Merging Photoredox with Br?nsted Acid Catalysis: The Cross-Dehydrogenative C?O Coupling for sp3 C?H Bond Peroxidation

Article abstract of DOI:10.1002/chem.201701755

A photoredox and Br?nsted acid synergistically catalyzed cross-dehydrogenative C?O coupling reaction is developed in which isochroman peroxyacetals are formed through sp³ C?H bond peroxidation. The reported method is characterized by its extremely mild reaction conditions, excellent yields, and broad substrate scope. An oxocarbenium ion p-chlorobenzenesulfonate was speculated to be the reactive intermediate. The role of hemiacetals and oxygenated dimers on the effective stabilization of the oxocarbenium ion was investigated; the presence of acid appeared to establish equilibrium between hemiacetals and oxygenated dimers with the oxocarbenium ion pairs. The broad applicability of the method highlights the potential of the protocol for molecule synthesis.

Full text of DOI:10.1002/chem.201701755

A Journal of
Accepted Article
Title: Merging Photoredox with Brønsted Acid Catalysis: The Cross-
Dehydrogenative C-O Coupling for sp3 C-H Bond Peroxidation
Authors: Qingmin Wang, Qing Xia, Qiang Wang, Changcun Yan,
Jianyang Dong, Hongjian Song, Ling Li, Yuxiu Liu, Xiangming
Liu, and Haibin Song
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To be cited as: Chem. Eur. J. 10.1002/chem.201701755
Link to VoR: http://dx.doi.org/10.1002/chem.201701755
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Merging Photoredox with Brønsted Acid Catalysis: The Cross-
Dehydrogenative C–O Coupling for sp3 C-H Bond Peroxidation
Qing Xia, Qiang Wang, Changcun Yan, Jianyang Dong, Hongjian Song, Ling Li, Yuxiu Liu, Qingmin
Wang,* Xiangming Liu, Haibin Song
Abstract: A photoredox and Brønsted acid synergistically catalyzed
cross-dehydrogenative C–O coupling reaction is developed, in which
isochroman peroxyacetals are formed through the sp3 C-H bond
peroxidation. The reported method is characterized by its extremely
mild reaction conditions, excellent yields and broad substrate scope.
An oxocarbenium ion p-chlorobenzenesulfonate was speculated to
be the reactive intermediate. The role of hemiacetals and
oxygenated dimers on the effective stabilization of the oxocarbenium
ion was investigated; the presence of added acid appeared capable
of establishing equilibrium between hemiacetals and oxygenated
dimers with the oxocarbenium ion pairs. Broad applicability will
highlight the capacity of the protocol in future molecule synthesis.
Introduction
Cross dehydrogenative coupling (CDC) reaction, which using
only C-H bonds to construct C-C bonds, represents a new
generation of coupling reaction. It can omit the preparation of
functional groups and thus make synthetic schemes shorter and
more efficient.[1] Since 2004, Li’s group has contributed lots of
elegant work on CDC, which allowed the connection of Csp-H,
Csp2-H, and even Csp3-H bonds with each other.[2] Focusing on
the tert-butyl hydroperoxide (TBHP)-engaged copper(I)-
catalyzed CDC Mannich-type reaction of tertiary amines
developed by Li’s group,[2c,2d] Klussmann and co-workers
Scheme 1. Different Approaches toward the Cross Dehydrogenative Coupling
demonstrated the existence of an on-cycle aza-peroxyacetal and
revealed the mechanism of this CDC reaction to be a hydrogen
Numerous peroxide-containing natural products have been
atom transfer (HAT) and a subsequent radical coupling (Scheme
isolated, and many of them possess highly potent antitumor,
1a).[3] However, Doyle and co-workers later proposed a different
antibacterial, and antimalarial activities.[6] For example,
mechanism in which the intermediate aza-peroxyacetal was
artemisinin (qinghaosu) has been proven a highly effective drug
supposed to form through a single electron transfer (SET) and a
for eradicating malaria, one of the most widespread and life-
subsequent nucleophilic reaction (Scheme 1b).[4] In addition,
threatening parasitic diseases.[7] Focused on the special
many other groups also presented elegant work on the CDC
peroxide structure, many pharmaceuticals and molecules with
reactions using the substrates of tertiary amines and ethers.[5] In
peroxide moieties have been designed and synthesized.[8]
general, mechanistic studies of these reactions are rare and still
Surpassingly, the Dussault’s group established series of
controversial, and the lack of a detailed understanding makes
methods for the construction of organic peroxides.[9] The group
further developments difficult.
of Deng have made significant advances in asymmetric
synthesis of organic peroxides by using cinchona alkaloid
derivatives as organocatalysts.[10] Elegant work have also been
contributed by the groups of Li, List and Antilla.[11] The
development of improved methods for peroxidation should have
value for the synthesis of natural products and the development
of new pharmaceuticals.
