Photoredox Catalysis toward 2-Sulfenylindole Synthesis through a Radical Cascade Process

Article abstract of DOI:10.1021/acs.orglett.0c01297

A radical cascade process initiated through visible-light induced thiyl radical coupling with ortho-substituted arylisocianides followed by an intramolecular cyclization and subsequent aromatization to access 2-sulfenylindoles is described. The key thiyl radicals are promptly generated via a hydrogen atom transfer event. The redox-neutral protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions. Furthermore, the implementation of a continuous flow variant allows smooth scalability with a short residence time through process intensification.

Full text of DOI:10.1021/acs.orglett.0c01297

pubs.acs.org/OrgLett
Letter
Photoredox Catalysis toward 2‑Sulfenylindole Synthesis through a
Radical Cascade Process
Marilia S. Santos, Hugo L. I. Betim, Camila M. Kisukuri, Jose Antonio Campos Delgado,
̂
́
̃
Arlene G. Correa, and Marcio W. Paixao*
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ABSTRACT: A radical cascade process initiated through visible-
light induced thiyl radical coupling with ortho-substituted
arylisocianides followed by an intramolecular cyclization and
subsequent aromatization to access 2-sulfenylindoles is described.
The key thiyl radicals are promptly generated via a hydrogen atom
transfer event. The redox-neutral protocol features broad substrate
scope, excellent functional group tolerance, and mild reaction
conditions. Furthermore, the implementation of a continuous flow
variant allows smooth scalability with a short residence time
through process intensification.
Fukuyama and co-workers6 encompassing radical isocyanide
he indole motif has been recognized as a privileged
Tframework frequently found in biologically active natural insertion followed by an intramolecular cyclization is still
products, agrochemicals, and pharmaceuticals.1 In particular,
attractive. Although the efficiency of this cascade strategy is
recognized, the radical generation often requires stoichiometric
amounts of a radical initiator (e.g., AIBN and SnBu4 among
others), which denotes that the approach was neither
environmentally friendly nor broad-functional group compat-
ible, justifying the search for alternative methods for radical
generation.7
Over the past decade, visible-light-induced photoredox
catalysis has emerged as a greener strategy to generate radicals
under mild reaction conditions.8 Accordingly, progress in
understanding reaction mechanisms and the properties of
photogenerated reactive intermediates has enabled photo-
catalytic construction of heterocycles and late-stage function-
alization.9 As a result, highly functionalized N-heterocycles
including indole-based scaffolds have been synthesized via
visible-light-mediated radical isocyanide insertion.10
Recently, an interesting visible-light promoted radical
cascade addition/cyclization protocol was reported toward
the construction of 2-thioarylated indole-3-glyoxylate deriva-
tives using of the iridium complex as photocatalyst and diaryl
disulfides.11 Additionally, photoredox catalysis has also been
applied in the synthesis of sulphenylated indoles under mild
reaction conditions.12 Although several methodologies have
this chemical architecture is present in almost 7% of the US
FDA approved drugs, consequently standing as one of the
most prevalent five-membered nitrogen-based heterocycles.2
Moreover, a structural analysis reveals that the majority of
these indole-based drugs predominantly possess functionaliza-
tion at the C3 and C5 positions, followed by the C2 position.
Recently, sulfenylindoles and derivatives have attracted more
attention due to their pronounced biological and pharmaceut-
ical activities, e.g. anti-inflammatory, antitumoral and antiviral
(Figure 1).3
Therefore, methods that enable selective functionalization or
efficient synthesis of sulfur-containing indole derivatives have
been pursued.4
Among the vast array of described methods for assembling
functionalized indoles5 the initial report disclosed by
Received: April 13, 2020
Figure 1. Selected examples of biologically active compounds
containing the sulfenylindole scaffold and derivatives.
https://dx.doi.org/10.1021/acs.orglett.0c01297
© XXXX American Chemical Society
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Letter
demonstrated success in obtaining S-aryl indoles,13 scarce
reports for the assembly of S-alkyl indols has been unveiled.
In considering complementary strategies to promote the
construction of sulfur-containing indole framework, an
alternative photoredox catalytic reaction to promote its
construction was envisioned.
As part of our research program on visible-light-promoted
radical cascade reaction in the synthesis of nitrogen-containing
heterocycles14 we herein report a general photocatalytic
approach to highly substituted 2-sulfenylindoles through
radical thiyl insertion to isocyanides where the thiyl radical
generation occurs from thiols under the already described
photoredox condition (Scheme 1).
previously applied in the visible-light photocatalytic thiol−ene
reaction, and they are distinguishable mainly by the photo-
catalyst and solvent of choice (Table 1, entries 1−5).
