Transition-metal-free C-N and C-C formation: Synthesis of benzo[4,5]imidazo[1,2-: A] pyridines and 2-pyridones from ynones

Article abstract of DOI:10.1039/c8gc00069g

Herein, a transition metal-free and efficient cascade reaction of ynones with 2-methylbenzimidazoles under mild conditions has been revealed. This cascade reaction involved a Michael addition/intramolecular cycloaddition/dehydration and provided the desired benzo[4,5]imidazo[1,2-a]pyridines in moderate to good yield. Furthermore, three benzo[4,5]imidazo[1,2-a]pyridines (3d, 3i, and 3q) exhibited good activities against Hep-G2 (human liver cancer), T-24 (human bladder cancer cell), and SK-OV-3 (human ovarian cancer) cell lines with IC₅₀ values in the range of 8.05-10.67 μmol L^-1. To investigate the mechanism of the effective inhibition of cell growth, further studies, including cell cycle analysis, apoptosis ratio detection, measurement of Ca²⁺ generation, ROS, mitochondrial membrane potential assay, and caspase-3/9 activation, were carried out on compound 3i.

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Transition-Metal-Free C-N and C-C Formation: Synthesis of
Benzo[4,5]imidazo[1,2-a]pyridines and 2-Pyridones From Ynones
Received 00th January 20xx,
Accepted 00th January 20xx
Qing-Hu Teng,a Xiang-Jun Peng,a, b Zu-Yu Mo,a Yan-Li Xu,c Hai-Tao Tang,a,* Heng-Shan Wang,a
Hong-Bin Sun,a and Ying-Ming Pana,*
DOI: 10.1039/x0xx00000x
A transition-metal-free and efficient cascade reaction of ynones with 2-methylbenzimidazoles under mild conditions has
been revealed. This cascade reaction processed a Michael addition/intramolecular cycloaddition/dehydration and offered
the desired benzo[4,5]imidazo[1,2-a]pyridines in moderate to good yields. Furthermore, three benzo[4,5]imidazo[1,2-
a]pyridines (3d, 3i, 3q) exhibited good activities against Hep-G2 (human liver cancer), T-24 (human bladder cancer cell) and
SK-OV-3 (human ovarian cancer) cell lines with IC50 in the range of 8.05–10.67 μmol/L. To investigate the mechanistic of
the effective cell growth inhibition, further studies of compound 3i, including cell cycle analysis, apoptosis ratio detection,
measurement of Ca2+ generation, ROS, mitochondrial membrane potential assay and caspase-3/9 activation, were carried
out.
www.rsc.org/
crown-6.12 In this reaction, the excess base were required. Recently,
significant achievements have been made in the transformation of
ynones and heteroaryl amines into imidazo[1,2-a]pyridines. The N-
pyridyl enaminones from ynones and heteroaryl amines underwent
Introduction
Ynones, equip with two reaction sites C≡C bond and carbanyl group,
have been considered as valuable substrates in organic synthesis.1
And the transformation of ynones has been widely applied in the
construction of high-value linear2 and cyclization products3.
Generally, the selective hydrogenations of α,β-unsaturated
carbonyls promoted by transition-metal catalyst lead to alkyl
ketones,4 propargylic alcohols,5 and E-chalcones6. And recently,
great interest was focus on the conversion of ynones into pyridine-
containing N-heterocycles.7
an intramolecular C–H bond cycloamination promoted by
hypervalent iodine and led to the imidazo[1,2-a]pyridines.13 Besides,
the intermolecular oxidative diamination of alkynones with 2-
aminopyridines promoted by the co-catalysis of copper(II) and
iron(III) also gave the imidazo[1,2-a]pyridines.14 Although the above
methods are useful to construct imidazo[1,2-a]pyridines, there are
Imidazo[1,2-a]pyridines not only exhibit various pharmaceutical
and biological activities8, but also be used to build blocks for the
preparation of a wide range of interesting heteroarene derivatives,9
that continuously
drive us to develop the new synthesis
approaches.10 In 1983, Tsuge and his coworkers reported
a
cycloaddition of nitrogen-bridged tetravalent sulfur compounds
with ynones, the cyclo adducts were easy to undergo
desulfurization and 10π cyclization, and offered 4,9c-
diazapentaleno-[1,6a,6:ab]-naphthalenes as product11 An efficent
.
strategy for the construction of benzo[4,5]imidazo[1,2-a]pyridine is
via the reaction of ynones with 2-benzimidazolyl-acetonitriles
promoted by the combination of potassium carbonate and 18-
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still some drawbacks, such as the limited substrates, the use of
transition-metal catalysts or strong oxidants, and multi-step
operation.
