Activation of C-H Bonds through Oxidant-Free Photoredox Catalysis: Cross-Coupling Hydrogen-Evolution Transformation of Isochromans and β-Keto Esters

Article abstract of DOI:10.1002/chem.201503361

The direct and controlled activation of a C(sp³)-H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an

Full text of DOI:10.1002/chem.201503361

DOI: 10.1002/chem.201503361
Communication
&
Photoredox Catalysis
Activation of CÀH Bonds through Oxidant-Free Photoredox
Catalysis: Cross-Coupling Hydrogen-Evolution Transformation of
Isochromans and b-Keto Esters
Ming Xiang,[a] Qing-Yuan Meng,[a] Jia-Xin Li,[a] Yi-Wen Zheng,[b] Chen Ye,[a] Zhi-Jun Li,[a]
Bin Chen,[a] Chen-Ho Tung,[a] and Li-Zhu Wu*[a]
amounts of an oxidant, such as 2,3-dichloro-5,6-dicyano-1,4-
Abstract: The direct and controlled activation of a C(sp3)À
benzoquinone (DDQ) or a peroxide, are always required to
remove an electron and a hydrogen atom of the ether, thereby
leading to the formation of an a-oxy radical or an oxonium in-
termediate for subsequent transformations under thermal syn-
thetic conditions (Scheme 1).[2–4]
H bond adjacent to an O atom is of particular synthetic
value for the conventional derivatization of ethers or alco-
hols. In general, stoichiometric amounts of an oxidant are
required to remove an electron and a hydrogen atom of
the ether for subsequent transformations. Herein, we
demonstrate that the activation of a CÀH bond next to an
O atom could be achieved under oxidant-free conditions
through photoredox-neutral catalysis. By using a commer-
cial dyad photosensitizer (Acr+-Mes ClO4À, 9-mesityl-10-
methylacridinium perchlorate) and an easily available co-
baloxime complex (Co(dmgBF2)2·2MeCN, dmg=dimethyl-
glyoxime), the nucleophilic addition of b-keto esters to
oxonium species, which is rarely observed in photocataly-
sis, leads to the corresponding coupling products and H2
in moderate to good yields under visible-light irradiation.
Mechanistic studies suggest that both isochroman and
the cobaloxime complex quench the electron-transfer
state of this dyad photosensitizer and that benzylic CÀH
bond cleavage is probably the rate-determining step of
this cross-coupling hydrogen-evolution transformation.
Scheme 1. CÀH bond activation of a-CH2-O systems.
Recently, the use of visible-light catalysis as a complementary
strategy for the functionalization of C(sp3)ÀH bonds has ach-
ieved a broad range of bond-forming reactions.[5] The photoca-
talytic generation of a-oxy radicals by hydrogen-atom-transfer
pathways and transformations by conjugate addition and radi-
cal coupling have been realized for the efficient derivatization
of ethers or alcohols.[6] However, successful photo-mediated
examples for the use of oxonium species, formed by two-elec-
tron oxidation, as reactive intermediates are very limited. Since
the oxidation of an aromatic ring is easier than that of an
oxygen atom, oxonium species ought to be obtained by
single-electron oxidation of electron-rich aromatic rings and,
thereafter, hydrogen-atom abstraction (or electron and proton
abstraction in a stepwise manner) from the benzylic position in
the case of benzylic ethers (Scheme 2).[7] To the best of our
knowledge, so far there are only very few reports on the for-
mation of oxocarbenium ions that are quenched by water to
yield the hydrolysis products. In these cases, BrCCl3 or H2O2
were used as the terminal oxidant.[7,8] Herein, we apply this oxi-
The formation of CÀC bonds through controlled activation of
C(sp3)ÀH bonds has become one of the most active research
fields in modern synthetic organic chemistry.[1] The direct func-
tionalization of a C(sp3)ÀH bond adjacent to an O atom is
a powerful tool for the conventional synthesis of O-containing
compounds.[2] However, this activation is much more challeng-
ing than the well-established activation of a CÀH bond adja-
cent to an N atom owing to its higher oxidation potential.[3] To
realize this type of CÀH bond activation, stoichiometric
[a] M. Xiang, Dr. Q.-Y. Meng, J.-X. Li, C. Ye, Dr. Z.-J. Li, Dr. B. Chen,
Prof. Dr. C.-H. Tung, Prof. Dr. L.-Z. Wu
Key Laboratory of Photochemical Conversion and Optoelectronic Materials
Technical Institute of Physics and Chemistry &
University of Chinese Academy of Sciences
Chinese Academy of Sciences, Beijing 100190 (P. R. China)
E-mail: lzwu@mail.ipc.ac.cn
[b] Y.-W. Zheng
School of Chemistry and Chemical Engineering
Shandong University, Jinan 250100 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503361.
