Mild and selective synthesis of an aryl boronic ester by equilibration of mixtures of boronic and borinic acid derivatives

Article abstract of DOI:10.1021/op800169s

Quenching of aryl Grignard reagents with 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (isopropyl pinacol borate) under noncryogenic conditions can lead to mixtures of the corresponding boronic ester along with, generally undesired, borinic acid derivatives. We have found that in certain cases gentle heating of the crude reaction mixtures leads to complete equilibration to give the borinic esters as the sole product which can then be isolated in high yield. This novel equilibration can reduce the need for use of cryogenic conditions or large excesses of reagents to obtain selectivity during boronic ester syntheses.

Full text of DOI:10.1021/op800169s

Organic Process Research & Development 2008, 12, 1265–1268
Communications to the Editor
Mild and Selective Synthesis of an Aryl Boronic Ester by Equilibration of Mixtures of
Boronic and Borinic Acid Derivatives
Vanessa F. Hawkins, Mark C. Wilkinson, and Matthew Whiting*
Synthetic Chemistry, Chemical DeVelopment, GlaxoSmithKline, Gunnels Wood Road, SteVenage, Hertfordshire SG1 2NY, U.K.
Abstract:
those involving electron-rich aryl groups, the borinic acid is
often still formed in significant quantities irrespective of the
reaction conditions used.6 We have found that in certain cases
mixtures of boronic and borinic acid derivatives formed under
relatively mild reaction conditions can be readily equilibrated
to give solely the boronic ester with high selectivity.
Quenching of aryl Grignard reagents with 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (isopropyl pinacol borate) under
noncryogenic conditions can lead to mixtures of the corresponding
boronic ester along with, generally undesired, borinic acid deriva-
tives. We have found that in certain cases gentle heating of the
crude reaction mixtures leads to complete equilibration to give
the borinic esters as the sole product which can then be isolated
in high yield. This novel equilibration can reduce the need for use
of cryogenic conditions or large excesses of reagents to obtain
selectivity during boronic ester syntheses.
Results and Discussion
On a small scale, selective formation of the desired boronic
ester 1 was readily accomplished in high yield by iodine
magnesium exchange of iodide 2 using i-PrMgCl in THF at
-10 °C followed by addition of isopropyl pinacol borate (3)
(Scheme 1). After warming to room temperature overnight and
Introduction
Scheme 1. Equilibration of mixtures of boronic and borinic
acid derivatives
As part of a synthetic programme a convenient procedure
was required for the synthesis of pinacol boronic ester 1 on
multikilogram (multi-kg) scale.
Aryl boronic acids and esters1 have become ubiquitous in
synthetic chemistry in both industrial and academic settings,
predominantly due to their straightforward use in a wide range
of transition metal-catalysed coupling reactions.2 The most
common way to access these compounds is by the electrophilic
trapping of aryl metal species (generally the aryllithium or
Grignard reagent) with a borate ester. Unfortunately this reaction
often leads to borinic acid and borane byproducts which arise
from second and third additions of the aryl metal reagent into
the borate ester. Several options are available to minimise
formation of these generally undesired byproducts, most notably
use of cryogenic conditions,3 in situ quenching protocols,4 and/
or large excesses of hindered alkyl borate esters3 such as
triisopropyl borate or isopropyl pinacol borate. Whilst the
necessity for use of such conditions does not prevent the reac-
tions from being carried out on large scale, use of more ambient
temperatures and only stoichiometric amounts of the borate
esters is highly desirable from a process efficiency and oper-
ability point of view.5 Also, in a number of cases, particularly
* Author for correspondence. E-mail: matthew.p.whiting@gsk.com.
(1) For leading references see: (a) Hall, D. G. Boronic Acids; Wiley: New
York, 2005.
(2) For leading references see: (a) De-Meijere, A.; Diederich, F. Metal
Catalyzed Cross Coupling Reactions; Wiley; New York, 2004.
(3) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316–1319.
