Protodeboronation of ortho- and para-phenol boronic acids and application to ortho and meta functionalization of phenols using boronic acids as blocking and directing groups

Article abstract of DOI:10.1021/jo402174v

The first metal-free thermal protodeboronation of ortho- and para-phenol boronic acids in DMSO was developed. The protodeboronation was successfully applied to the synthesis of ortho- and meta-functionalized phenols using the boronic acid moiety as a blocking group and a directing group, respectively. Mechanistic studies suggested that this protodeboronation proceeds through the coordination of water to the boron atom followed by σ-bond metathesis.

Full text of DOI:10.1021/jo402174v

Article
pubs.acs.org/joc
Protodeboronation of ortho- and para-Phenol Boronic Acids and
Application to ortho and meta Functionalization of Phenols Using
Boronic Acids as Blocking and Directing Groups
Chun-Young Lee, Su-Jin Ahn, and Cheol-Hong Cheon*
Department of Chemistry, Korea University, Anam-ro, Seongbuk-gu, Seoul 136701, Republic of Korea
S
* Supporting Information
ABSTRACT: The first metal-free thermal protodeboronation
of ortho- and para-phenol boronic acids in DMSO was
developed. The protodeboronation was successfully applied to
the synthesis of ortho- and meta-functionalized phenols using
the boronic acid moiety as a blocking group and a directing
group, respectively. Mechanistic studies suggested that this
protodeboronation proceeds through the coordination of
water to the boron atom followed by σ-bond metathesis.
a
Scheme 1. Selective Functionalization of Phenols
INTRODUCTION
■
Phenol and its derivatives have been considered one of the
most important commodity chemicals in modern chemical
science and have been widely used as precursors to many
materials and pharmaceutical drugs.1 Thus, great efforts have
been made to selectively functionalize phenols at specific
positions relative to the phenolic hydroxyl group. One of the
most common reactions used to introduce functional groups
onto the phenol ring is the electrophilic aromatic substitution
(EAS) reaction.2 In general, EAS reactions of phenol derivatives
afford para-functionalized phenols with ease (Scheme 1a),
whereas until recently few methods to access functionalized
phenol derivatives at other positions, particularly meta-
functionalized phenols, had been developed.3−5 Herein, we
report a novel method to access ortho- and meta-functionalized
phenol derivatives using a boronic acid as both a blocking
group6 and a directing group,7,8 respectively, and the
subsequent removal of the boronic acid moiety via proto-
deboronation (Scheme 1b). These results are based on our new
findings of metal-free thermal protodeboronations of ortho-
and para-phenol boronic acids in DMSO.
a
(a) Conventional approach for para functionalization. (b) New ortho
and meta functionalization using a boronic acid as a blocking and
directing group, respectively.
RESULTS AND DISCUSSION
synthetic method from the synthetic community. This is not
only because protodeboronation takes place under relatively
harsh reaction conditions but also because the exact reaction
mechanism and parameters to control such transformations are
poorly understood.
Very recently, we developed a new step-economical method
for the synthesis of both (R)- and (S)-BINOL derivatives
through the diastereomeric resolution of racemic BINOL
■
Boronic acids and their derivatives are deemed an attractive
class of synthetic intermediates because of their unique
reactivity, ready availability, and low toxicity9 and thus have
been widely used in organic synthesis, in particular, in metal-
catalyzed cross-coupling reactions.10,11 Although there were a
few reports of the protodeboronation of allylic and/or alkyl
boronic esters as stereoselective synthetic methods,12 the
protodeboronation of aryl boronic acids, which is known as
one of the most common side-reactions in metal-catalyzed
coupling protocols,13 has received little attention as a viable
Received: September 30, 2013
© XXXX American Chemical Society
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Scheme 2. Thermal Protodeboronation of 2-Naphthol Boronic Acid 1a
boronic acid with a chiral boron ligand and the subsequent
Suzuki reaction of the resulting (R)- and (S)-BINOL boronic
acid.14 Continuing our research in the development of efficient
methods for the preparation of axially chiral compounds, we
attempted to synthesize chiral BINOL derivatives through the
diastereoselective coupling reaction of 2-naphthol derivative 3a
bearing a chiral boronate at the 3-position and subsequent
Suzuki reaction. Throughout our attempts to introduce pinene-
derived iminodiacetic acid 2 (PIDA) into the boronic acid
moiety of compound 1a as a chiral boron ligand under the
previously developed conditions,15,16 no formation of PIDA
boronate 3a was observed; instead, an unexpected compound
was formed as the sole product. Careful structural analysis
showed that the unexpected product was 2-naphthol 4a,
presumably formed via thermal protodeboronation (Scheme 2).
