A scalable and green one-minute synthesis of substituted phenols

Article abstract of DOI:10.1039/d0ra08580d

A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols via ipso-hydroxylation of arylboronic acids in ethanol. The method utilizes the combination of aqueous hydrogen peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols in very good to excellent yields without chromatographic purification. The reaction is scalable up to at least 5 grams at room temperature with one-minute reaction time and can be combined in a one-pot sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly substituted phenols.

Full text of DOI:10.1039/d0ra08580d

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A scalable and green one-minute synthesis of
substituted phenols†
Cite this: RSC Adv., 2020, 10, 40582
*
Vijayaragavan Elumalai
and Jørn H. Hansen
A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols via ipso-
hydroxylation of arylboronic acids in ethanol. The method utilizes the combination of aqueous hydrogen
peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient
conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols in
very good to excellent yields without chromatographic purification. The reaction is scalable up to at least
5 grams at room temperature with one-minute reaction time and can be combined in a one-pot
sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly
substituted phenols.
Received 8th October 2020
Accepted 23rd October 2020
DOI: 10.1039/d0ra08580d
rsc.li/rsc-advances
the use of harmful solvents. Furthermore, in many of these
methods, scaled-up synthesis of phenols has not been demon-
Introduction
strated. When summarizing published papers on the use of
hydrogen peroxide,18g as one of the simplest and most available
green oxidants, surprisingly, we nd that virtually all of them
report using extra additives of some kind and relatively long
reaction times.
Phenols are indispensable in synthesis and constitute a privi-
leged structural scaffold present in pharmaceuticals, natural
products and synthetic polymers, among many other applica-
tions.1 Consequently, considerable attention has been focused
on the synthesis of phenol and its derivatives.2 Traditional
methods include nucleophilic aromatic substitution of aryl
halides,3 transition-metal catalyzed processes,4 hydroxylation of
benzene,5 oxidation of cumene6 and hydrolysis of diazo
compounds.7 These methods have some major limitations,
including harsh reaction conditions, reagent toxicities and the
need for additives and complex ligands. The ipso-hydroxylation
of boronic acids is an alternative route for the synthesis of
phenols which avoids many of the problems with previous
approaches. The boronic acids have low toxicity, higher stability
in air, are easy to handle and display high functional group
diversity. Aryl and heteroarylboronic acids are readily available
and have been employed in several studies on ipso-hydroxyl-
ation chemistry. These mainly involved transition metal catal-
ysis8 (Scheme 1A-i), photocatalysis9 (Scheme 1A-ii) or
stoichiometric oxidants such as H2O2,10 oxone,11 N-oxides,12
organic hypervalent iodine(III),13 benzoquinone,14 mCPBA,15
NaBO3 (ref. 16) and molecular oxygen17 (Scheme 1A-iii). More-
over, numerous variants have been reported recently for the
synthesis of substituted phenols from boronic acids.18 Despite
the high efficiency of many of these protocols, they are oen
characterized by high temperatures and long reaction times, the
use of transition metals, necessity of strong base addition and
Recognizing the power of the transformation in the synthesis
of diverse phenols, we set out to nd mild, practical and simple
reaction conditions with a minimum of additives, high chem-
ical yields and with a clear green prole. Herein we report a very
rapid, catalyst/additive-free and practical protocol for the
synthesis of phenols via the ipso-hydroxylation of arylboronic
acids using hydrogen peroxide in ethanol. The protocol repre-
sents a signicant advance in the eld as it works with
unprecedented efficiency under ambient, green conditions and
affords substantially improved chemical yields of phenols with
only one minute reaction time and without ash column
chromatography. Furthermore, adding hydrogen bromide
yields bromophenols directly in a completely novel one-pot
system which advances a truly practical and scalable approach
to access highly substituted phenols (Scheme 1B).
Results and discussion
Previous reports on the use of hydrogen peroxide as oxidant for
the ipso-hydroxylation were found to be of high interest because
of the simplicity and clear green prole of H2O2.10,18g Although
several solvent systems have been reported with hydrogen
peroxide, we decided to screen a range of solvents to ascertain
reaction performance at ambient temperature and atmosphere
with only one-minute reaction time. These reaction conditions
underline our search for a highly efficient and truly practical
transformation. In the solvent survey, conducted with the
UiT The Arctic University of Norway, Department of Chemistry, Chemical Synthesis
and Analysis Group, N9037 Tromsø, Norway. E-mail: jorn.h.hansen@uit.no
† Electronic supplementary information (ESI) available: Procedures, analytical
data and spectra is available online. See DOI: 10.1039/d0ra08580d
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range of commonly employed solvents such as methanol, THF,
acetone, ethyl acetate and acetonitrile afforded high yields (82–
89%), whereas water and DCM gave medium yields (50–55%).
The major issue appears to be poor solubility of the boronic acid
in the latter. The highest isolated yield of 94% was obtained in
ethanol, a readily accessible, convenient and green solvent.