(4) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen,
R. D.; Reider, P. J. Org. Chem. 2002, 67, 5394–5397.
(5) Gadamasetti, K. G. Process Chemistry in the Pharmaceutical Industry;
Marcel Dekker: New York, 1999.
aq workup the desired product could be obtained by crystalli-
sation from heptane. Levels of the undesired borinic acid
10.1021/op800169s CCC: $40.75
Published on Web 09/19/2008
2008 American Chemical Society
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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Scheme 2. Pilot-plant scale synthesis of boronate 1
derivatives 4 were shown to be kept to trace amounts either by
very slow addition of 3, maintaining the internal temperature
at -10 °C until complete addition had occurred or, alternatively,
by very rapid addition of the borolane in one portion. Con-
versely if only 0.6 equiv of 3 was added and the reaction
allowed to warm to room temperature, up to 60% of the borinic
acid 4 (R ) H) was formed. This did not look ideal for scale
up as very fast addition was likely to be impossible and very
slow addition is inefficient from a processing perspective.
Interestingly, during our development work we had noticed that
the borinic acid derivatives in the crude reaction mixture slowly
converted to the desired boronate 1 if the reaction mixture was
allowed to stir at room temperature for extended periods of time.
Gentle heating of these reaction mixtures accelerated this
equilibration, and thus, even a reaction mixture containing
artificially high levels of the borinic acid of up to 60% could
be completely equilibrated through to the desired boronic ester
simply by warming the reaction mixture to 50 °C for 1 h. This
observation meant that upon scale up we would be able to carry
out the addition in a relatively uncontrolled fashion and still
obtain high selectivity for the desired product. As far as we are
aware this type of equilibration has not been reported previously;
however, it is not entirely unexpected, as it is known that the
boronic acid derivatives are the thermodynamically more stable
species.1
On scale up to the pilot plant we opted to telescope the
boronate formation onto formation of iodide 2 the isolation of
which was complicated by a voluminous crystal form. Thus
4-chloro-2-iodophenol (5) was alkylated with 4-chloro-2-
fluorobenzyl bromide (6) using K2CO3 in acetone. After
concentration, dilution with toluene, and an aqueous workup
the toluene solution of 2 was dried by azeotropic distillation
before being cooled to -10 °C and treated with i-PrMgCl in
THF to effect iodine-magnesium exchange. The Grignard
reagent obtained was treated with 3 and allowed to warm to
room temperature, giving the desired boronic ester containing
up to 30% of the undesired borinic acid derivatives (Scheme
2). Warming this crude reaction mixture to 50 °C for 1 h
promoted complete equilibration to the desired product 1 which
was isolated by crystallisation from 2-propanol in 78% yield
and >99.9% purity.
upon warming no change in this mixture was observed even
after extended periods at reflux (Table 1, entry 1). Using
p-methoxyphenylmagnesium bromide, a 1:1.2 mixture of
borinic and boronic acid derivatives was formed, and again no
conversion was observed upon heating the reaction mixture
(entry 2). In contrast upon gentle warming of the reaction
mixture derived from o-methoxyphenylmagnesium bromide
rapid equilibration to almost entirely the boronate 8c was
observed (entry 3). In this series of experiments it therefore
appears that the presence of an o-alkoxy group is vital for this
equilibration to proceed.
Table 1. Use of simplified Grignard reagents
Several experiments were run to further probe this interesting
observation. The parent system, using phenyl magnesium
chloride (7a), along with simply substituted derivatives using
both p- and o-methoxy phenylmagnesium bromide (7b and 7c)
were investigated. Solutions of the desired boronates (8a-c)
containing artificially elevated levels of the borinic acid deriva-
tives 9a-c were prepared by addition of 1 equiv of Grignard
reagent to a solution of 0.6 equiv of the borolane at 0 °C. After
stirring for 30 min a further 0.6 equiv of borolane was added,
and the mixtures were then warmed to promote equilibration
to the boronate. The relative amounts of borinic acid and boronic
acid derivatives were monitored by LC/UV analysis using
dimethoxybenzene as an internal standard (Table 1).
product ratio 8:9
entry
Grignard
R
X
initial
final
1
2
3
7a
7b
7c
H
Cl
Br
Br
45:55
55:45
42:58
no conversiona
no conversiona
94:6b
p-OMe
o-OMe
a No conversion even after 16 h at reflux. b Ratio of products after 1.5 h at 50
°C.
We next briefly investigated use of alternative borate esters
(Table 2) in the hope we would be able use a more readily
available derivative in place of the relatively expensive isopropyl
pinacol borate (3).