Scheme 2. Photoredox-catalyzed utilization of oxonium species.
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Communication
dative strategy to the transformation of oxonium species by
the addition of appropriate nucleophiles to form new CÀC
bonds under oxidant-free conditions.
Table 1. Optimization of reaction conditions.[a]
It is generally accepted that for the functionalization of CÀH
bonds with other CÀH bonds stoichiometric oxidants are
needed.[3] Our group recently proposed a novel protocol for
the formation of a CÀC bond by two different CÀH bonds with
concomitant emission of hydrogen (H2) in the absence of stoi-
chiometric oxidants.[9] A series of amines have been converted
to imine (or iminium-ion) intermediates and, subsequently,
cross-coupling products and H2 have been obtained by the
coupling of two catalytic cycles.[10] Based on these results, we
questioned whether oxonium species could be obtained from
benzylic ethers with H2 emission by using an appropriate pho-
tosensitizer and a cooperative catalyst. More specifically, we fo-
cused our attention on 9-mesityl-10-methylacridinium perchlo-
Entry
Metal cat.
Solvent
Conversion
Yield
2a [%][b]
3a [%][b]
H2 [%][c,d]
1
2
3
4
5
6
7
none
none
none
CuBr2
CuCl2
Cu(OTf)2
FeCl3
Cu(OTf)2
Cu(OTf)2
CH2Cl2
MeCN
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
70
83
n.d.
85
75
95
79
80
64
88
n.d.
82
67
89
69
75
57
51
0
46
18
88
24
17
0
8[e]
9[f]
n.d.
n.d.
[a] Isochroman 1a (0.4 mmol), ethyl acetoacetate 2a (0.2 mmol), Acr+
-Mes (0.01 mmol, 5 mol%), Co(dmgBF2)2·2MeCN (0.02 mmol, 10 mol%),
and metal salt (0.02 mmol, 10 mol%) in solvent (1 mL) were irradiated by
blue LEDs for 24 h under argon atmosphere. [b] Determined by 1HNMR
spectroscopy using an internal standard. [c] Determined by gas chroma-
tography using an internal standard. [d] The amount of H2 that was gen-
erated by isochroman deprotonation has been deducted.
[e] Co(dmgH)2pyCl instead of Co(dmgBF2)2·2MeCN. [f] General conditions,
but without Acr+-Mes, Co(dmgBF2)2·2MeCN, or light. n.d.=not deter-
mined.
À
rate (Acr+-Mes ClO4 ), one of the strongest oxidizing photo-
sensitizers (E1/2red = +2.06 V vs. SCE), which can oxidize alkyl ar-
omatic compounds to produce the radical cation of the aro-
matic ring.[11] For the cooperative catalyst, we chose
a cobaloxime complex, which can efficiently accept electrons
and thereafter reduce protons to H2.[12] We envisioned that the
benzylic CÀH oxidation step would be electronically balanced
by a photocatalyst-mediated reduction of the cobaloxime com-
plex. The successful application of this strategy for the activa-
tion of a C(sp3)ÀH bond adjacent to an O atom is described as
follows (Scheme 3).
the pseudo-cross-coupling H2 evolution. For clarity, we sub-
tracted the amount of H2 from isochroman itself and would
present the yield of H2 only for the cross-coupling reaction
throughout this work.
