4CzIPN-tBu-Catalyzed Proton-Coupled Electron Transfer for Photosynthesis of Phosphorylated N-Heteroaromatics

Article abstract of DOI:10.1021/jacs.0c11138

2,4,5,6-Tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)isophthalonitrile (4CzIPN-tBu) was developed as a photocatalyst for the phosphorus-radical-initiated cascade cyclization reaction of isocyanides. By using 4CzIPN-tBu as catalyst, we developed a visible-light-induced proton-coupled electron transfer strategy for the generation of phosphorus-centered radicals, via which a wide range of phosphorylated phenanthridines, quinolines, and benzothiazoles were successfully constructed.

Full text of DOI:10.1021/jacs.0c11138

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Article
4CzIPN‑tBu-Catalyzed Proton-Coupled Electron Transfer for
Photosynthesis of Phosphorylated N‑Heteroaromatics
Yan Liu, Xiao-Lan Chen,* Xiao-Yun Li, Shan-Shan Zhu, Shi-Jun Li, Yan Song, Ling-Bo Qu,
and Bing Yu*
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ABSTRACT: 2,4,5,6-Tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)-
isophthalonitrile (4CzIPN-tBu) was developed as a photocatalyst for
the phosphorus-radical-initiated cascade cyclization reaction of
isocyanides. By using 4CzIPN-tBu as catalyst, we developed a visible-
light-induced proton-coupled electron transfer strategy for the
generation of phosphorus-centered radicals, via which a wide range of
phosphorylated phenanthridines, quinolines, and benzothiazoles were
successfully constructed.
toolbox of organic chemists.16 In particular, the 1,2,3,5-
tetrakis(carbazol-9-yl)4,6-dicyanobenzene (4CzIPN)17 is ubiq-
uitously applied in many photodriven transformations,
including organic dye/metal dual catalytic coupling reac-
tions,18 photoredox-enabled alkylation of imines,19 photo-
carboxylation with CO2,20 radical addition cyclization
cascades,21 etc. More importantly, by tailoring the number
and alignment of carbazolyl and cyano units on the benzene
ring, the HOMO−LUMO energy levels as well as photoredox
potentials of the resulting CDCBs can be easily adjusted.22
Phosphorus-radical-mediated approaches are a powerful tool
for the rapid and facile access to structurally diverse
phosphorus-containing scaffolds.23 Unfortunately, the direct
additions of electrophilic P-centered radical to electron-
deficient heteroarenes are less favored in contrast to alkenes
and alkynes.24 The radical cascade cyclization of isocyanides
can circumvent the aforementioned limitations by introducing
phosphoryl groups simultaneously with constructing N-hetero-
cycles. Considering the great significance of both heteroarene25
and organophosphorus motifs,26 the P-radical-initiated radical
cascade cyclization of isocyanides has been extensively
studied.27 Early methods for generating P-radicals required
stoichiometric amounts of Ag(I) or Mn(III) salts as radical
INTRODUCTION
■
Over the past decade, visible-light-driven photoredox catalysis
has stimulated a resurgence of interest in the exploration of
radical reactions.1 These attractive synthetic manifolds are
mainly spurred by the exploitation of exogenous photocatalysts
to facilitate the primary photoinduced events, such as single-
electron transfer (SET),2 hydrogen-atom transfer (HAT),3
energy transfer (EnT),4 and proton-coupled electron transfer
(PCET),5 to generate open-shell reactive species that enable
the molecular architectures upon photoexcitation.6 Among
them, ruthenium- and iridium-polypyridyl complexes stand at
the forefront, due to their strong absorptions, long-lived
excited states, and broad redox capabilities in the visible regime
of the light spectrum.7 Nevertheless, several intrinsic draw-
backs regarding toxicity of metals, high cost, as well as
restrictive conformational constraint hinder their large-scale
application in photosynthetic chemistry.8 In this context,
organic dyes offer a metal-free alternative to their transition-
metal counterparts, thus expending the accessibility to
photoredox catalysis in a more environmentally benign and
sustainable manner.8b,9
Currently, the structural design and development of organic
dyes relies on the (hetero)anthracene-based fluorescent
platform, from which a majority of classic photocatalysts
(e.g., 9,10-dicyanoanthracene,10 Eosin Y,11 methylene blue,12
Rhodamine B,13 Mes-Acr+,14 N-phenylphenothiazine,15 etc.)
were derived. This situation has been partially alleviated
because carbazolyl dicyanobenzenes (CDCBs) emerged as a
novel donor−acceptor (D−A) fluorophore with intriguing
photoelectric performance, greatly expanding the photocatalyst
Received: October 22, 2020
Published: December 29, 2020
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initiators to trigger the following isocyanide annulations
[Ir(ppy)2(dtbpy)]PF6 as photocatalyst leading to P(O)Ph2-
containing phenanthridines and isoquinolines.30 A concurrent
work by Yang et al. provided a photoinduced approach to the
construction of 2-phosphinoylindoles by using a ruthenium
photocatalyst (Scheme 1c).31 Despite that significant progress
has been achieved in this area, the dye-catalyzed P-radical-
initiated cascade cyclization of isocyanides to access
phosphoryl-functionalized N-heteroaromatics has not yet
been established. Herein, we would like to disclose the
application of 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-
yl)isophthalonitrile (4CzIPN-tBu) as a metal-free photocatalyst
for the visible-light-induced proton-coupled electron transfer
reaction to generate phosphorus-centered radicals, by which a
wide range of phosphorylated phenanthridines, quinolines, and
benzothiazoles were successfully synthesized. To the best of
our knowledge, this is the first example of applying
4CzIPN-tBu as a photocatalyst to trigger phosphorus-radicals
via an unprecedented photoredox-catalyzed proton-coupled
electron transfer process (Scheme 1d).
(Scheme 1a).28 In 2014, Lakhdar’s group reported a metal-
Scheme 1. P-Radical-Initiated Cascade Cyclization of
Isocyanides
free method in the presence of diphenyliodonium salt with
triethylamine to access various 6-phosphorylated phenanthri-
dines (Scheme 1b).29 Afterward, Lu and co-workers developed
a photoredox-mediated tandem cyclization of isocyanides with
Scheme 2. Excited-State Oxidative Potentials of CDCB-Based Photocatalysts and Screening of PC1−10 for the Photosynthesis
a
of 3a
a
The values of E1/2(*P/P−) and Eox (vs SCE in MeCN) were obtained in the reported literature.33a,c,34,35 Typical reaction conditions: 1a (0.2
mmol), 2a (2.0 equiv), PC (5 mol %), NaHCO3 (2.0 equiv), and TBHP (2.0 equiv) were mixed in 2 mL of MeCN under irradiation of blue LEDs
with N2 protection at rt for 12 h, and the corresponding 31P NMR yields of 3a were given with trioctylphosphine oxide as an internal standard. PC
= photocatalyst, 4CzTPN = 2,3,5,6-tetra(9H-carbazol-9-yl)terephthalonitrile, 4CzIPN = 3,4,5,6-tetra(9H-carbazol-9-yl)phthalonitrile, 4CzIPN =
2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile, 4DPAIPN = 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile, 4CzIPN-Br = 2,4,5,6-tetrakis(3,6-
dibromo-9H-carbazol-9-yl)isophthalonitrile, 4CzIPN-Cl = 2,4,5,6-tetrakis(3,6-dichloro-9H-carbazol-9-yl)isophthalonitrile, 4CzIPN-Ph = 2,4,5,6-
tetrakis(3,6-diphenyl-9H-carbazol-9-yl)isophthalonitrile, 4CzIPN-Me = 2,4,5,6-tetrakis(3,6-dimethyl-9H-carbazol-9-yl)isophthalonitrile, 4CzIPN-
OMe = 2,4,5,6-tetrakis(3,6-dimethoxy-9H-carbazol-9-yl)isophthalonitrile, 4CzIPN-tBu = 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)-
isophthalonitrile.
