Light-driven selective aerobic oxidation of (iso)quinoliniums and related heterocycles

Article abstract of DOI:10.1039/d1ra01226f

Selective C1-H/C4-H carbonylation of N-methylene iminium salts, catalyzed by visible-light photoredox and oxygen in the air, has been reported. A ruthenium complex acts as a chemical switch to conduct two different reaction pathways and to afford two diff

Full text of DOI:10.1039/d1ra01226f

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Light-driven selective aerobic oxidation of (iso)
quinoliniums and related heterocycles†
Cite this: RSC Adv., 2021, 11, 16246
a
Meimei Zhou,‡a Keyang Yu,‡b Jianxin Liu,c Weimei Shi,c Yingming Pan,
a
b
b
a
* *
*
Haitao Tang,
Xiangjun Peng,
Qian Liu and Hengshan Wang
Selective C1–H/C4–H carbonylation of N-methylene iminium salts, catalyzed by visible-light photoredox
and oxygen in the air, has been reported. A ruthenium complex acts as a chemical switch to conduct
two different reaction pathways and to afford two different kinds of products. In the absence of the
ruthenium complex, the Csp2–H bonds adjacent to the nitrogen atoms are oxidized to a-lactams by the
N-methyleneiminium substrates themselves as photosensitizers. In the presence of the ruthenium
complex, the oxidation reaction site of quinoliniums is switched to the C4 region, resulting in the
formation of 4-quinolones. The use of two transformations directly introduces oxygen into the nitrogen
heterocyclic skeletons under an air atmosphere.
Received 15th February 2021
Accepted 23rd March 2021
DOI: 10.1039/d1ra01226f
rsc.li/rsc-advances
However, most of these syntheses suffer from harsh reaction
conditions (high temperature, Eaton reagent, etc.), poor conver-
Introduction
sion of the substrates and the use of excessive oxidants or addi-
tives. Consequently, considerable efforts have been devoted to
establishing mild, environmentally friendly and sustainable
procedures for these valuable scaffolds.
The biomimetic characteristics of isoquinolone and quinolone
rings, reminiscent of the rigidly xed skeleton of N-
heterocycles, frequently emerge in many natural products and
pharmaceuticals.1 For example, the alkaloids doryanine and
sarcomejine have been isolated from Cryptocarya chinensis
(Lauraceae) and Sarcomelicope megistophylla (Rutaceae),
respectively.2 The isoquinolone scaffold is widely found as the
core structure in topoisomerase I (Top I) inhibitors.3 Elvitegravir
(EVG), which contains the elementary unit of the corresponding
quinolone, is a potent inhibitor of human immunodeciency
virus type 1 (HIV-1) integrase (Fig. 1).4 Due to their diverse
biological activities, tremendous effort has been devoted to the
effective synthesis of (iso)quinolones. The traditional methods
usually require stoichiometric amounts of K3Fe(CN)6 as an
oxidant, and this inevitably produces a considerable number of
toxic by-products such as K4Fe(CN)6.5 Other methods, such as
Conrad–Limpach and Niementowski reactions, have proven to be
powerful tactics using the condensation of amines with carboxyl
derivatives followed by cyclization to generate quinolone analogs.6
Using O2 (or ambient air) as an oxidant is the most ideal
methodology for direct oxygenation.7 Moreover, visible-light-
promoted aerobic oxidations have been demonstrated in the
synthesis of biologically active molecules in green and envi-
ronmentally friendly conditions.8 Recently, Fu et al. successfully
achieved the visible-light mediated ortho C–H oxidation of N-
alkyliminiums using Eosin Y as the photocatalyst and air as the
oxidant, obtaining isoquinoline-1-ones (Scheme 1a).9 Deng and
co-authors highlighted the photocatalytic oxidation and
subsequent cyclization protocol to transform indoles to quino-
lones.10 The attractive properties of these photocatalytic reac-
tions were their mild reaction conditions, low catalyst loading,
ubiquity and versatility functionality of directing C–H activation
with O2 (or air). In our designed method, the isoquinolinium
salts (1) formed excited isoquinolinium salts (1*) under visible-
light irradiation without other photosensitizers,11 and then
underwent photoinduced electron transfer (PET) to transform
the a-carbon radicals (A), which were captured by O2 to obtain
isoquinolones (2) (Scheme 1b). This process sets the stage for
aState 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. E-mail: whengshan@163.com
bKey Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular
Diseases of Ministry of Education, Gannan Medical University, Ganzhou 341000,
People's Republic of China. E-mail: pengxiangjun99@163.com; 18907979876@126.
