Boronated thiophenols: A preparation of 4-mercaptophenylboronic acid and derivatives

Article abstract of DOI:10.1016/S0022-328X(99)00086-8

4-Mercaptophenylboronic acid derivatives were prepared by a metallation/boration sequence from S-protected 4-bromothiophenols; the t-butyldimethylsilylthioether was found suitable to allow subsequent regeneration of the mercapto group after boration. The parent compound, 4-mercaptophenylboronic acid, could thus be obtained and was subsequently S-alkylated; 4-boronophenylthioacetic acid was prepared without the need to protect the boronic acid group.

Full text of DOI:10.1016/S0022-328X(99)00086-8

Journal of Organometallic Chemistry 581 (1999) 82–86
Boronated thiophenols: a preparation of 4-mercaptophenylboronic
acid and derivatives
Abdelghani Brikh, Christophe Morin *
Laboratoire d’Etudes Dynamiques et Structurales de la Se´lecti6ite´ (LEDSS), UMR CNRS 5616, Batiment 52, Chimie-Recherches,
Uni6ersite´ de Grenoble, F-38402 Saint Martin d’He`res, France
Received 12 August 1998; received in revised form 23 November 1998
Abstract
4-Mercaptophenylboronic acid derivatives were prepared by a metallation/boration sequence from S-protected 4-bromothiophe-
nols; the t-butyldimethylsilylthioether was found suitable to allow subsequent regeneration of the mercapto group after boration.
The parent compound, 4-mercaptophenylboronic acid, could thus be obtained and was subsequently S-alkylated; 4-
boronophenylthioacetic acid was prepared without the need to protect the boronic acid group. © 1999 Elsevier Science S.A. All
rights reserved.
Keywords: BNCT; Boronates; Boronic acid; Mercapto; Thioethers
boronic derivatives such as the hydroxy [8] or amino [9]
derivatives have been known for a long time. This
could underline some difficulties for an efficient prepa-
ration of 1 as we experienced during the present work
and as described below.
A boronic acid group is usually introduced on aro-
matic rings by a metallation/boration sequence as
shown in Eq. (1).
1. Introduction
There is current interest in the preparation of
boronated analogues of biomolecules [1], particularly in
light of their possible use for boron neutron capture
therapy (BNCT) [2,3]. A thiol-bearing boron cluster
B12H11SH [4]—known as borocaptate, mercaptoborate
or BSH—was the first clinically useful compound for
BNCT assays [5]. Here we present the preparation of
4-mercaptophenylboronic acid (1), which we believe
may interact in vivo similarly to borocaptate; further-
more this compound, by alkylation of the thiol group,
could provide access to boronated analogues of
thioethers known to interfere with melanogenesis [6,7]
and therefore possibly to give melanoma-seeking agents
suitable for BNCT.
(1)
Reaction of 4-bromo-thiophenol (X=Br, R=p-SH)
with two equivalents [10,11] of n-, sec- or t-butyl
lithium at −78°C followed by quenching with
trimethyl borate resulted in complicated reaction mix-
tures which gave no evidence of the formation of 1
(R=p-SH). The ortho-directing effect of the thiolate in
such metallations, which has been experienced previ-
ously [12,13], might here have played a detrimental role
and protection of the thiol group was thus considered.
First, the readily available p-methylthiophenyl
boronic acid (2) [14,15] was prepared but cleavage of
the S-methyl group of 2, using acidic conditions (such
as hydrochloric acid, boron tribromide) or
iodotrimethylsilane failed to give 1, boronic acid (2)
That boronic acid 1 had yet to be prepared was quite
surprising to us, as other para-functionalized phenyl-
* Corresponding author. Tel.: +33-4-76514250; fax: +33-4-
76514382.
E-mail address: christophe.morin@ujf-grenoble.fr (C. Morin)
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00086-8

