Catalyst free, C-3 functionalization of imidazo[1,2-a]pyridines to rapidly access new chemical space for drug discovery efforts

Article abstract of DOI:10.1039/C8CC07063F

Multicomponent reactions (MCRs) are robust tools for the rapid synthesis of complex, small molecule libraries for use in drug discovery and development. By utilizing MCR chemistry, we developed a protocol to functionalize the C-3 position of imidazo[1,2-a

Full text of DOI:10.1039/C8CC07063F

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Catalyst free, C-3 functionalization of
imidazo[1,2-a]pyridines to rapidly access new
chemical space for drug discovery efforts†
Cite this: Chem. Commun., 2018,
54, 12954
Received 31st August 2018,
Accepted 22nd October 2018
Naresh Gunaganti,
Anupreet Kharbanda, Naga Rajiv Lakkaniga, Lingtian Zhang,
Rose Cooper, Hong-yu Li* and Brendan Frett
*
DOI: 10.1039/c8cc07063f
rsc.li/chemcomm
Multicomponent reactions (MCRs) are robust tools for the rapid a variety of synthetic strategies have been developed to functio-
synthesis of complex, small molecule libraries for use in drug dis- nalize the heterocycle.15 The strategies require metal catalysis,
covery and development. By utilizing MCR chemistry, we developed multiple steps, and molar equivalence of oxidants. Therefore,
a protocol to functionalize the C-3 position of imidazo[1,2-a]pyridine rapid, operationally-simplistic, and eco-friendly methods are still
through a three component, decarboxylation reaction involving needed to functionalize imidazo[1,2-a]pyridines for use in drug
imidazo[1,2-a]pyridine, glyoxalic acid, and boronic acid.
discovery.
Because of the biological importance of C-3 substituted
Multicomponent reactions (MCRs) facilitate the rapid generation imidazo[1,2-a]pyridines and the nucleophilic nature of the
of diverse, chemical libraries with complex form and function, C-3 carbon, numerous C–H functionalization reactions, such as
which have vast use in drug discovery and development.1 MCRs sulfonylation, arylation, amination, carbonylation, annulation
represent a powerful tool to expeditiously expand chemical and oxidative homocoupling, have been developed in recent years
diversity and to reach novel, chemical space. Because of their to enhance C-3 diversity.16 One-pot methods are available to
utility in medicinal chemistry, MCRs have become an essential construct 2,3-disubstituted imidazo[1,2-a]pyridines but all require
tool to increase hit-to-lead efficiency while decreasing time metal catalysis.15a,17 Direct arylomethylations have been disclosed
exhausted in the medicinal chemistry iterative cycle.2 The advan- but are relatively rare, and neither methodology is catalyst free
tages of MCRs include one-pot synthesis, mild reaction condi- (Fig. 1).18 Accordingly, functionalizing imidazo[1,2-a]pyridines
tions, and post-MCR functionalization to help constrain rotatable through an operationally-simplistic, catalyst free reaction from
bonds and resolve stereochemistry.3 In an effort to develop MCR commercially available starting materials is highly warranted.
chemistries to help expand drug chemotypes, we designed a novel
decarboxylative, Petasis-like three component reaction to functio- eco-friendly MCR for the construction of aryl methane derivatives
nalize the C-3 position of imidazo[1,2-a]pyridine. of imidazo[1,2-a]pyridine using commercially available boronic
In the current protocol, we disclose an economical, catalyst free,
The imidazo[1,2-a]pyridine core is found in pharmaceuticals acids. The MCR was strategically designed to rapidly expand
and natural products that possess a broad range of biological accessible chemotypes with an imidazo[1,2-a]pyridine core.
and pharmacological activities such as anticancer,4 antibacterial,5
We began our investigation for arylomethylation with
anti-viral,6 antifungal,7 antiprotozoal,8 anti-inflammatory and 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine 1a, glyoxylic acid 2a,
antiulcer.9 Imidazo[1,2-a]pyridines such as alpidem, necopidem,
and saripidem are marketed as anxiolytic drugs10 and zolpidem
is used to treat insomnia.11 Another derivative, minodronic acid,
is used to treat osteoporosis12 and olprinone for heart failure.13
In particular, imidazo[1,2-a]pyridine derivatives are important
for exploratory drug discovery research, which has led to the
identification of novel kinase inhibitors with activities against
PI3K, p38, Nek2, and NFkB inducing kinase.14 Owing to the
biological importance of functionalized imidazo[1,2-a]pyridines,
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences,
Little Rock, 72205, USA. E-mail: BAFrett@uams.edu, HLi2@uams.edu
Fig. 1 Literature precedence for C-3 functionalization of imidazo[1,2-a]-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc07063f
pyridines.
