Pd-Catalyzed Hydroxylation of Aryl Boronic Acids Using In Situ Generated Hydrogen Peroxide

Article abstract of DOI:10.1002/chem.201702045

Herein, we describe a benign and efficient palladium-catalyzed hydroxylation of aryl boronic acids under mild conditions, with in situ generated hydrogen peroxide from carbon monoxide, water, and oxygen. This novel procedure combines catalytic production of hydrogen peroxide with an aerobic oxidation process in a sole reaction system. This system shows good functional group tolerance and provides a benign and efficient access to a variety of functionalized phenols. Furthermore, the in situ generated hydroperoxide can be well used for triphenylphosphine oxidation, in which the TON is up to 194. Isotope labelling studies provide important mechanistic insights for this process.

Full text of DOI:10.1002/chem.201702045

A Journal of
Accepted Article
Title: Pd-catalyzed Hydroxylation of Aryl Boronic Acids using in-situ
Generated Hydrogen Peroxide
Authors: Hong Yi and Aiwen Lei
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To be cited as: Chem. Eur. J. 10.1002/chem.201702045
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10.1002/chem.201702045
Chemistry - A European Journal
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Pd-catalyzed Hydroxylation of Aryl Boronic Acids using in-situ
Generated Hydrogen Peroxide
Hong Yi, and Aiwen Lei*
Abstract: In this work, we describe a benign and efficient palladium
catalyzed in-situ generated hydrogen peroxide from carbon
monoxide, water and oxygen under mild conditions. This novel
methodology combines catalytic hydrogen peroxides production with
aerobic oxidation process in a sole reaction system. This system
shows good functional group tolerance and provides a benign and
efficient access to a variety of functionalized phenols. Furthermore,
the in-situ generated hydroperoxide can be well used for
triphenylphosphine oxidation，in which the TON is up to 194. The
isotope labelling studies provides an important mechanistic insight
for this process.
catalyst was mainly due to the oxidation of the phosphine ligand
and subsequent precipitation of palladium metal. Researchers at
EniChem carried out this reaction in a bi-phase system in the
presence of bidentate nitrogen ligand and acid additive to
minimize the ligand oxidation. Although this catalysis system
showed high stability and catalytic activity,[4] the high CO/O2
pressure limited the usage in oxidative process.
Among the many chemical oxidants available to organic
chemists, hydrogen peroxide is one of the ‘greenest’ since the
only by-product from it is water. The annual world production of
hydrogen peroxide is over 2.2 million tons.[1] It is widely used in
most industrial fields, particularly in chemical industry and
environment protection. The current manufacture route,
anthraquinone oxidation process, is not an ideal method since it
generates wastes, consumes significant energy and requires
multiple unit operations.[1-2] As a result, the development of novel
and environmentally benign method for the production and
application of hydrogen peroxide is highly desirable.
One alternative route is the direct synthesis of hydrogen
peroxide from hydrogen and oxygen.[3] However, the noticeable
side reactions, including the direct formation of water and the
decomposition as well as reduction of hydrogen peroxide, are all
highly exothermic and thermodynamically favoured.[1] Clearly,
direct contact between hydrogen and oxygen also presents an
explosion risk. Thus, this process has not yet been put into
practice. The production of hydrogen peroxide is also possible
from a mixture of oxygen, carbon monoxide and water (Scheme
1A). The feasibility of this concept was first disclosed by using a
palladium triphenylphospine catalyst system. Despite the
favorable thermodynamics of this transformation (ΔG≠ = -134 kJ
mol-1), the reaction efficiency was quite low and a turnover
number of only 5 was obtained. The rapid deactivation of the
Scheme 1. (A) The production of hydrogen peroxide from a mixture
of oxygen, carbon monoxide and water. (B) Catalytic hydrogen
peroxides production with aerobic oxidation process in a sole
reaction system.
