A facile I2-catalyzed synthesis of imidazo[1,2-: A] pyridines via sp3 C-H functionalization of azaarenes and evaluation of anticancer activity

Article abstract of DOI:10.1039/c7ob01384a

A facile and efficient metal-free, one-pot, three component synthetic protocol has been developed for the synthesis of medicinally important substituted imidazo[1,2-a]pyridines via the iodine-catalysed oxidative amination of benzylic C-H bonds of azaarenes with 2-aminoazines and condensation with isocyanides. The presented methodology offers the advantages of wide substrate scope, moderate reaction conditions, environment friendliness, clean and simple protocol with high atom economy apart from higher yields. The synthesized compounds were screened for their anti-cancer activity in selected human cancer cell lines. Compounds 4a, 4b, 4c, 4i, 7a, 7b and 7m have significant IC₅₀ values ranging from 4.88 ± 0.28 to 14.55 ± 0.74 μM.

Full text of DOI:10.1039/c7ob01384a

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A facile I2‐catalyzed synthesis of imidazo[1,2‐a]pyridines via
sp3 C‐H functionalization of azaarenes and evaluation of
anticancer activity
Received 00th January 20xx,
Accepted 00th January 20xx
Geeta Sai Mani,a,b Siddiq Pasha Shaik,b Yellaiah Tangella,b Swarna Bale,a Chandraiah Godugua and
DOI: 10.1039/x0xx00000x
Ahmed Kamal*a,b
www.rsc.org/
A facile and efficient metal‐free one‐pot, three component synthetic protocol has been developed for the synthesis of
medicinally important substituted imidazo[1,2‐a]pyridines via iodine‐catalysed oxidative amination of benzylic C‐H bonds
of azaarenes with 2‐aminoazines and condensation with isocyanides. The presented methodology offers the advantages of
wide substrate scope, moderate reaction conditions, environmental friendliness, clean and simple protocol with high atom
economy apart from higher yields. The synthesized compounds were screened for their anti‐cancer activity in selected
human cancer cell lines. Compounds 4a, 4b, 4c, 4i, 7a, 7b and 7m have significant IC50 values ranging from 4.88 ± 0.28 to
14.55 ± 0.74 μM.
their elegant performance for multiple reactions into a
sequence of one reaction step without isolating the
intermediates or changing the reaction conditions. Moreover,
Introduction
Over the past few decades, synthetic organic chemistry has
gained much attention because of its vast scope in various
areas like pharmaceuticals, agrochemicals, speciality
chemicals. Sustainability has become one of the significant
scientific challenges nowadays, due to health, environmental
and societal concerns. Thus, there is a need for developing
efficient and non‐polluting synthetic protocols that reduce the
use of toxic reagents. It mostly encompasses designing
chemical products and processes that eliminate or reduce the
use of hazardous substances, volatile organic compounds,
unnecessary derivatization and generation of waste materials
like by‐product formation. One such approach, which involves
one‐pot chemistry1 drives towards pollution prevention and
environmental protection, and is now gaining prominence. In
this context, recently the use of molecular iodine as a catalyst
has attracted increasing attention in organic synthesis as a
promising strategy because iodine is low in cost, readily
available and nontoxic.2 Recently, we have also reported the
synthesis of biologically important heterocyclic motifs by
utilizing hypervalent iodine reagents.3
MCRs comply with the principles of green chemistry like atom
economy, structural complexity of products (structural
economy), bond‐forming efficiency (bond‐forming economy),
convergent synthesis and the feasibility of introducing
maximum chemical diversity elements in one‐pot operation.5
They are being increasingly fine‐tuned for synthesis of various
heterocyclic scaffolds which are particularly useful in the
preparation of diverse libraries of bioactive molecules.6
Fig. 1 The structure of some important drugs containing the imidazopyridine cores.
Multicomponent reactions (MCRs)4 have emerged as a
significant tool in synthetic organic chemistry mainly due to
Nitrogen‐containing
heterocyclic
compounds
are
considered to be privileged structures because of their
occurrence in many natural products and synthetic compounds
with interesting biological properties.7 Specially, imidazo[1,2‐
a]azine core has received significant attention in medicinal
chemistry due to their broad spectrum of pharmacological and
biological activities including antibacterial, antifungal,
antineoplastic, antidiabetic, antitumor, anxiolytic (Alpidem),
hypnotic (Zolpidem), immunomodulatory (Kifunensine),
a. Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad‐500 037, India,E‐mail:
ahmedkamal@iict.res.in
b. Medicinal Chemistry & Pharmacology, CSIR‐Indian Institute of Chemical
Technology, Hyderabad 500 007, India,
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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antiulcer (Zolmidine), sedative (Necopidem and Saripidem) and (entry 2, Table 1) after 12 h. The poor yield of 4a could have
anti‐HIV (GSK812397) as shown in Fig 1.8 Moreover, they have seen due to the low solubility of the reactants, therefore, in
also been shown to be selective cyclin dependent kinase order to reduce the reaction time and also to enhance the
inhibitors,9 topoisomerase II inhibitors,10 GABA and yields, this reaction was performed in DMSO. As expected, the
benzodiazepine receptor agonists11 and bradykinin B2 receptor
Table 1 Optimization of reaction conditions.a
antagonists.12 In view of their immense high pharmacological
importance, many synthetic protocols were developed. Typical
approaches include the heterocyclization of 2‐aminopyridine
with α‐halocarbonyl compounds, α,β‐unsaturated carbonyl
compounds or α‐diazoketones.13 Moreover, several isocyanide
based multi‐component condensation reactions have been
reported including the coupling reaction of 2‐aminopyridine
and aldehydes with isocyanides in the presence of Bronsted
acids14 like AcOH, HClO4, cellulose sulfuric acid, p‐toluene
sulfonic acid, and Lewis acids15 like Sc(OTf)3, MgCl2, SnCl2,
ZrCl4, ZnCl2, RuCl3 via Groebke‐Blackburn‐Bienaymé reaction,
and the condensation between 2‐aminopyridines, isocyanides,
and benzyl alcohols or benzyl halides.16 Nevertheless, many of
these synthetic methods suffer from one or more drawbacks
such as long reaction time, low yield, requirement for an inert
atmosphere, difficulties in work‐up procedure leading to the
generation of large amounts of toxic metal‐containing waste,
and the use of stoichiometric or relatively expensive reagents.
In order to overcome some of these drawbacks a few solid
supported and mild catalytic approaches such as the use of
montmorillonite K10 (microwave), γ‐Fe2O3@SiO2‐OSO3H
nanoparticles and resin supported reactions have been
reported.17 However, they too have certain disadvantages and
even though several methods are available for construction of
3‐aminoimidazo fused heterocycles, to date there has been no
report for the synthesis of such skeletons without using
chemically unstable aldehydes. Therefore, the development of
an inexpensive and efficient catalytic strategy is highly needed
for the synthesis of these fused heterocycles. So far, to the
best of our knowledge, the concept of oxidative addition via C‐
H bond amination followed by isocyanide insertion has not
been exploited. As part of our research program on the
development of environmentally benign new reaction
protocols for the synthesis of organic compounds and to
overcome the disadvantages of previous methods for the
construction of medicinally useful imidazo‐fused heterocycles
using isocyanide‐based MCRs, herein we report an iodine‐
catalyzed oxidative benzylic C‐H bond amination of azaarenes
to afford substituted imidazo[1,2‐a]azines under mild
Entry
Catalyst
(equiv.)
Solvent
Temperature
(oC)
Time
(h)
Yield (%)b
4a 5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
KI
‐
‐
RT
100
100
80
100
100
80
24
12
6
12
8
12
12
12
12
12
12
6
6
6
24
5
4
NF
30
60
40
50
28
35
30
NF
34
NF
68
76
70
NF
84
89
75
87
NF
10
25
20
18
13
16
14
NF
Trace
NF
17
Trace
Trace
NF
NF
NF
NF
NF
DMSO
CH3CN
DMF
toluene
DCE
THF
66
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
100
100
100
120
60
NIS
TBAI
I2 (0.5)
I2 (0.2)
I2 (0.1)
‐
I2 (0.2)c
I2 (0.2)c
I2 (0.2)c
I2 (0.2)c
12
4
160
aAll reactions were performed using 1a (1 mmol), 2a (1 mmol), 3a (1 mmol).
bIsolated yield. cIodine was added to a solution of 2a (1 mmol) in DMSO and
allowed under stirring for 30 minutes followed by addition of 1a (1 mmol) and 3a
(1 mmol). NF ‐ Not Formed
yield of both the products 4a and 5a increased to 60% and 25%
respectively (entry 3, Table 1) after 6 h of reaction time.
