Visible-Light-Driven Sulfonylation/Cyclization to Access Sulfonylated Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones

Article abstract of DOI:10.1002/asia.202100681

Visible-light-driven sulfonylation/cyclization of N-methacryloyl-2-phenylbenzoimidazoles has been successfully developed. Using commercially available sulfonyl chloride as sulfonylation reagent, a wide range of sulfonylated benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones with potential antitumor activity were provided in acceptable to excellent yields. This method has the advantages of mild reaction conditions and outstanding functional group tolerance, and provides a new strategy for the development of potential antitumor lead compounds.

Full text of DOI:10.1002/asia.202100681

doi.org/10.1002/asia.202100681
Communication
Visible-Light-Driven Sulfonylation/Cyclization to Access
Sulfonylated Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones
+
[a]
+ [b]
[c]
[a]
[a]
[a]
Chen Wang , Guoquan Sun , Hong-Li Huang, Jing Liu, Hua Tang, Yinghua Li,
[a]
[a]
[a]
Honggang Hu, Shipeng He,* and Fei Gao*
isoquinolin-6(5H)-one derivatives with CH CN/CF COOEt/CF
3
2
2
[21]
Abstract: Visible-light-driven sulfonylation/cyclization of
N-methacryloyl-2-phenylbenzoimidazoles has been success-
fully developed. Using commercially available sulfonyl
chloride as sulfonylation reagent, a wide range of sulfony-
lated benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones with
potential antitumor activity were provided in acceptable to
excellent yields. This method has the advantages of mild
reaction conditions and outstanding functional group
tolerance, and provides a new strategy for the development
of potential antitumor lead compounds.
was disclosed by Guan et al (Scheme 1,c). In consider of the
high reaction efficiengy, the expansion of the strategies using
N-methacryloyl-2-arylbenzoimidazoles for the construction of
benzo[4,5]imidazo[2, 1-a]isoquinolin-6(5H)-one dervatives under
photoredox-catalyzed conditions is highly desirable.
Recently, sulfonyl chlorides, as the readily available and
cheap reaction partners, have been widely employed to rapidly
constuct CÀ C and/or CÀ S bonds in various reactions. In photo-
redox transformations containing sulfonyl chlorides, a major
process is to develop CÀ C bond after the loss of SO , the
2
[22]
methods on the formation of CÀ S bond are very rare. Sulfone
functional groups with great synthetic potential are widely used
in the fields of agrochemicals and natural product synthesis,
and many sulfonyl-functionalized compounds have excellent
Benzimidazo-fused polycylic motifs, especially benzo[4,5]
imidazo[2,1-a]isoquinolin-6(5H)-one derivatives, have been fre-
quently found in numerous pharmaceutical molecules, natural
[23–33]
biological properties.
Herein, we reported a new and
[1–6]
products and synthetic materials.
As a consequence, consid-
efficient visible-light-induced sulfonylation/cyclization reaction
that used the sulfonyl chloride as the sulfonylation reagent and
oxidant to promote the reaction, leading to a series of
sulfonylated benzimidazo[2,1-a]isoquinolin-6(5H)-ones under
mild reaction conditions (Scheme 1,d).
erable efforts have been made to develop efficient methods for
the preparation of benzimidazo-fused polycylic compounds,
[
7,8]
[9–15]
such as condensation,
metal-catalyzed cross couplings
[16–18]
and radical cascade reactions.
Among them, visible light
photoredox catalysis strategies have attracted special attention
from chemists due to its mild reaction conditions, environ-
mental friendliness, and ease of operation. In 2019, Yu and co-
workers realized the rapid preparation of perfluoroalkyl-sub-
stituted benzimidazo[2,1-a]isoquinolin-6(5H)-ones via a metal-
free visible-light-promoted radical cyclization process
At the outset, we chose N-methacryloyl-2-phenylbenzoimi-
dazole 1a and p-toluene sulfonyl chloride 2a as the model
substrates to access the desired product 3aa in the presence of
fac-Ir(ppy)3 (5 mol%), K HPO (2.0 equiv.) and 5 W blue LED
lights in MeCN (1 mL) at room temperature. Gratifyingly, the
target product 3aa was obtained in 61% isolated yield (Table 1,
entry 1). Subsequently, we examined various parameters for the
optimal reaction conditions. After a series of screening of the
2
4
[19]
(Scheme 1,a). After then, a novel visible-light-induced diary-
lation of N-methacryloyl-2-arylbenzoimidazoles in the presence
of aryl diazonium salts was reported by Li’s group
photocatalyst, we were delighted to see that fac-Ir(ppy) was
3
[20]
(Scheme 1,b).
Another elegant visible-light-mediated trans-
formation for the synthesis of various benzo[4,5]imidazo[2,1-a]
+
[
a] C. Wang, J. Liu, H. Tang, Y. Li, Dr. H. Hu, S. He, F. Gao
Institute of Translation Medicine
Shanghai University
Shanghai, 200444 (P. R. China)
E-mail: heshipeng@shu.edu.cn
flyhightly@shu.edu.cn
+
[b] G. Sun
Xinhua Hospital
School of Medicine
Shanghai Jiao Tong University
Shanghai, 200092 (P. R. China)
[
[
c] H.-L. Huang
College of Chemistry and Chemical Engineering
Liaocheng University
Shandong 252059 (P. R. China)
] Chen Wang and Guoquan Sun contributed equally.
+
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100681
Scheme 1. Synthesis of benzimidazoisoquinolinone fused frameworks.
Chem Asian J. 2021, 16, 1–5
1
© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

