Cercosporin-photocatalyzed sp3 (C-H) activation for the synthesis of pyrrolo[3,4-: C] quinolones

Article abstract of DOI:10.1039/c9ob01946d

We reported a new method that visible light along with cercosporin, one of the naturally occurring perylenequinonoid pigments with excellent properties of photosensitization, photocatalyzed sp³ (C-H) activation for the synthesis of pyrrolo[3,4-

Full text of DOI:10.1039/c9ob01946d

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Cercosporin-photocatalyzed sp3 (C–H) activation
for the synthesis of pyrrolo[3,4-c]quinolones†
Cite this: Org. Biomol. Chem., 2019,
17, 8958
Jia Li,a Wenhao Bao,a Yan Zhang *b and Yijian Rao
*
a
Received 5th September 2019,
Accepted 27th September 2019
DOI: 10.1039/c9ob01946d
rsc.li/obc
We reported
a
new method that visible light along with tion for the sp2 (C–H) activation of arenes and heteroarenes
cercosporin, one of the naturally occurring perylenequinonoid (Scheme 1).7 Based on this successful activation of sp2 (C–H)
pigments with excellent properties of photosensitization, photoca- bonds and our continuous interest in photocatalytic C–H bond
talyzed sp3 (C–H) activation for the synthesis of pyrrolo[3,4-c]qui- activation, we next attempt to investigate the reactivity of cer-
nolones through the annulation of anilines and maleimides under cosporin in the least reactive sp3 (C–H) activation.
mild conditions.
sp3 (C–H) activated annulation of electron rich anilines and
maleimides has offered a powerful strategy for the synthesis of
an important organic intermediate [3,4-c]quinolone, which
is the core structural unit of a lot of bioactive molecules,
including caspase-3 inhibitors,8 5-HT4R antagonists,9 and
ADAMTS inhibitors.10 Apart from traditional annulation reac-
tions achieved with high-cost or toxic metal catalysts, or quan-
C–H bond activation or functionalization offers an efficient
and straightforward way for the synthesis of useful organic
compounds.1 Photocatalysis, which makes use of clean,
abundant and endlessly renewable light,2 has been widely
used for the activation of C–H bonds. However, the least reac-
tive sp3 (C–H) bond is difficult to be directly activated under
mild reactions. One of the alternative ways is to activate sp3
(C–H) bonds adjacent to N atoms, since amine is the most
electron-rich species and can be easily converted to a reactive
α-aminoalkyl radical through a photo-induced electron trans-
fer (PET) process,3 and then facilitates chemical reactions that
are otherwise difficult to proceed.3,4
Cercosporin (Scheme 1), one of the perylenequinonoid pig-
ments (PQP), is well known as a photodynamic therapy
reagent, owing to its ability of strong light absorption in
the UV-vis region and the ability of generating active oxygen
species through a single electron transfer (SET) process or
energy transfer process (ET) with high efficiency upon
irradiation.5,6 Although these properties make cercosporin a
potential photocatalyst, there is rarely a report of cercosporin
utilized in photocatalysis reactions, which has aroused our
great interest to probe its catalytic activity. Recently, our group
obtained cercosporin through low-cost liquid fermentation
and successfully applied cercosporin in the photocatalytic reac-
t
titative strong oxidants such as Bu-OOH, K2S2O8 and high
temperature,11–16 photocatalytic systems using toxic or expen-
sive metal complexes, such as Ir, Ru, etc., have been applied
for the synthesis of pyrrolo[3,4-c]quinolones.17–23 However,
metal-free photocatalytic protocols for the synthesis of pyrrolo
[3,4-c]quinolones have been less reported,24–29 most of which
utilized organic dyes24–26,28 or expensive chlorophy II as photo-
catalysts.29 So it is still highly desired to develop a cost-
effective and metal-free method for the effective synthesis of
pyrrolo[3,4-c]quinolones under mild conditions.
Herein we report a cercosporin-photocatalyzed sp3 (C–H)
bond activation for the synthesis of pyrrolo[3,4-c]quinolones
aKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education,
School of Biotechnology, Jiangnan University, Wuxi 214122, P. R. China.
