Eosin Y as a Redox Catalyst and Photosensitizer for Sequential Benzylic C?H Amination and Oxidation

Article abstract of DOI:10.1002/chem.201804229

A new synergistic multicatalytic activation mode of eosin Y has been discovered by exploiting the redox potential of its ground state and excited state. This catalytic strategy proves to be an enabling tool for visible-light-driven sequential benzylic C?H amination and oxidation of o-benzyl-N-methoxyl-benzamides when using Selectfluor as a hydrogen atom transfer (HAT) reagent and O₂ as oxidant. Efficient synthesis of a range of diversely functionalized 3-hydroxyisoindolinones can thus be achieved with good yields and selectivity at mild reaction conditions. Preliminary mechanistic studies and DFT calculations suggest that eosin Y works as a redox catalyst and photosensitizer.

Full text of DOI:10.1002/chem.201804229

A Journal of
Accepted Article
Title: Eosin Y as a Redox Catalyst and Photosensitizer for Sequential
Benzylic C-H Amination and Oxidation
Authors: Wen-Jing Xiao, Dong-Mei Yan, Quan-Qing Zhao, Li Rao, and
Jia-Rong Chen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201804229
Link to VoR: http://dx.doi.org/10.1002/chem.201804229
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Eosin Y as a Redox Catalyst and Photosensitizer for Sequential
Benzylic C-H Amination and Oxidation
Dong-Mei Yan, Quan-Qing Zhao, Li Rao, Jia-Rong Chen,* and Wen-Jing Xiao*
Abstract: A new synergistic multicatalytic activation mode of eosin Y
has been discovered for the first time by exploiting the redox potential
of its ground state and excited state. This catalytic strategy proves to
be an enabling new tool for visible light-driven sequential benzylic
C-H amination and oxidation of o-benzyl-N-methoxyl-benzamides
when using Selectfluor as HAT reagent and O2 as oxidants. Efficient
regulating the redox potential of rhodamine 6G, thus controlling
selective and sequential C-H photoarylations of arenes and
heteroarenes.[5b] On the other hand, MacMillan,[6] Nicewicz,[7]
Knowles,[8] and others[9] disclosed that incorporation of hydrogen
atom transfer (HAT) into visible light photocatalysis by adding
external organic radical precursors allowed the activation of the
inert C-H bonds to proceed with minimal dependence on the
electronic or steric properties of substrates. Surprisingly, to the
best of our knowledge, the potential of using both of the ground
state and excited state of photocatalysts in synergistic multiple
catalytic cycles has remained largely unexplored.
synthesis
of
a
range
of
diversely
functionalized
3-hydroxyisoindolinones can thus be achieved with good yields and
selectivity at mild reaction conditions. Preliminary mechanistic
studies and DFT calculations suggest that eosin Y works as a redox
catalyst and photosensitizer.
Eosin
Y has been widely used as economically and
ecologically superior alternative to transition metal complexes in
organic photochemistry due to its low cost, easy handling, and
eco-friendly.[1d,10] It has mostly been employed as a SET oxidant
or reductant upon conversion to its excited state by visible light
irradiation. Interestingly, the Wang group recently reported that
photoexcited eosin Y could function as phenolic acid to catalyze
direct addition of alcohols to glycols, allowing stereoselective
synthesis of 2-deoxyglycosides (Scheme 1a).[11a] In contrast, Wu
and coworkers identified photoexcited eosin Y as a direct
hydrogen atom transfer (HAT) catalyst to enable general
alkylation of C-H bonds with electron-deficient alkenes.[11b] These
two inspiring discoveries opened a new way to explore the new
photocatalytic activity mode of eosin Y.
Visible light-driven photoredox catalysis has recently been
established as a mild and powerful platform for organic molecule
activation and invention of many unique and valuable chemical
reactions.[1] However, in many cases, visible light-driven
synthetic transformations typically capitalize on the excited state
of photocatalysts since they are more reducing and more
oxidizing than their ground states. The merger of photocatalysts
with suitable transition metals or organocatalysts has brought
about a variety of versatile dual-catalyst methods that provide
access to the development of distinct and highly enabling
activation modes.[2] Moreover, rational design of light-responsive
chiral complexing agents, ligands or catalysts has provided a
potentially fruitful tool for engineering the stereocontrol in
photochemical reactions.[3,4] Despite their impressive catalytic
performances, key to the success of each of the aforementioned
methods mainly relies on the single electron transfer
(SET)-based activation of the substrates triggered by the excited
state photocatalysts through a single photocatalytic cycle, thus
limiting the synthetic scope of photocatalysis to somewhat
extent.
