Chemoselective oxidation of aryl organoboron systems enabled by boronic acid-selective phase transfer

Article abstract of DOI:10.1039/C6SC04014D

We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a priori. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling.

Full text of DOI:10.1039/C6SC04014D

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Chemoselective oxidation of aryl organoboron systems enabled
by boronic acid-selective phase transfer
John J. Molloy,a Thomas A. Clohessy,a,b Craig Irving,a Niall A. Anderson,b Guy C. Lloyd-Jonesc and
Allan J. B. Watsona*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron
www.rsc.org/
groups. Basic biphasic reaction conditions enable selective formation and phase transfer of
a boronic acid
trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria.
Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This
phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional
protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin
substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a
priori. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile
coupling.
reactivity profiles of boronic acids and esters,11 and the added
complication of speciation equilibria,11-13 establishing
chemoselective control within mixed organoboron systems
Introduction
The use of di- and multi-boron containing systems has become
powerful approach for the rapid synthesis of highly
represents a significant challenge. However, the identification
of new chemoselective control mechanisms would be a
fundamental advance, enabling the design and development
of new synthetic methods for systems containing more than
one reactive organoboron compound.
a
functionalized molecules from readily accessible starting
materials.1,2 Chemoselectivity in these systems is currently
achieved using only two approaches. Firstly, B-protecting
groups render a specific boron unit unreactive under the
prevailing reaction conditions. Widely used B-protecting
groups include N-methyliminodiacetic acid (MIDA) esters,3
diaminonaphthalene (DAN)-based aminoboranes,4 and
potassium organotrifluoroborates (RBF3K) (Scheme 1a).5-7
Secondly, self-activation/protection mechanisms allow
discrimination of geminal and vicinal diboron compounds,
enabling chemoselectivity within superficially equivalent
systems (Scheme 1b).8-10
a) Previous work: chemoselectivity via protecting groups (Burke, Hall, Li, Molander, Suginome)
R
B(OR)2
BPG
Me
F
B
K
BPG
N
HN
B
Pd or Ir/Ni
O
O
F
F
R
O
O
B
N
R
R
H
X
BF3K
BMIDA
BDAN
b) Previous work: chemoselectivity via self-activation/protection (Hall, Morken, Shibata)
BPin
BPin
BPin
BPin
BPin
Pd
Pd
BPin
R
R
R
R
X
R
R
R
R
X
B-protecting groups are the most widely adopted strategy
and are compatible with sp, sp2, and sp3 organoborons,1-7
while self-activation/protection is only applicable with sp3
organoborons.1,8,9 Accordingly, chemoselectivity within
systems containing more than one aryl organoboron
compound is currently only achievable by employing a suitable
protecting group strategy. Based on the broadly similar
c) This work: chemoselective oxidation via selective boronate formation/phase transfer
B(OH)2
BPin
OH
BPin
oxidant, base
R1
Boronic acid oxidation
BPin OH
R1
R2
R2
speciation controlled
phase transfer
BPin
BMIDA
oxidant, base
R1
R2
R1
R2
speciation controlled
phase transfer
BMIDA oxidation
Inverted chemoselectivity
= more reactive
Scheme 1. Chemoselective reactions of diboron systems.
Here, we establish a new method for achieving chem-
oselectivity within systems containing two unprotected aryl
organoboron compounds. Specifically, we show that
chemoselective oxidation of aryl boronic acid/BPin systems
can be achieved by selective boronate phase transfer while
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controlling potential solution speciation processes (Scheme composition and temperature (see ESI) revealed that
1c). In addition, we show that this approach can formally conversion and chemoselectivity could both be improved using
invert conventional chemoselectivity profiles using established additional H2O at 60 °C (entry 5). A solvent survey revealed
MIDA protecting group chemistry. Spectroscopic investigations CPME as the optimum organic phase that allowed quantitative
of the biphasic reactions provide insight into the mechanism oxidation of the boronic acid and with very high levels of
by which chemoselectivity is achieved and how this may be chemoselectivity at 70 °C under basic biphasic reaction
predicted a priori.
conditions (entry 6 – a range of solvents was evaluated, see
ESI).16
Results and discussion
To probe chemoselectivity in systems containing two non-
protected aryl organoboron compounds we selected a
workhorse reaction. The Brown oxidation of an organoboron
compound to the corresponding alcohol or phenol is a
fundamental method within the synthetic organic chemistry
toolbox.11,14 Boronic acids and esters are typically rapidly and
indiscriminately oxidized and, consequently, chemoselective
oxidation of a system containing two reactive organoboron
compounds is unknown.
