The Different Faces of [Ru(bpy)3Cl2] and fac[Ir(ppy)3] Photocatalysts: Redox Potential Controlled Synthesis of Sulfonylated Fluorenes and Pyrroloindoles from Unactivated Olefins and Sulfonyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.0c02760

A cascade alkene sulfonylation that simultaneously forges C-S and C-C bonds is a highly efficient and powerful approach for directly accessing structurally diverse sulfonylated compounds in a single operation. The reaction was enabled by visible-light-mediated regioselective radical addition of sulfonyl chlorides to 2-arylstyrenes using fac[Ir(ppy)3] as a photocatalyst, demonstrating its unique role in a photocascade process to execute atom transfer radical addition (ATRA) followed by photocyclization. A new class of sulfonyl-substituted fluorenes and pyrroloindoles, which are useful in the field of photoelectronic materials and medicinal chemistry, was produced in excellent yields by this photocascade reaction. In contrast, the cyclization was interrupted when using the [Ru(bpy)3Cl2] catalyst having lower reduction potential, leading only to the formation of a C-S bond and the production of acyclic sulfonylated 2-arylstyrenes under identical reaction conditions. The synthetic utility of the present room-temperature photocatalysis is enhanced by the broad availability of bench-stable sulfonyl chlorides and unactivated olefins, thereby providing a cost-effective and broad-scope protocol.

Full text of DOI:10.1021/acs.orglett.0c02760

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Letter
The Different Faces of [Ru(bpy)3Cl2] and fac[Ir(ppy)3] Photocatalysts:
Redox Potential Controlled Synthesis of Sulfonylated Fluorenes and
Pyrroloindoles from Unactivated Olefins and Sulfonyl Chlorides
Santosh K. Pagire, Naoya Kumagai,* and Masakatsu Shibasaki*
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ABSTRACT: A cascade alkene sulfonylation that simultaneously forges
C−S and C−C bonds is a highly efficient and powerful approach for
directly accessing structurally diverse sulfonylated compounds in a single
operation. The reaction was enabled by visible-light-mediated regiose-
lective radical addition of sulfonyl chlorides to 2-arylstyrenes using
fac[Ir(ppy)3] as a photocatalyst, demonstrating its unique role in a
photocascade process to execute atom transfer radical addition (ATRA)
followed by photocyclization. A new class of sulfonyl-substituted
fluorenes and pyrroloindoles, which are useful in the field of
photoelectronic materials and medicinal chemistry, was produced in
excellent yields by this photocascade reaction. In contrast, the cyclization
was interrupted when using the [Ru(bpy)3Cl2] catalyst having lower reduction potential, leading only to the formation of a C−S
bond and the production of acyclic sulfonylated 2-arylstyrenes under identical reaction conditions. The synthetic utility of the
present room-temperature photocatalysis is enhanced by the broad availability of bench-stable sulfonyl chlorides and unactivated
olefins, thereby providing a cost-effective and broad-scope protocol.
Scheme 1. State-of-the-Art: Representative Routes to
Fluorenes
ver the past few decades, fluorenes and pyrroloindoles
Owere identified as important building blocks for
synthetic, medicinal, and materials chemistry because of their
unique physical, chemical, and biological properties.1 Fluorene,
in particular, is a promising skeletal structure2 that is widely
used for manufacturing advanced materials,3 biologically and
pharmaceutically important compounds,4 ligands, as well as
unique protecting groups.5 To date, a number of research
groups exploring various synthetic strategies to access such
fused tricyclic systems have revealed transition-metal-cata-
lyzed/mediated reactions6 or Friedel−Crafts alkylations
promoted by Brønsted/Lewis acids.7 Despite the various
advantages of these conventional synthetic methods,8 recent
advances in this field identified the utility of radical reactions
with olefins as a more attractive tool9 that allows for the direct
use of unactivated and less engineered starting materials
(Scheme 1).10 Classical approaches,11 however, generally
require peroxides as a radical initiator and elevated temper-
atures,12 which severely limits their practical applications.13 We
reasoned that the recently emerging visible-light photocatalysis
could be strategically exploited for this purpose to promote
radical processes under sustainable and mild conditions.14 To
the best of our knowledge, radical-mediated synthesis of
fluorenes has rarely been explored.10a We anticipated that
photoredox sulfonylation using sulfonyl chlorides would be
suitable for integration into unactivated olefins,15 where a
sulfur-centered radical16 would play a pivotal role in
Received: August 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02760
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
constructing the requisite tricyclic systems with a resulting
pendant sulfone functionality. Arylsulfonyl chlorides are
inexpensive, bench-stable solids with many derivatives readily
available. The biological activity and/or physical properties of
the resulting organic compounds can be significantly enhanced
by the introduction of a sulfur group.17 Sulfonyl-containing
polycyclic compounds, in particular, have extensive applica-
tions in synthesis, agrochemical industries, and pharmaceut-
icals.18 Thus, sulfonylative construction of fluorenes warrants
further development. Herein, we report an efficient photo-
cascade protocol19 toward the synthesis of sulfonylated
fluorenes and pyrroloindoles, which is operationally simple
and works under mild and neutral conditions.