[a]
Q. Xia, Q. Wang, C.-C. Yan, J.-Y. Dong, H.-J. Song, L. Li, Y.-X. Liu,
X.-M. Liu, H.-B. Song, Prof. Q.-M. Wang
State Key Laboratory of Elemento-Organic Chemistry, Research
Institute of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, People’s Republic of China
E-mail: wangqm@nankai.edu.cn, wang98@263.net
Prof. Q.-M. Wang
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071, People’s Republic of China
The rapid growth of organic photoredox catalysis has
prompted a renewed interest in radical transformations initiated
by outer sphere electron transfer (ET).[12] Seminal studies of
MacMillan’s group demonstrated that the incorporation of HAT
catalysis and transition metal with the amine or ether substrates
enables photocatalytic formation of α-amino radical[13] or α-
oxyalkyl radical[14] and subsequent C-C bond formation. Inspired
by this work, herein we present a method for constructing
Supporting information for this article is given via a link at the end of
the document.
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isochroman peroxyacetals which merging photoredox catalysis
with cross-dehydrogenative C–O coupling reaction (Scheme 1c).
Primary mechanism studies demonstrated a plausible pathway
that photoredox and Brønsted acid dually catalyzed this
peroxidation, and we also elucidated the structure of the reactive
intermediate as well as the stabilizing effect of reservoir.
oxocarbenium ion may not stable enough. With water as
nucleophile, 5 and 6 were generated and established equilibrium
with the unstable oxocarbenium ion, therefore displaying a
stabilizing effect.[3b,16] Inspired by this speculation, we were
encouraged to investigate the influence of Brønsted acid
additives which could facilitate the breakdown of 5 and 6 into
oxocarbenium ion and on the other hand promote the
electrophilicity of oxocarbenium ion through binding a suitable
Brønsted acid anion (X−).[15b,17] Unsurprisingly, when 10 mol% of
p-chlorobenzenesulfonic acid (CBSA) was added to the reaction
mixture, after 10 h up to 80% yield of 3aa was obtained (entry 4).
Comparatively, only 45% yield of 3aa was generated in the
absence of Brønsted acid additive (entry 5). Extensive screening
of Brønsted acid was conducted but no higher yield was
observed (entries 6 and 7 and Table S5). Decreasing the
amount of CBSA to 5 mol% slightly reduced the yield of 3aa
(entry 8). Last, control experiments revealed the absolute
necessity of photocatalyst and light in this new peroxidation
protocol (entries 9 and 10).
Results and Discussion
Table 1. Optimization of the Reaction Conditions[a]
entry
deviation from standard
conditions
3aa (%)[b]
4 (%)[b]
1
none
64
20
13
36
7
2
DME instead of TBME
2 equiv of TBHP
10 mol% of CBSA
none
63
3
52
Table 2. Scope of the Substituted Isochroman[a][b]
4[c]
5[c]
6[c]
7[c]
8[c]
9
80
45
19
8
10 mol% of MSA
10 mol% of PTSA
5 mol% of CBSA
no photocatlyst
no light
73
72
9
76
13
8
trace
trace
10
7
[a]Standard conditions: 1a (0.5 mmol), 2a (1.5 mmol, 5.5 M in decane),
Ir(ppy)3 (0.005 mmol, 1 mol%) in TBME (1.5 mL) were irradiated by 13 W
white LED for 20 h under argon atmosphere. [b]Isolated yield. [c]Reaction
time 10 h. See Supporting Information for the details of optimization
studies.