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(Figure 1). These features of the orbital distribution are similar
to those of PC3 (4CzIPN), leading to the characteristic
RESULTS AND DISCUSSION
■
To avoid the use of expensive and toxic transition-metal
photocatalysts, we initiated our study by using CDCB-based
organic dyes. Previous studies on CDCBs generally focus on
the fine-tuned assembly of carbazolyl and cyano group-
s;16a,b,22a,32 however, the exploration of substituted CDCBs
remains scarce.33 Accordingly, as illustrated in Scheme 2, four
reported CDCB analogues (i.e., 4CzIPN, 4CzTPN, 4CzIPN,
and 4DPAIPN) as well as six substituted 4CzIPNs bearing
electron-withdrawing groups (i.e., 4CzIPN-Br and 4CzIPN-Cl)
or electron-donating groups (i.e., 4CzIPN-Ph, 4CzIPN-Me,
4CzIPN-OMe, and 4CzIPN-tBu) at the para-position on the
carbazoles were prepared through a reported one-step
nucleophilic substitution reaction followed by simple filtration
isolation (see the Supporting Information for details). An
obvious trend that adding electron-donating groups leads to a
lower oxidative potential of the excited state (E1/2(*P/P−) vs
SCE in MeCN), while the electron-withdrawing ones can
make it more oxidizing, was observed among our available
substituted 4CzIPNs, and the order of E1/2(*P/P−) values
Figure 1. Electronic transition calculated by DFT and TD-DFT
calculations and frontier orbitals of PC10.
extension of the absorption band to the visible region and
efficient intramolecular charge transfer (CT).22b,36
We next investigated the substrate scope of biphenyl
isocyanides and diphenylphosphine oxides by using PC10 as
a photocatalyst to access various 6-phosphorylated phenan-
thridines. As shown in Scheme 3, initially, the biphenyl
isocyanides bearing different groups at the 4′-position of Ar2
rings, such as H−, Me−, MeO−, F−, Cl−, Br−, CF3−, and
CN−, were tested to react with diphenylphosphines oxide 2a
itself, affording the corresponding products 3a−h in yields up
t
follows the sequence as Br > Cl > Ph > Me > OMe > Bu,
exhibiting widely distributed oxidative capabilities ranging
from +1.10 to +1.73 V (Scheme 2). Considering the essential
parameter of oxidative potential for a photoexcited catalyst in
the reductive quenching cycle to produce a radical by
oxidation, it is rational to envisage that our CDCB-based
photocatalysts could possibly oxidize P-radical precursors (e.g.,
diphenylphosphine oxide 2a with Eox = ∼+1.00 V vs SCE in
MeCN)34 to generate the corresponding radicals upon visible
light excitation.
Scheme 3. Synthesis of 6-Phosphorylated Phenanthridines
by Reacting Biphenyl Isocyanides with Diphenylphosphine
a
Oxides
We thereby turn to investigate the performance of our
CDCB-based organic dyes (PC1−PC10) in the visible-light-
driven radical cascade cyclization of isocyanides with
phosphorylation reagents. The model reaction conditions
were established as follows: 1a (0.2 mmol), 2a (2.0 equiv),
PC (5 mol %), NaHCO3 (2.0 equiv), and TBHP (2.0 equiv)
were mixed in 2 mL of MeCN under irradiation of blue LEDs
with N2 protection at rt for 12 h (see Tables S1−S3), and the
corresponding 31P NMR yields of the desired product 3a were
displayed in Scheme 2. Among the four reported CDCB
analogues (PC1−PC4), 4CzIPN, 4CzTPN, 4CzIPN, and
4DPAIPN, the 4CzIPN (PC3) with an appropriate oxidative
potential of the excited state (+1.35 V) led to 3a in a superior
yield of 78%. Intriguingly, as for the six substituted 4CzIPNs
(PC5−PC10), the yields of 3a increased constantly from 0 to
80% with the decline of E1/2(*P/P−) values from +1.73 to
+1.21 V, and 4CzIPN-tBu (PC10) outperformed the others to
produce 3a in 80%. Notably, the relatively poor reactivities of
4CzIPN-Br (PC5) and 4CzIPN-Cl (PC6) might be attributed
to their inferior solubility.33c After extensive experimentation,
4CzIPN-tBu was selected as the optimal photocatalyst to
continue our follow-up study.
DFT and TD-DFT computations of PC10 (4CzIPN-tBu)
revealed that the absorption band (λabs = 391 nm) is assigned
to the HOMO−LUMO transition (95%) with the largest
oscillator strength (f) of 0.1369. The carbazolyl moieties are
markedly distorted from the dicyanobenzene plane by steric
hindrance, resulting in the spatially separated highest occupied
molecular orbitals (HOMOs) and lowest unoccupied molec-
ular orbitals (LUMOs) of PC10. The HOMOs are mainly
localized in the carbazolyl moieties, while the LUMOs are
distributed over the dicyanobenzene moieties, respectively
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), PC10 (5 mol %),
TBHP (70% solution in water, 2.0 equiv), and NaHCO3 (2.0 equiv)
in 2 mL of MeCN under irradiation of blue LEDs with N2 protection
at rt for 12 h. Isolated yields were given on the basis of substrate 1.
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to 80%. Additionally, cyclization of polycyclic substituted
isocyanobenzenes occurred successfully to give phosphorylated
polyheteroarenes 3i−k in good to moderate yields. It was
observed that the biphenyl isocyanides with substituents of
Me−, F−, Cl−, and CN− on the Ar1 moiety also proceeded
smoothly in this reaction (3l−p). Furthermore, a variety of
phosphorus reagents, including 4-Me, 4-MeO, 4-F, 4-Cl, 3,5-
dimethyl, and 2,4-dimethyl-substituted diarylphosphine oxides,
were well tolerated to give their corresponding products 3q−v
with comparable yields. However, as for ethyl phenyl-
phosphinate (2w) and diethyl H-phosphonadtes (2x), the
corresponding products 3w and 3x were obtained in 31% and
trace yields, respectively, which might be attributed to the
higher theoretical bond dissociation energies (BDE) of the P−
H bonds (357 and 375 kJ/mol) and oxidative potentials (Eox,
1.62 and 1.65 V) (see Table S6).
Because of our continuous interest in the radical cascade
cyclization involving 2-isocyanoaryl thioethers,37 we proceeded
to probe the feasibility of this protocol for photosynthesis of
benzothiazoles. Much to our delight, the practicality of PC10
could be well extended to synthesize 2-phosphorylated
benzothiazoles 7 by treating 2-isocyanoaryl thioethers 6 with
diphenylphosphine oxides 2 in the presence of LPO and
NaHCO3 under irradiation of blue LEDs with N2 protection at
rt for 12 h (see Table S5). As shown in Scheme 5, it was found
Scheme 5. Synthesis of 2-Phosphorylated Benzothiazoles by
Reacting 2-Isocyanoaryl Thioethers with
a
Diphenylphosphine Oxides
Inspired by the primary results of the photosynthesis of 6-
phosphorylated phenanthridines, we decided to expand the
implementation of this strategy to other isocyanide systems.