Delightfully, when the photocatalytic condition previously
described by Yoon15 and co-workers for thiyl radical
generation were applied, the expected cascade product 3 was
obtained in 43% yield (entry 1). The described condition
employs [Ru(bpy)3](PF6)2 as the photocatalyst and p-
toluidine as electron-transfer mediator in DMSO under blue
LED radiation. Moreover, the compatibility of distinctive
photochemical protocols, for the thiyl radical generation, has
been further evaluated for this cascade annulation strategy
(Table 1, entries 2−5). Nonetheless, neither of these strategies
delivered the desired 2-sulfenylindole as efficiently as the
previous methodology (entry 1 vs entries 2−5, see the
Supporting Information for procedure details). After a set of
experiments, we focused on fine tuning the reaction conditions
presented in entry 1; first, by decreasing the photocatalyst
loading to 1 mol %, only a slight erosion in efficiency was
observed, with the desired product being obtained in 40% yield
(Table 1, entry 6). Furthermore, the solvent system was
completely degassed, and the photocatalytic radical cascade
reaction gave the indole-derivative in 60% yield (Table 1, entry
7). Fortunately, when the amount of benzenethiol was
increased to 1.2 equiv, the compound 3 could be obtained
in 70% yield (Table 1, entry 8). Next, a series of solvents were
screened (see the Supporting Information), and DMSO gave
the optimal result. We further consider whether the photo-
catalytic cascade triggered by thiyl radical could be accessed
using phenyl disulfide as the radical precursor. However, the
product was obtained in low yields under our conditions. This
result corroborates with the proposed reductive quenching
cycle of the photocatalyst, which precludes the reduction of the
disulfide for generation of thiyl radical (entry 9).
Scheme 1. Photoredox Approach for the Synthesis of 2-
Sulfenylindole via Photoredox Catalysis
Our optimization study began with the reaction using 1-
isocyano-2-styryl acetate (1a) and benzenethiol (2) as model
substrates (Table 1). We first examined some conditions for
thiyl radical generation.12,14−18 Such approaches have been
Table 1. Optimization of the Reaction Conditions
Aiming to gain insights into the reaction mechanism of the
photocatalytic-induced cascade reaction, we performed some
additional experiments. When a radical trap such as TEMPO
was added to the system, a complete inhibition of the reaction
was observed, strongly suggesting a radical pathway for this
transformation (entry 10). Accordingly, control experiments
reveal that there was no conversion either in the absence of
visible-light irradiation or photocatalyst (entries 12 and 13).
Finally, low conversion was observed in the absence of p-
toluidine, a Brønsted base co-catalyst (entry 11).
With the optimized reaction conditions in hand, we turned
our attention to evaluating the scope and limitation of our
cascade protocol toward a range of thiols and isocyanides. To
our satisfaction, the optimized reaction conditions were found
to be generally applicable for aromatic thiols bearing diverse
electronic properties (Scheme 2, compounds 3−11). The
reaction tolerated halogen, carboxylic acid and hydroxyl
groups in the aromatic rings. The electronic effect of these
substituents was not initially found to be problematic.
However, the methodology has demonstrated limitations
regarding aniline derivatives containing thiols affording the
corresponding products in poor yields (Scheme 2, compound
9). In addition, the redox-neutral photocatalytic protocol was
shown to be compatible with 2-mercaptopyrimidinea
heteroaryl framework present in biorelevant moleculesyielding
the corresponding indole scaffold 10 in 43% yield. Moreover,
5-(difluoromethoxy)-2-mercapto-1H-benzimidazole did not
interfere with the cascade reaction, although the desired
indole was obtained in low yield (Scheme 2, compound 11,
a
b
entry
1
photocatalyst
additive
solvent
yield (%)
[Ru(bpy)3](PF6)2
eosin Y
rose bengal
pyrylium salt
acetophenone
DMSO
CH3CN
DCM
CH3CN
THF
43
traces
18
traces
22
c
2
3
4
5
d
e
d
Deviation from the Optimal Conditions (Entry 1)
f
6
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
p-toluidine
p-toluidine
p-toluidine
p-toluidine
p-toluidine
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
40
60
70
26
0
fg
7 ,
fh
8
9
i
j
10
11
12
13
18
0
p-toluidine
p-toluidine
k
[Ru(bpy)3](PF6)2
0
a
Unless otherwise mentioned, reactions were performed in a 0.1
mmol scale; using 1 equiv of 1a, 1 equiv of 2a, 5 mol % of
photocatalyst, and 0.5 equiv of p-toluidine in 0.5 mL of solvent under
blue LED irradiation (see the SI for details). Yields were determined
by H NMR analysis of the crude mixture relative to an internal
standard. Green LEDs were used as radiation source (7 W).