com
cSchool of Pharmaceutical Science, Gannan Medical University, Ganzhou, Jiangxi
341000, P. R. China
† Electronic supplementary information (ESI) available: 1H, 19F and 13C NMR
spectra of compounds 2 and 3. See DOI: 10.1039/d1ra01226f
‡ These authors contributed equally to this work.
Fig. 1 Representative examples of natural products and pharmaceu-
ticals containing the (iso)quinolone structural motif.
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from the light source) at room temperature in an air atmo-
sphere. Aer complete conversion of the substrate (monitored
by TLC), the reaction mixture was diluted with 20 mL of EtOAc
and the solution was ltered by ash chromatography (petro-
leum ether/ethyl acetate 10 : 1). The ltrate was evaporated by
rotary evaporator and the residue was puried by silica gel
column chromatography to give the desired product 2.
The synthesis of 4-quinolones
Halogenated quinoliniums 1ag–1aq (0.2 mmol), DABCO (0.4
mmol), and Ru(bpy)3Cl2 (0.004 mmol) were added to a 10 mL
quartz tube in CH3CN (2 mL), and then the mixture was irra-
diated with blue LEDs (15 W) (approximately 1.5 cm away from
the light source) at room temperature in an air atmosphere.
Aer complete conversion of the substrate (monitored by TLC),
the reaction mixture was diluted with 20 mL of EtOAc, and the
solution was ltered by ash chromatography (petroleum ether/
ethyl acetate 2 : 1). The ltrate was evaporated by rotary evap-
orator and the residue was puried by silica gel column chro-
matography to give the desired product 3.
Scheme 1 The representative photocatalysis of oxidative approaches
to the construction of N-substituted isoquinolin-1(2H)-ones and 4-
quinolones (a), and our hypothesis (b).
carbonylation to the oxidation onto the C1-position of iso-
quinoliniums, and another successful strategy that obtains
quinoliniums by para(C4)-selective oxidation will signicantly
broaden the potential of remote site-selective functionalization.
Herein, we delineate the successful realization of different
reactive sites in (iso)quinoliniums and related heterocycles
through visible-light sources, orchestrating a Ru-photocatalyst,
which controls the ortho- or para-position of oxidation.
In vitro cardiovascular activities
The MOVAS (mouse aorta vascular smooth muscle cells),
HUVEC (human umbilical vein endothelial cells) and AC16
(human cardiomyocytes cells) cell lines were all obtained from
the Institute of Biochemistry and Cell Biology, China Academy
of Sciences. The cells were cultured in DMEM (Sigma), which
was supplemented with 10% fetal bovine serum in a humidied
Experimental section
General methods
Unless otherwise specied, commercial reagents and solvents
were used without further purication. All manipulations were
performed in air at room temperature. For ash column chro-
matography, 100–200 mesh and 300–400 mesh silica gels were
ꢀ
atmosphere of 5% CO2/95% air at 37 C. All compounds were
dissolved in phosphate buffered saline (PBS) with 1% DMSO to
obtain various concentrations in 96-well plates, whilst control
wells contained supplemented media with 1% DMSO, and the
used by eluting with petroleum ether/ethyl acetate. H and 13C
1
spectra were recorded on a 400 MHz spectrometer. The chem-
ical shis were reported in ppm. H NMR spectra were refer-
1
ꢀ
wells continued to be incubated for 48 h at 37 C in a 5% CO2
atmosphere. MTT (5 mg mLꢁ1) was added into the wells and the
plates were incubated at 37 ꢀC for 4 h. The MTT assay was
stopped by adding dimethyl sulfoxide (100 mL per well) and
mixing for 10 min vigorously before measuring the absorbance
at 490 nm in a multi-well plate reader. The cytotoxicity was
estimated based on the percentage cell survival in a dose
dependent manner relative to the negative control. The nal
IC50 (drug concentration that kills 50% of the cells) values were
calculated by the Bliss method. All target compounds were
tested on MOVAS, HUVEC and AC16 cell lines, respectively.