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Table 1 Optimization of reaction conditionsa
% of
% of
% of
Tempe. Time Yieldd Yieldd Yieldd
S. no. Solvent Promoter (1C)
(h)
(3aa)
(3aab) (3aac)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
Dioxane
EtOH
H2O
CH3CN
CH3CN pTSA
CH3CN KOtBu
—
—
—
—
—
—
—
100
120
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
12
24
24
24
24
24
24
24
24
24
24
24
12
24
24
24
24
10
30
40
30
—
—
40
20
75
60
65
45
50
60
—
—
—
50
60
50
25
55
50
50
50
10
20
30
40
40
40
50
40
40
15
20
30
40
30
25
—
—
—
—
—
—
9b
10
11
12
13
14c
15
16
17
DMF
KOtBu
CH3CN NaOtBu
CH3CN Cs2CO3
CH3CN KOtBu
CH3CN KOtBu
DMF
Toulene KOtBu
DCE KOtBu
PTSA
—
—
—
a
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), 3a (1.5 mmol).
Base, 1 mmol. Base, 1.5 mmol; solvent (4.0 mL). Isolated yield.
b
c
d
Fig. 2 Arylomethylation substrate scope with various boronic acids and
.
imidazo[1,2-a]pyridinesa,b a Reactions were conducted with 1.0 mmol of
and 4-methoxy phenylboronic acid 3a in dimethyl formamide
(DMF) as solvent at 100 1C for 12 h. With these conditions, only
10% of the desired product 3aa was obtained, while the major
products were a mixture of the imidazopyridine/glyoxylic acid
1a–1h, 1.5 mmol of 2a, 1.5 mmol of 3a–3s and 1.0 mmol of KOtBu in
CH3CN at 110 1C for 24 h. b Isolated yields.
adduct 3aab and the non-decarboxylated form of the desired to produce the desired product. This suggests that electron
product 3aac (Table 1, entry 1). density is important for product conversion, and the reaction is
The yield of the desired product 3aa increased to 30% when robust enough to handle mild electron withdrawing function-
the reaction was extended to 24 hours and heated to 120 1C ality. We further examined hetero aryl boronic acids for trans-
(Table 1, entry 2). This suggests that the desired decarboxyla- formation, such as benzothiophene and benzofuran (Fig. 2, 3ap
tion of intermediate 3aac could be achieved at higher tempera- and 3aq). Both were successful in producing the desired product
tures with longer reaction durations. Even with more aggressive in good yields, but monocyclic hetero aryl boronic acids, such as
conditions, however, satisfactory yields of 3aa were not obtained. pyridine, furan, and thiophene, did not furnish the desired
Various solvents were investigated to help increase transforma- product likely from delocalized electron density. The hindered
tion but all failed to improve yield other than acetonitrile, which substituted boronic acid 3an exhibited good transformation
furnished 3aa in 40% yield (Table 1, entry 7). Employment of suggesting that steric effects do not have a large impact on
p-toluenesulfonic acid to activate intermediate 3ab did not have product conversion.
a positive impact on overall yield (Table 1, entry 8). Further
Further, we diversified the imidazo[1,2-a]pyridine core using
investigation with various bases produced a dramatic improve- both electron rich and deficient functionalities and, among
ment in yield (Table 1, entries 9–14). With 1 eq. of KOtBu the them, electron donating groups furnished excellent to good
isolated yield of the desired product 3aa increased to 75% yields compared to their electron deficient counterparts (Fig. 3).
(Table 1, entry 9). Reaction optimization clearly indicated that a We expanded the imidazo[1,2-a]pyridine core to test trans-
strong, non-nucleophilic base is necessary to promote reaction formation with more complex derivatives and observed excellent
progression and, to efficiently decarboxylate intermediate 3aac, product conversion as seen with examples 4a–4n (Fig. 3).
an aprotic solvent is necessary.