Thereafter, the effect of solvents, such as acetonitrile, DMF,
toluene, DCE (1,2‐dichloroethane) and THF was examined,
however all of these solvents give lower yields compared to
DMSO (entries 4–8, Table 1), which could imply that the DMSO
participating in the oxidation of C(sp3)–H bond. Moreover to
improve the yield of the product 4a, we investigated the
reaction with different iodine sources like potassium iodide
(KI), N‐iodosuccinimide (NIS) and tetrabutylammonium iodide
(TBAI) instead of I2 in DMSO (entries 9‐11, Table 1). However,
these reagents were not much effective and only NIS produced
4a in 34% of yield (entry 10, Table 1). Once we established the
suitable solvent and iodine source for synthesis of imidazo[1,2‐
a]azines, we then focused on the quantity of iodine. Initially,
we used 1 equiv. of iodine and found the desired product 4a
formation in relatively low yield due to the formation of iodo
by‐product 5a. With these inspired results, then the reaction
was carried out with 0.5 equiv. of I2 to avoid formation of iodo
by‐product, but the reaction again yielded mixture of products
conditions through multicomponent one‐pot approach
.
Results and discussion
Our preliminary investigation began with the reaction of 2‐
aminopyridine (1a) and 2‐methylquinoline (2a) with tert‐butyl
isocyanide (3a) in the presence of iodine (1 equiv.) without
using the solvent (neat) at room temperature for 24 h, and the
formation of required product (4a) was not observed even
after prolonged reaction time (entry 1, Table 1). Interestingly
,
we were delighted to observe the formation of the desired
product 4a
,
albeit in low yield (30%) together with
o
unanticipated iodo by‐product 5a in 10% of yield at 100 C
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4a and 5a in 68% and 17% yields respectively (entry 12, Table substituted 2‐methylquinolines (methoxy, chloro and nitro)
1). Then the reaction was studied with catalytic loading of I2 were used and as predicted they gave excellent results (4i‐k).
(20 and 10 mol%) and interestingly we observed that this
Table 2 The I2‐catalyzed substrate scope synthesis of various 3‐aminoimidazo[1,2‐
a]pyridines with 2‐amino pyridines, 2‐methylquinolines and isocyanides a
reaction afforded 4a in 76% and 70% as well as 5a in trace
amounts (entries 13 and 14, Table 1). However when the
reaction was performed without the catalyst (iodine), the
product was not observed (entry 15, Table 1). This observation
confirmed that catalytic iodine is necessary for the success of
the reaction. Further, the reaction efficiency was enhanced to
a great extent providing exclusively 4a in 84% yield, when I2
(20 mol%) was added to the solution of 2a and the reaction
o
mixture was stirred at 120 C for 30 minutes and was added
1a, 3a then the reaction was allowed to stir at the same
temperature for 5h (entry 16, Table 1). Gratifyingly in this case
we observed the by‐product 5a in trace amounts. To our
delight, the yield of the desired product 4a was obtained in
89%, when the reaction was performed with 20mol% of I2 at
o
120 C for 4 h (entry 17, Table 1). If the reaction temperature
o
was lowered to 70 C, the yield of the product also decreased
(entry 18, Table 1) and whereas if the reaction temperature
o
was increased to 160 C, there was not much effect on the
yield of the product (entry 19, Table 1). Therefore, the
systematic screening of reaction conditions revealed that the
formation of 3‐aminoimidazo‐fused heterocycles is efficient
while using I2 (20 mol%) in DMSO at 120 oC (entry 17, Table 1).
In light of having optimized reaction conditions, we focused to
investigate the scope of this iodine‐catalyzed oxidative
benzylic C‐H bond amination protocol toward the synthesis of
various imidazo[1,2‐a]pyridines. For this purpose, a wide range
of structurally diverse 2‐aminopyridines bearing electron‐
withdrawing or electron‐releasing substituents and 2‐
methylquinoline with isocyanides (cyclohexyl and tert‐butyl)
were successfully condensed via a three component one‐pot
operation. As shown in Scheme 1, all of the reactions
proceeded smoothly and delivered the desired products in
good to excellent yields. The electronic nature of the
substituents on 2‐aminopyridine and 2‐methylquinoline had an
influence on the reaction efficiency as well as on the reaction
yields. For example, 2‐aminopyridines bearing electron‐
releasing groups (4e and 4f) reacted at a faster rate and
aAll reactions were performed with 1a‐f (1 mmol), 2a‐d (1 mmol), 3a‐b (1 mmol),
iodine ( 20 mol%) in DMSO at 120 oC for 4‐6 h.
After investigating the scope of 2‐methylquinolines, in
order to explore the generality of this oxidative benzylic C‐H
bond amination was carried out using various methyl pyridines
and 2‐aminopyridines with isocyanides under the optimized
conditions. To our delight, 2‐methyl pyridines and isocyanides
were turned out to be suitable substrates for this one‐pot,
three component transformation and yielded the
corresponding imidazopyridine derivatives (7a–p) in good
yields (Table 3). The electronic nature of the 2‐aminopyridine
had an influence on the reaction efficiency, and all the
corresponding products were obtained in good to excellent
yields. However, the substrates with an electron‐withdrawing
groups like nitro, cyano and amide delivered the
successfully
transformed
into
the
desired
3‐
aminoimidazopyridines in excellent yields (92% and 94%).
Whereas, the electron‐withdrawing groups like amide gave 4g
and 4h in moderate yields with prolonged reaction times.
Almost similar yields were obtained using either tert‐butyl
isocyanide or cyclohexyl isocyanide. Interestingly, methyl
group substitution at 4th position of 2‐aminopyridine (4f
)
corresponding imidazo[1,2‐a]pyridines
(7f–j) in moderate
yielded the corresponding product in slightly higher yield
(94%) over the substitution at 3rd position (4e, 92%). 2‐
Aminopyridine bearing halogen substituents such as chloro
and bromo substrates successfully provided the corresponding
products in about 82% and 80% yields respectively (4c and 4d).
In addition, we next turned our attention to the diversity and
scope of the other components of this reaction by examining
to extend the scope of the methodology. In this context,
yields and with longer reaction times, while electron donating
groups like methyl gave 7e in excellent yield (88%) with
shorter reaction times (Table 3). Similarly, chloro and bromo
substituted 2‐aminopyridine derivatives also afforded the
desired products in 79% and 78% yields respectively (7c and
7d). In order to demonstrate the efficiency and applicability of
our methodology, we performed the reaction with 4‐
methylpyridine, 2‐aminopyridines with isocyanides, the
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reaction became sluggish and produced the corresponding approach under these conditions makes it as a useful process
products (7k–n) in much lower yields. Furthermore, we carried for the synthesis of medicinally important molecules.
out the reaction with 2‐aminopyrimidine as well as with 2‐
morpholinoethyl isocyanide to observe that they were well
Table 4 The I2‐catalysed substrate scope synthesis of 3‐aminoimidazo[1,2‐a]pyridine
tolerated under the optimal conditions and provided 7o and
with 2‐aminoazines, methyl pyridines and isocyanides
7p in 78% and 90% yields respectively.
Table 3 TheI2‐catalysed substrate scope synthesis of 3‐aminoimidazo[1,2‐a]pyridine
with 2‐aminoazines, methyl pyridines and isocyanidesa
Cl
Br
N
N
N
N
N
N
N
N
N
N
N
N
H
H
H
H
N
N
N
N
aAll reactions were performed with 1a (1 mmol), 2 (1 mmol), 3a‐b (1 mmol),
iodine (3 mmol) in DMSO at 120 oC for 24 h .
7b, 84%
7d, 78%
7c, 79%
O2N
7a, 85%
CH3
O2N
CONH2
N
N
N
N
N
N
N
N
N
H
N
N
N
H
H
H
N
N
N
N
7f, 65%
7g, 66%
7h, 73%
7e, 88%
Cl
CONH2
N
CN
Scheme 1 Grams scale synthesis of 4a and 7a
N
N
N
N
N
N
N
N
N
H
N
H
N
H
H
To elucidate the reaction mechanism for the formation of
substituted imidazo[1,2‐a]pyridines, we performed few
mechanistic experiments (Scheme 2). In this context, we
carried out the reaction under standard conditions with 2‐
methylquinoline in the absence of 2‐aminopyridine (1a) to
N
N
N
N
7j, 68%
7k, 30%
7l, 28%
7i, 70%
Br
CN
N
N
N
N
N
N
N
N
N
N
HN
N
N
afford quinoline‐2‐carbaldehyde (9) in 35% yield, with 46% of
H
H
H
O
N
N
N
the starting material recovered (Scheme 2a). Considering
previous studies,18 the nucleophilic reactivity of 2‐
methylquinoline (2a) was catalyzed by a Brønsted acid, 2‐
methylquinoline might be prone to nucleophilic halogenation
N
N
7p, 90%
7m, 26%
7o, 78%
7n, 23%
aAll reactions were performed with 1a‐h (1 mmol), 6a‐b (1 mmol), 3a‐c (1 mmol),
iodine (20 mol%) in DMSO at 120 oC for 4‐6 h
with iodine to provide 2‐iodomethyl quinolone
(8).