Reaction was performed with two household bulbs (2 × 24 W).
Reaction was conducted using 2,4,6-tri(p-tolyl)pyrylium tetrafluor-
oborate salt as photocatalyst. Reaction was conducted using 1 mol %
of [Ru(bpy)3](PF6)2 as photocatalyst. Degassed solvent and argon
atmosphere. 1.2 equiv of 2a. Reaction was performed using 1.2
equiv of phenyl disulfide as thiyl radical precursor. Reaction was
performed in the presence of TEMPO. Reaction was performed in
the absence of light.
b
1
c
d
e
f
g
h
i
j
k
B
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a
Scheme 2. Substrate Scope with Varied Thiols and Isocyanides
a
Unless otherwise stated, reactions were conducted in a 0.10 mmol scale under argon atmosphere. Isolated yields are shown below the structure of
products (Supporting Information gives the experimental details: 0.1 mmol of 1a−g, 0.12 mmol of 2a−r, 1 mol % of photocatalyst, 0.05 mmol of p-
toluidine, 0.5 mL of degassed DMSO under blue LEDs radiation).
37% yield). However, under the optimized reaction conditions,
the radical annulation employing mercaptobenzothiazole and
mercaptobenzoxazole occurred in a small extent or did not
proceed. Thus, these substrates currently represent a limitation
of the described methodology (compounds 12 and 13).
We also tested the effectiveness of the protocol for a variety
of alkyl thiols, and some examples worked better than aryl
thiols. To our delight, aliphatic thiols, including benzylic,
cyclic, acyclic, and short and long chain, could be used
(compounds 14−20).
Scheme 3. Reaction Scope: Synthesis of 2-sulfenylindoles
from biomolecules
a
We next sought to explore the generality of this method-
ology with respect to the isocyanide partner (Scheme 2,
compounds 21−28). To this end, a variety of 2-alkenylar-
ylisocyanides were synthesized to explore the efficiency of this
method. Both electron-donating and -withdrawing groups
attached at altered positions of the aromatic ring in the
isocyanide 1a were tolerated, affording the corresponding
indole in good yields (compounds 24 and 25). Furthermore,
isocyanide partners bearing other substituents such as phenyl,
nitrile, and amide, performed well (compounds 26−28).
Given the broad generality and operational simplicity of this
photocatalytic cascade protocol triggered by the thiyl radical,
we intended to explore the application of the methodology to
late-stage diversification of highly functionalized biomolecules
(Scheme 3). At first, the photoinitiated cascade protocol was
then extended to glycosyl thiol for the synthesis of a hybrid
molecule containing both the indole and saccharide rings
(compound 29, 58% yield). Nonetheless, arabinosyl-6-
mercaptopurine was shown to be an excellent thiyl radical
precursor under the optimized reaction conditions, furnishing
a
Unless otherwise stated, reactions were conducted in a 0.10 mmol
scale under argon atmosphere. Isolated yields are shown below the
structure of products (Supporting Information gives the experimental
details: 0.1 mmol of 1, 0.12 mmol of 2s−v, 1 mol % of photocatalyst,
0.05 mmol of p-toluidine, 0.5 mL of degassed DMSO under blue
LEDs radiation).
the corresponding indole-derivative in high efficiency (com-
pound 30, 76% yield). Moreover, the redox-neutral photo-
catalytic method exhibits good tolerance to S-containing amino
acids. The reaction between N-Boc-cysteine-OMe and the
ortho-substituted arylisocyanide 1a readily underwent radical
C
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Letter
addition/cyclization to provide a new amino acid 31 in 60%
yield.
Scheme 5. Proposed Reaction Mechanism
We were pleased to find that the tripeptide glutathione was
compatible under the standard photocatalytic condition,
affording the desired indole-containing tripeptide 32 in 53%
yield. It can be anticipated that the unique features of this
photoredox-mediated radical cascade protocol would also
enable further exploration in both polypeptide cross-linking
and antibody−drug conjugation.19
Recognizing the potential value of these thiol-containing
indoles to the synthetic and pharmaceutical communities, we
envisioned exploring the scale-up potential of this method-
ology by utilizing microreactor technology. It is noteworthy
that besides efficiency of mass, energy, and electron transfer,
the continuous flow process offers other benefits, namely safety
and precision, therefore allowing process intensification.20
To this end, the designed flow setup was assembled
employing two syringe pumps, fluorinated ethylene propylene
(FEP) as capillary material, T-mixer, and a glass microreactor
chip placed between two 36 W blue LEDs light (see the
Supporting Information for details).