Table 1. Optimization of Cascade Cyclization of Ynones into N-
heterocycles.a
Owing to the rising environmental awareness among nations, the
transition-metal-free system has been popular in organic
synthesis.15 Really, the transition-metal-free reaction can
dramatically reduce the toxicity and cost, and make the pathways
more practical and environmentally friendly.16 Hence, a high-
efficiency and green method for synthesize imidazo[1,2-a]pyridines
is still highly desired. We are also interested in transition-metal-free
system, and have studied the transition-metal-free cascade reaction
of ynones to structure.17
Entry
Additive
K2CO3
Solvent
Yield (%)b
1
2
1,4-Dioxane
1,4-Dioxane
30
20
Cs2CO3
3
4
KHCO3
KOH
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
PhCl
15
85
78
15
40
0
Results and discussion
5
NaOH
Et3N
Very recently, our group developed a base promoted Michael
addition and intramolecular cyclodehydration of diynones with
glycine esters or 2-amino-acetophenone hydrochlorides to 3-
alkynylpyrrole-2-carboxylates.18 We envisioned that (1H)-N-
heterocycles should be add to the ynones to form α,β-enaminones,
6
7
CH3ONa
PTSA
Cu(OTf)2
KOH
8
which undergo
a cyclization to N-heterocycles under base
conditions. Firstly, We studied the addition of 2-
methylbenzimidazoles with ynones under the presence of K2CO3 (1
equiv.) in 1,4-Dioxane at 100 °C for 6 h (Table 1, entry 1). Excitingly,
1,3-diphenylbenzo[4,5]imidazo[1,2-a]pyridine 3a was obtained. This
9
0
10
11
12
13
14c
15d
16e
17f
Trace
70
73
30
45
87
86
60
KOH
Toluene
indicates
that
a
transition-metal-free
synthesis
and
of
2-
benzo[4,5]imidazo[1,2-a]pyridines
from ynones
KOH
DMF
methylbenzimidazoles can be realized. Encouraged by this result,
we started to optimize the reaction conditions (Table 1). Originally,
a screening of various kinds of additives such as Cs2CO3, KHCO3,
KOH, NaOH, Et3N, CH3Ona, PTSA and Cu(OTf)2, showed that
inorganic bases were more effective than organic bases, while the
acid or Lewis acid could not promote the reaction, and KOH was the
best (Table 1, entries 2-9). When the reaction was carried out in the
PhCl, only trace of 3a was detected (Table 1, entry 10). Other
solvents such as Toluene, DMF, and DMSO afforded the desire
product in 70%, 73%, 30% yields, respectively (Table 1, entries 11-
13). The control experiments indicated that the decrease amount of
KOH resulted in the significant loss of 3a, and the increase loading
of KOH didn’t obviously affect on this reaction (Table 1, entries 14
and 15). When a higher temperature was employed, not obvious
effect on the yield was observed (Table 1, entry 16). But the lower
temperature was unfavourable in the reaction, only 60% yield of 3a
was obtained (Table 1, entry 17). Finally, the optimal conditions for
this transformation are KOH (1 equiv.) in 1,4-Dioxane at 100 °C for 6
h.
KOH
DMSO
KOH
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
KOH
KOH
KOH
aReaction conditions: 1a (0.6 mmol), 2a (0.5 mmol),
additive (1 eq.), solvent (2 mL), at 100 oC, 6 h. bIsolated
yields. 0.5 eq. KOH was used. d1.5 eq. KOH was used. e At
c
120 oC. f At 80 oC.
yields (Table 2, 3a-3g). And the structure of 3b was further
confirmed by X-ray crystallographic analysis, which was
recrystallized from CHCl3.19a The heterocycle ynones were tolerated
in this reaction, furyl and thienyl offered 3h and 3i in 68% and 65%
yield, respectively(Table 2, 3h and 3i). Single aliphatic ynones were
suitable in this reaction, and gave the products in moderate yields
(Table 2, 3j-3l). While, dialkyl ynones were ineffective, only a trace
of products was detected (Table 2, 3m). However, not only the
terminal ynones could not work smoothly to produce the desired
product, but also 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-one (R1 =
TMS) failed to furnish the corresponding product. In the moiety of
2-methylbenzimidazoles, the electron-donating groups, halogen
and cyano were tolerant and gave the corresponding products in
With the optimized reaction conditions in hand, we subsequently
investigated the substrate scope of this cascade reaction, and the
results are summarized in Table 2. Firstly, various ynones were
explored, and the benzo[4,5] imidazo[1,2-a]pyridines were
obtained in moderate to good yields. When diphenyl ynones were
employed, both the electron-donating and electron-withdrawing
group in phenyl both generated the corresponding products in good
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Table 2. Synthesis of Benzo[4,5] imidazo[1,2-a]pyridines from
Table 3. Synthesis of 2-Pyridones from Ynones and Amides
Ynones and 2-Methylbenzimidazoles
aReaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), KOH (1 eq.),
1,4-Dioxane (2 mL), 6 h. bIsolated yields. c2 eq. KOH was used.