In the general sense, small differences in reactivity of
boronic acids and esters have been observed, albeit in non-
competitive systems.15 Accordingly, to initiate this study, we
examined the oxidation of naphthyl boronic acid 1a and BPin
ester 1b under a variety of reaction conditions.‡ Common
oxidants such as H2O2, NaBO3, m-CPBA provided an
uncontrollable oxidation from which no useful rate
discrimination was observed (a range of oxidants and reaction
conditions were surveyed, see ESI). However, milder oxidants
were useful and, in particular, a small rate difference favoring
a more rapid oxidation of 1a was found using Oxone® under
Chart 1. Oxidation of 1a and 1b using Oxone® under biphasic
reaction conditions (THF/H2O) over 30 min at 350 rpm (vide
infra). Determined by HPLC using an internal standard, see
ESI.†
Table 1. Chemoselective oxidation of B(OH)2 1a vs. BPin 2b
:
Reaction optimization.
B(OH)2
BPin
OH
OH
Oxone, base, H2O
solvent, temp. (°C), 1 h
Ph
Ph
biphasic reaction conditions (Scheme
2 and Chart 1).
1a, 1 equiv
2b, 1 equiv
1c
2c
Specifically, the oxidation of 1a appeared to show a significant
conversion in the burst phase while the oxidation of 1b
exhibited a more linear profile.
a
Entry
Base
Temp.
(°C)
20
Solvent
Conv. (1c:2c)
1
2
3
4
5
---
THF/H2O (1:1)
THF
95% (1.1:1)
---
20
0%
0%
B(OR)2
OH
Oxone, THF/H2O
rt, 30 min
1a: 98% conv.
1b: 22% conv.
K3PO4
K3PO4
K3PO4
20
THF
20
THF/H2O (1:1)
THF/H2O (1:1.5)
CPME/H2O
(1:1.5)
54% (13.5:1)
81% (18:1)
1c
1a: B(OR)2 = B(OH)2
1b: B(OR)2 = BPin
60
6
K3PO4
70
100% (>99:1)
Scheme 1. Oxidation of 1a and 1b using Oxone®.
a Determined by HPLC analysis using an internal standard. See ESI.
Based on the observed reactivity profiles in the non-
optimized, non-competitive system, we considered it might be
possible to leverage chemoselectivity in the corresponding
mixed system (i.e., containing both a boronic acid and BPin
ester). However, translating these reaction conditions to a
model system consisting of 1a and BPin 2b provided high
conversion but with only trace levels of chemoselectivity
(Table 1, entry 1).
Determination of the origin of chemoselectivity
Basic biphasic reaction conditions allow chemoselective
oxidation of boronic acid 1a over BPin 2b. While a small
difference in rate using 1a and 1b was observed in the non-
competitive system (Chart 1), oxidation was non-selective in
the equivalent mixed organoboron system (Table 1, entry 1),
suggesting that kinetic discrimination based on reactivities of
the organoboron reagents with the oxidant was not the origin
of the observed selectivity.
In a purely organic medium (THF), no conversion was
observed either in the absence or presence of base (entries 2
and 3 – a range of bases was evaluated, see ESI), likely due to
the poor solubility of Oxone®.16 However, upon addition of
K3PO4 to the original biphasic system (i.e., entry 1), we
immediately noted moderate conversion, now with significant
levels of chemoselectivity for the desired oxidation of 1a (entry
Several other data were notable: (i) Oxone® is poorly
soluble in organic solvents17 and in the absence of H2O, no
reaction was observed (Table 1, entries 2 and 3) suggesting a
phase transfer process; (ii) speciation behavior of 1a and 2b
was observed in similar basic biphasic media resulting in
4).
