Merging Visible Light Photocatalysis and l-/d-Proline Catalysis: Direct Asymmetric Oxidative Dearomatization of 2-Arylindoles to Access C2-Quaternary Indolin-3-ones

Article abstract of DOI:10.1021/acs.orglett.9b04613

A mild and effective method for asymmetric synthesis of C2-quaternary indolin-3-ones directly from 2-arylindoles by combining visible light photocatalysis and organocatalysis is described. In this reaction, 2-substituted indoles undergo photocatalyzed oxidative dearomatization, followed by an organocatalyzed asymmetric Mannich reaction with ketones or aldehydes. Products with opposite configurations are easily obtained in satisfactory yields with excellent enantio- A nd diastereoselectivity by employing readily available l- A nd d-proline as chiral organocatalysts.

Full text of DOI:10.1021/acs.orglett.9b04613

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Letter
Merging Visible Light Photocatalysis and L‑/D‑Proline Catalysis:
Direct Asymmetric Oxidative Dearomatization of 2‑Arylindoles To
Access C2-Quaternary Indolin-3-ones
Chun-Lin Dong, Xuan Ding, Lan-Qian Huang, Yan-Hong He,* and Zhi Guan*
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ABSTRACT: A mild and effective method for asymmetric synthesis of C2-quaternary indolin-3-ones directly from 2-arylindoles by
combining visible light photocatalysis and organocatalysis is described. In this reaction, 2-substituted indoles undergo photocatalyzed
oxidative dearomatization, followed by an organocatalyzed asymmetric Mannich reaction with ketones or aldehydes. Products with
opposite configurations are easily obtained in satisfactory yields with excellent enantio- and diastereoselectivity by employing readily
available L- and D-proline as chiral organocatalysts.
2-substituted indoles by combining photocatalysis and enzyme
catalysis. However, only moderate yields and enantioselectiv-
ities were obtained.5 Very recently, we combined electro-
chemistry and chiral organocatalysis (L- and D-proline) to
realize this reaction, which resulted in excellent enantiose-
lectivity but moderate yield.6 In 2019, Wang and Zhang
developed an organocatalytic method for the enantioselective
synthesis of C2-quaternary indol-3-ones from 2-phenylindoles
in good yields and high enantioselectivity.7 This work used L-
proline as an organocatalyst and a stoichiometric amount of
2,2,6,6-tetramethylpiperidinooxy (TEMPO) oxoammonium
salt (TEMPO+OTf−) as the oxidant, which needs to be
prepared in advance by oxidation of TEMPO. Considering the
importance of the C2-quaternary indolin-3-one structure, it is
necessary to further develop mild, environmentally friendly
synthetic methods to obtain such compounds with satisfactory
yields and enantioselectivity. Inspired by the previous efforts,
we have developed a milder and more effective method to
enable direct asymmetric preparation of C2-quanternary
indolin-3-ones through combination of visible light catalysis
and L- or D-proline catalysis. This method uses O2 as a clean
final oxidant, avoiding the use of stoichiometric oxidants that
may affect the environment. A variety of C2-quanternary
s an environmentally friendly, green, and natural
Arenewable energy source, visible light has been increas-
ingly used in organic synthesis.1 It can be utilized to construct
a wide variety of complex chemical structures under mild
conditions.2 However, because of the high reactivity and short
lifetime of the intermediate in photocatalytic reaction,
controlling the enantioselectivity of this process is far from
simple.3 Herein, we combined visible light photocatalysis with
organocatalysis to successfully achieve enantioselective syn-
thesis of C2-quaternary indolin-3-ones directly from 2-
substituted indoles. A C2-quaternary indolin-3-one structure
exists in many bioactive natural products and drug molecules,
such as aristotelone, (−) isatisine A, and austamide (Figure
1).4 To the best of our knowledge, there are only a few reports
on enantioselective preparation of C2-quaternary indolin-3-
ones via the asymmetric dearomatization of 2-arylindoles.5−7
In 2019, our laboratory reported a method for the
enantioselective synthesis of C2-quaternary indol-3-ones from
Received: December 23, 2019
Figure 1. Bioactive natural products and drug molecules with a C2-
quaternary indolin-3-one skeleton.
https://dx.doi.org/10.1021/acs.orglett.9b04613
© XXXX American Chemical Society
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Letter
indolin-3-ones can be obtained in satisfactory yields with
excellent enantio- and diastereoselectivity.
