Visible Light Photocatalytic Aerobic Oxygenation of Indoles and pH as a Chemoselective Switch

Article abstract of DOI:10.1021/acscatal.6b01969

An efficient chemodivergent strategy for visible light photocatalysis is developed. In the presence of a dicyanopyrazine-derived chromophore (DPZ) photocatalyst, aerobic photooxygenation of indoles could produce either isatins or formylformanilides in satisfactory yields by judiciously selecting inorganic salts or modulating the reaction pH. The current chemodivergent method is also effective with 2-substituted indoles, opening straightforward synthetic routes to valuable 2,2-disubstituted 3-oxindoles, formylformanilide derivatives, and benzoxazinones. Mechanistic investigations involving cyclic voltammetry studies further confirm that reaction pH influences the electrochemical properties of DPZ, thus affecting the oxidative pathway by which indoles are being transformed.

Full text of DOI:10.1021/acscatal.6b01969

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Article
Visible Light Photocatalytic Aerobic Oxygenation
of Indoles and pH as Chemoselective Switch
Chenhao Zhang, Sanliang Li, Filip Bures, Richmond Lee, Xinyi Ye, and Zhiyong Jiang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01969 • Publication Date (Web): 02 Sep 2016
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Visible Light Photocatalytic Aerobic Oxygenation of
Indoles and pH as Chemoselective Switch
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Chenhao Zhang,a,§ Sanliang Li,a,§ Filip Bureš,b Richmond Lee,c Xinyi Ye,d and Zhiyong Jiang*,a
a.Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan
b.Institute of Organic Chemistry and Technology, University of Pardubice, Faculty of Chemical Technology, Studentská 573, Pardubice,
53210, Czech Republic
c. ARC Centre of Excellence for Electromaterials Science and Research School of Chemistry, Australian National University, Canberra ACT
2601, Australia
d.Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, 637371, Singapore
ABSTRACT: An efficient chemodivergent strategy for visible light photocatalysis is developed.
In the presence of dicyanopyrazineꢀderived chromophore (DPZ) photocatalyst, aerobic
photooxygenation of indoles could present either isatins or formylformanilides in satisfactory
yields by judiciously selecting inorganic salts or modulating reaction pH. The current
chemodivergent method is also effective to 2ꢀsubstituted indoles, opening straightforward
synthetic routes to valuable 2,2ꢀdisubstituted 3ꢀoxindoles, formylformanilide derivatives and
benzoxazinones. Mechanistic investigations involving cyclic voltammetry studies further
confirm that reaction pH influences the electrochemical properties of DPZ, thus affecting the
oxidative pathway which indoles are being transformed.
KEYWORDS: photocatalysis, visible light, electron transfer, energy transfer, chemodivergence
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Introduction
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Tunable reactions that allow chemoselectivity under controlled experimental conditions
greatly expands molecular diversity.1 Therefore such reaction strategy is greatly important
in organic and medicinal chemistry.1 In recent years, visible light photocatalysis has
attracted significant attention,2 and as a result several elegant solutions to address
chemoselective switch have been developed.3 For example, molecular oxygen O2 was
found to influence and switch chemical routes by triggering the radical
addition/cyclization pathway, while in its absence a more straightforward intermolecular
addition pathway between tertiary amines and electronꢀdeficient alkenes is operative.3a
Inorganic salts were also found to effectively regulate radical processes, producing
selectively more than two kinds of products.3b,c In these examples, the chemical
manipulation of reactants to undergo different reaction pathways and be transformed to
different products is challenging but rewarding.
Photocatalysts are known to activate organic substrates via photosensitization,2a which could
be attributed by two main mechanistic considerations, namely the photoredox single electron
transfer (SET) or energy transfer (ET). While there are a number of reports on photocatalysts
which primarily behave as a photoredox agent,2 there are also reports where photocatalysis is
dominated by the energy transfer pathway.4 In the same vein, if a single photocatalyst could be
tuned by reaction conditions or additives and conferring it an amenable chemoselective
character, this would allow versatility in the manipulation of substrates to the desired product
efficiently and conveniently.
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In recent years, we have developed visible light photocatalysis using dicyanopyrazineꢀderived
chromophore (DPZ) based photocatalyst.3c,5 Herein we report an expedient and efficient
chemodivergent strategy catalyzed by DPZ towards photooxygenation of indoles and 2ꢀ
substituted indoles (Figure 1). By adjusting reaction pH, electrochemical properties of DPZ
could be tweaked thus allowing selective oxygenation pathways via two distinct pathways (see
mechanistic proposal). Several pairs of diverse nitrogenꢀcontaining molecules, including isatins,
trytanthrin, formylformanilides and derivatives, benzoxazinones, and 2ꢀindole/methoxyꢀ
substituted 3ꢀoxindoles could be synthesized with satisfactory results.