The mixture of borinic and boronic acid derivatives derived
from isopropyl pinacol borate, as has been seen, readily
equilibrated with gentle warming to give almost exclusively
boronate 9c (Table 2, entry 1). When triisopropyl borate is used
The parent case using phenyl magnesium chloride initially
gave a 1.2:1 mixture of borinic and boronic acid derivatives;
(6) Winkle, D. D.; Schaab, K. M. Org. Process Res. DeV. 2001, 5, 450–
451.
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instead, equilibration did occur; however, it was very slow, and
competitive proto-deboronation occurred (entry 2). When the
simplest borate ester trimethyl borate was used, no equilibration
of the initially formed mixture was observed (entry 3); it thus
appears that the use of isopropyl pinacol borate is a necessity
for efficient equilibration.
Preparation of Pinacol Boronic Ester 1. To a solution of
4-chloro-2-iodophenol (5) (21.5 kg, 84.5 mol) and 4-chloro-2-
fluorobenzyl bromide (6) (18.9 kg, 84.5 mol, 1 equiv) in acetone
(215 L) at 21 °C was added anhydrous 325 grade potassium
carbonate (23.4 kg, 169 mol, 2 equiv). The stirred suspension
was heated at reflux for 1 h. The solution was concentrated to
75 L by atmospheric pressure distillation, and toluene (150 L)
was added before the organic solution was washed with water
(2 × 172 L). Additional toluene (194 L) was added and the
solution concentrated to 172 L by atmospheric pressure
distillation.
Table 2. Use of alternative borate esters
The obtained solution was cooled to -10 °C (causing partial
precipitation of iodide 2) and then treated with isopropylmag-
nesium chloride in THF (47.3 kg, 48.6 L of a 20% w/w solution
in THF, 92.0 mol, 1.09 equiv) at a rate that maintained the
temperature between -5 and -12 °C. During this addition the
SM initially completely redissolved, and towards the end of
the addition the aryl Grignard reagent partially precipitated.
2-Isopropoxy-4,4,5,5-tetramethyldioxaborolane (19.6 kg, 21.5
L, 105 mol, 1.24 equiv) was added, causing the temperature to
rise to ∼10 °C. The reaction mixture was allowed to warm to
21 °C and then was further warmed to 50 °C for 1 h before
being cooled to 21 °C and quenched with 50% saturated NH4Cl
solution (183 L). The aqueous phase was separated, and the
organics were filtered before being washed with water (2 ×
172 L) and then concentrated by distillation at atmospheric
pressure to ∼65 L. IPA (366 L) was added and the solution
concentrated to 129 L by atmospheric pressure distillation and
then cooled to 70 °C before being seeded. The mixture was
held at 70 °C for 1 h, before being further cooled to 0 °C, and
held at that temperature for 1 h. The product was collected by
filtration and the cake washed with cold IPA (130 L at 0 °C).
The damp product was dried overnight in a vacuum oven at 30
°C to furnish 1 as a white solid, 26.3 kg, 78.4%, >99.9% a/a
purity by LC/UV. 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 12
H), 5.08 (s, 2 H), 6.86 (d, J ) 8.8 Hz, 1 H), 7.08 (dd, J ) 9.8,
2.0 Hz, 1 H), 7.17 (dd, J ) 8.3, 1.7 Hz, 1 H), 7.35 (dd, J )
8.8, 2.7 Hz, 1 H), 7.67 (d, J ) 2.7 Hz, 1 H), 7.94 (t, J ) 8.2
Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 24.9, 63.8, 83.8,
113.3, 115.6 (d, J ) 24 Hz), 123.3 (d, J ) 13 Hz), 124.3 (d, J
) 3 Hz), 126.2, 130.0 (d, J ) 5 Hz), 132.2, 133.9 (d, J ) 10
Hz), 136.4, 159.4 (d, J ) 247 Hz), 161.3. HRMS (EI+)
calculated for C13H9O35Cl2F (MH+ - BC6H12O2) 270.0014;
found 270.0003. Anal. Calcd for C19H20BCl2FO3: C, 57.36; H,
5.07; B, 2.97; Cl, 17.26; F, 3.36. Found: C, 57.42; H, 4.98; B,
3.01; Cl, 17.49; F, 3.11.
a Ratio of products after 1.5 h at 50 °C. b Ratio of products after 30 h at reflux,
under these conditions approximately 20% of the proto-deboronated product was
also observed. c No conversion observed even after 16 h at reflux.
