Anti-Markovnikov Oxidation of β-Alkyl Styrenes with H2O as the Terminal Oxidant

Article abstract of DOI:10.1021/jacs.6b07411

Oxygenation of alkenes is one of the most straightforward routes for the construction of carbonyl compounds. Wacker oxidation provides a broadly useful strategy to convert the mineral oil into higher value-added carbonyl chemicals. However, the conventional Wacker chemistry remains problematic, such as the poor activity for internal alkenes, the lack of anti-Markovnikov regioselectivity, and the high cost and chemical waste resulted from noble metal catalysts and stoichiometric oxidant. Here, we describe an unprecedented dehydrogenative oxygenation of β-alkyl styrenes and their derivatives with water under external-oxidant-free conditions by utilizing the synergistic effect of photocatalysis and proton-reduction catalysis that can address these challenges. This dual catalytic system possesses the single anti-Markovnikov selectivity due to the property of the visible-light-induced alkene radical cation intermediate.

Full text of DOI:10.1021/jacs.6b07411

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Communication
Anti-Markovnikov Oxidation of #-Alkyl
Styrenes with H2O as the Terminal Oxidant
Guoting Zhang, Xia Hu, Chien-Wei Chiang, Hong Yi, Pengkun Pei, Atul K. Singh, and Aiwen Lei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07411 • Publication Date (Web): 05 Sep 2016
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Anti-Markovnikov Oxidation of β-Alkyl Styrenes with H2O as
the Terminal Oxidant
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Guoting Zhang,a Xia Hu,a Chien-Wei Chiang,a Hong Yi,a Pengkun Pei,a Atul Kumar Singha and
Aiwen Lei *a,b
aCollege of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan,
Hubei 430072, P. R. China. bLanzhou Institute of Chemical Physics Chinese Academy of Sciences, Lanzhou 730000,
P. R. China.
Supporting Information Placeholder
the catalyst-dependent anti-Markovnikov selective Wacker-
ABSTRACT: Oxygenation of alkenes is one of the most
straightforward routes for the construction of carbonyl
oxidation by Grubbs6, Spencer7, and others8 through the
modification of catalytic factors, albeit restricted to terminal
olefins. Recently, the achievement of a tandem epoxidation-
isomerization (E-I) strategy resulting in net anti-
Markovnikov alkene oxygenation significantly complements
the classical Wacker-oxidation (Scheme 1B)9. However, the
employment of noble-metal catalysts, stoichiometric copper
and oxidant would bring high costs and chemical waste,
which is also a serious problem we are facing. Therefore, less
hazardous, cost-effective and noble-metal-free anti-
Markovnikov oxygenation of internal alkenes is an attractive
and worthwhile pursuit. Here, we present a direct anti-
Markovnikov dehydrogenative oxygenation of β-alkyl sty-
renes and its derivatives with water under external-oxidant-
free conditions by using a photoredox-metal dual catalytic
system10, as an ideal catalytic system to rapidly access to the
carbonyl compounds.
compounds. Wacker oxidation provides a broadly useful
strategy to convert the mineral oil into higher value-added
carbonyl chemicals. However, the conventional Wacker
chemistry remains problematic, such as the poor activity for
internal alkenes, the lack of anti-Markovnikov regioselectiv-
ity, the high cost and chemical waste resulted from noble
metal catalysts and stoichiometric oxidant. Here, we de-
scribe an unprecedented dehydrogenative oxygenation of β-
alkyl styrenes and its derivatives with water under external-
oxidant-free conditions by utilizing the synergistic effect of
photocatalysis and proton-reduction catalysis that can ad-
dress these challenges. This dual catalytic system possesses
the single anti-Markovnikov selectivity due to the property
of the visible-light-induced alkene radical cation intermedi-
ate.
The oxidation of olefins represents a powerful synthetic
tool for converting the mineral oil into high value-added
chemicals, such as epoxides, carbonyl compounds, and etc1.
For more than a half century, Wacker oxidation has been
proven as an industrially viable and synthetically useful
transformation for the construction of carbonyls due to its
high functional group tolerance, efficiency and reliability2. In
contrast to the Wacker-oxidation of terminal olefins that is
well-established, the efficient catalytic systems for the selec-
tive oxidation of internal alkenes have been sparsely report-
ed. It has been highly desirable and historically challenging
to achieve the Wacker-type oxidation of internal alkenes
with high activity3.