A systematic evaluation of the reaction medium
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pinacol transfer to produce a mixture of 1a, 1b,
2a, and 2b in more Lewis acidic than boronic acids;23 therefore, selective
approx. 1:1:1:1 ratio (Scheme 3), accordingly, pinacol exchange boronic acid trihydroxyboronate formation must be under
is avoided under the optimized reaction conditions;11-13,18 (iii) kinetic control – this is typically a very rapid (practically
chemoselectivity counter-intuitively increased with increasing barrier-less) process.24 To confirm this hypothesis, we
temperature (Table 1); and (iv) shearing profoundly impacted undertook detailed analysis of the basic biphasic reaction
the chemoselectivity of oxidation with high stirring rates mixture.
resulting in lower chemoselectivity and vice versa. The impact 1. HPLC analysis. The organic and aqueous phases of various
of stirring rate was clearly seen in the change of reaction relevant biphasic mixtures were analyzed by HPLC using a
profile of BPin oxidation where increasing the stirring rate calibrated internal standard to allow quantitative
changed the reaction profile from linear at 350 rpm to determination of phase distribution (Table 2).
exhibiting a burst phase at 900 rpm similar to the oxidation of
1a (Chart 2).19
In the absence of any inorganics, both 1a and 2b were
confined to the organic phase (entry 1). However, addition of
K3PO4 immediately distorted this distribution, with ca. 1:1
distribution of 1a in each phase but with no effect on the
distribution of 2b (entry 2). The concentration of 1a in the
aqueous phase increased with temperature, reaching ca. 70%
at the optimum reaction temperature of 70 °C, with the
distribution of 2b again remaining unchanged throughout
(entries 2-4). Addition of Oxone®-relevant inorganics (without
the active oxidant, KHSO5)25 had no effect on the distribution
of either 1a or 2b at any temperature, with similar results to
that observed in the absence of any inorganics (entries 5-7 vs.
entry 1). In the presence of K3PO4, KHSO4, and K2SO4, 1a was
once again observed to distribute in both phases, up to ca. 1:1
at 70 °C, while 2b remained confined to the organic phase,
even at elevated temperatures (entries 8-10). The lower
concentration of 1a in the aqueous phase in the presence of all
inorganics may be attributable to buffering. Lastly, no
speciation behavior (i.e., diol transfer, see Scheme 3) was
observed throughout. However, it should be noted that
speciation (diol transfer) was observed when mixtures of 1a
and 2a were left for extended time periods at elevated
temperatures.
K3PO4, THF,
BPin
B(OH)2
B(OH)2
BPin
H2O, 50 °C, 1 h
Ph
Ph
1a
2b
1b
2a
55%
46%
45%
54%
Scheme 3. Speciation equilibria of 1a and 2b in a basic biphasic
medium.
Chart 2. Oxidation of 1b to 1c using Oxone® under biphasic
reaction conditions (THF/H2O) over 30 min at 350 and 900
rpm. Determined by HPLC using an internal standard, see ESI.†
Table 2. Phase distribution of 1a and 2b in the presence of
relevant inorganics and with temperature variation.
BPin
B(OH)2
K2SO4, KHSO4, K3PO4
biphasic mixture of
In relation to speciation (Scheme 3), full equilibration was
1a and 2b
H2O, CPME, temp. (°C)
Ph
observed to occur in ca. 1 h. Since the oxidation reaction also
1a, 1 equiv
2b, 1 equiv
proceeds to completion in
1
h, we surmise that
Entry
Inorganics
Temp. (°C)
Organic:Aqueous (%)a
chemoselectivity is aided by Le Chateliers’s principle, i.e.,
consumption of 1a via oxidation inhibits diol exhchange and
enforces high levels of chemoselectivity.
1a
2b
1
2
3
4
5
6
7
---
20, 50, 70
>99:1
54:46
46:54
29:71
>99:1
>99:1
98:2
>99:1
>99:1
96:4
K3PO4
20
50
70
20
50
70
Based on all of the above, we suspected that oxidation was
taking place via a phase transfer process where boronic acid
was selectively transported to and oxidized in the aqueous
phase with the equivalent process for BPin ester much slower
in comparison.
