IPSO-hydroxylation of boronic acid via ozonolysis: A metal-, ligand-, and base-free method

Article abstract of DOI:10.1246/cl.151087

Here, we have developed a simple, efficient, and metal-, ligand-, and base-free method for the synthesis of functionalized aryl and alicyclic alcohols via ozonolysis of corresponding boronic acids in aqueous ethanol. The procedure is compatible with a variety of functional groups and can be utilized as an alternative method for the synthesis of hydroxy arenes and alicyclic alcohols.

Full text of DOI:10.1246/cl.151087

CL-151087
Received: November 24, 2015 | Accepted: December 21, 2015 | Web Released: December 29, 2015
IPSO-Hydroxylation of Boronic Acid via Ozonolysis: A Metal-, Ligand-, and Base-free Method
Yadaganahalli K. Bommegowda,1 Ningegowda Mallesha,2 Ajjampura C. Vinayaka,1 and Maralinganadoddi P. Sadashiva*1
1Department of Studies in Chemistry, University of Mysore, Mysuru, Karnataka, India
2Sri Ram Chem., R&D Center, Spl-52, Hebbal Industrial Estate, Hebbal, Mysuru, Karnataka, India
(E-mail: sadashivamp@chemistry.uni-mysore.ac.in)
Here, we have developed a simple, efficient, and metal-,
ligand-, and base-free method for the synthesis of functionalized
aryl and alicyclic alcohols via ozonolysis of corresponding
boronic acids in aqueous ethanol. The procedure is compatible
with a variety of functional groups and can be utilized as an
alternative method for the synthesis of hydroxy arenes and
alicyclic alcohols.
hydroxy-functionalized aryl, alkyl, and heterocyclic compounds.
For example, I2-H2O2,11 CuSO4-phenanthroline,12 H2O2,13 Ploy-
16
NH2OH,14 potassium peroxymonosulfate,15 and aqueous H2O2
were reported for the conversion of boronic acid to alcohols.
Although these methods can access functionalized alcohols, they
suffer from several disadvantages, including the use of toxic
metals as catalysts,12 1,10-phenanthroline as a ligand, oxidizing
agents,15 long reaction times,16 strong bases, low compatibility
with the functional groups, and difficult workup procedures. The
use of inorganic metals are having the possibility of adsorption
with the final product in higher concentrations and causes health
risks to humans,17 such as oxidative damage of DNA, apoptosis,
allergic dermatitis, and inhibit the activity of steroidogenic
enzymes. Hence, these limitations discourage the above methods
for the traditional synthesis of aryl or alkyl alcohols, particularly
in bulk drug manufacturing processes.
In the continuation of our research effort towards the
development of a facile method,18 here we are disclosing a
new metal-, ligand-, and base-free method for the synthesis
of hydroxy compounds through ipso-hydroxylation of boronic
acids via ozonolysis. The method presented here is efficient,
economical, and uses mild reaction condition.
Keywords: Alcohol
| Boronic acid | Ozonolysis
Hydroxy compounds are an important structural unit in the
synthetic organic chemistry field. In particular, phenolic com-
pounds are extensively used in functional group transformations.
Also, these are utilized in the medicinal chemistry as reactive
oxygen scavengers to treat oxidative stress and employed as
food preservatives to avoid the deterioration due to oxidation.1
Synthesized and natural compounds having a hydroxy group are
significantly used as therapeutic agents such as antimicrobial,2
anticancer,3 anti-inflammatory, and anti-aging agents.4 In this
perspective, the development of an effective synthetic strategy
for aryl and alicyclic alcohols from readily available starting
materials is highly desirable. For instance, ipso-hydroxylation
is one of the main strategies involved in the synthesis of aryl/
alkyl alcohols via an activated nucleophilic substitution reaction
of aryl halids,5 aryl silanes,6 aryl trifluroborate,7 aryl boronic
acids,8 aryl Bpin,9 and copper-catalyzed transformation of
diazoarenes10 (Figure 1). These days, boronic acids are widely
used in various transition-metal-catalyzed reactions for the
synthesis of aromatic and heteroaromatic compounds via C-C
bond formation. However, the versatility and remarkable
stability of boronic acid retains their consistency in various
organic syntheses and are explored as a major substrate for
In order to optimize the reaction conditions, phenyl boronic
acid (1a) was considered as a model substrate (Scheme 1);
the product yield and reaction conditions are summarized in
Tables 1 and 2. Initially, the reaction was performed in various
solvents at temperature ranging from 0 to 50 °C. First, we used
water as the reaction medium and purged ozone at temperature
between 0 and 50 °C, but the product formation was not
OH
B
OH
O3, Solvent
0 - 50 oC
OH
R-B(OH)2
R= Aryl & alicyclic
1a
2a
R
l
y
r
X
A
=
R
Scheme 1. IPSO hydroxylation of phenyl boronic acid.
r
e
f
.
8
Table 1. Optimization of reaction conditions in different
solvents at 0-50 °C
ref. 10
ref. 6b
R
N2
R OH
R Si
Entry
Solvent
Yield/%
1
2
3
4
5
6
7
8
Water
Dichloromethane
Ethanol
0
75
85
80
70
70
68
95
Bpin
BF3K
R
Methanol
R
RRS=iAMryel 2H
Ethyl acetate
Tetrahydrofuran
Methyl tert-butyl ether
Ethanol:water (9:1)
Figure 1. Existing important synthetic strategies for alcohol
synthesis via ipso-hydroxylation.
268 | Chem. Lett. 2016, 45, 268–270 | doi:10.1246/cl.151087
© 2016 The Chemical Society of Japan