enced to DMSO (2.50 ppm) or CDCl3 (7.26 ppm), and 13C NMR
spectra were referenced to DMSO (39.5 ppm) or CDCl3 (77.0
ppm). Peak multiplicities were designated by the following
abbreviations: s, singlet; d, doublet; t, triplet; m, multiplet, and J
is the coupling constant in Hz. HRMS spectra were recorded
with a Micromass QTOF2 Quadrupole/time-of-ight tandem
mass spectrometer using electron spray ionization.
The synthesis of halogenated N-methylene iminiums (1a as
the example)
A solution of isoquinoline (5 mmol), benzyl bromide (10 mmol)
and CH3CN (15 mL) was reuxed for 12 hours and cooled to room
temperature. Aer the addition of ethyl acetate, isoquinoline salt
was precipitated rapidly into a solid, and this was then ltered and
washed with ethyl acetate to obtain a white solid 1a. The volatile
solvents were removed by vacuum evaporation.
Results and discussion
We started to investigate the reactivity of N-benzylisoquinoli-
nium 1a as a model substrate in an air atmosphere and at room
temperature (Table 1; more details in the ESI†). The optimal
reaction was achieved with substrate 1a as the photosensitizer,
1,4-diazobicyclo[2.2.2]octane (DABCO) as a base, and air as an
oxidant in CH3CN under the irradiation of 15 W blue light-
The synthesis of a-lactams
A solution of isoquinoline (5 mmol), halogenated N-methylene emitting diodes (LEDs), thereby affording the carbonylation
iminiums 1 (0.2 mmol), and DABCO (0.4 mmol), was added to product 2a (entry 1). Inhibition of the reactivity was observed in
a 10 mL quartz tube in CH3CN (2 mL), and then the mixture was the presence of other solvents (entries 2 and 3). Other bases,
irradiated with green LEDs (15 W) (approximately 1.5 cm away such as Et3N and KOtBu, were also effective for this C–H
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Table 1 Model studies of ortho C–H oxidationa
Table 2 Model studies of C4-selective oxidationa
Entry
Substrate
Variation from standard conditions
2ab (%)
Entry
Substrate
Variation from standard conditions
3ab (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
None
87
22
58
54
67
63
21
NR
DMF instead of CH3CN
THF instead of CH3CN
Et3N instead of DABCO
KOtBu instead of DABCO
Addition 2 mol% Ru(bpy)3Cl2
Without light
1
2
3
4
5
6
1ag
1ag
1ag
1ag
1ag
1ag
None
68
NR
33
NR
Trace
NR
Eosin Y instead of Ru(bpy)3Cl2
1,4-Dioxane instead of CH3CN
Et3N instead of DABCO
Without light
Without base
Without base
a
Reaction conditions: N-methylene iminiums 1 (0.2 mmol), DABCO (2.0
a
Reaction conditions: N-methylene iminiums 1 (0.2 mmol), DABCO (2.0
equiv.), LED lamp as light source, room temperature, under air
atmosphere. b Isolated yield.
equiv.), Ru(bpy)3Cl2 (2.0 mol%), LED lamp as light source, room
temperature, under air atmosphere. Isolated yield.
b
in 75–88% yields. N-Benzylquinolinium was transformed into
the corresponding quinoline-2-one 2j. It is worth noting that
heteroarenium derivatives, such as quinazolinium, quinox-
alinium, benzothiazolium and 3-methoxypyridinium, were
produced smoothly by our standard protocol as products 2k–2n.