According to previous reports,24 the sulfonylation reaction is
expected to proceed via an atom-transfer radical addition
(ATRA)25 to form key intermediate I (Figure 1).24a Under the
Given the wide availability of industrially produced p-
toluenesulfonyl chloride 1a (TsCl), we initiated our studies by
investigating the reaction using 1a in combination with readily
prepared 2-phenyl-α-methylstyrene 2a. We first attempted to
perform the reaction with Na2CO3 in anhydrous CH3CN at
room temperature under an oxidative quenching cycle with the
[Ru(bpy)3Cl2]20 (E1/2(III/II*) = −0.81 V vs SCE, bpy = 2,2′-
bipyridine) photocatalyst (PC) and blue-light irradiation
(LED455) (Table 1, entry 1). Unexpectedly, acyclic sulfony-
a
Table 1. Optimization of the Reaction Parameters
Figure 1. Plausible reaction mechanism.
b
redox potentials of PC
yield (%)
Ru-PC photocatalytic conditions, intermediate I undergoes
rapid dehydrochlorination to form acyclic 4aa. In contrast, in
the case of Ir-PC, the subsequent single electron transfer from
photoexcited fac[Ir(ppy)3]* to I occurs to form a correspond-
ing stable benzylic radical II concurrent with the oxidation of
fac[Ir(ppy)3]* to fac[Ir(ppy)3]+ (Figure 1).26 The obvious
disparity in the photocatalytic reaction outcome is attributed to
the large difference in the excited-state reduction potentials
between the [Ru(bpy)3Cl2] and fac[Ir(ppy)3] PCs to reduce
the benzylic chloride unit of intermediate I.22,25e The excited-
state reduction potential of [Ru(bpy)3Cl2] is significantly lower
(−0.81 V vs SCE) than that of fac[Ir(ppy)3] (−1.73 V vs
SCE),22 which likely determines the fate of benzyl chloride
intermediate I. The formation of a tosyl radical was confirmed
by trapping it with TEMPO to give 5a (HRMS [M + Na]+ =
334.1551), whereas any attempt to trap benzylic radical II to
obtain 6aa failed (Scheme 2a), implying that intramolecular
cyclization of II rapidly proceeds to give radical III. III is likely
more prone to oxidation by fac[Ir(ppy)3]+, affording
carbocation IV with concurrent closing of the photocatalytic
cycle. The resulting IV rapidly aromatizes to deliver the desired
fluorene derivative 3aa.
As shown in Figure 1, the Ru-catalyzed reaction exclusively
gave exo-olefin product 4aa over vinyl sulfone 7aa, suggesting
that the steric factor overrides the inherent pKa of the protons
in this deprotonation process. When the flanking Me group
was replaced with phenyl (2b) to disrupt the terminal
deprotonation process, intramolecular cation cyclization
predominantly proceeded to afford cyclized product 3ab,
indicating the reluctance of the α-protons of the sulfone to
participate in the deprotonation (<10% of 7ab (E/Z mixture))
(Scheme 2b).27 In contrast, a truncated substituent (2c)
resulted in the exclusive formation of vinyl sulfone 7ac (E/Z
mixture), suggesting that the Thorpe−Ingold effect contrib-
+
−
entry
PC
EM
(V) EM*/M (V)
base
3aa
4aa
/M*
1
2
3
4
5
6
[Ru]
[Ru]
[Ir]
[Ir]
[Ru]
[Ir]
−0.81
−0.81
−1.73
−1.73
−0.81
−1.73
−1.73
+0.77
+0.77
+0.31
+0.31
+0.77
+0.31
+0.31
Na2CO3
0
0
76
61
0
79
61
10
14
45
13
0
Na2CO3
K2HPO4
K2HPO4
Na2CO3
Na2CO3
65
0
c
7
d
[Ir]
8
0
0
a
TsCl 1a (0.5 mmol, 1 equiv), 2a (0.75 mmol, 1.5 equiv), PC (1 mol
%), base (0.75 mmol, 1.5 equiv), dry CH3CN (2 mL), LED455, rt, 36
h. Isolated yields. Without a light source. Without PC. [Ru] =
b
c
d
[Ru(bpy)3Cl2] and [Ir] = fac[Ir(ppy)3].