E-mail: raoyijian@jiangnan.edu.cn
bSchool of Pharmaceutical Science, Jiangnan University, Wuxi 214122, P. R. China.
E-mail: zhangyan@jiangnan.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01946d
Scheme 1 Cercosporin photo-catalyzed C–H activation.
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through the annulation of anilines and maleimides
(Scheme 1). In this process, tertiary anilines and maleimides
were readily converted into pyrrolo[3,4-c]quinolones through a
PET pathway with the formation of a reactive α-aminoalkyl
radical. This method provides a great example for exploring
green, economical and mild reaction conditions for the syn-
thesis of pyrrolo[3,4-c]quinolones.
Results and discussion
The investigation was started by subjecting 1.0 equiv. of N,N,4-
trimethylbenzenamine (1a) to 1.0 equiv. of N-phenylmaleimide
(2a) with 1 mol% cercosporin as the photocatalyst. The reac-
tion was conducted with irradiation of a 15 W white CFL in
various solvents under an air atmosphere to test the reactivity
(Table 1). The results were unsatisfactory with trace to low
yields when the reactions were performed in CH3OH, CHCl3,
CH2Cl2 and THF (Table 1, entries 1–4). However, DMF and
DMSO gave much better yields of products (Table 1, entries 5
and 6). To our delight, the highest yield of the pyrrolo[3,4-c]
quinolone product 3a was obtained in 90% yield after 20 h
when the reaction was performed in CH3CN (Table 1, entry 7).
The control experiment showed that the existence of air was
prerequisite, as the yield of the reaction was low if we changed
the air atmosphere to nitrogen (Table 1, entry 8). When the
reaction was conducted under an oxygen atmosphere, we did
not observe the increase of the yield for the desired product
(Table 1, entry 9).
Additionally, control experiments showed that the presence
of light was necessary for the reaction (Table 1, entry 10).
Although the reaction can proceed slowly in air upon photoir-
radiation without cercosporin (Table 1, entry 11), the addition
of a catalytic amount of cercosporin largely improved the yield
of the reaction.
Scheme 2 Scope of pyrrolo[3,4-c]quinolones. Standard conditions:
tertiary amine (0.25 mmol), N-phenylmaleimide (0.25 mmol), cercos-
porin (1 mol%), CH3CN (2 mL), at room temperature in air, with the
irradiation of a 15 W white CFL for 20 h. a Determined by 1H-NMR.
Table 1 Screening of the conditions for the reaction of 1a and 2aa
Having established optimal reaction conditions, we next
started to probe the scope of substrates (Scheme 2). With the
optimized conditions, the desired products were obtained in
52–91% yields. N,N-Dimethylanilines can tolerate substitution
of meta- and para-methyl groups. They also tolerated halogen
atoms (F, Cl, and Br) on the phenyl ring, which facilitated
further functionalization. Meanwhile, maleimides were toler-
ated well with methyl-, phenyl- and benzyl-groups on the nitro-
gen atoms.
To unveil the mechanism of the photocatalytic reaction, we
next conducted the radical inhibition experiment. When the
radical inhibitor 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)
(Scheme 3a) was added to the reaction mixture under standard
conditions, the reaction was obviously quenched, which
showed that the photocatalytic process may proceed through a
PET process. Since cercosporin had strong ability to produce
singlet oxygen, then we designed the singlet oxygen inhibition
experiment to check whether singlet oxygen was involved in
Entry
Conditions
Yieldb
1
2
3
4
5
6
7
8
CH3OH
CHCl3
CH2Cl2
THF
DMF
DMSO
CH3CN
CH3CN, N2
CH3CN, O2
CH3CN, no light
CH3CN, no catalyst
No reaction
10%
30%
45%
75%
80%
90%
10%
82%
9
10
11
No reaction
30%
a All reactions were carried out on a scale of 0.25 mmol of 1a and
0.25 mmol of 2a in 2 mL of solvent at room temperature in air, with
the irradiation of a 15 W white CFL for 20 h. b Isolated yields.