Instead of modifying the molecular structure of the
photocatalysts, stimuli-driven adjustment of their redox potential
has emerged as another attractive strategy for activation of much
stronger chemical bonds. With fluorescent dye perylene diimide
as a photocatalyst, the Konig group pioneered the application of
consecutive photoinduced electron transfer to the reduction of
stable aryl halides into aryl radicals by utilizing the energies of
two photons in a single catalytic cycle.[5a] The same group has
also discovered that using different light color enabled finely
Scheme 1. Exploration of new catalytic modes of eosin Y catalyst and reaction
design of sequential C-H amination/oxidation. HAT = hydrogen atom transfer.
[*]
D.-M. Yan, Q.-Q. Zhao, Prof. Dr. L. Rao, Prof. Dr. J.-R. Chen, Prof.
Dr. W.-J. Xiao
As a matter of fact, the ground state of eosin Y itself also has
a redox potential, though relatively lower compared to its excited
state; until now, such a property has never been explored in the
context of catalysis. Drawing inspiration from the recent utility of
N-oxyl radicals[12a] and thiyl radicals[12b] in catalytic radical
reactions, we proposed that the ground state eosin Y might be
oxidized by external oxidant to form the related radical species in
situ, which would then serve to activate C-H bonds by a HAT
process. Further combination of this activity with visible
light-driven photoredox catalysis would probably enable the
CCNU-uOttawa Joint Research Centre, Hubei International Scientific
and Technological Cooperation Base of Pesticide and Green
Synthesis, Key Laboratory of Pesticides & Chemical Biology Ministry
of Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: chenjiarong@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn
Prof. Dr. W.-J. Xiao
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University
Lanzhou 730000 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201804229
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development of synergistic multiple catalytic cycles. Here, we
describe the first example of this concept, displaying that the
ground state and excited state of eosin Y serve as a redox
catalyst and photosensitizer, respectively. With this hypothesis in
mind and based on our continuing interest in photocatalytic
amination and oxidation,[13] we chose to develop a sequential
the reaction is very sensitive to the solvent; and no product or
only moderate NMR yields were observed when using THF,
CH2Cl2, MeOH, toluene or DMSO as the solvents (entries 3-7). In
sharp contrast, the use of PhI(OAc)2 as an oxidant resulted in
exclusive formation of aryl sp2 C-H amination product 3 instead
with 80% yield (entry 8). To confirm the necessity of all of the
reaction parameters such as Selectfluor, oxygen, eosin Y and
visible light for the present sequential C-H amination and
oxidation, a set of control experiments were then carried out.
Interestingly, we successfully isolated isoindolinone 4 as the sole
product when the reaction was performed under Ar atmosphere
(entry 9), indicating that 4 might be the reaction intermediate. In
the absence of Selectfluor, the reaction did not give any desired
product 2a (entries 10). Interestingly, in the absence of
photocatalyst, or without visible light irradiation, the desired
product 2a was formed in moderate NMR yields (entries 11 and
12). These results show that background reaction proceeding
through Selectfluor-mediated oxidation of benzylic C-H to
carbonyl group and ring-closing tautomerization might also work
to somewhat extent.[17b,19] Notably, replacement of Selectfluor
C-H
amination
and
oxidation
of
o-benzyl-N-methoxyl-benzamides for the first time (Scheme
1B).[14,15] Such reaction would provide a facile access to various
biologically and synthetically useful 3-hydroxyisoindolinone
derivatives, such as inhibitor of the in MDM2-p53 interaction, III
NU8231.[16]
Table 1: Optimization of the reaction conditions.[a]
t
with other commonly used oxidants, such as BuOOH, K2S2O8,
AgNO3, and MnO2 resulted in no formation of 2a. However,
combination of these oxidants with quinuclidine under otherwise
identical conditions resulted in moderate yields of 2a.[19] These
results implied that Selectfluor may not only serve as an oxidant,
but also play another important role, such as a HAT reagent.