lated compound 4aa (79%) was produced, and the desired
sulfonylated fluorene 3aa was not observed. We switched the
PC to fac[Ir(ppy)3],21 which has stronger reduction potential
(E1/2(IV/III*) −1.73 V vs SCE, ppy = 2-phenylpyridine).22
Intriguingly, photocatalysis with the latter Ir-based PC
significantly altered the product profile; the desired 3aa was
obtained in 76% yield with less than 10% of undesired acyclic
4aa (Table 1, entry 3). The Na2CO3 base improved the yield
and ratio of 3aa/4aa (Table 1, entries 3 vs 4), while other
inorganic bases, such as K2HPO4, were less effective in both
Ru- and Ir-based photocatalysis (Table 1, entries 5 and 6). The
results of control experiments indicated that achieving the
desired sulfonylation required the combination of light
irradiation and a PC (Table 1, entries 7 and 8).
The reductive quenching cycle is thermodynamically
unfavorable due to the large excited-state oxidation potential
−
difference between the photocatalysts (RuM*/M = +0.77 V;
IrM*/M = +0.31 V)23 and the olefins used (+1.0 to +1.75 V).22
−
B
https://dx.doi.org/10.1021/acs.orglett.0c02760
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(Table 2). In the case of para-monosubstituted arylsulfonyl
chlorides 1, irrespective of electron-donating (Me, Bu, MeO)
Scheme 2. Control Experiments
t
or electron-withdrawing (F, Cl, CF3, CN, NO2) substituents,
the Ir-catalyzed reaction predominantly gave cyclized fluorene
derivatives 3aa−3ia with a marginal amount of the
corresponding acyclic products 4 (Table 2, right). Ortho-
substitution was also accommodated, as exemplified by the
successful production of o-bromophenyl (3ja) and pentafluor-
ophenyl (3ka) derivatives, and the fluorenyl skeleton of the
latter was unambiguously confirmed by X-ray crystallography.
Other aromatics, e.g., 2-naphthyl (3la) and 2-thienyl (3ma), as
well as methyl (3na) substitution were compatible to give
corresponding sulfonylated fluorenes in high yield and with
high selectivity. By switching the PC from fac[Ir(ppy)3] to
[Ru(bpy)3Cl2] under otherwise identical conditions, the same
substrate sets exclusively provided acyclic sulfonylated
compounds 4 (Table 2, left).
Although a wide range of electronically diverse arylsulfonyl
chlorides were tolerated, the reaction employing MsCl failed to
produce mesylated styrene derivative 4na (Table 2, left). This
is presumably due to its higher reduction potential (−1.39 vs
SCE)24d than that of [Ru(bpy)3Cl2] (−0.81 V vs SCE), which
was not sufficient to generate the sulfonyl radical via the single-
electron-transfer process in this particular case.22,23
Encouraged by the Ir-catalyzed sulfonylative cascade
cyclization, we next investigated the scope of various olefins
2 with TsCl 1a as a standard sulfonylation reagent (Table 3).
Various para-substituted substrates afforded the corresponding
fluorene derivatives 3ad−3ag, irrespective of their electronic
nature (e.g., Me, MeO, MeS, F). o-Tolyl and m-xylyl substrates
uted to the override of the formation of cyclized product 3ab
in the case of 2b (Scheme 2b,c).28
Having developed the divergent sulfonylation protocols for
cyclic (fluorene derivatives) and acyclic products, we next
investigated the substrate generality. We initially tested a range
of commercially available arylsulfonyl chlorides 1 with 2-
phenyl-α-methylstyrene 2a using either Ru- or Ir-based PCs
a
Table 2. Scope of Sulfonyl Chlorides
a
Reaction conditions: arylsulfonyl chloride 1 (0.5 mmol, 1 equiv), 2a (0.75 mmol, 1.5 equiv), fac[Ir(ppy)3] or [Ru(bpy)3Cl2] (1 mol %), Na2CO3
b
c
d
(0.75 mmol, 1.5 equiv), dry CH3CN (2 mL), LED455, rt, 36 h. Isolated yields. The yields of the acyclic products 4 are reported in parentheses. 2
mmol scale reaction.
C
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Letter
a
densed polycyclic systems as a promising scaffold for
biologically active compounds and π-rich organic photo-
electronic materials.
Table 3. Scope of alkenes 3
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02760.
Experimental procedures and characterization of new
compounds (PDF)
Accession Codes
CCDC 2022778−2022780 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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.
