Facile and effective approach for oxidation of boronic acids

Article abstract of DOI:10.1016/j.tetlet.2017.10.059

This present work illustrates facile and effective approach for oxidation of boronic acids using environmentally benign dimethyl carbonate (DMC) as a solvent with H₂O₂ as an oxidant at room temperature. In contrast to previous reaction reports, which make use of metal catalyst, hazardous reagent and oxidants that creates environmental concern. This method provides good to excellent yield of products and showed better tolerance towards various functional groups present on boronic acids. Moreover, this developed process is an alternative in terms of inexpensive, non toxic and easy reaction conditions.

Full text of DOI:10.1016/j.tetlet.2017.10.059

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Facile and effective approach for oxidation of boronic acids
Ravindra B. Wagh, Jayashree M. Nagarkar
PII:
S0040-4039(17)31351-5
https://doi.org/10.1016/j.tetlet.2017.10.059
TETL 49421
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Reference:
Tetrahedron Letters
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26 September 2017
22 October 2017
Please cite this article as: Wagh, R.B., Nagarkar, J.M., Facile and effective approach for oxidation of boronic acids,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.059
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Facile and effective approach for oxidation
of boronic acids
Ravindra B. Wagh and Jayashree M. Nagarkar *

1
Tetrahedron Letters
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Facile and effective approach for oxidation of boronic acids
Ravindra B. Wagh and Jayashree M. Nagarkar ∗
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai – 400019, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
This present work illustrates facile and effective approach for oxidation of boronic acids using
environmentally benign dimethyl carbonate (DMC) as a solvent with H2O2 as an oxidant at room
temperature. In contrast to previous reaction reports, which make use of metal catalyst,
hazardous reagent and oxidants that creates environmental concern. This method provides good
to excellent yield of products and showed better tolerance towards various functional groups
present on boronic acids. Moreover, this developed process is an alternative in terms of
inexpensive, non toxic and easy reaction conditions.
Received in revised form
Accepted
Available online
Keywords:
Oxidation
2017 Elsevier Ltd. All rights reserved.
Synthetic organic
Boronic acid
Dimethyl carbonate
Peroxides
1. Introduction
efficient method for this type of oxidation is still a stimulating task.
Dimethyl carbonate (DMC) is an exigent green reagent, which
used as an alternative in organic synthesis.27-29 The biodegradability
and non-toxic nature of DMC makes it economical and
environmentally attractive in both academic and industrial
applications. The use of hydrogen peroxide as a green oxidant is
safe, cheap with water as a byproduct. Recently, we have reported
oxidation of arylboronic acid to phenol compounds using silica
chloride as an efficient promoter with H2O2 as an oxidant.30 Even
though the said reaction was carried out in presence of silica chloride
as a heterogeneous catalyst. Since it was easy to remove from
reaction mixture but preparation method for silica chloride from
SOCl2 was hazardous because of evolution of SO2 in environment
causes pollution. Thus, as continuation of our research work to
develop eco-friendly conditions for oxidation of organic
compounds.31-32 Herein, we report oxidation of boronic acids by
using DMC as solvent with H2O2 as an oxidant at room temperature.
This method is purely based on principle of green chemistry with
objective of designing chemical process, which is harmless to human
health and environment. To the best of our knowledge, this is the
first DMC/Solvent based oxidation system that is an alternative for
transitional metal catalyst, toxic organic reagents and oxidants.
Oxidations of organic compounds are useful transformation in
organic chemistry as these compounds are widely used in industries.
Phenols are one of the well-known class of organic compounds
mainly used in synthesis of pharmaceuticals, agro-chemicals,
polymers etc.1-3 Traditionally synthesis of phenol includes
substitution of aryl halides. However, due to the harsh reaction
conditions with toxic reagents, chemicals and transition metals make
this approach unsuitable for environment.4-8 The oxidation of boronic
acid to phenol compounds is favourable functional group reactions in
the organic chemistry. Therefore, replacement of aryl/alkyl halides
with boronic acids is a good alternative as they are inexpensive,
stable, safe to use and key reagent found in synthetic chemistry.9-10
Ample oxidizing systems have been reported for this oxidation
purpose. The oxidation of boronic acids using a suitable oxidizing
agent is the simplest route for the synthesis of these phenols.
Oxidation of boronic acids was carried out in the presence of
metals such as Cu and Ru.11-12 Conventionally, this oxidation was
performed with the help of several non-metals.13-19 This type of
oxidation was also reported in presence of H2O2.20-25 An
electromediated technique under an air atmosphere was also applied
for this type of oxidation.26 These oxidation reactions are quite useful
but these oxidants are expensive, hazardous or toxic. Moreover, toxic
reagents are usually used to dissolve oxidizing agents and a large
amount of inorganic wastes are generated after workup. Hence, due
to economical and environment concern, oxidation processes with
inexpensive and environmental-friendly oxidants are very much
required. Therefore, by acknowledging all reported work in this
field, it is demanding need to develop an eco-friendly method for
oxidation of boronic acids. Thus, developing a simple, highly
———
The reaction conditions were optimized by using
phenylboronic acid 1a (PBA) as key substrate. Oxidation of 1a to 2a
was studied as a model reaction (Table 1) with H2O2 as an oxidant at
room temperature. When mixture of 1a (1 mmol) and H2O2 (2.0
equiv.) were stirred at room temperature for about 7 h only 9%
conversion was observed due to insolubility of reaction mixture
(Table 1, entry 1). Therefore, we have decided to carry out this
oxidation using various solvents considering solubility issue of 1a
with H2O2. Thus, we have tried oxidation of 1a to 2a with different
∗ Corresponding author. Tel.: +91 22 33611111/2222; fax: +91 22 33611020; e-mail: jm.nagarkar@ictmumbai.edu.in