Our initial studies focused on the construction of isochroman
tert-butylperoxyacetal (3aa, Table 1). When a solution of
isochroman (1a) and TBHP (2a, 3 equiv) in the presence of
Ir(ppy)3 (1 mol%) as photocatalyst in TBME (0.3 M) was
illuminated with a 13 W white LED under argon atmosphere at
room temperature for 20 h, 3aa was obtained in 64% yield along
with 20% yield of by-product isochromanone (4) (Table 1, entry
1; For the details of optimization studies, see Supporting
Information). The efficiency of the reaction was highly dependent
on the solvent. Ether solvents performed applicably for this
reaction, and TBME outperformed both DME and dioxane (entry
2 and Table S2). Reduce the amount of TBHP to 2 equivalent
apparently lowered the yield of 3aa (entry 3). With the condition
of entry 1 in Table 1, besides 3aa and 4, a modicum of
hemiacetal 5 (7%) and oxygenated dimer 6 (4%) was also
isolated. According to precedent mechanistic studies on the
ether oxidation,[15] we speculated that the generated
[a]Conditions: 1b-1o (0.5 mmol), 2a (1.5 mmol, 5.5 M in decane), Ir(ppy)3
(0.005 mmol, 1 mol%) and CBSA (0.05 mmol, 10 mol%) in TBME (1.5 mL)
were irradiated by 13 W white LED for 20 h under argon atmosphere.
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[b]Isolated yield. [c]Diastereoisomer ratios (dr) determined by 1H NMR.
[a]Conditions: 1q-1y (0.5 mmol), 2a (1.5 mmol, 5.5 M in decane), Ir(ppy)3
(0.005 mmol, 1 mol%) and CBSA (0.05 mmol, 10 mol%) in TBME (1.5 mL)
were irradiated by 13 W white LED for 20 h under argon atmosphere.
[b]Isolated yield.
Encouraged by these results, we turned our attention to the
influence of substituted isochroman through this protocol (Table
2). In general, the reactions proceeded smoothly to generate the
desired isochroman tert-butylperoxyacetals in good yields (66-
94%). The electron-withdrawing substituents as well as electron-
donating substituents performed satisfactorily, and the position
effect of substituents was inconspicuous. The substrate 3-methyl
isochroman was oxidized smoothly, affording 3la in 94% yield
with moderate diastereoselectivity (dr = 10: 1). Analogously, 3-
ethyl and 4-methyl isochromans reacted well and provided
satisfactory yield of 3ma (93% yield) and 3ka (93% yield) but
with low diastereoselectivity (dr = 2:1 and 1.5:1 respectively).
Furthermore, the substrate scopes including other ethers and
even benzylic systems were investigated (Table 3). When six-
and seven-membered cyclic benzyl ethers were used, single
addition of the tert-butylperoxide proceeded selectively to form
3qa (77% yield) and 3ra (61% yield). The mild peroxidation
method could also selectively functionalize the very electron-rich
thienopyrans to give the dehydrogenative α-peroxidation
products 3sa and 3ta in acceptable yields (44% and 36%)
without affecting the sensitive heterocyclic ring. Besides the
substituted ethers, the substrate scope could be extended to
series of benzylic systems without adjacent oxygen (3ua-3xa,
30-59% yields).[18] In addition, 3-pyridinemethyl silyl ether 1y
was infrequently applicative for this reaction and gave a 50%
yield of peroxyacetal product 3ya.
Mechanistic investigations
This observed broad substrate scope in such mild
reaction conditions was unprecedented, which prompted us
to investigate the mechanism of the reaction. We firstly
conducted the radical-trapping experiments. When using
1.5 equiv of TEMPO as the radical-trapping reagent, the
reaction was totally shut down, along with the formation of
trapping product of α-isochroman radical detected by
HRMS analysis (Scheme 2 and Supporting Information).
These results strongly supported that α-isochroman radical
7
existed in the reactions.
Scheme 2. Radical-trapping Experiments for Mechanistic Studies
Empirically, the C-H functionalization of noncyclic benzylic
ethers proceeded through oxocarbenium ion intermediates along
with the generation of hemiacetal and subsequent hydrolysis.