Gratifying, we observed that a residence time (tR) of 5 min
was adequate to achieve complete conversion of the isocyanide
intermediate delivering the desired product in 63% yield (for
comparison: under batch conditions, 3 h reaction time, 70%
yield). Moreover, by employing the continuous-flow setup, 3.5
mmol of starting material could be continuously converted into
the indole derivative around 7 h (2.13 mmol; 660 mg),
exhibiting the same selectivity compared to the batch process
(Scheme 4).
abstraction (HAT) eventcould oxidize the thiol, therefor
generating the thiyl radical (Scheme 5). Next, the thiyl radical
addition onto the isocyanide VI triggers a chemo- and
regioselective radical cascade process, producing the imidoyl
radical (VII). The intermediate radical further undergoes 5-
exo-trig cyclization to produce the α-carbonyl radical (VIII),
which is then quenched by the reduced photocatalyst to
produce the carbanion IX and regenerate the catalyst Ru2+ to
complete the photoredox cycle. Ultimately, IX could be easily
protonated to generate the final S-containing indole product X.
Regarding the reaction with arylthiols, it is not possible to
exclude the potential presence of benzenethiolate in the
reaction media; for that case, the mechanism could start after
an electron transfer from thiolate to the *Ru2+. The quenching
of the photoexcited catalyst leads to the generation of thiyl
radical which could be intercepted by the isocyanide.22
Scheme 4. Continuous Flow Synthesis of the Indole
Derivative and Synthetic Transformation
In summary, we have developed a highly efficient visible-
light-mediated radical cascade reaction which provides access
to a range of highly S-functionalized indoles in a sustainable
perspective. Because of the distinct way of generating the thiyl
radical, our approach should be seen as an alternative
methodology to Reiser’s work,11 which allows the synthesis
of 2-thioindoles with different architectures. This operationally
simple methodology was shown to be compatible with both
aromatic and aliphatic thiols. Furthermore, many sensitive
functional groups were tolerated, therefore enabling the
application of late stage functionalization of S-containing
biomolecules. This mild and versatile strategy offers a
complementary alternative to the previous reported method-
ologies. Under the continuous-flow regime, we have demon-
strated the scalability of our methodology with a residence
time of 5 min through process intensification. Further studies
on the applications of this methodology are underway.
On the basis of literature precedents by Yoon’s group and
those outlined in our optimization (Table 1), a reaction
mechanism was proposed (Scheme 5). Upon excitation with
visible light, the ground-state photocatalyst Ru2+ is promoted
to oxidizing the metal-to-ligand charge transfer (MLCT)
excited state (*E1/2*
II/I = +0.77 V vs SCE)21 which undergoes
ASSOCIATED CONTENT
* Supporting Information
■
reductive quenching with the Brønsted base p-toluidine (E0 =
+0.72 V),12 affording reduced form of the photocatalyst Ru+
along with the generation of an aniline radical cation. Then,
the aminium radical cationthrough a hydrogen atom
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01297.
D
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
́
Marcio W. Paixa
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao Carlos, Sao Carlos, SP
̃
o − Center of Excellence for Research in
̃
̃
13565-905, Brazil; orcid.org/0000-0002-0421-2831;
Email: mwpaixao@ufscar.br
Authors
Marilia S. Santos − Center of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao Carlos, Sao Carlos, SP
̃ ̃
13565-905, Brazil
Hugo L. I. Betim − Center of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao Carlos, Sao Carlos, SP
̃ ̃
13565-905, Brazil
Camila M. Kisukuri − Center of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
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Chemistry, Federal University of Sao Carlos, Sao Carlos, SP
̃ ̃
13565-905, Brazil
Jose Antonio Campos Delgado − Center of Excellence for
Research in Sustainable Chemistry (CERSusChem),
Department of Chemistry, Federal University of Sao
Sao Carlos, SP 13565-905, Brazil
̃
Carlos,
̃
̂
Arlene G. Correa − Center of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao Carlos, Sao Carlos, SP
̃ ̃
13565-905, Brazil; orcid.org/0000-0003-4247-2228
̂
M.; Narayanaperumal, S.; Correa, A. G.; Paixao, M. W. Eur. J. Org.
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Chem. 2013, 2013, 5917−5922. For reviews, see: (j) Inman, M.;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01297
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful to CNPq (INCT Catalise), FAPESP (14/
50249-8, 15/17141-1, 17/03120-8, and 18/12986-1) for
■
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3080−3082. (b) Yamazaki, O.; Togo, H.; Matsubayashi, S.;
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financial support. GSK is also acknowledged for the financial
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T. P. Science 2016, 354, 1391−1395. (b) Tay, N. E. S.; Nicewicz, D.
A. J. Am. Chem. Soc. 2017, 139, 16100−16104. (c) Ghosh, I.; Shaikh,
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(CAPES) - Finance Code 001.
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