K3PO4
K3PO4
98:2
KHSO4, K2SO4
KHSO4, K2SO4
KHSO4, K2SO4
K3PO4, KHSO4,
K2SO4
>99:1
>99:1
>99:1
Hall has shown that various polyols can be used to
stoichiometrically transfer boronic acids to an aqueous phase
as their boronate derivatives to allow purification by phase
8
9
20
50
70
67:33
59:41
54:46
>99:1
>99:1
>99:1
K3PO4, KHSO4,
K2SO4
separation20 as well as providing
a
method for
bioconjugation.21 No such phase-transfer catalyst was
employed in the present oxidation; however, boronates are
considerably more soluble in aqueous media than organic,10
suggesting chemoselective boronate formation could be taking
place (boronic acid over BPin)22 while avoiding speciation
processes in the basic biphasic medium. Boronic esters are
K3PO4, KHSO4,
10
K2SO4
a Determined by HPLC analysis using an internal standard. See ESI.
2. NMR analysis. While HPLC analysis allowed quantification of
1a and 2b in each phase, determination of speciation (neutral
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and charged species) was not possible; i.e., whether 1a/
2b Hydroxyboronates 1d and 2e are distinguishable by 11B NMR
existed as the neutral boronic acid/ester species or their (see ESI) and the assignment of the observed 11B NMR signal at
cognate hydroxyboronates in the aqueous phase and the 3.7 ppm was attributed to 1d. However, it is conceivable that
relationship, if any, between these in the presence of the in situ hydrolysis of 2b could occur to deliver 2a and ultimately
added inorganics. A complementary analysis was therefore its trihydroxyboronate derivative (2d), which has a similar 11B
conducted using a series of biphasic NMR experiments in NMR resonance to 1d (3.6 ppm, see ESI). The 2d signal may be
which a single phase could be observed in isolation (see ESI for obscured by 1d, preventing detection at low concentration. To
full details).
ensure a robust assignment, we analyzed two mono-
Initial control experiments were informative and provided fluorinated diboron systems by 11B and 19F NMR analysis
further
empirical
evidence
to
support
selective (Scheme 5).
while
K
K
hydroxyboronate
formation.
Specifically,
B(OH)2
BPin
B(OH)3
BPin(OH)
trihydroxyboronate 1d could be formed using aq. K3PO4, BPin
hydroxyboronate 2e was not observed under similar
conditions. Indeed, 2e was only observed upon treatment with
aq. KOH, which also led to extensive hydrolysis,26 generating
the corresponding boronic acid 2a and, consequently, its
trihydroxyboronate derivative. This supported the hypothesis
that under the reaction conditions, boronic acid
trihydroxyboronates may be formed selectively, thereby
allowing selective phase transport and subsequent
chemoselective oxidation.
F
F
F
F
3a
3b
11B NMR: 30.5 ppm
19F NMR: -108.5 ppm 19F NMR: -118.7 ppm 19F NMR: -119.1 ppm
3d
3e
11B NMR: 29.0 ppm
19F NMR: -105.8 ppm
11B NMR: 3.5 ppm
11B NMR: 6.2 ppm
(a) 11B NMR analysis of biphasic mixture containing 1a and 3b
BPin
B(OH)2
aqueous phase
11B NMR: 3.7 ppm
19F NMR: no signal
K2SO4, KHSO4, K3PO4
CPME, D2O, 70 °C
F
1a, 1 equiv
3b, 1 equiv
(b) 11B NMR analysis of biphasic mixture containing 1b and 3a
11B NMR analysis of the aqueous phase of the biphasic
monoboron system containing 1a and relevant inorganics
(again without KHSO5) showed the presence of a single boron
B(OH)2
BPin
aqueous phase
11B NMR: 3.6 ppm
19F NMR: -118.6 ppm
K2SO4, KHSO4, K3PO4
CPME, D2O, 70 °C
F
1b, 1 equiv
3a, 1 equiv
species with a resonance at 3.7 ppm, consistent with Scheme 5. 11B and 19F NMR analysis of mono-fluorinated
trihydroxyboronate 1d (Scheme 4a) while no signal was diboron systems under representative biphasic conditions.