Unfortunately, we could not isolate the iodo intermediate
probably due to its instability, which undergoes subsequent
To extend the synthetic applicability of this I2‐catalyzed
reaction focused on the synthesis of iodinated by‐product
which is a valuable intermediate for coupling reactions.
Interestingly, the slight change in present protocol (addition
order of reactants) is capable of producing iodinated
imidazo[1,2‐a]azines, which could be employed as an
intermediate for introducing this functionality. For instance,
the substrate 1a delivered the iodinated imidazo[1,2‐a]azines
5a‐c in good yields in the presence of iodine (3 equiv.).
Kornblum oxidation to produce quinoline‐2‐carbaldehyde (
this is similar to the report by Wu and co‐workers.19 To skip
the Kornblum oxidation step,20 2‐iodomethylquinoline (
9),
8
)
might also undergo nucleophilic amination with 2‐
aminopyridine (1a) directly to generate the intermediate 11,
we performed the reaction of 1a and tert‐butylisocyanide (3a
)
with 2‐chloromethylquinoline 10 under the optimal
(
)
conditions, which afforded the desired product (4a) in
quantitative yield (Scheme 2b). This reaction may proceed
In order to demonstrate the efficiency and utility of this
protocol, gram‐scale reactions were carried out by employing
through
chloromethylquinoline (10) to 2‐iodomethyl quinoline (
the presence of iodine. Alternatively, the next condensation of
quinoline‐2‐carbaldehyde ( ) with 1a and 3a takes place in
a
facile insitu halide exchange from 2‐
substrates 1a (5g, 53.1 mmol) and 3a (4.4g, 53.1 mmol) with
2
8
) in
(7.5g, 53.1 mmol) and (4.9g, 53.1 mmol) under the optimal
6
reaction conditions. To our delight, reactions proceeded
smoothly to give the corresponding products 4a and 7a in 85%
and 80% isolated yields (Scheme 1). This Lewis acid metal‐free
9
both these cases in the presence and absence of catalytic
amount of molecular iodine, however the reaction was albeit
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much faster in the presence of iodine (Scheme 2c). Therefore imine intermediate
both 2‐iodomethyl quinoline (
) could serve as intermediates in this methodology.
V
.
Alternatively, in pathway b,
8
) and quinoline‐2‐carbaldehyde intermediate II undergoes nucleophilic amination directly with
(
9
2‐aminopyridine (1a) to give the intermediate IV, which is
further oxidized by molecular iodine to afford the
corresponding imine
V. Finally, the attack of nucleophilic
isocyanide 3a on the activated imine leads to the formation of
intermediate VI, which will further undergo [1,3]‐H shift to
produce the desired product. The molecular iodine as a
catalyst can be readily regenerated by the oxidation of iodide
anions with DMSO.
Cytotoxicity
It was considered of interest, all the synthesized compounds
4a‐k and 7a‐p have been evaluated for their cytotoxicity
towards a panel of five cancer cell lines A549 (lung cancer),
MCF‐7 (breast cancer), PC‐3 (prostate cancer), MDA‐MB‐231
(triple negative breast cancer) and B16‐F10 (melanoma skin
cancer) by tetrazolium based colorimetric cytotoxicity assay
also known as MTT assay. Cell lines were treated with test
compounds at 15 µM concentration for 48 h and percentage
Scheme 2 Mechanistic experiments for the molecular iodine‐catalyzed oxidative
condensation.
(%) cytotoxicity was recorded. Compounds 4a, 4b, 4c, 4i, 7a,
7b and 7m exhibited above 50% cytotoxicity at 15 µM and
were selected to screen for concentration dependent
responses and IC50 values of those compounds only are
reported. Doxorubicin was employed as a reference standard
drug and the effect of selected compounds on the cell viability
for each cell line after exposure to different concentrations is
summarized in Table 5. Screening results showed that
On the basis of the results of the control experiment
described above and literature reports, a probable mechanistic
pathway for the formation of imidazo[1,2‐a]pyridines is
outlined in Fig. 2. Initially, 2‐methylazaarene is converted into
its more nucleophilic enamine form (I) via imine‐enamine
tautomerization, which undergoes subsequent nucleophilic
substitution with iodine to form 2‐iodomethylazaarene (II).
Next, in this pathway a, an intermediate II reacts with DMSO
to afford the corresponding aldehyde III via Kornblum
oxidation, followed by condensation with 1a to provide the
compounds 4a
panel of studied cell lines with IC50 values ranging from 4.88 ±
0.28 to 14.55 ± 0.74 µM. Among the tested compounds, 4a 4c
, 4b, 4c, 4i, 7a, 7b and 7m are potent against a
,
and 4i displayed significant anti proliferative activity against
MDA MB 231 cell line when compared to other tested cancer
cell lines and which were comparable to standard drug
Doxorubicin. Based on the in vitro cytotoxicity assay results,
the structure activity relationships for these compounds were
established. The cytotoxicity data of most potential
compounds 4a
a]pyridine/6‐chloroimidazo[1,2‐a]pyridine
,
4c and 4i deciphered that, imidazo[1,2‐
scaffold with
quinoline/7‐chloroquinoline ring at C2‐position and tertiary
butyl group having amine functional group at C3‐position are
essential for the cytotoxic potential. It was observed that
replacement of imidazo[1,2‐a]pyridine scaffold (7a) with
imidazo[1,2‐a]pyrimidine (7o) leads to decrease in activity on
the examined cell lines. Further, cytotoxicity of the potent
compounds was evaluated in normal cell line HaCaT (skin
keratinocytes) so that selectivity index of the compounds can
be identified which is a prerequisite for a lead compound to be
potent anti‐cancer agent. Interestingly, all the potent
compounds were non‐toxic in normal cells at the reported
concentrations of their cytotoxicity in cancer cells.
Approximately, more than 8 folds selectivity index (ratio of
cytotoxicity of normal cell line to that of cancer cell line) was
observed with the reported compounds, suggesting that these
compounds can further be investigated at molecular level to
emerge as promising anti‐cancer agents.
Fig.
condensation
2 Plausible reaction mechanism for the iodine‐catalyzed oxidative
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Table 5. Cytotoxicity of compounds 4a‐k and 7a‐p on different cell lines
Compound
A 549b
MCF‐7c
PC‐3d
MDA‐MB‐231e
B16F10f
HaCaT g
4a
>15
>15
>15
6.12 ± 1.02 (31.60)*
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
>15
NT
193.43±9.36
4b
14.55 ± 0.74 (8.03)*
>15
11.05 ± 0.98 (10.57)*
>15
116.88±2.78
4c
>15
>15
>15
5.01 ± 0.7 (23.16)*
116.05±3.23
4d
>15
>15
>15
>15
NT
4e
>15
>15
>15
>15
NT
4f
>15
>15
>15
>15
NT
4g
>15
>15
>15
>15
NT
4h
>15
>15
>15
>15
NT
4i
>15
>15
>15
5.72 ± 1.09 (20.47)*
117.12±1.03
4j
>15
>15
>15
>15
>15
NT
4k
>15
>15
>15
NT
7a
7.67 ± 1.24 (14.13)*
4.88 ± 0.28 (22.20)*
9.73 ± 0.15 (11.13)*
>15
108.38±4.72
7b
>15
>15
>15
8.89 ± 0.17 (11.73)*
>15
104.35±0.92
7c
>15
>15
>15
>15
NT
7d
>15
>15
>15
NT
7e
>15
>15
>15
>15
NT
7f
>15
>15
>15
>15
NT
7g
>15
>15
>15
>15
NT
7h
>15
>15
>15
>15
NT
7i
>15
>15
>15
>15
NT
7j
>15
>15
>15
>15
NT
7k
>15
>15
>15
>15
NT
7l
>15
>15
>15
>15
NT
7m
>15
12.68 ± 0.88 (14.66)*
>15
>15
185.98±10.97
7n
7o
>15
>15
>15
>15
>15
NT
NT
NT
NT
>15
>15
>15
7p
>15
>15
>15
>15
Doxorubicin
1.64 ± 0.38
0.14± 0.02
0.55 ± 0.03
4.21±0.55
a 50% inhibitory concentration after 48 h of drug treatment and the values are average of three individual experiments. b human lung cancer cell line. c human breast
cancer cell line. d human prostate cancer cell line. e human breast adeno carcinoma epithelial cell line. f murine skin cancer cell line. g human normal keratinocyte cell
line. NT = Not Tested.
