Efficient Access to Imidazo[1,2- a] pyridines/pyrazines/pyrimidines via Catalyst-Free Annulation Reaction under Microwave Irradiation in Green Solvent

Article abstract of DOI:10.1021/acscombsci.7b00173

An expeditious catalyst-free heteroannulation reaction for imidazo[1,2-a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using H₂O-IPA as the reaction medium, various substituted 2-aminopyridines/pyra

Full text of DOI:10.1021/acscombsci.7b00173

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Article
Efficient access to imidazo[1,2-a]pyridines/pyrazines/pyrimidines via catalyst
free annulation reaction under microwave irradiation in green solvent
R Nishanth Rao, Balamurali MM, Barnali Maiti, Ranjit Thakuria, and Kaushik Chanda
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00173 • Publication Date (Web): 26 Jan 2018
Downloaded from http://pubs.acs.org on January 26, 2018
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Efficient access to imidazo[1,2-a]pyridines/pyrazines/pyrimidines via catalyst
free annulation reaction under microwave irradiation in green solvent
R Nishanth Rao,a Balamurali MM,b Barnali Maiti,a Ranjit Thakuria,c Kaushik Chandaa*
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aDepartment of Chemistry, School of Advanced Sciences, VIT University, Velloreꢀ632014, India
b Department of Chemistry, School of Advanced Sciences, VIT University, Chennaiꢀ632014,
India
cDepartment of Chemistry, Gauhati University, Guwahatiꢀ781014, India
Email: chandakaushik1@gmail.com
This article is dedicated to Prof Chung Ming Sun for his enormous contribution in combinatorial
chemistry
Abstract:
An expeditious catalyst free heteroannulation reaction for imidazo[1,2ꢀa]pyridines/pyrimidines
/pyrazines was developed in green solvent under microwave irradiation. Using H2OꢀIPA as the
reaction medium, various substituted 2ꢀaminopyridines/pyrazines/pyrimidines underwent
annulation reaction with αꢀbromoketones under microwave irradiation to provide the
corresponding imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic
methodology appears to be very simple and superior to the already reported procedures with the
high abundance of commercial reagents and great ability in expanding the molecular diversity.
The present synthetic sequence is visualized as an environmentally benign process which allows
the introduction of three points of structural diversity to expand chemical space with excellent
purity and yields. The antiꢀinflammatory and antimicrobial activities of the derivatives were
evaluated. Screening results uncovered three derivatives with strong inhibition of albumin
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denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive
bioassay results implied that the library of potential antiꢀinflammatory agents could be rapidly
prepared in an ecoꢀfriendly manner, and provided new insights into drug discovery for medicinal
chemists.
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Graphical abstract
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Introduction
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Synthesis of highly functionalized, fusedꢀheterocyclic compounds is important as these are the
key structural elements frequently encountered in many natural products and biomolecules.1
Among nitrogen fused azoles, imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines are prevalent
heterocycles in the medicinal chemistry, organometallics and material science research.2
Molecules with imidazo[1,2ꢀa]pyridine/pyrimidine/pyrazine moieties have a wide range of
biological properties such as antifungal, antibacterial, antiviral, anticancer, analgesic
antiepileptic, cardiac stimulating agent, and uterine relaxant.3 However, in addition to these
biological activities, these privileged scaffolds also exhibit numerous photophysical properties.4
The core structure of imidazo[1,2ꢀa]pyridines/pyrimidines has also been found in many drugs
such as zolpidem (A), alpidem (B), zolimidine (C), olprinone (D), divaplon (E) and fasiplon (F)
where as the imidazo[1,2ꢀa]pyrazine moiety are the structural analogs of purine (G)5 in figure 1.