Next, a few common solvents were examined, with MeCN
providing the optimal medium and being selected for further
optimizations (Table 1, entry 2). Then, we aimed at improving
the yield of H2; we expected that H2 emission could be facili-
tated by the presence of certain transition-metal salts, which
have the ability of activating the nucleophile and the benzylic
CÀH bonds.[3] Several readily accessible and inexpensive
copper and iron salts, such as CuBr2, CuCl2, Cu(OTf)2, and FeCl3,
were then screened. Most of them proved unsuccessful, except
for a catalytic amount of Cu(OTf)2. It is important to note that
under this conditions almost complete conversion of 2a (95%)
and good yields for 3a (89%) and H2 (88%) were achieved
(Table 1, entry 6). Additionally, replacing Co(dmgBF2)2·2MeCN
Scheme 3. Cross-coupling hydrogen-evolution transformation of isochro-
mans and b-keto esters by visible-light catalysis.
To begin this study, isochroman (1a) and ethyl acetoacetate
(2a) were chosen as the standard substrates for the desired
coupling reaction. As shown in Table 1, 5 mol% of Acr+-Mes
with
Co(dmgH)2pyCl
(py=pyridine)
diminished
the
reaction efficiency (Table 1, entry 8). A control experiment
proved the requirement of light, a cobaloxime complex
(Co(dmgBF2)2·2MeCN), and a photosensitizer (Acr+-Mes ClO4 ),
À
À
ClO4 and 10 mol% of Co(dmgBF2)2·2MeCN (dmg=dimethyl-
glyoxime) were added to a solution of 1a and 2a in an organic
solvent under ambient argon atmosphere. After 24 h of irradia-
tion with blue LEDs (l=450Æ10 nm), 64% and 57% yield of
the desired crossing-coupling product 3a and H2 were ob-
tained, respectively, with 70% conversion of 2a in CH2Cl2
(Table 1, entry 1). A comparative experiment revealed that the
generated amount of H2 actually contains two parts: one re-
sults from isochroman deprotonation (Table S1), because part
of isochroman plays the role of sacrificial electron donor and
proton source for the generation of H2, and the other is due to
since the reaction did not proceed in the absence of these
components (Table 1, entry 9).
Under the optimized conditions, various active b-keto esters
were then treated in the nucleophilic addition with isochro-
man variants; representative results are listed in Table 2. Both
aliphatic and electronically varied aromatic b-keto esters were
effective in the reaction. There was no evident difference in
the reactivity among them, and the desired cross-coupling
products and H2 were obtained in moderate to good yields
with a diastereomeric ratio of 1:1 to 1:2. Owing to the impor-
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tempted to utilize other types of nucleophiles, such
as 1,3-dicarbonyl compounds (2,4-pentanedione),
and the coupling product was obtained in a reasona-
ble yield while the corresponding H2 was not ob-
served. Subsequently, the substituent effect of iso-
chroman was investigated. Alkyl substituents, such as
a methyl group at C5 or C7 and a tert-butyl group at
C7 of the isochroman, resulted in slightly reduced
yields compared with the model reaction, probably
owing to the increased steric hindrance. In sharp
contrast, a methoxy substituent at the C7 position
and 4-methoxymethyl anisole afforded no reaction.
This observation was consistent with the mechanistic
studies of DDQ-mediated ether functionalizations by
Floreancig.[13] Although attaching an electron-donat-
ing group to the substrate would lower its oxidation
potential, it would form a stabilized aromatic radical
cation upon single-electron oxidation and increase
the bond-dissociation energy of the benzylic CÀH
bond. It also demonstrated that the formation of an
aromatic radical cation prior to benzylic CÀH bond
cleavage was not rate determining. Therefore, a simi-
lar key intermediate (aromatic radical cation) proba-
bly exists in our reaction pathway. Given the relative-
ly high oxidation potential of the electron-poor aro-
matic moiety, a very low cross-coupling yield (<20%)
was obtained when a chloro-substituent was placed
at the C7 position. This partly indicates that the iso-
chroman derivative initially loses the electron of the
aromatic group to form the aromatic radical cation.