Note: Values entered in parenthesis with asterisk (*) indicates selectivity index of specific compounds in specific cell line compared to normal skin keratinocyte cell
line.
this protocol could find applications in the drug discovery and
Conclusion
natural product synthesis. All the synthesized compounds have
been evaluated for their cytotoxic potential, and compounds
4a, 4b, 4c, 4i, 7a, 7b and 7m were found to be effective in
selected human cancer cell lines. Further applications of this
approach to the synthesis of various natural and
pharmaceutically relevant heterocyclic compounds are
ongoing in our laboratory.
In summary, we have developed an efficient and clean
methodology for the synthesis of substituted imidazo[1,2‐
a]pyridines using
a three component coupling of 2‐
aminoazines, azaarenes and isocyanides with molecular iodine
as a catalyst via oxidative amination of benzylic C‐H bonds of
azaarenes. The significant features of this methodology are
mild conditions, operational simplicity, high yield, atom
economy and low environmental impact. Moreover, this
reaction utilizes range of substrates and proceeds under
metal‐free conditions with DMSO as the terminal oxidant.
Importantly, the grams scale synthesis was accomplished and
Experimental section
General information
6 | J. Name., 2012, 00, 1‐3
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All the reagents and chemicals were obtained from 294 mg (86%) of 4b was obtained as a yellow solid; Rf = 0.37
o
1
commercial sources and used without further purification. (ethyl acetate/n‐hexane, 1:1); Mp. 180‐181 C; H NMR (500
Analytical thin layer chromatography (TLC) was performed MHz, CDCl3) δ 8.38 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H),
with silica gel MERCK silica gel 60‐ F254 (0.5 mm) precoated 8.02 (dd, J = 7.4, 4.7 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (t, J =
glass plates. Column chromatography was performed using 7.6 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.13
100‐200 mesh silica gel. 1H and 13C NMR spectra were – 7.07 (m, 1H), 6.78 (t, J = 6.7 Hz, 1H), 3.24 (s, 1H), 1.95 (d, J =
recorded with 300, 400 and 500 MHz NMR instruments in 10.7 Hz, 2H), 1.77 – 1.71 (m, 2H), 1.56 (d, J = 4.2 Hz, 1H), 1.46 –
CDCl3 with tetramethylsilane (TMS) as an internal standard. 1.35 (m, 2H), 1.30 – 1.18 (m, 4H); 13C NMR (126 MHz, CDCl3) δ
Chemical shifts (δ) and coupling constants (J) are reported in 155.29, 147.51, 140.69, 136.26, 132.41, 129.92, 129.44,
parts per million (ppm), Hertz (Hz) respectively. Melting points 128.52, 127.77, 127.01, 125.57, 123.32, 123.15, 119.21,
were determined using an Electrothermal apparatus (Model 118.08, 111.87, 55.78, 34.19, 25.82, 24.91; HRMS: calcd for
IA9200) and are uncorrected. High‐resolution mass spectra C22H23N4 [M+H]+ 343.1923, found 343.1924.
(HRMS) were recorded on LC‐QTOF mass spectrometer.
MDA‐MB‐231 and MCF‐7 (breast cancer cell lines), A549 (lung
cancer cell line), PC‐3 (prostate cancer cell line) and B16‐F10 3‐amine (4c)
(mouse melanoma cell line) cell lines were obtained from 287 mg (82%) of 4c was obtained as a yellow solid; Rf = 0.50
N‐(tert‐butyl)‐6‐chloro‐2‐(quinolin‐2‐yl)imidazo[1,2‐a]pyridin‐
o
1
NCCS Pune. HaCaT cell lines were obtained as kind gift sample (ethyl acetate/n‐hexane, 1:1); Mp. 149‐150 C; H NMR (400
from Munia Ganguli, IGIB (CSIR). L‐12, DMEM, RPMI culture MHz, CDCl3) δ 8.43 – 8.30 (m, 2H), 8.23 (d, J = 8.6 Hz, 1H), 8.03
media,
MTT
[3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐ (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.71 (ddd, J = 8.4,
diphenyltetrazoliumbromide] and Trypsin EDTA were procured 6.9, 1.4 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.08 (dd, J = 9.5, 2.0 Hz,
from Sigma Chemicals Co (st.Louis, MO), Fetal bovine serum 1H), 5.90 (s, 1H), 1.22 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
were purchased from Gibco, USA, 96 well flat bottom tissue 154.64, 147.33, 139.94, 136.43, 135.53, 130.44, 129.60,
culture plates were obtained from Tarson.
128.66, 127.80, 127.28, 126.08, 125.43, 122.11, 120.06,
119.74, 118.11, 57.14, 30.23; HRMS: calcd for C20H20ClN4
[M+H]+ 321.1376, found 321.1377.
General procedure for synthesis of imidazo[1,2‐a]pyridine: (4a‐k,
7a‐p)
In a 25 ml round bottomed flask, methyl quinoline (1 mmol) 6‐bromo‐
and iodine (20 mol%) in DMSO were refluxed at 120 oC
]pyridin‐3‐amine (4d)
followed by addition of amino pyridine (1 mmol), isocyanide (1 315 mg (80%) of 4d was obtained as a yellow solid; Rf = 0.56
N‐(tert‐butyl)‐2‐(quinolin‐2‐yl)imidazo[1,2‐
a
o
o
1
mmol) after 30 min., continued to reflux at 120 C for 4 h. (ethyl acetate/n‐hexane, 1:1); Mp. 164‐165 C; H NMR (500
After completion of reaction (monitored with TLC), reaction MHz, CDCl3) δ 8.47 – 8.44 (m, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.24
mixture was quenched with saturated solution of sodium (d, J = 8.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.1 Hz,
thiosulphate and extracted with ethyl acetate. The combined 1H), 7.71 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.54 – 7.50 (m, 1H),
organic layers were washed with water and brine, dried over 7.46 (d, J = 9.5 Hz, 1H), 7.18 (dd, J = 9.5, 1.9 Hz, 1H), 5.91 (s,
anhydrous Na2SO4, filtered and concentrated under reduced 1H), 1.22 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 154.54, 147.31,
pressure. The residue obtained was purified by silica‐gel 139.96, 136.48, 135.34, 130.28, 129.63, 128.65, 127.81,
column chromatography using ethyl acetate–hexane as the 127.52, 127.29, 126.11, 124.41, 119.62, 118.34, 106.63, 57.40,
eluent in increasing polarity to afford the desired imidazo 30.22; HRMS : calcd for C20H20BrN4 [M+H]+ 395.0871, found
pyridines 4a‐k and 7a‐p
.
395.0870.
N
‐(tert‐butyl)‐2‐(quinolin‐2‐yl)imidazo[1,2‐
(4a)
281 mg (89%) of 4a was obtained as a yellow solid; Rf = 0.45 303 mg (92%) of 4e was obtained as a yellow solid; Rf = 0.43
a
]pyridin‐3‐amine
N
‐(tert‐butyl)‐6‐methyl‐2‐(quinolin‐2‐yl)imidazo[1,2‐
a
]pyridin‐3‐amine (4e)
o
1
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 139‐141 C; H NMR (500 (ethyl acetate/n‐hexane, 1:1); Mp. 165‐166 C; H NMR (500
MHz, CDCl3) δ 8.39 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 6.9 Hz, 1H), MHz, CDCl3) δ 8.37 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H),
8.23 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.1 8.10 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.50 (t, J 7.72 – 7.66 (m, 1H), 7.48 (dd, J = 13.2, 8.1 Hz, 2H), 6.98 (dd, J =
= 7.5 Hz, 1H), 7.13 (dd, J = 8.3, 7.3 Hz, 1H), 6.76 (t, J = 6.7 Hz, 9.2, 1.3 Hz, 1H), 5.94 (s, 1H), 2.34 (s, 3H), 1.22 (s, 9H); 13C NMR
1H), 5.98 (s, 1H), 1.22 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (75 MHz, CDCl3) δ 155.28, 147.37, 140.89, 136.23, 134.37,
155.15, 147.49, 141.43, 136.30, 134.28, 130.15, 129.48, 129.87, 129.42, 128.60, 127.76, 127.35, 127.15, 125.77,
128.65, 127.78, 127.20, 125.87, 124.33, 124.06, 119.86, 121.81, 121.00, 119.81, 117.01, 57.20, 30.22, 18.46; HRMS:
117.72, 111.46, 57.24, 30.23; HRMS: calcd for C20H21N4 [M+H]+ calcd for C21H23N4 [M+H]+ 331.1923, found 331.1938.