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Figure 1. Chemodivergence in DPZꢀcatalyzed visible light aerobic photooxygenation of indoles
and 2ꢀsubstituted indoles.
Catalytic oxidation6 of readily available indoles has been acknowledged as a powerful tool to
access valuable isatins7. However, no successful example with visible light photocatalysis has
been reported to date. Hollmann and coꢀworkers8 demonstrated that visible lightꢀdriven
oxygenation of indoles using chloroperoxidase as the catalyst afforded 2ꢀindolinones but not
isatins. The oxidative cleavage of C1ꢀC2 double bonds of indoles to generate
formylformanilides, that are the ubiquitous synthetic features of pharmaceuticals,9ꢀ11 also
representing a highly desirable task in visible light photocatalysis. The extensive employment of
indoles in photocatalytic crossꢀdehydrogenative coupling (CDC) reactions12 under ambient
conditions and atmosphere precisely demonstrates their relative stability. Indoles featuring
substituents on positions 2ꢀ, 3ꢀ or both are shown to more easily undergo oxygenation through
SET3a,13 or ET14 process under visible light activation. However, only a few examples in
photooxygenation of 2ꢀsubstituted indoles to afford biologically important formylformanilide
derivatives,8−10 2ꢀindole/methoxyꢀsubsituted 3ꢀoxindoles15 and benzoxazinones,16 have been
disclosed.13a,14cꢀe
Results and Discussion
Optimization of reaction conditions. We initiated our study with Nꢀmethyl indole 1a as
the model starting material using 0.5 mol% of DPZ as the photocatalyst under oxygen
o
atmosphere at 25 C and irradiation with a 3 W blue LED (450−455 nm) (Table 1). The
reaction was first carried out in CH2Cl2 and toluene but the desired products were formed
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only in negligible amounts (entries 1 and 2). However, by changing the solvent to
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acetonitrile, the reaction was completed within 11 hours affording two products,
isatin 2a and 2'ꢀformylformanilide 3a, in the ratio of 5:1 (entry 3).
Table 1. Optimization of the Reaction Conditionsa
Nꢀmethyl
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conv.
entry
conditions
2a/3ab
(%)b
7
1
CH2Cl2, 0.1 M
N.D.
N.D.
5:1
2
Toluene, 0.1 M
6
3
CH3CN, 0.1 M
>99
>99
>99c
>99d
13
4
NaH2PO4 (0.1 eq.), CH3CN, 0.1 M
9:1
5
LiBr (0.1 eq.), CH3CN, 0.1 M
18:1
25:1
1:3
6
LiBr (0.2 eq.), H2O (30 eq.), CH3CN, 0.05 M
K3PO4 (1.0 eq.), CH3CN, 0.1 M
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K3PO4 (3.0 eq.), CH3CN/H2O = 10:1, 0.05 M
LiBr (0.2 eq.), H2O (30 eq.), CH3CN, 0.05 M, no light
K3PO4 (3.0 eq.), CH3CN/H2O = 10:1, 0.05 M, no light
no DPZ, LiBr (0.2 eq.), H2O (30 eq.), CH3CN, 0.05 M, 48 h
no DPZ, K3PO4 (3.0 eq.), CH3CN/H2O = 10:1, 0.05 M, 48 h
80e
1:20
N.A.
N.A.
N.A.
N.A.
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N.R.
N.R.
N.R.
N.R.
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aThe reaction was performed on a 0.05 mmol scale, 3 W blue LED (450−455 nm), 25 °C,
b
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ambient atmosphere. Determined by H NMR spectra of the crude reaction mixture.
cIsolated yield of 2a = 41 %. Isolated yield of 2a = 68 %. Isolated yield of 3a = 74 %.
d
e
N.R. = no reaction. N.A. = not available.
Subsequently, we attempted to screen various additives in order to improve the
chemoselectivity (entries 4−5). It was found that the ratio increased to 18:1 when using 0.1 eq. of
LiBr (entry 5). The isolated yield is 41 %, and an unknown precipitate was observed suspected
due to radical polymerization.17 The yield of 2a increased to 68 % when the amount of LiBr was
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increased to 0.2 eq. and an extra 30 eq. of H2O was added to dilute the reaction mixture (entry 6).
Alternatively, K3PO4 used as an additive was found to tune the chemoselectivity towards 3a
(entry 7). When 3.0 eq. of K3PO4 was used in CH3CN/H2O (10:1), 3a was obtained as the major
product in 74% yield (entry 8). No reaction was observed with just DPZ in absence of light
(entries 9−10). Similarly, when no DPZ was added but under irradiation, no 2a or 3a products
were observed (entries 11−12). Photoactivation thus requires the presence of both light and the
photocatalyst DPZ as essential ingredients for the photooxygenation reaction to occur.
