Porous organic polymer-derived nanopalladium catalysts for chemoselective synthesis of antitumor benzofuro[2,3-b]pyrazine from 2-Bromophenol and Isonitriles

Article abstract of DOI:10.1021/acs.orglett.9b01230

An efficient strategy for the synthesis of benzofuro[2,3-b]pyrazines was developed. These tricyclic scaffolds were formed through a multistep cascade sequence, which includes double insertion of isonitriles and chemoselective bicyclization. In this reaction, a nanopalladium was used as a recyclable catalyst. Product 3w exhibited excellent anticancer activity toward T-24 (IC₅₀ = 12.5 ± 0.9 μM) and HeLa (IC₅₀ = 14.7 ± 1.6 μM) cells. We also explored the action mechanism of 3w on T-24 cells.

Full text of DOI:10.1021/acs.orglett.9b01230

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Porous Organic Polymer-Derived Nanopalladium Catalysts for
Chemoselective Synthesis of Antitumor Benzofuro[2,3‑b]pyrazine
from 2‑Bromophenol and Isonitriles
Mao-Rui Wang, Li Deng, Guo-Chen Liu, Ling Wen, Jin-Ge Wang, Ke-Bin Huang, Hai-Tao Tang,*
and Ying-Ming Pan*
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical
Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient strategy for the synthesis of benzofuro[2,3-
b]pyrazines was developed. These tricyclic scaffolds were formed
through a multistep cascade sequence, which includes double insertion
of isonitriles and chemoselective bicyclization. In this reaction, a
nanopalladium was used as a recyclable catalyst. Product 3w exhibited
excellent anticancer activity toward T-24 (IC50 = 12.5 0.9 μM) and
HeLa (IC50 = 14.7
1.6 μM) cells. We also explored the action
mechanism of 3w on T-24 cells.
olycyclic fused nitrogen-containing heterocycles play an
involve multiple steps or prefunctionalization of starting
materials. Therefore, scholars must develop facile and efficient
approaches for the synthesis of benzofuro[2,3-b]pyrazine from
commercially available substrates and determine its pharmaco-
logical activity.
P
important role in modern organic synthesis due to their
ubiquity in many biologically significant natural products and
pharmaceuticals and their broad applications in materials
science.1 Among numerous nitrogen-containing aromatic
polycyclic compounds, benzofuran-fused N-heterocycles are
well-recognized structural units in drug candidates and
biologically active compounds (Figure 1). For example,
As important C1 building blocks, isonitriles are useful
synthons.6 Insertions of palladium-catalyzed isonitrile into
carbon−heteroatom, carbon−hydrogen, and carbon−halogen
bonds have been extensively studied.7 This strategy has been
used to prepare numerous nitrogen-containing compounds
with excellent pharmacological activity.8 However, these
homogeneous palladium catalysts are more difficult to recycle
from the final products than their corresponding heteroge-
neous catalytic systems with fixed metal catalysts on large-
surface area materials. In view of the highly active and diverse
reactivity of isonitriles, controlling their selectivity for
participation in chemical reactions is a major challenge. Recent
studies have reported on using porous organic polymers
(POPs) as catalyst supports and ligands for various metal
catalysts to improve reaction selectivity.9 For example, a series
of P-containing POPs with excellent regioselectivity and
chemoselectivity were used as recyclable catalysts in hydro-
genation, hydroformylation, and decarbonylation.10 In our
previous work,11 we developed a highly chemoselective
method with this type of heterogeneous catalyst for the
synthesis of polysubstituted thiazoles from isonitriles.11b Thus,
we were inspired to develop a new method for the synthesis of
benzofuran derivatives 7 from easily available ortho-halogen-
ated phenol 1 with isonitriles (Scheme 1). First, substrates 1a
and 2a were treated with a homogeneous palladium catalyst.
Figure 1. Benzofuran-fused N-heterocycles and their pharmacological
activity.
benzofuro[2,3-b]pyridine derivatives (I) are commonly used
as inhibitors of multifarious cyclin-dependent kinases.2
Benzofuro[3,2-d]pyrimidine derivatives (compound II) are
potent histamine H4 modulators.3 Compound III is a new
inhibitor of multitarget tyrosine kinase and is currently
undergoing phase I clinical trials.4 However, few studies have
investigated the synthesis method and pharmacological activity
of benzofuro[2,3-b]pyrazine derivatives (compound IV). In
recent decades, only a few methods have been reported for the
preparation of benzofuro[2,3-b]pyrazine.5 These methods
Received: April 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01230
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heterogeneous Pd (2 mol %) as a catalyst in 1,4-dioxane and
reaction at 130 °C in air for 8 h (Table 1, entry 10).
Scheme 1. Possibilities for the Formation of Different
Benzofuran Derivatives
We then extensively evaluated the substrate scope of this
chemistry (Scheme 2) under the conditions described above.