Whereas vinyl isocyanides have recently demonstrated the
synthetic versatility in radical chemistry and garnered particular
recognition in the preparation of isoquinoline derivatives, we
hence commence exploring their scalable application in the
synthesis of 1-phosphorylated isoquinoline derivatives. The
studies were ongoing to use PC10 as a photocatalyst for
screening the experimental parameters of the model reaction,
and the optimized conditions were established (see Table S4).
As can be seen in Scheme 4, a large range of vinyl isocyanides 4
were reacted successfully with diphenylphosphine oxides 2 to
provide diverse 1-phosphorylated isoquinolines 5a−n in
satisfactory yields ranging from 33% to 79%.
a
(a) Reaction conditions: 6 (0.2 mmol), 2 (0.4 mmol), PC10 (5 mol
%), LPO (2.0 equiv), and NaHCO3 (2.0 equiv) in 2 mL of MeCN
under irradiation of blue LEDs with N2 protection at rt for 12 h.
Isolated yields were given on the basis of substrate 6. (b) Gram-scale
synthesis of 7a with the assistance of a specially designed reactor (see
the Supporting Information for details).
Scheme 4. Synthesis of 1-Phosphorylated Isoquinolines by
Reacting Vinyl Isocyanides with Diphenylphosphine
a
that 2-isocyanoaryl thioethers 6 bearing different substituents,
such as H−, Me−, MeO−, F−, Cl−, Br−, CF3−, and CN− at
the 4-positions of the benzene rings, underwent cycloaddition
smoothly to give the corresponding products 7a−h from
moderate to excellent yields. A range of H-phosphorus oxides
were also evaluated to react with 6a under standard conditions
leading to the desired products (7i−n). Notably, the gram-
scale synthesis of benzo[d]thiazol-2-yldiphenylphosphine oxide
(7a) was performed via our specially designed reactor (Figure
S2) with an isolated yield of 68%.
Oxides
To gain a deeper insight into the reaction mechanism, a
series of mechanistic studies were carried out (Scheme 6).
Initially, two well-known radical scavengers, (2,2,6,6-tetrame-
thylpiperidin-1-yl)-oxidanyl) TEMPO and 2,6-di-tert-butyl-4-
methylphenol (BHT), were employed in the prevention
experiments, resulting in a significant loss in yield of 3a in
each case. A BHT-2a adduct was detected by high-resolution
mass spectrometry (HRMS), reminding us that phosphoryl
radical might be generated photochemically (Scheme 6a; see
Figure S3 for details). The intermolecular kinetic isotope effect
(KIE) experiments were carried out with a 1:1 mixture of
substrates 1a and deuterium-labeled substrates 1a-d5 to verify
the rate-determining step, and the kH/kD for deuterium-labeled
product was found to be 1.2, implying that the cleavage of the
C(sp2)−H bond might not be the rate-determining step and
radical aromatic substitution might be involved in the
cyclization step38 (Scheme 6b; see Figures S4−S6 for details).
The radical species were further confirmed by electron
a
Reaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), PC10 (5 mol %),
TBHP (70% solution in water, 2.0 equiv), and K2CO3 (2.0 equiv) in 2
mL of MeCN under irradiation of blue LEDs with N2 protection at rt
for 12 h. Isolated yields were given on the basis of substrate 4.
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reduced from 1.2 to 1.0 V (Scheme 6d; see Figure S10 for
details).
Scheme 6. Mechanistic Studies
On the basis of our experimental results, a tentative
mechanism for this protocol was proposed as shown in
Scheme 7. Initially, ground-state PC10 is photoactivated to its
Scheme 7. Proposed Mechanism
excited state (PC10*), which leaves a vacancy in a ground-
state orbital that can be filled by an electron donor.
Diphenylphosphine oxide (2a) often exists in rapid equilibrium
with its minor tautomer hydroxydiphenylphophine (2a′).40
A
proton-coupled electron transfer (PCET) process is followed,
proceeding through an electron transfer from 2a′ to PC10*
−
accompanying proton transfer from 2a′ to base (HCO3 ),
giving phosphoryl radical A as well as photocatalyst radical
anion PC10•−, which subsequently reacts with TBHP, via SET
from PC10•− to TBHP, giving rise to hydroxide ion (OH−)
and tert-butoxyl radical together with regenerated PC10.
Thereafter, A undergoes a radical addition to the isocyano
group of substrate 1a to afford the corresponding imidoyl
intermediate B. Intramolecular cyclization of B subsequently
occurs to render the radical intermediate C, which then
paramagnetic resonance (EPR) experiments using tert-butyl-α-
phenylnitrone (DMPO) as a spin trap.39 No signals were
observed in the control group of 2a and DMPO in MeCN
under the irradiation of blue LEDs (gray line). When PC10
and NaHCO3 were added, a strong spectrum signal assigned to
the spin adduct P(O)Ph2−DMPO appeared as a multiplet of
peaks (blue line). In the absence of NaHCO3, the signal was
significantly weakened (red line), and this suggested that the
phosphoryl radical is a key intermediate and its generation
relies on the presence of PC10 and base (Scheme 6c; see
Figure S7 for details). In 2019, Yu’s group20e reported that the
excited state of 4CzIPN can be quenched by 2a and K2CO3;
our luminescence quenching experiments also verified that the
excited state of PC10 was only quenched in the presence of 2a
and NaHCO3 (see Figure S9 for details). Finally, cyclic
voltammetry (CV) experiments indicate that, with the addition
of NaHCO3, the oxidation potential of 2a can be effectively
t
immediately loses an electron to BuO• to form tert-butoxide
anion and cation intermediate D. Because cation intermediate
D is extremely inclined to donate a proton to base, to give
structurally stable N-heteropolyaromatic product 3a, the whole
reaction is thus quickly driven to completion. Besides, a
quantum yield (Φ = 0.3) was calculated, which was well
consistent with our proposed mechanism shown in Scheme 7,
excluding the radical chain process (see the Supporting
Information for details).
Proton-coupled electron transfer (PCET) is a chemical
process that involves the concerted shift of a single electron
and a single proton. PCET contrasts sharply with stepwise
mechanisms in which the electron and proton are transferred
sequentially.41 To explore the possible pathways for the
generation of phosphoryl radical in our case, the density
functional theory (DFT) calculations have been performed at
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Notes
the M06-2X/DZVP level. The calculation results indicate that
the individual electron transfer (ET) and proton transfer (PT)
pathways operate at higher activation energies than does the
concerted pathway, and the PCET pathway should be the most
energetically favorable one among the three possible pathways
(see Figure S13 for details).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the National
Natural Science Foundation of China (21971224, 22071222),
the 111 Project (D20003), and the Key Research Projects of
Universities in Henan Province (20A150006, 20B350001,
21A150053).
CONCLUSION
■
2,4,5,6-Tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)-
isophthalonitrile (4CzIPN-tBu) was synthesized and demon-
strated to be an efficient photocatalyst for the phosphorus-
radical-initiated cascade cyclization reaction of isocyanides.
With the catalysis of 4CzIPN-tBu, a wide range of
phosphorylated aromatics including phenanthridines, quino-
lines, and benzothiazoles were successfully synthesized via a
visible-light-induced proton-coupled electron transfer strategy.