317.1766, found 317.1785.
N
a
‐(tert‐butyl)‐7‐methyl‐2‐(quinolin‐2‐yl)imidazo[1,2‐
]pyridin‐3‐amine (4f)
310 mg (94%) of 4f was obtained as a brick red solid; Rf = 0.34
N
‐cyclohexyl‐2‐(quinolin‐2‐yl)imidazo[1,2‐
a
]pyridin‐3‐amine
(4b)
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 185‐186 C; H NMR (500
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MHz, CDCl3) δ 8.37 (d, J = 8.6 Hz, 1H), 8.21 (t, J = 7.3 Hz, 2H), MHz, CDCl3) δ 8.54 (d, J = 8.7 Hz, 1H), 8.33 (t, J = 8.8 Hz, 2H),
8.01 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 – 7.67 (m, 8.13 – 8.08 (m, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.60 – 7.52 (m, 2H),
1H), 7.51 – 7.46 (m, 1H), 7.32 (s, 1H), 6.60 (dd, J = 7.1, 1.4 Hz, 7.20 – 7.14 (m, 1H), 6.79 (t, J = 6.7 Hz, 1H), 5.53 (s, 1H), 1.18 (s,
1H), 5.93 (s, 1H), 2.40 (s, 3H), 1.21 (s, 9H); 13C NMR (126 MHz, 9H); 13C NMR (101 MHz, CDCl3) δ 157.24, 147.06, 141.86,
CDCl3) δ 155.27, 147.39, 142.17, 136.14, 134.97, 133.94, 138.99, 136.54, 133.85, 132.39, 131.08, 128.06, 124.97,
129.79, 129.42, 128.61, 127.76, 127.14, 125.75, 123.55, 124.84, 124.63, 124.31, 121.73, 117.58, 111.74, 57.84, 29.48;
119.87, 115.92, 114.25, 56.96, 30.20, 21.37; HRMS : calcd for HRMS: calcd for C20H20N5O2 [M+H]+ 362.1617, found 362.1622.
C21H23N4 [M+H]+ 331.1923, found 331.1936.
N
a
‐(tert‐butyl)‐2‐(6‐methoxyquinolin‐2‐yl)imidazo[1,2‐
]pyridin‐3‐amine (4k)
314 mg (91%) of 4k was obtained as a yellow solid; Rf = 0.21
3‐(tert‐butylamino)‐2‐(quinolin‐2‐yl)imidazo[1,2‐
carboxamide (4g)
a
]pyridine‐8‐
o
1
265 mg (75%) of 4g was obtained as a yellow solid; Rf = 0.26 (ethyl acetate/n‐hexane, 1:1); Mp. 160‐161 C; H NMR (500
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 210‐211 C; H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 7.3 Hz, 2H), 8.13 (d, J = 8.3 Hz, 1H),
MHz, CDCl3) δ 10.17 (s, 1H), 8.49 (dd, J = 6.9, 1.3 Hz, 1H), 8.34 7.93 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.2
(d, J = 8.6 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.21 – 8.15 (m, 1H), Hz, 1H), 7.11 (d, J = 12.5 Hz, 2H), 6.76 (s, 1H), 5.88 (s, 1H), 3.95
8.04 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.73 (ddd, J = (s, 3H), 1.20 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 157.54,
8.4, 6.9, 1.4 Hz, 1H), 7.53 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.97 – 152.68, 143.36, 141.59, 135.17, 134.53, 130.09, 129.44,
6.89 (m, 1H), 6.15 (s, 1H), 5.93 (s, 1H), 1.23 (s, 9H); 13C NMR 128.09, 124.26, 124.07, 122.18, 120.15, 117.50, 111.47,
(101 MHz, CDCl3) δ 165.55, 154.29, 147.36, 139.63, 136.36, 105.47, 57.16, 55.37, 30.18; HRMS: calcd for C21H23N4O [M+H]+
133.78, 130.53, 129.62, 128.69, 128.28, 127.81, 127.44, 347.1872, found 347.1874.
127.27, 126.20, 120.65, 119.76, 111.21, 57.49, 30.25; HRMS:
calcd for C21H22N5O [M+H]+ 360.1824, found 360.1809.
N
‐(tert‐butyl)‐2‐(pyridin‐2‐yl)imidazo[1,2‐
(7a)
226 mg (85%) of 7a was obtained as a yellow solid; Rf = 0.31
a]pyridin‐3‐amine
3‐(cyclohexylamino)‐2‐(quinolin‐2‐yl)imidazo[1,2‐
8‐carboxamide (4h)
a]pyridine‐
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 138‐139 C; H NMR (400
281 mg (73%) of 4h was obtained as a yellow solid; Rf = 0.43 MHz, CDCl3) δ 8.57 (d, J = 4.0 Hz, 1H), 8.29 (d, J = 6.9 Hz, 1H),
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 266‐268 C; H NMR (400 8.17 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.0 Hz, 1H), 7.52 (d, J = 9.0
MHz, CDCl3) δ 10.16 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.22 (d, J = Hz, 1H), 7.18 – 7.14 (m, 1H), 7.13 – 7.08 (m, 1H), 6.73 (t, J = 6.6
8.6 Hz, 1H), 8.16 (dd, J = 10.2, 7.0 Hz, 2H), 8.03 (d, J = 8.4 Hz, Hz, 1H), 5.44 (s, 1H), 1.15 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
1H), 7.83 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 155.10, 148.32, 141.73, 136.50, 134.82, 128.91, 124.27,
7.5 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.78 (s, 1H), 6.09 (s, 1H), 123.95, 121.64, 121.29, 117.50, 111.21, 57.13, 30.06; HRMS:
3.23 (s, 1H), 1.96 (d, J = 12.6 Hz, 2H), 1.80 – 1.71 (m, 2H), 1.42 calcd for C16H19N4 [M+H]+ 267.1610, found 267.1619.
(dd, J = 21.6, 11.3 Hz, 2H), 1.24 (dd, J = 19.4, 10.6 Hz, 4H); 13
NMR (101 MHz, CDCl3) δ 165.50, 154.47, 147.50, 138.61,
136.35, 132.73, 129.68, 129.39, 128.59, 127.81, 127.48, (7b)
127.10, 126.21, 125.93, 120.92, 119.13, 111.63, 55.68, 34.21, 245 mg (84%) of 7b was obtained as a yellow solid; Rf = 0.45
C
N
‐cyclohexyl‐2‐(pyridin‐2‐yl)imidazo[1,2‐a]pyridin‐3‐amine
o
1
25.75, 24.88; HRMS: calcd for C23H24N5O [M+H]+ 386.1980, (ethyl acetate/n‐hexane, 1:1); Mp. 147‐148 C; H NMR (400
found 386.1970.
MHz, CDCl3) δ 8.55 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H),
7.98 (d, J = 6.9 Hz, 1H), 7.74 (td, J = 7.8, 1.7 Hz, 1H), 7.53 (d, J =
9.1 Hz, 1H), 7.20 – 7.00 (m, 2H), 6.75 (t, J = 6.7 Hz, 1H), 6.25 (d,
J = 8.8 Hz, 1H), 3.19 – 2.98 (m, 1H), 1.90 (d, J = 12.7 Hz, 2H),
N
‐(tert‐butyl)‐2‐(7‐chloroquinolin‐2‐yl)imidazo[1,2‐
a]pyridin‐
3‐amine (4i)
280 mg (80%) of 4i was obtained as a yellow solid; Rf = 0.75 1.72 (dd, J = 8.3, 4.6 Hz, 2H), 1.57 (s, 1H), 1.38 – 1.27 (m, 2H),
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 235‐236 C; H NMR (300 1.21 (t, J = 8.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.10,
MHz, CDCl3) δ 8.39 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 7.0 Hz, 1H), 148.31, 140.75, 136.69, 131.18, 130.20, 123.27, 123.06,
8.20 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.7 121.05, 120.22, 117.82, 111.63, 55.51, 34.07, 25.81, 25.02;
Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.45 (dd, J = 8.6, 2.0 Hz, 1H), HRMS: calcd for C18H21N4 [M+H]+ 293.1766, found 293.1777.