Communication
[a]
Table 1. Optimization of the Reaction Conditions.
[b]
Entry
Photocatalyst
fac-Ir(ppy)
Base
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
3
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
HPO
HPO
HPO
HPO
HPO
HPO
HPO
HPO
HPO
4
4
4
4
4
4
4
4
4
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
THF
DCM
MeOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
61
Ru(bpy) Cl
[Ir{dF(CF ppy)}
Ir(ppy) (dtbbpy)(PF
Eosin Y
3
2
trace
trace
11
trace
trace
63
72
65
96
<10
54
72
80
84
44
67
33
0
0
3
2 6
(dtbbpy)] PF
2
6
)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
3
3
3
3
10
11
12
13
14
15
16
1
1
1
2
fac-Ir(ppy)
3
2,6-Lutidine
DBU
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
none
3
3
Na
CO
NaHCO
Cs CO
KH PO
2
CO
3
3
3
3
3
3
3
3
K
2
3
3
2
3
2
4
c
7
8
9
0
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
d
e
[
a] Reaction conditions: the mixture of 1a (1.0 equiv, 0.1 mmol), 2a (2.0 equiv, 0.2 mmol), photocatalyst (5 mol%) and base (2.0 equiv, 0.2 mmol) in the
solvent (anhydrous,1 mL) was irradiated by blue LEDs (5 W) under Ar at room temperature for 24 h. [b] Isolated yields. [c] fac-Ir(ppy) (3 mol%). [d] fac-
Ir(ppy) (1 mol%). [e] No irradiation.
3
3
still the best choice for this transformation (Table 1, entries 2–
). Further examination on diverse solvents showed that DCM
5
could provide a slight improvement in reaction yield (Table 1,
entries 6–9). Then, different bases were also tested, such as 2,6-
Lutidine, DBU, Na CO , K CO , NaHCO , Cs CO and KH PO , and
2
3
2
3
3
2
3
2
4
a satisfactory yield of 96% was obtained when using 2,6-
Lutidine (Table 1, entries 10–16). In addition, we also evaluated
the effect of the photocatalyst dosage on the reaction
efficiency. The results showed that decreasing the photocatalyst
dosage led to the product 3aa in a lower yield (Table 1,
entries 17–18). Finally, control experiments confirmed that this
transformation was completely suppressed in the absence of
either visible light or the photocatalyst (Table 1, entries 19–20).
Having established the optimized reaction conditions, we
then investigated the scope of N-methacryloyl-2-phenylbenzoi-
midazoles 1. As described in Scheme 2, a variety of structurally
diverse benzoimidazole derivatives were all successfully led to
the corresponding cascade cyclization products in moderate to
excellent yields. Substrates incorporated with different substitu-
Scheme 2. Scope of N-methacryloyl-2-phenylbenzoimidazoles 1. Reaction
conditions: 1a–1k (1.0 equiv, 0.1 mmol), 2a (2.0 equiv, 0.2 mmol), fac-
Ir(ppy)
3
(5 mol%) and 2,6-Lutidine (2.0 equiv, 0.2 mmol), anhydrous DCM
(
1 mL), 5 W blue LEDs, Ar, rt, 24 h, isolated yields.
t
ents, like À Me, À Bu, À OMe and À F at the para position of the 2-
good yields (3fa–3ga). Note that steric hindrance affected the
reaction efficiency, employing ortho-substituted 2-arylbenzoimi-
dazoles as the starting compounds, lower yields of the expected
products were obtained (3ha and 3ia, 31% and 44%,
respectively). As expected, this method could be successfully
applied to 4,5-dichlorobenzene-1,2-diamine (3ja). Finally, when
N-methacryloyl-2,3-diphenylindole was employed as a starting
substrate, sulfonylated indolo[2,1-a]isoquinolin-6(5H)-one (3ka)
was obtained in 64% yield.
phenyl moiety were all competent partners in this trans-
t
formation (3aa–3ea), especially substrate 1c with a À Bu group
was smoothly converted to 3ca in 92% yield. To our delight,
the yield of product 3aa also remained positive when this
transformation was carried out even at gram scale. In addition,
we were pleased to observe that substrates bearing À Me or À Br
at the meta-position of the 2-phenyl moiety performed well
under the reaction conditions to form the expected products in
Chem Asian J. 2021, 16, 1–5
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© 2021 Wiley-VCH GmbH
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Communication
Then, the scope of different sulfonyl chlorides was surveyed
for the synthesis of various sulfonylated benzo[4,5]imidazo[2,1-
a]isoquinolin-6(5H)-ones (Scheme 3). As a result of this endeav-
or, a series of sulfonyl chlorides 2 all worked smoothly. Different
expected, this process was extended to aliphatic sulfonyl