Scheme 2. Synthesis of Benzofuro[2,3-b]pyrazines from o-
a,b
Halophenols with Diverse Isonitriles
Product 7 was not observed, and 2,3-diphenylbenzofuro[2,3-
b]pyrazine 3a was obtained in 34% yield. The structure of 3a
was confirmed by single-crystal X-ray analysis. Herein, we
report the development of this palladium-catalyzed chemo-
selective bicyclization reaction for the synthesis of a wide
variety of benzofuro[2,3-b]pyrazines.
The reaction parameters were comprehensively analyzed,
and the results are summarized in Table 1.We used 1a and 2a
a b
,
Table 1. Optimization of the Reaction Conditions
entry
catalyst
ligand
solvent
MeCN
yield (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2
PdCl2
PdCl2
PdCl2
PdCl2
−
−
41
47
53
49
54
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DCE
PPh3
Dppm
Dppe
xantphos
−
−
−
−
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), K3PO4 (0.45
mmol), Pd/POL-xantphos (2 mol %), 1,4-dioxane (2 mL), 130 °C, 8
h. Unless otherwise noted, all X groups of substrates 1 are Br groups.
PdCl2
56
c
b
Pd/POL-xantphos
Pd/POL-xantphos
Pd/POL-xantphos
Pd/POL-xantphos
77
NR
47
Isolated yields.
c
c
c
o-Bromophenols with various aromatic substituents reacted
smoothly to afford the target products in moderate to good
yields. When the Br group was replaced with the Cl group, we
isolated product 3a in 21% yield (Scheme 2, 3a). o-
Bromophenol with alkyl groups reacted smoothly, and target
products 3 were isolated in high yields (Scheme 2, 3b−3e).
The 3, 4, and 5 substitutions on the phenyl ring of o-
bromophenol did not significantly affect the product yield. o-
Halophenols with various substituents and electronic proper-
ties at the phenyl ring (R = 5-CF3, 4-CF3, 3-F, 6-F, 4-
COOCH3, 5-COOCH3, 4-Br, 4-Cl, 5-OCF3, 5-OCH3, or 4-
CN) reacted smoothly to afford the target products in
moderate to good yields (Scheme 2, 3f−3r, respectively).
Other special substrates, including 3-bromo-2-naphthol, 7-
bromo-5-chloro-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyqui-
noline, and 1,3-dibromo-5,6,7,8-tetrahydronaphthalen-2-ol,
were tolerated (Scheme 2, 3s−3v, respectively). In the
isonitrile moiety, benzyl isocyanides with different groups
were suitable substrates (Scheme 2, 3w−3y). Alkyl isocyanides
also reacted with o-bromophenol to afford product 3z in 36%
yield. By replacing the oxygen atom with the sulfur atom, we
isolated 2,3-diphenylbenzo[4,5]thieno[2,3-b]pyrazine 3a′ in
22% yield.
10
1,4-dioxane
91
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), homogeneous
catalyst (5 mol %), K3PO4 (0.45 mmol), ligand (10 mol %), solvent
b
c
(2 mL), 130 °C, 8 h. Isolated yield. Heterogeneous catalyst (2 mol
%).
as model substrates. When the reaction proceeded with 5 mol
% Pd(PPh3)2Cl2 in CH3CN at 130 °C, we obtained the desired
2,3-diphenylbenzofuro[2,3-b]pyrazine 3a in 41% yield (Table
1, entry 1). When homogeneous PdCl2 was used, product 3a
was isolated in 47% yield (Table 1, entry 2). In addition, the
use of PPh3 ligands increased the yield of 3a to 53% (Table 1,
entry 3). Ligand screening revealed that xantphos was better
(Table 1, entries 4−6). According to our previous reports,
palladium-metalated porous organic polymers can significantly
increase the selectivity and catalytic activity in the reaction for
the synthesis of heterocycles. Thus, we attempted to optimize
the reaction conditions with this method. When the
heterogeneous catalyst Pd NPs/POL-xantphos was used,12
the yield of 3a improved to 77% (Table 1, entry 7). Further
results suggested that 1,4-dioxane was the optimal solvent
(Table 1, entries 8−10). Using bipyridine or phenanthroline as
the ligand did not improve the yield (Scheme S1). Therefore,
the optimal conditions for preparing 3a were as follows:
When 2-bromo-1-phenylethan-1-one, which is similar to o-
bromophenol, was used as the reaction substrate, 2,3,6-
triphenylfuro[2,3-b]pyrazine 6 was obtained in 28% yield.
B
DOI: 10.1021/acs.orglett.9b01230
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Organic Letters
Letter
Hence, the proposed method has a wide substrate scope
(Scheme 3).
Scheme 4. Proposed Mechanism
Scheme 3. Synthesis of 2,3,6-Triphenylfuro[2,3-b]pyrazine
from 2-Bromo-1-phenylethan-1-one and Benzyl Isocyanide
To evaluate the reusability of Pd NPs/POL-xantphos, we
selected the reaction of 1a and benzyl isocyanide 2a as an
example. After each run, the heterogeneous catalyst Pd NPs/
POL-xantphos was recovered through filtration and washed
with water, 1,4-dioxane, and acetone. This catalyst was
effectively used for at least 10 cycles without a loss of
efficiency (Figure 2a). The TEM images show the formation of
reaction proceeds through isomerization to give intermediate F
and oxidation to give intermediate G. Analysis of the reaction
mixture by LC-MS showed the presence of intermediate G.
