Synthesis of substituted phenols via hydroxylation of arenes using hydrogen peroxide in the presence of hexaphenyloxodiphosphonium triflate

Article abstract of DOI:10.2174/1570178615666180430121524

A mild and efficient protocol for the synthesis of phenols from arenes has been developed using aqueous hydrogen peroxide as an oxidizing agent and hexaphenyloxodiphosphonium triflate as a promoter. The reactions were carried out with the simple procedure in EtOH-H₂O at room temperature in short reaction times.

Full text of DOI:10.2174/1570178615666180430121524

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Letters in Organic Chemistry, 2018, 15, 878-882
RESEARCH ARTICLE
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Synthesis of Substituted Phenols via Hydroxylation of Arenes Using Hy-
drogen Peroxide in the Presence of Hexaphenyloxodiphosphonium Triflate
BENTHAM
S
CIENCE
Mohammad Mehdi Khodaei*, Abdolhamid Alizadeh* and Hadis Afshar Hezarkhani
Department of Organic Chemistry, Razi University, Kermanshah 67149-67346, Iran
Abstract: A mild and efficient protocol for the synthesis of phenols from arenes has been developed
using aqueous hydrogen peroxide as an oxidizing agent and hexaphenyloxodiphosphonium triflate as a
A R T I C L E H I S T O R Y
promoter. The reactions were carried out with the simple procedure in EtOH-H2O at room temperature
in short reaction times.
Received: August 11, 2017
Revised: April 11, 2018
Accepted: April 19, 2018
DOI:
10.2174/1570178615666180430121524
Keywords: Substituted phenols, hexaphenyloxodiphosphonium triflate, hydroxylation, hydrogen peroxide, arene.
1. INTRODUCTION
Thus, the development of catalytic systems or promoters
that are readily accessible, air and moisture stable, and that
can promote these reactions with high selectivity and good
product yields under mild reaction conditions are still desir-
able.
Phenol and its derivatives are important chemical inter-
mediates in manufacturing pharmaceuticals, natural prod-
ucts, polymers, and dyes [1]. Classical methods for prepara-
tion of such phenols involve nucleophilic substitution of aryl
halides and copper-catalyzed transformation of diazoarenes
[2]. However, strict electron-rich requirements, incompati-
bilities with many functional groups, and harsh reaction con-
ditions lead in limitations in its application. Impressive pro-
gress in the transition-metal-catalyzed synthesis of phenols
from aryl halides has been achieved [3-9]. Transformation of
arylboronic acids to the corresponding phenols with metal-
catalyst under air conditions was reported [10]. In addition,
some investigations indicate that arylboronic acids can be
converted into phenols under metal-free conditions by using
air as oxidant [11]. Other oxidants including H2O2 [12], ozone
[13], MCPBA [14] or N-oxides [15] used for this transforma-
tion, have been reported. Some of these approaches have dis-
advantages including the use of ligand/base [10], the use of
toxic chlorinated solvents [12d, 16] and require longer reac-
tion times [11, 12]. The direct aromatic oxygenation reaction
of arenes to phenols has attracted much attention due to its
importance in commercial point in phenol production. This
method has been chosen as an alternative route using envi-
ronmentally benign oxidant such as O2 or H2O2 [17-22].
Among the oxidants, hydrogen peroxide is an economi-
cally and environmentally benign oxidant which is widely
used as an electrophilic reagent and can react with many
functional groups. It has a simple process, and water is the
only by-product.
Trifluoromethanesulfonic anhydride, Tf2O, is known for
its utility for the conversion of an OH group into an OTf
leaving group [25]. Tf2O reacts exothermically with Ph3PO
in CH2Cl2 to give a white precipitate of hexapheny-
loxodiphosphonium triflate (Reagent B) (Scheme 1) [26].
OTf
Ph
OTf
Ph
Ph
Ph P O
Ph
15 min
+
Tf2O
2
P
P
Ph
Ph
O
CH2Cl2, 0 °C to rt
Ph
Ph
Reagent B
Scheme (1). Synthesis of hexaphenyloxodiphosphonium triflate.
The direct introduction of OH group into the aromatic C-
H bond with such oxidants is challenging due to low product
selectivity which made by overoxidation of phenols and low
reactivity of aromatic C-H bond [23, 24].
This reagent, commonly called Hendrickson`s reagent,
was shown to be a powerful dehydrating agent and promoter,
and promising reagent for some organic reactions [26-28].
2. RESULTS AND DISCUSSION
*Address correspondence to these authors at the Department of Organic
Chemistry, Razi University, Kermanshah 67149-67346, Iran; Tel: +98-833-
427-9296; E-mails: mmkhoda@razi.ac.ir; ahalizadeh22@hotmail.com
As part of our ongoing efforts to develop electrophilic
aromatic substitution reaction using Tf2O or the Tf2O deriva-
1875-6255/18 $58.00+.00
© 2018 Bentham Science Publishers

