Synthesis and crystal structure of 4-amino-3-fluorophenylboronic acid

Article abstract of DOI:10.1016/j.tetlet.2003.08.094

4-Amino-3-fluorophenyl boronic acid has been synthesized from 4-bromo-2-fluoroaniline by protecting the amine group and then carrying out a lithium-bromine exchange, followed by addition of trimethyl borate and then acidic hydrolysis. We obtained a 47% yi

Full text of DOI:10.1016/j.tetlet.2003.08.094

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7719–7722
Synthesis and crystal structure of
4-amino-3-fluorophenylboronic acid
Sasmita Das, Vladimir L. Alexeev, Anjal C. Sharma, Steven J. Geib and Sanford A. Asher*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 4 August 2003; revised 22 August 2003; accepted 26 August 2003
Abstract—4-Amino-3-fluorophenyl boronic acid has been synthesized from 4-bromo-2-fluoroaniline by protecting the amine group
and then carrying out a lithium–bromine exchange, followed by addition of trimethyl borate and then acidic hydrolysis. We
obtained a 47% yield. We also measured the X-ray crystal structure. This derivative has a relatively low boronic acid pKa value
of 7.8 when acetylated or attached to acrylamide hydrogels. It also contains a pendant amine which facilitates attachment to
polymers, for example. We are using this compound to construct glucose sensing materials that operates at the physiological pH
of bodily fluids.
© 2003 Published by Elsevier Ltd.
There is a continuing interest in the synthesis of new
boronic acid derivatives. This interest stems from the
importance of boronic acids in the synthesis of biologi-
cally active compounds, and the use of boronic acids
themselves as pharmaceutical agents. In the area of
synthetic chemistry, boronic acids have been widely
used in Suzuki cross-coupling reactions,1 Petasis reac-
tion,2 asymmetric synthesis of amino acids,3 Diels–
Alder reactions,4 protection of diols,5 selective
reduction of aldehydes,6 carboxylic acid activation,7,8
and as reagents and starting materials in organic
synthesis.9
resolution of sugars.18 In addition, boronic acid deriva-
tives have been widely utilized for carbohydrate sens-
ing.20–38 The use of boronic acids for carbohydrate
sensing was recently reviewed by James and Shinkai.39
We have been using boronic acid derivatives to fabri-
cate novel carbohydrate and glucose sensing photonic
crystal materials.27,28 We have attached boronic acid
derivatives to an acrylamide hydrogel which contains
an embedded array of ꢀ100 nm polystyrene particles
where the spacing is ꢀ200 nm. This array Bragg dif-
fracts light to report on the hydrogel volume. These
carbohydrate and glucose sensing materials are called
intelligent polymerized crystalline colloidal arrays
(IPCCA) and are designed to determine glucose in body
fluids such as in blood and in tear fluid. We have
developed a photonic glucose sensor, which utilizes
phenylboronic acid groups as the glucose recognition
element.28 Glucose binds to two boronate sites to form
crosslinks. These crosslinks cause the hydrogel volume
to shrink, which results in a blue shift of the diffracted
light in proportion to the glucose concentration.
In the field of medicinal chemistry, amino-boronic acids
have been used as boron neutron capture (BNCT)
therapy agents,10 as transduction components in feed-
back controlled drug delivery polymers,11 for the devel-
opment of enzyme inhibitors like protease inhibitors,12
and as antibody mimics for polysaccharides.13,14
Boronic acid derivatives have also been used for carbo-
hydrate affinity chromatography.15,16
The ability of boronic acids to reversibly bind to sugars
has long been recognized.17 For example, boronic acid
derivatives have been polymerized in the presence of
sugars to create imprinted sugar binding sites,18,19
which have been utilized, for example, in the racemic
Our first IPCCA sensors utilized aminophenylboronic
acid which had a pKa bound to the hydrogel of ꢀ8.5.
Since our target is to sense glucose in bodily fluids it
was essential to synthesize a boronic acid derivative
whose pKa was closer to the physiological pH 7.4. The
boronic acid pKa value strongly influences its affinity
for carbohydrate derivatives containing cis diols at any
solution pH. The boronate derivatives show much
higher affinities to carbohydrates than do the boronic
Keywords: 4-amino-3-fluorophenylboronic acid; synthesis; crystal
structure; X-ray diffraction; glucose sensor; polymerized crystalline
colloidal array.
* Corresponding author. E-mail: asher@pitt.edu
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.08.094

