Photocatalytic Synthesis of Polycyclic Indolones

Article abstract of DOI:10.1002/chem.202001324

In this work, a photocatalytic strategy for a rapid and modular access to polycyclic indolones starting from readily available indoles is reported. This strategy relies on the use of redox-active esters in combination with an iridium-based photocatalyst under visible-light irradiation. The generation of alkyl radicals through decarboxylative single electron reductions enables intramolecular homolytic aromatic substitutions with a pending indole moiety to afford pyrrolo- and pyridoindolone derivatives under mild conditions. Furthermore, it was demonstrated that these radicals could also be engaged into cascades consisting of an intermolecular Giese-type addition followed by an intramolecular homolytic aromatic substitution to rapidly assemble valuable azepinoindolones.

Full text of DOI:10.1002/chem.202001324

Accepted Article
Accepted Article
Title: Photocatalytic Synthesis of Polycyclic Indolones
Authors: Tanguy Saget and Burkhard König
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Chemistry - A European Journal
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Photocatalytic Synthesis of Polycyclic Indolones
Tanguy Saget*[a,b] and Burkhard König*[b]
In memory of Professor Rolf Huisgen
Abstract: We report herein a photocatalytic strategy for a rapid and
modular access to polycyclic indolones starting from readily
available indoles. This strategy relies on the use of redox-active
esters in combination with an iridium-based photocatalyst under
visible light irradiation. The generation of alkyl radicals through
decarboxylative single electron reductions enables intramolecular
homolytic aromatic substitutions with a pending indole moiety to
afford pyrrolo- and pyridoindolone derivatives under mild conditions.
Furthermore, we demonstrated that these radicals could also be
engaged into cascades consisting of an intermolecular Giese-type
addition followed by an intramolecular homolytic aromatic
substitution to rapidly assemble valuable azepinoindolones.
Over the last decade, photoredox catalysis has emerged as a
powerful tool for organic synthesis allowing the generation of
reactive free radical species under mild conditions and from
simple precursors.6 Notably, photoredox catalysis can be an
efficient tool for indole functionalization.7 Redox-active esters
such as N-acyloxyphthalimides (NAPs) are versatile precursors
of alkyl radicals through single-electron reduction followed by
decarboxylation.8 In particular, NAPs have been used in
photocatalytic Minisci-type reactions to generate nucleophilic
alkyl radicals which reacts with electron deficient heterocycles
such as pyridines or (iso)quinolines.9 However, NAPs have
rarely been applied to the functionalization of electron rich
heterocycles like indoles.10 We reasoned that an intramolecular
cyclization could overcome the mismatch polarity of radicals with
a nucleophilic character reacting with electron-rich aromatics.
To this purpose, we studied the use of NAPs 2 derived from
carboxylic acids obtained from the reaction of indoles and
commercially available cyclic anhydrides (Scheme 2a). We
expected these NAPs to undergo a single-electron transfer with
an excited reducing photocatalyst leading to alkyl radical 3 after
fragmentation followed by decarboxylation. Radical 3 would then
Indoles are prevalent motifs in bioactive natural products and
pharmaceuticals.1 Therefore, the development of methods for
the synthesis of functionalized of indoles under mild conditions is
an important task in synthetic chemistry.2 In this respect,
catalytic transformations enabling the direct functionalization of
indole C-H bonds are particularly valuable because they afford
complex indole structures with an excellent step and atom-
economy.3 We report herein a catalytic access to diverse
polycyclic indolones starting from cheap and readily available
indole precursors (Scheme 1). Importantly, such indolone motifs
undergo
a 5-exo-trig cyclization leading to dearomatized
intermediate 4 which after oxidation and proton elimination
would afford indolone product 6 (Scheme 2b).
4
are found in a range of indole alkaloids and are valuable
intermediates in the total synthesis of related natural products.5
Scheme 1. A photocatalytic strategy to access valuable polycyclic indolones.
[
[
a]
b]
Dr. T. Saget
Scheme 2. Catalytic cycle of the envisaged strategy.
Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
Univ. Paris-Sud, Université Paris-Saclay
We studied the feasibility of the envisioned process with
substrate 2a, readily accessed in two steps from indole and
succinic anhydride. We first evaluated the use of organic dyes
1
, av. de la Terrasse, 91198 Gif-sur-Yvette (France)
tanguy.saget@cnrs.fr
Dr. T. Saget, Prof. Dr. B. König
Institut für Organische Chemie
Universität Regensburg
Universitätsstrasse 31, Germany
Burkhard.Koenig@chemie.uni-regensburg.de
11
as photocatalysts. When 2a was reacted with 5 mol% of
commonly used 4-CzIPN12 (PC1, E = -1.04 V vs. SCE) in
DMSO under blue light irradiation, a small amount of 6a could
be detected but most of the crude mixture consisted of
red
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unreacted starting material (Table 1, entry 1). Given the highly
red
negative reduction potential of NAPs (E = -1.3 V vs. SCE), we
reasoned that a more reducing photocatalyst would facilitate a
photoinduced electron transfer (PET) to the substrate, thus
increasing the conversion of 2a. To this purpose we performed
Table 2. Optimization of a one-pot protocol starting from 7a.
the reaction in the presence of PC2,
a highly reducing
phenoxazine photocatalyst recently developed by Miyake and
red*
13
coworkers (E
= -1.93 V vs. SCE). Pleasingly, the yield of 6a
significantly increased to 58% (entry 2). Based on these results,
Entry
Coupling agent
Additive
Isolated yield
25%
red*
we then further evaluated fac-Ir(ppy)
3
(E
= -1.73 V vs. SCE)
1
2
3
DCC
DIC
DIC
-
which proved to be a very efficient photocatalyst for the targeted
transformation leading to 6a in 67% isolated yield (entry 3). The
use of other common solvents such as DMA or DMF was
detrimental (entry 4-5). Of note, the presence of up to ten
equivalents of water does not affect the yield of the reaction so
technical grade DMSO could be used as solvent for this study
-
66%
DMAP (10 mol%)
53%
General conditions: i) 7a (0.25 mmol), NPht-OH (0.25 mmol) and coupling
agent (0.25 mmol) in THF (0.2M) for 16h; ii) fac-Ir(ppy) (1 mol%) in 5 mL of
DMSO (0.05 M) under a N atmosphere with 455 nm light irradiation for 8 h.
NPht-OH = N-hydroxyphtalimide; DCC = dicyclohexylcarbodiimide; DIC =
diisopropylcarbodiimide; DMAP = 4-dimethylaminopyridine.
3
2
(
entry 6). Furthermore, a control experiment revealed that the
photocatalyst is required to observe the desired reactivity (entry
). Finally, the use of a reduced catalyst loading (0.5 mol%) led
7
to a similar yield after 14h (entry 8).
Table 1. Optimization of the decarboxylative cyclization.
Entry
PC
Solvent
DMSO
Yielda
12%
1
2
3
4
5
6
7
8
PC1 (5 mol%)
PC2 (5 mol%)
PC3 (1 mol%)
PC3 (1 mol%)
PC3 (1 mol%)
PC3 (1 mol%)
-
DMSO
58%
87% [67%]b
DMSO
DMA
70%
DMF
55%
DMSO (10 eq. H
2
O)
88%
DMSO
<3%
PC3 (0.5 mol%)
DMSO
88%
General conditions: 2a (0.1 mmol) and PC in 2 mL of solvent (0.05 M) under a
atmosphere with 455 nm light irradiation for 14 h. [a] Yield determined by
GC-FID with an internal standard. [b] Isolated yield on a 0.25 mmol scale.
DMSO dimethylsulfoxide; DMA dimethylacetamide; DMF
dimethylformamide.
N
2
=
=
=
With optimal conditions in hand to promote the desired
cyclization, we developed a more efficient one-pot protocol
enabling the synthesis of indolone 6a starting directly from
carboxylic acid 7a. To this purpose, we investigated the use of
coupling agents such as dicyclohexylcarbodiimide (DCC) and
diisopropylcarbodiimide (DIC) (Table 2, entry 1-2). Pleasingly,
the use of DIC led to a similar yield when compared to our
previously optimized two-step protocol (entry 2). The low yield
obtained with DCC may be due to the formation of a poorly
Scheme 3. Scope of the reaction.
The scope of the reaction was then evaluated with a range of
different anhydrides and indole derivatives (Scheme 3).
Substrates derived from several succinic anhydrides and leading
to the formation of primary, secondary and tertiary radicals
afforded the desired pyrroloindolones 6a-d in good overall
yields. Importantly, compounds 6b and 6c were obtained as
soluble dicyclohexylurea byproduct which might prevent
a
sufficient light penetration into the reaction medium. Of note, the
addition of a catalytic amount of DMAP for the coupling was
detrimental to the overall process (entry 3).
