Synthesis of sulfonyl chlorides of phenylboronic acids

Article abstract of DOI:10.1055/s-2004-817758

Sulfonyl chlorides of phenylboronic esters have been made available by selective lithiation of bromo N-methyl-diethanolamine phenylboronates to give lithium sulfinyl phenylboronates as intermediates. Oxidations with N-chlorosuccinimide give the target sul

Full text of DOI:10.1055/s-2004-817758

892
LETTER
Synthesis of Sulfonyl Chlorides of Phenylboronic Acids
S
ulfonyl Chlo
e
ride
s
of Phe
r
nylboronic
Ac
V
ids edsø,* Preben H. Olesen, Thomas Hoeg-Jensen*
Novo Nordisk, Novo Alle 6B2.54, 2880 Bagsvaerd, Denmark
Fax +45(44)444256; E-mail: tshj@novonordisk.com
Received 26 November 2003
tionalities, e.g. alcohols and carboxylic acids must usually
be used in protected form.
Abstract: Sulfonyl chlorides of phenylboronic esters have been
made available by selective lithiation of bromo N-methyl-di-
ethanolamine phenylboronates to give lithium sulfinyl phenylbor-
onates as intermediates. Oxidations with N-chlorosuccinimide give
the target sulfonyl chlorides, which may be isolated or used in situ
for further reactions. The novel reagents are useful in preparation of
among other sulfonamides of phenylboronic acids for use in Pd(0)
catalysed cross-couplings. They also hold potential as carbohydrate
binders with physiological pKa.
Obviously, sulfonyl halides of aryl boronic acids would
be attractive building blocks for the formation of the de-
sired sulfonamides, but such sulfonyl halides are hitherto
unknown according to CAS. We report here a method for
the preparation of sulfonyl chlorides of phenylboronic ac-
ids via selective bromo–lithium exchange of bromo N-
methyl-diethanolamine phenylboronates, followed by re-
action with sulfur dioxide and N-chlorosuccinimide oxi-
dation of the resulting lithium sulfinates. The sulfonyl
chlorides may be isolated by aqueous workup, but are
somewhat unstable, and are therefore preferably applied
as in situ reagents. The usefulness of the novel building
blocks has been demonstrated by preparation of a set of
sulfonamides and a Suzuki–Miyaura coupling.
Key words: boronic acid, pKa, sulfonamides, lithiation, cross-cou-
pling
Aryl boronic acids have become a very important func-
tional class, with synthetic applications in the popular
Suzuki–Miyaura cross-coupling reaction,1 and recently
also in several novel Pd(0) catalysed reactions with for-
mation of C-O, C-N or C-S bonds.2–4 Additionally, the an-
ionic form of boronic acids, boronates, are known for their
reversible binding to various carbohydrates. This feature
has been exploited in preparation of among other glucose
sensors.5 However, since the pKa of simple arylboronic
acid is 8.5, glucose binding is usually strong only under
alkaline conditions. For use under neutral and/or physio-
gical conditions, the boronate pKa can be corrected by de-
rivatising the aromatic nucleus with strongly electron-
withdrawing groups. The electron-withdrawing effect of
the carboxy group is relatively weak, and pKa of 4-car-
boxy-phenylboronic acid is approximately 8.6 The nitro
group is more effective,7 but this group is usually less at-
tractive from a pharmacological point of view. With these
aspects in mind, we recently took interest in sulfonyl are-
ne boronic acids, in particular sulfonamides, which may
simultaneously function as strongly electron-withdrawing
groups and as handles for attachment of the carbohydrate
binders to drugs or reporter groups (fluorophores etc.).
Sulfonamides of aryl boronic acids have previously been
made for Suzuki–Miyaura application by among other
ortho-directed metalation, followed by borylation with
trialkyl borate.8,9 An alternative method relies on Pd(0)
catalysed coupling of aryl halides with tetra-
alkoxydiboron10 or dialkoxyborane.11 Unfortunately, the
Pd(0) catalysed boronation often yields debrominated
side product (C-H). Furthermore, neither of the mentioned
methods is particularly tolerant with respect to other func-
We initially investigated the bromine–lithium exchange
with pinacol, neopentylglycol, and N-methyl-diethanol-
amine protected esters of 3-bromo and 4-bromo phenyl-
boronic acid. Treatment of pinacol or neopentylglycol
boronic esters with n-butyl lithium at –100 °C for 15 min-
utes and subsequent quench with sulfur dioxide12 did not