Table 2. Yield of products at different temperature in ethanol-
water mixture (9:1, v/v)
Continued:
Time Yield
/min /%a
Entry
Starting material
Product
Entry
Temp./°C
Yield/%
1
2
3
4
5
0-10
10-20
20-30
30-40
40-50
70
84
98
67
60
OH
B
OH
9
OH
2i
30
35
87
89
Cl
Cl
Cl
Cl
OH
B
OH
OH
10
2j
Table 3. Conversion of boronic acids to corresponding
hydroxy compounds
OH
OH
Time Yield
B
Entry
1
Starting material
Product
/min /%a
11
12
13
OH
2k
2l
30
42
30
85
80
85
I
OH
I
OH
B
2a
2b
25
35
90
89
OH
OH
OH
B
OH
OH
OH
B
Cl
Cl
OH
B
2
3
OH
OH
OH
F
OH
2m
F
OH
B
O2N
Br
O2N
Br
OH
OH
2c
30
40
89
89
OH
B
O
OH
O
14
15
2n
2o
30
30
85
88
OH
OH
B
OH
4
2d
OH
OH
B
OH
OH
O2N
OH
OH
O2N
B
5
6
2e
35
35
85
73
OH
B
16
17
OH
OH
2p
2q
30
30
83
80
OH
OH
Cl
OH
B
Cl
B
OH
OH
OH
2f
OH
B
Cl
Cl
OH
OH
OH
B
18
2r
30
®
HO
OH
B
HO
7
8
2g
2h
30
35
90
85
OH
OH
aIsolated yields based on the added boronic acid.
OH
B
NC
OH
NC
OH
ethanol and water. It was our delight that product 2a was formed
in excellent yield in the 9:1 ratio of ethanol and water (95%
yield, Entry 8). Hence, in view of the safe solvent system and
easy product purification, we have chosen the ethanol-water
(9:1) solvent to study the effect of temperature on the product
yield.
Initially, ozone was purged to the ethanol-water solution of
1a at various temperature ranges (Table 2) and calculated the
percentage yield with respect to boronic acid 1a by monitoring
the reaction progress using TLC. The product conversion was
good at the temperatures ranges of 0-10 and 10-20 °C with the
yields of 70% and 84%, respectively (Table 2, Entries 1 and 2).
The significant increase in the product yield (98%) was noticed
Continued on next column:
observed even under prolonged reaction time (Entry 1). Further,
we turned our attention to study the progress of reaction in
solvents such as dichloromethane, ethanol, methanol, ethyl
acetate, tetrahydrofuran, and methyl tert-butyl ether individu-
ally. Product 2a was formed in moderate to good yields in all the
solvents (Entries 2-7); especially in ethanol, we observed the
highest yield (Entry 3). Further, we continued our optimization
study of the ozonolysis reaction in an environmentally benign
solvent system. We have checked the reaction in the mixture of
Chem. Lett. 2016, 45, 268–270 | doi:10.1246/cl.151087
© 2016 The Chemical Society of Japan | 269

References
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To understand the versatility and applicability of our method
for the synthesis of hydroxy compounds, the reaction was
performed with various aryl boronic acids bearing electron-
releasing methoxy, methyl, and isopropyl substituents and also
electron-withdrawing chloro, fluro, dicloro, nitro, and cyano
substituents (Table 3). The reaction was facile with both types of
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products in excellent yield (Table 3, Entries 15, 16, and 17);
no over oxidation was evident. However, the method failed to
hydroxylate phenyl-1,4-diboronic acid (Entry 18), presumably
due to over oxidation.
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absence of ozone, with ethanol-water as the solvent and the
reaction solution was stirred for 10 h, but there was no product
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Supporting Information is available on http://dx.doi.org/
10.1246/cl.151087.
270 | Chem. Lett. 2016, 45, 268–270 | doi:10.1246/cl.151087
© 2016 The Chemical Society of Japan