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Figure 1. Biologically active imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines moieties
In view of their wide ranging bioactivities, several synthetic methods have been developed for
imidazo[1,2ꢀa]pyridine/pyrimidine/pyrazine moieties. Several of them are classified as
cyclocondensation, oxidative coupling, tandem reaction, aminooxygenation, and hydroamination
reactions.6 However, the most traditional approach for the synthesis of imidazo[1,2ꢀ
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a]pyridine/pyrimidine/pyrazine derivatives involves the condensation reaction of αꢀhaloketones
with 2ꢀaminopyridines/pyrimidines/pyrazines with or without catalysis. Since then a plethora of
catalysts have been reported for the synthesis of imidazo[1,2ꢀa]pyridine/pyrimidine/pyrazine
derivatives, such as neutral Al2O3, NaHCO3, solvent free conditions, microware irradiation,
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I2/ketone, NaI, TiCl4, and K2CO3. To find an alternative, some researchers also used αꢀ
diazoketones and αꢀtosyloxy ketone instead of αꢀhaloketones catalyzed by Lewis acids or ionic
liquids to obtain the imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines.8 Recently Lin et. al.
developed the microwave assisted, solvent and catalystꢀfree synthesis of imidazo[1,2ꢀa]pyridines
with limited substrate scope.9 Nonetheless, most of the synthetic methodologies have some
drawbacks such as the cost of synthesis, longer reaction time, harsh reaction conditions with the
use of bases, use of toxic high boiling organic solvents, decomposition of substrates during
overheating, limited substrate scope, and lower yields of the products. In comparison to the
conventional heating, the application of microwave irradiation accelerates the synthetic process
for a rapid transformation, with high yields, and mild reaction profile. Microwave assisted
organic synthesis in water has attracted considerable attention owing to the nonꢀtoxic and nonꢀ
flammable nature of water.10 However the low solubility of organic compounds in water has
been overcome by the use of an organic coꢀsolvent, the exploitation of hydrophobic effects and
the use of water at high temperatures under microwave irradiation. Using the application of
microwave irradiation in H2OꢀIPA as the reaction medium we therefore, wished to develop a
convenient,
microwave
assisted
catalyst
free
synthesis
of
imidazo[1,2ꢀ
a]pyridines/pyrazines/pyrimidines. In comparison to already reported synthetic protocols
described above, the present methodology for the synthesis of imidazo[1,2ꢀ
a]pyridines/pyrazines/pyrimidines offered several advantages such as the use of microwave
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irradiation which reduces the reaction time to minutes for the fast delivery of target compounds,
H2OꢀIPA as a green and ecoꢀfriendly solvent, excellent yields with high purity and a broad
substrate scope.
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In continuation of our research to develop newer synthetic methodologies for the
construction of bioactive heterocycles,11 we aim to utilize microwaveꢀassisted reaction in green
solvents for the synthesis of imidazo[1,2ꢀa]pyridines/pyrazines/pyrimidines from readily
available chemicals in excellent yields.
Results and Discussion
In a model reaction, 2ꢀaminopyridine 1{1}, and 2ꢀbromoꢀ1ꢀ(2ꢀnitrophenyl)ethanone 2{1}, were
chosen as substrates to optimize the reaction conditions. We initiated our studies by examining
the conversion to imidazo[1,2ꢀa]pyridines 3{1,1} at room temperature under neat conditions.
Disappointingly, only unreacted starting materials 1{1} and 2{1} were recovered from the
reaction mixture (Table 1, entry 1). Increasing the temperature to 100 °C, a new spot was
observed (Table 1, entry 2). The desired product was formed in only 30% yield using standard
heating. Unfortunately, the reaction did not afford any cyclized product using polar aprotic
solvents such as CH3CN, and DMSO (Table 1, entries 3, 4). However, by changing the solvent
system to H2OꢀIPA at 100 oC, the reaction was completed in 2 hours with an 80% yield (Table 1,
entry 5). The same reaction was performed under microwave irradiation to further enhance its
efficiency. Initially the same set of reaction that was performed in EtOH under microwave
irradiation took 25 minutes for completion with 85% yield (Table 1, entry 6). However, the
desired product 3{1,1} was obtained in better yield when the reaction was performed under
microwave irradiation for 5 min using H2OꢀIPA as solvent (95% yield, Table 1, entry 7).
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Table 1. Optimization of catalyst free heteroannulation reaction of 2ꢀaminopyridine 1{1}, and 2ꢀ
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bromoꢀ1ꢀ(2ꢀnitrophenyl)ethanone 2{1}.
