Asymmetric Dearomatization of Indole Derivatives with N-Hydroxycarbamates Enabled by Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201911144

Dearomatization of indoles provides efficient synthetic routes for substituted indolines. In most cases, indoles serve as nucleophiles. Reported here is an asymmetric dearomatization reaction of indole derivatives that function as electrophiles. The combination of a photocatalyst and chiral phosphoric acid open to air unlocks the umpolung reactivity of indoles, enabling their dearomatization with N-hydroxycarbamates as nucleophiles. A variety of fused indolines bearing intriguing oxy-amines were constructed in excellent yields with moderate to high enantioselectivities. Mechanistic studies show that the realization of two sequential single-electron transfer oxidations of the indole derivatives is key, generating the configurationally biased carbocation species while providing the source of stereochemical induction. These results not only provide an efficient synthesis of enantioenriched indoline derivatives, but also offer a novel strategy for further designing asymmetric dearomatization reactions.

Full text of DOI:10.1002/anie.201911144

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Accepted Article
Title: Asymmetric Dearomatization of Indole Derivatives with N-
Hydroxycarbamates Enabled by Photoredox Catalysis
Authors: Shuli You, Yuan-Zheng Cheng, Qing-Ru Zhao, Xiao Zhang,
and Shu-Li You
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Angewandte Chemie International Edition
10.1002/anie.201911144
RESEARCH ARTICLE
Asymmetric Dearomatization of Indole Derivatives with N-
Hydroxycarbamates Enabled by Photoredox Catalysis
[
a]
[a,b]
[a]
[a,b]
Yuan-Zheng Cheng, Qing-Ru Zhao,
Xiao Zhang, * and Shu-Li You
*
In memory of Professor Dieter Enders
[
7]
Abstract: Dearomatization of indoles and their derivatives provides
efficient synthetic routes for substituted indolines. In most cases,
indoles serve as nucleophiles by reacting with electrophiles at the
C3 position. Herein, we report an asymmetric dearomatization
reaction of indole derivatives that function as electrophiles. The
combined utilization of photocatalyst and chiral phosphoric acid in air
unlocks the umpolung reactivity of indoles, enabling enantioselective
dearomatization of indole derivatives with N-hydroxycarbamates as
nucleophiles. A variety of optically active fused indolines bearing
intriguing oxy-amines were constructed in excellent yields with
moderate to high enantioselectivity. As suggested by preliminary
mechanistic studies, key to the success is the realization of two
sequential SET oxidation of indole derivatives under dual catalysis
that can generate the configurationally biased carbocation species
while providing the source of stereochemical induction. The current
results not only provide an efficient synthesis of highly
enantioenriched indoline derivatives, but also offer a novel strategy
for further designing asymmetric dearomatization reactions.
phosphate base-assisted single electron oxidation.
These
open-shelled species, which were supposed to interact with a
chiral phosphate base via hydrogen-bonding interactions, can be
further intercepted by the consistent nitroxyl radical TEMPO• to
form the alkoxyamine-substituted pyrroloindolines in good yields
with high enantioselectivity. The same reaction was achieved in
[8]
a
photocatalyst-free fashion by Xia and co-workers.
Mechanistically, excited state TEMPO• acted as a HAT catalyst
to deliver the corresponding tryptamine radicals, which were
enantioselectively captured by TEMPO• in the presence of chiral
phosphoric acid. Notably, both examples elegantly showcased
that tryptamines serve as radical species in asymmetric
dearomatization reactions (b, Scheme 1).
Introduction
Indoles, as one of the most important and abundant
heteroaromatics, have centuries found broad applications in
areas including pigments, fragrances, pharmaceuticals,
[
1]
agrochemicals, and materials science. Of particular note,
catalytic asymmetric dearomatization (CADA) reactions of
indoles and their derivatives allow easy access to
enantioenriched fused indolines, a privileged scaffold in alkaloid
[2]
natural products and biologically active molecules. There have
been many elegant asymmetric dearomatization reactions of
[
3,4]
[5]
indoles, such as Friedel-Crafts type alkylation,
and halogenation
oxidation,
[
6]
in the presence of catalysts including
enzymes, transition metal complexes, and organocatalysts.