Because protodeboronations of simple arene boronic acids
are known to take place under relatively harsh conditions, such
as in the presence of metal catalysts and/or strong acid/base at
high temperatures,9,13 and metal-free protodeboronations of
arene boronic acids have not been previously described under
neutral conditions even at high temperatures, we decided to
investigate this unusual metal-free thermal protodeboronation
of hydroxyarene boronic acids.
First, we attempted to prepare 2-hydroxyphenyl boronic acid
1b as a model compound for protodeboronation studies by
following a literature procedure.17 Surprisingly, we were not
able to obtain this compound in a pure form. Even more
surprisingly, compound 1b purchased from several commercial
suppliers also contained similar impurities.18 Without further
purification of 1b, we decided to subject 1b to protodeboro-
nation under the aforementioned reaction conditions. The
protodeboronation proceeded smoothly, and phenol 4b was
obtained as the only product despite the presence of
unidentifiable impurities in the starting boronic acid (Table 1,
entry 1).19 Initially, we suspected that PIDA 2 might play some
role in protodeboronation. However, when the same reaction
was performed in the absence of 2, protodeboronation still
occurred, leading to the conclusion that PIDA has no effect on
the protodeboronation (Table 1, entry 2). The choice of
solvent had a significant effect on the protodeboronation
(Table 1, entries 2−6); the protodeboronation reaction
proceeded in DMSO and DMF, whereas no apparent reaction
was observed in other solvents. Because protodeboronation
proceeded much faster in DMSO than in DMF, DMSO was
selected as the solvent of choice. Reaction temperature had also
a strong influence on the protodeboronation (Table 1, entries
2, 7−8). Protodeboronation progressed very slowly at 80 °C
(Table 1, entry 7); an increase to 100 °C resulted in a more
rapid reaction (24 h, quantitative; Table 1, entry 8), and further
temperature increase to 120 °C promoted complete proto-
deboronation within 4 h (Table 1, entry 2). The reaction
Table 1. Investigation of Reaction Parameters
a
entry
solvent
temp. (°C)
time (h)
yield (%)
b
1
DMSO
DMSO
DMF
120
120
120
120
120
120
80
4
100
100
40
2
3
4
5
6
7
8
4
72
24
24
24
24
24
4
c
dioxane
toluene
n-BuOH
DMSO
DMSO
DMSO
N.R.
c
N.R.
c
N.R.
20
100
120
100
100
d
9
e
c
10
DMSO
120
24
N.R.
a
b
1
Determined by H NMR analysis. 1.5 equiv of PIDA 2 was used.
c
d
e
N.R., no reaction. Under an argon atmosphere. Reaction was
́
conducted in the presence of 4 Å molecular sieves.
atmosphere had very little effect on the protodeboronation, as
reaction under an inert atmosphere provided 4b in similar yield
as that conducted in air (Table 1, entries 2 and 9). Interestingly,
water was found to play a very important role in
protodeboronation: boronic acid 1b remained intact in the
presence of molecular sieves (Table 1, entry 10).
Under these conditions (DMSO, 120 °C, and open flask), we
investigated the effect of substituent (X) on arene boronic acids
1 on the protodeboronation (Table 2). First, we investigated
Table 2. Effect of Substituents on the Protodeboronation
a
entry
1
(OR)2
X
time (h)
yield (%)
b
1
1b
1c
(OH)2
(OH)2
(OH)2
(OH)2
(OH)2
(OH)2
(OH)2
(OH)2
pinacol
pinacol
2-OH
4
100 (95)
c
2
2-Me
24
24
24
24
24
12
24
24
24
N.R.
c
3
1b-Me
1b-MOM
1b-Bn
1d
2-OMe
2-OMOM
2-OBn
3-OH
N.R.
c
4
N.R.
c
5
N.R.
c
6
N.R.
b
7
1e
4-OH
100 (96)
d
8
1e-Me
1b-pin
1e-pin
4-OMe
2-OH
trace
b
b
9
100 (96)
100 (94)
10
4-OH
a
b
Determined by 1H NMR analysis. Yields in parentheses were
c
d
isolated yields. N.R., no reaction. <5% yield.
