Potassium: Tert -butoxide mediated aerobic hydroxylation of arylboronic acids: An application towards the synthesis of (E)-phenoxy acrylates

Article abstract of DOI:10.1039/c9nj02121c

The first example of potassium tert-butoxide mediated aerobic hydroxylation of arylboronic acids is described. A variety of arylboronic acids bearing both electron donating and withdrawing substituents successfully participated in the reaction and furnished phenols in good yields. This strategy also provides access to one pot synthesis of (E)-3-phenoxy acrylates from arylboronic acids and propiolates. The solvent plays an important role and a binary solvent system comprising CH₃CN/THF is found to be the best.

Full text of DOI:10.1039/c9nj02121c

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Jason B. Benedict et al.
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DOI: 10.1039/C9NJ02121C
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Potassium tert-Butoxide Mediated Aerobic Hydroxylation of
Arylboronic Acids: An Application towards the Synthesis of (E)-
Phenoxy Acrylates
Received 00th January 20xx,
Accepted 00th January 20xx
Ibrahim Muhammada, Madasamy Hari Balakrishnanc, Manickam Sasidharana* and Subramaniyan
Mannathan b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first example of potassium tert-butoxide mediated aerobic necessary. Despite these significant developments, the aerobic
hydroxylation of arylboronic acids is described. A variety of hydroxylation of arylboronic acids mediated by base in the
arylboronic acids bearing both electron donating and withdrawing absence of metal- and photocatalyst is relatively unknown.12
substituents successfully participated in the reaction and furnished Alternatively, synthesis of phenols from aryl halides has also
phenols in good yields. This strategy also provides access for one been recognized as one of the valuable approaches.3 However,
pot synthesis of (E)-3-phenoxy acrylates from arylboronic acids and to achieve such transformations, use of metal catalyst is
propiolates. The solvent plays an important role and a binary inevitable. Thus, there is always a demand in developing new
solvent system comprising CH3CN/THF is appeared to be the and convenient protocols, particularly metal free approach,
best.
toward the synthesis of phenols under mild reaction conditions.
Phenols are important scaffolds found in many biological
systems, pharmaceuticals and polymers.1 Besides, they also
serve as versatile intermediates in organic synthesis.2
Therefore, several methods have been developed towards the
synthesis of phenols.3 Among them, oxidative hydroxylation of
arylboronic acids represents a straight forward method to
access phenols in an effective manner. Previously,
stoichiometric amount of oxidants such as peroxides4, Oxone5,
benzoquinones6, N-oxides7 and hypervalent iodine8 compounds
were commonly used reagents to achieve such transformation.
However, nowadays, environmentally friendly and inexpensive
molecular oxygen (O2 and air) is found to be an effective oxidant
in the presence of transition-metal catalysts9, and photoredox
catalysts10. Recently, photoredox oxidative hydroxylation of
boronic acids in the absence of metal catalyst is also well
described11. Notably under photochemical conditions, the
formation of superoxide radical anion, the key intermediate, is
proposed to act as the highly active terminal oxidant.
Nevertheless, to perform this transformation, in most cases, use
of stoichiometric amount of amines, as electron donor is always
Scheme 1: Hydroxylation of arylboronic acids
Potassium tert-butoxide (KOtBu) is one of the commercially
available and most commonly used alkoxide base, which has
been reported to promote a number of organic transformations
including C-C and C-N bond formation reactions.13 Beside to its
role as a strong base, KOtBu may also act as a single electron
donor to initiate the radical reactions.13 Extensive studies have
been devoted to KOtBu mediated/catalyzed coupling reactions
involving aryl halides that are believed to proceed via radical
intermediate.13 In 2013, Li and co-workers reported an
interesting study describing a KOtBu mediated alkenylation of
quinazolines with terminal alkynes.14 In the reaction, they
proposed that a superoxide radical anion could be formed via
direct reduction of O2 by KOtBu. Inspired by this report on
a.SRM Research Institute, SRM Institute of Science and Technology (formerly known
as SRM University), Kattankulathur, Tamilnadu, India
b.Department of Chemistry, SRM University-AP, Amaravati, Andhra Pradesh, India.