Substituent R represents the phenyl group, such as the various
electron-donating groups (Me, tBu, OMe, and Ph) and electron-
withdrawing groups (Cl, NO2, CN, CF3, and F), that can be
transformed smoothly to obtain corresponding products (2o–
2z). Many functional groups, including benzyl and alkyl, were
well tolerated (2aa–2ad). Among them, isoquinolinium halides
(X ¼ Cl and I) also proceeded in good yields (2q and 2ab). In
addition, the heterocyclic substrates were well tolerated in the
oxidative reactions, and target products 2ae and 2af were ob-
tained with yields of 87% and 83%, respectively.
When 3-methylquinolinium (1ag) instead of N-benzyliso-
quinolinium bromide (1a) was applied to this system, 4-qui-
nolone 3a was successfully achieved in a 68% yield using the Ru-
catalyst (Table 2, entry 1). Further screening of the reactions
could not be effectively performed with other photocatalysts,
solvents and bases (entries 2–4). No aerobic oxidation occurred
in the absence of light or base, demonstrating that these
components were essential factors (entries 5 and 6).
oxidation transformation, but in inferior yields (entries 4 and
5). There was a negative effect on the reaction with the addition
of the photocatalyst Ru(bpy)3Cl2 or without light (entries 6 and
7). The experiments showed that no desired product was formed
in the absence of base, revealing the crucial role of the base in
this reaction (entry 8).
According to the readily available optimization conditions,
we signicantly extended the scope of ortho-selective oxidation
to synthesize a-lactams. As shown in Scheme 2, isoquinolinium
chloride (X ¼ Cl) showed good reaction activity and the target
product 2a was obtained in 85% yield. Moderate yields were
realized when the pyridine ring contained Me, Cl and Br func-
tional groups (2b–2d). Substituting the benzene ring with
electron-donating groups, such as methyl and methoxy groups,
and with electron-withdrawing groups, such as chloro- and
nitro-groups, proceeded smoothly to give isoquinolones 2e–2i
Subsequently, we assessed the reaction of quinolinium
substrates with a ruthenium catalyst, and this protocol straight-
forwardly photocatalyzed the carbonylation of the Csp2ꢁH bond to
afford the desired products with excellent C4-regiocontrol, as
illustrated in Scheme 3. The quinoline ring bearing various groups,
such as methyl, chloro- and bromo-groups, were successfully
engaged in the current photocatalytic oxidation reaction (3b–3d).
The benzene ring with different electronic groups, connected to
the nitrogen atom, maintained selectivity for the C4-site (3e–3g).
The substrate with the benzyl group was still suitable for the
reaction, and the product 3h was obtained in a 75% yield. Other
alkyl quinoliniums, such as cyclohexane, n-propyl, and vinyl, were
also well-tolerated and provided the corresponding products (3i–
3k) in 78%–80% yields. Thiophene quinolinium was tolerated to
give the desired product 3l in a good yield.
Scheme 2 The ortho C–H selective oxidation reaction using N-
methylene iminium salts.a Reaction conditions: N-methylene imi-
niums 1 (0.2 mmol), DABCO (2.0 equiv.), blue LED (15 W), room
temperature, under air atmosphere. b Isolated yield.