Scheme 1. Substrate Scope for the Reaction with L-Proline
as the Chiral Catalyst
a
L-Proline, as a cheap and readily available chiral organo-
catalyst, has been used to catalyze various asymmetric
reactions, such as aldol,8 Michael,9 Mannich,10 and Robinson11
reactions, and has achieved excellent asymmetric induction.
Meanwhile, on the basis of the previous reports,6,7 we selected
L-proline as a chiral organocatalyst for this reaction. In our
preliminary study, the reaction of 2-phenylindole (1a) and
cyclohexanone (2a) was chosen as a model reaction. After
several common photocatalysts were screened [Supporting
Information (SI), Table S1], Ru(bpy)3Cl2·6H2O (bpy = 2,2′-
bipyridine) was selected as the photocatalyst. The solvents
were subsequently screened (SI, Table S2) in view of the fact
that they often have a significant effect on the reactivity of
organic reactions. Among the tested solvents, ethanol gave the
best results. After the photocatalyst loading, the L-proline
loading, and the ratio of substrates were optimized (SI, Tables
S3−S5), the desired product 3a can be obtained in 62% yield
with 19:1 d.r. and 98% ee (SI. Table S5, entry 4). Next, we
investigated the effect of additives on the reaction (SI, Tables
S6 and S7) and found that when 4 equiv of 2,6-lutidine was
added to the reaction system, product 3a can be obtained in
improved yield (79%) with excellent diastereo- and enantio-
selectivity (>20:1 d.r. and 99% ee) (SI. Table S7, entry 5).
This may be because the addition of 2,6-lutidine can maintain
the pH of the reaction system within a suitable range, thereby
effectively avoiding the undesired dimerization of 2-phenyl-
indole.12,13 Therefore, the optimal conditions for this reaction
were determined as 1a (1.0 equiv), 2a (2.0 equiv), Ru-
(bpy)3Cl2·6H2O (3 mol %), L-proline (40 mol %), 2,6-lutidine
(4 equiv), irradiation using 9 W blue LEDs, and EtOH as a
solvent under O2 atmosphere.
a
Unless otherwise noted, conditions: 1 (0.25 mmol), 2 (0.50 mmol),
Under optimized conditions, a broad range of 2-substituted
indoles and carbonyl compounds were studied to reveal the
substrate scope of the reaction (Scheme 1). Generally, 2-
phenylindoles bearing various substituent groups at different
positions of 2-phenyl reacted with cyclohexanone 2a smoothly,
giving the expected products in good results (55−86% yield,
9:1 → 20:1 d.r., and 95−99% ee) (3a−3i). The 2-
phenylindoles with electron-donating groups on 2-phenyl
provided lower yields than those with electron-withdrawing
groups at the same positions (3e vs 3b−3d and 3f; 3h vs 3i).
2-Phenylindoles with substituents (F, Cl, Br, or OMe) at
different positions on the indole moiety can react with
cyclohexanone 2a, giving the corresponding products (3j−3n).
Among them, 5-methoxy and 5-F-substituted indoles only gave
corresponding products in low yields (3j and 3m), and a large
amount of raw materials remained, which may be due to their
poor solubility in the reaction system. 2-Thienylindole was also
suitable for this reaction, which reacted with cyclohexanone 2a
to give 3o in a good yield and excellent diastereo- and
enantioselectivity. Besides cyclohexanone 2a, chain ketones
(acetone and butanone) and other cyclic ketones (methyl
cyclohexanone and cyclopentanone) can also react smoothly
with 2-phenylindole, giving corresponding products with good
results (3p−3s). In addition, the aldehyde substrates were also
well tolerated under these photocatalysis conditions. 1a reacted
well with phenylpropyl aldehyde and decanal, respectively,
affording corresponding products in satisfactory yields (73−
75%) with good selectivity (>20:1 d.r. and 95−99% ee) (3t
and 3u). Unfortunately, when N-1-substituted indole or
L-proline (40 mol %), Ru(bpy)3Cl2·6H2O (3 mol %), and 2,6-lutidine
(4 equiv) in EtOH (1 mL) irradiated with 9 W blue LEDs under O2
atmosphere (O2 balloon) at rt for 24 h. Listed below the compount is
the yield of isolated product (%). The ee and d.r. were determined by
b
HPLC analysis with a chiral column (AD-H). The reaction was run
c
d
in 1.0 mmol scale. The reaction was extended to 3 days. The ee and
d.r. were determined by HPLC analysis with a chiral column (OD-H).
aromatic ketone was used as a reactant, no product was
detected.