AUTHOR INFORMATION
Corresponding Authors
■
Naoya Kumagai − Institute of Microbial Chemistry
(BIKAKEN), Tokyo 141-0021, Japan; orcid.org/0000-
0003-1843-2592; Email: nkumagai@bikaken.or.jp
Masakatsu Shibasaki − Institute of Microbial Chemistry
(BIKAKEN), Tokyo 141-0021, Japan; orcid.org/0000-
0001-8862-582X; Email: mshibasa@bikaken.or.jp
a
Reaction conditions: TsCl 1a (0.5 mmol, 1 equiv), 2 (0.75 mmol,
1.5 equiv), fac[Ir(ppy)3] (1 mol %), Na2CO3 (0.75 mmol, 1.5 equiv),
dry CH3CN (2 mL), LED455, room temperature, 36 h. Yields of
acyclic products 4 are reported in parentheses.
Author
Santosh K. Pagire − Institute of Microbial Chemistry
(BIKAKEN), Tokyo 141-0021, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02760
were compatible (3ah and 3ai), and intriguingly, mono m-
MeO-substituted substrates gave 3aj almost exclusively over
regioisomeric 3aj′, likely due to steric effects. The naphthalene
and phenanthrene units could be employed to undergo radical
cyclization, delivering fluorene derivatives 3ak and 3al fused
with the π-system. Heteroaromatic substrates were successfully
implemented to expand the synthetic utility of the present
photocatalysis. A substrate containing an oxygen-functionalized
benzofuran as well as various nitrogen-functionalized hetero-
cycles were amenable to provide a range of polycyclic systems
without appreciable contamination of undesired acyclic
products 4. Integration with pyrrole and indole units allowed
for rapid access to a polycyclic pyrroloindole system (3an−
3as) in good to excellent yields (Table 3). Notably, these
structurally more complex pyrroloindole derivatives are found
in a myriad of biologically active molecules.1b,29 Introducing a
sulfonyl handle into the privileged skeleton produced a unique
class of fused pyrroloindoles. The marginal formation of
undesired acyclic product 4ar may be due to the presence of an
electron-withdrawing methoxycarbonyl group, which poten-
tially retards radical cyclization en route to the desired 3ar.
In conclusion, we exploited differences in the redox
potentials of photocatalysts to control the synthesis of
structurally different products from the same set of substrates.
Sulfonylated fluorenes and pyrroloindoles were rapidly
assembled using readily accessible olefins and commercially
available sulfonyl chlorides under operationally simple room-
temperature protocols utilizing the clean visible-light photo-
chemical conditions. This photocascade method provides a
new avenue for designing various sulfonyl-containing con-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Nos. JP19K22192 (Grant-in-Aid for Exploratory Research)
and JP20H02746 (Grant-in-Aid for Scientific Research (B)) to
N.K. S.K.P. thanks the German Research Foundation (DFG:
PA 3350/1-1; Project No. 407495001) for the postdoctoral
research fellowship. We are grateful to Dr. Kiyoko Iijima, Dr.
Ryuichi Sawa, Yumiko Kubota, and Yuko Takahashi (all from
Institute of Microbial Chemistry, BIKAKEN) for technical
assistance with the NMR and MS analyses. We thank Dr.
Tomoyuki Kimura (Institute of Microbial Chemistry,
BIKAKEN) for the single-crystal X-ray analyses of 3ka, 4aa,
and 4ga.
REFERENCES
■
(1) (a) Monakhova, N.; Ryabova, S.; Makarov, V. Synthesis and
Some Biological Properties of Pyrrolo[1,2-a]indoles. J. Heterocycl.
Chem. 2016, 53, 685−709. (b) Bass, P. D.; Gubler, D. A.; Judd, T. C.;
Williams, R. M. Mitomycinoid alkaloids: mechanism of action,
biosynthesis, total syntheses, and synthetic approaches. Chem. Rev.
2013, 113, 6816−6863. (c) Wang, C.; Dong, H.; Hu, W.; Liu, Y.;
Zhu, D. Semiconducting pi-conjugated systems in field-effect
transistors: a material odyssey of organic electronics. Chem. Rev.
2012, 112, 2208−2267. (d) Bradner, W. T.; Mitomycin, C. a clinical
update. Cancer Treat. Rev. 2001, 27, 35−50.