When using an acylic substrate (1-(methoxymethyl)-
4-methylbenzene), no cross-coupling product was
observed, while 4-methylbenzaldehyde was the main
identifiable product through analyzing the 1H NMR
spectra of the reaction mixture.
Table 2. Cross-coupling hydrogen-evolution transformation of isochromans and b-
keto esters.[a]
Entry Product
Yield
H2
[%][b] [%][c,d]
Entry Product
Yield
H2
[%][b] [%][c,d]
3
3
3
3
76
(1.5:1)
84
9
71
0[e]
1
2
69
(1.7:1)
59
10
59
(1.8:1)
73
65
(1:1)
80
99
11
12
57
(1.1:1)
61
68
3
4
76
(1.3:1)
56
(1.7:1)
71
(1:1)
64
41
46
13
14
15
63
(1.9:1)
61
64
67
5
6
7
61
(1.9:1)
58
(1.1:1)
69
(1.5:1)
55
(1.5:1)
To obtain further information on the reaction path-
way, we investigated the reaction of [D2]-1a with
[D2]-2a under the same conditions (Scheme 4a).
After purification, the corresponding cross-coupling
product [D2]-3a[14] was obtained in 75% yield and D2
(instead of H2) was detected. Furthermore, no deute-
rium incorporation of 3a or D2 was observed in the
reaction of 1a with 2a in CD3CN (Scheme 4b). These
results indicate that the source of H atoms in the
product H2 derives from the a-proton of 1a and the
activated methylene proton of 2a. Subsequently, as
shown in Scheme 4c, we investigated the kinetic iso-
topic effect (KIE) by competition experiments. The in-
termolecular kH/kD was determined to be 2.3 based
on 1H NMR spectroscopic analysis of the isolated
products. This isotopic effect implies that benzylic CÀ
H bond cleavage is probably involved in the rate-de-
60
(2:1)
49
16
57
(1.8:1)
69
8
[a] Isochromans (0.4 mmol), b-keto esters (0.2 mmol), Acr+-Mes (0.01 mmol, 5 mol%),
Co(dmgBF2)2·2MeCN (0.02 mmol, 10 mol%), and Cu(OTf)2 (0.02 mmol, 10 mol%) in
MeCN (1 mL) were irradiated by blue LEDs for 24 h under argon atmosphere. [b] Yields
of isolated products. The ratio of the two diastereomers is reported in parentheses.
[c] Determined by gas chromatography using an internal standard. [d] The amount of
H2 that was generated by isochroman deprotonation has been deducted. [e] The
amount of H2 caused by isochroman decomposition was higher than that of the reac-
tion evolution.
tance of the chloro-functionality in organic synthesis, we were
delighted to find that product 3g was obtained in a relatively
high yield. However, the use of butyl acetoacetate provided H2
and the desired product in small amounts, which could hardly
be separated from undesired side products. In addition, we at-
termining step of the reaction.
Furthermore, we conducted a series of time-resolved transi-
ent absorption spectrum measurements with Acr+-Mes ClO4
À
,
1a, and Co(dmgBF2)2·2MeCN. Considering the transient ab-
sorption of electron-transfer state of Acr -Mes (Acr -Mes +) at
+
C
C
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ing proceed simultaneously in
this new photoredox coupling
reaction. In other words, the
single-electron transfer (SET)
process occurs not only between
+
C
C
Acr -Mes
and
1a,
but
and
+
C
C
also between Acr -Mes
Co(dmgBF2)2·2MeCN.
In view of these experimental
results, a possible mechanistic
rationale of this transformation
is outlined in Scheme 5. The ini-
tial step involves an intramolecu-
lar photoinduced electron trans-
fer from the mesitylene moiety
to the singlet excited state of
the acridinium ion, resulting in
the formation of an extremely
long-lived (e.g., 2 h at 203 K)[11a]
Scheme 4. Deuterium experiments.
