Visible-Light-Mediated Aerobic Oxidation of N-Alkylpyridinium Salts under Organic Photocatalysis

Article abstract of DOI:10.1021/jacs.7b07883

Quinolones and isoquinolones exhibit diverse biological and pharmaceutical activities, and their synthesis is highly desirable under mild conditions. Here, a highly efficient and environmentally friendly visible light-mediated aerobic oxidation of readily available N-alkylpyridinium salts has been developed with Eosin Y as the organic photocatalyst and air as the terminal oxidant, and the reaction provided quinolones and isoquinolones in good yields. The method shows numerous advantages including mild and environmentally friendly conditions, high efficiency, tolerance of wide functional groups and low cost. Furthermore, 4-desoxylonimide with important pharmaceutical activities was effectively prepared by using our method. Therefore, the present method should provide a novel and useful strategy for synthesis and modification of N-heterocycles.

Full text of DOI:10.1021/jacs.7b07883

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Article
Visible Light-Mediated Aerobic Oxidation of N-
Alkylpyridinium Salts under Organic Photocatalysis
Yunhe Jin, Lunyu Ou, Haijun Yang, and Hua Fu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Sep 2017
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Journal of the American Chemical Society
Visible Light-Mediated Aerobic Oxidation of N-Alkylpyridinium
Salts under Organic Photocatalysis
1
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4
Yunhe Jin, Lunyu Ou, Haijun Yang, and Hua Fu*
5
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8
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, China
9
photocatalyts. From an environmental point of view, molecular
oxygen (O2 and air) is an appealing oxidant in sustainable
oxidative chemistry, and its advantages include abundance, low
cost, and water as main by-product.23 As part of our continuing
development on the visible-light photoredox organic reactions,24
we report herein a highly efficient and environmentally friendly
visible light-mediated aerobic oxidation of N-alkylpyridinium
salts with air under organic photocatalysis at room temperature.
ABSTRACT: Quinolones and isoquinolones exhibit diverse
biological and pharmaceutical activities, and their synthesis is
highly desirable under mild conditions. Here, a highly efficient
and environmentally friendly visible light-mediated aerobic
oxidation of readily available N-alkylpyridinium salts has been
developed with Eosin Y as the organic photocatalyst and air as
the terminal oxidant, and the reaction provided quinolones and
isoquinolones in good yields. The method shows numerous
advantages including mild and environmentally friendly
conditions, high efficiency, tolerance of wide functional
groups and low cost. Furthermore, 4-desoxylonimide with
important pharmaceutical activities was effectively prepared
by using our method. Therefore, the present method should
provide a novel and useful strategy for synthesis and
modification of N-heterocycles.
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Table 1. Optimization of Conditions for Visible-Light Photoredox
Aerobic Oxidation of 1-Methylquinolinium Iodide (1c) Leading to 1-
Methyl-2-quinolinone (2c)a
N-Heterocycles are ubiquitous in natural products and biologically
active molecules,1 and they are assigned as privileged motifs in
drug development.2 The diverse functions of nitrogen-containing
compounds highly depend on their characteristic structures, so the
elaboration of N-heterocycles and the late-stage modification of
drug candidates with N-heterocycles have emerged as an
important strategy in organic synthetic chemistry and drug
discovery.3 N-Heterocycles containing a pyridine nucleus such as
quinolines and isoquinolines are privileged scaffolds, and they
occupy key roles in many medicinally related molecules.4
However, the functionalization on the pyridine ring is a great
challenge due to the low reactivity of π-electron-deficient pyridine
skeleton.5 Fortunately, it is easy to get N-alkylpyridinium salts via
N-alkylation of pyridine ring. On the other hand, quinolones and
isoquinolones exhibit diverse biological and pharmaceutical
activities. For example, quinolones show anticancer,6 antibiotic,7