Then, intermediate G transforms into H through a 6π-
electrocyclic ring closure and oxidation sequence to give
compound 3.
We conducted the methylthiazolyltetrazolium (MTT) assay
to evaluate the antitumor activity of products 3a−3z against
four human tumor cell lines (MGC-803, T-24, HeLa, and HL-
7402) and one normal cell line (WI-38). 5-FU and cisplatin
were used for comparison. Compound 3w exhibited
preferential cytotoxicity toward MGC-803, T-24, HeLa, and
HL-7402 cells, with IC50 values of 20.2 1.4, 12.5 0.9, 14.7
1.6, and 25.4 0.9 μM, respectively (Table 2). These results
indicate that product 3w displayed better antiproliferative
activity toward tumor cells than toward WI-38 cells.
Compound 3w exhibited better antitumor activity on HeLa
cells but lower cytotoxicity against WI-38 cells compared with
5-FU and cisplatin. Confocal microscopy analysis was
conducted to investigate the cytotoxicity mechanisms of
compound 3w in T-24 cells. The results suggested that
compound 3w inhibited tubulin polymerization, induced
apoptosis, increased the rate of intracellular Ca2+ release, and
supported ROS regulation in T-24 cells (Supporting
Information).
In conclusion, we developed an efficient and chemoselective
one-step method for the synthesis of benzofuro[2,3-b]-
pyrazines by using recyclable heterogeneous catalysts. The
Pd NPs/POL-xantphos was effectively used for at least 10
cycles without a loss of efficiency. The in vitro antitumor
activity of the products was studied. Product 3w exhibited
satisfactory anticancer activity toward T-24 (IC50 = 12.5 0.9
μM) and HeLa (IC50 = 14.7 1.6 μM) cells. Furthermore, we
also explored the mechanism of action of 3w on T-24 cells.
Figure 2. (a) Recycling experiments. (b) TEM characterization of our
fresh Pd nanocatalyst. (c) TEM characterization of our used Pd
nanocatalyst.
a heterogeneous Pd catalyst without obvious aggregation after
the 10th run (Figure 2b,c). More importantly, ICP-MS showed
that the Pd metal can be stably fixed on POP materials (<2
ppb in the filtrate) during the recycling, which is perfect for the
synthesis of drug intermediates. These results explain the
recyclability and high activity of the prepared catalyst. The
reaction of 1.038 g of o-bromophenol 1a with isonitriles 2a
produced 3a in 86% yield (1.246 g).
On the basis of our previous work,11 a rational mechanism of
this reaction can be proposed (Scheme 4). An oxidative
addition reaction of o-halophenol 1 with the Pd(0) catalyst will
generate Pd(II) species A. Then, intermediate A reacts with
two molecules of isonitriles 2 to afford C. Cyclization of C will
produce six-membered cyclic compound D. Reductive
elimination of D will afford benzofuran derivative E. The
C
DOI: 10.1021/acs.orglett.9b01230
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. IC50 (micromolar) Values of Compound 3w, 5-FU, and Cisplatin against Five Cell Lines
compound
MGC-803
T-24
HeLa
HL-7402
WI-38
>40
>40
10.5 0.5
3w
5-FU
cisplatin
20.2 1.4
32.5 1.1
8.9 0.9
12.5 0.9
37.6 0.8
9.6 1.3
14.7 1.6
>40
16.1 0.8
25.4 0.9
>40
11.7 1.5
C. K.; Von Hoff, D. D.; Grand, C. L. PCT Int. Appl. WO 2005/
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ASSOCIATED CONTENT
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Accession Codes
CCDC 1868852 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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(7) (a) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257−
5269. (b) Song, B.; Xu, B. Chem. Soc. Rev. 2017, 46, 1103−1123.
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Corresponding Authors
*E-mail: httang@gxnu.edu.cn.
*E-mail: panym@mailbox.gxnu.edu.cn.
ORCID
Ke-Bin Huang: 0000-0003-4773-4442
Hai-Tao Tang: 0000-0001-7531-0458
Ying-Ming Pan: 0000-0002-3625-7647
́
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E.; Sutanto, F.; Kurpiewska, K.; Kalinowska-Tłuscik, J.; Domling, A.
Org. Lett. 2018, 20, 3871−3874. (f) Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.;
Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. ACS Catal. 2014, 4, 49−52. (g) Senadi,
G. C.; Guo, B.-C.; Chang, Y.-C.; Hu, W.-P.; Wang, J.-J. Adv. Synth.
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Notes
The authors declare no competing financial interest.
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■
The authors thank the National Natural Science Foundation of
China (21861006), the Guangxi Natural Science Foundation
of China (2018GXNSFBA281151), and the State Key
Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (CMEMR2017-A02 and CMEMR2017-
A07) for financial support.
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DOI: 10.1021/acs.orglett.9b01230
Org. Lett. XXXX, XXX, XXX−XXX