Despite the great achievements made to date, most of these
methods exploit the inherent nucleophilicity of indoles by
reacting with electrophiles (a, Scheme 1).
Unveiling new reactivity of indole derivatives offers
opportunities for complementary asymmetric dearomatization
reactions, but still remains a formidable challenge. It is until
recently that Knowles and co-workers reported a photocatalytic
approach to generate tryptamine radical cations through chiral
Scheme 1. Catalytic Asymmetric Dearomatization of Indole Derivatives.
Regarding the expansion to new substrate scope, exploring
reactivity of indole derivatives beyond is still highly desirable.
However, to the best of our knowledge, we are not aware of any
asymmetric dearomatization examples by reversing the inherent
reactivity of the indoles to electrophiles through oxidative
conditions. The difficulties might arise from both the reactivity
and enantioselective control. Herein, we report the first catalytic
asymmetric dearomatization reaction of indole derivatives that
capitalize on their electrophilic properties upon loss of two
electrons. With N-hydroxycarbamates as nucleophiles, good to
excellent yields and high enantioselectivity have been achieved
[
a]
Dr. Y.-Z. Cheng, Q.-R. Zhao, Prof. Dr. X. Zhang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
E-mail: *zhangxiao@sioc.ac.cn
*
slyou@sioc.ac.cn
[
b]
Q.-R. Zhao, Prof. Dr. S.-L. You
School of Physical Science and Technology, ShanghaiTech
University, 100 Haike Road, Shanghai 201210, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
for the fused indoline products via cooperation of a photocatalyst
and chiral phosphoric acid (c, Scheme 1).
requirement of CPA for both reactivity and enantioselectivity,
CPA is proposed to participate in assisting the second SET
[
7,8]
oxidation of tryptophol. Different from previous reports,
in our
hands, the addition of TEMPO• quenched the photoexcited C4*
Results and Discussion
directly and
Visible-light photoredox catalysis has been widely employed in
organic synthesis to generate reactive species under extremely
[a]
Table 1. Optimization of the Reaction Conditions.
[
9]
mild conditions in recent years. However, its applications in
[10]
asymmetric dearomatization reactions are rare.
At the
beginning, we noticed that highly reactive nitrosocarbonyl
intermediates could be generated catalytically from bench-stable
N-hydroxycarbamates in the presence of a photocatalyst under
[
11,12]
air.
Based on these results, our original design was to
explore the natural nucleophilicity of indoles for chiral phosphoric
[
13]
acid-catalyzed
asymmetric dearomatization with transient
electrophilic nitrosocarbonyl species using visible-light as a mild
driving energy. However, the reactions between tryptophol (1a)
and N-hydroxycarbamate (2a') performed under previously
[
12]
described photochemical conditions did not occur at all.
Further investigations revealed the desired transformation could
only
be
ppy)
achieved
(bpy)PF as the photocatalyst (entries 1-4, Table 1
different
upon
using
more
oxidizing
Ir(dFCF
3
2
6
and SI). These preliminary results indicated
a
mechanism might be operative, which encouraged us to further
optimize the reaction conditions. Various parameters including
chiral phosphoric acid, N-hydroxycarbamate, solvent, and
loading of the photocatalyst were next evaluated (entries 5-13,
Table 1 and SI). It was found that the utilization of blue LEDs in
[b]
[c]
entry
PC
C1
C2
C3
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
CPA
PA1
PA1
PA1
PA1
PA2
PA3
PA4
PA1
PA1
PA1
PA1
PA1
PA1
-
solvent
MTBE
yield (%)
trace
trace
trace
85
er (%)
N.D.
N.D.
N.D.