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Scheme 4 Proposed reaction mechanism.
were determined by the reaction of 2a with the mixture of N,N-
di(trideuteriomethyl) aniline and N,N-dimethyl aniline as well
as the reaction of 2a and N-methyl-N-trideuteriomethyl aniline
to be 5.25 and 4.26, respectively, and were larger than the
values for the electron/proton transfer process.30 So, we con-
clude that both the electron/proton transfer (ET/–H+) and the
hydrogen atom transfer (HAT) were involved in the formation
process of α-aminoalkyl radicals A.
Scheme 3 Mechanistic experiments.
Based on the results of our control experiments and pre-
vious reports,18,20,29 we proposed the mechanism for the reac-
tion (Scheme 4). First, cercosporin CP was excited to excited
state CP* upon irradiation. Then one electron transferred
from aniline 1 to CP*, which produced an amine cation
radical and cercosporin radical anion CP•− at the same
time. In the next step, the amine cation radical was converted
the reaction. When the singlet oxygen scavenger histidine was
added to the reaction mixture under optimized reaction con-
ditions (Scheme 3a), the reaction can proceed smoothly
without obvious depression, which implied that the singlet
oxygen pathway could be ruled out from the reaction.
We next attempted to verify the PET process using spec-
troscopy. As shown in Fig. S1,† cercosporin exhibits maximum
absorption at 470 nm. With excitation, cercosporin shows
maximum emission at 597 nm. Then titration experiments
were conducted to monitor the PET process. When 1a was
gradually added to the solution of cercosporin with irradiation,
both the characteristic absorption and emission of cercosporin
were gradually quenched due to the PET process (Scheme 3b
and see the ESI†). We concluded that the electron transferred
from 1a to cercosporin according to the redox potential
(CP*/CP•−) = +1.87 V vs. SCE,7 (1a•+/1a) = +0.79 V vs. SCE.2b,20
The same titration experiment was conducted for cercosporin
and 2a, but 2a could not quench the absorption and emission
of cercosporin (Scheme 3b and see the ESI†). The Stern–
Volmer plots also clearly showed that N,N-dimethylaniline (1a)
can obviously quench the emission of cercosporin in degassed
CH3CN due to the PET process from 1a to cercosporin (see
the ESI†).
to α-aminoalkyl radical
A
through
a
deprotonation
process.18,20,29 Upon addition of maleimide 2, A attacked the
double bond of 2 to generate the intermediate B, which sub-
sequently underwent intra-cyclization to form radical C. Then
C was rapidly oxidized by O2 to produce aromatic pyrrolo[3,4-
c]quinolone 3 after losing an electron and proton.18,20,29 O2
was reduced to superoxide radical anion HOO• at the same
time. HOO• could abstract one hydrogen atom from 1, which
opened another route for the formation of α-aminoalkyl
radical A.18,20,29 The catalyst cercosporin could be recovered
from CP− through the oxidation of oxygen, with the for-
mation of superoxide radical anion HOO•.
Conclusions
In conclusion, we have developed a metal-free cercosporin-
Finally, we designed experiments for both inter- and intra- photocatalyzed sp3 (C–H) activation system for the synthesis of
molecular deuterium isotope effects, and the results were pyrrolo[3,4-c]quinolones. The reaction proceeded effectively
shown in Scheme 3c. The (kH/kD) inter and (kH/kD) intra values upon 15 W white CFL irradiation under an air atmosphere at
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room temperature without the addition of extra oxidants. The
reaction mechanism was deeply investigated by conducting
control experiments, showing that both the electron/proton
transfer (ET/–H+) and the hydrogen atom transfer (HAT) may
involve in the reaction.
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Conflicts of interest
There are no conflicts to declare.
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We thank the National Key R&D Program of China
(2018YFA0901700), the Natural Science Foundation of Jiangsu
Province (Grant No. BK20160167), the Thousand Talents Plan
(Young Professionals), the Fundamental Research Funds for
the Central Universities (JUSRP51712B), the National First-
class Discipline Program of Light Industry Technology and
Engineering (LITE2018-14) and Postdoctoral Foundation in
Jiangsu Province (2018K153C) for the funding support.
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