B
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a
the influence of the type of substituent at the ortho position of
boronic acids 1 on the protodeboronation (Table 2, entries 1−
5). Interestingly, no arene boronic acids bearing substituents
other than a hydroxyl group at the ortho position underwent
the protodeboronation reaction. For example, ortho-toluene
boronic acid 1c did not undergo any protodeboronation
reaction even after 24 h (Table 2, entry 2). Furthermore, when
the hydroxyl group of boronic acid 1b was protected as either
the methyl, methoxymethyl (MOM), or benzyl groups,
protodeboronation did not occur under the same conditions
(Table 2, entries 1, 3−5). Next, we examined an effect of the
position of the phenolic hydroxyl group in the phenyl ring on
the protodeboronation. Positions of the phenolic hydroxyl
group exhibited significant effects on the protodeboronation
(Table 2, entries 1, 6, and 7). Boronic acids 1b and 1e bearing
the hydroxyl group at the ortho and para positions, respectively,
readily underwent the protodeboronation (Table 2, entries 1
and 7), whereas meta-phenol boronic acid 1d remained
unreacted even after a prolonged reaction time (Table 2,
entry 6). Similar to ortho-phenol boronic acid 1b, the presence
of a free phenolic hydroxyl group of para-phenol boronic acid
1e turned out to be critical for protodeboronation. When the
hydroxyl group in 1e was protected as the corresponding
methyl ether, no protodeboronation occurred (Table 2, entry
8). We also investigated the effect of a free hydroxyl group at
the boronic acid moiety on protodeboronation. When the
boronic acid moieties in compounds 1b and 1e were converted
into the corresponding pinacol boronates, 1b-pin and 1e-pin,
protodeboronation still proceeded, albeit at slower rates (Table
2, entries 9 and 10).
Table 3. Substrate Scope
a
Reaction conditions: ortho-hydroxyaryl boronic acid 1 (0.20 mmol),
DMSO (1.0 mL), 120 °C, open flask. Isolated yields.
b
Scheme 3. ortho Functionalization of Phenols Using a
Boronic Acid Moiety as a Blocking Group
With these results in hand, we investigated the generality of
the protodeboronation reaction of ortho-hydroxyaryl boronic
acids 1 bearing a substituent on the arene rings. Because many
ortho-hydroxyaryl boronic acids are commercially available,20
we purchased several ortho-hydroxyaryl boronic acids and
attempted to subject them directly to the protodeboronation
reaction (Table 3). When these commercially available
compounds were subjected directly to protodeboronation
under the optimized conditions without further purification,
the corresponding phenols were obtained as the sole products
regardless of the steric and electronic nature of phenol rings in
boronic acids 1 (Table 3, entries 1−7). Furthermore, this
protodeboronation reaction is not limited to simple phenol
boronic acid derivatives and can be extended to fused aromatic
systems. For example, 2-naphthol boronic acid 1a bearing a
hydroxyl group at the 3-position underwent protodeboronation
to afford 2-naphthol 4a (Table 3, entry 8). In addition, a chiral
BINOL derivative 1l bearing boronic acids at the 3,3′-positions
smoothly underwent protodeboronation to provide (R)-
BINOL (Table 3, entry 9).
With these results in hand, we attempted to develop novel
synthetic methods using this protodeboronation of phenol
boronic acids. Although EAS reactions of phenols have been
used extensively to prepare functionalized phenols, EAS
reactions in general afford the para-functionalized phenols.
Thus, we first attempted to develop a protocol for the synthesis
of ortho-functionalized phenols by using a boronic acid moiety
as a blocking group in EAS reactions followed by the removal of
the boronic acid moiety through protodeboronation. Unfortu-
nately, when 1e was treated with N-bromosuccimide (NBS),
bromodeboronation took place to afford 4-bromophenol 4k in
quantitative yield (Scheme 3, eq 1).21 However, when the
corresponding pinacol boronate 1e-pin was used instead, the
bromodeboronation could be avoided and bromination took
place only at the ortho position of phenol to afford 2-
bromophenol 5 in 87% yield after the removal of the boronic
acid moiety (Scheme 3, eq 2).22 Furthermore, when an excess
of NBS (>2 equiv) was used, bromination took place only at
the ortho position, and no bromodeboronation was observed
even in the presence of remaining NBS. After the removal of
boronic acid, 2,6-dibromophenol 6 was obtained in excellent
yield (Scheme 3, eq 3).
With the successful application of a boronic acid moiety as a
blocking group in the EAS reactions, we attempted to develop
further the meta functionalization of phenols using boronic acid
as a directing group7,8 and the subsequent protodeboronation.
For example, a removable directing group (RDG) introduced
into boronic acid 1e could lead to ortho-functionalization to
afford an ortho-functionalized boronic acid 8. Removal of both
RDG and the boronic acid moiety would eventually provide a
meta-functionalized phenol (Scheme 4).