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Substrate scope towards indoles. With the optimized conditions determined, we then
extended the scope of oxygenation of indoles to isatins (0.5 mol% of DPZ, 0.2 eq. of
o
LiBr, 30 eq. of H2O, CH3CN, 25 C, 3 W blue LED, oxygen atmosphere: Conditions A)
(Table 2). Indoles 1a-j with various substituents at the
Nꢀ, 4ꢀ, 5ꢀ, 6ꢀ and 7ꢀpositions
underwent this reaction readily and delivered the expected isatins 2a-j in moderate yields.
Starting material 1k with the fused pyridine ring was also compatible with the reaction
conditions. Under Conditions A formylformanilides were not observed in all reactions.
The same substrates 1aꢀk were also examined in photooxygenation to formylformanilides
under the reaction Conditions B (0.5 mol% of DPZ, 3.0 eq. of K3PO4, CH3CN:H2O =
o
10:1, 25 C, 3 W blue LED, ambient atmosphere). A series of formylformanilides 3a-k
were obtained in 53−86% yields within 16 hours.
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Table 2. Chemoselective Synthesis of 2 and 3a
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DPZ (0.5 mol%)
LiBr (0.2 equiv)
DPZ (0.5 mol%)
K3PO4 (3.0 equiv)
MeCN:H2O = 10:1
3 W blue LED
O
N
O
H
R2
R1
MeCN, H2O (30 equiv)
3 W blue LED
O2, 25 oC, 12-13 h
R1
R1
O
N
X
X
N
R2
R2
X
O2, 25 oC, 16 h
9
2
1: X = C or N
3
O
H
(Conditions A)
(Conditions B)
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2, yield (%)b
3, yield (%)b
(Conditions B)
substrate
(Conditions A)
O
CHO
Me
O
N
Me
N
N
Me
1a
1b
2a: 63%
3a: 78% (86%)
3b: 76% (96%)
CHO
CHO
O
O
O
Bn
N
N
Bn
N
Bn
2b: 65%
2c: 67%
CHO
O
CHO
Ph
N
N
N
1c
3c: 71% (85%)
Ph
Ph
CHO
OMe
OMe
OMe
O
CHO
O
Me
N
N
N
1d
1e
1f
2d: 60%
2e: 65%
2f: 71%
3d: 58%c (89%)
3e: 75% (87%)
3f: 86% (92%)
Me
Me
O
CHO
F
CHO
F
F
O
Me
N
N
N
Me
Me
CHO
O
Cl
CHO
Cl
Cl
O
Me
N
N
N
Me
Me
CHO
O
Br
CHO
Br
Br
O
Me
N
N
N
1g
2g: 60%
3g: 72% (86%)
Me
Me
CHO
O
Me
CHO
Me
Me
O
O
Me
N
N
N
Me
1h
1i
2h: 64%
2i: 66%
3h: 66%d (84%)
3i: 78% (88%)
Me
CHO
O
CHO
Me
N
Br
N
N
Me
Br
Br
Me
CHO
O
CHO
O
Me
N
BnO
N
N
BnO
BnO
1j
2j: 56%
2k: 66%
3j: 53%e (85%)
3k: 62% (86%)
Me
Me
CHO
O
CHO
O
Me
N
N
N
N
N
N
1k
Me
Me
CHO
aThe reaction was performed on a 0.1 mmol scale. See Supporting Information for detailed
Conditions A and Conditions B. In parentheses, the isolated yield was obtained by utilizing 10%
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TEMPO as additives after 17-18 h. Yields of isolated products. 2d was obtained in 10% yield.
d2h was obtained in 10% yield. e2j was obtained in 18% yield.
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The unsubstituted N-H Indole 4 was attempted next (eqn. 1). Under the reaction Conditions A
and using LiCl as the additive, the reaction completed in 15 hours, affording isatin 5 in 45%
yield. Chemoselectivity switch was accomplished under the reaction Conditions B (Cs2CO3
instead of K3PO4 was used), giving tryptanthrin 6 in 56% yield. The tryptanthrin alkaloid 6 is an
important bioactive compound, possessing antifungal, antibacterial and cytotoxic activity against
Bꢀ16 melanoma cells.18
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Mechanistic Observations. To gain mechanistic insights into this chemoselective reaction,
investigations using Nꢀmethyl indole 1a as the model substrate were further carried out (eqn. 2).
Addition of TEMPO as radical scavenger under the reaction Conditions A suppressed the
formation of 2a and only traces of 3a was detected. On the other hand, using 1.5 equivalents of a
singletꢀoxygen quencher DABCO, the reaction was sluggish but 2a was obtained in 32% yield
after 72 hours. Under the reaction Conditions B, DABCO effectively inhibited the reaction but
surprisingly for TEMPO as additive, the yield of 3a spiked to 85%. This led us to hypothesize
that by inhibiting formation of reactive radical species through SET, the photosensitization
pathway via ET will be preferred. When 10 mol % of TEMPO was used (versus none) 1 was
transformed to formylformanilides 3 in significantly improved yields (84−96%, Table 2, see the
data in parentheses). Taken together, the formation of isatins 2 would be believed to originate
from SET process and alternatively, an ET process derives formylformanilides 3 from indoles 1.