In spite of this impressive achievement, the transport, storage
and handling of bulky hydrogen peroxide involve potential safety
hazard and extra expense. It is widely recognized that hydrogen
peroxide is a strong oxidant, which can oxidize a wide range of
substrates under very mild conditions.[5] Therefore, we
envisioned that the combination of in-situ generation of
hydrogen peroxide and an effective oxidation process could
avoid the accumulation of hydrogen peroxide in the reaction
system, and thus prevent the deactivation of the palladium
catalyst. As far as form is concerned, the aerobic oxidation of
the substrate was directly achieved using oxygen as the terminal
oxidant.[6] Here, we present a palladium catalyzed in-situ
generated hydrogen peroxide formation from carbon monoxide,
water and oxygen (Scheme 1B). This novel methodology
combines catalytic hydrogen peroxides production with aerobic
oxidation process in a sole reaction system. This transformation
shows highly efficiency and tolerance for arylboronic acids
oxidation and triphenylphosphine oxidation (PPh3) oxidation.
Phenols are biologically active compounds and widely serve
as versatile synthetic intermediates.[7] Meanwhile, the oxidative
hydroxylation of arylboronic acids to produce phenols using
hydrogen peroxide is a very efficient transformation.[8] Based on
the above mentioned strategy, herein we describe a palladium
catalyzed aerobic oxidative hydroxylation of arylboronic acids via
in-situ generated hydrogen peroxide from oxygen, carbon
monoxide and water.[9] We initiated our investigation by
[a]
Dr. H. Yi, Prof. Dr. A. Lei
College of Chemistry and Molecular Sciences, the Institute for
Advanced Studies (IAS), Wuhan University
Wuhan, Hubei 430072, P. R. China
E-mail: aiwenlei@whu.edu.cn
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
[b]
Prof. Dr. A. Lei
Beijing National Laboratory for Molecular Sciences,
CAS Key Laboratory of Molecular Recognization and Function
Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, P. R. China
Supporting information for this article is given via a link at the end of
the document.
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[a] Reaction conditions: 1a (0.25 mmol), additive (0.5 mmol), Pd catalyst
(0.0125 mmol), CO/O2 (3:1) at 1 atm pressure in 2.0 mL of solvent and 150 μL
H2O. [b] GC yields. [c] Under 1 atm of O2 without CO.
examining the feasibility of the Pd-catalyzed hydroxylation of
phenylboronic acid 1a (Table 1). Representative Pd catalysts,
ligands, additives and solvents were examined to boost the
efficiency of this transformation (See Supporting Information
Table S1-S3 for more detail). The combination of 5 mol%
PdCl2(PPh3)2/2 equivalents of KF in tBuOH under balloon
pressure of 3:1 CO/O2 at 40 °C gave the best result (up to 98%
yield) for the oxidative hydroxylation of 1a (Table 1, entry 1).
Among the palladium catalysts examined (Table 1, entries 1-5),
only PdCl2(PPh3)2 showed high catalytic activity, while other
tested bidentate ligands and catalyst precursors gave poor
yields for hydroxylated product 2a. The screening of different
additives illustrated that KF also played a key role to facilitate
this transformation under these conditions (Table 1, entries 1
and 7-9). Moreover, a survey of the solvent effects revealed that
over 90% reaction yields could be obtained in the presence of
either tBuOH or MeCN as the solvent (Table 1, entries 1, 11 and
12). Finally, the reaction proceeded under O2 atmosphere
without CO afforded 80% yield of the oxidative homo-coupling
product instead of hydroxylation product 2a, which displayed
that CO was crucial for the selectivity control (Table 1, entry 10).
When using Pd(PPh3)4 as the catalyst under O2 atmosphere
without CO, 70% diphenyl was achieved.
To gain more insights of this reaction, the gas phases was
initially detected during the reaction process. CO2 was found to
be generated along with the production of phenol 2a tested by
the clear water solution of Ca(OH)2. To verify where the oxygen
in CO2 came from, isotope labelling experiments were performed
utilizing GC-Mass spectroscopy. When using the H218O as the
labeling source, the mass spectrum showed the increase of CO2
with molecular weight of 46 and the molecular weight of 44 was
not detected during the reaction, which indicated that one
oxygen in CO2 came from water (Figure 1A). To further confirm
this result, 18O2 was also used as the labeling source under the
same conditions, the mass spectrum showed the increase CO2
with molecular weight of 44 and the molecular weight of 46 was
not detected during the reaction (Figure 1B). These above
results revealed that the formed CO2 in this oxidative
hydroxylation reaction come from water and CO.