antiviral and antihypertensive8 activities, and they are used as
cannabinoid CB2 receptor inverse agonists,9 neuronal maxi-K
channel activators,10 and AMPA/kainate and glycine
antagonists.11 Isoquinolones are useful antagonists of NK3,12
agonists of melatonin MT1 and MT2 receptors,13 and inhibitors of
Rho-kinase,14 JNK15 and thymidylate synthase,16 and the
isoquinolin-1(2H)-one pharmacophore is used in treatment of
stomach tumors and diseases of human brain cells.17 Therefore, it
is highly desirable to develop a convenient, efficient and practical
transformation from readily available quinolines and
isoquinolines to quinolones and isoquinolones. To the best of our
knowledge, the most common method is oxidation of N-
alkylpyridinium salts using an excess of K3Fe(CN)6 as the
oxidant.18 Unfortunately, a large amounts of harmful K4Fe(CN)6
as waste appear together with the products. Recently, copper or
iodine-catalyzed oxidative functionalizations of isoquinolines
leading to isoquinolones have been reported.19 However, the
substrate scope is very limited. Recently, visible-light photoredox
catalysis as an environmentally friendly, sustainable and unique
process has received significant attention,20 in which organic
dyes21 and Ru and Ir complexes22 have been widely used as the
entry
1
PC
A
B
C
D
E
-
base
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Na2CO3
NaHCO3
NEt3
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
THF
EtOH
DCE
yield (%)b
57
2
41
3
46
4
22
5
64
6
8
7
E
E
E
E
E
E
E
E
E
E
E
E
E
E
68
8
33
9
19
10
11
12
13
14
15
16
17d
18e
19f
20g
trace
NR
80
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
49
87 (84c)
63
54
THF
NR
85
THF
THF
86
THF
NR
a
Reaction conditions: air atmosphere and irradiation of visible light with
40 W CFL, 1-methylquinolinium iodide (1c) (0.2 mmol), photocatalyst
o
(PC) (4 μmol), base (0.3 mmol), solvent (2 mL), temperature (rt, ~25 C),
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time (10 h) in a 10-mL glass tube. b Conversion yields were determined by
1H NMR using trichloroethylene as the internal standard. c Isolated yield. d
No light. e The reaction was performed under irradiation of 3 W green
LED instead of CFL for 24 h. f Oxygen atmosphere instead of air. g Argon
atmosphere instead of air. PC = photocatalyst. DCE = 1,2-dichloroethane.
CFL = compact fluorescent light. NR = no reaction.
Table 2. Substrate Scope for Visible Light-Mediated Aerobic
Oxidation of N-Methylpyridinium Saltsa
1
2
3
4
5
6
7
2 (time, yieldb)
First, the visible-light photoredox aerobic oxidation of
1-methylquinolinium iodide (1c) was selected as the model to
optimize the reaction conditions. As shown in Table 1, several
common photocatalysts including Ir and Ru complexes,
Ir(ppy)2(dtbbpy)(PF6) (A), Ir(dF(CF3)ppy)2(dtbbpy)(PF6) (B),
[fac-Ir(ppy)3] (C) and [Ru(bpy)3]Cl2 (D), and an organic dye,
Eosin Y (E), were screened with K3PO4 as the base and DMF as
the solvent under air atmosphere and irradiation of 40 W compact
fluorescent light (CFL) for 10 h (entries 1-5), and we found that
Eosin Y (E) provided the highest yield (entry 5). Only 8% yield
was obtained in the absence of photocatalyst (entry 6).
Subsequently, other four bases, Cs2CO3, Na2CO3, NaHCO3 and
NEt3, were attempted, and Cs2CO3 was found to be a suitable base
(compare entries 5, 7-10). No aerobic oxidation occurred in the
absence of base (entry 11). Next, effect of solvents was
investigated, and THF provided the highest yield (compare entries
7, 12-16) although substrate 1c and photocatalyst E were of low
solubility in THF. On the contrary, DMF (entry 7) and DMSO
(entry 12) with good solubility gave lower yields. A possible
reason is that a low concentration of substrate in the reaction
solution is favorable for control of reaction rate, which leads to
formation of less by-products. Furthermore, the reaction did not
work without irradiation of visible light (entry 17). A similar yield
was obtained when the reaction was performed under irradiation
of 3 W green LED instead of CFL for 24 h (entry 18). Finally,
influence of atmosphere was surveyed, and reaction under oxygen
atmosphere almost provided the same yield as that under air
atmosphere (entry 19), but no product was observed under argon
atmosphere (entry 20).