We looked next at how this photocatalytic process is affected by attenuating the redox
properties of DPZ, and thus probed the catalyst with a series of cyclic voltammetry (CV)
measurements.19 First, LiBr was found to slightly enhance DPZ’s redox ability but with K3PO4,
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the oxidative cycle of DPZ was suppressed significantly. The pH under the reaction Conditions
A and B were determined as 5.3 and 12.7 respectively, and under basic conditions a higher ratio
of 3a/2a was observed (Figure 2A). The same tendency could be duplicated when using diverse
pH buffers instead of water under the reaction Conditions B but without K3PO4 (Figure 2B).
Thus, reaction pH is crucial in affecting the redox properties of DPZ. When we measured the
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3
phosphorescence of DPZ, the emission maxima at 566 nm indicates a triplet state DPZ, DPZ*.
A robust decreasing tendency was observed when increasing the concentration of 2a in
phosphorescence quenching experiments.19 So K3PO4 either suppresses the indole reduction of
3DPZ* to DPZ−• or the O2 oxidation of DPZ−• to DPZ in the SET cycle. Naturally by shutting
down the SET pathway, ET would be operative instead. Our theoretical calculations indicate that
the triplet energy (ET) of DPZ is 46.4 kcal/mol,19 which implies that triplet photosensitization of
3O2 to O2 (E(1∆ꢀ3Σ) = 22.5 kcal/mol)20 by the DPZ* is feasible (see proposed mechanism
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3
3
Scheme 1). On the contrary, ET between DPZ* and indole is impossible (e.g. Nꢀmethyl indole
has ET = 69.3 kcal/mol21). Based on the cyclic voltammogram, DPZ* is a strong oxidant [Et
(S*/S−•) = 0.91 V vs SCE in CH2Cl2] and is able to oxidize indoles (E ~ −0.04 V vs SCE)13b
through a SET process. The generated DPZ−• (Ered1/2 = −1.45 V vs SCE in CH2Cl2) has the ability
3
red
1/2
red
1/2
to reduce molecular oxygen (E = −1.23 V vs SCE) to afford O2−• species. On the basis of these
observations, it is reasonable that by modulating the reaction pH, electrochemical properties of
•−
DPZ could be tuned by different additives and generating either the reduced O2 or excited
1
singlet O2 species. The outcome of ROS affects the oxidative pathway of indoles to either
products 2 or 3.
a
Figure 2. Chemoselectivity influenced by the strength of bases and pH buffers. Determined by
crude 1H NMR.
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To further demonstrate the utility of DPZ in generating O2 species, aerobic oxidation of 4ꢀ
(phenylamino)pentꢀ3ꢀenꢀ2ꢀone 7 employing DPZ as the catalyst under irradiation was carried out
(eqn. 3). A secondary enamino ketone 8 was isolated in 55% yield, which is formed through
singlet O2 initiated 1,2ꢀacyl migration as previously reported by Li4c and Wu4d groups. When
1
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the solvent was changed to MeCN, the chemoselectivity switched and the reaction proceeded by
SET process affording amide 9 as the product in 74% yield. The SET process was also possible
in a 10:1 mixture of CH3CN and MeOH. To our knowledge, this is the first example of
photocatalytic oxidative cleavage of secondary enamino ketones to generate amides.
O
O
O
DPZ (0.5 mol%)
3 W blue LED
O2, 25 oC, 12 h
DPZ (0.5 mol%)
3 W blue LED
MeOH
Ph
Ph
(eqn. 3)
Me
O
N
O
N
H
NH
H
Ph
8
7
9
O2, 25 oC, 13 h
Sol.: MeCN, 74% yield
Sol.: MeCN:MeOH = 10:1, 63% yield
55% yield
Isotopeꢀlabeling studies were subsequently performed, and the results are summarized in
Figure 3. When photoꢀoxygenation reaction of Nꢀmethyl indole 1a was conducted under the
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reaction Conditions A and the Oꢀlabeled H2 O introduced, 2a was found to have about 30%
with single 18O atom incorporation, while the rest were nonꢀlabeled 2a. Subsequently, the
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reaction was attempted using H2 O with O2, and only single or double labeledꢀ18O 2a was
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detected. Double Oꢀlabeled 2a was obtained in a ratio of 1.2:1 to single Oꢀlabeled 2a. When
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both H2 O and O2 were used, a high level of two Oꢀlabeled 2a was achieved. These results
suggest that the complex reaction mechanism involves molecular oxygen and water to a lesser
extent. Isotopeꢀlabeling studies for the transformation of 1a to 3a under the reaction Conditions
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B was also carried out. First, with Oꢀlabeled water, 3a was generated with single labeled O
atom in 1:1 ratio to nonꢀlabeled, suggesting that H2O is involved in the reaction. The 18O
incorporation could originate from exchange between the aldehyde and water,22 and since double
18Oꢀlabeled 3a (FW = 167) was not detected, the 16Oꢀ18O exchange could be slow. Reaction with
heavy isotope 18O2 and nonꢀlabeled water gave 3a labeled by at least an 18O atom, but the
incorporation level of 3a with FW = 165 was slightly higher, revealing that one oxygen atom
18
stems from O2 and another derived from H2O. Meanwhile, the reaction in the presence of H2 O
and 18O2 gave 3a with FW = 167 in high incorporation degree.