detected in the aqueous phase for the equivalent experiment
using only 2b (Scheme 4b). Analysis of the corresponding
11B and 19F NMR analysis of the aqueous phase of the
model system containing both 1a and 2b revealed a single system containing 1a and 3b revealed a single 11B NMR signal
signal in the aqueous phase at 3.7 ppm, consistent with 1d at 3.7 ppm, consistent with 1d; no 19F NMR signals were
(Scheme 4c). This analysis agreed with the HPLC data (Table 2) detected (Scheme 5a). Conversely, analysis of the mixture of
and also supported selective phase transport of 1a to the 1b and 3a showed one 11B NMR signal at 3.6 ppm and one 19
aqueous phase as its trihydroxyboronate derivative, 1d 27
No NMR signal at -118.6 ppm, both of which were consistent with
charged species (1d or 2e) or anhydride formation were trihydroxyboronate 3d (Scheme 5b). Thus, these experiments
observed in a complementary analysis of the organic phase – support the hypothesis of selective boronic acid
F
.
a
only the neutral species (1a and 2b) were observed.
trihydroxyboronate formation and that diol transfer is
inhibited.
K
K
BPin
BPin(OH)
B(OH)2
B(OH)3
Temporal profiling of the aqueous phase via variable
temperature NMR provided further data to assist in explaining
the observed trends (Figure 1 – for temperature/temporal
profiling of all systems, see ESI). Consistent with the HPLC
analysis (Table 2), variable temperature 11B NMR revealed that
Ph
Ph
1a
11B NMR: 29.7 ppm
1d
11B NMR: 3.7 ppm
2b
11B NMR: 31.0 ppm
2e
11B NMR: 6.0 ppm
(a) 11B NMR analysis of biphasic mixture containing 1a
[
1d] increased with temperature, with no detectable increase
B(OH)2
aqueous phase
11B NMR: 3.7 ppm
K2SO4, KHSO4, K3PO4
in [1a], [2b] or [2e].28
[1d] also increased over time (see ESI).
CPME or CDCl3
D2O, 70 °C
This combined HPLC and NMR data set assists with the
interpretation of the non-intuitive temperature-proportional
increase in chemoselectivity.29
1a
(b) 11B NMR analysis of biphasic mixture containing 2b
BPin
K2SO4, KHSO4, K3PO4
aqueous phase
11B NMR: no signal
The rate of oxidation was found to be rapid in the burst
phase (see Chart 1 and ESI). Therefore, the rate determining
process for oxidation under the developed biphasic reaction
conditions appears to be phase transfer of the organoboron
species to the aqueous phase, which is assisted by
trihydroxyboronate formation. Since oxidation occurs
exclusively in the aqueous phase and BPin hydroxyboronate
formation was not observed under the reaction conditions,
chemoselective oxidation is achieved since boronic acid phase
CPME or CDCl3
D2O, 70 °C
Ph
2b
(c) 11B NMR analysis of biphasic mixture containing 1a and 2b
BPin
B(OH)2
aqueous phase
11B NMR: 3.7 ppm
K2SO4, KHSO4, K3PO4
CPME, D2O, 70 °C
Ph
1a, 1 equiv
2b, 1 equiv
Scheme 4. 11B NMR analysis of mono- and diboron systems of
1a and 2b under representative biphasic conditions.
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transfer is significantly more favorable than BPin transfer
(Scheme 6).
3.7 ppm (1d)
1a or 2b
2e not observed
not observed
–
3.1 ppm (B(OH)4
)
3.2 ppm (1d)
–
2.5 ppm (B(OH)4
)
–
2.0 ppm (B(OH)4
)
Figure 1. Temperature- and time-proportional concentration
of 1d in the aqueous phase by 11B NMR analysis.
organic phase
aqueous phase
OH
B
2–
OH
B(OH)2
OH
OH
HO– (fast)
SO5
1c
1a
observed
(HPLC, NMR)
1d
observed
(HPLC, NMR)
OH
B
OH
BPin
O
O
HO– (slow)
2–
SO5
Ph
2c
Ph
2b
observed
(HPLC, NMR)
Ph
2e
not observed
(HPLC, NMR)
Scheme 6. Spectroscopically observed organoboron species.
Scheme 7. Chemoselective oxidation of aryl diboron system:
B(OH)2 vs. BPin substrate scope. Ratio given for oxidation of
Interestingly, in the absence of the active oxidant (KHSO5),
protodeboronation was observed to increase proportionally
Xa:Xb. Determined by HPLC, see ESI.
with both time and temperature giving the expected product
– 30,31
B(OH)4 .
