Hydroxylation of aryl- and alkylboronic acids/esters mediated by iodobenzene diacetate - An avenue for using organoboronic acids/esters as nucleophiles for hydroxylation reactions

Article abstract of DOI:10.1016/j.tetlet.2014.11.058

A metal free, mild, and highly efficient methodology for ipso-hydroxylation of diversely functionalized aryl- and alkylboronic acids/esters mediated by iodobenzene diacetate (DAIB) under ambient temperature has been developed. This protocol is also applicable to N-heterocyclic boronic acids and esters. In the course of understanding the mechanism of this protocol, it is anticipated that organoboronic acid/ester, even being an electron demanding moiety, is acting as a nucleophile in the presence of DAIB for the hydroxylation reaction.

Full text of DOI:10.1016/j.tetlet.2014.11.058

Accepted Manuscript
Hydroxylation of Aryl- and Alkylboronic Acids/Esters Mediated by Iodoben-
zene Diacetate – An Avenue for Using Organoboronic Acids/Esters as Nucle-
ophiles for Hydroxylation Reactions
Nachiketa Chatterjee, Hrishikesh Chowdhury, Kumar Sneh, Avijit Goswami
PII:
S0040-4039(14)01951-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.058
TETL 45442
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 September 2014
11 November 2014
13 November 2014
Please cite this article as: Chatterjee, N., Chowdhury, H., Sneh, K., Goswami, A., Hydroxylation of Aryl- and
Alkylboronic Acids/Esters Mediated by Iodobenzene Diacetate – An Avenue for Using Organoboronic Acids/Esters
as Nucleophiles for Hydroxylation Reactions, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2
014.11.058
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Hydroxylation of Aryl- and Alkylboronic Acids/Esters
Mediated by Iodobenzene Diacetate – An Avenue for
Using Organoboronic Acids/Esters as Nucleophiles for Hydroxylation Reactions
Nachiketa Chatterjee, Hrishikesh Chowdhury, Kumar Sneh, Avijit Goswami*
no metal
mild conditions
PhI(OAc) / Et N
2
3
R-B(OH)2
no hazardous reagents
rapid & quantitative conversion
open flask
R-OH
CH CN-H O
rt, 10 min
3
2
R = aryl, alkyl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Hydroxylation of Aryl- and Alkylboronic Acids/Esters Mediated by Iodobenzene
Diacetate – An Avenue for Using Organoboronic Acids/Esters as Nucleophiles
for Hydroxylation Reactions
Nachiketa Chatterjee, Hrishikesh Chowdhury, Kumar Sneh, Avijit Goswami*
Department of Chemistry, Indian Institute of Technology, Ropar (IIT Ropar), Nangal Road, Rupnagar, Punjab 140001, India.
E-mail: agoswami@iitrpr.ac.in Tel: +91-1881-242121
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal free, mild and highly efficient methodology for ipso-hydroxylation of diversely
functionalized aryl- and alkylboronic acids/esters mediated by iodobenzene diacetate (DAIB)
under ambient temperature has been developed. This protocol is also applicable to N-
heterocyclic boronic acids and esters. In the course of understanding the mechanism of this
protocol, it is anticipated that organoboronic acid/ester, even being an electron demanding
moiety, is acting as a nucleophile in presence of DAIB for the hydroxylation reaction.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
1
2
3
4
5
. aliphatic alcohols
. aromatic alcohols
. hydroxylation
. hypervalent iodine, DAIB
. organoboronic acids/esters
1
0
11
12
Phenol is a far-reaching structural unit found in a vast array of
natural products and pharmaceuticals and could be present in
both monomeric and polymeric forms. Phenol and their
mCPBA, NaClO -H O, HOF-CH CN, as oxidants have also
2
2
3
been developed. All these methodologies, however, have
drawbacks of their own, such as toxicity factors, environmental
issues, relatively longer reaction time, non compatibility with C-
C double bonds and inaccessibility to alkylboronic acids.