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Figure 3. 18OꢀLabeling Experiments. The ratio was determined by GCꢀMS analysis.
Two plausible mechanisms for visible lightꢀdriven aerobic photooxygenation of indoles are
proposed in Scheme 1. Employing the reaction Conditions A, indole substrates could be oxidized
by the triplet 3DPZ* to indole radical cation I through a reductive quenching process. To further
−•
regenerate the catalyst, molecular oxygen is reduced to superoxide ion O2 by DPZ−• to
regenerate DPZ. The highly reactive ROS, O2−• then oxidizes I to form iminium II. The iminium
•
II is further reaction with water and two possible pathways involving addition (path a) or HO2
generated from O2−• (path b)23 to form isatins could be operative. Conversely under the reaction
Conditions B, the oxidative cycle of DPZ is postulated to be suppressed by K3PO4 and indoles
will react with the 1O2 generated by energy transfer and sensitization with 3DPZ*. The dioxetane
intermediate III then finally affords formylformanilides 3 possibly through paths c and d24. Our
isotopeꢀlabeling studies do suggest that paths b and d are possible together with paths a and c.
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Scheme 1. Proposed Mechanism.
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Substrate Scope of 2-Substituted Indoles. Encouraged by the potential of the discovery of a
chemodivergent photoꢀoxidative synthesis of indoles, we extended our protocol in the aerobic
oxygenation of 1,2ꢀdisubstituted indoles 10, which are considered relatively stable (Scheme
2a).25 First, we attempted the photoredox oxygenation under the slightly modified reaction
Conditions A (CF3CH2OH as a solvent and in the absence of LiBr). It was observed that the
reactions were accomplished within 12−13 hours, and a series of cross dimerized products, i.e. 2ꢀ
indoleꢀsubstituted 3ꢀoxindoles 11a-e, were achieved with good chemoselectivity. Most of the
products (11a-c, 11e) were obtained in excellent yields (82−91 %). Having a phenyl substituent
in 10d led only to moderate yield of 11d possibly due to steric and electronic effects These
results suggest that the an insitu iminium intermediate is generated and further attacked by
nucleophiles. By using methanol as a nucleophile to afford 2ꢀmethoxyꢀ3ꢀoxoindoles, structurally
important and bioactive molecules such as matemone,15a mitomycin C,15b and cephalinone B
might be possible.15c The reaction with methanol was not highly chemoselective, but the desired
methoxy derivatives 12a-e were obtained in moderate to good yields when additional 2.0 eq. of
DABCO was utilized.
We then conducted oxygenation of 10 under the reaction Conditions B. Products 13a-e, the
analogues of 3, were attained in satisfactory yields. The employment of 10 mol% of DABCO
was also effective to enhance the yields of 13 (Scheme 2a). Moreover, it was discovered that
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oxygenation of 2ꢀsubstituted indoles 14 showed the same chemoselectivity (Scheme 2b).
Products 15 and 16 were obtained under two reaction conditions in moderate to excellent yields.
It is worth mentioning that products 16 are 2ꢀsubstituted benzo[d]oxazinones representing key
structural motifs in biologically relevant molecules.16 The chemoselectivity was also realized in
the oxidation of 1,3ꢀdisubstituted and 1,2,3ꢀtrisubstituted indoles.19
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Scheme 2. Oxygenation of 2-Substituted Indoles 10 and 14.
a10 mol% of TEMPO was used, t = 17 hour
The Investigation on Utilities of Formylformanilides. This DPZꢀcatalyzed chemodivergent
photooxygenation allowed access to a variety of Nꢀheterocyclic compounds such as isatins,
tryptanthrin, 2ꢀmethoxyꢀ3ꢀoxoindoles, and benzooxazinones that are of biological importance.
The utility of this newly developed tool can further be demonstrated on transformations of
formylformanilide 3a. As shown in eqn. 4, hydrolysis of 3a with NaOH afforded Nꢀ
methylanthranilaldehyde 17 in 81% yield. And the subsequent condensation with indole
provided smoothly neocryptolepine9 18 which exhibits antiplasmodia activity.
