S. Gupta et al. / Tetrahedron Letters 57 (2016) 2506–2510
2507
OH
butanol and water took slightly longer reaction time (Table 1,
entries 7–10). It is interesting to note that the reactivity of 30%
aqueous hydrogen peroxide in methanol is found to be relatively
efficient when compared with acetonitrile which provides 69% of
the desired product after 60 min at room temperature (Table 1,
entry 11). Nevertheless, the oxidative ipso-hydroxylation of
phenylboronic acid was achieved in a high yield under solid-state
condition (i.e., solvent free) with UHP, however the reaction
requires an external heat (45 °C) for melting the substrates
OH
HO
HO
COOH
NH2
OH
OMe
BHA
L-DOPA
Propofol
Thymol
Anꢀ-Depressent
Anesthesia
Anꢀoxidant
Anꢀsepꢀc
O
OH
NH
HO
S
OH
(
Table 1, entry 12). Based on the optimization study, methanol
O
N
N
CH3
was found to be an efficient medium for the ipso-hydroxylation
reaction with UHP at room temperature under catalyst free
condition (Table 1, entry 7).
As optimized condition in the hand, a general applicability of
the method was further explored by subjecting various substituted
arylboronic acids for the ipso-hydroxylation and the results are
O
Ph
HO
O
CH3
Alvimopan
μ-opioid antagonist
N
OH
Raloxifene
Tolterodine
Estrogen
receptor modulator
Anꢀmuscarinic
summarized in Table 2. Similar to phenylboronic acid,
a- and b-
Figure 1. Phenolic compounds in clinical applications.
naphthylboronic acids were converted into corresponding naph-
thols in 96% yields (Table 2, 2b–2c). In addition, the electron rich,
i.e., ethyl, methoxy and phenyl substituted arylboronic acids
underwent ipso-hydroxylation in excellent yields (>95%) within
the period of 15 min at room temperature (Table 2, 2d–2f). On
the other hand, deactivated arylboronic acids such as nitro, fluoro,
chloro, and bromo substituted arylboronic acids have also under-
gone ipso-hydroxylation smoothly to provide the desired products
in a comparable yield (>95%) to those of activated arylboronic acids
(Table 2, 2g–2k). Also, aryl diboronic compound such as 1,4-
phenylenediboronic acid was successfully converted to hydro-
quinone in a quantitative yield with 2.0 equiv of urea-hydrogen
peroxide at room temperature (Table 2, 2l).
disinfectant and bleaching agent.9 Our research group is mainly
focused on the development of efficient and eco-friendly methods
for organic synthesis. In this context, here we report an efficient
and practical method for the conversion of arylboronic acids into
corresponding phenols using urea-hydrogen peroxide at room
temperature under catalyst and metal free conditions.
At the outset, commercially available phenylboronic acid (1a)
was chosen as a model substrate and subjected for ipso-hydroxyla-
tion with UHP in various solvents and solvent free condition
1
0
(Table 1). All the reactions were performed at room temperature
with 1.0 equiv of urea-hydrogen peroxide under catalyst free con-
dition. Among the aprotic solvents, only acetonitrile provided the
desired product in a quantitative yield (97%) within 15 min
It has been widely observed that urea-hydrogen peroxide (UHP)
cannot oxidize the organic functional groups (e.g., sulfides, thiols,
amines, olefins, alcohols, aldehydes, etc.) efficiently in the absence
(Table 1, entry 5) while tetrahydrofuran (THF), toluene, diethyl
8
a–c
ether and chloroform did not lead to completion even after pro-
longed reaction time (Table 1, entries 1–4). It is also important to
note that by replacing UHP with 30% aqueous hydrogen peroxide
of catalyst.
However, the current study reveals that ipso-
hydroxylation of arylboronic acids can be achieved very
efficiently under catalyst free condition at room temperature. By
considering these facts, we have anticipated that UHP can be
used as a chemo-selective oxidant for the ipso-hydroxylation of
arylboronic acids which contain oxidation susceptible functional
groups. To test the hypothesis, olefin, aldehyde, alcohol, and
sulfide functionalized arylboronic acids (1m–1r) as well as
heteroaryl boronic acids (1s–1t) were subjected for the ipso-
hydroxylation reactions under optimized condition. However,
during the course of ipso-hydroxylation in methanol, we have
observed a formation of minor amount of undesired products
in acetonitrile the reaction did not lead to completion even after
j
6
0 min (Table 1, entry 6).6 The low yields in this reaction may
be attributed to the formation of peroxyimidic acid. In the case
of protic solvents, methanol was found to be very efficient to
provide 97% of the desired product within 5 min while ethanol, t-
Table 1
a
Oxidation of phenylboronic acid using urea-hydrogen peroxide (UHP)
(
ꢀ10–15%), particularly in the case of substrates with aldehyde
HO OH
B
OH
11
UHP (1.0 equiv.)
Solvent, RT
(1n, 1o) and sulfide (1r) functional groups. Therefore, the reac-
tions of sensitive group functionalized arylboronic acids were per-
formed in acetonitrile which took slightly longer time for
completion, however with high chemoselectivity (Table 2, 2m–2t).
In general, olefins are prone to epoxidation or dihydroxylation
in the presence of oxidizing agents (e.g., MCPBA, tBuOOH, Oxone,
etc.). Interestingly, olefin was found to be remained intact during
the ipso-hydroxylation with UHP and gave the desired product in
9
1a
2a
Entry
Solvent
THF
Toluene
Diethyl ether
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
120
120
120
120
15
60
5
35
40
40
30
68
20
97
1
2
CHCl
3
5% yield (Table 2, 2m). Similarly, aryl aldehydes and ketones are
CH
CH
CH
3
3
3
CN
CN
OH
c
known to undergo different oxidation reactions including Dakin
07
1
2
oxidation, Baeyer–Villiger oxidation, etc. In addition, aryl alco-
hols can get easily oxidized to corresponding aldehydes or car-
boxylic acids in the presence of oxidizing agents. Interestingly, all
these functionalities were well tolerated during the ipso-hydroxy-
lation and gave the desired phenols in >92% yields (Table 2, 2n–
97
90
80
65
C
2
H
5
OH
t-BuOH
O
10
11
12
H
2
90
60
30
c
CH
3
OH
69
95
d
Solvent free
2
q). It is well known that sulfides are highly oxophilic in nature
which readily undergo oxidation to sulfoxide or sulfone with most
of the oxidizing agents (e.g., MCPBA, H with different catalysts,
Therefore a sulfide containing arylboronic acid
(i.e., 4-(thiomethyl)phenylboronic acid, 1r) was tested for ipso-
a
Reaction conditions: Substrate (1.0 mmol) and UHP (1.0 equiv) was stirred in
mL of solvents at room temperature.
3
b
2 2
O
Isolated yield.
1
2,13
c
oxone, etc.).
Instead of UHP, 30% aqueous hydrogen peroxide was used.
Reaction was carried out at 45 °C.
d