7.18 – 7.10 (m, 1H), 6.78 (dd, J = 9.9, 3.7 Hz, 1H), 5.82 (s, 1H),
1.23 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.15, 147.78,
141.78, 136.11, 135.29, 133.99, 130.46, 129.01, 127.48, 3‐amine (7c)
126.81, 125.55, 124.41, 124.32, 120.11, 117.75, 111.59, 57.57, 237 mg (79%) of 7c was obtained as a yellow solid; Rf = 0.40
N‐(tert‐butyl)‐6‐chloro‐2‐(pyridin‐2‐yl)imidazo[1,2‐a]pyridin‐
o
1
30.28; HRMS: calcd for C20H20ClN4 [M+H]+ 351.1376, found (ethyl acetate/n‐hexane, 1:1); Mp. 140‐141 C; H NMR (400
351.1397.
MHz, CDCl3) δ 8.57 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.31 (dd, J =
2.0, 0.8 Hz, 1H), 8.15 (dt, J = 8.0, 1.0 Hz, 1H), 7.77 (td, J = 7.8,
N
‐(tert‐butyl)‐2‐(8‐nitroquinolin‐2‐yl)imidazo[1,2‐
a
]pyridin‐3‐ 1.8 Hz, 1H), 7.46 (dd, J = 9.5, 0.7 Hz, 1H), 7.18 (ddd, J = 7.5, 4.9,
1.2 Hz, 1H), 7.10 – 7.04 (m, 1H), 5.39 (s, 1H), 1.15 (s, 9H); 13C
amine (4j)
241 mg (67%) of 4j was obtained as a yellow solid; Rf = 0.15 NMR (75 MHz, CDCl3) δ 154.65, 148.37, 139.95, 136.55,
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 160‐161 C; H NMR (400 135.97, 129.26, 125.27, 122.05, 121.91, 121.32, 119.77,
8 | J. Name., 2012, 00, 1‐3
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117.90, 57.24, 30.05; HRMS: calcd for C16H18ClN4 [M+H]+ MHz, CDCl3) δ 10.14 (s, 1H), 8.61 – 8.58 (m, 1H), 8.45 (dd, J =
301.1220, found 301.1210.
6.9, 1.2 Hz, 1H), 8.17 – 8.13 (m, 2H), 7.91 – 7.66 (m, 1H), 7.20
(ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 6.97 – 6.85 (m, 1H), 6.16 (s, 1H),
5.43 (s, 1H), 1.16 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 165.70,
154.28, 148.47, 139.65, 136.53, 134.16, 129.33, 128.16,
6‐bromo‐
N‐(tert‐butyl)‐2‐(pyridin‐2‐yl)imidazo[1,2‐a]pyridin‐
3‐amine (7d)
268 mg (78%) of 7d was obtained as a white solid; Rf = 0.30 127.38, 122.03, 121.45, 120.45, 111.12, 57.30, 30.07; HRMS:
o
1
(ethyl acetate/n‐hexane, 1:1); Mp. 155‐156 C; H NMR (500 calcd for C17H20N5O [M+H]+ 310.1668, found 310.1657.
MHz, CDCl3) δ 8.57 (d, J = 4.6 Hz, 1H), 8.41 (s, 1H), 8.14 (d, J =
8.0 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 9.5 Hz, 1H), 7.20 3‐(cyclohexylamino)‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a]pyridine‐8‐
– 7.13 (m, 2H), 5.40 (s, 1H), 1.15 (s, 9H); 13C NMR (126 MHz, carboxamide (7i)
CDCl3) δ 154.60, 148.39, 140.01, 136.58, 135.70, 129.11, 234 mg (70%) of 7i was obtained as a yellow solid; Rf = 0.21
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1
127.32, 124.36, 121.94, 121.37, 118.17, 106.30, 57.27, 30.06; (ethyl acetate/n‐hexane, 1:1); Mp. 220‐221 C; H NMR (400
HRMS : calcd for C16H18BrN4 [M+H]+ 345.0715, found 345.0717. MHz, CDCl3) δ 10.13 (s, 1H), 8.61 (t, J = 24.3 Hz, 1H), 8.13 (dd, J
= 7.4, 4.3 Hz, 3H), 7.76 (td, J = 7.8, 1.6 Hz, 1H), 7.17 (dd, J = 6.9,
N
‐cyclohexyl‐7‐methyl‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a
]pyridin‐
5.4 Hz, 1H), 6.92 (t, J = 6.9 Hz, 1H), 6.19 (s, 1H), 3.08 (t, J = 9.8
Hz, 1H), 1.88 (t, J = 17.0 Hz, 2H), 1.74 (d, J = 8.3 Hz, 2H), 1.58 (s,
3‐amine (7e)
269 mg (88%) of 7e was obtained as a yellow solid; Rf = 0.43 1H), 1.40 – 1.29 (m, 2H), 1.23 (dd, J = 15.3, 5.9 Hz, 4H); 13C
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1
(ethyl acetate/n‐hexane, 1:1); Mp. 208‐209 C; H NMR (400 NMR (126 MHz, CDCl3) δ 165.54, 154.37, 148.60, 138.87,
MHz, CDCl3) δ 8.54 (d, J = 3.4 Hz, 1H), 8.32 (s, 1H), 8.13 (d, J = 136.75, 131.56, 129.85, 127.39, 126.26, 121.46, 120.71,
7.7 Hz, 1H), 7.74 (t, J = 7.3 Hz, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 120.39, 111.39, 55.81, 34.08, 25.96, 24.98; HRMS: calcd for
7.13 (d, J = 5.3 Hz, 1H), 6.14 (s, 1H), 3.04 (s, 1H), 2.45 (s, 3H), C19H22N5O [M+H]+ 336.1824, found 336.1802.
1.88 (d, J = 10.2 Hz, 2H), 1.71 (s, 2H), 1.57 (s, 1H), 1.27 (dd, J =
24.1, 11.9 Hz, 5H); 13C NMR (101 MHz, CDCl3) δ 154.77, 148.37, 3‐(tert‐butylamino)‐2‐(pyridin‐2‐yl)imidazo[1,2‐
140.46, 136.51, 135.58, 130.46, 130.06, 128.41, 121.20, carbonitrile (7j)
a]pyridine‐8‐
120.33, 115.89, 83.31, 55.70, 34.40, 27.44, 25.78, 25.26. 197 mg (68%) of 7j was obtained as a yellow solid; Rf = 0.52
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1
HRMS: calcd for C19H23N4 [M+H]+ 307.1923, found 307.1325.
(ethyl acetate/n‐hexane, 1:1); Mp. 153‐154 C; H NMR (500
MHz, CDCl3) δ 8.63 – 8.54 (m, 1H), 8.50 – 8.46 (m, 1H), 8.31
(dd, J = 7.9, 0.7 Hz, 1H), 7.84 – 7.77 (m, 1H), 7.56 (dd, J = 7.0,
1.1 Hz, 1H), 7.23 – 7.19 (m, 1H), 6.81 (t, J = 7.0 Hz, 1H), 5.50 (s,
N
‐(tert‐butyl)‐6‐nitro‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a]pyridin‐3‐
amine (7f)
202 mg (65%) of 7f was obtained as an orange red solid; Rf = 1H), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 154.06, 148.32,
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1
0.37 (ethyl acetate/n‐hexane, 1:1); Mp. 225‐226 C; H NMR 138.80, 136.71, 136.30, 130.84, 130.11, 128.31, 122.33,
(400 MHz, CDCl3) δ 9.41 (d, J = 1.7 Hz, 1H), 8.61 (d, J = 4.1 Hz, 122.10, 115.36, 110.12, 102.30, 57.46, 30.05; HRMS: calcd for
1H), 8.18 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 9.9, 2.2 Hz, 1H), 7.81 C17H18N5 [M+H]+ 292.1562, found 292.1561.