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Conclusions
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We have developed a novel and efficient chemodivergent photocatalytic method, using lowꢀ
energy and operationally convenient visible light. By modulating reaction additives that affect
pH the electrochemical properties of the DPZ photocatalyst is tuned, allowing selective catalytic
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•−
aerobic photooxygenation of indoles: by either undergoing SET (O2 ) or ET (1O2) oxidative
process. As a result, two series of important Nꢀheterocyclic compounds, i.e. isatins and
formylformanilides (or tryptanthrin), were obtained in satisfactory yields. This methodology was
also effective to furnish photooxygenation of 2ꢀsubsituted indoles, leading to expedient syntheses
of four series of valuable Nꢀcontaining molecules, especially including 2ꢀmethoxyꢀ3ꢀoxoindoles
and 2ꢀsubstituted benzoxazinones.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chmjzy@henu.edu.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript. §These authors contributed equally.
Notes
The authors declare no competing financial interest.
Supporting Information.
Supporting Information Available: [Representative experimental procedures, cyclic voltammetry
measurements, NMR spectral data for all the compounds, computational methods and data] This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
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We are grateful for the grants from NSFC (21072044, 21672052) and Henan Province
(14IRTSTHN006, 152300410057). We also thank Prof. Xiaoming Liu (Jiaxing University), Prof.
Jianying Qu and Prof. Hua Wang (Henan University) for valuable discussions and suggestions.
9
REFERENCES
10
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
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50
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53
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55
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59
60
(1) For selected examples, see: (a) Menard, F.; Lautens, M. Angew. Chem., Int. Ed. 2008, 47,
2085−2088. (b) Kirchberg, S.; Fröhlich, R.; Studer, A. Angew. Chem., Int. Ed. 2009, 48,
4235−4238. (c) Bruch, A.; Ambrosius, A.; Fröhlich, R.; Studer, A.; Guthrie, D. B.; Zhang,
H.; Curran, D. P. J. Am. Chem. Soc. 2010, 132, 11452−11454. (d) Sridharan, V.; Ribelles, P.;
Estévez, V.; Villacampa, M.; Ramos, M. T.; Perumal, P. T.; Menéndez, J. C. Chem. Eur. J.
2012, 18, 5056−5063. (e) Wang, M.; Zhang, X.; Zhuang, Y.ꢀX.; Xu, Y.ꢀH.; Loh, T.ꢀP. J. Am.
Chem. Soc. 2015, 137, 1341−1347.
(2) For selected recent reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem.
Rev. 2013, 113, 5322−5363. (b) Zhao, J.; Wu, W.; Sun, J.; Guo, S. Chem. Soc. Rev. 2013, 42,
5323−5351. (c) Lang, X.; Chen, X.; Zhao, J. Chem. Soc. Rev. 2014, 43, 473−486. (d)
Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355−360. (e) Schultz, D. M.; Yoon, T.
P. Science 2014, 343, 1239176; (f) Xuan, J.; Zhang, Z.ꢀG.; Xiao, W.ꢀJ. Angew. Chem., Int.
Ed. 2015, 54, 15632−15641. (g) Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015,
48, 1474−1484.
(3) (a) Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M. J. Am. Chem. Soc. 2013,
135, 1823−1829. (b) Yu, C.; Iqbal, N.; Park, S.; Cho, E. J. Chem. Commun. 2014, 50,
12884−12887. (c) Liu, X.; Ye, X.; Bureš, F.; Liu, H.; Jiang, Z. Angew. Chem., Int. Ed. 2015,
54, 11443−11447.
(4) (a) Lu, Z.; Yoon, T. P. Angew. Chem., Int. Ed. 2012, 51, 10329−10332. (b) Zou, Y.ꢀQ.;
Duan, S.ꢀW.; Meng, X.ꢀG.; Hu, X.ꢀG.; Gao, S.; Chen, J.ꢀR.; Xiao, W.ꢀJ. Tetrahedron 2012,
68, 6914−6919. (c) Fan, W.; Li, P. Angew. Chem., Int. Ed. 2014, 53, 12201−12204. (d)
Meng, Q.ꢀY.; Lei, T.; Zhao, L.ꢀM.; Wu, C.ꢀJ.; Zhong, J.ꢀJ.; Gao, X.ꢀW.; Tung, C.ꢀH.; Wu,
L.ꢀZ. Org. Lett. 2014, 16, 5968−5971. (e) Farney, E. P.; Yoon, T. P. Angew. Chem., Int. Ed.
2014, 53, 793−797.
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Page 15 of 18
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1
2
3
4
5
6
7
8
(5) (a) Zhao, Y.; Zhang, C.; Chin, K. F.; Pytela, O.; Wei, G.; Liu, H.; Bureš, F.; Jiang, Z. RSC
Adv. 2014, 4, 30062−30067. (b) Wei, G.; Zhang, C.; Bureš, F.; Ye, X.; Tan, C.ꢀH.; Jiang, Z.