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under continuous visible light irradiation. Subsequently, the
nitrogen-centered cation A could undergo photoinduced elec-
tron transfer to generate the a-amino radical B (trapped by
TEMPO),12 and DABCO was simultaneously oxidized to DABCO+
(trapped by TEMPO). The radical B was coupled with oxygen in
the air to produce the peroxide radical C.13 The other route for
radical B involved being oxidized to the ground state iso-
quinolinium 1a, while O2 was reduced to O2, and so the pho-
tocatalytic cycle was completed. Intermediate C continued to
form the carbon radical D (trapped by TEMPO) through
hydrogen atom transfer (HAT), and then D was oxidized to the
oxygen cation E by DABCO+, and was then simultaneously
reduced to DABCO. Finally, treatment of the cation E with
NaOH and Brꢁ afforded the desired adduct 2a (Scheme 4b).14
Similarly, a trace amount of 4-quinolone 3a was observed in
an argon atmosphere (Scheme 4c). The reaction was inhibited
by adding the free radical inhibitors TEMPO or BHT under the
optimal reaction conditions, indicating that the conversion
involves a radical process. Based on these control experiments,
we speculated the following mechanism (Scheme 4d). Photo-
activated Ru(II)* could be reduced to Ru(I) species by DABCO.
The redox potential of Ru(bpy)3Cl2 was E1/2 Ru(II)*/Ru(I) ¼ 0.77 V
vs. SCE in CH3CN,15 and this was higher than E1/2 DABCO ¼
0.6 V vs. SCE.16 Therefore, the photoredox reactions could occur
spontaneously between Ru(bpy)3Cl2 and DABCO. 3-Methyl-
quinolinium (1ag) could accept a single electron from the Ru(I)
species to form the C4-site quinoline radical I,11b,17 which was
coupled with oxygen to form the peroxy radical II. The C4-
position radical III was generated from II, which was
Scheme 3 The C4-selective oxidation reaction using N-benzylqui-
a
nolinium salts.
Reaction conditions: quinoliniums 1ag–1ar (0.2
mmol), DABCO (2.0 equiv.), Ru(bpy)3Cl2 (2.0 mol%), blue LED (15 W),
ambient temperature, under air atmosphere. b Isolated yield.
Having established our developed methods and scope for
a wide range of applications, we investigated the proposed
mechanism. Isotope experiments indicated that the oxygen
atom in the target products was mainly derived from oxygen in
the atmosphere (Scheme 4a). Only a trace amount of iso-
quinolinone 2a was observed in an argon atmosphere. Under
the optimal reaction conditions, the reaction was clearly
inhibited by the addition of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT), indicating
that the conversion could have undergone a free radical
process. It is well known that N-functionalized onium salts act
as photosensitizers.11 Hence, the excited state A was formed
Scheme 4 Control experiments (a and c) and the proposed mechanism (b and d).
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Table 3 IC50 values of the tested compoundsa
IC50b (mM)
Guangxi Province (AB17292075) and Guangxi Funds for
Distinguished Experts.
Compound
MOVAS
HUVEC
AC16
Notes and references
2g
2t
59.14 ꢂ 2.31
94.93 ꢂ 4.57
>100
>100
>100
>100
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(mouse aorta vascular smooth muscle cells), HUVEC (human
umbilical vein endothelial cells) and AC16 (human cardiomyocytes
cells). As reported in Table 3, the biological activities were
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of 59.14 ꢂ 2.31 and 94.93 ꢂ 4.57, respectively. The results showed
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vascular smooth muscle cells. Unfortunately, the products did not
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Conclusions
In summary, we have developed the selective oxidation of Csp2–
H functionalization by employing oxygen under light-driven condi-
tions. Clearly, the ruthenium complex was used as a chemical switch
to trigger two different oxidation pathways of the N-onium salts. In
the absence of the Ru-complex, the N-functionalized onium ions
were irradiated from the a-amino radicals of tertiary amines to the
corresponding amides using air as an oxidant. On the other hand,
the quinoliniums underwent single electron transfer to form the C4-
site quinoline radical using the Ru(bpy)3Cl2 catalyst, and this was
shown to be smoothly carried out by the formation of 4-quinolones.
The outstanding advantages of these transformations are that
carbonylation at different sites of the N-methyleneiminiums could
be directly oxidized to obtain diverse ketones under air and at room
temperature.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (21977021 and 81760626), the Ministry of
Education
Innovation
Team
Fund
(IRT_16R15,
2016GXNSFGA380005), and the Natural Science Foundation of
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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