D
https://dx.doi.org/10.1021/acs.orglett.0c02760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(2) (a) Crossley, D. L.; Cade, I. A.; Clark, E. R.; Escande, A.;
Humphries, M. J.; King, S. M.; Vitorica-Yrezabal, I.; Ingleson, M. J.;
Turner, M. L. Enhancing electron affinity and tuning band gap in
donor-acceptor organic semiconductors by benzothiadiazole directed
C-H borylation. Chem. Sci. 2015, 6, 5144−5151. (b) Fulton, J. R.;
Bouwkamp, M. W.; Bergman, R. G. Reactivity of a Parent
Amidoruthenium Complex: A Transition Metal Amide of Exception-
ally High Basicity. J. Am. Chem. Soc. 2000, 122, 8799−8800. (c) Ni,
S.; Yuan, Y.; Huang, J.; Mao, X.; Lv, M.; Zhu, J.; Shen, X.; Pei, J.; Lai,
L.; Jiang, H.; Li, J. Discovering potent small molecule inhibitors of
cyclophilin A using de novo drug design approach. J. Med. Chem.
2009, 52, 5295−5298.
(3) (a) Bernius, M. T.; Inbasekaran, M.; O’Brien, J.; Wu, W.
Progress with Light-Emitting Polymers. Adv. Mater. 2000, 12, 1737−
1750. (b) Zhen, C.-G.; Chen, Z.-K.; Liu, Q.-D.; Dai, Y.-F.; Shin, R. Y.
C.; Chang, S.-Y.; Kieffer, J. Fluorene-Based Oligomers for Highly
Efficient and Stable Organic Blue-Light-Emitting Diodes. Adv. Mater.
2009, 21, 2425−2429. (c) Yu, T.; Liu, L.; Xie, Z.; Ma, Y. Progress in
small-molecule luminescent materials for organic light-emitting
diodes. Sci. China: Chem. 2015, 58, 907−915. (d) Xu, Y. X.;
Chueh, C. C.; Yip, H. L.; Ding, F. Z.; Li, Y. X.; Li, C. Z.; Li, X.; Chen,
W. C.; Jen, A. K. Improved charge transport and absorption
coefficient in indacenodithieno[3,2-b]thiophene-based ladder-type
polymer leading to highly efficient polymer solar cells. Adv. Mater.
2012, 24, 6356−6361. (e) Scherf, U.; List, E. J. W. Semiconducting
Polyfluorenes - Towards Reliable Structure-Property Relationships.
Adv. Mater. 2002, 14, 477−487.
(4) (a) Banala, A. K.; Levy, B. A.; Khatri, S. S.; Furman, C. A.; Roof,
R. A.; Mishra, Y.; Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.;
Newman, A. H. N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)-
piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3
receptor ligands: critical role of the carboxamide linker for D3
receptor selectivity. J. Med. Chem. 2011, 54, 3581−3594. (b) Burch,
R. M.; Weitzberg, M.; Blok, N.; Muhlhauser, R.; Martin, D.; Farmer,
S. G.; Bator, J. M.; Connor, J. R.; Ko, C.; Kuhn, W.; McMillan, B. A.;
Raynor, M.; Shearer, B. G.; Tifany, C.; Wilkins, D. E. N-(Fluorenyl-9-
methoxycarbonyl) amino acids, a class of antiinflammatory agents
with a different mechanism of action. Proc. Natl. Acad. Sci. U. S. A.
1991, 88, 355−359.
(5) (a) Bassas, O.; Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P.
A Simple Organocatalytic Enantioselective Synthesis of Pregabalin.
Eur. J. Org. Chem. 2009, 2009, 1340−1351. (b) Zhong, L.; Cui, K.;
Xie, P.; Chen, J.-Z.; Ma, Z. A new titanium (IV) complex bearing
phenoxyimine-fluorene ligand and its use as catalyst for ethylene
homo- and copolymerization. J. Polym. Sci., Part A: Polym. Chem.
2010, 48, 1617−1621. (c) Rathore, R.; Chebny, V. J.; Abdelwahed, S.
H. A Versatile and Conformationally Adaptable Fluorene-Based
Receptor for Efficient Binding of Silver Cation. J. Am. Chem. Soc.
2005, 127, 8012−8013. (d) Ivchenko, P. V.; Nifant’ev, I. E.; Ezersky,
V. A.; Churakov, A. V. Hexadecahydrotetrabenzo[a,c,d,f]fluorene −
Ligand, available by Friedel−Crafts fluorene cycloalkylation. Syn-
thesis, crystal and molecular structure of (η5-C29H34)(η5-C5H5)-
ZrCl2. J. Organomet. Chem. 2011, 696, 1931−1934.
Suzuki−Miyaura coupling and acid-catalyzed Friedel−Crafts reactions
as key steps. Tetrahedron 2008, 64, 9033−9043.
(8) (a) Kern, N.; Hoffmann, M.; Blanc, A.; Weibel, J.-M.; Pale, P.