1
2
3
4
5
6
7
MTBE
MTBE
the presence of Ir(dFCF
3/1) enabled the dearomatization reaction in 98% yield,
furnishing furoindoline 3a with 91:9 er under air (entry 13, Table
). Furthermore, a series of control experiments verified that the
3 2 6
ppy) (bpy)PF and PA1 in DME/hexane
MTBE
85:15 (R)
67:33 (S)
84:16 (S)
85:15 (S)
89:11 (R)
93:7 (R)
N.D.
(
MTBE
79
MTBE
93
1
MTBE
36
chiral phosphoric acid, photocatalyst, light, and air were all
essential components (entries 14-17, Table 1).
[d]
8
MTBE
91
[d]
9
DME
40
Next, several experiments were performed to shed light on
the reaction pathway. Initially, we undertook a series of Stern-
Volmer luminescence quenching experiments. The results
showed that the excited state of the photocatalyst was only
quenched in the presence of tryptophol (1a), suggesting that
SET oxidation of tryptophol was likely the initiation point of the
photoredox catalytic cycle (a, Scheme 2). Subsequent cyclic
[d]
10
11
12
THF
trace
90
[d]
[d]
toluene
88:12 (R)
90:10 (R)
91:9 (R)
N.D.
DME/hexane (3/1)
DME/hexane (3/1)
DME/hexane (3/1)
DME/hexane (3/1)
DME/hexane (3/1)
DME/hexane (3/1)
98
[d,e]
13
98
[d,e,f]
14
trace
trace
trace
trace
[d,g]
15
PA1
PA1
PA1
N.D.
[d,e,h]
16
N.D.
voltammetry experiments further supported single-electron
[d,e,i]
17
N.D.
ox
transfer from tryptophol (E1/2 = +1.06 V vs. Ag/AgCl in CH
3
CN)
ox
[a] Reaction conditions: unless otherwise noted, a solution of 1a (0.1 mmol),
2a' (0.15 mmol), PC (2 mol%) and CPA (10 mol%) in solvent (2.0 mL) was
irradiated by 24 W blue LEDs at room temperature under air for the indicated
time. Cbz = benzyloxycarbonyl, TMCbz = trimethyl-benzyloxycarbonyl, PC =
photocatalyst, CPA = chiral phosphoric acid, MTBE = methyl tert-butyl ether,
THF = tetrahydrofuran, DME = dimethyl ether, N.D. = not determined. [b]
Isolated yield. [c] Determined by HPLC analysis. [d] 2a was used instead of
rather than N-hydroxycarbamate (2a) [E1/2 (2a) = +1.95 V vs.
-
[14]
3
Ag/AgCl in CH CN] to C4* [E1/2(C4*/ C4 ) = +1.32 V vs. SCE]
(
b, Scheme 2). In addition, tryptophol is amenable to undergoing
ox
3
a second SET oxidation (E1/2 = +1.23 V vs. Ag/AgCl in CH CN).
A particularly notable finding was an enhanced peak for the
second SET oxidation when the amount of diphenyl phosphoric
acid was increased (c, Scheme 2). Together with the
2a'. [e] Ir(dFCF
3
ppy)
2
(bpy)PF
6
(0.2 mol%). [f] In the absence of PA1. [g] In the
. [h] In dark. [i] Under argon.
aforementioned control
experiment
demonstrating the
absence of Ir(dFCF
3
ppy)
2
(bpy)PF
6
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Scheme 2. Mechanistic Studies. (a) Stern-Volmer luminescence quenching experiments. (b) Cyclic voltammetry experiments (1a and 2a). (c) Cyclic voltammetry
experiments of 1a with varing amounts of PA (PA = diphenylphosphoric acid). Boc = tert-butylcarbonyl.
Scheme 3. Proposed Mechanism.
-
inhibited the whole reaction without generating any TEMPO-
adducts (eq 1). As a further illustration, no detectable product
intermediate (I) along with the reduced photocatalyst C4 .
