Synthesis of some para-functionalized phenylboronic acid derivatives

Article abstract of DOI:10.1081/SCC-120006031

Straightforward preparations of para-, carboxy-, hydroxymethyl- and bromo methyl phenylboronic acid derivatives from para-formyl-phenylboronic acid as a common precursor are presented.

Full text of DOI:10.1081/SCC-120006031

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SYNTHESIS OF SOME PARA-FUNCTIONALIZED
PHENYLBORONIC ACID DERIVATIVES
Arnault de Filippis a , Christophe Morin b & Christian Thimon a
a Laboratoire d’Etudes Dynamiques et Structurales de la Sélectivité, (UMR CNRS n° 5616),
Université Joseph Fourier, Grenoble, 38041, France
b Laboratoire d’Etudes Dynamiques et Structurales de la Sélectivité, (UMR CNRS n° 5616),
Université Joseph Fourier, Grenoble, 38041, France
Version of record first published: 20 Aug 2006.
To cite this article: Arnault de Filippis, Christophe Morin & Christian Thimon (2002): SYNTHESIS OF SOME PARA-
FUNCTIONALIZED PHENYLBORONIC ACID DERIVATIVES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:17, 2669-2676
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 17, pp. 2669–2676, 2002
SYNTHESIS OF SOME PARA-
FUNCTIONALIZED PHENYLBORONIC
ACID DERIVATIVES
*
Arnault de Filippis, Christophe Morin,
and Christian Thimon
Laboratoire d’Etudes Dynamiques et Structurales de la
Selectivite, (UMR CNRS nꢀ 5616), Universite Joseph
Fourier, 38041 Grenoble, France
ABSTRACT
Straightforward preparations of para-, carboxy-, hydroxy-
methyl- and bromo methyl phenylboronic acid derivatives
from para-formyl-phenylboronic acid as a common precursor
are presented.
The chemistry of boron neutron capture therapy[1,2] and more generally
the preparation of boronated analogues of biomecules[3] rely on the avail-
ability of suitable boronated building blocks which include phenylboronic
derivatives[4] such as carboxylic acid 1,[5] bromide 2,[6] amine 3[7] or thiol 4.[8]
Illustrating the need for its efficient preparation, 1 has been used in
applications such as chemical resolution,[9] transport of hydrophilic com-
pounds across membranes,[10] sugar-sensing probes,[11] liquid crystals,[12]
*Corresponding author. E-mail: christophe.morin@ujf-grenoble.fr
2669
DOI: 10.1081/SCC-120006031
Copyright & 2002 by Marcel Dekker, Inc.
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2670
DE FILIPPIS, MORIN, AND THIMON
melanoma-seeking agents[13] or boronated polymers;[14] it has also been used
as a traceless linker[15] for solid-phase synthesis or as a component of Ugi
reactions and Suzuki-Miayura cvouplings.[15,16] Unfortunately, to get 1,
Cr-based oxidations of toluene derivatives to carboxylic acids[17] are not
compatible with a carbon–boron bond;[18,19] nevertheless 1 has been
obtained by borylation of 4-carboxyphenyl-tributylstannane[20] or more
straightforwardly by potassium permanganate oxidation of p-tolyl-boronic
acid;[5,21] however we,[22] and others,[23] have met difficulties in reproducibly
achieving literature yields (58–80%),[12,21] which calls for a more reliable
preparation of 1.
In attempts to achieve this, we considered oxidation of other readily
available phenylboronic derivatives, such as vinyl 5[24,25] and aldehyde 6.[26]
While oxidation of the former failed to give 1, we found that upon reaction
with potassium permanganate, 6 did afford 4-carboxy-phenylboronic acid in
preparative yield (90%), no purification being required. Protection of the
boronic acid group of 1 as a boronate (such as a pinacol ester 7[16]) could be
effected quantitatively by azeotropic removal of water in the presence of
pinacol.
Alcohol 8 and its ester derivative 9 are other boronatd building blocks
of interest;[27] they were previously available by metallation/boration
sequences from O-protected bromophenyl derivatives[28] or by hydrolysis[29]
or bromide 2[6] but, given the availability of protected aldehyde 10,[30]
a
more straightforward sequence would appear to be its reductive treatment.
Although catalytic hydrogenation of 10 failed to cleanly provide 9,[31] its
reaction with sodium borohydride in methanol at 4ꢀC was reliably effective,
thus securing a preparative method.
Then, from 9, the preparation of bromide 13[32] was attempted as such
boronated alkylating agents have been used in the preparation of boronated
amino-acid analogues,[33] hypoxia-imaging agents[34] or glycomimetic selec-
tin inhibitors.[35] The procedure we found most convenient was a two-step
one, namely sulfonylation followed by displacement with halide; thus, after
treatment of 9 with mesyl chloride, a moisture of mesylate 11 and chloride
12 was detected; however, as both of them could lead to 1, the crude reac-
tion mixture was then treated with lithium bromide, and this procedure lead
to 13 as the sole product in 88% yield from 9.

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para-FUNCTIONALIZED PHENYLBORONIC ACID
2671
Thus carboxy, hydroxymethyl and bromomethyl para-phenylboronic
acid derivatives 1, 2, 7, 9 and 13 could be derived from a common precursor,
aldehyde 6 which is a readily available compound;[26] noteworthy is the fact
that during the preparation of each of these boronated buiding blocks,
which besides applications in biological chemistry could also be of use of
Suzuki-Miayura couplings, no purification steps were needed.

