a microwave-assisted four-component coupling in
one pot. J. Org. Chem. 2007, 72, 1013−1016. (c) Chen, Y.; Lam, Y.;
Lai, Y. H. Solid-phase synthesis of imidazo[1,2-a]pyridine using
sodium benzenesulfinate as a traceless linker. Org. Lett. 2002, 4, 3935−
3937. (d) Kamal, A.; Devaiah, V.; Reddy, K. L.; Shetti, R. V. C. R. N.
C.; Shankaraiah, N. Efficient solid-phase synthesis of a library of
imidazo[1,2-a]pyridine-8-carboxamides. J. Comb. Chem. 2007, 9, 267−
274. (e) Sucunza, D.; Samadi, A.; Chioua, M.; Silva, D. B.; Yunta, C.;
Infantes, L.; Carreiras, M. C.; Sorianoa, E.; Contelles, J. M. A practical
two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-
yl)pyridin-2-amines. Chem. Commun. 2011, 47, 5043−5045. (f) Yan,
R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Huang, G. S.; Liang, Y.
M. Cu(I)-catalyzed synthesis of imidazo[1,2-a]pyridines from amino-
pyridines and nitroolefins using air as the oxidant. J. Org. Chem. 2012,
77, 2024−2028.
(12) (a) Maiti, B.; Chanda, K.; Sun, C. M. Traceless synthesis of
hydantoin fused tetrahydro-beta-carboline on ionic liquid support in
green media. Org. Lett. 2009, 11, 4826−4829. (b) Yellol, G. S.; Tsai,
W. C.; Sun, C. M. Novel cyclization of bis-Boc-guanidines: Expeditive
traceless synthesis of 1,3,5-oxadiazinones under microwave conditions.
Chem. Commun. 2010, 46, 9170−9172. (c) Chen, C. H.; Yellol, G. S.;
Lin, P. T.; Sun, C. M. Base-catalyzed Povarov reaction: An unusual
[1,3] sigmatropic rearrangement to dihydropyrimidobenzimidazoles.
Org. Lett. 2011, 13, 5120−5123.
(13) (a) Polshettiwar, V.; Varma, R. S. Microwave-assisted organic
synthesis and transformations using benign reaction media. Acc. Chem.
Res. 2008, 41, 629−639. (b) Maiti, B.; Sun, C. M. Novel approach
towards the synthesis of skeletally diverse benzimidazole-pyrrolo[1,2-
a]quinoxaline by SNAr/Pictet−Spengler reaction under focused
microwave irradiation. New J. Chem. 2011, 35, 1385−1396.
(c) Chanda, K.; Maiti, B.; Tseng, C. C.; Sun, C. M. Microwave-
assisted linear approach toward highly substituted benzo[d]oxazol-5-
yl-1H-benzo[d]imidazole on ionic liquid support. ACS Comb. Sci.
2012, 14, 115−123.
(14) (a) Groebke, K.; Weber, L.; Mehlin, F. Synthesis of imidazo[1,2-
a]annulated pyridines, pyrazines, and pyrimidines by a novel three
G
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