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Scheme 4. Traceless meta Functionalization of Phenols
Scheme 6. Synthesis of meta Iodophenol via a Boronic Acid-
Directed Functionalization
of 1b (Table 1, entry 10). Thus, we decided to investigate the
effect of water on the protodeboronation (Scheme 7). When
Scheme 7. Effect of Water on the Protodeboronation of 1e
Based on this idea, we attempted to prepare a meta-
functionalized phenol directly from 1e using 2-pyrazol-5-
ylaniline (pza) as a removable directing group (RDG), which
was developed by the Suginome group,7 on the boron atom.
However, 1e did not provide the desired product; instead
complex mixtures were obtained (Scheme 5, eq 4). Because
Scheme 5. meta Functionalization of Phenols Using a
Boronic Acid Moiety as a Directing Group
the protodeboronation of 1e23 was performed in the presence
of molecular sieves, no significant reaction was observed even
after a long reaction time (Scheme 7, eq 6). Moreover, upon
the addition of a small amount of water to the above mixture in
eq 6, protodeboronation again proceeded to afford phenol 2b
in quantitative yield (Scheme 7, eq 7). Furthermore, when the
reaction was carried out in the presence of D2O, deuterium was
incorporated in the carbon originally connected to the boron
atom (Scheme 7, eq 8).
In addition, it was also found that the corresponding pinacol
boronate 1e-pin displayed significantly lower reactivity than the
parent boronic acid 1e in the protodeboronation reaction
(Table 2, entries 7 and 10). From these results, we envisaged
that the Lewis acidity on the boron atom might play a role in
the protodeboronation. Thus, several boronates possessing
different Lewis acidities were prepared,24 and their reactivities
toward protodeboronation were investigated (Scheme 8).
Interestingly, the attenuation of the Lewis acidity on the
boron significantly slowed the protodeboronation. For example,
DAN boronate from 1e bearing low Lewis acidity underwent
complications in the pza-directed ortho functionalization might
be ascribed to the free hydroxyl group in 1e, we decided to use
a protected phenol boronic acid 1e-Me instead. To our delight,
the ortho-directed silylation proceeded smoothly to provide the
corresponding pinacol boronate 10 in 75% yield over three
steps. Deprotection with BBr3 and subsequent thermal
protodeboronation afforded meta-silylated phenol 9 in 93%
yield (Scheme 5, eq 5). Furthermore, 9 could be obtained with
similar efficiency (53% over five steps) from 1e-Me through
pza-directed ortho functionalization without isolation of
intermediate 10.
Furthermore, meta functionalization of phenols could be
demonstrated through the ortho-metalation of the boronic acid
moiety in 1e-Me followed by trapping with an electrophile.
Subsequent deprodection and protodeboronation could afford
a meta-functionalized phenol. Reaction of 1e-Me with
(TMP)2Mg (TMP2,2,6,6-tetramethylpiperidine) using N-
methyl-1,3-propanediamine as an RDG and subsequent
trapping with I2 afforded ortho-iodoborylated intermediate
11.8 Without isolation of 11, deprotection with BBr3 and
subsequent protodeboronation yielded meta-iodophenol 12 in
58% (Scheme 6).
Scheme 8. Protodeboronation of Boronates Bearing
Different Lewis Acidities
With these results in hand, we endeavored to elucidate the
reaction mechanism for this protodeboronation. During the
optimization of reaction conditions, we found that the presence
of water exhibited a significant effect on the protodeboronation
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minimal protodeboronation at 120 °C even after 10 days.
Furthermore, the corresponding MIDA boronate remained
intact even after 3 weeks under the standard conditions for
protodeboronation.
On the basis of these results, we believed that the
protodeboronation reaction might proceed via a two-step
sequence (Scheme 9): the water coordinates to the boron atom
in a boronic acid moiety to form an ate complex and
subsequent σ-bond metathesis provides the corresponding
phenol and a boric acid.
EXPERIMENT SECTION
■
General. All reactions were carried out in oven- or flame-dried
glassware under a nitrogen atmosphere unless otherwise noted. Except
as otherwise indicated, all reactions were magnetically stirred and
monitored by analytical thin-layer chromatography (TLC) using
precoated silica gel glass plates (0.25 mm) with F254 indicator.