Synthesis of Substituted Phenols via Hydroxylation of Arenes Using Hydrogen
Letters in Organic Chemistry, 2018, Vol. 15, No. 10 879
tives [29], we wish to report hydroxylation of arenes using
Reagent B/H2O2 system in H2O-EtOH at room temperature
(Scheme 2).
did not show any noticeable differences with respect to the
yield and reaction time. Therefore, the optimized reaction
conditions for this reaction are Reagent B (1 equiv) in H2O-
EtOH (1:2) at room temperature. A control experiment con-
ducted without Reagent B indicated that the reaction did not
take place, and the mesitylene remained unreacted at the end
of the reaction.
R
R
H
OH
Reagent B
H2O2
2
+
To study the generality of this procedure, we examined
the reaction using several arenes under the optimized reac-
tion conditions (Table 2). The arenes with electron releasing
groups react with shorter reaction times and good yields,
while the reactions of arenes with electron withdrawing
groups carried out with longer reaction times and lower
yields. The rate differences between electron rich and poor
arenes are so low, it may be due to the high reactivity of
Reagent B.
H2O, Ethanol
rt
3(a-o)
1(a-o)
Scheme (2). Hydroxylation of arenes using Reagent B/H2O2 sys-
tem.
Table 1. Hydroxylation of mesitylene using Reagent B/H2O2
system in different solvents at room temperature.
The hydroxylation of 1a was carried out under the reac-
tion conditions, and 3a was obtained in 65% yield (Table 2,
entry 1). The overoxidation product, benzoquinone, was not
produced. In addition, no polyhydroxylation product was
observed. The reaction of 3a under the same reaction condi-
tions was accompanied by the formation of several by- prod-
ucts, and efforts to obtain the corresponding phenols were
not successful.
H
OH
Reagent B
H2O2
+
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
H2O-Ethanol (1:1)
H2O-Ethanol (1:2)
H2O-Ethanol (1:3)
H2O-Ethanol (2:1)
Ethanol
50
35
60
50
60
95
90
95
95
70
80
75
50
70
50
40
45
40
The arene 1b with an electron donor group reacted with
H2O2 under the same reaction conditions and the mixture of
isomeric products of 3b was obtained in 55% yield (Table 2,
entry 2). The hydroxylation of 1c-1e afforded the corre-
sponding products 3c-3e in 70, 78 and 75% yields, respec-
tively due to having two methyl groups (Table 2, entries 3, 4
and 5). The compound 1f with three methyl groups reacted
with H2O2 to give 3f in 80% yield (Table 2, entry 6). The
reaction of 1g with the moderate electron donor group was
carried out with high regioselectivity to afford 3g in 75%
yield (Table 2, entry 7). Hydroxylation of 1h with the strong
electron releasing group was performed to give a mixture of
o- and p-isomers of 3h with ratio 31:69 in 80% yield (Table
2, entry 8). In this case, the C-hydroxylation product was
obtained and no N-hydroxylation produced. The reason for
this observation may have arisen from this fact that there is a
H2O
CH2Cl2
MeCN
CHCl3
aMesitylene (1 mmol, 0.138 mL), H2O2 (4 mmol, 0.4 mL), Reagent B (1 mmol, 0.814
g) in 3 mL H2O-EtOH: 1:2 at room temperature. b isolated yield.
+
hard-soft interaction between the nitrogen of 1h and OH of
As a starting point for optimization of the reaction condi-
tions, mesitylene was chosen as a model substrate for inves-
tigation. The reaction initiated in a H2O-EtOH (1:1) solution
using H2O2 as the oxidant in the presence of Reagent B as a
promoter. The result was promising, and the product pro-
duced in 70% yield (Table 1, entry 1). Increasing the amount
of EtOH in the EtOH-H2O solution led to a higher yield of
product (80%, Table 1, entry 2). However, a further increase
of ethanol (Table 1, entry 3) or increase of water (Table 1,
entry 4), resulted in a decreased yield of the corresponding
product. Pure ethanol (Table 1, entry 5) or pure water (Table
1, entry 6) as a solvent was also examined and the results
indicated that the yield of the corresponding product re-
duced. This observation showed that the reaction reactivity
was depended on the ratio of EtOH/H2O. Investigation of the
effect of other solvents including CH2Cl2, CH3CN and
CHCl3 resulted in a lower yield of the product. The effect of
amount of Reagent B on the reaction was also examined and
it was found that 1 mmol of Reagent B was the best choice.
When 1.2 and 1.4 mmol of Reagent B were used, the results
H2O2. This hard-soft interaction intensifies the nucleophilic
ability of carbon of 1h in comparison with its nitrogen; so
the carbon of 1h reacted rapidly with H2O2 and it did not
allow nitrogen to react (Scheme 3).
NH2
OH
NH2
Reagent B
H2O, Ethanol
rt
80%
+
H2O2
HO
NH
0%
Scheme (3). Hydroxylation of 1h on carbon using Reagent B /H2O2
system.