In the oxidative system this was not particularly
The biphasic reaction conditions were found to be general
problematic, since the rate of oxidation was rapid. However,
this has clear implications for transition metal catalysis using
organoboron species under basic biphasic reaction conditions
(e.g., Suzuki-Miyaura cross-coupling) in which transmetallation
proceeds via the neutral organoboron species15 and must
engage a presumably largely organic phase-bound catalyst.
Lastly, formation of trihydroxyboronate from the boronic
acid or hydroxyboronate from the BPin ester requires access to
HO–. Boronic acids have typically greater aqueous solubility
than the corresponding BPin.11 cLogP calculations (see ESI)
indeed indicate greater aqueous solubility for boronic acids vs.
BPins and this was also found for the corresponding boronate
adducts. For example, boronic acid 1a has cLogP = 2.64 while
BPin 1b has cLogP = 5.58. The corresponding boronates display
the same trend with 1d cLogP = 0.50 and 1e cLogP = 3.44.
Accordingly, since no charged species were observed in the
organic phase, we believe that selective ionization of the
boronic acid occurs either at the organic/aqueous interface or
in the aqueous phase following transfer of the neutral species
due to its comparatively greater solubility.
across a wide variety of aryl boronic acid and BPin ester
reaction partners. Conversion to products over a 1 h reaction
time were generally high and the chemoselectivity for boronic
acid oxidation was typically >20:1 and exclusively selective
(>99:1) in many cases, regardless of functionality or
regiochemistry and whether boronic acid or BPin (e.g., 3a
vs. 3b 8b). Alkenyl boronic acids were less effective substrates,
giving mixtures of products.
-8a
-
With a framework for chemoselective oxidation of reactive
diboron systems established, we sought to explore whether
this biphasic protocol could challenge conventional reactivity
profiles. BPin esters are typically readily oxidized in the
presence of BMIDA esters.13d However, we reasoned that it
might be possible to reverse this profile and selectively oxidize
the BMIDA component of a BMIDA/BPin aryl diboron system
via speciation-controlled hydrolysis of the BMIDA32 and
oxidation of the latent boronic acid (Scheme 8).
In the event, heating the reaction mixture to 80 °C for 15
min in the absence of Oxone® provided a smooth hydrolysis,
which avoided any diol equilibration, and returning to 70 °C
before addition of the oxidant allowed chemoselective
oxidation of ArBMIDA in the presence of ArBPin (Scheme 9).
Generality of the chemoselective oxidation process
With effective reaction conditions for this model system, the
generality of the chemoselective oxidation was explored
(Scheme 7).
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B(OH)2
BPin
BPin
BPin
BMIDA
B(OH)2
OH
BMIDA
oxidant
oxidant
R1
R2
R1
R2
HO
HO
BMIDA
22a
1%
22b
3%
K3PO4 (3 equiv), CPME
H2O (5 equiv), 80 °C;
BPin oxidation
established chemoselectivity
HO
Oxone (2.5 equiv)
70 °C, 1 h
PinB
OH
BPin
BPin
OH
27
R1
R2
R1
R2
HO
PinB
22c
5%
28
43%
formal BMIDA oxidation
inverted chemoselectivity
Scheme 10. Attempted chemoselective oxidation of diboron
compound 27. Determined by HPLC, see ESI.
Scheme 8. Inverting established chemoselectivity: oxidation of
BMIDA in the presence of BPin.
Chemoselective oxidation of diboronic acid systems
K3PO4 (3 equiv), CPME
H2O (5 equiv), 80 °C;
OH
OH
BPin
BMIDA
R1
R2
R1
R2
Chemoselectivity in this system has been driven by
Oxone (2.5 equiv)
70 °C, 1 h
Xb
Xf
competing
boronate
formation
between
dissimilar
BPin oxidation
BMIDA oxidation
organoboron compounds (B(OH)2 vs. BPin). However, the
formation of aryl boronates, and therefore aqueous solubility,
is heavily influenced by the electronics of the aryl unit.19
Specifically, substitution on the aryl unit will influence the
Lewis acidity of the boronic acid and can heavily influence the
aqueous solubility. Based on this, we reasoned that
chemoselective discrimination within a system containing two
boronic acids might be achievable by exploiting electronic
effects to drive competitive boronate formation and
subsequent selective phase transfer. The relative
chemoselectivity might then be gauged a priori by assessing
the phase separation by HPLC or NMR. This proved to be
feasible and was initially evaluated using several electronically
distinct phenylboronic acids vs. 2-naphthyl boronic acid 1a
(Scheme 11).