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a
Reaction conditions: air atmosphere and irradiation of visible light with
40 W CFL, N-methylpyridinium salt (1) (0.2 mmol), Eosin Y (4 μmol),
o
Cs2CO3 (0.3 mmol), THF (2 mL), temperature (rt, ~25 C), time (6-15 h)
in a 10-mL glass tube. b Isolated yield. c Using DMSO as the solvent
instead of THF. Boc = tert-butyloxycarbonyl.
Table 3. Substrate Scope for Visible Light-Mediated Aerobic
Oxidation of N-Alkylisoquinolinium Saltsa
With the optimized visible-light photoredox aerobic
oxidation conditions in hand, the substrate scope of N-
methylpyridinium salts was surveyed (Table 2). First, we
attempted different substituted monocyclic N-methylpyridinium
salts, and the results showed that the substrates with meta-
electron-withdrawing groups provided the corresponding
N-methyl pyridones in moderate yields (see 2a and 2b). However,
other N-methylpyridinium salts were not good substrates. Next,
2 (time, yieldb)
various
N-methylquinolinium
(see
2c-l)
and
N-methylisoquinolinium salts (see 2m-t) were used as the
substrates, and they gave the corresponding quinolones and
isoquinolones in good to excellent yields. We found that the
substrates containing electron-withdrawing groups on the phenyl
rings exhibited higher reactivity than those containing
electron-donating groups. The substrate with two N-
methylpyridinium rings provided a satisfactory result (62% yield)
(see 2l). N-Methylquinolinium salt linking with dipeptide
(Met-Ala) also was a good substrate (see 2t). The present method
could tolerate various functional groups including cyano (see 2a),
ester (see 2b), ether (see 2f and 2o), nitro (see 2g and 2s) and
amide (see 2t) groups, C-F (see 2h), C-Cl (see 2p) and C-Br (see
2q and 2r) bonds.
a
Reaction conditions: air atmosphere and irradiation of visible light with
40 W CFL, N-alkylisoquinolinium salt (1) (0.2 mmol), Eosin Y (4 μmol),
o
Cs2CO3 (0.3 mmol), THF (2 mL), temperature (rt, ~25 C), time (7-12 h)
in a 10-mL glass tube. b Isolated yield. c Using DMSO as the solvent
instead of THF.
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Subsequently, reactivity of different alkyl substituted
excited at 372 nm, and addition of 1-methylquinolinium iodide
(1c) made the fluorescence intensity dramatically decrease.
Meanwhile, the experiments indicated that other reagents such as
oxygen in the system did not quench the fluorescence (see Figures
S2-S7 in Supporting Information for the details), which indicated
a single electron transfer between Eosin Y and 1c. Furthermore,
the redox potentials of 1c were measured to be E1/2red (1c) =
-0.685 V vs SCE (see Figure S8 in Supporting Information for
details) that is higher than E1/2ox (E*) = -1.15 V vs SCE,26 and the
results showed that 1c could acquire a single electron from Eosin
Y under irradiation of visible light.
Next, we surveyed types of the radicals produced under
different conditions by electron spin resonance (ESR) in the
presence of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as the spin
trapping agent (Figure 1B). A mixture of Eosin Y (2 mol %),
Cs2CO3 (15 mM) and DMPO (10 mM) in DMSO was irradiated
with 40 W CFL for 5 min under air atmosphere, and then a small
amount of the solution was transferred to a capillary. The ESR
spectrum showed that no signal was observed (Figure 1Ba). ESR
spectrum for mixture of Eosin Y (2 mol %), 1c (10 mM), Cs2CO3
(15 mM) and DMPO (10 mM) in DMSO without irradiation of
visible light only showed a triplet-signal with aN = 1.451 mT and
g = 1.9996, which was probably attributed to reduction of DMPO
by 1c (Figure 1Bb). After irradiation of 40 W CFL for 5 min, ESR
spectrum for mixture of Eosin Y (2 mol %), 1c (10 mM), Cs2CO3
(15 mM) and DMPO (10 mM) in DMSO exhibited a new
sextet-signal (aN = 1.373 mT, and aH = 1.164 mT, g = 1.9994)
(Figure 1Bc), which indicated an alkdioxyl DMPO radical adduct
occurred27 (see Figure S1 in Supporting Information for the
details).