-
-
Subsequently, oxidation of C4 [E1/2(C4/C4 ) = -1.37 V vs. SCE]
[
14]
[16]
(
3x) was observed when the reaction between tryptophol (1a)
by molecular oxygen regenerates the ground-state C4 and
•-
and BocNHOH was conducted with MnO as the terminal
2
2
delivers the superoxide anion. Upon deprotonation of I by O ,
[
15]
oxidant (eq 2).
Based on the experimental observations,
mechanism was proposed. As depicted in Scheme 3 (using 1a +
3a as an example), irradiation of photocatalyst
ppy) (bpy)PF (C4) with visible light generates the
CPA-mediated cyclization/second SET oxidation (III→IV→V)
occurs in the presence of photoexcited C4* to afford the
configurationally biased tertiary pyrroloindoline carbocation
intermediate that interacts with chiral phosphate anion via
electrostatic interactions (V). Then, the reduced photocatalyst
a
plausible
2
a →
Ir(dFCF
3
2
6
-
• [16]
-
excited state species C4*, which is a strong oxidant. The
photoexcited C4* species then participates in the first SET
oxidation of tryptophol (1a) to afford the radical cation
C4 is proposed to be oxidized by HO
2
.
The HO
2
is
concomitantly released, followed by protonation to afford H
2
2
O .
Finally, the transient electrophilic species V would be trapped by
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
3 2 6
Scheme 4. Substrate Scope. [a] Reaction conditions: unless otherwise noted, a solution of 1 (0.1 mmol), 2 (0.15 mmol), Ir(dFCF ppy) (bpy)PF (0.2 mol%) and
PA1 (10 mol%) in DME/hexane (3/1) (2.0 mL) was irradiated by 24 W blue LEDs at room temperature under air for 24 h. [b] Isolated yield. [c] Determined by
HPLC analysis. Ac = acetyl. Ms = methylsulfonyl. Ts = 4-methylbenzenesulfonyl.
N-hydroxycarbamate 2a, which might also invoke hydrogen-
bonding interactions with the chiral phosphate anion, to furnish
the optically enriched furoindoline (3a) and complete the CPA
catalytic cycle.
independent synthesis of VI and re-subjecting it to the standard
conditions failed to give any desired product (3a), we could not
fully exclude such an alternative pathway (IV→VI→V). Overall,
the current method provides a mechanistically distinct pathway
towards previously described chemistry involving N-
Notably, on the basis of previous studies, the intermediate
[
11,12,18]
IV might also be intercepted by O
2
to yield the hydroperoxide-
hydroxycarbamates under oxidative conditions.
It also
substituted furoindoline product (VI), which would lead to the
offers
a
novel umpolung strategy, through sequential
[
17]
[19]
same intermediate V with the assistance of CPA.
Although
photocatalytic SET oxidations, to invert the indole derivatives
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
(
maximum emission wavelength = 450 nm). Then the mixture was stirred
from nucleophiles to electrophilic species, which would react in
turn with external nucleophiles.
open to air irradiated by 24 W blue LEDs at room temperature. After the
reaction was complete (monitored by TLC analysis), the solution was
quenched by water and extracted with EtOAc (5 mL × 3). The combined
organic layers were washed with brine, dried over anhydrous Na SO
2 4
and concentrated in vacuo. The residue was purified by column
With these encouraging results in hand, we next explored
the substrate scope for the asymmetric dearomatization
reactions. As shown in Scheme 4, a wide range of differentially
substituted tryptophols were readily converted into their
corresponding furoindolines with moderate to high levels of
enantioselectivity (38-98% yields, 87:13-95:5 er, 3a-3h). It is
worth noting that introducing an EWG group such as -F, -Cl, or -
Br, on the indole core appears more beneficial for
enantioselectivity than that with an EDG group (-Me).
chromatography on silica gel to afford the desired product 3 or 4.