The regioselectivity issue of oxygenation of olefins repre-
sents another longstanding challenge in traditional Wacker
chemistry2g. Especially, the anti-Markovnikov oxidation of
internal alkenes remains huge problematic. In most cases of
conventional Wacker oxidation, the selectivity outcome is
generally controlled by the substrate obeying Markovnikov’s
rule (Scheme 1A)4. Only for some certain substrates, which
are bearing a chelating group located at a suitable position,
anti-Markovnikov selectivity can be observed2e,5. Apart from
this, significant breakthroughs have been achieved toward
Scheme 1. Regiocontrol strategies on the anti-Markovnikov
Wacker oxidation. (A) Palladium mediated Wacker oxidation; (B)
Epoxidation-isomerization (E-I) strategy for the anti-Markovnikov
olefins oxidation; (C) Radical cation mediated anti-Markovnikov
oxidation of styrenes.
Our strategy for the regioselectivity control is based on an
alkene radical cation intermediate I (Scheme 1C). Followed
by the nucleophilic attack of water, the attained distonic
radical cation II tends to deprotonate to produce the anti-
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Markovnikov intermediate III rather than Markovnikov se-
oximate monoanion, py = pyridine), a well-known proton-
reducing catalyst in the context of hydrogen evolution14c
lective adduct VI, because of the better stability of III11. The
subsequent single-electron-oxidation, elimination and keto-
enol tautomerism would generate the corresponding carbon-
yls directly. However, the severe oxidative conditions, such
as strong oxidants, for the overoxidation of III easily leads
the cleavage of C−C double bond12, which restricts the fur-
ther use of this alternative Wacker-like oxidation strategy.
Therefore, to overcome this difficulty, we suggest to merge
an in-situ generated “alkene radical cation” with a proton-
reduction catalysis to improve the catalytic reaction under
oxidant-free conditions. Alkene radical cation, generated by
the photo-induced system, has been established as an attrac-
tive strategy for the anti-Markovnikov hydrofunctionaliza-
tion of alkenes13. Although the photocatalytic production of
hydrogen from water is a well-known chemistry14, no dual
catalytic system of photoredox/proton reduction15 for the
alkene C-H bond functionalization with water was reported.
Herein, we envisioned that a proper catalytic system via the
synergistic effect of this dual catalytic system should be
achievable to proceed the direct anti-Markovnikov oxidation
of olefins with H2 liberation.
,
were chosen and combined as the photosensitizer and syner-
gistic catalyst respectively. Encouragingly, in the presence of
5 mol% of photosensitizer 3 and 3 mol% of cobalt complex 4,
desired 2-tetralone 2a can be isolated in 83% yield, after the
irradiation of blue LEDs light for 24 h (Scheme 2, 2a). Mean-
while, 90% yield of H2 was detected by GC, supporting our
mechanistic hypothesis. Control experiments indicated no
desired reaction would be observed when either light, photo-
sensitizer 3, or catalyst 4 was omitted (Supplementary Fig.
S1).
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To probe the versatility of this catalytic system, the scope
of alkenes was successfully evaluated. As shown in Scheme 2,
the synergetic catalysis could be employed on a variety of
styrene derivatives to achieve the production of carbonyl
compounds in good to excellent yields and single anti-
Markovnikov selectivity (regioisomeric ratios were deter-
1
mined by GC-MS and H NMR). 1,2-dihydronaphthlene 1a,
indene 1b, 6,7-dihydro-5H-benzoannulene 1c and their de-
rivatives can be used to enable facile access to corresponding
cycloketones (2a–2g). Moreover, tetralones 2f and 2g have
been used as medicinal intermediate in the synthesis of an
antitussive drug nepinalone17 and an anti-Parkinson drug
rotigotine18. Additionally, under the radical-cation pathway,
β-methyl-styrene afforded full anti-Markovnikov regioselec-
tivity (1h, 64%), which is drastically different from the previ-
ous Pd-mediated system3a. Then the functional group toler-
ance of this transformation was explored by using various β-
methyl-substituted styrenes (cis- and trans- mixture) bearing
either electron-donating (1i, 1j) or electron-withdrawing
groups (1k–1p), which produced the corresponding ketones
up to 95% yield. The procedure can tolerate several function-
al groups such as alkyl (1i, 1j), cyano (1l), ester (1m) and hal-
ogen (1n−1p), which is particularly important for the subse-
quent functionalization. Moreover, other acyclic β-alkyl sty-
renes (1q−1s) are also suitable substrates for the ketones
formation (2q−2s). The alkynyl functional group (2s, 83%)
can be well tolerated and provide an excellent handle for
subsequent synthetic derivatization. Notably, the diene 1t
was oxidized to afford the β,γ-unsaturated ketone 2t in 61%
yield by using higher catalyst loading. When we prolong re-
action time, the further oxidation of 2t to diketone can also
be observed.