C
electron-transfer state (Acr -
500 nm,[11a] this kinetic decay of transient absorption clearly
Mes +). The acridinyl radical moiety delivers an electron to
C
+
C
demonstrates that both isochroman and the cobaloxime com-
Co(dmgBF2)2·2MeCN, whereas the Mes moiety accepts an
+
C
C
plex indeed decrease the lifetime of Acr -Mes with increasing
concentration of either (Figure 1a and c). In addition, the rate
constant for the addition of 1a was determined from the slope
electron from isochroman (1a). After that, the photosensitizer
(Acr+-Mes) is regenerated. Subsequently, the produced radical
cation 4 leads to the corresponding oxocarbenium intermedi-
ate 6 through deprotonation, followed by a second electron
transfer. When two equivalents of 2,2,6,6-tetramethylpiperidin-
1-yloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) were
added into the reaction system, nearly no product was gener-
ated. This observation suggests
of the liner plot of kdecay versus [1a] to be 3.5”108 mÀ1 À1, and
s
Co(dmgBF2)2·2MeCN had a comparative quenching rate con-
stant of 9.0”108 mÀ1 sÀ1 (Figure 1b and d). These observations
collectively support that the oxidative and reductive quench-
that
a radical intermediate 5
might be involved in the reac-
tion pathway. Meanwhile, the
one-electron-reduced form of
the cobaloxime complex, which
then accepts a proton, is respon-
sible for the evolution of H2. Fi-
nally, the attack of nucleophile
(2a), activated by a CuII salt,
onto the oxonium species fur-
nishes the CÀC coupling product
(3a).
In conclusion, we have devel-
oped an efficient method for the
visible-light-promoted utilization
of oxocarbenium ions. Although
to date the scope of ethers is
limited to a certain extent, we
were able to realize the addition
of a variety of b-keto esters to
oxonium species, which are gen-
erated by photocatalytic CÀH
bond oxidation. We also found
that this photocatalytic reaction
requires no sacrificial oxidants as
it proceeds via a redox neutral
pathway. Remarkably, the results
+
C
C
Figure 1. Quenching experiments. a) Decay of transient absorbance of Acr -Mes at 500 nm in the absence and
presence of isochroman (0–3 mm) in deaerated MeCN containing Acr+-Mes (0.05 mm) after nanosecond laser
flash photolysis (lex =430 nm). b) Plot of kdecay versus [isochroman] for the reaction of Acr -Mes with isochroman.
c) Decay of transient absorbance of Acr -Mes at 500 nm in the absence and presence of Co(dmgBF2)2·2MeCN (0–
0.2 mm) in deaerated MeCN containing Acr+-Mes (0.05 mm) after nanosecond laser flash photolysis (lex =430 nm).
+
C
C
+
C
C
+
C
C
d) Plot of kdecay versus [Co(dmgBF2)2·2MeCN] for the reaction of Acr -Mes with Co(dmgBF2)2·2MeCN.
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described herein provide a generic catalytic approach to the
direct photoredox-mediated functionalization of C(sp3)ÀH
bonds adjacent to the O atom of ethers at room temperature.
Further work to broaden the synthetic application of the oxo-
nium species under visible-light irradiation is in process.
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Financial support for this research from the Ministry of Science
and Technology of China (2013CB834804, 2014CB239402, and
2013CB834505), the National Natural Science Foundation of
China (21390404, 91427303, and 21402217), the Key Research
Programme of the Chinese Academy of Sciences (KGZD-EW-
T05), and the Chinese Academy of Sciences is gratefully ac-
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[14] Before purification, the crossing-coupling product [D2]-3a was detected
by MS analysis. However, the product [D1]-3a (>99% D-enriched at the
benzyl proton, and >99% H-enriched at the activated methane
proton) was indeed obtained by column chromatography on silica gel
due to the quick exchange of hydrogen in silica gel with the activated
deuterium from the product.
Keywords: CÀH activation
·
isochromans
·
oxonium
·
photoredox catalysis
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Received: August 25, 2015
Published online on October 30, 2015
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