Gold(I)-Catalyzed Rearrangement of N-Aryl 2-Alkynylazetidines to
Pyrrolo[1,2-a]indoles. Org. Lett. 2013, 15, 836−839. (b) Morimoto,
K.; Itoh, M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka, K.; Miura, M.
Synthesis of fluorene derivatives through rhodium-catalyzed dehy-
drogenative cyclization. Angew. Chem., Int. Ed. 2012, 51, 5359−5362.
(9) Xiao, W.-J.; Chen, J.-R.; Yu, X.-Y. Tandem Radical Cyclization of
N-Arylacrylamides: An Emerging Platform for the Construction of
3,3-Disubstituted Oxindoles. Synthesis 2015, 47, 604−629.
(10) (a) Chu, X.-Q.; Xing, Z.-H.; Meng, H.; Xu, X.-P.; Ji, S.-J.
Copper-mediated radical alkylarylation of unactivated alkenes with
acetonitrile leading to fluorenes and pyrroloindoles. Org. Chem. Front.
2016, 3, 165−169. (b) Chu, X. Q.; Liu, D.; Xing, Z. H.; Xu, X. P.; Ji,
S. J. Palladium-Catalyzed Cyclization of Alkenes with Organohalides.
Org. Lett. 2016, 18, 776−779.
(11) Clive, D. L. J.; Sunasee, R. Formation of Benzo-Fused
Carbocycles by Formal Radical Cyclization onto an Aromatic Ring.
Org. Lett. 2007, 9, 2677−2680.
(12) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Formation
of five- and six-membered heterocyclic rings under radical cyclisation
conditions. Tetrahedron 2004, 60, 6239−6278.
(13) Zhang, B.; Studer, A. 2-Trifluoromethylated indoles via radical
trifluoromethylation of isonitriles. Org. Lett. 2014, 16, 1216−1219.
(14) (a) Yu, X. Y.; Zhao, Q. Q.; Chen, J.; Xiao, W. J.; Chen, J. R.
When Light Meets Nitrogen-Centered Radicals: From Reagents to
Catalysts. Acc. Chem. Res. 2020, 53, 1066−1083. (b) Pagire, S. K.;
Foll, T.; Reiser, O. Shining Visible Light on Vinyl Halides: Expanding
the Horizons of Photocatalysis. Acc. Chem. Res. 2020, 53, 782−791.
(c) Troian-Gautier, L.; Turlington, M. D.; Wehlin, S. A. M.; Maurer,
A. B.; Brady, M. D.; Swords, W. B.; Meyer, G. J. Halide Photoredox
Chemistry. Chem. Rev. 2019, 119, 4628−4683. (d) Wang, C. S.;
Dixneuf, P. H.; Soule, J. F. Photoredox Catalysis for Building C-C
Bonds from C(sp(2))-H Bonds. Chem. Rev. 2018, 118, 7532−7585.
(e) Marzo, L.; Pagire, S. K.; Reiser, O.; Konig, B. Visible-Light
Photocatalysis: Does It Make a Difference in Organic Synthesis?
Angew. Chem., Int. Ed. 2018, 57, 10034−10072. (f) Staveness, D.;
Bosque, I.; Stephenson, C. R. Free Radical Chemistry Enabled by
Visible Light-Induced Electron Transfer. Acc. Chem. Res. 2016, 49,
2295−2306. (g) Shaw, M. H.; Twilton, J.; MacMillan, D. W.
Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81,
6898−6926. (h) Romero, N. A.; Nicewicz, D. A. Organic Photoredox
Catalysis. Chem. Rev. 2016, 116, 10075−10166. (i) Ravelli, D.; Protti,
S.; Fagnoni, M. Carbon-Carbon Bond Forming Reactions via
Photogenerated Intermediates. Chem. Rev. 2016, 116, 9850−9913.
(j) Tucker, J. W.; Stephenson, C. R. Shining light on photoredox
catalysis: theory and synthetic applications. J. Org. Chem. 2012, 77,
1617−1622.
(15) (a) Chaudhary, R.; Natarajan, P. Visible Light Photoredox
Activation of Sulfonyl Chlorides: Applications in Organic Synthesis.
ChemistrySelect 2017, 2, 6458−6479. (b) Jiang, H.; Cheng, Y.; Zhang,
Y.; Yu, S. Sulfonation and Trifluoromethylation of Enol Acetates with
Sulfonyl Chlorides Using Visible-Light Photoredox Catalysis. Eur. J.
Org. Chem. 2013, 2013, 5485−5492.
(16) Chen, M.; Huang, Z. T.; Zheng, Q. Y. Visible light-induced 3-
sulfenylation of N-methylindoles with arylsulfonyl chlorides. Chem.