Such findings should be of great interest for the development
of novel transition-metal-free photocatalysts for efficient
organic synthesis.
REFERENCES
■
(1) (a) Matsui, J. K.; Lang, S. B.; Heitz, D. R.; Molander, G. A.
Photoredox-Mediated Routes to Radicals: The Value of Catalytic
Radical Generation in Synthetic Methods Development. ACS Catal.
2017, 7, 2563. (b) Goddard, J.-P.; Ollivier, C.; Fensterbank, L.
Photoredox Catalysis for the Generation of Carbon Centered
Radicals. Acc. Chem. Res. 2016, 49, 1924. (c) Liu, X.-Y.; Qin, Y.
Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical
Cascade Reactions. Acc. Chem. Res. 2019, 52, 1877. (d) Nakajima, K.;
Miyake, Y.; Nishibayashi, Y. Synthetic Utilization of alpha-Aminoalkyl
Radicals and Related Species in Visible Light Photoredox Catalysis.
Acc. Chem. Res. 2016, 49, 1946. (e) Matsui, J. K.; Lang, S. B.; Heitz, D.
R.; Molander, G. A. Photoredox-Mediated Routes to Radicals: The
Value of Catalytic Radical Generation in Synthetic Methods
Development. ACS Catal. 2017, 7, 2563. (f) Chen, J.-R.; Hu, X.-Q.;
Lu, L.-Q.; Xiao, W.-J. Visible light photoredox-controlled reactions of
N-radicals and radical ions. Chem. Soc. Rev. 2016, 45, 2044. (g) Jia, K.;
Chen, Y. Visible-light-induced alkoxyl radical generation for inert
chemical bond cleavage/functionalization. Chem. Commun. 2018, 54,
6105. (h) Xie, J.; Jin, H.; Hashmi, A. S. K. The recent achievements of
redox-neutral radical C-C cross-coupling enabled by visible-light.
Chem. Soc. Rev. 2017, 46, 5193.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11138.
Synthetic procedures, compound characterization, and
additional data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Xiao-Lan Chen − College of Chemistry, Green Catalysis
Centre, Zhengzhou University, Zhengzhou, Henan Province
450001, China; orcid.org/0000-0003-2135-0838;
Email: chenxl@zzu.edu.cn
(2) (a) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Free Radical
Chemistry Enabled by Visible Light-Induced Electron Transfer. Acc.
Chem. Res. 2016, 49, 2295. (b) Plesniak, M. P.; Huang, H.-M.;
Procter, D. J. Radical cascade reactions triggered by single electron
transfer. Nat. Rev. Chem. 2017, 1, 0077.
(3) (a) Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A
Versatile Strategy for Substrate Activation in Photocatalyzed Organic
Synthesis. Eur. J. Org. Chem. 2017, 2017, 2056. (b) Yuan, X.; Yang,
G.; Yu, B. Photoinduced Decatungstate-Catalyzed C-H Functionaliza-
tion. Chin. J. Org. Chem. 2020, 40, 3620−3632.
(4) (a) Strieth-Kalthoff, F.; James, M. J.; Teders, M.; Pitzer, L.;
Glorius, F. Energy transfer catalysis mediated by visible light:
principles, applications, directions. Chem. Soc. Rev. 2018, 47, 7190.
(b) Zhou, Q.-Q.; Zou, Y.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible-Light-
Induced Organic Photochemical Reactions through Energy-Transfer
Pathways. Angew. Chem., Int. Ed. 2019, 58, 1586.
Bing Yu − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China; orcid.org/0000-0002-2423-1212;
Email: bingyu@zzu.edu.cn
Authors
Yan Liu − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China; College of Biological and Pharmaceutical Engineering,
Xinyang Agriculture & Forestry University, Xinyang 464000,
China
Xiao-Yun Li − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China
Shan-Shan Zhu − College of Chemistry, Green Catalysis
Centre, Zhengzhou University, Zhengzhou, Henan Province
450001, China
Shi-Jun Li − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China
Yan Song − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China
(5) Hoffmann, N. Proton-Coupled Electron Transfer in Photoredox
Catalytic Reactions. Eur. J. Org. Chem. 2017, 2017, 1982.
(6) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Visible light
photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev.
2011, 40, 102. (b) Xuan, J.; Xiao, W.-J. Visible-Light Photoredox
Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828. (c) Arias-Rotondo,
D. M.; McCusker, J. K. The photophysics of photoredox catalysis: a
roadmap for catalyst design. Chem. Soc. Rev. 2016, 45, 5803.
(d) Corrigan, N.; Shanmugam, S.; Xu, J.; Boyer, C. Photocatalysis
in organic and polymer synthesis. Chem. Soc. Rev. 2016, 45, 6165.
(e) Ravelli, D.; Fagnoni, M.; Albini, A. Photoorganocatalysis. What
for? Chem. Soc. Rev. 2013, 42, 97. (f) Schultz, D. M.; Yoon, T. P. Solar
synthesis: prospects in visible light photocatalysis. Science 2014, 343,
1239176.
(7) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. Visible light
photoredox catalysis with transition metal complexes: applications in
organic synthesis. Chem. Rev. 2013, 113, 5322. (b) Koike, T.; Akita,
M. Visible-light radical reaction designed by Ru- and Ir-based
photoredox catalysis. Inorg. Chem. Front. 2014, 1, 562. (c) Lang, X.;
Ling-Bo Qu − College of Chemistry, Green Catalysis Centre,
Zhengzhou University, Zhengzhou, Henan Province 450001,
China
Complete contact information is available at:
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Journal of the American Chemical Society
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Article
Zhao, J.; Chen, X. Cooperative photoredox catalysis. Chem. Soc. Rev.
2016, 45, 3026.
(8) (a) Hossain, A.; Bhattacharyya, A.; Reiser, O. Copper’s rapid
ascent in visible-light photoredox catalysis. Science 2019, 364, 450.
(b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075.
(9) Fukuzumi, S.; Ohkubo, K. Organic synthetic transformations
using organic dyes as photoredox catalysts. Org. Biomol. Chem. 2014,
12, 6059.
on through Enzymatic or Long Wavelength Photocatalytic Activation
of Tetrazine Ligation. J. Am. Chem. Soc. 2016, 138, 5978. (k) Ding, Y.;
Li, H.; Meng, Y.; Zhang, T.; Li, J.; Chen, Q.-Y.; Zhu, C. Direct
synthesis of hydrazones by visible light mediated aerobic oxidative
cleavage of the C = C bond. Org. Chem. Front. 2017, 4, 1611.
(l) Kalaitzakis, D.; Daskalakis, K.; Triantafyllakis, M.; Sofiadis, M.;
Vassilikogiannakis, G. Singlet-Oxygen-Mediated Synthesis of Pan-
danusine A and Pandalizine C and Structural Revision of Pandanusine
B. Org. Lett. 2019, 21, 5467.
(10) (a) Kim, H.; Kim, H.; Lambert, T. H.; Lin, S. Reductive
Electrophotocatalysis: Merging Electricity and Light To Achieve
Extreme Reduction Potentials. J. Am. Chem. Soc. 2020, 142, 2087.
(b) Pandey, G.; Laha, R. Visible-Light-Catalyzed Direct Benzylic
C(sp3)-H Amination Reaction by Cross-Dehydrogenative Coupling.