A. Brikh, C. Morin / Journal of Organometallic Chemistry 581 (1999) 82–86
83
being recovered. Similar disappointing results were ob-
served with the protected boronate 3, obtained by
esterification of 2 with d,l-1,3-diphenylpropane-1,3-diol
(a method recently disclosed for protection of boronic
acids [16]). As the use of basic conditions [17,18] to
regenerate the thiol group from thiomethyl ethers are
incompatible with the base-sensitive boronic acid of 2
or 3, other S-protecting groups were then evaluated,
starting with the known [19] tetrahydropyranyl deriva-
tive 4.
To get a more efficient preparation of 1, other thiol
protecting groups (trityl, silyl) were examined and the
t-butyldimethylsilyl (TBDMS) thioether [23] proved to be
the right choice. Lithiation of 10 at −78°C was followed
by reaction with an excess of triisopropyl borate to afford
the S-silylated boronic acid 11 (77%). The thiol-protecting
group of 11 could then be removed by reaction with
trifluoroacetic acid to afford 1 (88%), without damage to
the boronic acid; this straightforward procedure thus
yielded 4-mercaptophenylboronic acid in preparative
yield (\60% overall from 4-bromothiophenol).
After metallation of 4 with n-butyl lithium and treat-
ment with triisopropylborate at low temperature, the
S-protected boronic acid 5 was isolated (90%), which
could be esterified to 6 (90%) by reaction [16] with
d,l-1,3-diphenylpropane-1,3-diol. From both 5 or 6,
however, acidic treatment (H+, BBr3, or (CH3)3SiI) as
well as reactions with Ag+ or Hg2+ salts known for
their affinity to sulphur, failed to cleanly deprotect the
S-THP ether.
Protection of the boronic acid group of 1 could be
effected by reaction with a diol, such as d,l-1,3-diphenyl-
propan-1,3-diol [16] or N-methyldiethanolamine, to give
esters 12 (86%) or 13 (85%), respectively. To confirm its
structure, 1 was also converted by reaction with methyl
iodide to the known S-methyl thio ether 2 [13,14].
The use of a more acid-sensitive protecting group
was then considered and upon reaction of 4-bromo-
thiophenol with 2-methyl-but-1-ene, the t- amyl (TAM)
[20] thioether (7) was prepared (95%); this, to our
knowledge, is the first example of the use of TAM for
protection of a thiol group. Thioether 7 was then
converted to boronic acid 8 (85%) by the general metal-
lation/boration sequence (Eq. (1)). Upon treatment of 8
with ortho-nitrosulphenyl chloride [21], cleavage of the
S-TAM protecting group was observed and yielded the
expected unsymmetrical disulfide 9 (70%). Subsequent
reduction [22] of this dithioether with sodium borohy-
dride then afforded the desired 4-mercaptophenyl-
boronic acid 1, but in low yield (B20%).