Commun. (Cambridge, U. K.) 2012, 48, 11686−11688.
(17) (a) Pinnen, F.; Cacciatore, I.; Cornacchia, C.; Sozio, P.; Cerasa,
L. S.; Iannitelli, A.; Nasuti, C.; Cantalamessa, F.; Sekar, D.;
Gabbianelli, R.; Falcioni, M. L.; Stefano, A. D. Codrugs Linking L-
Dopa and Sulfur-Containing Antioxidants: New Pharmacological
Tools against Parkinson’s Disease. J. Med. Chem. 2009, 52, 559−563.
(b) Asai, T.; Takeuchi, T.; Diffenderfer, J.; Sibley, L. D. Identification
of small-molecule inhibitors of nucleoside triphosphate hydrolase in
Toxoplasma gondii. Antimicrob. Agents Chemother. 2002, 46, 2393−
2399.
(6) (a) Zhou, A. H.; Pan, F.; Zhu, C.; Ye, L. W. Recent Progress
towards Transition-Metal-Catalyzed Synthesis of Fluorenes. Chem. -
Eur. J. 2015, 21, 10278−10288. (b) Liu, T. P.; Xing, C. H.; Hu, Q. S.
Synthesis of fluorene and indenofluorene compounds: tandem
palladium-catalyzed suzuki cross-coupling and cyclization. Angew.
Chem., Int. Ed. 2010, 49, 2909−2912.
(7) (a) Sarkar, S.; Maiti, S.; Bera, K.; Jalal, S.; Jana, U. Highly
efficient synthesis of polysubstituted fluorene via iron-catalyzed
intramolecular Friedel−Crafts alkylation of biaryl alcohols. Tetrahe-
dron Lett. 2012, 53, 5544−5547. (b) Hao, L.; Pan, Y.; Wang, T.; Lin,
M.; Chen, L.; Zhan, Z.-p. Chemoselective Cascade Synthesis of N-
Fused Heterocycles via Silver(I) Triflate-Catalyzed Friedel-Crafts/N-
C Bond Formation Sequence. Adv. Synth. Catal. 2010, 352, 3215−
3222. (c) Li, G.; Wang, E.; Chen, H.; Li, H.; Liu, Y.; Wang, P. G. A
general and efficient synthesis of substituted fluorenes and hetero-
cycle-fused indenes containing thiophene or indole rings utilizing a
(18) (a) Benhamu, B.; Martin-Fontecha, M.; Vazquez-Villa, H.;
Pardo, L.; Lopez-Rodriguez, M. L. Serotonin 5-HT6 receptor
E
https://dx.doi.org/10.1021/acs.orglett.0c02760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
antagonists for the treatment of cognitive deficiency in Alzheimer’s
disease. J. Med. Chem. 2014, 57, 7160−7181. (b) Gijsen, H. J.; De
Cleyn, M. A.; Surkyn, M.; Van Lommen, G. R.; Verbist, B. M.; Nijsen,
M. J.; Meert, T.; Wauwe, J. V.; Aerssens, J. 5-sulfonyl-benzimidazoles
as selective CB2 agonists-part 2. Bioorg. Med. Chem. Lett. 2012, 22,
547−552. (c) La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.;
Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.;
Balzarini, J.; Novellino, E.; Silvestri, R. Indolylarylsulfones as HIV-1
non-nucleoside reverse transcriptase inhibitors: new cyclic substitu-
ents at indole-2-carboxamide. J. Med. Chem. 2011, 54, 1587−1598.
(d) Tong, L.; Shankar, B. B.; Chen, L.; Rizvi, R.; Kelly, J.; Gilbert, E.;
Huang, C.; Yang, D. Y.; Kozlowski, J. A.; Shih, N. Y.; Gonsiorek, W.;
Hipkin, R. W.; Malikzay, A.; Lunn, C. A.; Lundell, D. J. Expansion of
SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands.
Bioorg. Med. Chem. Lett. 2010, 20, 6785−6789.
(27) In the case of 2b, the resulting ATRA intermediate would be
easily reduced and formation of a more stable benzhydryl radical
becomes prevalent with [Ru(bpy)3Cl2]* as well, allowing the
cyclization to a fluorene derivative 3ab.
(28) (a) Levine, M. N.; Raines, R. T. Trimethyl lock: A trigger for
molecular release in chemistry, biology, and pharmacology. Chem. Sci.
2012, 3, 2412−2420. (b) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F.
The formation and stability of spiro-compounds. Part I. spiro-
Compounds from cyclohexane. J. Chem. Soc., Trans. 1915, 107, 1080−
1106.