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single diastereoisomers. Pleasingly, substrates 7e-g derived
from glutaric anhydrides also led to the formation of
pyridoindolones through a cyclisation step which then occurs via
a 6-exo-trig addition. Then, a variety of indoles with different
substitution patterns were also evaluated for this process.
Substrates bearing both electron-withdrawing and electron-
donating groups were successfully implemented in our
methodology as shown with indolones 6h-v. The use of
chlorinated and brominated indoles led to the desired indolones
pyrroloindolones could be detected.20 This strategy allowed us to
access valuable azepinoindolones 13a-f in moderate to good
yields (Scheme 5b).
6m-o uneventfully and allow for further modifications through
cross-coupling reactions. A pyrrole-derived substrate was also
competent for this process as shown with 6p. Finally, a range of
3
-substituted indoles could be used to access indolones 6q-v.
Notably, several complex substrates derived from tryptamine,
melatonine and tryptophan were successfully transformed into
valuable indolones 6t-v in good yields. The structure of 6v was
unambiguously confirmed by X-ray crystallographic analysis.14
Scheme 5. Synthesis of azepinoindolones.
In summary, we have developed a photocatalytic C-H alkylation
strategy mediated by visible light that provides an efficient
access to a variety of relevant polycyclic indolones. The reaction
is scalable and the indolone products can be further used as
valuable synthetic intermediates to access other important
scaffolds such as pyrroloindoles and (pyrrolo)indolines. Finally,
the development of a challenging two-component process
enabled the straightforward synthesis of functionalized
Scheme 4. Gram-scale reaction and synthetic applications.
To showcase the scalability of the process, we performed a
gram-scale reaction using 4.25 mmol of 2q and a reduced
catalyst loading of only 0.2 mol% without impacting the outcome
of the reaction (Scheme 4). Then, to further demonstrate the
utility of this method we performed some transformations on
compounds 6 to prove their versatility as synthetic intermediates.
azepinoindolones. We expect this methodology to find
a
widespread use in the synthesis of indole-containing natural
products and bioactive compounds.
First, 6q was reduced with borane to access in a single step the Acknowledgements
pyrroloindole scaffold (see 8) which is found is many bioactive
15
16
compounds, including the flinderole alkaloids and many
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme under the
European Research Council (ERC) grant agreement No. 741623
17
pharmaceutically relevant small molecules. Importantly, 6q
could also be selectively hydrogenated with a catalytic amount
of palladium on charcoal to access the important indoline
scaffold quantitatively (see 10). Then, the indolone moiety was
also reacted with soft nucleophiles to afford C2-alkylated free
indoles as exemplified with compound 9. Finally, electrophilic
bromination of compound 6v led to complex pyrroloindoline 11
(B.K.) and the Marie Skłodowska-Curie grant agreement No.
838108 (T.S.).
which is reminiscent of many naturally occurring alkaloids Conflict of interest
18
exhibiting a diverse range of biological activities.
The commercial availability of many succinic and glutaric
anhydrides enabled us to efficiently synthesize a range of
pyrrolo- and pyridoindolones using our methodology. However,
the scarce availability of adipic anhydrides, prevented us to
The authors declare no conflict of interest.
access the valuable azepinoindolone scaffold.4a-b,19 To Author contributions
circumvent this issue, we envisaged to intercept radical 3 with
an external olefin to access radical 12 which would then add to
T. S. developed the project, optimized the reaction, prepared the
the indole moiety to afford azepinoindolone 13 as described in
Scheme 5a. As an inherent challenge to this strategy, the
intermolecular Giese-type addition to the olefin must be
kinetically favored over the intramolecular 5-exo-trig cyclization
to the indole. After some experimentation, we discovered that
the use of acrylonitrile as a trapping olefin efficiently led to the
desired azepinoindolones while only traces of the corresponding
substrate scope and the manuscript. B. K. supervised the project
and the preparation of the manuscript.
Keywords: Photoredox catalysis • Visible light • Indoles • C-H
functionalization • Indolones
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Chemistry - A European Journal
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COMMUNICATION
A
variety of indoles were readily
Tanguy Saget, Burkhard König*
transformed into valuable polycyclic
indolones using a photocatalytic C-H
alkylation strategy. The use of redox-
active esters in combination with a
reducing photocatalyst enabled the
smooth generation of alkyl radicals
1 – 5
Modular Synthesis of Polyclic
Indolones via a Photocatalytic C-H
Alkylation Strategy
which
could
undergo
an
a
intramolecular cyclization via
homolytic nucleophilic substitution
pathway. The obtained indolones are
useful synthetic intermediates for the
synthesis of bioactive compounds.
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