2
Tetrahedron Letters
solvents such as Methanol (MeOH), Acetone, Acetonitrile
The optimized reaction conditions using DMC as a solvent with
H2O2 as an oxidant were further applied to investigate the effect of
different oxidant and temperature on the oxidation of 1a to 2a (Table
2). Screening other oxidants in present reaction conditions, We are
pleased to find that H2O2 provided finer results than other oxidants
(Table 2, entries 1-4). It was observed that other oxidants such as
70% TBHP, Oxone and m-CPBA gave 77%, 65% and 82%
conversion for 2a in 7 h respectively (Table 2, entries 1-3). In the
case of UHP, we could get conversion only up to 48% in 7 h. This
shows that other oxidants gave insufficient conversion of 1a to 2a
even after keeping the reaction at room temperature for 7 h. H2O2 is
excellent than other oxidants with its eco-friendly ability of
improving oxidation performance. Furthermore, oxidation of 1a
under different temperatures was also investigated in this method. It
was observed that reaction was incomplete at lower temperature,
thus prolonging the reaction time (Table 2, entry 5-7). Hence, room
temperature (30°C) was chosen for further work as a clean method.
(MeCN), Dimethyl carbonate (DMC), H2O, Toluene, Pet ether,
Chloroform (CHCl3) and Dichloromethane (DCM) (Table 1, entries
2-10). Among the solvent studies, we found that 100% conversion
was highest and observed only with DMC in 5 h (Table 1, entry 5).
While in the case of other solvents such as MeOH, acetone, MeCN
less conversion of 1a to 2a was observed in 7 h (Table 1, entries 2-
4). We have tried oxidation of 1a to 2a in green solvent such as H2O
but insolubility of reaction mixture causes incomplete conversion
29% of 1a to 2a in 7 h (Table 1, entry 6). Additionally, with
nonpolar solvents such as toluene and pet ether, 23% and 35%
conversion for 2a was observed in 7 h (Table 1, entries 7-8).
Oxidation of 1a to 2a using halogenated solvents such as CHCl3 and
DCM resulted in 39% and 36% conversion respectively in 7 h (Table
1, entries 9-10). This indicates that the reaction is sensitive to
solvents. It was further concluded that higher conversion for
oxidation of 1a to 2a is solubility dependent and excellent under
homogenous conditions. DMC helps the reaction to proceed in
homogeneous phase which provides proper mixing of substrate with
H2O2. Considering the hazards of using above organic solvents, we
decided DMC as the best solvent for this oxidation as it is devoid of
any mutagenic effect.
Table 2 Effect of different oxidants and temperature on
1a
Entry
Oxidant
(equiv.)
Time
(h)
Temperature
(°C)
Conv.a
(%)
During the solvent study, we observed that when DMC was used
as solvent, 100% conversion of product was obtained. We have
further study the oxidation of 1a to 2a with different H2O2 quantities