Visualization was accomplished by UV light (254 nm) with a
combination of potassium permanganate and/or phosphomolybdic
acid solution as an indicator. Flash column chromatography was
performed according to the method of Still using silica gel 60 (230−
400 mesh). Yields refer to chromatographically and spectrographically
pure compounds, unless otherwise noted. All hydroxy arene boronic
acids 1 were purchased from commercial suppliers. H NMR and 13C
NMR spectra were recorded on 300 and 100 MHz NMR
spectrometers, respectively. Tetramethylsilane and the solvent
1
Scheme 9. Proposed Reaction Mechanism for
a
Protodeboronation
1
resonance were used as internal standards for H NMR (δ 0.0 ppm)
and 13C NMR, respectively. The proton spectra are reported as follows
δ (position of proton, multiplicity, coupling constant J, number of
protons). Multiplicities are indicated by s (singlet), d (doublet), t
(triplet), q (quartet), p (quintet), h (septet), m (multiplet), and br
(broad). High-resolution mass spectra (HRMS) were obtained using
quadrupole instrument with FAB as the ionization method.
a
A similar mechanism could be applied to ortho-phenol boronic acid
1b.
General Procedure for Protodeboronation of ortho-Phenol
Boronic Acid Derivatives 1 (Table 3). A solution of arene boronic
acid 1 (0.20 mmol) in either DMSO or DMSO-d6 (1.0 mL) was
stirred at 120 °C. The reaction mixture was monitored by TLC and 1H
NMR. After complete consumption of boronic acid 1 by TLC and/or
1H NMR analysis, the reaction mixture was cooled to room
temperature, quenched with H2O, and extracted with ether. The
organic layer was combined, washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was purified by
column chromatography on silica (hexanes/EtOAc 5:1) to afford the
corresponding phenol derivative 4.
This proposed reaction mechanism could explain the unique
reactivity of ortho- and para-phenol boronic acids on
protodeboronation. The higher reactivity of ortho- and para-
phenol boronic acids compared with meta-phenol boronic acid
could be explained based on the partial ionization of these
phenol boronic acids, which would further increase electron
density at the ortho and para positions of the phenol ring.
Along this line, a strong solvent dependence on reactivity might
also support such a partial ionization of the phenolic hydroxy
group.25 To test this idea, we actually prepared an ionized form
of 1e-pin and compared its reactivity with that of the parent 1e-
pin (Scheme 10). When 1e-pin was subjected to protodeboro-
2-Naphthol (4a). The spectroscopic data were in good agreement
with a commercially available sample.26 Yield: 28 mg, 98%. H NMR
1
(300 MHz, CDCl3) δ 7.77−7.73 (m, 2H), 7.66 (d, J = 8.24 Hz, 1H),
7.42 (t, J = 7.42 Hz), 7.32 (t, J = 7.14 Hz), 7.13−7.07 (m, 2H), 5.14 (s,
1H).
Scheme 10. Protodeboroantion of 1e-pin in the Presence of
K2CO3
Phenol (4b). The spectroscopic data were in good agreement with a
commercially available sample.26 Yield: 18 mg, 95%. H NMR (400
1
MHz, CDCl3) δ 7.23 (t, J = 7.83 Hz, 2H), 6.93 (t, J = 7.43 Hz, 1H),
6.83 (d, J = 7.83 Hz, 2H), 5.39 (br, 1H).
2-Methoxyphenol (4f). The spectroscopic data were in good
agreement with the literature.27 Yield: 23 mg, 93%. H NMR (400
1
MHz, CDCl3) δ 7.01−6.69 (m, 4H), 5.68 (br, 1H), 3.86 (s, 3H).
2-Methylphenol (4g). The spectroscopic data were in good
agreement with a commercially available sample.26 Yield: 21 mg,
96%. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (br, 1H), 7.03−6.93 (m,
2H), 6.74 (d, J = 7.69 Hz, 1H), 6.65 (t, J = 7.28 Hz), 5.16 (br, 1H),
2.09 (s, 3H).
nation in the presence of K2CO3, delightfully, protodeborona-
tion was complete within 2 h. This result clearly demonstrated
that ionization of phenol significantly enhanced the reactivity
for protodeboronation of para-phenol boronic acid.
2-Fluorophenol (4h). The spectroscopic data were in good
agreement with a commercially available sample.26 Yield: 20 mg,
1
91%. H NMR (400 MHz, CDCl3) δ 7.09−6.84 (m, 4H), 5.15 (br,
In conclusion, we have reported the first metal-free thermal
protodeboronation of arene boronic acids bearing a hydroxyl
group at the ortho and para positions relative to the boronic
acid moiety in DMSO under neutral conditions. Under these
conditions, various ortho- and para-phenol boronic acids
underwent protodeboronation to afford the corresponding
phenol derivatives in excellent yields. Furthermore, we have
developed a novel protocol for exclusive ortho and meta
functionalization of phenols using a boronic acid moiety as a
blocking group and a directing group, respectively, followed by
the removal of the boronic acid moiety via protodeboronation.
Mechanistic studies suggested that protodeboronation proceeds
through coordination of water to the boron atom on the
boronic acid followed by σ-bond metathesis.