1
2
3
4
5
6
7
8
N-alkylisoquinolinium salts (1) was investigated (Table 3), and
they showed similar results to the substrates in Table 2 providing
the corresponding isoquinolones in good to excellent yields. The
substrate with two N-alkylisoquinolinium salts afforded product
2ah with isoquinolone rings in 83% yield. Some functional group
tolerance was also observed including C-Cl (see 2x) and C-Br
(see 2ad) bonds, ester (see 2y), acetal (see 2z), ether (see 2ac) and
cyano (see 2ae) groups.
9
To demonstrate synthetic practicability of the present
visible-light photoredox aerobic oxidative protocol, a gram-scale
experiment was performed. As shown Scheme 1A, photocatalytic
aerobic oxidation of 2-methyl-5-nitroisoquinolin-2-ium iodide (1s)
(1.58 g) was performed under the standard conditions, and
2-methyl-5-nitroisoquinolin-1(2H)-one (2s) was obtained in 92%
yield (0.94 g), which was similar to the small-scale reaction in
Table 2 almost without loss of efficiency. 4-Desoxylinomide (6)
has shown to own antiangiogenic activity and potential in the
treatment of autoimmune disease such as rheumatoid arthritis,
systemic lupus erythematosis and multiple functions in clinical
trials,25 so it is highly desirable to develop a simple route to 6. As
shown in Scheme 1B, coupling of commercially available
quinoline-3-carboxylic acid (3) with N-methylaniline provided
amide 4 in 85% yield, and N-methylation of 4 gave 5 in almost
quantitative yield. Finally, photocatalytic aerobic oxidation of 5
by using our method afforded the desired target product (6) in a
three-step total yield of 74%. We attempted photocatalytic aerobic
oxidation of 1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (7)
under the standard conditions (Scheme 1C). To our pleasure,
1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (8) was obtained in
93% yield. The results above showed that our newly developed
method was very effective and practical.
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Scheme
1.
(A)
A
Gram-Scale
Synthesis
of
2-Methyl-5-nitroisoquinolin-1(2H)-one (2s). (B) Synthesis of
4-Desoxylonimide (6) by Using Our Method. (C) Photocatalytic
Aerobic Oxidation of 1,3-Dimethyl-1H-benzo[d]imidazol-3-ium Iodide
(7) Leading to 1,3-Dimethyl-1H-benzo[d]imidazol-2(3H)-one (8).
Figure 1. (A) The fluorescence emission spectra of Eosin Y (1 mM) with
different concentration of 1c excited at 372 nm. (B): (a) ESR spectrum of
mixture of Eosin Y (2 mol %), Cs2CO3 (15 mM) and DMPO (10 mM) in
DMSO under irradiation of 40 W CFL for 5 min. (b) ESR spectrum of
mixture of Eosin Y (2 mol %), 1c (10 mM), Cs2CO3 (15 mM) and DMPO
(10 mM) in DMSO in the dark for 5 min. (c) ESR spectrum of mixture of
To explore mechanism of the visible light-mediated aerobic
oxidation, Stern–Volmer fluorescence quenching experiments
were first carried out. As shown in Figure 1A, 576 nm
fluorescence launched by Eosin Y was observed when it was
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oxygen produces alkdioxyl radical II (detected by ESR).27
Eosin Y (2 mol %), 1c (10 mM), Cs2CO3 (15 mM) and DMPO (10 mM) in
DMSO under irradiation of 40 W CFL for 5 min.