Based on previous reports19 and control experiments, we
With the optimized conditions in hand, we sequentially proposed a mechanism for the arylomethylation reaction, which
examined the substrate scope using commercially available consists of a Petasis-like mechanism followed by decarboxylation
boronic acids (Fig. 2).
to generate the desired product (Fig. 4). To support the mecha-
It was identified that electron donating boronic acids nism, we completed extensive control experiments and identi-
furnished good to excellent yields, while electron withdrawing fied molecular ion peaks that correspond to intermediates 3aab
boronic acids gave lower yields. However, strongly electron and 3aac (see ESI†). With this evidence, we proposed that the
withdrawing boronic acids, such as –NO2 and –CN, were unable reaction initiates from the nucleophilic attack of glyoxylic acid by
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Table 2 Antiproliferative activity and selectivity of 3aa, 4g, and 4da
Cell GI50 (mM)
Comp.
H460
HCC827
LC-2/ad
3aa
4g
4d
41
41
41
0.15 Æ 0.01
0.60 Æ 0.18
0.063 Æ 0.029
0.39 Æ 0.07
2.03 Æ 0.56
0.28 Æ 0.040
a
GI50 values are expressed in mM units and are the results of three
independent experiments.
Products from the arylomethylation were screened against
cancer cell lines to help identify novel chemotypes that impair
cancer cell growth (Table 2). The cell lines employed for the
studies were HCC827 (EGFR-driven), LC-2/ad (RET-driven), and
H460 (non-oncogene). We identified that 3aa, which was the
first compound synthesized, did not exhibit strong activity
against any cell line tested (GI50 4 1 mM). From screening the
entire library of the arylomethylation series, it was identified
that compounds 4g and 4d were able to potently inhibit cancer
cell growth and exhibited sub-micromolar growth inhibition
(GI50) values. The most active compound, 4g, exhibited a GI50
on LC-2/ad cells of 0.063 Æ 0.029 mM. The compound exhibited
some selectivity between H460 and LC-2/ad, suggesting 4g may
be more active against RET-driven cell lines. Further studies are
underway to determine the exact mechanism by which 4g and
4d elicit antiproliferative effects.
Fig. 3 More diverse imidazopyridines for arylomethylation.a,b a Reactions
were conducted with 1.0 mmol of 1j–1n & 1t–1x, 1.5 mmol of 2a, 1.5 mmol
of 3a, 3i & 3l and 1.0 mmol of KOtBu in CH3CN at 110 1C for 24 h. b Isolated
yields.
In conclusion, we have developed an innovative, catalyst free
route to access distinctly substituted, C-3 arylomethylation deri-
vatives of imidazo[1,2-a]pyridines. For ease of use, the method
was developed to utilize commercially available boronic acids
and glyoxylic acid, through a three component Petasis-like
reaction followed by decarboxylation in one pot. The current
protocol improves on prior methods, which all require the use of
a metal catalyst and oxidizing agents. By using this methodology,
we have achieved broad substrate scope with 39 variously sub-
stituted analogues, and we also evaluated antiproliferative activity
in cancer cell lines. From the study, 4g and 4d were identified as
promising hit, anticancer candidates, which support the use of
this new methodology to identify novel, bioactive molecules.
This work was supported by an Institutional Development
Award (IDeA) from the National Institute of General Medical
Sciences of the National Institutes of Health under grant
number ‘‘P20 GM109005’’. H. L. was supported by the grants
NIH 1R01CA194094-010 and 1R01CA197178-01A1 and UAMS
start-up funding. B. F. was supported by the UAMS Seeds of
Science cancer research grant, the UAMS College of Pharmacy
Seed Grant, and an ATA/Thyca research grant.
Fig. 4 Proposed reaction mechanism.
imidazo[1,2-a]pyridine to afford the stable intermediate 3aab
through A. Under high temperature and basic conditions, the
boronic acid can complex with intermediate 3aab to generate B.
The resulting adduct is converted to intermediate C through
phenyl migration to the benzylic position of imidazo[1,2-a]-
pyridine. The final step is decarboxylation of C to generate the
desired arylomethylated product. It is important to note that
intermediate 3aab can be isolated and converted to the desired
product with addition of base and boronic acid, supporting the
proposed mechanism (see ESI†).
Conflicts of interest
There are no conflicts to declare.
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