Therefore, ethanol was the solvent of choice for further studies.
The most striking result from our studies is that the reaction
time of only one minute in ethanol provides excellent yields at
ambient temperature in an open ask. Our observations and
simple conditions have not been reported in previous works to
the best of our knowledge.
The effect of oxidant equivalency was briey investigated
next (Table 2). Using one equivalent of peroxide yielded 50%
(NMR) of the product aer a set one minute reaction time.
Increasing to two equivalents gave full conversion to product in
99% NMR-yield aer one minute. Prolonging the reaction time
to 5 minutes did not induce any observable changes. Also,
further increasing the oxidant equivalency to 3 retained 99%
NMR-yield of the desired product. In further scope studies we
decided to employ 3 equivalents of hydrogen peroxide in order
to ensure full conversion at one minute reaction time. However,
it should be noted that near equimolar amounts of oxidant may
be sufficient with somewhat prolonged reaction times.
A range of commercially available boronic acids were
surveyed as substrates for the chemistry in order to ascertain
the generality of our conditions. To our delight, good to excel-
lent chemical yields (60–98%) were obtained across the board in
23 examples detailed in Scheme 2. Notably, most of the exam-
ples were isolated by simple extraction in pure form and further
purication was not necessary. A range of p-substituted phe-
nylboronic acids containing electron donating (methoxy, ethyl,
acetamido, Boc-amino) and electron withdrawing groups
(chloro, bromo, cyano, acetyl, carboxaldehyde, carboxylic acid)
afforded 94–98% and 82–97% yields, respectively. Thus, elec-
tronic diversity in the substituents are well tolerated in the
transformation. Notably, 2n is the commercial pharmaceutical
paracetamol and was formed in 97% isolated yield from our
Scheme 1 Ipso-hydroxylation of phenylboronic acids.
reaction between phenylboronic acid 1a and hydrogen peroxide
to generate phenol 2a (Table 1), we were pleased to observe that
medium to excellent yields were obtainable across the board. A
Table 1 Survey of solvents
Table 2 Effect of H2O2 ratio with reaction time on overall product
yield
Entrya
Solvent
Yield 2ab (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
THF
EtOAc
H2O
Acetone
MeCN
DCM
87
92
82
Entrya
H2O2 (equiv.)
Time (min)
Yield 2ab(%)
89
55c,d
84
1
2
3
4
1
2
2
3
1
1
5
1
50
99
99
99
86
50c,d
a
Reaction procedure: to a stirred solution of phenylboronic acid 1a (1.0
a
mmol) in EtOH (3 mL) was added H2O2 (30%, 3 equiv.) and stirred for
one minute at room temperature. Isolated yield. NMR-yield. Poor mmol) in EtOH (3 mL) was added H2O2 (30%) and stirred for one minute
solubility of 1a.
Reaction procedure: to a stirred solution of phenylboronic acid 1 (1.0
b
c
d
b
at room temperature. NMR-yield.
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Scheme 3 Gram-scale synthesis of phenols.
In order to further demonstrate the applicability of our
reaction conditions, three of the ipso-hydroxylations were con-
ducted at 5 gram-scale by simple scale-up of p-substituted
systems. 85–90% isolated yields were obtained with electron-
donating (methoxy), electron-withdrawing (cyano) and
electron-neutral (H) examples shown in Scheme 3 (2a, 2b and
2g). This suggests that our conditions should be the method of
choice for such a transformation conducted at larger scales for
synthetic purposes.
The mechanism for the ipso-hydroxylation of boronic acids is
presumed to be as outlined in Scheme 4.19 The boronic acid can
form an adduct with hydrogen peroxide which can undergo
rapid proton transfer (particularly in protic solvents) to afford
intermediate 1a–H2O2–2, set up for 1,2-aryl migration with
departure of water, which gives the boronic ester readily
amenable to hydrolysis to afford the phenol.
Treatment of phenols with HBr under oxidative conditions is
known to yield bromophenols via electrophilic aromatic sub-
stitution.10f To our delight, the addition of hydrogen bromide to
the ipso-hydroxylation reaction from the very start yielded
brominated phenols 3a–k directly (Scheme 5), even though the
reaction time was still kept at one minute. This direct one-pot
protocol for generation of bromophenols from arylboronic
acids is novel. The reaction likely proceeds by tandem ipso-
hydroxylation-bromination, both processes which are facili-
tated by hydrogen peroxide. All the reactions involved must be
rapid, since only a minute total reaction time afforded medium
to excellent yields of the bromophenols (53–95% yield). The
simple phenylboronic acid 1a afforded the tribrominated
phenol 3a in excellent 95% yield. The electron-withdrawing p-
cyano system 1b gave only slightly diminished yield (89%) of 3b.