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A. Brikh, C. Morin / Journal of Organometallic Chemistry 581 (1999) 82–86
Reaction of boronates 12 and 13 with t-butyl bro-
n-butyl lithium (37.5 ml, 1.6 M in n-hexane, 60.8 mmol,
1.6 equiv) was added dropwise. After stirring for 15
min, tri-isopropyl borate (46.2 ml, 198 mmol, 5.2 equiv)
was added. The mixture was stirred at −78°C for 2 h,
then at −20°C for 2 h and finally overnight at room
temperature. Water (20 ml) was added and the mixture
was concentrated to one third under reduced pressure.
Extraction was performed with diethyl ether and the
organic layer was washed with water, dried (sodium
sulfate) and concentrated under reduced pressure. The
residue was taken up in diethyl ether/n-pentane to
afford 11 (7.96 g, 77%) as white cristals; the yield was
moacetate in the presence of a base afforded the corre-
sponding S-alkyl derivatives 14 (71%) and 15 (65%),
respectively; this was followed by treatment with trifl-
uoroacetic acid, which removed only the carboxylic
ester protecting group from 14 (to give 16) but both acid
protecting groups of 15 (to give 17). A shorter route
to 17, a boronated analogue of p-hydroxyphenylth-
ioacetic acid, is given by direct alkylation of 1 with
t-butyl bromoacetate (to give 18) followed by acidic
deprotection, i.e. without need to protect the boronic
acid group.
4-Mercaptophenylboronic acid 1 being now made
readily available, the preparation of boronated ana-
logues of aromatic thio derivatives which might interfere
with melanogenesis can now be initiated; the prepara-
tion of such boronated melanoma-seeking agents for
potential use in BNCT is presently undertaken in our
laboratory.
1
86% on a 1 mmol scale. Mp 253–255°C. H-NMR (300
MHz, CDCl3): l 0.2 (s, 6H), 1.0 (s, 9H), 7.55 (m, 2H),
8.05 (m, 2H). 13C-NMR (CDCl3, 75 MHz): l −3.2,
19.1, 26.4, 133.6, 134.9, 135.7, 137.9.
2.4. 4-Mercaptophenylboronic acid (1)
To
a solution of 11 (2.49 g, 10 mmol) in
dichloromethane (10 ml) was added trifluoroacetic acid
(7.7 ml, 100 mmol, 10 equiv) and the now purple
solution was stirred overnight. After evaporation of the
volatiles under reduced pressure, the residue was taken
up in water to afford 1 (1.35 g, 88%) as white crystals.
Mp 218–220°C. IR: w 3273, 2338, 2374, 1587, 1395
2. Experimental
2.1. General
Dry tetrahydrofuran was obtained by distillation over
sodium/benzophenone under Ar and acetonitrile was
1
cm−1. H-NMR (250 MHz, CDCl3+CD3OD) l 7.1
,
stored on 4 A molecular sieves before use. d,l-1,3-
(m, 2H), 7.6 (m, 2H).13C-NMR (62.5 MHz, CDCl3+
CD3OD) l 125.5, 127.4, 134.0.
Diphenylpropane-1,3-diol was prepared according to
the literature [24]. Standard abbreviations are used for
NMR description of spectra and the residual absorption
of the NMR solvent was taken as the internal reference.
2.5. 4-Methylthiophenylboronic acid (2)
To a solution of 1 (154 mg, 1 mmol) in acetonitrile (5
ml) were added potassium carbonate (456 mg, 3.3
mmol, 3.3 equiv), and methyl iodide (0.62 ml, 10 mmol,
10 equiv). After stirring overnight, water was added and
the mixture was extracted with dichloromethane. The
organic layer was washed with water, dried (sodium
sulfate) and the volatiles were removed under reduced
pressure. The white powder thus obtained was recrys-
tallised (diethyl ether) to afford 2 (103 mg, 61%) as
white crystals; this material was compared to an authen-
tic sample prepared according to reference [15]. M.p.:
206–207°C (literature: 208.5–209.5 [14], 205–208°C
[15]).
2.2. (4-Bromophenylthio)-dimethyl-tertbutyl-silane (10)
To a solution of 4-bromothiophenol (9.45 g, 50
mmol) in dry tetrahydrofuran (30 ml) stirred under Ar
at 4°C, was added sodium hydride (2.2 g of a 60%
dispersion in mineral oil, 55 mmol, 1.1 equiv). After
evolution of gas had ceased (30 min), t-butyldimethylsi-
lyl chloride (11.3 g, 75 mmol, 1.5 equiv) was added and
the reaction mixture was stirred at room temperature
(r.t.) for 14 h. After filtration on Celite and evaporation
of the volatiles, bulb-to-bulb distillation (50°C at 5
mmHg) afforded 10 (13.6 g, 92%) as a colorless liquid
which crystallized on standing. Mp 253–255°C; (litera-
ture: Eb 93–94°C (1 mmHg) [23]).1H-NMR (250 MHz,
CDCl3): l 0.2 (s, 6H), 1.0 (s, 9H), 7.55 (m, 2H), 8.05 (m,
2H). 13C-NMR (CDCl3, 66.5 MHz): l −3.7, 17.8, 25.5,
123.6, 128.8, 130.4, 131.6.
2.6. d,l-(4,6-Diphenyl-2-(4-mercaptophenyl)-
1,3,2-dioxaborinane (12)
To a solution of 1 (770 mg, 5 mmol) in tetrahydro-
furan (10 ml) was added d,l-1,3-diphenylpropane-1-3
diol (1.1 g, 5 mmol, 1 equiv). The solution was stirred
for 30 min and dried with sodium sulfate. After filtra-
tion and evaporation of the volatiles, the residue was
purified by chromatography on silica gel (dichloro-
methane) to afford 12 (1.490 g, 86%) as white crystals.
2.3. 4-[(Dimethyl-tertbutyl-silyl)thio]-phenylboronic acid
(11)
Under Ar, a solution of 10 (11.36 g, 38 mmol) in dry
tetrahydrofuran (20 ml) was stirred at −78°C and