1H).
4-Fluorophenol (4i). The spectroscopic data were in good
agreement with a commercially available sample.26 Yield: 21 mg,
1
94%. H NMR (400 MHz, CDCl3) δ 7.95 −6.75 (m, 4H), 5.05 (br,
1H).
4-Chlorophenol (4j). The spectroscopic data were in good
agreement with a commercially available sample.26 Yield: 24 mg,
1
95%. H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.61 Hz, 2H), 6.77
(d, J = 8.61 Hz, 2H), 5.13 (br, 1H).
4-Bromophenol (4k). The spectroscopic data were in good
agreement with a commercially available sample.26 Yield: 32 mg,
1
92%. H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.22 Hz, 2H), 6.71
(d, J = 8.22 Hz, 2H), 5.16 (br, 1H).
(R)-2,2′-Dihydroxy-1,1′-dinaphthyl (4l). The spectroscopic data
were in good agreement with a commercially available sample.26 Yield:
54 mg, 94%. 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 8.79 Hz, 1H),
E
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7.90 (d, J = 7.97 Hz, 1H), 7.40−7.28 (m, 6H), 7.16 (d, J = 8.79 Hz,
2H), 5.04 (s, 3H).
1H), 6.82 (dd, J = 7.97, 1.92 Hz, 1H), 0.96 (t, J = 7.55 Hz, 9H), 0.81−
0.73 (m, 6H).
General Procedures for ortho Functionalization of Phenols. To a
solution of 1e-pin (0.44 g, 2.0 mmol; 1.0 equiv) in CH2Cl2 (10 mL)
was added NBS (1.0 or 3.0 equiv). The reaction mixture was stirred at
room temperature and monitored by TLC. After complete
consumption of 1e-pin, the reaction mixture was quenched with
water and extracted with EtOAc (3 × 30 mL). The organic layer was
combined, dried over MgSO4, and concentrated under reduced
pressure. The crude mixture was directly subjected to protodeboro-
nation without further purification. The residue obtained above was
dissolved in DMSO (10 mL) and H2O (2 mL). The reaction mixture
was stirred at 120 °C and monitored by TLC. After complete
consumption of the resulting boronate, the reaction mixture was
cooled to room temperature and extracted with ether. The organic
layer was combined, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica (hexanes/EtOAc 5:1).
When the crude mixture of compound 10 could be directly applied
to the protodeboronation without further purification, compound 9
was obtained in comparable yield as that above.
General Procedure for Synthesis of meta-Iodophenol 12 via
ortho-Boryl Directed Metalation and Trapping with I2 followed by
Protodeboronation.8 Preparation of (TMP)2Mg. n-BuLi (10 mL, 25
mmol, 2.5 M in hexanes) was added dropwise to a solution of TMPH
(4.2 mL, 25 mmol) in THP (25 mL) at −78 °C, and the reaction
mixture was stirred at −20 °C for 30 min to give THPLi. To the above
solution was added MgBr2·OEt2 (3.23 g, 12.5 mmol) in several
portions at −78 °C over 10 min. Then the reaction mixture was stirred
at 0 °C for 2 h to produce (TMP)2Mg in THP.
Synthesis of meta-Iodo Phenol (12). A solution of 1e-Me (2.0 g,
9.8 mmol) and N-methyl-1,3-diaminopropane (1.05 mL, 10.1 mmol)
in toluene (100 mL) was refluxed with azeotropic removal of water
using a Dean−Stark condenser for 4 h. Then, the solvent was removed
under reduced pressure to afford the crude mixture. The crude mixture
was subjected to bulb-to-bulb distillation to yield the resulting
boronate bearing an RDG. The resulting boronate was directly used
for the netx step. A solution of the boronate bearing an RDG obtained
above was added to the solution of (TMP)2Mg in THP prepared
above at 0 °C. Then, the reaction mixture was stirred at room
temperature for 30 min and refluxed for additional 2 h. Then, the
reaction mixture was cooled to room temperature and treated with a
solution of I2 (15 g, 58.8 mmol) in THF (200 mL) and warmed to
room temperature with stirring overnight. The crude diaminoborane
was obtained as residue after evaporation of the solvents. To the
residue was added saturated NH4Cl (10 mL). The white suspension of
the reaction mixture was stirred at room temperature for 1 day. Then,
the reaction mixture was extracted with EtOAc. The combined organic
layer was dried over MgSO4 and concentrated to afford the crude
residue of 11. Compound 11 was subjected to deprotection and
protodeboronation without further purification. BBr3 (1.9 mL, 20
mmol) was added dropwise to the crude residue of 11 obtained above
in dichloromethane (100 mL) at 0 °C. Then, the reaction mixture was
warmed to room temperature and stirred for 12 h. The reaction
mixture was quenched with H2O and extracted with EtOAc. The
organic layer was combined and concentrated. The residue was
dissolved in DMSO (20 mL), and H2O (1.0 mL) was added to the
reaction mixture. The reaction mixture was allowed to stir at 120 °C in
an open flask for 24 h. After the protodeboronation was completed,
the reaction mixture was quenched with H2O, extracted with EtOAc,
dried over MgSO4, and concentrated. The residue was purified by
column chromatography on silica (hexanes/EtOAc 4:1) to afford
meta-iodo phenol 12. The spectroscopic data were in good agreement
2-Bromophenol (5). Reaction with 1.0 equiv of NBS (0.36 g, 2.0
mmol). Compound 5 was obtained as colorless oil, and the
spectroscopic data were in good agreement with a commercially
available sample.26 Yield: 0.30 g, 87%. 1H NMR (300 MHz, CDCl3) δ
7.47 (dd, J = 8.10, 1.24 Hz, 1H), 7.22 (t, J = 7.69 Hz, 1H), 7.02 (dd, J
= 8.10, 1.24 Hz, 1H), 6.80 (t, J = 7.69 Hz, 1H), 5.52 (br, 1H).