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2672
DE FILIPPIS, MORIN, AND THIMON
EXPERIMENTAL
4-Carboxyphenylboronic Acid 1
A solution of aldehyde 6[26] (1 g, 6.67 mmol) in aqueous sodium hydro-
xide (5.4 mL of a 2.5 M soln.) was diluted with water (40 mL) before the
addition of a freshly prepared soln. of potassium permanganate (246 mg,
1.56 mmol, 0.23 eq) in water (7.5 mL). This addition was repeated twice at
1 h intervals. After stirring overnight, ehtanol (3 mL) was added and the
mixture stirred at 50ꢀC for 10 min. after cooling and filtration on Celite,
the filtrate was acidified to pH 2.5with 0.5M hydrochloric acid. Filtration
of the precipitate gave pure 1 as a white powder (992 mg, 90%). 1 was
identical (nmr, tlc) to an authentic sample prepared by oxidation of p-tolyl-
boronic acid[5,12] m.p. 229ꢀC; litt; 225ꢀC;[5] 232–234ꢀC.[12] 1H NMR
(300 MHz, D2O) ꢀ: 7.95(m, 2H, H ar); 7.70 (m, 2H, Har). 13C NMR
(50 MHz, CD3OD) ꢀ: 171.65(CO H); 134.80; 129.65(C ar); 132.75(C ).
2
4
2-(40-Carboxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7
To a mixture of 1 (537 mg, 3.24 mmol) and pinacol (383 mg, 3.24 mmol,
1 eq.) were added THF (10 mL) and toluene (10 mL). The mixture was con-
centrated to dryness under reduced pressure and this procedure (solvents
addition/evaporation) was repeated thrice, which afforded pure 7 (802 mg,
100%) as a white powder which did not require further purification. M.p.
224ꢀC; 1H NMR (300 MHz, CDCl3) ꢀ: 8.1 and 7.9 (AA ‘XX’ system,
4H, Japp ¼ 8.3 Hz, Har); 1.36 (s, 12H, CH3); 13C NMR (75MHz, CDCl 3)
0
ꢀ: 171.7 (CO2H); 134.9; 129.3 (CHar); 131.5(C 4 ); 84.4 (C4, C5); 25.0 (CH3).
2-(40-Hydroxymethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 9
To a solution 10 (206 mg; 0.89 mmol) in methanol (1 mL) stirred at
4ꢀC, was added sodium borohydride (34 mg, 0.89 mmol, 1 eq) in two por-
tions within 1 min. The reaction mixture was then stirred for 10 min before
being poured into a pH 7 aqueous buffer solution (3 mL). The solution was
then concentrated to one third and extracted with dichloromethane
(3*2 mL). The combined organic layers were dried (Na2SO4) and solvents
were removed under reduced pressure to obtain 9 (167 mg, 80%) as a white
powder which did not require purification. M.p. 62–64ꢀC; 1H NMR
(300 MHz, CDCl3) ꢀ: 7.75and 7.30 (AA ‘XX’, 4H, Japp ¼ 8.0 Hz, Har);
4.60 (s, 2H, CH2) 3.05(s, 1H, OH); 1.35(s, 12H, CH 3). 13C NMR

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para-FUNCTIONALIZED PHENYLBORONIC ACID
2673
0
(75MHz, CDCl 3) ꢀ: 144.2 (C4); 134.9; 126.1 (CHar); 83.8 (C4 ); 64.8 (CH2);
24.8 (CH3).
2-(40-Formylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 10
To a mixture of a 6[26] (1 g, 6.67 mmol) and pinacol (788 mg,
6.67 mmol, 1 eq.) were added THF (10 mL) and toluene (10 mL). The mix-
ture was concentrated to dryness under reduced pressure and this procedure
(solvent addition/evaporation) was repeated thrice, which afforded pure 10
(1.55 g-100%) as a white power. M.p. 54–56ꢀC; 1H NMR (300 MHz, CDCl3)
ꢀ: 10.05(s, 1H, CHO); 7.95and 7.85(AA ‘XX’ system, 4H, Japp ¼ 8.2 Hz,
HAr); 1.35(s, 12H, CH 3); 13C NMR (75MHz, CDCl 3) ꢀ: 192.7 (C¼O); 138.3
0
(C4 ); 135.4 and 128.9 (CHAr); 84.5(C 4,5); 25.1 (CH3).
2-(40-Bromomethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 13
Under argon, to a stirred solution of 9 (592 mg, 2.53 mmol) in dry
dichloromethane (15mL) at 4 ꢀC, were added triethylamine (530 mL,
3.8 mmol, 1.5eq) and mesyl chloride (235mL, 3 mmol, 1.2 eq). After 1 h
stirring, the solution was washed with water (3*4 mL) and the organic
layer was dried and volatiles were removed under reduced pressure. Dry
acetone (15mL) was then added, followed by lithium bromide (2.2 g,
25.3 mmol, 10 eq) and the solution was refluxed overnight. After cooling,
the acetone was removed under reduced pressure; the residue was taken up
in dichloromethane (15mL) and the mixture was washed with water
(3*4 mL). After drying of the organic layer, evaporation of the volatiles
afforded pure bromide 13 (660 mg, 88%) as a white solid. M.p.: 75–77ꢀC
(litt 79–81ꢀC).[32] 1H NMR identical to Ref. [32]. 13C NMR (75MHz,
0
CDCl3) ꢀ: 140.8 (C4 ); 135.3; 128.4 (CHar); 84.0 (C4-C5); 33.4 (CH2);
25.0 (CH3).
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2674
DE FILIPPIS, MORIN, AND THIMON
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Received in the Netherlands September 13, 2001