A. Brikh, C. Morin / Journal of Organometallic Chemistry 581 (1999) 82–86
85
1
1
M.p. 271–272 °C. H-NMR (CDCl3, 200 MHz) l 2.4
with water and dried to yield 16 (122 mg, 54%). H-
NMR (CDCl3, 300 MHz) l 2.4 (m, 2H), 3.6 (s, 2H), 5.2
(m, 2H), 7.1 and 7.9 (AA’XX’ system, 2×2H each),
7.3–7.6 (m, 10H).
(m, 2 H), 5.2 (m, 2 H), 7.1 and 7.9 (AA’XX’ system,
2×2H each), 7.3–7.6 (m, 10H). 13C-NMR
((CD3)2CO), 75 MHz) l 42.0, 71.1, 125.9, 126.3, 127.3,
127.4, 128.2, 128.3, 128.8, 129.2, 135.3, 143.1.
2.11. 4-Carboxymethylthiophenyl boronic acid (17)
2.7. 2-(4-Mercaptophenyl)-
6-methyl-1,3,6,2-dioxaazaborocane (13)
From 15, or 18, the above procedure, used for the
deprotection of 14, was used; the white powder thus
obtained was thoroughly washed with diethyl ether to
To a solution of 1 (770 mg, 5 mmol) in tetrahydro-
furan (10 ml) was added N-methyl-diethanolamine
(0.63 ml, 5.5 mmol, 1.1 equiv). After stirring for 30
min, diethyl ether was added (20 ml) and this solution
was washed with water (4×20 ml). Drying (sodium
sulfate) of the organic layer and evaporation of the
volatiles afforded 13 (1.007 g, 85%) as white crystals.
yield 17 (80%). IR: w 3480, 3257, 1775, 1383 cm−1
.
1H-NMR (CDCl3+CD3OD, 200 MHz) l 3.5 (s, 2H),
7.1 (m, 2H) 7.5 (m, 2H). 13C-NMR (CDCl3+CD3OD,
75 MHz) l 37.9, 127.6, 134.0, 137.6, 171.7.
2.12. 4-(t-Butyloxycarbonylmethylthio)-phenyl boronic
acid (18)
1
M.p. 226–228°C. H-NMR (CDCl3, 200 MHz) l 2.25
(s, 3 H), 2.8–3.2 (m, 4 H), 4.0–4.3 (m, 4 H), 7.5 and 8.1
(AA’XX’ system, 2×2H each). 13C-NMR (CDCl3, 62.5
MHz): l 47.5, 60.1, 62.0, 125.4, 127.2, 134.1, 140.4.
To a solution of 1 (462 mg, 3 mmol) in acetonitrile
(10 ml) were added potassium carbonate (1.368 g, 9.9
mmol, 3.3 equiv), t-butyl bromoacetate (1.29 ml, 9.9
mmol, 3.3 equiv) and sodium iodide (50 mg, 0.33
mmol, 0.33 equiv). After 20 h stirring, the volatiles were
removed under reduced pressure. The residue was parti-
tioned between water and dichloromethane. The or-
ganic layer was washed with water, dried (sodium
sulfate) and evaporated under reduced pressure. The
yellow oil was purified by chromatography on silica gel
to afford 18, eluting with 49:1 CH2Cl2/CH3OH, (0.57 g,
71%) as a colorless oil. IR: w 3249, 2963, 1722, 1591
2.8. d,l-2-(4-(t-Butyloxycarbonylmethylthiophenyl)-
4,6-diphenyl-1,3,2-dioxaborinane (14)
To a solution of 12 (338 mg, 0.98 mmol) in dry
acetonitrile (3 ml) were added potassium carbonate
(207 mg, 1.5 mmol, 1.5 equiv), t-butyl bromoacetate
(0.20 ml, 1.5 mmol, 1.5 equiv) and sodium iodide (22
mg, 0.15 mmol, 0.15 equiv). After stirring for 20 h, the
solution was concentrated under reduced pressure and
water was added to the residue. The mixture was
extracted with dichloromethane and after washing and
drying, the yellow oil was purified by chromatography
on silica gel (dichloromethane) to afford 14 (321 mg,
1
cm−1. H-NMR (CDCl3, 300 MHz) l 1.4 (s, 9H), 3.55
(s, 2H), 7.3 (m, 2H), 7.6 (m, 2H). 13C-NMR (CDCl3, 75
MHz) l 27.8, 36.6, 82.1, 127.8, 133.9, 134.8, 168.8.
1
70%) as a colorless oil. H-NMR (CDCl3, 300 MHz) l
1.4 (s, 9H), 3.6 (s, 2H), 7.2 and 7.9 (AA’XX’ system,
2×2H each), 7.3–7.6 (m, 10H).
Acknowledgements
J. Norrild (University of Copenhagen, Denmark) is
thanked for critical reading of the manuscript and A.
Claussner (Roussel-Uclaf, Romainville, France) for a
copy of material contained in patent EPA 471612 [19].
2.9. 2-(4-(t-Butyloxycarbonylmethylthiophenyl)-6-
methyl- 1,3,6,2-dioxaazaborocane (15)
Starting with 13 (249 mg, 1 mmol), the procedure
used for the preparation of 14 was chromatography on
silica gel, 99:1 CH2Cl2/CH3OH, then gave 15 (213 mg,
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7.4 (m, 2H), 8.0 (m, 2H).
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