Table 1. Optimization of Reaction Conditions [a]
Entry
[Pd]
additive
solvent
Yield 2a[b]
0
10
20
30
40
1
2
PdCl2(PPh3)2
PdCl2(dppf)
Pd(OAc)2/bipy
Pd(OAc)2
KF
KF
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DMF
98
6
Time / min
3
KF
8
4
KF
12
12
trace
9
5
Pd(MeCN)2Cl2
none
KF
6
KF
7
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Et3N
KOH
K3PO4
KF
8
41
11
trace
41
92
9
10[c]
11
12
10
15
20
Time/min
KF
Figure 1. (A) Gas phase detection using isotope labelling
experiments. (B) Gas phase detection using isotope labelling
experiments.
KF
MeCN
Furthermore,
isotope
labelling
experiments
results
demonstrated that O2 participated in this transformation and the
oxygen atom transferred into the hydroxylated product 2a’. On
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the contrary, 18O labelled water didn’t produce any labelled
product 2a’ [Scheme 2, Eqs (1) and (2)]. From the above, the
overall reaction could be speculated as shown in Scheme 2, Eq
(3): oxidative hydroxylation of 1a in the presence of O2, CO and
water produced phenol 2a, CO2 4 and boronic acid 5. The
presence of KF as the additive is essential to achieve the
PdCl2(PPh3)2 catalysed hydroxylation reaction.
Scheme 3. The KF effects for Pd (II) and Pd (0) catalyzed
hydroxylation reactions
Based on above experiment observations, the proposed
mechanism was listed in Scheme 4. As above mentioned, the
Pd(II) catalyst precursor was initially transformed to palladium
peroxo complex 6, which could be coordinated by phenylboronic
acid 1a to form a new Pd complex 6’.[13] Hydrolysis of 6’ would
generate palladium hydroxide species 7 and the adduct of
hydrogen peroxide and phenylboronic acid. The latter would
undergo a fast oxidative hydroxylation process affording phenol
2a and boric acid 5. Then CO insertion into the intermediate 7
afforded acyl palladium complex 8, which proceeded β-hydrogen
elimination to create palladium hydride species 9 and liberate
carbon dioxide. Finally, reductive elimination of 9 produced
water and Pd(0) species, which was oxidized to palladium
peroxo complex 6’ in the presence of oxygen and 1a. Agreeably,
this reaction mechanism accorded with the above isotope
labelling experiment results, in which the oxygen atom involved
in phenol comes from oxygen. In the meanwhile, CO2 could be
also formed along with the production of phenol.
Scheme 2. Isotope labelling experiments.
There is no reaction without the assistance of KF using Pd (II)
catalyst [Scheme 3, Eq (1)]. When Pd (0) catalyst was employed
as the catalyst in the presence of KF, this transformation
afforded excellent yield within a much shorter reaction time
comparing to Pd (II) catalyzed reaction. Nevertheless, Pd (0)
catalyzed reaction could also proceed smoothly in defect of KF
as the additive [Scheme 3, Eq (2)]. As we know, fluoride plays
important roles in arylboronic acid derivatives involved coupling
reactions.[10] We assumed that it mainly promoted the reduction
of Pd (II) catalyst precursor to Pd (0) species in this
PdCl2(PPh3)2 catalyzed oxidative hydroxylation reaction and the
catalyst precursor activation process was probably the rate
determined step of this catalytic reaction with Pd(II) catalyst.[11]
Moreover, the Pd (0) species is easily to be oxidized to form
palladium peroxo complex 6 under the oxygen atmosphere,[12]
which is possible catalytic active species of this reaction. To
verify this hypothesis, the stoichiometric reaction of 1a and 6
under the standard conditions was implemented and generated
2a with high yield [Scheme 3, Eq (3)]. This result further proved
palladium peroxo complex 6 was most likely involved in the
catalytic cycle. When performing reaction with Pd-oxo complex 6
in MeCN using 1a' as the substrate, only trace phenol product
was detected, which excluded the direct oxidation pathway from
Pd-oxo species.
Scheme 4. Proposed mechanism.
Previously, we have reported a palladium catalyzed oxidative
carbonylation reaction under similar reaction conditions.[14] In
that case, additional 10 mol% PPh3 can completely shut down
the reaction [Scheme 5, Eq (1)]. It might be due to the excess
PPh3 constrain the CO coordination and insertion steps.