Email: mannathan.s@srmap.edu.in
c. Department of Chemistry, SRM Institute of Science and Technology (formerly
known as SRM University), Kattankulathur, Tamilnadu, India
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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superoxide radical anion formation and our continued interest tolyl-
in the chemistry of organoboronic acids15, we set out to perform corresponding phenols 2b-d in 75-84 yields. Importantly, p-aryl
an oxidative hydroxylation of organoboronic acids using KOtBu. diboronic acid (1e) also gave 2e in 73% yield. Similarly,
Herein we report a potassium tert-butoxide mediated aerobic arylboronic acids (1f-j) bearing fluoro-, chloro- and bromo-
oxidative hydroxylation of aryl boronic acids that can give substituents furnished the products 2f-j in 65-78% yield.
phenols. In addition, one pot phenoxylation involving Likewise, 2-naphthol (2k) was also obtained in 71% yield.
Journal Name
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(1c) and m-tolylboronic
(1d
)
acids afforded their
View Article Online
DOI: 10.1039/C9NJ02121C
propiolates and aryl boronic acids forming substituted (E)- Arylboronic acids
(1l-m) bearing electron withdrawing
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phenoxy acrylates is also described. The present method allows substituents also participated well in the reaction and afforded
us to use commercially available and air stable arylboronic the respective products in 70-77% yield. It is noteworthy to
acids. Importantly, it avoids the use of transition metal catalyst mention that under present reaction conditions, heteroaryl-
and photocatalyst. Moreover, the reaction is performed under and styrylboronic acids did not furnish the hydroxylated
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air which makes the reaction operationally simple.
product.
The reaction of phenylboronic acid (1a) with KOtBu (2.0
equiv.) in the presence of air at 75 ⁰C using CH3CN/THF as a
binary solvent in a ratio of 4:1 for 12 h afforded phenol (2a) in
79% isolated yield (Table 1). Control experiments revealed that
2a was not observed in the absence of either air or KOtBu
(entries 2 and 3). The solvent plays an important role and a
binary solvent system comprising CH3CN/THF is appeared to be
the best. When the reaction was carried out in THF, 2a was
obtained in 49% yield whereas in CH3CN, only 55% yield was
observed. Other solvents such as DMF and toluene were not
suitable (entries 6 to 7). When the reaction was carried out with
1.0 equivalent of KOtBu phenol (2a) was obtained in 60% yield
(entry 8). Likewise, changing the base from KOtBu to KOH, Et3N
and K2CO3 also gave the desired product in low yields (entries 9
to 11). Similarly, lowering the reaction temperature to 50 ⁰C
afforded the desired product only in 44% yield after 12 h (entry
12).
Table 2: Results of Aerobic Oxidative Hydroxylation Organoboronic Acidsa,b
Table 1: Results of Aerobic Oxidative Hydroxylation Organoboronic Acidsa,b
a) All reactions were carried out using aryl boronic acid (1) (1.00 mmol) and KOtBu (2.0
mmol) in the presence of air using CH3CN/THF (4:1) solvent at 75 ⁰C for 12 h. b) Isolated
Yields.
Entry
1
2
3
4
5
6
7
8
Base
KOtBu
-
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBud
KOH
Solvents
CH3CN /THF
CH3CN /THF
CH3CN /THF
THF
CH3CN
DMF
toluene
CH3CN /THF
CH3CN /THF
CH3CN /THF
CH3CN /THF
CH3CN /THF
CH3CN /THF
CH3CN /THF
Temperature
yield
79
0
75
75
75
75
75
75
75
75
75
75
75
50
100
75
0c
49
55
0
After successfully establishing the scope of aryl boronic acid,
we also studied the one pot hydrophenoxylation of propiolates
(Table 3). Unlike hydroxylation reaction, this transformation
requires a higher reaction temperature of 100 ⁰C to furnish the
desired product in high yields. The scope of the reaction was
examined by treating various arylboronic acids with ethyl
propiolate (3a). As expected, aryl boronic acids bearing both
electron-donating and electro withdrawing substituents
successfully participated in the reaction and furnished (E)-ethyl
3-phenoxyacrylates (4a-j) in 55-95% yield in a highly regio- and
0
60
11
18
12
44
77
40
9
10
11
12
13
14
Et3N
K2CO3
KOtBu
KOtBu
NaOtBu
a) All reactions were carried out using phenyl boronic acid (1a) (1.0 mmol) and KOtBu
(2.0 mmol) in the presence of air for 24 h. b) Isolated Yield. c) The reaction was carried
in inert atmosphere. d) 1.0 mmol of KOtBu was used
stereoselective manner. Likewise, methyl hex-2-ynoate (3b
)
and ethyl pent-2-ynoate (3c) gave the desired product in good
yield. It is noteworthy to mention that no reaction was observed
with 3-aryl propiolates.