ranging from 0.5-2.1 equiv. (Table 1, entries 11-15). This showed
that H2O2 turned out to be the best oxidant as it gave 100%
conversion of the product (Table 1, entry 5,15) at room temperature
in 5 h. Therefore, 2.0 equiv. of H2O2 is enough for complete
conversion of 1a to 2a (Table 1, entry 5). When the oxidation of
PBA was carried out using less quantities of H2O2 differing from
0.5-1.7 equiv. of oxidant, the reaction was incomplete (Table 1,
entries 11-14). However, absence of H2O2 in model reaction showed
no conversion of product (Table 1, entry 16).
Oxidant study
1
2
3
4
TBHP (70%)
07
07
07
07
30
30
30
30
77
65
82
48
Oxone
m-CPBA
UHP
Temperature study
5
6
7
H2O2
H2O2
H2O2
06
05
05
15
20
25
40
65
84
Reaction conditions: 1a (1 mmol), DMC (1.0 mL), oxidant (2.0 equiv.),
temperature (°C),
aconversion determined by GC with the area normalization method.
Therefore, the optimized reaction conditions found for the
oxidation of 1a to 2a (1 mmol of substrate, 1.0 mL of DMC as a
solvent, 2.0 equiv. of 30% H2O2 as an oxidant and 30 °C (room
temperature)) were chosen as model reaction conditions for the
studies. Moreover, this oxidation method is free from catalyst such
as metal, ligand or alkali. No significant amounts of byproducts were
formed in this reaction. In order to generalize the scope of this
protocol, we have carried out first oxidation of arylboronic acids
with various functional groups present on it under optimized reaction
conditions and the results are presented in Scheme 1. The influence
of electron donating or withdrawing group on substrate was not
significant in this method. The substrates bearing electron donating,
withdrawing or halo groups were easily oxidized to respective
phenols with excellent yields (Scheme 1, 2b-2k). Interestingly,
similar results were obtained upon subjecting naphthylboronic acid
substrates, which gave good yields with high purity (Scheme 1, 2l-
2m). We have further carried out oxidation of heteroarene derivative
such as pyridin-3-ylboronic acid that smoothly undergoes oxidation
to give corresponding product (Scheme 1, 2n) to the reaction
conditions.
Table 1 Optimization of reaction parameters for 1a
Entry
Solvent
Oxidant
H2O2
(equiv.)
Time
(h)
Conv.a
(%)
Solvent study
1
-
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
07
07
07
07
05
07
07
07
07
07
09
44
40
43
100
29
23
35
39
36
2
3
4
5
MeOH
Acetone
MeCN
DMC
6
H2O
7
Toluene
Pet Ether
CHCl3
DCM
8
9
10
Oxidant loading
11
12
13
14
15
16
DMC
0.5
1.0
1.5
1.7
2.1
-
07
07
06
06
05
05
37
66
79
86
100
0
DMC
DMC
DMC
DMC
DMC
Scheme 1 Oxidation of various arylboronic acids
Reaction conditions: 1a (1 mmol), solvent (1.0 mL), 30% H2O2 (equiv.),
temperature (30 °C),
aconversion determined by GC with the area normalization method.