chlorides (3ap–3ar).
Based on the above experimental data and previous
[
19,20,33,34]
reports,
a plausible reaction mechanism for visible-
i
t
substituents, including À Pr, À Bu, À Cl, À CF and À F at the para
light-mediated sulfonylation/cyclization reaction was de-
scribed in Scheme 4. Under the irradiation of 5 W blue LEDs,
3
position of the benzene moiety, were well tolerated to afford
the target products in excellent yields (67–93%, 3ac–3ag). By
contrast, substrate 2b with a -OMe group at the para-position
of the benzene moiety generated the corresponding product
III
III
the photosensizer fac-[Ir (ppy) ] was excited to fac-[Ir (ppy) ]*,
3
3
which was readily oxidated by p-toluene sulfonyl chloride 2a
to produce the corresponding radical species A. Subsequently,
the radical species A was trapped by substrate 1a with the
formation of the radical intermediate B. Following intramolec-
ular addition cyclization with the benzene ring, the resulting
intermediate C underwent a single electron oxidation to
3
ab in 16% yield. Gratifyingly, when using sulfonyl chlorides
with various substituents at the ortho or meta position of the
benzene moiety, the reaction could still occur smoothly in
acceptable to high yields (3ah-3am). In the case of sulfonyl
chlorides with a naphthyl group or a thienyl group, the
cyclization products were isolated in good yields (3an–3ao). As
generate the cation intermediate D and the photosensitizer
III
fac-[Ir (ppy) ] was regenerated for next run. After abstraction
3
of a proton, the cation intermediate D was transformed into
the final product 3aa.
Breast cancer has become the most common cancer in the
[
35]
whole world.
(5H)-one derivatives exhibit widely pharmaceutical activities,
such as modulating of potassium ion flux, anticancer activity
Many benzo[4,5]imidazo[2,1-a]isoquinolin-
6
[
36]
and so on.
For this reason, we investigated several
representative sulfonylated products. As pictured in Figure 1,
these compounds 3ag, 3am, 3an and 3ao exhibited definite
antitumor activity against MCF-7 cells (human breast cancer
cells), expecially the IC50 of 3an and 3ao were 16.1 μM and
1
9.8 μM, respectivelly. They represent a novel class of potential
antitumor compounds. The further structural optimization and
bioactivity studies are under way.
In summary, we have disclosed a novel and efficient
visible-light-induced sulfonylation/cyclization strategy for the
construction of various sulfonylated benzo[4,5]imidazo[2,1-a]
isoquinolin-6(5H)-ones, some of which have definite antitumor
activity for MCF-7 cells. In contrast to previously reported
works, this research exhibits great functional group tolerance,
wide range of substrates, and acceptable to excellent yields.
We believe that this method will be widely used in
pharmaceutical chemistry.
Scheme 3. Scope of sulfonyl chlorides 2. Reaction conditions: 1a (1.0 equiv,
0
.1 mmol), 2b–2r (2.0 equiv, 0.2 mmol), fac-Ir(ppy)
Lutidine (2.0 equiv, 0.2 mmol), anhydrous DCM (1 mL), 5 W blue LEDs, Ar, rt,
4 h, isolated yields.
3
(5 mol%) and 2,6-
2
Scheme 4. Plausible mechanism.
Chem Asian J. 2021, 16, 1–5
Figure 1. Cytotoxicity of 3ag, 3am, 3an and 3ao against MCF-7 cells for 72 h.
www.chemasianj.org
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Communication
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[
[
1
Keywords: visible light · photoredox catalysis · radical cascade
cyclization · sulfonylation · sulfonylated benzo[4,5]imidaz-o[2,1-
a]isoquinolin-6(5H)-ones
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Manuscript received: June 23, 2021
Revised manuscript received: July 18, 2021
Version of record online: ■■■, ■■■■
Chem Asian J. 2021, 16, 1–5
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© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

Communication
COMMUNICATION
C. Wang, G. Sun, H.-L. Huang, J. Liu,
H. Tang, Y. Li, Dr. H. Hu, S. He*, F.
Gao*
1
– 5
Visible-Light-Driven Sulfonyla-
tion/Cyclization to Access Sulfony-
lated Benzo[4,5]imidazo[2,1-a]
isoquinolin-6(5H)-ones
Various sulfonylated benzo[4,5]
imidazo[2,1-a]isoquinolin-6(5H)-ones
with potential antitumor activity were
provided by visible-light-driven sulfo-
nylation/cyclization in acceptable to
excellent yields.