(td, J = 7.8, 1.6 Hz, 1H), 7.56 (d, J = 9.8 Hz, 1H), 7.24 (dd, J = 7.0,
5.4 Hz, 1H), 5.53 (s, 1H), 1.19 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 153.75, 148.59, 141.19, 137.80, 136.78, 136.71, (7k)
N‐(tert‐butyl)‐2‐(pyridin‐4‐yl)imidazo[1,2‐a]pyridin‐3‐amine
131.05, 124.77, 122.56, 121.56, 117.97, 117.02, 57.49, 30.12; 80 mg (30%) of 7k was obtained as a yellow solid; Rf = 0.13
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HRMS: calcd for C16H18N5O2 [M+H]+ 312.1460, found 312.1461. (ethyl acetate/n‐hexane, 1:1); Mp. 204‐205 C; H NMR (300
MHz, CDCl3) δ 8.66 (d, J = 4.4 Hz, 2H), 8.21 (d, J = 6.9 Hz, 1H),
N
‐cyclohexyl‐6‐nitro‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a
]pyridin‐3‐
7.96 (d, J = 5.6 Hz, 2H), 7.56 (d, J = 9.1 Hz, 1H), 7.22 – 7.15 (m,
1H), 6.82 (t, J = 6.5 Hz, 1H), 3.05 (s, 1H), 1.10 (s, 9H); 13C NMR
amine (7g)
222 mg (66%) of 7g was obtained as an orange red solid; Rf = (101 MHz, CDCl3) δ 149.78, 142.92, 142.50, 136.57, 124.97,
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1
0.50 (ethyl acetate/n‐hexane, 1:1); Mp. 211‐212 C; H NMR 124.86, 123.48, 122.27, 117.78, 111.91, 56.97, 30.50; HRMS:
(500 MHz, CDCl3) δ 9.10 (d, J = 1.4 Hz, 1H), 8.60 (d, J = 4.2 Hz, calcd for C16H19N4 [M+H]+ 267.1610, found 267.1615.
1H), 8.17 (d, J = 7.9 Hz, 1H), 7.84 (dd, J = 9.9, 2.0 Hz, 1H), 7.81 –
7.77 (m, 1H), 7.55 (d, J = 9.9 Hz, 1H), 7.21 (dd, J = 6.8, 5.4 Hz, 6‐chloro‐
1H), 6.36 (d, J = 9.6 Hz, 1H), 3.29 – 3.06 (m, 1H), 1.92 (d, J = amine (7l)
10.9 Hz, 2H), 1.74 (d, J = 7.2 Hz, 2H), 1.40 – 1.31 (m, 2H), 1.30 – 103 mg (28%) of 7l was obtained as a pale yellow solid; Rf =
N‐cyclohexyl‐2‐(pyridin‐4‐yl)imidazo[1,2‐a]pyridin‐3‐
1.20 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 153.97, 148.59, 0.15 (ethyl acetate/n‐hexane, 1:1); Mp. 225‐226 C; H NMR
140.13, 136.90, 136.79, 133.26, 133.19, 123.58, 121.92, (500 MHz, CDCl3) δ 8.67 (d, J = 4.7 Hz, 2H), 8.12 (s, 1H), 7.96 (d,
120.68, 117.34, 117.06, 56.04, 34.08, 25.66, 24.82; HRMS: J = 5.1 Hz, 1H), 7.50 (d, J = 9.5 Hz, 2H), 7.14 (d, J = 9.5 Hz, 1H),
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1
calcd for C18H20N5O2 [M+H]+ 338.1617, found 338.1616.
3.10 (s, 1H), 2.99 (s, 1H), 1.83 (d, J = 12.2 Hz, 2H), 1.73 (d, J =
6.6 Hz, 2H), 1.63 (s, 1H), 1.33 – 1.15 (m, 5H); 13C NMR (101
MHz, CDCl3) δ 149.90, 141.82, 140.27, 134.86, 127.13, 126.43,
121.11, 120.78, 120.67, 118.33, 57.13, 34.27, 25.59, 24.82;
3‐(tert‐butylamino)‐2‐(pyridin‐2‐yl)imidazo[1,2‐a]pyridine‐8‐
carboxamide (7h)
225 mg (73%) of 7h was obtained as a yellow solid; Rf = 0.15 HRMS: calcd for C18H20ClN4 [M+H]+ 327.1376, found 327.1376.
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1
(ethyl acetate/n‐hexane, 1:1); Mp. 216‐217 C; H NMR (400
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J. Name., 2013, 00, 1‐3 | 9
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01384A
ARTICLE
Journal Name
6‐bromo‐
3‐amine (7m)
N
‐(tert‐butyl)‐2‐(pyridin‐4‐yl)imidazo[1,2‐
a
]pyridin‐
The residue obtained was purified by silica‐gel column
chromatography using ethyl acetate–hexane as the eluent in
89mg (26%) of 7m was obtained as a pale yellow solid; Rf = increasing polarity to afford the desired products 5a–c
.
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1
0.15 (ethyl acetate/n‐hexane, 9:1 ); Mp. 250‐251 C; H NMR
(500 MHz, CDCl3) δ 8.67 (d, J = 5.8 Hz, 2H), 8.33 (dd, J = 1.7, 0.6
N
‐(tert‐butyl)‐6‐iodo‐2‐(quinolin‐2‐yl)imidazo[1,2‐
a
]pyridin‐3‐
Hz, 1H), 7.92 (dd, J = 4.6, 1.4 Hz, 2H), 7.45 (dd, J = 9.5, 0.6 Hz, amine (5a)
1H), 7.24 (dd, J = 9.5, 1.9 Hz, 1H), 3.07 (s, 1H), 1.10 (s, 9H); 13
344 mg (78%) of 5a was obtained as a yellow solid; Rf = 0.66
C
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1
NMR (126 MHz, CDCl3) δ 149.68, 142.61, 140.78, 137.45, (ethyl acetate/n‐hexane, 1:1); Mp. 175‐177 C; H NMR (500
128.33, 125.19, 123.72, 122.29, 118.57, 107.16, 56.78. 30.49; MHz, CDCl3) δ 8.57 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.23 (d, J =
HRMS: calcd for C16H18BrN4 [M+H]+ 345.0715, found 345.0683.
8.6 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.75
– 7.67 (m, 1H), 7.57 – 7.47 (m, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.28
(dd, J = 9.4, 1.6 Hz, 1H), 5.91 (s, 1H), 1.22 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 154.63, 147.34, 140.09, 136.40, 134.79, 131.78,
3‐(tert‐butylamino)‐2‐(pyridin‐4‐yl)imidazo[1,2‐
carbonitrile (7n)
a]pyridine‐8‐
67 mg (23%) of 7n was obtained as a yellow solid; Rf = 0.12 129.86, 129.58, 129.45, 128.66, 127.79, 127.27, 126.06,
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(ethyl acetate/n‐hexane, 1:1); Mp. 160‐161 C; H NMR (300 119.79, 118.76, 74.46, 57.38, 30.22; HRMS: calcd for C20H20IN4
MHz, CDCl3) δ 8.68 (d, J = 4.8 Hz, 2H), 8.44 (d, J = 6.8 Hz, 1H), [M+H]+ 443.0732, found 443.0748.
7.98 (d, J = 5.1 Hz, 2H), 7.64 (d, J = 6.9 Hz, 1H), 6.90 (t, J = 6.9
Hz, 1H), 3.17 (s, 1H), 1.10 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
149.72, 141.97, 139.71, 138.28, 131.92, 127.67, 126.34, amine (5b)
122.50, 115.07, 110.85, 102.76, 57.45, 30.48. HRMS: calcd for 334 mg (80%) of 5b was obtained as a yellow solid; Rf = 0.50
N‐cyclohexyl‐6‐iodo‐2‐(pyridin‐2‐yl)imidazo[1,2‐a]pyridin‐3‐
C17H18N5 [M+H]+292.1562, found 292.1561.
(ethyl acetate/n‐hexane, 1:1); Mp. 208‐209 oC ; 1H NMR (500
MHz, CDCl3) δ 8.55 (d, J = 4.0 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J =
7.9 Hz, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 7.23
(d, J = 9.3 Hz, 1H), 7.17 – 7.12 (m, 1H), 6.21 (s, 1H), 3.06 (s, 1H),
N
‐(tert‐butyl)‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a]pyrimidin‐3‐
amine (7o)
208 mg (78%) of 7o was obtained as a yellow solid; Rf = 0.11 1.88 (d, J = 11.0 Hz, 2H), 1.78 – 1.52 (m, 3H), 1.36 – 1.18 (m,
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1
(ethyl acetate/n‐hexane, 9:1); Mp. 178‐180 C; H NMR (400 5H); 13C NMR (101 MHz, CDCl3) δ 154.54, 148.39, 139.11,
MHz, CDCl3) δ 8.56 (d, J = 5.5 Hz, 2H), 8.47 (d, J = 1.5 Hz, 1H), 136.59, 131.12, 130.86, 130.71, 128.03, 121.40, 120.42,
8.31 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 7.22 – 7.16 (m, 118.81, 74.93, 55.52, 33.99, 25.76, 24.89; HRMS: calcd for
1H), 6.79 (dd, J = 6.6, 4.0 Hz, 1H), 5.54 (s, 1H), 1.16 (s, 9H); 13
C
C18H20IN4 [M+H]+ 419.0732, found 419.0735.