1
In addition, the H NMR of the crude mixture showed that there
was a trace amount of dibrominated compound.
2,6-Dibromophenol (6). Reaction with 3.0 equiv of NBS (1.1 g, 6.0
mmol). Compound 6 was obtained as a white solid, and the
spectroscopic data were in good agreement with a commercially
available sample.26 Yield: 0.46 g, 93%. 1H NMR (300 MHz, CDCl3) δ
7.45 (d, J = 7.97 Hz, 2H), 6.71 (t, J = 7.97 Hz, 1H), 5.89 (br, 1H).
General Procedure for Synthesis of meta-Silylated Phenol 9 via
ortho-Boryl Directed C−H Activation followed by Protodeborona-
tion:7 A mixture of boronic acid 1e-Me (0.23 g; 1.5 mmol) and 2-
pyrazol-5-ylaniline (pza, 0.24 g; 1.5 mmol) in toluene (6.0 mL) was
heated under reflux with a Dean−Stark condenser for 1 h. After the
reaction mixture was cooled to room temperature, the solvent was
removed under reduced pressure. To the residue was added
RuH2(CO)(PPh3)3 (83 mg; 0.090 mmol). Then, norbornene (0.71
g; 7.5 mmol), triethylsilane (0.87 g; 7.5 mmol), and toluene (2.0 mL)
were added under an argon atmosphere. The reaction mixture was
heated at 135 °C for 12 h. The reaction mixture was cooled to room
temperature. The crude mixture was converted to the corresponding
pinacol ester by adding pinacol (0.35g; 3.0 mmol), p-toluenesulfonic
acid monohydrate (57 mg, 0.15 mmol), and THF (5.0 mL) at room
temperature. The reaction mixture was allowed to stir for additional 3
h, quenched with water (10 mL), and extracted with EtOAc (10 mL ×
3). The combined organic layer was dried with MgSO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica (hexanes/EtOAc 10:1) to afford
compounds 10. The spectroscopic data were in good agreement with
with the literature.29 Yield: 1.3 g, colorless oil, 58% over six steps. H
1
NMR (300 MHz, CDCl3) δ 7.33−7.20 (m, 2H), 6.95 (t, J = 7.97 Hz,
1H), 6.80 (dd, J = 8.24, 1.92 Hz, 1H), 5.66 (br, 1H).
the literature.28 Yield: 0.39 g, colorless oil, 75%. H NMR (300 MHz,
1
General Procedure for Preparation of 4-Phenol Boronates
Bearing Lower Lewis Acidity. A solution of (4-hydroxyphenyl)boronic
acid 1e (0.14 g, 1.0 mmol), 1,8-diaminonaphthalene (0.24 g, 1.5
CDCl3) δ 7.89 (d, J = 8.24 Hz, 1H), 7.12 (d, J = 2.75 Hz, 1H), 6.84
(dd, J = 8.24, 2.75 Hz, 1H), 3.82 (s, 3H), 1.33 (s, 12H), 0.92 (s, 15H).
Compound 10 was dissolved in dichloromethane (10 mL) and
treated with BBr3 (0.28 mL, 0.75 g; 3.0 mmol; 2.0 equiv) at 0 °C, and
the reaction mixture was warmed to room temperature. After 12 h, the
reaction was quenched with water (20 mL), and the aqueous layer was
extracted with dichloromethane (20 mL × 3). The combined organic
layer was dried with MgSO4 and concentrated under reduced pressure.