Therefore, the corresponding benzaldehyde and alcohol were
obtained (Scheme 3a).[19] Conversely, compared with the
noncyclic benzylic hemiacetals, the cyclic benzylic hemiacetals
like 6 and oxygenated dimer 5 are more stable (Scheme 3b).[16]
Inspired by this speculation, we thought utilizing our photoredox
catalyzed peroxidation protocol to test the noncyclic benzylic
ether substrates would be a reliable evidence for the existence
of oxocarbenium ion in this reaction. After putting noncyclic
benzylic ethers into the standard reactions (entry 4, Table 1),
unsurprisingly, all of them decomposed smoothly to
corresponding benzaldehydes (Scheme S1). Thus, there is
sufficient evidence for that the oxocarbenium ion intermediates
do exist in our photoredox catalyzed peroxidation strategy.
Table 3. Scope of the Substituted Ethers and Benzylic Methylene
Compounds[a][b]
3xa
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Scheme 3. Pathway of the Cyclic and Noncyclic Benzylic Ether
In order to further understand this reaction, we firstly gain
mechanistic insights into the peroxidation with the absence of
Brønsted acid. Empirically 5 and 6 acted as stable reservoirs for
the reactive oxocarbenium ion intermediate. However, after 5 or
6 (previously synthesized, see Supporting Information) was
injected respectively to the reaction system without Brønsted
acid additives, no 3aa was detected (Scheme 4a and 4b). These
results demonstrated that 5 and 6 could not be broken down to
form the oxocarbenium ion, thus they were not the true
intermediates of this peroxidation in the absence of Brønsted
acid. Although the reaction could generate 64% yiled of 3aa
when the reaction time was extended to 20 h, this peroxidation
still performed inefficiently compared with that in the presence of
CBSA (entry 4, Table 1). We speculated that with the absence of
Brønsted acid, the low production yield probably resulted from
Scheme 4. Identification of the Reaction Intermediates
Based on above results, a plausible catalytic cycle can be
proposed which contains two synergistic catalytic cycles
(Scheme 5). The sequence would be initiated through visible
light irradiation of IrIII(ppy)3 to give the excited state *IrIII(ppy)3.[21]
Then t-BuOOH could be reduced by *IrIII(ppy)3 [E1/2(IrIV/*IrIII) = −
1.73 V vs SCE in CH3CN][21] via SET, which would in turn
induce scission of its weak O-O bond to generate tert-butoxyl
radical (tBuO•) along with oxidant IrIV(ppy)3. Subsequently,
tBuO• might abstract a hydrogen atom from 1a via HAT to
produce 7 and tert-butanol (tBuOH). Then an electron could
transfer from 7 to IrIV(ppy)3 [E1/2(IrIV/IrIII) = + 0.77 V vs SCE in
CH3CN][21] via another SET process to regenerate IrIII(ppy)3 and
complete the photoredox catalytic cycle. Meanwhile, the
Brønsted acid catalytic cycle could be initiated via the
isochroman oxocarbenium ion combined with H-X to form the
oxocarbenium ion p-chlorobenzenesulfonate 8. Subsequently, 8
could undergo nucleophilic attack by TBHP to generate 3aa and
complete the Brønsted acid catalytic cycle. Accordingly, 8
appears to be the reactive species in the catalytic cycle which is
in off-cycle equilibrium with 5 and 6 in the presence of water.
This balance seems to provide a reservoir, which could have a
stabilizing effect of 8 and meanwhile release X- to participate in
Bronsted acid cycle again.[3a] As far as we are concerned, the
by-product isochromanone (4) was probably formed through the
oxidation of 5 and 6 by TBHP. In addition, it cannot be ruled out
that 7 was generated through HAT of tert-butylperoxyl radical
(tBuOO•), and the mechanism was shown in Scheme S2.[3c]
the irreversible generation of
5 and 6 as byproducts.
Furthermore, undesired decomposition reactions of the unstable
oxocarbenium ion could also reduce the reaction yield.
Next, for further figuring out the potential role of Brønsted acid,
more mechanistic studies were conducted. After quenched the
reaction in the standard conditions (entry 4, Table 1) 1 h later, 5
and 6 were detected by HRMS analysis (Supporting Information).