NMR (126 MHz, CDCl3) δ 154.57, 149.29, 148.23, 144.55,
136.64, 135.82, 131.70, 127.37, 122.09, 122.04, 107.70, 57.45,
30.18; HRMS: calcd for C15H18N5 [M+H]+ 268.1562, found
268.1561.
N
‐tert‐butyl‐2‐(7‐chloroquinolin‐2‐yl)‐6‐iodoimidazo[1,2‐
a
]pyridin‐3‐amine (5c)
357 mg (75%) of 5c was obtained as a yellow solid; Rf = 0.50
(ethyl acetate/n‐hexane, 1:1); Mp. 170‐171 C; 1H NMR (400
o
N
‐(2‐morpholinoethyl)‐2‐(pyridin‐2‐yl)imidazo[1,2‐
a
]pyridin‐
MHz, CDCl3) δ 8.56 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.20 (d, J =
8.6 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.5
3‐amine (7p)
290 mg (90%) of 7p was obtained as a yellow solid; Rf = 0.26 Hz, 1H), 7.32 (dd, J = 21.9, 8.3 Hz, 2H), 5.75 (s, 1H), 1.22 (s, 9H);
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1
(ethyl acetate/n‐hexane, 1:1); Mp. 139‐141 C; H NMR (400 13C NMR (126 MHz, CDCl3) δ 155.60, 147.74, 140.12, 136.24,
MHz, CDCl3) δ 8.54 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 135.44, 134.29, 132.12, 130.13, 129.53, 129.03, 127.51,
8.05 (d, J = 6.8 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.52 (t, J = 9.5 127.03, 125.62, 120.06, 118.64, 74.97, 57.69, 30.28; HRMS:
Hz, 1H), 7.19 – 7.05 (m, 2H), 6.76 (t, J = 6.6 Hz, 1H), 6.49 (s, calcd for C20H19ClIN4 [M+H]+477.0342, found 477.0351.
1H), 3.79 – 3.65 (m, 4H), 3.19 (t, J = 5.6 Hz, 2H), 2.60 (t, J = 5.8
Hz, 2H), 2.46 (s, 4H); 13C NMR (126 MHz, CDCl3) δ 155.02,
148.46, 140.78, 136.58, 131.96, 129.76, 123.46, 122.80,
Biology
Maintenance of cell lines and drug treatment
121.16, 120.29, 117.86, 111.73, 67.01, 58.43, 53.60, 43.52;
MDA‐MB‐231, B16‐F10 and HaCaT cells were grown in DMEM
HRMS: calcd for C18H22N5O [M+H]+ 324.1824, found 324.1839.
media while MCF‐7, A549 and PC‐3 were grown in RPMI media
respectively as adherent cell lines supplemented with 10%
fetal bovine serum, 100 µg / ml penicillin, 200 µg/ ml
General procedure for synthesis of 6‐iodoimidazo[1,2‐
a
]pyridines (5a‐c):
streptomycin, 2 mM L‐glutamine, and culture was maintained
in a humidified atmosphere with 5% CO2, while MDA‐MB‐231
cell line was grown as adherent in L‐12 media devoid of CO2.
The compounds were dissolved in DMSO to prepare the stock
solution of 15 mM. Dilutions were made with respective media
to get required concentration.
In a 25 ml round bottomed flask, 2‐amino pyridine (1 mmol),
isocyanide (1 mmol), 2‐methyl quinoline (1mmol) and iodine (3
mmol) in DMSO were refluxed at 120 C for 24 hours. After
completion of reaction (monitored with TLC), reaction mixture
was quenched with saturated solution of sodium thiosulphate
and extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
o
Cytotoxicity evaluation using MTT cell based assay
10 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C7OB01384A
ARTICLE
Acc. Chem. Res., 2009, 42, 463; (d) J. D. Sunderhaus, S. F.
Martin, Chem.–Eur. J., 2009, 15, 1300; (e) D. Cheng, F. Ling,
C. Zheng, C. Ma, Org. Lett., 2016, 18, 2435; (f) C. G.
Neochoritis, S. Stotani, B. Mishra , A. Dömling, Org. Lett.,
2015, 17, 2002.
Cytotoxicity of formulations were determined by MTT cell
based assay based on the principle of mitochondrial reduction
of yellow MTT tetrazolium dye to formazan crystals, which on
addition of DMSO appears blue colour. 1X105 cells were
seeded in 96 ‐ well plates, and then incubated with
compounds and standard at various concentrations for 48 h at
37 oC in respective media with 10% FBS. After incubation, cells
were treated with 10 µl of MTT reagent (5 mg / ml) per well
5
(a) G. V. Der Heijden, E. Ruijter, R. V. A. Orru, Synlett, 2013,
24, 0666; (b) B. Maiti, K. Chanda, M. Selvaraju, C.‐C. Tseng,
C.‐M. Sun, Comb. Sci., 2013, 15, 291; (c) F. De Moliner, C.
Hulme, Org. Lett., 2012, 14, 1354; (d) S. S. Panda, M. A.
Ibrahim, A. A. Oliferenko, A. M. Asiri, A. R. Katritzky, Green
o
and plates were incubated at 37 C for 4 h, after 4 h of MTT
Chem., 2013, 15, 2709; (e) Y. Gu, Green Chem., 2012, 14
2091; (f) D. B. Ramachary, S. Jain, Org. Biomol. Chem., 2011,
, 1277; (g) R. U. Gutierrez, H. C. Correa, R. Bautista, J. L.
,
addition, media from the plates was replaced with 200 µl of
DMSO and incubated at 37 oC for 10 min. The absorbance was
measured at 570 nm on a spectrophotometer (spectra max,
Molecular devices). IC50 values were determined from plot: %
cell inhibition versus concentration.
9
Vargas, A. V. Jerezano, F. Delgado, J. Tamariz, J. Org. Chem.,
2013, 78, 9614; (h) B. Jiang, S.‐J. Tu, P. Kaur, W. Wever, G. Li,
J. Am. Chem. Soc., 2009, 131, 11660.
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(a) Y. Rival, G. Grassy, G. Michel, Chem. Pharm. Bull., 1992,
40, 1170; (b) T. Kercher, C. Rao, J. R. Bencsik, J. A. Josey, J.
Comb. Chem., 2007,
9, 1177; (c) Y. Rival, G. Grassy, A.
Taudou, R. Ecalle, Eur. J. Med. Chem., 1991, 26, 13; (d) M. H.
Fisher, A. Lusi, J. Med. Chem., 1972, 15, 982; (e) A. Gueiffier,
S. Mavel, M. Lhassani, A. Elhakmaoui, R. Snoeck, G. Andrei,
O. Chavignon, J. C. Teulade, M. Witvrouw, J. Balzarini, E. De
Clercq, J. P. Chapat, J. Med. Chem., 1998, 41, 5108; (f) M. A.
Ismail, R. Brun, T. Wenzler, F. A. Tanious, W. D. Wilson, D. W.
Boykin, J. Med. Chem., 2004, 47, 3658; (g) E. Abignente,
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J. Benavides, B. Scatton, Adv. Biochem. Psychopharmacol.,
1990, 46, 61; (j) C. Hamdouchi, B. Zhong, J. Mendoza, E.
Collins, C. Jaramillo, J. E. De Diego, D. Robertson, C. D.
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Conflicts of interest
There are no conflicts of interest to declare
Acknowledgement
G. S. M is thankful to the Department of Pharmaceuticals, the
Ministry of Chemicals and Fertilizers Govt. Of India, New Delhi
for the award of a Research Fellowship.
7
8
(a) R. D. Carpenter and M. J. Kurth, Nat. Protoc.,2010, 5,
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DOI: 10.1039/C7OB01384A
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01384A
A facile I2-catalyzed synthesis of imidazo[1,2-a]pyridines via sp3 C-H
functionalization of azaarenes and evaluation of anticancer activity
Geeta Sai Mani,a,b Siddiq Pasha Shaik,b Yellaiah Tangella,b Swarna Bale,a Chandraiah
Godugua and Ahmed Kamal*a,b
A three component synthetic protocol has been developed for the synthesis of medicinally
important imidazo[1,2-a]pyridines via iodine-catalyzed oxidative amination of benzylic C-H
bonds of azaarenes. All the synthesized compounds were evaluated for their anti-cancer
activity in selected cancer cell lines. Compounds 4a, 4b, 4c, 4i, 7a, 7b and 7m have showed
significant IC50 values ranging from 4.88 ± 0.28 to 14.55 ± 0.74 µM.