The residue was dissolved in DMSO (1.5 mL) and H2O (0.1 mL).
The reaction mixture was stirred at 120 °C and monitored by TLC.
After complete protodeboronation, the reaction mixture was cooled to
room temperature, quenched with H2O, and extracted with ether. The
organic layer was combined, washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was purified by
column chromatography on silica (hexanes/EtOAc 5:1). The
spectroscopic data were in good agreement with the literature.29
́
mmol), and molecular sieves (4 Å, 50 mg) in a mixture of DMSO and
toluene (1:10, 3 mL) was refluxed with azeotropic removal of water
using a Dean−Stark condenser under an air atmosphere. After 12 h,
the reaction mixture was cooled to room temperature. The reaction
mixture was poured into water and extracted with EtOAc (20 mL).
The organic layer was combined, washed with brine (20 mL), dried
with MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluting with
EtOAc/hexanes (1:1).
DAN-boronate.30 Yield: 0.25g, red solid, 96%. 1H NMR (300 MHz,
DMSO-d6) δ 9.65 (br, 1H), 8.11 (s, 2H), 7.76 (d, J = 8.24 Hz, 2H),
7.06 (t, J = 7.83 Hz, 2H), 6.87 (d, J = 7.97 Hz, 2H), 6.81 (d, J = 8.52
Hz, 2H), 6.56 (d, J = 7.69 Hz, 2H).
MIDA-boronate.25 Yield: 0.23 g, 94%. 1H NMR (300 MHz,
DMSO-d6) δ 9.42 (br, 1H), 7.22 (d, J = 8.24 Hz, 2H), 6.74 (d, J = 8.24
Hz, 2H), 4.31−4.02 (dd, J = 72 Hz, J = 18 Hz, 4H), 2.46 (s, 3H).
1
Yield: 0.17 g, colorless oil, 53%. H NMR (300 MHz, CDCl3) δ 7.24
(t, J = 7.42 Hz, 1H), 7.06 (d, J = 7.14 Hz, 1H), 6.95 (d, J = 2.20 Hz,
F
dx.doi.org/10.1021/jo402174v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2164−2166. (b) Beckett, M. A.; Gilmore, R. J.; Idrees, K. J. Organomet.
Chem. 1993, 455, 47−49.
(14) Lee, C.-Y.; Cheon, C.-H. J. Org. Chem. 2013, 78, 7086−7092.
(15) For a review of preparation and application of MIDA boronates,
see: Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17−27.
(16) For the preparation of PIDA boronates, see: Li, J.; Burke, M. D.
J. Am. Chem. Soc. 2011, 133, 13774−13777.
(17) For the preparation of 1b, see: Konakahara, T.; Kiran, Y. B.;
Okuno, Y.; Ikeda, R.; Sakai, N. Tetrahedron Lett. 2010, 51, 2335−2338.
(18) Boronic acid 1b purchased from both Aldrich and TCI contains
similar impurities.
(19) We believed that the impurities might be intermediates in the
course of protodeboronation, which is responsible for the formation of
phenol 4b as the sole product even though starting boronic acid 1b
contains impurities.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data for phenol derivatives 4−6, 9, 10, and 12 as
well as para-phenol boronates with lower Lewis acidity. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cheon@korea.ac.kr.
Notes
The authors declare no competing financial interest.
(20) On the basis of a SciFinder substructure search using ortho-
hydroxyphenl boronic acid, more than 100 ortho-phenol boronic acid
derivatives, including boronic acids in Table 2, are commercially
available as of August 2013.
(21) For an example of halodeboronation, see: Szumigala, R. H., Jr.;
Devine, P. N.; Gauthier, D. R., Jr.; Volante, R. P. J. Org. Chem. 2004,
69, 566−569.
(22) A trace amount of 2,6-dibromophenol 6 was observed as a side-
product (<5%).
ACKNOWLEDGMENTS
■
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT, and Future Planning
(2013R1A1A1008434). C.H.C. is also thankful for financial
support from a NRF fund by the Ministry of Education
(NRF20100020209).
(23) Because 1b is more prone to undergo protodeboronation than
1e, we used 1e for mechanistic studies rather than 1b.
(24) For the preparation of DAN and MIDA boronates, see the
Supporting Information. The preparation of MIDA boronates from 1b
and 1e will be reported in due course.
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dx.doi.org/10.1021/jo402174v | J. Org. Chem. XXXX, XXX, XXX−XXX