1
derivatives act as key synthetic precursors in constructing aryl
2
ethers and O-heterocycles. In medicinal chemistry, they are
found to exhibit antitumor, antiviral, antibacterial, cardio-
protective, pro-oxidant and antimutagenecity activities.
[
a]
3
Table 1: Optimization of reaction conditions
Consequently, efficient access to phenols under mild and eco-
friendly conditions, especially in the presence of other functional
groups is always of great significance.
B(OH)2
OH
PhI(OAc) / Et N
2
3
CH CN-H O
The traditional procedures for the syntheses of aromatic
alcohols such as activated aromatic nucleophilic substitution
methodology and the benzyne protocols have some drawbacks of
their own, they normally require harsh conditions to succeed and
3
2
rt, 10 min
1a
oxidant
2a
entry
base
equiv. of
time
yield[
(%) 2a
trace
b]
base
4
has problem with the selectivity issues. Over the last few
1
2
PhI(OAc)
2
2
no base
-
6 h
decades, arylboronic acids and their other surrogates have
emerged as important moieties in the field of synthetic
PhI(OAc)
Et
Et
Et
3
N
1.0
10
min
65
5
chemistry. Among the many known metal catalyzed protocols
3
4
5
PhI(OAc)
2
3
N
2.0
2.0
-
10
min
10
min
6 h
97
for functional group transformation of arylboronic acids/esters,
Cu and Pd catalyzed methods are widely used for hydroxylation
[c]
6
PhI(OAc)
2
3
N
96
of arylboronic acids. However, from pharmaceutical perspective,
metal free protocols are always preferred over metal promoted
methods. From this point of view, few metal free methodologies
for hydroxylation of arylboronic acids have also been achieved.
The classical metal free methodology involves hydrogen
PhI(OCOCF
3
3
)
2
2
no base
Et
Et N
trace
64
6
7
PhI(OCOCF
)
3
N
1.0
2.0
10
min
7
[d]
peroxide as oxidant in presence of base such as NaOH or
PhI(OCOCF3)2
10
min
96
3
8
Na CO and oxone in the absence of base. Recently, Zhu et al.
2
3
[
a]
has reported aromatic N-oxide promoted hydroxylation of
reaction conditions: 1a (0.5 mmol), PhI(OAc)
2 3
(0.75 mmol), Et N (1.0
9
mmol), CH CN (5 mL), H O (11 μL, 0.6 mmol), rt, 10 min, open flask;
3
2
arylboronic acids. In addition, other methods involving

2
Tetrahedron
[b]
Having optimized the reaction conditions, we subsequently
isolated yield;
explored the substrate scope of the hydroxylation methodology
and the results are summarized in Scheme 1. Successful
hydroxylations of diversely substituted arylboronic acids exhibit
excellent compatibility towards various functional groups (e.g.
halide, nitro, aldehyde, keto and nitrile). The smooth
hydroxylations of the ortho-substituted arylboronic acids to
corresponding aromatic alcohols (2k, 2l, 2m) clearly indicate that
steric effect has no significant role in the reaction outcome. It is
noticed that arylboronic acids having electron donating and
withdrawing groups show similar reactivity towards
hydroxylation.
It is important to mention that arylboronic acids with oxidation
sensitive functional group such as aldehydes (2m, 2n) tolerate the
reaction conditions without suffering over-oxidation. N-
Heterocyclic boronic acid can also be applied for hydroxylation
to 3-hydroxy pyridine (2e) by this protocol. Interestingly, halide
substituted arylboronic acids can be converted to corresponding
halo- substituted alcohols (2h, 2i, 2k), which are precursors of
further functionalization.
[
c]
the reaction was carried out under argon atmosphere;
[
d]
the reactions gave comparable yields both with PIFA and DAIB, as DAIB
is cheaper and more air stable compared to PIFA, former was preferred to be
used as an oxidant.