Scheme 2 Scope of ipso-hydroxylation chemistry.
one-minute protocol. Even ortho-substituted boronic acids work
well in high to excellent chemical yields (83–96%). Notably, 2i
and 2p were formed in excellent 95% and 96% yields, respec-
tively, thus demonstrating very high tolerance to steric
hindrance around the boronic acid moiety. Likewise, meta-
substituted substrates were well tolerated across electronic
diversity (80–92%), except of the meta-nitro substituted boronic
acid 1e, which afforded 60% yield of 2e. This was the only entry
that required ash column chromatography to obtain pure
material. Furthermore, the chemistry is compatible with
heterocycles as demonstrated with thiophene-2-boronic acid 1u
and indole-5-boronic acid 1v. The former was isolated as the
keto-form 2u, which is a more stable tautomer of the corre-
sponding aromatic hydroxy compound, in 80% yield. The 5-
hydroxyindole product 2v was isolated in 91% yield. To our
delight, the polyaromatic pyrene boronic acid 1w underwent
a highly efficient transformation to 2w in 98% yield. Thus, in
addition to very short reaction time and practical conditions,
the chemistry appears to be relatively independent of the elec-
tronic and steric nature of the substrate. The transformation
under our conditions clearly has a broad scope and potential
great synthetic utility in the formation of aromatic hydroxy
compounds.
Scheme 4 Hypothesized reaction mechanism for the ipso-hydroxyl-
ation of boronic acids.
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Scheme 5 Tandem ipso-hydroxylation-bromination.
The remaining p-substituted systems afforded medium to good
yields of o-dibrominated products in 52–84% yields. Ortho- and
meta-substituted systems afforded ortho,para-dibrominated
products in 55–88% yields. The meta-brominated substrate 1j
afforded the tetrabromophenol 3j in 52% yield. The para-acet-
amidoboronic acid 1k afforded the ortho-dibrominated phenol
3k in 54% yield, which represents a formal synthesis of bromo-
functionalized pharmaceutical agent paracetamol. In this case,
another product 3k0 was also isolated which turned out to be
para-bromoacetamidobenzene in 38% yield. This represents
a formal ipso-bromination of the boronic acid.20 The tandem
ipso-hydroxylation – bromination procedure appears to work
quite well with a range of substrate and affords medium to
excellent yields of bromophenols. This represents an attractive
and direct route to this class of compounds due to its high
efficiency and convenient procedure.
Our development of the one minute route to bromophenols,
triggered us to investigate whether another reaction could be
combined in the same pot in order to access further function-
alized phenols. The presence of bromo-substituents would
allow access to arylated phenols via cross-coupling chemistry.
By generating bromophenols as described above, followed by
Scheme
6
One-pot ipso-hydroxylation-bromination and Suzuki
coupling to generate aryl-substituted phenols.
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addition of base, 5 equivalents of a new boronic acid, tetrakis-
palladiumtriphenylphosphine (6 mol%) and degassing with
nitrogen, the Suzuki–Miyaura coupling products 4a–c were
generated in 20–67% yields (over 3 steps) upon microwave
heating for 30 min (Scheme 6). 4a was formed in diminished
20% yield using 3 equivalents of boronic acid and base with
4 mol% of Pd-catalyst loading. However, by increasing to 5
equivalents of boronic acid and base with 6 mol% of catalyst
loading (2 mol% per coupling), the yields increased to 65% and
67% for 4b and 4c, respectively. Over 3 steps this is close to 90%
average yield per step (unoptimized), thus, it constitutes an
impressive one-pot procedure for generating such highly
substituted phenols. Furthermore, 4b is not symmetrical and
demonstrates that this methodology can be applied to generate
relatively complex phenols.
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Conclusions
In summary, we have developed a very rapid and green
synthesis of phenols from boronic acids via ipso-hydroxylation
mediated by hydrogen peroxide in ethanol at ambient condi-
tions. The method appears quite general and affords very good
to excellent yields across a range of sterically and electronically
diverse substituent patterns. By addition of hydrogen bromide
to the reaction mixture, diverse bromophenols are available
through a tandem hydroxylation/bromination process. The
chemistry has been applied to develop a synthesis of highly
substituted arylphenols via
a one-pot ipso-hydroxylation/
bromination/Suzuki–Miyaura coupling sequence. The results
should be of broad interest to the chemical community and
represent major advances in the synthesis of complex phenols.
Conflicts of interest
There are no conicts to declare.
´
E. Echeverrıa, F. E. Torres and J. Zhang, ACS Catal., 2015,
Acknowledgements
5, 5283; (e) A. K. Simlandy, B. Bhattacharyya, A. Pandey
and S. Mukherjee, ACS Catal., 2018, 8, 5206; (f) H.-P. Liang,
Q. Chen and B.-H. Han, ACS Catal., 2018, 8, 5313; (g)
S. P. Pitre, C. D. McTiernan, H. Ismaili and J. C. Scaiano, J.
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The authors acknowledge generous funding for this project by
the Research Council of Norway (Grant no. 275043 CasCat) and
the Department of Chemistry at UiT The Arctic University of
Norway.
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