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S. Das et al. / Tetrahedron Letters 44 (2003) 7719–7722
acid forms.22,39–41 Thus, for physiological glucose sens-
ing, we require boronic acid derivatives with pKa close
to or below the physiological pH 7.4.
nitrogen atmosphere. 36.2 ml (57.9 mmol) of n-BuLi in
1.6 M of hexane (Aldrich) was added by using a syringe
and syringe pump over 2.5 h while keeping the reaction
mixture at 0°C. The reaction mixture turned dark pur-
ple and finally dark brown. Then 7.5 ml (57.9 mmol) of
trimethylsilyl chloride (TMSCl, Aldrich) was added to
the flask by using a syringe and syringe pump over 1.5
hours. The reaction flask was warmed to room temper-
ature and stirred overnight under nitrogen. The solvent
was removed via vacuum evaporation, and the thick
black residue was vacuum distilled. Four fractions were
collected over a boiling range of 30–70°C, 70–80°C,
80–90°C, and above 90°C. The last two colorless frac-
tions contained 4.5 g of the pure compound A (Scheme
Many attempts have been made to synthesize low pKa
boronic acid ligands. A commonly used expedient to
lower the pKa value of boronic acid derivatives is to
introduce electron-withdrawing groups such as nitro-,
fluoro- or carboxy groups into the aromatic ring.42,43
For instance, p-nitrophenylboronic acid42 has a pKa
value 7.0 according to Singhal et al., but the application
of this derivative for in vivo glucose monitoring is
problematic due to its potential carcinogenicity. 4-Car-
boxyphenylboronic acid has a pKa value of 7.86 in the
form of methylamide derivative.44 Unfortunately, this
derivative is insufficiently soluble in water (5 mM of
4-carboxybenzeneboronic acid forms cloudy suspension
in water).44 Fluoro-containing boronic acid derivatives
have lower pKa values, such as 7.2 for [3,5-bis(trifl-
uromethyl)phenyl]boronic acid.45 Unfortunately, this
derivative does not have a functional group to couple
to a polymer matrix.
1
1), yield 47%. H NMR (CDCl3): l 7.28 (d, 2H), 6.84
(t, 1H), 0.3 (s, 18H). 13C NMR (CDCl3): l 133, 127,
124, 123, 119, 115, 1.8. MS (EI) m/z calcd for
C12H21BrFNSi2: 334. Found: 335 (M+H).
1.2. (B) Preparation of 4-amino-3-fluorophenylboronic
acid
A 100 ml round-bottomed flask equipped with a stir-
ring bar was flame dried. 4.5 g (13.5 mmol) of com-
pound A was introduced into the flask and was
degassed with six vacuum–nitrogen backfill cycles. 7.5
ml of dry ether (Aldrich) was added to the flask and the
container was cooled to −78°C in a dry ice/acetone
bath. 17.5 ml (29.6 mmol) of tert-butyl lithium (t-BuLi,
1.7 M in pentane, Aldrich) was added to the flask using
a syringe and syringe pump over 0.5 h. The reaction
mixture turned pale yellow. In a separate flame dried
flask, a solution of trimethylborate (B(OMe)3, 5.5 ml,
Aldrich) in 5.8 ml of THF was cooled to −78°C. The
contents of the first flask containing compound A and
t-BuLi (as well as, dry ether washings) were rapidly
transferred into the second flask with a syringe.
This motivated us to synthesize 4-amino-3-fluorophenyl
boronic acid as a low pKa boronic acid derivative,
which contains an amino group for easy coupling to the
carboxyls of hydrolyzed acrylamide hydrogels. Thus,
we, for the first time, synthesized a fluoro derivative of
amino phenyl boronic acid. This species shows a pKa of
7.8 when attached to the hydrogel. In addition, this
fluoro derivative of phenyl boronic acid may also be a
useful starting material for the preparation of drug
candidate molecules and enzyme inhibitors.46
1. Experimental
Anhydrous solvents were used as provided (in sure/seal
bottles) and reactions were performed under a nitrogen
atmosphere. All glassware was flame dried under nitro-
The reaction mixture was stirred for 15–20 min, at
which point it turned orange and a white precipitate
appeared. The flask was slowly warmed to room tem-
perature, at which point 63 ml of 0.1 N HCl was added.
The reaction mixture was stirred overnight, and then
extracted with ether (2×10 ml) and the water layer was
removed. The organic layer was dried over anhydrous
Na2SO4, filtered and evaporated to yield a yellowish oil
which was precipitated in pentane at 0°C to give a light
yellow solid in 1.3 g (45%) yield. The substance is
moisture sensitive and should be stored under a nitro-
1
gen atmosphere prior to use. H and 13C NMR were
collected at 300 and 75 MHz, respectively, in either
CDCl3 or D2O.
1.1. (A) Preparation of trimethylsilyl-protected 4-
bromo-2-fluoroaniline
In
a 250 ml three-necked round-bottomed flask
equipped with stirring bar, 5 g (26.3 mmol) of 4-bromo-
2-fluoro aniline (Acros) was dissolved in approximately
50 ml of dry tetrahydrofuran (THF, Aldrich) under
1
gen atmosphere in a refrigerator. H NMR (D2O): l
7.28 (d, 2H), 6.84 (t, 1H). 13C NMR (D2O): l 153, 150,
Scheme 1. Synthesis of 4-amino-3-fluorophenylboronic acid.

S. Das et al. / Tetrahedron Letters 44 (2003) 7719–7722
7721
137, 130, 120, 117. MS m/z cacld for C9H11BFNO3:
211.00. Found: 211.05 (M+Gly−2H2O). m/z cacld for
C16H21BFNO2: 289.160. Found: 289.165 (pinanediol
derivative).
blood and tear fluid28 at physiologically relevant glu-
cose concentrations.
Acknowledgements
1.3. Crystal structure of 4-amino-3-fluorophenylboronic
acid
We gratefully acknowledge financial support from NIH
grant DK55348.
Crystals of 4-amino-3-fluorophenylboronic acid were
grown from aqueous solution at a temperature of −8°C.
A clear needle-like crystal of 0.29×0.12×0.12 mm3 was
used for data collection. X-Ray diffraction was mea-
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