Preparation of phenolic compounds through catalyst-free ipso-hydroxylation of arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2014.02.048

A novel method for the preparation of phenolic compounds through ipso-hydroxylation of the corresponding widely available arylboronic acid precursors is described. Through application of a novel PEG400-H ₂O₂ reactant system, a variety of substituted phenols and other aromatic analogues have been prepared in excellent yields at room temperature in the absence of any catalyst.

Full text of DOI:10.1016/j.tetlet.2014.02.048

Tetrahedron Letters 55 (2014) 2082–2084
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Tetrahedron Letters
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Preparation of phenolic compounds through catalyst-free
ipso-hydroxylation of arylboronic acids
⇑
Mukut Gohain, Maretha du Plessis, Johannes H. van Tonder, Barend C. B. Bezuidenhoudt
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein ZA9300, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel method for the preparation of phenolic compounds through ipso-hydroxylation of the
Received 7 November 2013
Revised 23 January 2014
Accepted 12 February 2014
Available online 22 February 2014
corresponding widely available arylboronic acid precursors is described. Through application of a novel
PEG400-H2O2 reactant system, a variety of substituted phenols and other aromatic analogues have been
prepared in excellent yields at room temperature in the absence of any catalyst.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Polyethylene glycol
Hydrogen peroxide
Arylboronic acid
Hydroxylation
Catalyst-free
Phenolic compounds
Phenolic compounds are structural constituents of various
pharmaceutical compounds, polymers, and naturally occurring
molecules.1,2 As a result of their versatility, phenols and related
aromatics frequently serve as key synthetic intermediates for the
construction of a number of more complex compounds, mostly of
industrial importance.3 Establishing mild and efficient access to
phenols and related aromatic moieties, especially in the presence
of polyfunctional groups, is thus of great significance.
Traditionally, non-oxidative methods toward the preparation of
phenolic compounds include nucleophilic aromatic substitution of
activated aryl halides and copper-promoted conversion of diazoa-
renes, as well as benzyne protocols, all of which are limited with
respect to the availability of starting materials and, in some cases,
harsh reaction conditions.4–7
Arylboronic acids, as well as analogous aromatic/hetero-aro-
matic boronate esters, are readily available and have found broad
applications in synthetic chemistry.8–10 Several methods have
therefore been reported for the conversion of these compounds
into their corresponding phenols, of which the majority utilize
transition metal catalysts and/or an excess of oxidant. One such
method has been reported by Wang and co-workers wherein cop-
per-catalyzed hydroxylation of arylboronic acids is achieved in the
presence of stoichiometric amounts of inorganic bases (KOH11 and
NaOH) at room temperature.12 Following these reports, several
base-free13,14 and palladium-catalyzed15 methodologies were
developed as alternatives.
An excess of H2O2 was demonstrated by Bora and co-worker to
be an active oxidant for this transformation when utilized with cat-
alytic amounts of either I216 or acidic alumina.17 Zhu et al. reported
hydroxylation conditions for aryl and heteroaryl boronic acids, as
well as boronate esters, in the presence of stoichiometric amounts
of N-oxides, which are not readily available.18 All of these methods,
including the less favorable methods which incorporate toxic sol-
vents or chemicals,19 motivate the need to develop more efficient,
cost-effective, and green processes for the synthesis of phenolics
and other aromatic analogues.
Polyethylene glycol (PEG) was recently claimed to be a green sol-
vent20 and is useful in many applications, in particular substitution,
oxidation, and reduction reactions.21–26 Low cost, low flammability,
low toxicity, high thermal stability, recyclability, non-halogenated
composition, facile degradability, and good miscibility with a wide
variety of organic solvents and compounds are some of the
properties that render PEG as an excellent solvent in organic
synthesis.27–32 Furthermore, the good biocompatibility and low
immunogenicity of PEG have resulted in it being placed on the Food
and Drug Administration (FDA) GRAS (Compounds Generally
Recognized as Safe) list, so it has been approved by the FDA for inter-
nal consumption.33 The number of recent reviews describing PEG
and its applications in biotechnology and medicine34–36 has further
inspired the utilization of this eco-friendly and recyclable solvent
toward the synthesis of phenols under metal-free conditions.
⇑
Corresponding author. Tel.: +27 51 401 9021; fax: +27 51 444 6384.
E-mail address: bezuidbc@ufs.ac.za (B.C.B. Bezuidenhoudt).
http://dx.doi.org/10.1016/j.tetlet.2014.02.048
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. Gohain et al. / Tetrahedron Letters 55 (2014) 2082–2084
2083
n
m
OH
OH
HO
O
O
O
δ-
O
O
H
OH
OH2
δ+
O
O
O
O
H+
B(OH)2
B(OH)2
B(OH)2
2a
3a
1a
-H2O
H
H
OH
-B(OH)3
O
H2O
B(OH)2
B(OH)2
Hydrolysis
O
O
4a
5a
1b
Scheme 1. Proposed mechanism for phenol formation from an arylboronic acid.
Table 1
Another advantage is the stability of PEG in the presence of