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O
N
Br
Catalyst free
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+
N
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Reaction conditions
N
NH2
NO2
O2N
1{1}
3{1.1}
2
{1}
c
3
{1.1} yield%
entry
solvent
temperature
time
1
2
Neat
Neat
rt
8 h
4 h
0%
100 oC
reflux
30%
CH3CN
3
4
6 h
6 h
0%
0%
130 oC
100oC
DMSO
H2O-IPA
EtOH
5
6
2 h
80%
85%
MWb, 75 oC
MWb, 75 oC
25 min
H2O-IPA
7
5 min
95%
a reaction was performed using 1{1} (1 mmol), 2{1} (1 mmol), H2O-IPA (4 mL, 1:1),
b Microwave reactions were carried out in Microwave Model No. CATA R (Catalyst systems, Pune)
using power 240 watt, c Yield of the isolated product.
We next evaluated the scope of the reaction by employing 2ꢀaminopyridine 1{1ꢀ5} and
phenacyl bromide 2{1ꢀ7}. Interestingly, the reaction efficiency was not affected by the
substituent groups on both 2ꢀaminopyridines 1{1ꢀ5} and phenacyl bromides 2{1ꢀ7}. Both the
electronꢀwithdrawing and electronꢀdonating substituents were well tolerated under the
microwave reaction conditions and proceeded smoothly to give the corresponding imidazo[1,2ꢀ
a]pyridines derivatives 3 in excellent yields. All these reactions were performed under an open
atmosphere. The overall reaction time is typically 5ꢀ8 mins as shown in Scheme 1.
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Scheme 1. Synthesis of imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines 3.
To further examine the efficiency of this heteroannulation reaction and to swiftly expand our
unique compound library, we extended the substrate scope to 2ꢀaminopyrimidine and 2ꢀamino
pyrazine as suitable substrates. As depicted in Table 2, entries 16ꢀ23, we were pleased to find
that 2ꢀaminopyrimidines 1{6} and 2ꢀaminopyrazines 1{7} could be smoothly transformed to
imidazo[1,2ꢀa]pyrimidines/pyrazines 3. After completion of the reaction, the corresponding
imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazine derivatives were obtained with excellent yields
followed by a simple workꢀup involving removal of solvents under reduced pressure, extraction,
and solvent evaporation. Finally the crude products were purified by column chromatography
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followed by spectroscopic characterization using HNMR, 13C NMR, and mass spectroscopy
(MS). More recently, it has been realized that in designing efficient, economic and ecofriendly
strategies for chemical synthesis the concept of sustainable development plays an important role.
In view of this, Sheldon et al introduced the Eꢀfactor, or environmental impact factor which
helps to compute the amount of waste generated per kilogram of product to assess the
“environmental acceptability” of a manufacturing process.12 Furthermore, our green synthetic
reaction conditions display lower Eꢀfactors (Table 2) for synthesizing the imidazo[1,2ꢀ
a]pyridines/pyrimidines/pyrazines 3 which is consistent with the principles of atom economy in
supporting information. Next, to measure the orally available drug properties, we calculated the
physicochemical properties of the synthesized library using Lipinski’s rule of five13 by
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calculating the molecular weight, c log P, the number of hydrogen bond donors and acceptors
and the number of rotatable bonds of each member of the library. According to this rule, a
potential molecule can have drugꢀlike physical properties if the molecular weight is less than
500, the c log P value, which addresses bioavailability and delivery issues, is not more than 5,
the hydrogen bond acceptors are not more than 10, the hydrogen bond donors are not more than
5 and there is not more than 10 rotatable bonds. However, for the design of a potential molecule,
one Lipinski violation is allowed. Interestingly the predicted values of drugꢀlike properties for
these library members are within the accepted limits of Lipinski’s rule of five for the entire
portion of the library as shown in Table 2.
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Table 2. Substrate Scope of the Reaction and Physical Properties of Compound 3
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aIsolated yields. bLRMS was recorded by GCꢀMS method. cEstimated c log P by ChemBioOffice 2010.
Additionally, we have investigated the potential synthetic applicability of this method on the
gram scale using the model reaction. As depicted in Scheme 2, the reaction could afford 2.15 g
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of 3{1,1} in 90% yield without any significant loss of its efficiency, demonstrating the potential
applications of the present method for a large scale synthesis of imidazo[1,2ꢀa]pyridine
scaffolds.
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Scheme 2. Gramꢀscale synthesis of imidazo[1,2ꢀa]pyridines 3{1,1}.
A plausible mechanistic pathway for this heteroannulation reaction is outlined in Scheme 3.