2-naphthyl (1f) BMIDA vs.:
BPin
BPin
BPin
BPin
S
MeO2C
MeO
5b: 82%, >99:1
BPin
4b: 56%, >99:1
BPin
7b: 85%, 4:1
18b: 83%, 6:1
BPin
BPin
Me
HO
22b: 67%, >99:1
Cl
MeO
N
Me
21b: 63%, >99:1
23b: 87%, >99:1
24b: 69%, 9:1
4-biphenyl BPin (2b) vs.:
BMIDA
BMIDA
BMIDA
BMIDA
N
F
Me
H
3f: 72%, >99:1
4f: 58%, 58:1
8f: 55%, >99:1
9f: 84%, 84:1
BMIDA
BMIDA
O
BMIDA
BMIDA
O
HO
Br
Me
Me
13f: 76%, 25:1
22f: 50%, 50:1
25f: quant., >99:1
26f: 71%, 24:1
B(OH)2
B(OH)2
OH
OH
Oxone
Scheme 9. Chemoselective oxidation of aryl diboron system:
BMIDA vs. BPin substrate scope. Ratio given for oxidation of
K3PO4, H2O
CPME, 70 °C
R
R
Xa
1a
Xc
1c
Xf
:Xb. Determined by HPLC, see ESI.
R
H
F
MeO
O2N
MeO2C
Once more, the efficiencies and selectivities of the process
5
4
3
29
7
Org/Aq
Selectivity
(Xc/1c)
0/100
4:1 (5c:1c)
5/95
20/80
11/14
9/91
were typically excellent, with some diminished selectivity
observed using specific heterocyclic derivatives (e.g., 18b
6.5:1 (4c:1c)
8:1 (3c:1c)
4.5:1 (31c:1c)
3:1 (7c:1c)
,
24b). Addition of Oxone® after the hydrolysis event was
necessary to avoid buffering of the basic medium. This
buffering effect impeded the rate of hydrolysis providing
sufficient time for equilibration and ultimately diminishing the
chemoselectivity of the process.
Scheme 11. Phase distribution and chemoselective oxidation
of electronically distinct aryl boronic acids vs. 1a. Determined
by HPLC, see ESI.
Under representative reaction conditions in the absence of
This BMIDA oxidation process provided the opportunity to
further confirm the hypothesis of the requirement to
physically separate the two boron residues in order to achieve
chemoselectivity. Diboron compound 27 (where both boron
residues were located on the same aryl unit) was a very poor
substrate that, under optimized conditions, delivered a
mixture of the desired phenol 22b as well as 22a (the product
of BPin oxidation and BMIDA hydrolysis), 22c (the product of
global oxidation), but mainly 28 (the product of equilibration)
(Scheme 10).32
oxidant, phenylboronic acids 3a, 4a, 5a, and 7a were found to
preferentially distribute to the aqueous phase while 1a
remained comparatively more organic phase-bound (1a
Org/Aq average = 71/29). This translated to chemoselective
oxidation of the phenyl boronic acid species over 1a in all
cases. In the case of the strongly electron-deficient boronic
acid 29a, protodeboronation occurred rapidly and phase
distribution was less reliable as an indicator of selectivity.
While the measured phase distribution allowed prediction of
the favored oxidation, the exact ratio of oxidation products
could not be extrapolated from this analysis. This phenomenon
was also found to be transferable across a range of substrates
(Table 3).
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Table 3. Chemoselective oxidation of aryl boronic acids.
B(OH)2
provides a novel and step-efficient synthesis of valuable
chemotypes from readily accessible precursors.
B(OH)2
Oxone (2.5 equiv)
OH
OH
R1
R2
R1
R2
K3PO4 (3 equiv), H2O
CPME, 70 °C, 30 min
Entry
R1B(OH)2
R2B(OH)2
Conv.a
Oxidation
(R1:R2)a,b
Conclusions
In conclusion, chemoselective oxidation of boronic
acid/BPin systems can be readily achieved in a basic biphasic
reaction medium. Conventional protecting group strategies
can be overturned to allow oxidation of BMIDA compounds in
the presence of a normally more reactive BPin species.