Encouraged by the results of the combination of photo-
catalysis and L-proline catalysis, we used D-proline in this
reaction to obtain products with opposite configurations.
Delightfully, D-proline was also found to perform very well in
this reaction, providing desired products with satisfactory
results (Scheme 2). Therefore, by using L- or D-proline, highly
enantioselective synthesis of various C2-quaternary indolin-3-
ones with opposite configurations can be easily achieved. The
absolute configurations of products 3i and 4d were
unambiguously determined by single-crystal X-ray diffraction
analysis (3i: CCDC 1968725; 4d: CCDC 1968746). The
absolute configuration of other products derived from ketones
was determined by analogy, and the absolute configuration of
products (3t and 3u) derived from aldehyde substrates was
assigned by comparison with reported chiral HPLC analysis.7
In order to better understand the reaction mechanism, some
control experiments were performed (Table 1). The
experimental results revealed that both visible light and L-
proline are essential, because no product can be detected
B
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Scheme 2. Substrate Scope for the Reaction with D-Proline
as the Chiral Catalyst
Scheme 3. Mechanism Studies
a
a
Reaction conditions: 1 (0.25 mmol), 2a (0.50 mmol), D-proline (40
Ru(II), while 2a did not show a significant quenching effect.
On the other hand, considering that Ru(II) can also act as a
photosensitizer to convert triplet oxygen (3O2) to singlet
oxygen (1O2),14 the fluorescence quenching experiments of
Ru(II)* with O2 and Ar were carried out in ethanol (SI, Figure
S4), which suggested that O2 could quench Ru(II)* efficiently.
Then, to verify whether 1O2 is involved in the reaction, the 1O2
quencher β-carotene15 (4 equiv) was added to the model
reaction. It was found that product 3a could still be obtained in
the presence of β-carotene, but the yield significantly decreased
(from 79 to 30%) (Scheme 3b). The result suggested that
there may be an energy transfer (ET) process involving 1O2 in
the reaction, but it is not the only reaction pathway. To clarify
whether there is a single-electron transfer (SET) process
involved in the reaction, the cyclic voltammetry (CV)
measurement of 1a (SI, Figure S6) was performed. The
oxidation potential of 1a was determined as 1a (Eox = +0.08 V
mol %), Ru(bpy)3Cl2·6H2O (3 mol %), and 2,6-lutidine (4 equiv) in
EtOH (1 mL) irradiated with 9 W blue LEDs under O2 atmosphere
(O2 balloon) at rt for 24 h. Listed below the compount is the yield of
isolated product (%). The ee and d.r. were determined by HPLC
analysis with a chiral column (AD-H).
a
Table 1. Control Experiments
b
c
c
entry
conditions
yield (%)
ee (%)
d.r.
1
2
3
4
5
standard conditions
dark
no L-proline
no Ru(bpy)3Cl2·6H2O
argon instead of O2
79
n.d.
n.d.
22
99
--
--
99
--
>20:1
--
--
>20:1
--
vs SCE in MeCN). The data indicated that 1a can be oxidized
II/I
by the excited Ru(II)* (E1/2
*
= +0.77 V vs SCE in
n.d.
MeCN),16 suggesting that Ru(II)* can be quenched through a
SET process by 1a. Therefore, based on these experimental
results, we speculate that both ET and SET may be involved in
the reaction process.
a
Unless otherwise noted, conditions: 1a (0.25 mmol), 2a (0.50
mmol), L-proline (40 mol %), Ru(bpy)3Cl2·6H2O (3 mol %), and 2,6-
lutidine (4 equiv) in EtOH (1 mL) irradiated with 9 W blue LEDs
under O2 atmosphere (O2 balloon) at rt for 24 h. Yield of isolated
product. Determined by HPLC analysis with a chiral column (AD-
b
c
Next, on the basis of previous work,5−7,17 we speculated that
1a may first be oxidized to the intermediate 2-phenyl-3H-
indol-3-one (IV), which then reacts with 2a to form product
3a. Therefore, to verify this speculation, we synthesized IV and
allowed it to react with cyclohexanone (2a) under the standard
reaction conditions, which gave 3a in a yield of 70% with good
selectivity (>20:1 d.r. and 99% ee) (Scheme 3c). This result
suggested that IV may be a key intermediate for this reaction.