high yields (Table 2, 3n-3r). Furthermore, benzo[4,5] imidazo[1,2-
a]pyridine 3s was yielded in 65% when the R4 was CN (Table 2, 3s).
aReaction conditions: 1 (0.6 mmol), 4 (0.5 mmol), KOH (1 eq.),
1,4-Dioxane (2 mL), 6 h. bIsolated yields. c2 eq. KOH was used.
succeeded to generate the desired product 3b in 83% yield under
We found that amides were also applicable in this cascade reaction,
and the results were showed in Table 3. As expected, all kinds of
ynones and amides reacted successfully under the standard
conditions. Ynones with electron-withdrawing, electron-donating
groups and heterocycle groups afforded the corresponding 2-
pyridones in appreciable yields (65–90%, Table 3, 5a–5g). To our
delight, the single aliphatic ynones bearing tertiary butyl and
cyclopropyl reacted smoothly and afforded the desired products 5h
and 5i in 80% and 63% yields, respectively (Table 3, 5h and 5i). The
terminal ynones also worked successfully to generate the 2-
pyridones 5j and 5k in 48% and 50% yields (Table 3, 5j and 5k).
Then, various aromatic amides equip with electron-withdrawing
groups, electron-donating groups and N-heterocycle groups were
explored, and provided the cyclization products in moderate to
good yields, (Table 3, 5l–5v). The structure of 5o was further
confirmed by X-ray crystallographic analysis which was
recrystallized from CHCl3.19b To our delight, the N-methylacetamide
also worked well in the reaction and resulted to the 2-pyridone 5w
in 45% yield (Table 3, 5w). Unfortunately, the acetamide failed to
produce the corresponding product. While, 30−92% yields of the
corresponding products (5x-5z) were obtained when R4 was Me, Ph
and Ac (Table 3, 5x–5z).
the standard conditions (Scheme 2, (2)).
N
O
N
N
O
KOH (1 equiv.)
+
(1)
1,4-Dioxane
25 oC, 1.5 h
N
H
2a
1b
A
, 92%
N
N
standard conditions
N
O
N
(2)
Ph
3b, 83%
A
Scheme 2. Controlled experiments.
On the basis of above results and literatures, a plausible mechanism
is proposed in Scheme 3. Initially, the Michael addition of 2a with
1a generated
intermediate A was ready to undergo deprotonation with KOH and
form B. An intramolecular cycloaddition of produced the
a
α,β-enaminone intermediate A.20 Then the
B
cyclization product C. Finally, the desired product 3a was obtained
via the protonation and dehydration of C.21
N
N
N
N
N
OH
N
H
O
O
2a
OH
O
Ph
Ph
B
A
Ph
1b
To estimate the plausible mechanism of this transformation, some
controlled experiments were performed and the results were
showed in Scheme 2. At first, the reaction of 1b and 2a in the
precence of KOH (1 equiv.) in 1,4-dioxane at 25 oC provided the
intermediate A in 92% yield (Scheme 2, (1)). Next, the intermediate A
Ph
N
N
Ph
N
OH
+ H+
- H2O
O
N
N
Ph
N
D
3b
C
Scheme 3. Plausible reaction mechanism.
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3i could potentially arrest the cell cycle at G1 phase in
concentration-dependent manner.22
a
The apoptosis ration induced by 3i in T-24 cell line was detected by
flow cytometry with propidium iodide and Annexin V stained cells.
As shown in Fig. 3, after treated with different concentrations (10,
20 and 30 μM) of 3i, the apoptosis rate of T-24 cells increased to
14.35%, 35.83% and 64.51% from 1.6%. The results indicated that 3i
might suppress cell proliferation by inducing apotosis. Further
mechanistic studies showed that 3i could elevate intracellular ROS
levels and Ca2+ levels, decrease the mitochondrial membrane
potential, mitochondrial dysfunction and analysis of MMP, activate
the expression of Caspase-3/9 (supporting information Fig. 1-4.).