880 Letters in Organic Chemistry, 2018, Vol. 15, No. 10
Khodaei et al.
Table 2. Hydroxylation of arenes with H2O2 using Reagent B.
Entry
ArH
Product
OH
Time (min)
Yielda (%)
1
55
65
70
1a
3a
CH3
OH
H3C
H3C
2
3
55
40
3b
1b
CH3
CH3
CH3
70
78
75
1c
OH
CH3
3c
H3C
CH3
4
5
40
40
OH
3d
CH3
CH3
1d
OH
H3C
CH3
CH3
3e
CH3
CH3
1e
OH
H3C
6
35
80
H3C
CH3
1f
CH3
3f
OCH3
H3CO
7
8
44
40
75
OH
3g
1g
1h
NH2
NH2
OH
80b
3h
H3C CH3
H3C CH3
N
N
9
60
55
OH
1i
3i
Br
Br
10
11
45
50
60
65
OH
3j
1j
Cl
Cl
OH
3k
3l
1k
Cl
Cl
HO
Cl
12
50
70
Cl
Cl
Cl
1l
NO2
O2N
OH
13
14
60
50
60
50
68c
55
3m
1m
OH
1n
3n
15
N
N
1o
OH
3o
aIsolated yield.
bThe ratio of ortho:para was determined with 1H NMR. Ratio = 69:31.
cThe ratio of α:β was determined with 1H NMR. Ratio = 62:38.