With the optimized reaction conditions in hand, the scope
of the organoboronic acids was examined (Table 2). In general,
aryl boronic acids are compatible for the reaction whereas alkyl
boronic acids did not yield the desired product. As shown in
Table 2, aryl boronic acids bearing both electron-donating and
electro withdrawing substituents furnished the products in
good yields. For instance, the reaction of p-methoxy (1b), p-
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Table 3: Results of Phenoxylation of Propiolatesa,b
acids using stoichiometric amount of KOtBu in the presence of
air. A variety of arylboronic acids bearing both electron
View Article Online
DOI: 10.1039/C9NJ02121C
donating and withdrawing substituents successfully
participated in the reaction and furnished phenols in good
yields. To further, one pot synthesis of (E)-3-phenoxy acrylates
from arylboronic acids and propiolates is also demonstrated.
Advantageously, this method avoids the use of any noble metal
catalyst or photocatalyst. Thus, this operationally simple
protocol can be very useful in academic and possibly may be
extended to industrial applications as well.. Extension of the
scope of the reaction and the detailed mechanistic study are
currently under study.
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We thank Department of Science and Technology (DST), New
Delhi, India (DST/INSPIRE/04/2015/002987) for support of this
research under DST-INSPIRE faculty scheme.
Conflicts of interest
There are no conflicts to declare
a) All reactions were carried out using aryl boronic acid (1) (1.00 mmol), propiolates (3)
(0.50 mmol) and KOtBu (2.00 mmol) in the presence of air using CH3CN/THF (4:1) solvent
at 100 ⁰C for 12 h. b) Isolated Yields
Notes and references
1
(a) S. Quideau, D. Deffieux, C. D. Casassus and L. Pouysegu,
Angew. Chem. Int. Ed., 2011, 50, 586; (b) Z. Rappoport, The
Chemistry of Phenols, Wiley-VCH: Weinheim, 2003.
J. H. P. Tyman, Synthetic and Natural Phenols (Elsevier, New
York, 1996).
The reaction mechanism for the present reaction remains
uncertain. However, a plausible mechanism is proposed based
on the available literature report.13,14 The reaction may be
2
3
For selected examples, see: (a) K. W. Anderson, T. Ikawa, R. E.
Tundel and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128
,
initiated by forming superoxide radical ion
transfer from KOtBu to O2. Then, superoxide radical anion may
react with 1a to give the intermediate . Subsequent
protonation of intermediate and further 1,2-aryl shift gives
5 via single electron
10694; (b) D. Zhao, N. Wu, S. Zhang, P. Xi, X. Su, J. Lan and J.
You, Angew. Chem. Int. Ed., 2009, 48, 8729; (c) T. Schulz,
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the final phenol product. An alternative mechanism that
proceeds through PhB(OH)2-O2 adduct, which was then reduced
by KOtBu to form the intermediate cannot be ruled out
completely. To realize the radical pathway mechanism, a radical
trapping experiment was performed using TEMPO as the radical
inhibitor. Under standard reaction conditions, the reaction of
phenyl boronic acid 1a with 1 equivalent of TEMPO gave phenol
2a in 27% yields, however, with 2.5 equivalent of TEMPO, no 2a
was observed. The results depict that the reaction may proceed
through a radical pathway in the presence of KOtBu.
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Scheme 2: Proposed mechanistic pathway
In conclusion, we have successfully described a practical and
efficient method for the synthesis of phenols from arylboronic
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Table of Content
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The first example of potassium tert-butoxide mediated aerobic hydroxylation of arylboronic acids
affording phenols is described.
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OH
KOt-Bu (2.0 equiv.)
R1
B(OH)2 KOt-Bu (2.0 equiv.)
O
air
R
air
OR2
CH3CN/THF,
O
CH3CN/THF,
75 C, 12 h
R
R
100 C, 12 h
2
O
70-95% yield
R1
65-84% yield
R1, R2 = alkyl
OR2