Fig. 1. Anticancer activity of benzo[4,5] imidazo[1,2-
a]pyridines.
Meanwhile, the in vitro cytotoxicity of 3a–3s, and 5a–5z against
four human tumor cell lines: human gastric cancer cell line (MGC-
803), human bladder cancer cell line (T-24), human ovarian cancer
cell line (SK-OV-3), human liver cancer cell line (Hep-G2) and normal
liver cell line (WI-38) were determined by methylthiazoltetrazolium
(MTT) assay, and the 5-fluorouracil (5-FU) was used as the positive
control (Supporting Information Table 1). Fortunately, compounds
3i (IC50 = 10.2 ± 0.7 μM) and 3q (IC50 = 10.4 ± 0.7 μM) exhibited
potent inhibitory activity against T-24 cell lines (Fig. 1). Compounds
Conclusion
In conclusion, we have developed a transition-metal-free, efficient,
and practical procedure for the synthesis of benzo[4,5]imidazo[1,2-
a]pyridines
and
2-pyridones
from
ynones
and
2-
methylbenzimidazoles or acetamides. And this transformation
involves C-N and C-C bonds formation. Furthermore, three
compounds (3d, 3i, 3q) showed potent anticancer activities in vitro.
The further mechanistic studies showed that compound 3i
effectively inhibited cell growth by triggering G1 phase arrest and
inducing apoptosis through the mitochondria-mediated pathway.
Experimental
1. General procedure for the synthesis of 3 and 5: To a sealed
tube was added with ynones 1 (0.6 mmol), acetamides 2 or 2-
methylbenzimidazoles 4 (0.5 mmol), KOH (0.5 mmol) and 1,4-
Dixoane (2.0 mL). Then the mixture was stirred at 100 °C for 6
h. After completed, the mixture was diluted with water (5 mL)
and extracted with ethyl acetate (3 × 5 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was
purified by flash column chromatography to give the desired
product give 3 or 5.
3d (IC50 = 8.1 ± 0.8 μM) and 3q (IC50 = 10.8 ± 1.0 μM) were found to
be powerful cytotoxic agents against SK-OV-3 and Hep-G2 cell lines,
respectively (Fig. 1). In addition, comparing with the IC50 values of
cancer and normal cell lines, all compounds have more obvious
inhibitory effect on tumor cells than human normal cell line WI-38.
Then the compound 3i was selected for cell cycle analysis and
apoptosis analysis in T-24 cells for 24 h.
2. Biological Assays: the detailed procedures for other
experimental methods are described in SI.
Conflicts of interest
Fig. 3. Apoptosis ratio of T-24 cells treated with 3i by Annexin
There are no conflicts to declare.
V/PI assay.
Acknowledgements
We would like to thank the National Natural Science Foundation of
China (21362002), Guangxi Natural Science Foundation of China (20
16GXNSFEA380001 and 2016GXNSFGA380005), Ministry of Educati
on of China (IRT_16R15), State Key Laboratory for Chemistry and M
olecular Engineering of Medicinal Resources (Guangxi Normal Unive
rsity) (CMEMR2017-A02 and CMEMR2017A07) and BAGUI Scholar
Program of Guangxi Province of China (2016A13) for their financial s
upports.
Primarily, the effect of 3i on cell cycles was investigated by flow
cytometry with propidium iodide stained cells. As shown in Fig. 2,
with the increasing concentration of compound 3i, the percentage
of G1 phase cell increased from 37.36% to 59.05%. And compared
with the 37.36% in the control group, the percentage of S-phase T-
24 cells decreased to 49.93% (10 μM), 35.94% (20 μM), and 29.24%
(30 μM), respectively. The results evidently demonstrated that the
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12, 372.
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DOI: 10.1039/C8GC00069G
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single-crystal structure of product 3b is included in Supporting
Information. (b) CCDC 1813403 (5o) contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
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www.ccdc.cam.ac.uk/data_request/cif. The single-crystal
structure of product 5o is included in Supporting Information.
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6 | J. Name., 2012, 00, 1-3
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Green Chemistry
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DOI: 10.1039/C8GC00069G
We
have
developed
a
facile
method
for
the
synthesis
of
benzo[4,5]imidazo[1,2-a]pyridines and 2-pyridones from available ynones and
2-methylbenzimidazoles or acetamides.