Scheme 2. Substrate scope for the selective oxidation of sty-
renesa
-
5 mol% Acr-Mes ClO4
O
HO
3 mol% Co(dmgH)2pyCl
+
CH3CN/H2O (10:1)
r.t., blue LEDs, 24h
a Olefin 1 (0.2 mmol), 3 (5 mol%), 4 (3 mol%), water (200 μL), CH3CN
2aa, 27%
1aa
2ab, 37%
(2 mL), 12W blue LEDs, 24 h; isolated yields are shown and regioi-
-
5 mol% Acr-Mes ClO4
1
b
c
O
someric ratios were determined by GC-MS and H NMR. 48 h.
3
HO
HO
3 mol% Co(dmgH)2pyCl
d
1
+
+
(10 mol%), 4 (6 mol%). The yields were determined by H NMR
CH3CN/H2O (10:1)
r.t., blue LEDs, 24h
analysis.
1ba
2ba, 10%
2bb, 5%
2bc,3%
Scheme 3. Photocatalytic oxygenation of 1-substituted cyclo-
hexene.
To examine the feasibility of the propose strategy, 1,2-
dihydronaphthalene 1a was chosen as the model substrate
for the investigation of a suitable catalytic system to produce
the 2-tetralone derivatives, which are valuable intermediates
in the synthesis of natural products and pharmaceuticals. In
order to proceed this transformation, 9-mesityl-10-
methylacridinium perchlorate 3, which can gain an electron
from alkenes and arenes to generate the radical cation under
its excited-state16, and Co(dmgH)2pyCl (dmgH: dimethylgly-
Furthermore, the anti-Markovnikov oxygenation of mono-
and di-substituted terminal alkenes into corresponding alde-
hydes (2u–2z) can also be reached as well. Styrene deriva-
tives (1x–1z) bearing electron-donating groups permit access
to the substituted 2-phenylacetaldehyde in relatively low
yields. Unexpectedly, 1-phenylcyclohexene 1aa would afford a
mixture of 2-phenylcyclohexanone 2aa and 2,3,4,5-
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Scheme 4. Isotope labelling experiments.
tetrahydro-[1,1'-biphenyl]-2-ol 2ab (Scheme 3). This isomeri-
zation might be generated from the different elimination
pathway of the cation intermediate. In sharp contrast, the
epoxide of 1-pheylcylohexene preferably undergoes rapid
alkyl migration during the isomerization to give the ring
contract product (1-phenyl-1-cyclopentane carboxaldehyde)9c
in previous epoxidation-isomerization (E-I) process. This
obvious discrepancy could eliminate an epoxide intermediate
in the conversion. A trisubstituted aliphatic alkene, 1-
methylcyclohexene 1ba, can provide the anti-Markovnikov
oxygenation product in relatively lower yield (Scheme 3, the
yields were determined by GC), while no photocatalytic oxy-
genation of the chain aliphatic olefin, 1-hexene, occurs under
the present experimental conditions due to its much higher
oxidation potential (E1/2 ox = 2.85 V vs SCE)19.
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9
A number of isotope labelling experiments were conducted
to examine the mechanistic hypothesis (Scheme 4). When
D2O was used instead of water in the anti-Markovnikov oxi-
dation of 1e, the deuterized at the α-position of carbonyl 2e-
D can be observed. However, the direct oxidation of deuteri-
um olefin 1e-D hardly afforded the same deuterium ketone.
These results indicated the epoxidation-isomerization path-
way can be ruled out. To investigate the O-source of the car-
bonyl compounds, the oxygenation of 1a was performed in an
acetonitrile/H218O mixture, which gave almost completely
18O labelled 2-tetralone. Therefore, we suggest that the O-
atom of carbonyl compounds originates from water, and the
proposed ketone-enol tautomerization mechanism is reason-
able.
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Figure 1. Proposed mechanism for photocatalytic Wacker-like oxidation of alkenes.