ACS Catal. 2016, 6, 3708−3712.
9
(6) (a) Yadav, J. S.; Subba Reddy, B. V.; Suresh Reddy, Ch.; Krishma, A. D. Synthesis 2007,
693−696. (b) Yadav, J. S.; Subba Reddy, B. V.; Suresh Reddy, Ch.; Krishna, A. D.
Tetrahedron Lett. 2007, 48, 2029−2032. (c) Kumar, C. N. S. S. P.; Devi, C. L. V.; Rao, J.;
Palaniappan, S. Synlett 2008, 2023−2027. (d) Chen, S.; Liu, Z.; Shi, E.; Chen, L.; Wei, W.;
Li, H.; Cheng, Y.; Wan, X. Org. Lett. 2011, 13, 2274−2277.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, T. R.; Ogawa, A.
Tetrahedron 2004, 60, 3493−3503. (b) Sassatelli, M.; Debiton, E.; Aboab, B.; Prudhomme,
M.; Moreau, P. Eur. J. Med. Chem. 2006, 41, 709−716. (c) Vine, K. L.; Locke, J. M.;
Ranson, M.; Pyne, S. G.; Bremner, J. B. J. Med. Chem. 2007, 50, 5109−5117.
(8) (a) Wani, M. C.; Nicholas, A. W.; Manikumar, G.; Wall, M. E. J. Med. Chem. 1987, 30,
1774−1779. (b) Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.; Colson, P.; De
PauwꢀGillet, M.ꢀC.; van den Heuvel, H.; Claeys, M.; Lemière, F.; Esmans, E. L.; Rozenski,
J.; Quirijnen, L.; Maes, L.; Dommisse, R.; Lemière, G. L. F.; Vlietinck, A.; Pieters, L. J.
Med. Chem. 2002, 45, 3497−3508.
(9) (a) Ida, Y.; Matsubara, A.; Nemoto, T.; Saito, M.; Hirayama, S.; Fujii, H.; Nagase, H.
Bioorg. Med. Chem. 2012, 20, 5810−5831. (b) Zheng, F.; Zhan, M.; Huang, X.; Abdul
Hameed, M. D. M.; Zhan, C.ꢀG. Bioorg. Med. Chem. 2014, 22, 538−549. (c) Darras, F. H.;
Wehle, S.; Huang, G.; Sotriffer, C. A.; Decker, M. Bioorg. Med. Chem. 2014, 22,
4867−4881.
(10)(a) Yates, C. M.; Brown, P. J.; Stewart, E. L.; Patten, C.; Austin, R. J. H.; Holt, J. A.;
Maglich, J. M.; Angell, D. C.; Sasse, R. Z.; Taylor, S. J.; Uings, I. J.; Trump, R. P. J. Med.
Chem. 2010, 53, 4531−4544. (b) Dessole, G.; Branca, D.; Ferrigno, F.; Kinzel, O.; Muraglia,
E.; Palumbi, M. C.; Rowley, M.; Serafini, S.; Steinkuhler, C.; Jones, P. Bioorg. Med. Chem.
Lett. 2009, 19, 4191−4195. (c) Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G. E.;
Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez, P. A.; Glen, R. C.; Goggin, M. C.;
Hobbs, A. J.; Kling, M. R.; Liu, Q.; Madge, D. J.; Meillerais, S.; Powell, K. L.; Reynolds, K.;
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5
6
Spacey, G. D.; Stables, J. N.; Tatlock, M. A.; Wheeler, K. A.; Woo, C. K. J. Med. Chem.
2001, 44, 78−93.
7
8
(11)Perez, D. I.; Grau, M. M.; Arends, I. W. C. E.; Hollmann, F. Chem. Commun. 2009,
9
6848−6850.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12)(a) Zhong, J.ꢀJ.; Meng, Q.ꢀY.; Wang, G.ꢀX.; Liu, Q.; Chen, B.; Feng, K.; Tung, C.ꢀH.; Wu,
L.ꢀZ. Chem. Eur. J. 2013, 19, 6443−6450. (b) Yamagushi, T.; Nobuta, T.; Tada, N.; Miura,
T.; Nakayama, T.; Uno, B.; Itoh, A. Synlett 2014, 25, 1453−1457. (c) Wu, C.ꢀJ.; Zhong, J.ꢀJ.;
Meng, Q.ꢀY.; Lei, T.; Gao, X.ꢀW.; Tung, C.ꢀH.; Wu, L.ꢀZ. Org. Lett. 2015, 17, 884−887.