In summary we have shown that in certain cases reaction
mixtures containing both borinic and boronic acid derivatives,
obtained by the quenching of aryl Grignard reagents with
isopropyl pinacol borate, undergo equilibration upon gentle
warming to give only the boronic ester with high selectivity.
This observation enables the selective synthesis of certain
boronic esters under milder conditions than previously realisable,
thus facilitating reaction scale up. We have demonstrated this
process on multi-kg scale by the successful synthesis of pinacol
boronic ester 1 and expect it to be applicable to the synthesis
of a range of other building blocks in the pharmaceutical and
fine chemicals industries.
Experimental Section
Reagents and solvents were purchased from commercial
sources and were used as received. 1H NMR spectra were
recorded at 400 MHz. Data are presented as follows:
chemical shift (ppm), multiplicity (s ) singlet, d )
doublet, t) triplet, q ) quartet, quin ) quintet, sep )
septet, m ) multiplet, b ) broad), coupling constant, J
(Hz) and integration. 13C NMR spectra were recorded at
100 MHz. Data for 13C NMR are reported in terms of
chemical shifts (ppm), and multiplicity (as above) followed
by coupling constant (Hz) for fluorine-containing com-
pounds. High-resolution mass spectra (HRMS) were re-
corded by the Chemical Development Analytical Sciences
department at GSK, Stevenage. Elemental analysis was
carried out at Butterworth Laboratories Ltd., Teddington.
Preparation of Borinic Acid 4 (R ) H). An authentic
sample of 4 (R ) H) was isolated by preparative chromatog-
raphy from a mixture of the boronate and borinic acid: A
solution of iodide 2 (5 g, 12.6 mmol, 1 equiv) in toluene 40
mL was cooled to -10 °C before being treated with a 2 M
solution of isopropylmagnesium chloride in THF (6.9 mL, 13.8
mmol, 1.1 equiv) at a rate that maintained the temperature below
-3 °C. The reaction was allowed to warm to 0 °C before being
treated with 2-isopropoxy-4,4,5,5-tetramethyldioxaborolane (1.55
mL, 7.6 mmol, 0.6 equiv) and then being allowed to warm
further to room temp. After 10 min at room temp the reaction
was quenched by addition of saturated NH4Cl solution (40 mL).
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The aqueous phase was separated and the organic phase further
washed with water (2 × 40 mL) before being concentrated to
dryness under reduced pressure. The crude product obtained
was dissolved in hot IPA (30 mL) and the solution then cooled
to 0 °C, promoting precipitation of the product. The suspension
was held at 0 °C for 1 h before the solids were collected by
filtration, washing with cold IPA (2 × 15 mL). The damp
product was dried under vacuum at 30 °C overnight to furnish
2.0 g of a white solid shown by LC/UV analysis to be a 2:3
mixture of the borinic acid 4 (R ) H) and the boronate 1. A
small sample of the pure borinic acid 4 (R ) H) (10 mg, 99.1%
a/a purity by LC/UV) for analysis was obtained by preparative
mass directed HPLC. 1H NMR (400 MHz, CDCl3) δ 5.11 (s,
4 H), 6.90 (d, J ) 9.5 Hz, 2 H), 7.05 (dd, J ) 8.2, 1.6 Hz, 2
H), 7.09 (dd, J ) 9.8, 2.0 Hz, 2 H), 7.20 (t, J ) 8.0 Hz, 2 H),
7.33 - 7.36 (m, 4 H), 8.42 (bs, 1 H). 13C NMR (100 MHz,
DMSO-d6) δ 62.9, 113.1, 115.7 (d, J ) 25 Hz), 122.9 (d, J )
14 Hz), 124.3 (d, J ) 4 Hz), 124.6, 129.5, 130.7 (d, J ) 5 Hz),
132.6, 133.1 (d, J ) 11 Hz), 159.5 (d, J ) 249 Hz), 159.7.
HRMS (ESI+) calculated for C36H17O3B35Cl337ClF2Na (MNa)+
590.9861; found 590.9841.
Acknowledgment
We thank Alec Simpson, Gemma Ellison, and Ian Collin
for analytical assistance.
Supporting Information Available
Experimental details and analytical data for the synthesis of
o- and p-methoxyphenylborinic acids; experimental details for
equilibration experiments; details of HPLC methods and reten-
tion times for all described compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Received for review July 21, 2008.
OP800169S
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