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not be ignored14a. Another reaction pathway involving the
insertion of benzylic radical III to Co(II) species 7 and β-H
elimination24 might be also possible and cannot be complete-
ly ruled out at current stage (Supplementary Fig. S7). How-
ever, the formation of the Co(I) species can be observed by
using UV-vis absorption spectra, made cation intermediate
more favorable25.
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1e in CH3CN/H2O
1e-D in CH3CN/H2O
1e in CH3CN/D2O
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0
k(H)obs = 0.2222 ± 0.0013 mM⋅min-1
k(1e-D)obs = 0.2099 ± 0.0013 mM⋅min-1
In conclusion, we have demonstrated that the combination
of Fukuzumi’s catalyst and cobaloxime enables the anti-
Markovnikov oxidation of styrenes with water, which pro-
vides an unprecedented method for the construction of car-
bonyl compounds form alkenes under external-oxidant-free
conditions. Through the visible-light-induced alkene radical
cation, the high anti-Markovnikov regioselectivity of oxida-
tion process can be achieved. The mechanistic experiments
suggest that the oxygen atom of carbonyl group is originated
from water. Moreover, the mildness and high atomic econo-
my of this approach makes it appealing for the further appli-
cation into the anti-Markovnikov C−H functionalization of
olefins.
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k(D2O)obs = 0.08775 ± 0.0009 mM⋅min-1
100 150 200 250
0
50
Reaction time (min)
Scheme 5. Kinetic isotope effect experiments. Black curve: ki-
netic plots of anti-Markovnikov oxidation of 1e; Red curve:
kinetic plots of oxidation of 1e-D with H2O; blue curve: ki-
netic plots of oxidation of 1e with D2O.
ASSOCIATED CONTENT
Additionally, the kinetic isotope effect experiments were
conducted by using in-situ IR (Scheme 5). A new peak at 1720
cm-1 belonged to carbonyl group of 2e can be observed ac-
company with the consumption of olefin. As shown in
Scheme 5, the initial rate of this anti-Markovnikov oxygena-
tion for 1e was determined as 0.2222 mM∙min-1. Then, the
comparison of the initial rates of oxidation of substrate 1e
Supporting Information
The experimental procedure, characterization data, and cop-
1
ies of H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
versus its deuterated analogue 1e-D provided a (kH/k1e-D
)
obs
value of 1.1, which suggests that C H bond breaking of the
olefin is not involved in the rate-determining step of the re-
action. In contrast, the water-mediated olefin oxygenation
reaction proceeds more slowly in D2O than in H2O (Scheme
5). A (kH2O/kD2O)obs of 2.5 is observed, indicating that the
rate-determining step of the transformation might involve
the O H bond cleavage of water.
aiwenlei@whu.edu.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the 973 Program (2011CB808600,
2012CB725302, 2013CB834804), the National Natural Science
Foundation of China (21390400, 21272180, 21302148, 2109343
and 21402217), and the Research Fund for the Doctoral Pro-
gram of Higher Education of China (20120141130002) and the
Ministry of Science and Technology of China (2012YQ120060)
and the Program for Changjiang Scholars and Innovative
Research Team in University (IRT1030).The Program of In-
troducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
Consequently, a detailed description of the proposed
mechanism can be revealed in Figure 1. Alkene 1, firstly, can
be oxidized by the excited-state of photosensitizer (3*, E1/2 red
[Acr•-Mes•+/Acr•-Mes] = +2.06 V vs SCE)16a,16e,20 to generate
the radical cation intermediate I. Subsequently, the anti-
Markovnikov addition of water and deprotonation would
furnish a C-radical intermediate III, which is further oxidized
by 4 (E1/2 red [CoIII/CoII] = −0.67 V vs SCE)21 to form a cation
intermediate IV and Co(II) species 6 respectively. Since the
relatively high oxidation potential of III22, 3* might also be
possible to assist the oxidation of III, then 5 reacts with
Co(III) species 4 to regenerate catalyst 3 and Co(II) species 6.
Afterwards, the elimination and keto-enol tautomerism
would produce the corresponding carbonyl compounds 2.
On the other hand, in the cobalt side, a single-electron re-
duction of Co(II) species 6 (E1/2 red [CoII/CoI] = −1.12 V vs
SCE)21 can be provided by 5 to obtain a Co(I) species 7. The
protonation of 7 gained 8, which sequentially produced
CoIII-H 9 through possible intramolecular proton transfer23.
As a result, the protonation of cobalt hydride released H2 and
completed the catalytic cycle. The alternative homolytic
mechanism involved two CoIII−H hydrides to form H2 could
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