Acknowledgements ((optional))
We thank MOST (2016YFA0202900), the NSFC (21821002 and
2
1801248), the Chinese Academy of Sciences (XDB20000000,
Tryptamines with diverse protecting groups including -CO
2
Me, -
QYZDY-SSW-SLH012), the Youth Innovation Promotion
Association (2019255) of CAS and Shanghai Sailing Program
Cbz, -Boc, -Ac, -SO Ph, and -Ms as well as the indoles bearing
2
an amide side chain were well accommodated in this
transformation. A series of enantioenriched pyrroloindolines
were obtained in 47-97% yields with 90:10-96:4 er (3i-3w). In
addition, the protecting group of hydroxylamine could be
replaced by -Boc, furnishing the desired product 3x in 95% yield
with 92:8 er. The absolute configuration of 3x was determined
by X-ray crystallographic diffraction of its enantiopure sample,
(
18YF1428900) for generous financial support. We also thank
Prof. Wei-Shi Li for assistance with the luminescence quenching
experiments and Prof. Tian-Sheng Mei for assistance with the
cyclic voltammetry experiments. Dr. Yuan-Zheng Cheng thanks
AstraZeneca and Pharmaron for a postdoctoral fellowship.
Keywords: Asymmetric Catalysis• Dearomatization • Indole • N-
hydroxycarbamate • Visible light
[
20]
and those of other products were assigned analogously.
Gratifyingly, this protocol is also applicable to indoles with a
tethered aniline. The intriguing indolo[2,3-b] quinoline skeletons
bearing a fully-substituted quaternary center were constructed in
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4-98% yields with 90:10-93:7 er (4a-4g). In all cases, exclusive
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C-O bond forming selectivity is observed, which was in good
agreement with the suggested mechanism. Considering that
some dearomative products (3a-3d, 3f, 3g, 3i, 3l-3n, 3r, 3u, 3v,
4
b) were unstable, N-protection with -Boc was operated before
[
2]
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final isolation.
Conclusion
In conclusion, we have developed the first catalytic asymmetric
dearomatization reaction of indole derivatives under oxidative
conditions in which indole acts as an electrophile. By taking
advantage of the dual-catalyst system consisting of
a
419; k) J.-B. Chen, Y.-X. Jia. Org. Biomol. Chem. 2017, 15, 3550; l) Y.-
photoredox catalyst and chiral phosphoric acid, the preliminary
mechanisitic studies suggest indole derivatives could be
transformed into the configurationally biased carbocation
intermediates upon two sequential SET oxidations induced by
visible light. The transient electrophilic species reacts in turn with
N-hydroxycarbamates, resulting in a wide range of structurally
diverse and optically active oxy-amine-tethered fused indolines.
Further applications of this strategy in novel asymmetric
dearomatization reactions are currently underway in our
laboratory.
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Experimental Section
General procedure for asymmetric dearomatization of indole
derivatives with N-hydroxycarbamates. To a Schlenk tube equipped
with a rubber septum and magnetic stir bar were added 1, 2, PA1, and
3 2 6
Ir(dFCF ppy) (bpy)PF . DME/hexane (3/1) was added, and the Schlenk
tube was positioned approximately 10 cm from 24 W blue LEDs
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
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Angewandte Chemie International Edition
10.1002/anie.201911144
RESEARCH ARTICLE
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Yuan-Zheng Cheng, Qing-Ru Zhao,
Xiao Zhang,* and Shu-Li You*
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Asymmetric Dearomatization of
Indole Derivatives with N-
Hydroxycarbamates Enabled by
Photoredox Catalysis
Dearomatization of indoles and their derivatives provides efficient synthetic routes for substituted indolines. In most cases, indoles
serve as nucleophiles by reacting with electrophiles at the C3 position. Herein, we report an asymmetric dearomatization reaction of
indole derivatives that function as electrophiles. The combined utilization of photocatalyst and chiral phosphoric acid in air unlocks the
umpolung reactivity of indoles, enabling enantioselective dearomatization of indole derivatives with N-hydroxycarbamates as
nucleophiles.
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