Angew. Chem., Int. Ed. 2015, 54, 14875. (c) Neumeier, M.; Sampedro,
D.; Majek, M.; de la Pena O’Shea, V. A.; Jacobi von Wangelin, A.;
Perez-Ruiz, R. Dichromatic photocatalytic substitutions of aryl halides
with a small organic dye. Chem. - Eur. J. 2018, 24, 105. (d) Alfonzo,
E.; Beeler, A. B. A sterically encumbered photoredox catalyst enables
the unified synthesis of the classical lignan family of natural products.
Chem. Sci. 2019, 10, 7746. (e) Hofstra, J. L.; Grassbaugh, B. R.; Tran,
Q. M.; Armada, N. R.; de Lijser, H. J. P. Catalytic Oxidative
Cyclization of 2′-Arylbenzaldehyde Oxime Ethers under Photo-
induced Electron Transfer Conditions. J. Org. Chem. 2015, 80, 256.
(f) Kammer, L. M.; Lipp, B.; Opatz, T. Photoredox alkenylation of
carboxylic acids and peptides: Synthesis of covalent enzyme
inhibitors. J. Org. Chem. 2019, 84, 2379. (g) Yang, C.; Yang, J.-D.;
Li, Y.-H.; Li, X.; Cheng, J.-P. 9,10-Dicyanoanthracene Catalyzed
Decarboxylative Alkynylation of Carboxylic Acids under Visible-Light
Irradiation. J. Org. Chem. 2016, 81, 12357. (h) Lipp, B.; Lipp, A.;
Detert, H.; Opatz, T. Light-Induced Alkylation of (Hetero)aromatic
Nitriles in a Transition-Metal-Free C-C-Bond Metathesis. Org. Lett.
2017, 19, 2054.
(13) (a) Yoo, W.-J.; Kobayashi, S. Hydrophosphinylation of un-
activated alkenes with secondary phosphine oxides under visible-light
photocatalysis. Green Chem. 2013, 15, 1844. (b) Xie, L.-Y.; Hu, J.-L.;
Song, Y.-X.; Jia, G.-K.; Lin, Y.-W.; He, J.-Y.; Cao, Z.; He, W.-M.
Visible-Light-Initiated Cross-Dehydrogenative Coupling of Quinox-
alin-2(1H)-ones and Simple Amides with Air as an Oxidant. ACS
Sustainable Chem. Eng. 2019, 7, 19993. (c) Xie, P.; Fan, J.; Liu, Y.;
Wo, X.; Fu, W.; Loh, T.-P. Bronsted Acid/Organic Photoredox
Cooperative Catalysis: Easy Access to Tri- and Tetrasubstituted
Alkenylphosphorus Compounds from Alcohols and P-H Species. Org.
Lett. 2018, 20, 3341. (d) Yoshioka, E.; Kohtani, S.; Jichu, T.;
Fukazawa, T.; Nagai, T.; Kawashima, A.; Takemoto, Y.; Miyabe, H.
Aqueous-Medium Carbon-Carbon Bond-Forming Radical Reactions
Catalyzed by Excited Rhodamine B as a Metal-Free Organic Dye
under Visible Light Irradiation. J. Org. Chem. 2016, 81, 7217.
(e) Kalaitzakis, D.; Triantafyllakis, M.; Alexopoulou, I.; Sofiadis, M.;
Vassilikogiannakis, G. One-Pot Transformation of Simple Furans into
4-Hydroxy-2-cyclopentenones in Water. Angew. Chem., Int. Ed. 2014,
53, 13201. (f) Kalaitzakis, D.; Triantafyllakis, M.; Sofiadis, M.;
Noutsias, D.; Vassilikogiannakis, G. Photooxygenation of Furylalkyl-
amines: Easy Access to Pyrrolizidine and Indolizidine Scaffolds.
Angew. Chem., Int. Ed. 2016, 55, 4605. (g) Kouridaki, A.; Montagnon,
T.; Tofi, M.; Vassilikogiannakis, G. Photooxidations of 2-(γ,ε-
Dihydroxyalkyl) Furans in Water: Synthesis of DE-Bicycles of the
Pectenotoxins. Org. Lett. 2012, 14, 2374.
(14) Margrey, K. A.; Nicewicz, D. A. A General Approach to
Catalytic Alkene Anti-Markovnikov Hydrofunctionalization Reactions
via Acridinium Photoredox Catalysis. Acc. Chem. Res. 2016, 49, 1997.
(15) (a) Boyington, A. J.; Seath, C. P.; Zearfoss, A. M.; Xu, Z.; Jui,
N. T. Catalytic Strategy for Regioselective Arylethylamine Synthesis. J.
Am. Chem. Soc. 2019, 141, 4147. (b) Lu, F.-D.; Liu, D.; Zhu, L.; Lu,
L.-Q.; Yang, Q.; Zhou, Q.-Q.; Wei, Y.; Lan, Y.; Xiao, W.-J.
Asymmetric Propargylic Radical Cyanation Enabled by Dual Organo-
photoredox and Copper Catalysis. J. Am. Chem. Soc. 2019, 141, 6167.
(c) Pan, X.; Fang, C.; Fantin, M.; Malhotra, N.; So, W. Y.; Peteanu, L.
A.; Isse, A. A.; Gennaro, A.; Liu, P.; Matyjaszewski, K. Mechanism of
Photoinduced Metal-Free Atom Transfer Radical Polymerization:
Experimental and Computational Studies. J. Am. Chem. Soc. 2016,
138, 2411. (d) Aukland, M. H.; Siauciulis, M.; West, A.; Perry, G. J.
P.; Procter, D. J. Metal-free photoredox-catalysed formal C-H/C-H
coupling of arenes enabled by interrupted Pummerer activation. Nat.
Catal. 2020, 3, 163.
(11) Yan, D.-M.; Chen, J.-R.; Xiao, W.-J. New Roles for
Photoexcited Eosin Y in Photochemical Reactions. Angew. Chem.,
Int. Ed. 2019, 58, 378.
(12) (a) Pitre, S. P.; McTiernan, C. D.; Ismaili, H.; Scaiano, J. C.
Metal-Free Photocatalytic Radical Trifluoromethylation Utilizing
Methylene Blue and Visible Light Irradiation. ACS Catal. 2014, 4,
2530. (b) Kalaitzakis, D.; Kouridaki, A.; Noutsias, D.; Montagnon, T.;
Vassilikogiannakis, G. Methylene Blue as a Photosensitizer and Redox
Agent: Synthesis of 5-Hydroxy-1H-pyrrol-2(5H)-ones from Furans.
Angew. Chem., Int. Ed. 2015, 54, 6283. (c) Li, G. Q.; Yan, Q. L.; Gong,
X. Q.; Dou, X. M.; Yang, D. S. Photocatalyst-Free Regioselective C-H
Thiocyanation of 4-Anilinocoumarins under Visible Light. ACS
Sustainable Chem. Eng. 2019, 7, 14009. (d) Shao, A.; Luo, X.;
Chiang, C.-W.; Gao, M.; Lei, A. Furans Accessed through Visible-
Light-Mediated Oxidative [3 + 2] Cycloaddition of Enols and
Alkynes. Chem. - Eur. J. 2017, 23, 17874. (e) Xu, T.; Cao, T.; Feng,
Q.; Huang, S.; Liao, S. Metal-free dehydrosulfurization of thioamides
to nitriles under visible light. Chem. Commun. 2020, 56, 5151.