3
which shows presence of methanol. This evidence proves that
oxidation of 1a to 2a proceeds by this pathway.
Fig. 1 Possible mechanism for oxidation of 1a to 2a
O
O
H2O2
O
-MeOH
MeO
O
H
MeO
OMe
a
OB(OH)2
OH
B
OH
B
HO
O
O
OH
[a]
O
-MeOH
H
OMe
-CO2
1a
H2O
H
O
H
O
B
OH
OH
-B(OH)3
OH
Reaction conditions: arylboronic acid (1 mmol), DMC (1.0 mL), 30% H2O2
(2.0 equiv.), time (5 h), temp. (30°C),
aIsolated Yield, *Indicates purification by column chromatography.
2a
In the course of our research, we have established a simple,
Encouraged by these results, we further applied this optimized
reaction conditions to alicyclic and alkyl boronic acids which are
presented in Scheme 2. The cyclohexylboronic acid efficiently
undergoes oxidation to give good yield of cyclohexanol (Scheme 2,
2o). Finally, we investigated alkyl boronic acid under present
optimized reaction condition. Alkyl boronic acid such as
heptylboronic acid satisfactorily undergoes oxidation resulted in
heptan-1-ol (Scheme 2, 2p). Oxidation of isobutylboronic acid to its
corresponding product gives good yield (Scheme 2, 2q). Due to this
simple procedure and easy work up condition, this method is
practical and controllable providing excellent yields and purity.
highly efficient method for the oxidation of boronic acids. The
optimized reaction parameters resulted in good to excellent yield of
products with short reaction time. Universality of substrates confirms
encouraging applications of this method in organic synthesis. It is
noteworthy that this catalyst free oxidation method does not require
any toxic metal, ligand, additive, hazardous reagent and oxidant. A
cost effective, safe approach with easy work up and scale up
procedure makes this method environmentally benign. This method
provides a better and practical alternative to the existing procedures.
Acknowledgments
Scheme 2 Oxidation of various alkyl boronic acids
The author (RBW) is greatly thankful to the UGC (University
Grant Commission, India) for the award of research fellowship.
.
References and notes
1.
2.
Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New
York, 1996.
Owen, R. W.; Giacosa, A.; Haubner, R.; Spiegel-Hader, B.;
Bartsch, H. Eur. J. Cancer, 2000, 36, 1235-1247.
Pilato, L. React. Funct. Polym., 2013, 73, 270-277.
Hoarau, C.; Pettus, T. R. R. Synlett, 2003, 1, 127-137.
Hanson, P.; Jones, J. R. ; Taylor, A. B.; Walton, P. H.; Timms, A.
W.; J. Chem. Soc., Perkin Trans. 2, 2002, 1135-1150.
George, T.; Mabon, R.; Sweeney, G.; Sweeney, J. B.; Tavassoli,
A. J. Chem. Soc., Perkin Trans. 1, 2000, 2529-2574.
Schulz, T.; Torborg, C.; Schaffner, B.; Huang, J.; Zapf,
A.;Kadyrov, R.; Borner, A.; Beller, M. Angew. Chem., Int. Ed.,
2009, 48, 918-921.
3.
4.
5.
6.
7.
Reaction conditions: aliphatic boronic acid (1 mmol), DMC (1.0 mL), 30%
H2O2 (2.0 equiv.), time (5 h), temp. (30°C),
aIsolated Yield, *Indicates purification by column chromatography
To further illustrate the practicality of this eco-friendly
procedure, a scale-up study was carried out using phenylboronic acid
as a substrate (1.22 g, 10 mmol scale) under optimized reaction
conditions. The reaction was completed in 6.5 h followed by work-
up procedure, which gave product yield up to 98%. Based on
literature report, a possible reaction mechanism for the oxidation of
phenylboronic acid 1a is shown in Fig. 1. In this method, DMC plays
a vital role. DMC reacts with H2O2 forming “Monoperoxy carbonic
acid methyl ester” (a) which is the active oxidant.33 This active
oxidant (a) then attacks on PBA and undergoes rearrangement
followed by hydrolysis to give phenol. This mechanistic pathway
was further confirmed by carrying out GC-MS analysis of aqueous
layer as well as recovered ethyl acetate obtained from reaction,
8.
9.
Anderson, K. W.; Ikawa, T.;Tundel, R. E.;Buchwald, S. L. J. Am.
Chem. Soc., 2006, 128, 10694-10695.
Hall, D. G. Boronic Acids: Preparation and Applications
inorganic synthesis and Medicine, Wiley-VCH: Weinheim, 2007.
10. Suzuki, A. Angew. Chem. Int. Ed., 2011, 50, 6722-6737.
11. Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett.,
2010, 12, 1964-1967.
12. Gogoi, N.; Gogoi, P.; Borah, G.; Bora, U. Tetrahedron Lett., 2016,
57, 4050-4052.
13. Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett.,
2007, 48, 2713-2715.
14. Clay, J. M.; Vedejs, E. J. J. Am. Chem. Soc., 2005, 127, 5766-
5767.
15. Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. III J
Am.Chem. Soc., 2003, 125, 7792-7793.