Entry
Oxidant
O2
Solvent
Yield [%][b]
1
2[d]
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
PhI(OAc)2
Selectfluor
-
+
+
+
+
+
+
+
+
-
CH3CN
CH3CN
THF
87(85)[c]
68[c]
15
13
9
3
4
CH2Cl2
MeOH
toluene
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
6
4
7
0
8
0[e]
0[f]
0
9
10
11[g]
12[h]
+
+
+
Selectfluor
Selectfluor
31
39
[a] Reaction conditions: 1a (0.1 mmol), oxidant (0.1 mmol), eosin Y (5 mol%),
solvent (2.0 mL), 7 W blue LEDs, 1 atmosphere of O2, at room temperature for
6 h. [b] Determined by 1H NMR analysis with triphenylmethane as an internal
standard. [c] Isolated yield. [d] Using green LEDs as a light source. [e] No
desired product 2a was detected, and aryl sp2 C-H amination product 3 was
formed exclusively in 80% yield. [f] No desired product 2a was detected, and
isoindolinone 4 was isolated in 73% yield. [g] Without photocatalyst eosin Y. [h]
Without visible light irradiation.
Our study began with the sequential C-H amination and
oxidation of readily accessible o-benzyl-N-methoxyl-benzamide
1a under visible light irradiation and an oxygen atmosphere using
Selectfluor as an external oxidant because of its unique oxidizing
ability (Table 1).[17] Moreover, the Selectfluor-derived N-radical
dication might also initiate a HAT process.[18] Pleasingly, a brief
screen of commonly used photocatalysts revealed that the eosin
Y catalyst proved to be superior to others, leading to a clean
reaction and giving the desired 3-hydroxyisoindolinone 2a
exclusively in 85% isolated yield (entry 1),[19] which was also
unambiguously confirmed by single crystal X-ray crystallographic
analysis.[20] However, switching the blue LEDs to green LEDs as
the light source resulted in a significant decrease of the yield
(entry 2). A simple evaluation of the reaction media showed that
Scheme 2. Mechanistic studies.
To gain insights into the reaction mechanism, a set of control
and comparison experiments were then conducted with model
substrate 1a (Scheme 2). First, inspired by the formation of
isoindolinone 4 observed during the course of optimization study
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(Table 1, entry 9), we hypothesized that the reaction might
proceed through the intermediacy of such compound.
Interestingly, a series of control reactions confirmed that only in
the presence of Selectfluor and eosin Y can the substrate 1a be
transformed to isoindolinone 4 in 73% yield even in the dark
under Ar atmosphere. Specifically, the C-H bond amination step
(1a→4) is not a visible light-driven photocatalytic process, but
eosin Y is critical to this step.[19] Notably, Shi, Houk, and their
coworkers recently disclosed an elegant iodoarene-catalyzed
intramolecular C-H amination of o-alkyl-N-methoxyl-benzamides
for the synthesis of analogues of isoindolinone 4 using m-CPBA
as oxidant under thermal conditions.[21] Then, we carried out a
step-by-step, one-pot reaction of 1a (Scheme 2a). Upon almost
full conversion of 1a to 4, we subjected the reaction mixture to an
atmosphere of oxygen under irradiation of 7 W blue LEDs for
another 24 h. Though the reaction proceeded with lower
efficiency compared to that carried out under standard conditions
(Table 1, entry 1), we successfully isolated desired product 2a in
59% yield. Interestingly, the reaction of the isolated compound 4
under the standard conditions of entry 1 of Table 1 completed
within 6 h, affording 2a in 82% yield (Scheme 2b). This result
suggests that the C-H oxidation of compound 4 might proceed
through an oxidative quenching cycle, since Selectfluor could
easily oxidize the photoexcited eosin Y* (supporting information,
Fig. S5).[10] Moreover, replacement of Selectfluor with its reduced
form 7 under otherwise same conditions could also facilitate the
conversion of 4 into product 2a though with relatively lower
efficiency (Scheme 2c). Taken together, these results verify that
4 is the reaction intermediate, and both of Selectfluor and
reduced form 7 might be involved in the catalytic cycles. In the
presence of 3.0 equiv of radical scavenger TEMPO, the yield of 4
was reduced to 32%; and TEMPO-adduct 5 was also detected by
HRMS analysis of the reaction mixture (Scheme 2d).[19] These
findings suggest the involvement of a benzyl radical species in
this transformation. As expected, the isotope labeling experiment
of 1a showed that the oxygen of hydroxyl group in product 2a
originated from molecular dioxygen (Scheme 2e).
examined the effect of Selectfluor on the absorption of eosin Y.
To our surprise, the solution of eosin Y and Selectfluor in
acetonitrile was light yellow instead of usual red color.[19] Though
the neutral eosin Y has a characteristic absorption peak at ~539
nm caused by its monoanionic form (Figure 1, red line),[10] the
addition of Selectfluor resulted in complete disappearance of its
characteristic absorption peak (green line). Thus, we believe this
to be a consequence of facile acid-base equilibration of the eosin
Y, since the max absorption peak at ~539 nm appeared again
upon addition of base Na2CO3 (orange line).