Hypervalent iodine reagent is widely considered as a unique and
powerful oxidant with no toxic or environmental issues and is
1
3
sufficiently stable to heat, air and moisture. However, to the
best of our knowledge, no substantial documentation of
hypervalent iodine mediated hydroxylation of aryl/alkylboronic
acids has been made so far. Herein, we reveal the first
iodobenzene diacetate (DAIB) mediated general route for
hydroxylation of both aryl- and alkylboronic acids and esters
including N-heteroaryl ones.
Table 1 summarizes the optimization results of PhI(OAc)2
(DAIB) mediated hydroxylation of arylboronic acids in open air,
under ambient temperature. 3-Methylphenlylboronic acid (1a)
was chosen as the model substrate in optimization of the reaction
conditions for obtaining m-cresol (2a). An initial optimization
revealed that in the absence of a base no hydroxylation occurred,
irrespective of oxidants and solvents used (entries 1, 5).
Triethylamine is found to be the most effective base for smooth
progress of this reaction, while other bases such as pyridine and
diisopropylamine could not give satisfactory results (not shown
in the table). The amount of base plays an important role for
quantitative conversion of the organoboronic acids (entries 2, 3,
PhI(OAc) / Et N
2
3
R-B(OH)2
R-OH
4
CH CN-H O
3
2
3
rt, 10 min
OH
OH
Me
OH
6
, 7).
PhI(OAc) / Et N
2
3
4a (83%)
4
c (92%)
Ar-B(OH)2
Ar-OH
2
4b (91%)
CH CN-H O
3
2
1
reaction conditions: 3 (2.0 mmol), PhI(OAc)
2 3
(3.0 mmol), Et N (4.0 mmol),
rt, 10 min
CH CN (5 mL), H O (44 μL, 2.4 mmol), rt, 10 min, open flask;
3
2
OH
OH
OH
OH
Scheme 2: ipso-Hydroxylation of alkylboronic acids
H C
MeO
Encouraged by these results, the protocol was applied to
alkylboronic acids to obtain aliphatic alcohols (Scheme 2). In
general, aliphatic alcohols, especially primary alcohols are hard
to synthesize through oxidative methods as they are prone to get
3
2
a (97%)
2b (92%)
2c(97%)
2d (96%)
OH
OH
OH
OH
1
4
over-oxidized easily.
Interestingly, the newly developed
N
Br
protocol did not exhibit such problem. This protocol, in a similar
way to arylboronic acids, goes equally well with alkylboronic
acids. Excellent yields were obtained for both primary (4a, 4b)
and secondary alcohols (4c).
2
g (90%)
2h (92%)
2e (90%)
2f (92%)
OH
OH
OH
OH
I
Br
NO2
Remarkably, not only the aromatic/aliphatic boronic acids, but
other alkyl/arylboronates also were found suitable for
hydroxylation in this method (Figure 1). However, unlike
aryl/alkylboronic acids, the reactions with the organoboronates
were relatively sluggish with moderate yields. It should be
indicated that reaction did not go to completion either at room
CF3
2j (90%)
2
i (90%)
2k (93%)
2l (91%)
OH
OH
OH
OH
CHO
OHC
0
temperature or on heating at 40 C for 4 h. In this context, it is to
H COC
NC
3
be mentioned that this methodology is found to be compatible
with the olefinic moiety without causing any oxidation to the C-C
double bond of 5d.