Subsequently, an 18O-labeling experiment was performed to
explore the source of C3-carbonyl oxygen atom of 3a. The
model reaction was conducted under 18O2 atmosphere (18O2
balloon), and the 18O-labeled product 3a′ (determined by
HRMS, SI, Figure S4) was obtained with 72% yield (Scheme
3d), demonstrating that the carbonyl oxygen atom is derived
from O2.
H).
without one of them (Table 1, entries 2 and 3). When the
reaction was performed in the absence of photocatalyst, 3a was
obtained in only 22% yield (Table 1, entry 4), indicating that
although the reaction can occur without a photocatalyst
(proposed possible mechanism for the reaction without
photocatalyst, see SI, Scheme S1), the presence of the
photocatalyst can greatly improve the reaction efficiency.
Moreover, product 3a was not detected when the reaction was
conducted under argon instead of O2 (Table 1, entry 5).
Therefore, it can be concluded that visible light irradiation,
photocatalyst, L-proline, and O2 are crucial for this reaction.
The reaction in the presence of the radical scavenger
TEMPO yielded product 3a in only 17% yield (Scheme 3a),
indicating that a radical process may be involved in the
reaction. Next, fluorescence quenching experiments (SI,
Figures S1−S3) showed that 1a could quench the excited
Finally, based on our experiments and previous re-
ports,5−7,13,17 a plausible mechanism was proposed, which
includes SET and ET pathways (Scheme 4). In SET pathway
(path a), the excited state Ru(II)* generated from the ground
C
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Authors
Yan-Hong He − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China;
orcid.org/0000-0002-6405-285X; Email: heyh@
swu.edu.cn
Zhi Guan − Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, China; orcid.org/
0000-0002-0369-6141; Email: guanzhi@swu.edu.cn
Authors
Chun-Lin Dong − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China
Xuan Ding − Yunnan Branch, Institute of Medicinal Plant
Development, Chinese Academy of Medical Sciences & Peking
Union Medical College, Yunnan 666100, China
Lan-Qian Huang − Key Laboratory of Applied Chemistry of
Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, China
state under the irradiation of visible light is reduced by 2-
phenylindole 1a via a SET process to produce the intermediate
I and Ru(I). Then, the coupling of I with the superoxide anion
O2•−, which is produced via the SET process of Ru(I) and O2
in the photoredox catalysis cycle, affords the intermediate II. II
undergoes a proton transfer to form III. In the ET pathway
(path b), the excited state Ru(II)* acts as a photosensitizer to
convert O2 to O2. Subsequently, the addition of O2 to 1a
forms the intermediate VI,13 which further transforms into III.
III loses a molecule of water to produce IV. L-Proline acts as a
difunctional catalyst in the reaction system to activate two
reactants simultaneously.7 As a Brønsted acid, the acidic
proton of L-proline can activate the intermediate IV through a
hydrogen bond. On the other hand, ketone 2a can be activated
by L-proline via forming the corresponding enamine V. Finally,
the asymmetric Mannich reaction between IV and V yields the
desired product 3a.
In summary, we have successfully developed a mild and
effective procedure for asymmetric preparation of C2-
quaternary indolin-3-ones directly from 2-substituted indoles
through the combination of visible light photocatalysis with
organocatalysis. In this reaction, 2-substituted indoles undergo
photocatalyzed oxidative dearomatization, followed by organo-
catalyzed asymmetric Mannich reaction with ketones or
aldehydes. By using cheap and commercially available L- and
D-proline as chiral organocatalysts, products with opposite
configurations can be easily obtained. This procedure features
good tolerance of functional groups and a wide substrate
scope. Various chiral C2-quaternary indolin-3-ones were easily
prepared in satisfactory yields (up to 92%) with excellent
enantioselectivity (up to 99% ee) and diastereoselectivity (up
to >20:1), showing great potential in organic synthesis.
3
1
1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04613
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21672174 and 21977084)
and the Natural Science Foundation of Chongqing (No.
cstc2019jcyj-msxmX0297).
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04613.
Experimental procedures; mechanistic investigation;
characterization data; spectral data (PDF)
Accession Codes
CCDC 1968725 and 1968746 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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