Probably the reaction occurs via a sequence of nucleophilic bromoꢀsubstitution followed by an
intramolecular cyclization and subsequent elimination of water. Initially the bromoꢀgroup of
phenacyl bromides 2 underwent nucleophilic substitution by pyridine Nꢀatom through the
electronic resonance of the 2ꢀamino group of 1 leading to the Nꢀalkylated adduct a which on
liberation of HBr obtained the intermediate b. The next step of the reaction involves the
intramolecular cyclization through the condensation of amine with carbonyl functionality of
ketone followed by proton exchange to obtain the cyclic intermediate c. The final step of the
reaction involves the elimination of a water molecule from intermediate c to afford imidazo[1,2ꢀ
a]pyridines 3 derivatives.
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Scheme 3. Possible mechanism for heteroannulation reaction to imidazo[1,2ꢀa]pyridines 3
derivatives.
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To further confirm the structure, we undertook the Xꢀray crystallographic study of compound
3{4,6}.14 The Figure 2 depicts the ORTEP diagram of compound 3{4,6} (Xꢀray crystallographic
data were specified in Supporting Information). The Xꢀray crystal structure of compound 3{4,6}
indicates that the 4ꢀmethoxy phenyl group was present at C7 carbon and the C6 carbon bears
hydrogen atom which unequivocally confirms its structure.
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Figure 2. ORTEP diagram of compound 3{4,6}.
To determine the antiꢀinflammatory activities of imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines
3, inhibition of the albumin denaturation power was evaluated.15 It is well known that
inflammation is a complex process, that can be associated with increased vascular permeability,
protein denaturation, membrane alteration etc. There are many in vitro assays, available for the
preliminary screening of compounds exhibiting antiꢀinflammatory activity. Albumin
denaturation assay is one among those. Moreover, it has been reported that many compounds that
are known to inhibit protein denaturation are good antiꢀinflammatory agents.16 Because of in vivo
denaturation of proteins, autoꢀantigens are produced in certain rheumatic diseases. The
evaluations were carried out inꢀvitro at different concentrations and compared to wellꢀknown
antiꢀinflammatory drug diclofenac sodium (Table 3). The inhibitory activity was carried out at
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different concentrations and the percentage inhibition at 100 µM concentration of each
compound in 2 % DMSO has been reported.
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Table 3. % Inhibition of albumin denaturation.
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The estimated inhibitory activity of imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines 3 were
measured and results were shown in Table 3. Most of the compounds exhibited moderate to
strong activity with the exception of compounds 3{1,1}, 3{2,4}, and 3{7,4} with 2ꢀnitro and pꢀ
tolyl substitution on the imidazo[1,2ꢀa]pyridine ring.
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Likewise, imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines 3 were screened for inꢀvitro
antimicrobial activity against Gramꢀnegative (Escherichia coli, Pseudomonas aeruginosa,
Proteus, and Klebsiella) and Gramꢀpositive (Staphylococcus aureus) bacteria by the
conventional serial dilution method as shown in Table 4.
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Table 4. Antimicrobial activities of imidazo[1,2ꢀa]pyridines/pyrimidines/pyrazines 3.
Minimum inhibitory concentration (MIC) values were evaluated and ciprofloxacin whose MIC
values are reported in the literature was used as a standard reference drug only as a positive
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control and is in no way related to the MIC values obtained for our test samples. Most of the
compounds displayed antibacterial activities and is shown in Table 4. MIC values of compounds
3{1,1}, 3{2,4}, 3{4,4}, and 3{4,6} showed the ability to inhibit the growth of E. coli and
Proteus whereas compounds 3{1,3}, 3{2,4}, 3{3,4}, 3{4,4}, and 3{4,6} were effective towards
Pseudomonas and Staphylococcus bacteria. Among all the compounds, only compounds 3{4,4},
and 3{4,6} were active towards inhibiting the growth of both gram negative and gram positive
bacteria as shown in Table 4. The observed antibacterial activities of the synthesized compounds
demonstrated the preliminary structureꢀactivity relationships. Particularly, compounds 3{4,4},
and 3{4,6} bearing pꢀtolyl and pꢀOMe substitution as electron donating substituents were active
towards inhibiting the growth of Proteus and Klebsiella bacteria. These results indicated that
some of these compounds possessed selective antimicrobial activities and further development of
such compounds might be of interest to medicinal chemists.