Synthesis of Substituted Phenols via Hydroxylation of Arenes Using Hydrogen
Letters in Organic Chemistry, 2018, Vol. 15, No. 10 881
The substrate 1i was also reacted with H2O2 and the cor-
responding mixture of products 3i was obtained in 55% yield
(Table 2, entry 9).
via a two-step process at low temperature [28]. The produced
phosphonium cation (Reagent B) accepts a nucleophilic
compound and the triflate leaving group exits simultaneously
[29d and 29e]. Replacement of triflate with the oxygen of
H2O2 generates intermediate C. The intermediate C was
characterized by FT-IR and NMR spectra (Supporting in-
formation). The presence of this intermediate might be con-
Hydroxylation of 1j and 1k with electron withdrawing
groups under the present reaction conditions also occurred
with high regioselectivity and the p-isomers of 3j and 3k
were obtained as sole products (Table 2, entries 10 and 11).
1l also reacted with H2O2 to afford the corresponding prod-
uct 3l in 70% yield (Table 2, entry 12). The arene 1m with
strong electron withdrawing group reacted to give 3m in
50% yield (Table 2, entry 13).
1
firmed by the observation of H NMR peaks at 10.3 ppm
attributed to the hydroxyl proton, and 7-9 ppm ascribed to
the phenyl protons. The 13C NMR spectrum of intermediate
C also shows the peaks of the phenyl carbons. Furthermore,
FT-IR peak at 3340 cm-1 related to the stretching vibrations
of hydroxyl group. Thus, the resulting intermediate was used
for successful hydroxylation of arene via an ordinary elec-
trophilic aromatic substitution reaction.
The reaction of 1n and H2O2 gave a mixture of isomers
of 3n with ratio 62:38 in 68% yield (Table 2, entry 14). It
was found that over oxidations in these reactions did not
occur since no quinones were observed. The hydroxylation
of 1o occurred with high regioselectivity and 3o was ob-
tained as the only product in 55% yield (Table 2, entry 15). It
is interesting to note that for substrate bearing oxidizable
nitrogen including 1i and 1o, no N-oxide product was found
in the products. Unfortunately, the reactions of benzaldehyde
led to producing several by-products, and efforts to obtain
the desired phenol was useless. In addition, hydroxylation
reaction of benzyl alcohol was also unsuccessful.
3. EXPERIMENTAL SECTION
3.1. General Information
All the chemicals were obtained from Merck Company
and used as received. All products are known and character-
ized by comparison of spectral (1H NMR, 13C NMR) data
with those reported in the literature. All yields refer to iso-
lated products. NMR spectra were recorded on Brucker
Avance spectrophotometer (400 MHz) in CDCl3 using TMS
as an internal standard.
O
O
F3C S O S CF3
Ph3P O
+
Ph3P O Tf
3.2. General Procedure for the Hydroxylation of Arenes
O
O
OTf
A
In a 25 mL flask, to a solution of Reagent B (0.814 g, 1
mmol) in 3 mL of H2O/ethanol (1:2), H2O2 (4 mmol, 0.4
mL) was added and the mixture allowed stirring for 15 min
at room temperature. Then, arene (1 mmol) was added and
the reaction mixture allowed stirring for the appropriate time
(Table 2). Upon completion of the reaction, the crude prod-
uct was purified by a column chromatography using ethyl
acetate/n-hexane to afford the corresponding phenol. The
products are all known compounds.
Ph
Ph
P
P Ph
Ph3P O Tf
+
+
Ph
Ph3P O
O
Ph
Ph
OTf
OTf OTf
Reagent B
Ph
Ph
P
P Ph
Ph
H
-TfOH
Ph
O
Ph
H2O2
Ph3P O O
-Ph3PO
OTf
OTf
CONCLUSION
OTf
C
R
Reagent B
R
In conclusion, we have developed a salt-promoted, clean,
mild, rapid, and efficient method for direct aromatic oxy-
genation reaction of arenes to phenols. The protocol uses
readily available aromatic compounds as the substrates, in-
expensive hydrogen peroxide as a hydroxylation agent, Rea-
gent B as a promoter, and a mixture of water/ethanol as the
solvent. This method could tolerate various functional
groups and performed at room temperature without forma-
tion of by-products.
H
Ph3P O O
+
H
H
-Ph3PO
OH
OTf
C
H
R
R
OTf
H
-TfOH
CONSENT FOR PUBLICATION
OH
OH
H
Not applicable.
Scheme (4). Proposed reaction mechanism.
CONFLICT OF INTEREST
As a result of this observation, the above mechanism
indicated in Scheme 4 was proposed for the synthesis of
phenols promoted by Reagent B. This reagent was prepared
The authors declare no conflict of interest, financial or
otherwise.

882 Letters in Organic Chemistry, 2018, Vol. 15, No. 10
Khodaei et al.
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ACKNOWLEDGEMENTS
We thank the Razi University for generous financial sup-
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