1
2
3
4
5
6
Migration of a hydrogen radical in II forms carbon radical III,
and another SET from III to E·+ affords an oxygen-centered
cation IV with regenerating the photocatalyst (E). Meanwhile, a
radical chain reaction between III and 1c through SET gives I and
IV. Finally, treatment of IV with Cs2CO3 and I- gets the target
product (2c) with leaving CsHCO3, CsI and 0.5 equiv of oxygen.30
Scheme 2. (A) Visible-Light Photoredox Aerobic Oxidation of 1-
Methylquinolinium Iodide (1c) in the Presence of 18O-Labeling Water.
(B) Visible-Light Photoredox Aerobic Oxidation of 1-
Methylquinolinium Iodide (1c) under 18O-Labeling Oxygen
Atmosphere.
7
8
Scheme 3. A Possible Mechanism for the Visible-Light Photoredox
Aerobic Oxidation of N-Alkylpyridinium Salts
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To further investigate mechanism of the photoredox aerobic
oxidation, some control experiments were carried out. Firstly, two
18O-labeling experiments were handled as follows: (a)
Visible-light
photoredox
aerobic
oxidation
of
1-
methylquinolinium iodide (1c) was performed in the presence of
18O-labeling water, and high resolution positive ion electrospray
mass spectrum showed that 2c was main product with minor
18O-labeling product 2'c appearing (Scheme 2A) (see Figure S9 in
Supporting Information for details). (b) When 18O-labeling
oxygen replaced common oxygen as atmosphere, 18O-labeling
product 2'c was major (Scheme 2B) (see Figure S10 in
Supporting Information for details). The experimental results
showed that the added oxygen atoms in the obtained products (2)
in Tables 2 and 3 were mainly from molecular oxygen rather than
water. When 2,2,6,6-tetramethylpiperidinooxy (TEMPO) or
2,6-di-tert-butyl-4-methylphenol (BHT) was added to the reaction
system of 1c, yields of 2c obviously decreased, which indicated
that the reaction could involve a radical process (see Figure
S11a,b in Supporting Information for details). The single oxygen
pathway was ruled out in the visible-light photoredox aerobic
oxidation through the experiments in the presence of
1,4-diazabicyclo[2.2.2]octane (DABCO) or THF-d8 (see Figure
S11c,d in Supporting Information for details). In the previous
researches, the electron donor-acceptor (EDA) complexes
between Eosin Y (E) and pyridinium salts were found,28 so we
also investigated interaction between 1c and E in DMSO or
DMSO-d6 by UV-Vis and NMR spectroscopies, and the results
showed that no EDA complex was observed in our reaction
system (see Figures S12-S15 in Supporting Information for
details). In addition, quantum yield of the reaction using 1c as the
substrate was detected by following Yoon’s method,29 and the
experiments implied the involvement of radical chain processes
(see Figures S16 and S17 in Supporting Information for details).
In conclusion, we have developed a highly efficient and
environmentally friendly visible light-mediated aerobic oxidation
of N-alkylpyridinium salts with air under organic photocatalysis at
room temperature. The corresponding N-methyl pyridones,
quinolones and isoquinolones were obtained in good yields, and
4-desoxylonimide with important pharmaceutical value was
prepared in a high yield by using our method. The present method
exhibits some advantages including mild and environmentally
friendly conditions, high efficiency, tolerance of wide functional
groups and low cost. We believe that the method will find wide
application in synthesis and modification of N-heterocycles.
ASSOCIATED CONTENT
Supporting_Information. Synthetic procedures, mechanism
1
investigations, characterization data and H, 13C NMR spectra of
these synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
fuhua@mail.tsinghua.edu.cn
ORCID
Hua Fu: 0000-0001-7250-0053
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank Dr. Haifang Li in this department
for her great helps in analysis of high resolution mass
spectrometry, and the National Natural Science Foundation of
China (Grant Nos. 21372139 and 21772108) for financial support.
REFERENCES
According to the results above, a possible mechanism for the
visible light-mediated aerobic oxidation is proposed in Scheme 3.
First, organic photocatalyst, Eosin Y, transforms into its excited
state E* under irradiation of visible light. Next, a single electron
transfer (SET) from E* to 1c (here, 1c is selected as an example)
provides two radicals I and E·+ (confirmed by fluorescence
quenching experiments). Sequentially, coupling of radical I with
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