(f) Ding, Y.; Zhang, W.; Li, H.; Meng, Y.; Zhang, T.; Chen, Q.-Y.;
Zhu, C. Metal-free synthesis of ketones by visible-light induced
aerobic oxidative radical addition of aryl hydrazines to alkenes. Green
Chem. 2017, 19, 2941. (g) Jiang, H.; Mao, G.; Wu, H.; An, Q.; Zuo,
M.; Guo, W.; Xu, C.; Sun, Z.; Chu, W. Synthesis of dibenzocyclo-
ketones by acyl radical cyclization from aromatic carboxylic acids
using methylene blue as a photocatalyst. Green Chem. 2019, 21, 5368.
(h) Aguirre-Soto, A.; Lim, C.-H.; Hwang, A. T.; Musgrave, C. B.;
Stansbury, J. W. Visible-Light Organic Photocatalysis for Latent
Radical-Initiated Polymerization via 2e−/1H+ Transfers: Initiation
with Parallels to Photosynthesis. J. Am. Chem. Soc. 2014, 136, 7418.
(i) Pitre, S. P.; McTiernan, C. D.; Ismaili, H.; Scaiano, J. C.
Mechanistic Insights and Kinetic Analysis for the Oxidative
Hydroxylation of Arylboronic Acids by Visible Light Photoredox
Catalysis: A Metal-Free Alternative. J. Am. Chem. Soc. 2013, 135,
13286. (j) Zhang, H.; Trout, W. S.; Liu, S.; Andrade, G. A.; Hudson,
D. A.; Scinto, S. L.; Dicker, K. T.; Li, Y.; Lazouski, N.; Rosenthal, J.;
Thorpe, C.; Jia, X.; Fox, J. M. Rapid Bioorthogonal Chemistry Turn-
(16) (a) Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox
Approach To Construct Broadly Applicable Metal-Free Catalysts for
Photoredox Chemistry: Deliberate Tuning of Redox Potentials and
Importance of Halogens in Donor-Acceptor Cyanoarenes. J. Am.
Chem. Soc. 2018, 140, 15353. (b) Singh, V. K.; Yu, C.; Badgujar, S.;
Kim, Y.; Kwon, Y.; Kim, D.; Lee, J.; Akhter, T.; Thangavel, G.; Park,
L. S.; Lee, J.; Nandajan, P. C.; Wannemacher, R.; Milian-Medina, B.;
Luer, L.; Kim, K. S.; Gierschner, J.; Kwon, M. S. Highly efficient
organic photocatalysts discovered via a computer-aided-design
strategy for visible-light-driven atom transfer radical polymerization.
Nat. Catal. 2018, 1, 794. (c) Zhou, C.; Lei, T.; Wei, X.-Z.; Ye, C.; Liu,
Z.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Metal-Free, Redox-Neutral, Site-
Selective Access to Heteroarylamine via Direct Radical-Radical Cross-
Coupling Powered by Visible Light Photocatalysis. J. Am. Chem. Soc.
2020, 142, 16805.
(17) Shang, T.-Y.; Lu, L.-H.; Cao, Z.; Liu, Y.; He, W.-M.; Yu, B.
Recent advances of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
970
https://dx.doi.org/10.1021/jacs.0c11138
J. Am. Chem. Soc. 2021, 143, 964−972

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(4CzIPN) in photocatalytic transformations. Chem. Commun. 2019,
55, 5408.
Reactions (RPARs) Enable the Modular Construction of Cyclo-
propanes. Org. Lett. 2018, 20, 6840. (e) Wang, Z.-J.; Zheng, S.;
Romero, E.; Matsui, J. K.; Molander, G. A. Regioselective Single-
Electron Tsuji-Trost Reaction of Allylic Alcohols: A Photoredox/
Nickel Dual Catalytic Approach. Org. Lett. 2019, 21, 6543. (f) Liu, X.-
C.; Chen, X.-L.; Liu, Y.; Sun, K.; Peng, Y.-Y.; Qu, L.-B.; Yu, B. Visible-
Light-Induced Metal-Free Synthesis of 2-Phosphorylated Thiofla-
vones in Water. ChemSusChem 2020, 13, 298.
(22) (a) Lu, J.; Pattengale, B.; Liu, Q.; Yang, S.; Shi, W.; Li, S.;
Huang, J.; Zhang, J. Donor-Acceptor Fluorophores for Energy-
Transfer-Mediated Photocatalysis. J. Am. Chem. Soc. 2018, 140,
13719. (b) Uoyama, H.; Goushi, K.; Shizu, K.; Nomura, H.; Adachi,
C. Highly efficient organic light-emitting diodes from delayed
fluorescence. Nature 2012, 492, 234.
(23) (a) Leca, D.; Fensterbank, L.; Lacote, E.; Malacria, M. Recent
advances in the use of phosphorus-centered radicals in organic
chemistry. Chem. Soc. Rev. 2005, 34, 858. (b) Gao, Y.; Tang, G.; Zhao,
Y. Recent Advances of Phosphorus-Centered Radical Promoted
Difunctionalization of Unsaturated Carbon-Carbon Bonds. Chin. J.
Org. Chem. 2018, 38, 62. (c) Pan, X.-Q.; Zou, J.-P.; Yi, W.-B.; Zhang,
W. Recent advances in sulfur- and phosphorous-centered radical
reactions for the formation of S−C and P−C bonds. Tetrahedron
2015, 71, 7481. (d) Quint, V.; Noel-Duchesneau, L.; Lagadic, E.;
Morlet-Savary, F.; Lalevee, J.; Gaumont, A.-C.; Lakhdar, S. Metal-Free
Generation of Phosphorus-Centered Radicals for the Synthesis of
Phosphorus-Based Heterocycles: A Personal Account. Synthesis 2017,
49, 3444. (e) Kim, I.; Kang, G.; Lee, K.; Park, B.; Kang, D.; Jung, H.;
He, Y.-T.; Baik, M.-H.; Hong, S. Site-Selective Functionalization of
Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with
Quinolinone. J. Am. Chem. Soc. 2019, 141, 9239. (f) Cai, B.-G.; Xuan,
J.; Xiao, W.-J. Visible light-mediated CP bond formation reactions. Sci.
Bull. 2019, 64, 337. (g) Niu, L.; Liu, J.; Yi, H.; Wang, S.; Liang, X.-A.;
Singh, A. K.; Chiang, C.-W.; Lei, A. Visible-Light-Induced External
Oxidant-Free Oxidative Phosphonylation of C(sp2)-H Bonds. ACS
Catal. 2017, 7, 7412.
(18) (a) Badir, S. O.; Dumoulin, A.; Matsui, J. K.; Molander, G. A.
Synthesis of Reversed C-Acyl Glycosides through Ni/Photoredox
Dual Catalysis. Angew. Chem., Int. Ed. 2018, 57, 6610. (b) Dumoulin,
A.; Matsui, J. K.; Gutierrez-Bonet, A.; Molander, G. A. Synthesis of
Non-Classical Arylated C-Saccharides through Nickel/Photoredox
Dual Catalysis. Angew. Chem., Int. Ed. 2018, 57, 6614. (c) Matsui, J.
K.; Gutierrez-Bonet, A.; Rotella, M.; Alam, R.; Gutierrez, O.;
Molander, G. A. Photoredox/Nickel-Catalyzed Single-Electron
Tsuji-Trost Reaction: Development and Mechanistic Insights.