(13)(a) Lerch, S.; Unkel, L.ꢀN.; Brasholz, M. Angew. Chem., Int. Ed. 2014, 53, 6558−6562. (b)
Ding, W.; Zhou, Q.ꢀQ.; Xuan, J.; Li, T.ꢀR.; Lu, L.ꢀQ.; Xiao, W.ꢀJ. Tetrahedron Lett. 2014,
55, 4648−4652. (c) Zhang, M.; Duan, Y.; Li, W.; Cheng, Y.; Zhu, C. Chem. Commun. 2016,
52, 4761−4763.
(14)For selected examples, see: (a) Saito, I.; Imuta, M.; Matsugo, S.; Matsuura, T. J. Am. Chem.
Soc. 1975, 97, 7191−7193. (b) Saito, I.; Imuta, M.; Matsugo, S.; Yamamoto, H.; Matsuura,
T. Synthesis, 1976, 255−256. (c) d’Ischia, M.; Prota, G. Gazz. Chim. Ital. 1986, 116,
407−410. (d) Garg, H. S.; Bhakuni, D. S. Indian J. Chem. B 1986, 25B, 973−974. (e) Ling,
K.ꢀQ. Synth. Commun. 1995, 25, 3831−3835.
(15)(a) Carletti, I.; Banaigs, B.; Amade, P. J. Nat. Prod. 2000, 63, 981−983. (b) Altinis Kiraz, C.
I.; Emge, T. J.; Jimenez, L. S. J. Org. Chem. 2004, 69, 2200−2202. (c) Wu, P.ꢀL.; Hsu, Y.ꢀL.;
Jao, C.ꢀW. J. Nat. Prod. 2006, 69, 1467−1470. (d) Nge, C.ꢀE.; Gan, C.ꢀY.; Lim, K.ꢀH.; Ting,
K.ꢀN.; Low, Y.ꢀY.; Kam, T.ꢀS. Org. Lett. 2014, 16, 6330−6333.
(16)(a) Varsha, J.; Pradeep, M.; Sushil, K.; Stables, J. P. Eur. J. Med. Chem. 2008, 43, 135−141.
(b) Kumar, P.; Shrivastava, B.; Pandeya, S. N.; Stables, J. P. Eur. J. Med. Chem. 2011, 46,
1006−1018. (c) Gupta, A.; Kashaw, S. K.; Jain, N.; Rajak, H.; Soni, A.; Stables, J. P. Med.
Chem. Res. 2011, 20, 1638−1642. (d) Sharma, P.; Kumar, A.; Kumari, P.; Singh, J.; Kaushik,
M. P. Med. Chem. Res. 2012, 21, 1136−1148.
(17)Messina, M. S.; Axtell, J. C.; Wang, Y.; Chong, P.; Wixtrom, A. I.; Kirlikovali, K. O.;
Upton, B. M.; Hunter, B. M.; Shafaat, O. S.; Khan, S. I.; Winkler, J. R.; Gray, H. B.;
Alexandrova, A. N.; Maynard, H. D.; Spokoyny, A. M. J. Am. Chem. Soc. 2016, 138,
6952−6955.
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7
8
9
(18)(a) Bhattacharjee, A. K.; Skanchy, D. J.; Jennings, B.; Hudson, T. H.; Brendle, J. J.;
Werbovetz, K. A. Bioorg. Med. Chem. 2002, 10, 1979−1982. (b) Jao, C.ꢀW.; Lin, W.ꢀC.;
Wu, Y.ꢀT.; Wu, P.ꢀL. J. Nat. Prod. 2008, 71, 1275−1279. (c) Yang, S.; Li, X.; Hu, F.; Li, Y.;
Yang, Y.; Yan, J.; Kuang, C.; Yang, Q. J. Med. Chem. 2013, 56, 8321−9331.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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34
35
36
37
38
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44
45
46
47
48
49
50
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52
53
54
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56
57
58
59
60
(19)See the Supporting Information for details.
(20)Herzberg, G.; Molecular Spectra and Molecular Structure: Spectra of Diatomic Molecules,
2nd ed., VonNostrand, New York, 1950, Vol. I, 559−560.
(21)Wilkinson, F.; Garner, A. Photochem. Photobiol. 1978, 27, 659−670.
(22)Meng, C.; Yang, K.; Fu, X.; Yuan, R. ACS Catal. 2015, 5, 3760−3766.
(23)Zi, Y.; Cai, Z.ꢀJ.; Wang, S.ꢀY.; Ji, S.ꢀJ. Org. Lett. 2014, 16, 3094−3097.
(24)Suga, K.; Ohkubo, K.; Fukuzumi, S. J. Phys. Chem. A 2003, 107, 4339−4346.
(25)(a) Saito, I.; Imuta, M.; Matsuura, T. Chem. Lett. 1972, 1, 1173−1176. (b) Li, X.; Gu, X.; Li,
Y.; Li, P. ACS Catal. 2014, 4, 1897−1900.
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