Scheme 3. DFT calculation studies on the benzylic C-H amination.
To better understand the mechanism, we first performed DFT
calculations to investigate the possibility of SET process between
the ground state eosin Y and Selectfluor.[19] The calculations
indicate that the SET oxidation of neutral eosin Y by Selectfluor is
exothermic by 9.7 kcal/mol, producing delocalized spirocyclic
eosin Y radical and Selectfluor radical cation 7-A (Scheme 3a).
Then, Selectfluor radical cation 7-A serves as a HAT reagent to
abstract a hydrogen atom from 1a to give ammonium ion 7-B and
benzyl radical 1a-A,[22] which is also a exothermic process (ΔG =
-22.1 kcal/mol) (Scheme 3b). Fortunately, we successfully
isolated reduced Selectfluor 7 by simple workup procedure,
which was fully characterized by NMR and HRMS methods.[19]
Figure 1. UV-Vis absorption spectra of the related mixtures recorded in CH3CN.
Base = Na2CO3. The dianionic eosin Y Na2 shows absorption peak at 528 nm.
Eosin Y has pronounced acid-base properties due to its
unique structural scaffold, and can exist as an equilibrating
mixture of four components depending on the reaction conditions
(solvents), including the neutral spirocyclic eosin Y-H2spiro and
ring-opened eosin Y-H2, monoanionic form and dianionic form.[10]
These four structures typically exhibit different visible absorption
and photocatalytic activity. To assist the understanding of the
interaction involved between Selectfluor and eosin Y, we
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Moreover, the cyclization of benzyl radical 1a-A is exergonic by
catalytic cycle after deprotonation. Then, the radical species
1a-B could be intercepted by O2 radical anion, followed by
protonation to furnish hydroperoxide 1a-C. Reduction of 1a-C by
another molecule of isoindolinone 4 leads to formation of the final
product 2a. It should be noted that based on the control
experimental results of Scheme 2b, Selectfluor (E1/2 = +0.33 V vs
SCE in CH3CN)[17] might also be involved in this C-H oxidation
step through oxidative quenching cycle given their oxidation
potential of the excited state eosin Y* (E1/2ox = -1.11 V vs SCE in
CH3CN) (path b).[19,15k] Although the system is complex, and a
precise understanding of the roles of eosin Y awaits further
studies, these control experiments actually also confirm that
eosin Y should be critical to both C-H amination and oxidation
steps.[11b,23] Future studies along this line will be carried out in the
near future.
means of eosin Y radical-promoted concerted SET/cyclization
(ΔG
=
-38.8 kcal/mol) (Scheme 3c). The subsequent
deprotonation has an activation energy barrier of just 1.4
kcal/mol, resulting in facile formation of C-H amination product 4
and regeneration of neutral eosin Y. Overall, the cyclization of
benzyl radical 1a-A is exergonic by 65.6 kcal/mol. Taken
together, the benzylic C-H amination step (1→4) should proceed
through a redox catalytic cycle (Scheme 4). In this catalytic cycle,
the ground state eosin Y serves as a redox catalyst, and
Selectfluor acts as an external oxidant and HAT reagent.
Table 2: Substrate scope.[a,b]
Scheme 4. Possible mechanism.
Moreover, drawing from the mechanistic insights obtained in
the control experiments and recent HAT catalysis of tertiary
amine,[9,22] we thus presume that amine 7 could also participate
in the proposed synergistic HAT and photoredox catalysis to
promote benzylic C-H oxidation (4→2a) (Scheme 4, path a). At
this stage, visible light irradiation of the ground state eosin Y
produces the long-lived excited state eosin Y* (E1/2red = +0.83 V),
which is sufficiently oxidizing to undergo reduction quenching by
the HAT reagent 7 (E1/2ox = +0.79 V vs SCE in CH3CN)[19] via an
SET process, generating amine radical cation 7-A and the
reduced form of eosin Y.[22] Then, the reduced photocatalyst can
be oxidized by O2 to regenerate the ground state eosin Y with
release of O2 radical anion, closing the photoredox catalytic cycle.
We believe that the transiently formed electron-defficient amine
radical cation 7-A would then engender a kinetically favorable
HAT event at the benzylic position of 4, thereby delivering benzyl
radical 1a-B and ammonium ion 7-B and completing the HAT
[a] Reaction conditions: 1a (0.2 mmol), Selectfluor (0.2 mmol), eosin Y (5
mol%), CH3CN (4.0 mL), 7 W blue LEDs, 1 atmosphere of O2, at room
temperature for 6 h. [b] Isolated yields.