Spectroscopic investigations revealed that chemoselectivity is
derived from a selective boronate formation and phase
transfer of boronic acids to the aqueous phase. We have also
shown that it is possible to chemoselectively oxidize a mixture
of two boronic acids and predict the outcome of the reaction a
priori by HPLC analysis of the phase distribution of the reacting
partners. Lastly, the concept of chemoselectivity via medium
control enabled the development of a chemoselective
oxidative nucleophile coupling. The data in this study has
significant ramifications for enabling chemoselectivity in non-
protected organoboron systems as well as for the
understanding of catalytic reactions of organoboron
compounds in biphasic media.
O
O
B(OH)2
B(OH)2
1
2
3
4
86%
62%
71%
85%
42%
4:1
3:1
3:1
2:1
2:1
30a
1a
B(OH)2
B(OH)2
1a
N
N
N
N
OMe 14a
B(OH)2
O
B(OH)2
i-Pr
26a
B(OH)2
OMe 14a
B(OH)2
31a
1a
B(OH)2
B(OH)2
5
OMe 14a
Br
25a
a
b
Determined by HPLC analysis using an internal standard. See ESI.
Ratio given for oxidation of R1-B(OH)2: R2-B(OH)2.
The efficiencies and chemoselectivities of the process were
not as pronounced as more substantially differentiated
diboron systems (e.g., B(OH)2 vs. BPin in the studies above);
however, this represents the first chemoselective oxidation of
two ostensibly equivalent boronic acid species based on subtle
differences in the substitution of the pendant aryl unit.33,34
Acknowledgements
Chemoselective oxidative nucleophile coupling
The research leading to these results has received funding
from the European Research Council under the European
Union's Seventh Framework Programme (FP7/2007-2013)/ERC
grant agreement no. [340163]. This work was supported by the
EPSRC. We thank the EPSRC and GlaxoSmithKline (GSK) for PhD
studentships (JJM and TAC), the EPSRC UK National Mass
Spectrometry Facility at Swansea University for analyses, and
Dr Vipul K. Patel and GlaxoSmithKline for financial support and
chemical resources.
The medium-controlled chemoselective reaction manifold
can potentially be leveraged to provide a number of enabling
synthetic methods. As a demonstration, we have developed a
chemoselective oxidative nucleophile coupling (Scheme 12).
BPin i) Oxone, K3PO4, H2O, CPME, 70 °C
ii) Cu(OAc)2, Et3N, MeCN, EtOH, 80 °C
O
B(OH)2
R1
R2
R1
R2
Chemoselective oxidative
nucleophile coupling
O
O
O
O
MeO2C
CF3
Ph
Notes and references
32, 82%
33, 73%
34, 64%
‡ The following numbering key has been used throughout:
=
=
been fitted.
–
Me
OMe
O
R(BOH)2 = Xa; RBPin = Xb; ROH = Xc; RB(OH)3
Xd; RBPin(OH)–
Xe; RBMIDA = Xf. † Line added as a visual aid – no function has
MeO
O
O
MeO
O
OCF3
F
OMe
Abbreviations. CPME, cyclopentyl methyl ether; DAN,
liquid
chromatography; MIDA, N-methyliminodiacetic acid/ N-
methyliminodiacetate; NMR, nuclear magnetic resonance; Pin,
pinacolato; rt, room temperature.
35, 73%
36, 36%
37, 61%
diaminonaphthalene;
HPLC,
high
performance
Scheme 12. Chemoselective oxidative nucleophile coupling.
Following chemoselective oxidation, a Chan-Evans-Lam
etherification35,36 of the generated phenol with the remaining
BPin can be effected. This process proceeds with high
efficiency for the desired cross-coupled product with minimal
homo-coupling detected. Biaryl ethers are prominent scaffolds
in natural products, pharmaceuticals, agrochemicals, and
1
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Modern catalysis methods, such as Ir-catalyzed C-H
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borylated arenes with substitution patterns that are not
readily accessible by other methods. As such, this
chemoselective oxidative nucleophile coupling process
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Journal Name
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