Subjecting 5 or 6 to TBHP in the presence of catalytic amounts
of CBSA gave 3aa in nearly quantitative isolated yield after 1 h
(Scheme 4c and 4d). These results indicated that with the
presence of CBSA, 5 and 6 can be discounted as a true reactive
intermediate in the catalytic cycle. They can obviously act as
stable reservoirs for the reactive oxocarbenium ion pairs, which
could improve the yield and diminish undesired decomposition
reactions.[20] Then for investigating the effect of counterion, we
included 4 Å molecular sieves into the reaction conditions to
eliminate the impact of reservoir. With the presence of CBSA,
about 66% yield of 3aa was isolated after 10 h (Scheme 4e);
comparatively, 35% yield of 3aa was obtained with the absence
of CBSA (Scheme 4f). These results suggested that CBSA may
provide a suitable counterion to improve the electrophilicity of
oxocarbenium ion and reduce the undesired decomposition
reactions. In general, condition experiments verified our
assumption that the catalytic amounts of Brønsted acid not only
facilitated the reservoir participating in catalytic cycle, but also
enhanced the electrophilicity of oxocarbenium ion.
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Scheme 5. Proposed Mechanism
Scheme 6. Synthetic Application of tert-Butylperoxyl Compounds
Practical applications
Intrigued by the common existence of 1-substituted
isochromans that constitute the framework of many natural and
synthetic bioactive products,[22] the versatility and potential
application of the isochroman peroxyacetals were illustrated for
the construction of various 1-substituted isochromans and other
isochroman framework (Scheme 6a). In the presence of Lewis
acid, the C-OO bond could be broken down, and isochroman
oxocarbenium ion could be regenerated and attacked by
nucleophile to form various 1-substituted isochromans such as
1-allylisochroman (11a) and isochroman-1-carbonitrile (11b) in
favorable yields (86% and 79%). In addition, DBU could catalyze
Kornblum-DelaMare rearrangement to construct smoothly
isochromanone (4) with 82% yield.[23] Gram scale experiment
was also conducted, which produced 1.26 g (71% yield) 3aa in
one pot with the use of 0.5 mol% of photoredox catalyst
(Scheme 6b). Furthermore, the decomposition of a peroxy
linkage through the Pd/C-catalyzed hydrogenation can give the
corresponding tertiary alcohol 11c with good efficiency (75%
yield, Scheme 6c).
Conclusions
In summary, the photoredox and Brønsted acid catalyzed
peroxidation has allowed successful and general introduction of
an interesting tert-butylperoxyl group into isochroman to form the
versatile peroxyacetals. The mild reactions proceed under
visible light at ambient temperature with excellent yields, and
they exhibit a broad scope with respect to both the substituted
ethers and benzylic methylene compounds with high functional
group tolerance. Preliminary mechanistic studies suggest an
innovative dual catalytic cycles. The isochroman oxocarbenium
ion pairs 8 appears to be the reactive intermediate in the
catalytic cycle, and two intermediates 5 and 6 are illustrated to
be the off-cycle equilibrium of 8, which have stabilizing effect as
a reservoir. We hope the present work will contribute to the
development of proxides with highly sustainable conditions and
synthetically important applications.
Experimental Section
See the Supporting Information for full experimental details.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21421062, 21372131, 21562023, 21672117) and the
Tianjin Natural Science Foundation (16JCZDJC32400) for
generous financial support for our programs.
Keywords: photoredox catalysis • Brønsted acid • synergistic
catalysis • peroxidation • reservoir
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10.1002/chem.201701755
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Qing Xia, Qiang Wang, Changcun Yan,
Jianyang Dong, Hongjian Song, Ling Li,
Yuxiu Liu, Qingmin Wang,* Xiangming
Liu, Haibin Song
Page No. – Page No.
Merging Photoredox with Brønsted
Acid Catalysis: The Cross-
Text for Table of Contents
Dehydrogenative C–O Coupling for
sp3 C-H Bond Peroxidation
Synergistic catalysis: Isochroman peroxyacetals can be accomplished by photoredox and Brønsted acid synergistically catalyzed
cross-dehydrogenative C–O coupling reaction. The role of hemiacetals and oxygenated dimers on the effective stabilization of the
oxocarbenium ion was investigated; the presence of added acid appeared capable of establishing equilibrium between hemiacetals
and oxygenated dimers with the oxocarbenium ion pairs. Broad applicability will highlight the capacity of the protocol in future
molecule synthesis.
This article is protected by copyright. All rights reserved.