With this synergistic multicatalytic activation mode of eosin Y
established, we then evaluated its synthetic potential across a
representative set of substrates on a 0.2 mmol scale. As shown
in Table 2, the catalytic system shows wide substrate scope and
good functional group tolerance. First investigation into the effect
of the R1 group on the nitrogen atom displays that, in addition to
the methoxyl group, neutral phenyl ring as well as those with
electron-withdrawing (e.g., Br) or weakly electron-donating (e.g.,
Me) groups are well tolerated, giving the corresponding products
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2b-2d in 50-70% yields (Table 2a). When R1 are alkyl groups,
such as labile benzyl, cyclohexyl, and protected amino ethyl, the
reactions all proceeded smoothly to deliver products 2e-2g with
good yields. Next, we examined the effect of variation of the R2
substituent on the reaction (Table 2b). With R2 as an aryl group,
we found that the reactions of substrates 1h-1m bearing a chloro,
methyl, methoxyl, phenyl or tert-butyl group at the para-position
or ortho-position of the phenyl ring worked well to furnish
products 2h-2m in a range of 54-76% yields. As shown in the
synthesis of multi-substituted 2n, the substitution pattern and
steric hindrance of the aromatic ring has no influence on the
We are grateful to the NNSFC (21472057, 21472058, 21622201
and 21772053), the Science and Technology Department of
Hubei Province (2016CFA050 and 2017AHB047), and the
Program of Introducing Talents of Discipline to Universities of
China (111 Program, B17019) for support of this research. We
offer special thanks to Profs. Axel Jacobi von Wangelin and
Burkhard König for valuable discussions and suggestions.
Conflict of interest
reaction either. As
a limitation of the method, however,
substrates with R2 substituent being alkyl groups proved to be
not suitable for the reaction at the current stage (results not
shown). Notably, the reactions of substrates 1o-1q with R3 group
being chloro, methoxyl or other alkoxyl groups also underwent
the expected benzylic C-H amination and oxidation efficiently to
give the corresponding products 2o-2q in 40-67% yields.
The authors declare no conflict of interest.
Keywords: photoredox catalysis • redox catalysis • oxidation •
amination • isoindolinones
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we also carried out the model reaction of 1a under sunlight
irradiation; and comparable yield was still obtained after 5 h (80%
yield) [Eq. (1)]. Moreover, the scalability of this procedure was
demonstrated by a 5.0 mmol (1.21 g) reaction of 1a under the
standard conditions, which proceeded smoothly to give 2a in
64% yield (0.82 g) [Eq. (2)]. The standard conditions also proved
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which allows easy further synthesis of MDM2-p53 inhibitor III
NU8231 by conversion to chloride and treatment with syringic
alcohol 8 in a two-step, one-pot manner [Eq. (3)].[16]
In summary, we have developed a synergistic multicatalytic
activation mode of eosin Y for the first time by exploiting both of
the redox properties of its ground state and excited state. This
catalytic strategy provides an enabling new tool for visible
light-driven sequential benzylic C-H amination and oxidation of
o-benzyl-N-methoxyl-benzamides. Efficient synthesis of a range
of diversely functionalized 3-hydroxyisoindolinones can thus be
achieved with good yields at mild conditions.[24] Preliminarily
evidence suggests that Eosin Y works as a redox catalyst and
photosensitizer. More detailed mechanistic studies and efforts to
extend eosin Y to other C-H bond functionalization are currently
ongoing.
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Acknowledgements
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10.1002/chem.201804229
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Photochemistry
Dong-Mei Yan, Quan-Qing Zhao, Li Rao,
Jia-Rong Chen,* and Wen-Jing Xiao*
Page No. – Page No.
Eosin Y as a Redox Catalyst and
Photosensitizer for Sequential Benzylic C-H
Amination and Oxidation
A new synergistic multicatalytic activation mode of eosin Y has been
discovered for the first time by exploiting the redox potential of its ground
state and excited state. This catalytic strategy proves to be an enabling new
tool for visible light-driven sequential benzylic C-H amination and oxidation
of o-benzyl-N-methoxyl-benzamides when using Selectfluor as HAT reagent
and O2 as oxidants. Efficient synthesis of a range of diversely functionalized
3-hydroxyisoindolinones can thus be achieved with good yields and
selectivity at mild reaction conditions. Preliminary mechanistic studies and
DFT calculations suggest that Eosin Y works as a redox catalyst and
photosensitizer.
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