H2O2,20 which was exploited in the current study. To the best of
our knowledge, this is the first report of phenol preparation from
arylboronic acids employing H2O2 as the oxidant in PEG400 under
catalyst-free conditions at room temperature.37 This phenomenon
is speculated to be the result of a synergistic interaction between
the solvent and the oxidant. Due to the fact that a base is generally
required to activate hydrogen peroxide, it is suggested that strong
hydrogen bonding between the PEG400 and the hydrogen peroxide
promotes sufficient nucleophilicity for its addition to the boronic
acid without the need for deprotonation by a base (Scheme 1).
Upon successful nucleophilic attack by the oxidant on the sub-
strate, aryl migration may follow with subsequent hydrolysis
yielding the desired phenol.
The oxidation of phenylboronic acid (1a) was utilized as a mod-
el reaction during optimization of the reaction conditions. The ini-
tial reaction was performed with equimolar quantities of
phenylboronic acid (2 mmol) and 30% aqueous H2O2 in PEG400
(1 mL), which afforded complete conversion of the starting mate-
rial after five hours at room temperature. Upon increasing the
amount of H2O2 to 1.5 equiv the rate of the reaction was found
to increase exponentially to produce phenol in an excellent yield
after only 10 min (monitored by TLC and 1H NMR). Although it
was found that the reaction can also be executed in PEG200,
PEG400 proved to be superior to the 200 equiv especially with re-
spect to removal of water from the PEG if it is to be recycled.
PEG400 was therefore used in all subsequent reactions.
The scope of the reaction was explored next by employing var-
ious arylboronic acid derivatives under similar conditions (Table 1).
Electron-withdrawing [e.g. nitro (entry 4), halogen (entries 2, 7, 10,
and 12) and carbonyl entities (entries 5 and 6)], as well as electron-
donating [e.g. methoxy (entries 3 and 13) and alkyl (entries 8 and
9)] substituents were introduced on the phenyl ring in order to
establish their effect on the transformation. Furthermore, the sub-
stitution varied between ortho, meta, and para positions relative to
the boronic acid functionality. Interestingly, all of the substrates
were converted in excellent yield into their corresponding phenols
suggesting that the reactivity is not governed by the nucleophilic-
ity of the aromatic system. Similar results were obtained upon
subjecting a sterically more demanding substrate, that is 1-naph-
thaleneboronic acid (entry 14), as well as a heteroarene derivative,
2-thiopheneboronic acid (entry 15), to the reaction conditions.
The recyclability of the PEG400 was evaluated by recovering the
solvent from phenylboronic acid reactions in the following way:
after extraction of the phenolic product into diethyl ether or ethyl
acetate, the water was removed from the PEG by vacuum distilla-
tion, resulting in an 80% recovery of the PEG. The recovered PEG
was employed as the solvent in subsequent phenylboronic acid
Various phenols obtained according to Scheme 1a
Entry
Substrate
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Phenylboronic acid
10
8
10
8
8
10
8
10
8
8
10
10
10
10
12
97
95
97
97
97
97
97
97
95
95
96
96
97
97
90
4-Chlorophenylboronic acid
4-Methoxyphenylboronic acid
4-Nitrophenylboronic acid
4-Acetylphenylboronic acid
4-Methoxycarbonylboronic acid
4-Fluorophenylboronic acid
4-tert-Butylphenylboronic acid
3-Methylphenylboronic acid
3-Chlorophenylboronic acid
3-Nitrophenylboronic acid
3-Bromophenylboronic acid
2-Methoxyphenylboronic acid
1-Naphthaleneboronic acid
2-Thiopheneboronic acid
a
Reaction conditions: arylboronic acid (2 mmol), H2O2 (30% aq., 0.26 mL,
1.5 equiv), PEG400 (2 mL), room temperature.
b
Isolated yield.
reactions without any further purification. Apart from losses occur-
ring during the recovery of the PEG, no changes with respect to
reaction rate and product yield were observed for up to four cycles.
In conclusion, a novel and highly efficient protocol for the syn-
thesis of phenols, in the absence of catalyst, utilizing a novel
PEG400-H2O2 solvent system has been described. This protocol
avoids the use of toxic organic solvents and harsh reaction condi-
tions. Furthermore, the procedure offers several advantages includ-
ing cleaner reactions, general applicability, improved yields, and a
simple experimental procedure, which should make it a useful
strategy for the preparation of phenol substrates from phenylbo-
ronic acid precursors.
Acknowledgment
Sasol Ltd is hereby acknowledged for financial support.
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37. General procedure for the hydroxylation of arylboronic acids: A 50 mL round
bottom flask, containing 2 mL of PEG400, was charged with 30% aqueous H2O2
(1.5 equiv w/v) and stirred for 2 min at room temperature. The arylboronic acid
(2 mmol) was added to the prepared PEG400-H2O2 reagent system, after which
stirring was continued at room temperature. Upon completion of the reaction
(monitored by TLC, GC, and 1H NMR) the corresponding phenol product was
extracted into Et2O (3 Â 20 mL). The organic layers were combined, washed
with brine (3 Â 20 mL), dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure (ca. 40 °C). Purification of the crude product
was achieved by column chromatography on silica gel (hexane/EtOAc; 20:1) to
afford the desired product. The purity of the product was confirmed by 1H
NMR, 13C NMR, GC, and GCMS.