(29) (a) Tomasz, M.; Palom, Y. The Mitomycin Bioreductive
Antitumor Agents: Cross-Linking and Alkylation of DNA as the
Molecular Basis of Their Activity. Pharmacol. Ther. 1997, 76, 73−87.
(b) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.;
Zhang, X.-M.; Ma, Y.-B. Isatisine A, a Novel Alkaloid with an
Unprecedented Skeleton from Leaves of Isatis indigotica. Org. Lett.
2007, 9, 4127−4129.
(19) (a) Chen, J.-R.; Yan, D.-M.; Wei, Q.; Xiao, W.-J. Photocascade
Catalysis: A New Strategy for Cascade Reactions. ChemPhotoChem.
2017, 1, 148−158. (b) Hossain, A.; Pagire, S. K.; Reiser, O. Visible-
Light-Mediated Synthesis of Pyrazines from Vinyl Azides Utilizing a
Photocascade Process. Synlett 2017, 28, 1707−1714.
́
(20) Teply, F. Photoredox catalysis by [Ru(bpy)3]2+ to trigger
transformations of organic molecules. Organic synthesis using visible-
light photocatalysis and its 20th century roots. Collect. Czech. Chem.
Commun. 2011, 76, 859−917.
(21) Sun, J.; Wu, W.; Zhao, J. Long-lived room-temperature deep-
red-emissive intraligand triplet excited state of naphthalimide in
cyclometalated Ir(III) complexes and its application in triplet-triplet
annihilation-based upconversion. Chem. - Eur. J. 2012, 18, 8100−
8112.
(22) Nicewicz, D.; Roth, H.; Romero, N. Experimental and
Calculated Electrochemical Potentials of Common Organic Molecules
for Applications to Single-Electron Redox Chemistry. Synlett 2016,
27, 714−723.
(23) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(24) (a) Wallentin, C. J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson,
C. R. Visible light-mediated atom transfer radical addition via
oxidative and reductive quenching of photocatalysts. J. Am. Chem. Soc.
2012, 134, 8875−8884. (b) Pagire, S. K.; Paria, S.; Reiser, O.
Synthesis of beta-Hydroxysulfones from Sulfonyl Chlorides and
Alkenes Utilizing Visible Light Photocatalytic Sequences. Org. Lett.
2016, 18, 2106−2109. (c) Fu, R.; Hao, W.-J.; Wu, Y.-N.; Wang, N.-
N.; Tu, S.-J.; Li, G.; Jiang, B. Sulfonyl radical-enabled 6-endo-trig
cyclization for regiospecific synthesis of unsymmetrical diaryl sulfones.
Org. Chem. Front. 2016, 3, 1452−1456. (d) Pagire, S. K.; Hossain, A.;
Reiser, O. Temperature Controlled Selective C-S or C-C Bond
Formation: Photocatalytic Sulfonylation versus Arylation of Unac-
tivated Heterocycles Utilizing Aryl Sulfonyl Chlorides. Org. Lett.
2018, 20, 648−651.
(25) (a) Reiser, O. Shining Light on Copper: Unique Opportunities
for Visible-Light-Catalyzed Atom Transfer Radical Addition Reactions
and Related Processes. Acc. Chem. Res. 2016, 49, 1990−1996.
(b) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage, B.
M.; Reiser, O. Trifluoromethylchlorosulfonylation of alkenes:
evidence for an inner-sphere mechanism by a copper phenanthroline
photoredox catalyst. Angew. Chem., Int. Ed. 2015, 54, 6999−7002.
(c) Paria, S.; Reiser, O. Copper in Photocatalysis. ChemCatChem
2014, 6, 2477−2483. (d) Knorn, M.; Rawner, T.; Czerwieniec, R.;
Reiser, O. [Copper(phenanthroline)(bisisonitrile)]+-Complexes for
the Visible-Light-Mediated Atom Transfer Radical Addition and
Allylation Reactions. ACS Catal. 2015, 5, 5186−5193. (e) Reiser, O.;
Paria, S.; Pirtsch, M.; Kais, V. Visible-Light-Induced Intermolecular
Atom-Transfer Radical Addition of Benzyl Halides to Olefins: Facile
Synthesis of Tetrahydroquinolines. Synthesis 2013, 45, 2689−2698.
(26) Hironaka, K.; Fukuzumi, S.; Tanaka, T. Tris(bipyridyl)-
ruthenium(II)-photosensitized reaction of 1-benzyl-1,4-dihydronico-
tinamide with benzyl bromide. J. Chem. Soc., Perkin Trans. 2 1984, 2,
1705−1709.
F
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Org. Lett. XXXX, XXX, XXX−XXX