Conversely, no ligand inhibition effect was observed when
excess PPh3 was added in this oxidative hydroxylation reaction
[Scheme 5, Eq (2)]. As we know, PPh3 can be oxidized by
hydrogen peroxide very fast. As hydrogen peroxide is generated
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during the reaction process, the excess PPh3 can be oxidized to
triphenyl phosphine oxide and thus do not inhibit this
transformation. Actually, the catalytic aerobic oxidation of
triphenyl phosphine could be achieved proficiently under the
standard conditions with 194 turnover number (TON) [Scheme 5,
Eq (3)], which further approved our proposed mechanism.
[a] Reaction conditions: ArB(OH)2 (0.25 mmol), KF (0.5 mmol), PdCl2(PPh3)2
(0.0125 mmol), CO/O2 (3:1) at 1 atm pressure in 2 mL of tBuOH and 150 μL
H2O. [b] GC yields. [c] Isolated yields. [d] PdCl2(PPh3)2 (0.019 mmol) was used.
In summary, we have developed a mild condition for hydrogen
peroxide generation from carbon monoxide, water and oxygen
by Pd catalyst. This methodology combines catalytic hydrogen
peroxides production with aerobic oxidation process in one
system. This transformation shows highly efficiency and widely
tolerance for arylboronic acids oxidation and triphenylphosphine
oxidation (PPh3) oxidation. A serial of investigations indicated
that the in-situ generation of hydrogen peroxide along with
carbon dioxide, and that both oxygen and water contributed in
this transformation and the oxygen atom in the hydroxylated
product originated from oxygen. Further synthetic application of
this catalytic hydrogen peroxide formation reaction system and
more detailed mechanistic studies are the subjects of on-going
in our lab.
Experimental Section
General procedure: In a schlenk tube equipped with a stir-bar, Pd
catalyst (0.0125 mmol), additive (0.5 mmol) and phenyl boronic acid
(0.25 mmol) were combined. A balloon filled with CO and O2（CO: O2 =
3:1）was connected to the Schlenk tube via the side tube. The reaction
tube was purged with the mixed gas for 1 minute. t-Butanol (2 mL) and
150 μL H2O were then added to the reaction tube via a syringe. The
Schlenk tube was placed in an oil-bath and heated to 40 ℃ for 12 hours
and then cooled to room temperature. The yields of product were
determined by GC.
Scheme 5. PPh3 effect on oxidative hydroxylation of arylboronic
acids and PPh3 oxidation
With the optimized reaction conditions in hand, we examined
the substrate scope of the palladium catalyzed aerobic oxidative
hydroxylation of arylboronic acids (Scheme 6). A variety of
arylboronic acids were smoothly oxidized to the corresponding
phenols in good to excellent yields. Electron-neutral, electron-
donating, and electron-withdrawing functional groups were all
well tolerated in this transformation. The reactions of steric
hindered substrates provided excellent results as well (Scheme
6, 2d, 2n, 2o and 2p). More importantly, the electron-rich and
bromo- substituted phenols, which are difficult to obtain from the
traditional nucleophilic substitution and transition-metal
catalyzed hydroxylation of aryl halides,[15] could be
straightforwardly synthesized using this catalytic oxidative
hydroxylation protocol (Scheme 6, 2e, 2j and 2m).
Acknowledgements
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21520102003, 21272180 and 21302148), the Hubei Province
Natural Science Foundation of China (2013CFA081), the
Research Fund for the Doctoral Program of Higher Education of
China (20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated. We thank Prof Qiang Liu and Dr
Jie Liu for the contribution and discussion of this work.
Scheme 6. Palladium catalyzed aerobic oxidative hydroxylation of
arylboronic acids.[a]
Keywords: palladium catalysis
•
aerobic oxidation
•
hydroperoxide • dioxygen activation • oxidative coupling
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Hong Yi, Aiwen Lei*
Page No. – Page No.
Pd-catalyzed Hydroxylation of Aryl
Boronic Acids using in-situ
Text for Table of Contents
Generated Hydrogen Peroxide
A benign and efficient palladium catalyzed in-situ generated hydrogen peroxide from carbon monoxide, water and
oxygen under mild conditions is developed in this work. This system shows good functional group tolerance and
provides a new route to a variety of functionalized phenols.
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