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Conclusion
In conclusion, we have developed catalyst free heteroannulation for imidazo[1,2ꢀ
a]pyridines/pyrimidines/pyrazines in green solvent under microwave irradiation. The salient
features of this strategy include milder reaction conditions, inexpensive reagents, highꢀatom
economy, and short reaction time in a single synthetic operation. All the synthetic compounds
were studied for their antiꢀinflammatory activities in vitro and antimicrobial activities. Antiꢀ
inflammatory data indicated that compounds with 2ꢀnitro or 4ꢀmethyl substituent on the
imidazo[1,2ꢀa]pyridine moiety showed significant albumin denaturation power and moreover
some of tested compounds demonstrated the antimicrobial activity by inhibiting the growth of
Proteus and Klebsiella bacteria. These results suggested that these heterocyclic molecules might
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serve as interesting lead compounds for the development of new antiꢀinflammatory and/or
5
6
antimicrobial
agents.
Further
medicinal
applications
of
the
imidazo[1,2ꢀ
7
8
a]pyridines/pyrimidines/pyrazines derivatives are currently under investigation in our laboratory.
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Experimental section
Representative Procedure for the Synthesis of 2-(2-nitrophenyl)imidazo[1,2-a]pyridine
3{1,1}. In a round bottomed flask, a mixture of 2ꢀaminopyridine 1{1}(0.1 g, 1.06 mmol, 1.0
equiv), and 2ꢀbromoꢀ1ꢀ(2ꢀnitrophenyl)ethanone 2{1} (0.256 g, 1.06 mmol, 1.0 equiv) was added
to 5 mL solution of H2OꢀIPA (1:1). The reaction mixture was irradiated under microwave
heating at 240 watt for 5 min at 75 ºC. The progress of the reaction was monitored by TLC. After
completion, the reaction mixture was cooled to room temperature and extracted with ethyl
acetate (10 mL, twice). The combined organic layer was dried over anhydrous MgSO4. The
combined filtrate was subjected to evaporation to obtain the crude compound, which was
purified over silica gel column (60–120 mesh) using 5% ethyl acetate in hexane as eluent to
obtain the corresponding 2ꢀ(2ꢀnitrophenyl)imidazo[1,2ꢀa]pyridine 3{1,1}as the product.
2ꢀ(2ꢀnitrophenyl)imidazo[1,2ꢀa]pyridine 3{1,1}.
1
Yield: 95%; Yellow solid; mp: 151ꢀ152 °C; Rf = 0.5 (20%EtOAc/nꢀhexane); H NMR (400
MHz, CDCl3) δ 8.10 (d, J = 6.76 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.71(d, J =
8.04 Hz, 1H), 7.62 (t, J = 6.9 Hz, 2H), 7.45 (t, J =7.8 Hz, 1H), 7.19 (t, J=7.24 Hz, 1H), 6.80 (t, J
= 6.76 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.0, 140.0, 134.9, 126.5, 126.1, 123.2, 122.4,
120.5, 120.0, 118.2, 112.6, 107.6, 105.3; MS (GCꢀMS): 239; HRMS (EI, m/z) calcd for
C13H9N3O2: m/z 239.0695; Found 239.0697; IR (cmꢀ1, KBr) 3149, 3020, 1519, 1354, 1276,
1193.
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Acknowledgements
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The authors thank the Chancellor and Vice Chancellor of VIT University for providing
opportunity to carry out this study. Further the authors wish to thank the management of this
university for providing seed money as research grant. Kaushik Chanda thanks CSIRꢀGovt of
India for funding through Grant no 01(2913)/17/EMRꢀII. Thanks are also to Central
instrumentation facility VIT University for recording the spectra. Ranjit Thakuria thanks
Sophisticated Analytical Instrumentation Facility (SAIF), GU, for use of the singleꢀcrystal Xꢀray
diffractometer.
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Supporting Information Available.
The Supporting Information is available free of charge on the Publications website at. along with
1H and 13CNMR spectra of compounds 3. Assays for the antiꢀinflammatory and antimicrobial
assay for compounds 3, calculation of Eꢀfactor, and Xꢀray data of compound 3{4,6}.
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