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Tetrahedron Letters
16. Benjamin, R.;Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J.
Org. Chem., 2002, 20, 3429-3434.
washed with distilled water (5.0 mL). The resulting organic
extract was dried over anhydrous sodium sulphate. The solvent
was removed under vacuum to get crude product which was
purified (if necessary) by column chromatography using silica gel
with pet ether and ethyl acetate as solvent system to obtain the
pure product. The structure of the product was confirmed by GC-
MS, M.P. and 1H NMR spectroscopic techniques.
17. Webb, K. S.; Levy, D. Tetrahedron Lett., 1995, 36, 5117-5118.
18. Gogoi, P.; Bezboruah, P.; Gogoi, J.; Boruah, R. C. Eur. J.
Org.Chem., 2013, 32, 7291-7294.
19. Chen, D- S; Huang, J-M. Synlett, 2013, 24, 499-501.
20. Gogoi, A.; Bora, U. Synlett, 2012, 7, 1079-1081.
21. Gogoi, A.; Bora, U. Tetrahedron Lett., 2013, 54, 1821-1823.
22. Wang, L.; Dai, D-Y; Chen, Q.; He, M-Y. Asian J. Org. Chem.,
2013, 2, 1040-1043.
23. Gogoi, K.;Dewan, A.; Gogoi, A.; Borah, G.; Bora, U. Heteroatom
Chem., 2014, 25, 127-130.
24. Gohin, M.;Plessis, M. D.; Tonder, J. H. V.; Bezuidenhoudt, B. C.
B. Tetrahedron Lett., 2014, 55, 2082-2084.
25. Mahanta, M.; Adhikari, P.; Bora, U.; Thakur A. J. Tetrahedron
Lett., 2015, 56, 1780-1783.
26. Jiang, H.; Lykke, L.; Pedersen, S. U.; Xiao, W-J; Jorgensen, K. A.
Chem. Commun., 2012, 48, 7203-7205.
27. Arico, F.; Tundo, P. Russ. Chem. Rev., 2010, 79, 479-489.
28. Tundo, P.;Selva, M. Acc. Chem. Res., 2002, 35, 706-716.
29. Tundo, P. Pure Appl. Chem., 2001, 73, 1117-1124.
30. Wagh, R. B.; Nagarkar, J. M. Tetrahedron Lett., 2017, 58, 3323-
3326.
31. Wagh, R. B.; Nagarkar, J. M. Catal. Lett., 2017, 147, 181-187.
32. Wagh, R. B.; Gund, S. H., Nagarkar, J. M. J. Chem. Sci., 2016,
128, 1321-1325.
Supplementary Material
33. Kraiem, J.; Ghedira, D.; Ollevier, T. Green Chem. 2016, 18, 4859-
4864.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
34. General procedure for the oxidation of boronic acids:
A mixture of boronic acid (1 mmol), DMC (1.0 mL) was taken in
25 mL round bottom flask with magnetic stirring bar. Then the
reaction was activated by addition of 30% H2O2 (2.0 equiv.) and
stirred at room temperature for 5 h. The progress of reaction was
monitored by TLC. After disappearance of starting material, added
H2O (1.0 mL) in to the reaction mixture. The reaction mixture was
then further diluted with ethyl acetate (30 mL) and subsequently

5
Highlights
•
•
•
•
•
Simple approach
Mild reaction conditions
Good to excellent yield of Products
Oxidation using green oxidant and solvent
Broad substrate scope