2
m (95%)
2n (95%)
2o (97%)
2p (96%)
Scheme 1: ipso-Hydroxylation of aromatic boronic acids
Increasing the amount of base from 1.0 equiv. to 2.0 equiv.
resulted in a dramatic shift in the reaction outcome leading to
almost quantitative hydroxylation (entries 2-3, 6-7). In the course
of optimization of oxidant, it was noticed that the reaction goes
equally well with bis(trifluoroacetoxy)iodo-benzene (PIFA)
O
B
O
B
O
B
O
B
O
O
O
O
N
5a (1 h, 58%)
5
5c (1 h, 59%) 5d (1 h, 67%)[c]
b (1 h, 61%)
(entries 6, 7). However, DAIB being cheaper and relatively more
air-stable compared to PIFA, the former was chosen as a suitable
oxidant for this methodology. It is important to mention that the
reaction can also proceed quantitatively under an inert
environment (entry 4), clearly demonstrating no involvement of
molecular oxygen in the aforesaid hydroxylation process.
[a]
reaction conditions: organoboron compound 5 (0.5 mmol), PhI(OAc)
2
(1.0
mmol), Et
3
N (1.0 mmol), CH CN (5 mL), H O (11 μL, 0.6 mmol), rt, 1 h,
3
2
[b]
open flask; the reaction did not go to completion in any of the cases even on
0
[c]
heating at 40 C for 4 h; the reaction with 5d was carried out in 2.0 mmol
scale.

3
[a,b]
Figure 1: ipso-Hydroxylation of other boronic acid surrogates
hydroxylation of aryl/alkylboronic acids and their other
A probable mechanistic pathway is shown in scheme 3.
Quantitative hydroxylation of the arylboronic acid under inert
environment rules out the involvement of molecular oxygen in
the oxidation procedure. Therefore, two pathways can be
proposed for this type of hydroxylation reaction. In pathway A,
nucleophilic attack of the organoboron specie to DAIB took place
to produce another meta-stable hypervalent iodine species (I),
surrogates. Further investigations in the direction of detailed
mechanistic studies and the scope of using hypervalent iodine as
catalyst for the hydroxylation reaction are currently underway.
Acknowledgments
which in presence of Et N transformed to the tetra coordinated
We would like to express our gratitude to Professor Sentaro
Okamoto, Kanagawa University, Yokohama, Japan, for his
valuable feedback in preparing the manuscript. We are grateful to
CSIR, New Delhi, India for their generous financial support and
IIT Ropar for infrastructural facilities. NC and HC would like to
thank IIT Ropar for their fellowship.
3
boron compound (II). The subsequent intra-molecular [1,2] aryl
shift of compound (II) results in formation of the desired phenol.
Similarly, it can be mentioned that in the case of organoboronic
esters, they are first converting to the corresponding boronic
1
5
acids in presence of DAIB prior to the hydroxylation reactions.
However, in the presence of a base the conversion of boronic
esters to acids is not getting complete.
The second possibility (pathway B) is that the arylboronic
Supplementary Material
acid is first converted to tetra coordinated species (III) with Et N
3
1
6
and subsequently underwent iodine-boron exchange to produce
iodonium salt (IV); which on further reaction with water could
transform to phenol and expected aromatic alcohol. However,
under these circumstances, formation of phenol was not observed
along with the desired aromatic alcohols.
Supplementary data (general procedure for synthesis,
1
13
characterization data and copies of H and C NMR spectra of
all the compounds) associated with this article can be found, in
the online version, at
References and notes
NEt3
O
Ph
B(OH)2
OH
Ph
B
I
O
OH
Path A
B
I
OH
B
OAc
O
PhI(OAc)2
Et3N
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+
(III)
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(
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Ph-OH
Scheme 3: Plausible mechanistic pathway
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anhydrous acetonitrile in presence of 6.0 equiv. of H O
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isotopic oxygen (Ar- OH) was traced in GC-MS. Therefore, it
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4
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(
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OH
PhI(OAc) / Et N
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18
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Ar- OH
3
2
not detected
in
GC-MS
Bpin
OH
same conditions
1
9
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1
0 minutes at room temperature. A notable feature of this
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(
2
arylboronic acid in spite of being an electron deficient
[
17]
compound, can be predicted to act as a nucleophile. To the
best of our knowledge, it is a unique study in the field of