Angew. Chem., Int. Ed. 2018, 57, 15847. (d) Santandrea, J.; Minozzi,
C.; Cruche, C.; Collins, S. K. Photochemical Dual-Catalytic Synthesis
of Alkynyl Sulfides. Angew. Chem., Int. Ed. 2017, 56, 12255. (e) Stache,
E. E.; Rovis, T.; Doyle, A. G. Dual Nickel- and Photoredox-Catalyzed
Enantioselective Desymmetrization of Cyclic meso-Anhydrides.
Angew. Chem., Int. Ed. 2017, 56, 3679. (f) Yan, H.; Hou, Z.-W.; Xu,
H.-C. Photoelectrochemical C-H Alkylation of Heteroarenes with
Organotrifluoroborates. Angew. Chem., Int. Ed. 2019, 58, 4592.
(g) Dauncey, E. M.; Dighe, S. U.; Douglas, J. J.; Leonori, D. A dual
photoredox-nickel strategy for remote functionalization via iminyl
radicals: radical ring-opening-arylation, -vinylation and -alkylation
cascades. Chem. Sci. 2019, 10, 7728. (h) Phelan, J. P.; Lang, S. B.; Sim,
J.; Berritt, S.; Peat, A. J.; Billings, K.; Fan, L.; Molander, G. A. Open-
Air Alkylation Reactions in Photoredox-Catalyzed DNA-Encoded
Library Synthesis. J. Am. Chem. Soc. 2019, 141, 3723. (i) Matsui, J. K.;
Molander, G. A. Direct α-Arylation/Heteroarylation of 2-Trifluor-
oboratochromanones via Photoredox/Nickel Dual Catalysis. Org. Lett.
2017, 19, 436. (j) Raynor, K. D.; May, G. D.; Bandarage, U. K.; Boyd,
M. J. Generation of Diversity Sets with High sp3 Fraction Using the
Photoredox Coupling of Organotrifluoroborates and Organosilicates
with Heteroaryl/Aryl Bromides in Continuous Flow. J. Org. Chem.
2018, 83, 1551.
(19) (a) Patel, N. R.; Kelly, C. B.; Siegenfeld, A. P.; Molander, G. A.
Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic
Photocatalyst. ACS Catal. 2017, 7, 1766. (b) Yi, J.; Badir, S. O.; Alam,
R.; Molander, G. A. Photoredox-Catalyzed Multicomponent Petasis
Reaction with Alkyltrifluoroborates. Org. Lett. 2019, 21, 4853.
(c) Guo, J.; Wu, Q.-L.; Xie, Y.; Weng, J.; Lu, G. Visible-Light-
Mediated Decarboxylative Benzylation of Imines with Arylacetic
Acids. J. Org. Chem. 2018, 83, 12559.
(20) (a) Hou, J.; Ee, A.; Cao, H.; Ong, H.-W.; Xu, J.-H.; Wu, J.
Visible-Light-Mediated Metal-Free Difunctionalization of Alkenes
with CO2 and Silanes or C(sp3)-H Alkanes. Angew. Chem., Int. Ed.
2018, 57, 17220. (b) Huang, H.; Li, X.; Yu, C.; Zhang, Y.; Mariano, P.
S.; Wang, W. Visible-Light-Promoted Nickel- and Organic-Dye-
Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and
Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent.
Angew. Chem., Int. Ed. 2017, 56, 1500. (c) Ju, T.; Fu, Q.; Ye, J.-H.;
Zhang, Z.; Liao, L.-L.; Yan, S.-S.; Tian, X.-Y.; Luo, S.-P.; Li, J.; Yu, D.-
G. Selective and catalytic hydrocarboxylation of enamides and imines
with CO2 to generate α,α-disubstituted α-amino acids. Angew. Chem.,
Int. Ed. 2018, 57, 13897. (d) Meng, Q.-Y.; Schirmer, T. E.; Berger, A.
L.; Donabauer, K.; Koenig, B. Photocarboxylation of Benzylic C-H
Bonds. J. Am. Chem. Soc. 2019, 141, 11393. (e) Fu, Q.; Bo, Z.-Y.; Ye,
J.-H.; Ju, T.; Huang, H.; Liao, L.-L.; Yu, D.-G. Transition metal-free
phosphonocarboxylation of alkenes with carbon dioxide via visible-
light photoredox catalysis. Nat. Commun. 2019, 10, 3592.
(24) Buquoi, J. Q.; Lear, J. M.; Gu, X.; Nagib, D. A. Heteroarene
Phosphinylalkylation via a Catalytic, Polarity-Reversing Radical
Cascade. ACS Catal. 2019, 9, 5330.
(25) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of The
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257.
(26) (a) Moonen, K.; Laureyn, I.; Stevens, C. V. Synthetic Methods
for Azaheterocyclic Phosphonates and Their Biological Activity.
Chem. Rev. 2004, 104, 6177. (b) Redmore, D. Heterocyclic Systems
Bearing Phosphorus Substituents. Synthesis and Chemistry. Chem.
Rev. 1971, 71, 314. (c) Smith, B. R.; Eastman, C. M.; Njardarson, J. T.
Beyond C, H, O, and N! Analysis of the Elemental Composition of
U.S. FDA Approved Drug Architectures. J. Med. Chem. 2014, 57,
9764.
(27) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A.
K.; Lei, A. Recent Advances in Radical C-H Activation/Radical Cross-
Coupling. Chem. Rev. 2017, 117, 9016. (b) Song, B.; Xu, B. Metal-
catalyzed C-H functionalization involving isocyanides. Chem. Soc. Rev.
2017, 46, 1103. (c) Zhang, B.; Studer, A. Recent advances in the
synthesis of nitrogen heterocycles via radical cascade reactions using
isonitriles as radical acceptors. Chem. Soc. Rev. 2015, 44, 3505.
(28) (a) Zhang, B.; Daniliuc, C. G.; Studer, A. 6-Phosphorylated
Phenanthridines from 2-Isocyanobiphenyls via Radical C-P and C-C
Bond Formation. Org. Lett. 2014, 16, 250. (b) Gao, Y.; Wu, J.; Xu, J.;
Wang, X.; Tang, G.; Zhao, Y. Synthesis of 6-Phenanthridinephosph-
onates via a Radical Phosphonation and Cyclization Process Mediated
by Manganese(III) Acetate. Asian J. Org. Chem. 2014, 3, 691. (c) Li,
D.; Mao, T.; Huang, J.; Zhu, Q. Denitrogenative Imidoyl Radical
Cyclization: Synthesis of 2-Substituted Benzimidazoles from 1-Azido-
2-isocyanoarenes. Org. Lett. 2017, 19, 3223. (d) Liu, Y.; Chen, X.-L.;
Zeng, F.-L.; Sun, K.; Qu, C.; Fan, L.-L.; An, Z.-L.; Li, R.; Jing, C.-F.;
Wei, S.-K.; Qu, L.-B.; Yu, B.; Sun, Y.-Q.; Zhao, Y.-F. Phosphorus
Radical-Initiated Cascade Reaction To Access 2-Phosphoryl-Sub-
(21) (a) Shu, C.; Mega, R. S.; Andreassen, B. J.; Noble, A.; Aggarwal,
V. K. Synthesis of Functionalized Cyclopropanes from Carboxylic
Acids by a Radical Addition-Polar Cyclization Cascade. Angew. Chem.,
Int. Ed. 2018, 57, 15430. (b) Shu, C.; Noble, A.; Aggarwal, V. K.
Photoredox-Catalyzed Cyclobutane Synthesis by a Deboronative
Radical Addition-Polar Cyclization Cascade. Angew. Chem., Int. Ed.
2019, 58, 3870. (c) Phelan, J. P.; Lang, S. B.; Compton, J. S.; Kelly, C.
B.; Dykstra, R.; Gutierrez, O.; Molander, G. A. Redox-Neutral
Photocatalytic Cyclopropanation via Radical/Polar Crossover. J. Am.
Chem. Soc. 2018, 140, 8037. (d) Milligan, J. A.; Phelan, J. P.; Polites,
V. C.; Kelly, C. B.; Molander, G. A. Radical/Polar Annulation
971
https://dx.doi.org/10.1021/jacs.0c11138
J. Am. Chem. Soc. 2021, 143, 964−972

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
stituted Quinoxalines. J. Org. Chem. 2018, 83, 11727. (e) Yang, W. C.;
Wei, K.; Sun, X.; Zhu, J.; Wu, L. Cascade C(sp(3))-S Bond Cleavage
and Imidoyl C-S Formation: Radical Cyclization of 2-Isocyanoaryl
Thioethers toward 2-Substituted Benzothiazoles. Org. Lett. 2018, 20,
3144. (f) Liu, Y.; Li, S.-J.; Chen, X.-L.; Fan, L.-L.; Li, X.-Y.; Zhu, S.-S.;
Qu, L.-B.; Yu, B. Mn(III)-Mediated Regioselective 6-endo-trig
Radical Cyclization of o-Vinylaryl Isocyanides to Access 2-Function-
alized Quinolines. Adv. Synth. Catal. 2020, 362, 688. (g) Li, Y.; Qiu,
G.; Ding, Q.; Wu, J. Synthesis of phenanthridin-6-yldiphenylphos-
phine oxides by oxidative cyclization of 2-isocyanobiphenyls with
diarylphosphine oxides. Tetrahedron 2014, 70, 4652.
D. H.; McCafferty, D. G.; Meyer, T. J. Proton-Coupled Electron
Transfer. Chem. Rev. 2012, 112, 4016. (c) Hammes-Schiffer, S.
Theoretical Perspectives on Proton-Coupled Electron Transfer
Reactions. Acc. Chem. Res. 2001, 34, 273.
(29) Noel-Duchesneau, L.; Lagadic, E.; Morlet-Savary, F.; Lohier, J.-
F.; Chataigner, I.; Breugst, M.; Lalevee, J.; Gaumont, A.-C.; Lakhdar,
S. Metal-Free Synthesis of 6-Phosphorylated Phenanthridines:
Synthetic and Mechanistic Insights. Org. Lett. 2016, 18, 5900.
(30) Li, C. X.; Tu, D. S.; Yao, R.; Yan, H.; Lu, C. S. Visible-Light-
Induced Cascade Reaction of Isocyanides and N-Arylacrylamides with
Diphenylphosphine Oxide via Radical C-P and C-C Bond Formation.
Org. Lett. 2016, 18, 4928.
(31) Wang, C.-H.; Li, Y.-H.; Yang, S.-D. Autoxidation Photoredox
Catalysis for the Synthesis of 2-Phosphinoylindoles. Org. Lett. 2018,
20, 2382.
(32) Luo, J.; Zhang, J. Donor-Acceptor Fluorophores for Visible-
Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic
C(sp3)-C(sp2) Cross-Coupling. ACS Catal. 2016, 6, 873.
(33) (a) Garreau, M.; Le Vaillant, F.; Waser, J. C-Terminal
bioconjugation of peptides through photoredox catalyzed decarbox-
ylative alkynylation. Angew. Chem., Int. Ed. 2019, 58, 8182. (b) Wiles,
R. J.; Phelan, J. P.; Molander, G. A. Metal-free defluorinative arylation
of trifluoromethyl alkenes via photoredox catalysis. Chem. Commun.
2019, 55, 7599. (c) Le Vaillant, F.; Garreau, M.; Nicolai, S.; Gryn’ova,
G.; Corminboeuf, C.; Waser, J. Fine-tuned organic photoredox
catalysts for fragmentation-alkynylation cascades of cyclic oxime
ethers. Chem. Sci. 2018, 9, 5883.
(34) Liu, W.-Q.; Lei, T.; Zhou, S.; Yang, X.-L.; Li, J.; Chen, B.;
Sivaguru, J.; Tung, C.-H.; Wu, L.-Z. Cobaloxime Catalysis: Selective
Synthesis of Alkenylphosphine Oxides under Visible Light. J. Am.
Chem. Soc. 2019, 141, 13941.
(35) Ishimatsu, R.; Edura, T.; Adachi, C.; Nakano, K.; Imato, T.
Photophysical Properties and Efficient, Stable, Electrogenerated
Chemiluminescence of Donor-Acceptor Molecules Exhibiting Ther-
mal Spin Upconversion. Chem. - Eur. J. 2016, 22, 4889.
(36) (a) Fischer, C.; Kerzig, C.; Zilate, B.; Wenger, O. S.; Sparr, C.
Modulation of Acridinium Organophotoredox Catalysts Guided by
Photophysical Studies. ACS Catal. 2020, 10, 210. (b) Noto, N.;
Koike, T.; Akita, M. Visible-Light-Triggered Monofluoromethylation
of Alkenes by Strongly Reducing 1,4-Bis(diphenylamino)naphthalene
Photoredox Catalysis. ACS Catal. 2019, 9, 4382.
(37) Liu, Y.; Chen, X.-L.; Sun, K.; Li, X.-Y.; Zeng, F. L.; Liu, X.-C.;
Qu, L.-B.; Zhao, Y.-F.; Yu, B. Visible-Light Induced Radical
Perfluoroalkylation/Cyclization Strategy To Access 2-Perfluoroalkyl-
benzothiazoles/Benzoselenazoles by EDA Complex. Org. Lett. 2019,
21, 4019.
(38) (a) Tunge, J. A.; Foresee, L. N. Mechanistic Studies of Fujiwara
Hydroarylation. C-H Activation versus Electrophilic Aromatic
Substitution. Organometallics 2005, 24, 6440. (b) Jones, W. D.
Isotope Effects in C-H Bond Activation Reactions by Transition
Metals. Acc. Chem. Res. 2003, 36, 140.
(39) Wang, H.; Li, Y.; Tang, Z.; Wang, S.; Zhang, H.; Cong, H.; Lei,
A. Z-Selective Addition of Diaryl Phosphine Oxides to Alkynes via
Photoredox Catalysis. ACS Catal. 2018, 8, 10599.
(40) Christiansen, A.; Li, C.; Garland, M.; Selent, D.; Ludwig, R.;
̈
Spannenberg, A.; Baumann, W.; Franke, R.; Borner, A. On the
Tautomerism of Secondary Phosphane Oxides. Eur. J. Org. Chem.
2010, 2010, 2733.
(41) (a) Warren, J. J.; Tronic, T. A.; Mayer, J. M. Thermochemistry
of Proton-Coupled Electron Transfer Reagents and its Implications.
Chem. Rev. 2010, 110, 6961. (b) Weinberg, D. R.; Gagliardi, C. J.;
Hull, J. F.; Murphy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess,
972
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