produce the desired lithium sulfinates. Instead, complicat-
ed mixtures were formed. In contrast to these results we
found that similar treatment of the corresponding N-meth-
yldiethanolamine boronates protected esters 1 resulted in
clean bromine–lithium exchange,13 and subsequent
quench with sulfur dioxide resulted in immediate precipi-
tation of the lithium sulfinates (2a,b) which could be iso-
lated in yields of 94% and 99%, respectively (Scheme 1).
Possibly the nitrogen atom in the N-methyldiethanola-
mine protection group brings the boron atom in a tetrahe-
dral and more protected state via B-N interaction, thereby
making it less susceptible for attack of the butyl lithium.
The protocols are straightforward and could easily be per-
formed on a 20 g scale. Notably, the use of 0.9 equivalents
of n-BuLi in the lithiation step was found to be advanta-
geous, since contamination with lithium butyl sulfinate
was otherwise observed. Attempts to selectively lithiate
and sulfinate ortho-bromo N-methyl-diethanolamine phe-
nylboronate were unsuccessful as only complex mixtures
were obtained. The lithium sulfinates 2a,b undergoes
mild oxidation to the corresponding sulfonyl chlorides
3a,b upon treatment with N-chlorosuccinimide. The sul-
fonyl chlorides are slightly unstable but could be isolated
in 50–55% yield after aqueous work up. Alternatively, in
situ reaction of 3a,b with primary or secondary amines
followed by hydrolysis of the N-methyl-diethanolamine
boron ester by dilute HCl or Dowex cation exchange resin
SYNLETT 2004, No. 5, pp 0892–0894
0
2.
0
4.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817758; Art ID: G33503ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sulfonyl Chlorides of Phenylboronic Acids
893
+
-
Table 1 Sulfonamide Phenylboronic Acid Productsa
+
N
B
N
-
O
Compound Structure
number
Yield (%)
B
1. BuLi, –100 °C
2. SO2 (g)
O
O
O
2a para
2b meta
O
S
HO
HO
HO
HO
4
5
50
61
SO2Li
Br
B
B
NHCH2CH2Ph
1
O
NCS, CH2Cl2
O
S
N(Me)CH2CH2Ph
O
O
+
N
B
1. 1° or 2° amine
2. H3O+
HO
OH
-
O
B
O
S
HO
6
7
8
72
37
54
O
B
B
N
O
HO
HO
O
SO2NR1R2
4–12
O
S
SO2Cl
H
N
OH
3a para
3b meta
HO
O
Scheme 1
O
S
HO
HO
B
NH
OH
BocHN
O
and simple aqueous workup, gave the corresponsing
sulfonamide phenylboronic acids in moderate to high
yields and good purities (>90%), see Table 1.
COOH
9
55
O
HO
HO
As mentioned, the method of Pd(0) catalysed borylation
from diboron usually requires protection of alcohols and
carboxylic acids. On the contrary, use of the novel sulfo-
nyl chlorides for formation of sulfonamides allows the
employment of alcohol and carboxy functions in unpro-
tected form (N-selective sulfonylation), as exemplified by
the reaction of in situ generated 3a with 4-aminophenol,
6-aminohexanol and Na-Boc-L-lysine (7, 8 and 9,
Table 1).
Suzuki–Miyaura reaction14 of the novel sulfonamide-phe-
nylboronic acids was exemplified by reaction of com-
pound 5 with 4-bromo-anisole under Pd(0) catalysis15 to
isolate 4-(N-methyl-N-phenethyl-sulfonamide)-4¢-meth-
oxy-biphenyl 13 in 88% yield (Scheme 2) upon flash
chromatography (the amounts of Pd catalysts were adjust-
ed to give Pd/phosphine stochiometry of 1:1).
B
S
NH
O
OH
OH
HO
B
10
11
12
37
76
68
O
S
NHBz
O
HO
B
B
O
S
N
O
OH
HO
O
S
N(Me)Bu
O
The pKa of 4-(N-methyl-sulfonamide) phenylboronic acid
was evaluated by titration with 0.01 M NaOH (Figure 1)
and the value was 7.4. Accordingly, sulfonamide phenyl-
boronic acids can be expected to bind carbohydrates
strongly at physiological conditions. Additionally, the po-
lar nature of the sulfonamide function seems to generally
improve the aqueous solubility of the compounds. Solu-
bility in water has been problematic with many other bor-
onate-based carbohydrate sensors,16 and they have usually
been tested in 50% methanol.17
a Compound identities and purities were evaluated by NMR and
LCMS.
Me
O
Ph
N
S
Pd(P(tBu)3)2 (1.5 %)
Pd2(dibenzylidineacetone)3 (0.75 % )
KF (3.3 equiv), THF
Br
O
+
5
OMe
B
Utilisation of the novel sulfonamide phenylboronic acid
building blocks in construction of novel carbohydrate
sensors will be reported in due course.
HO
OH
O
S
Me
MeO
N
O
Ph
13 (88 %)
Scheme 2
Synlett 2004, No. 5, 892–894 © Thieme Stuttgart · New York

894
P. Vedsø et al.
LETTER
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(5)
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mmol) in CH2Cl2 (2 mL) were stirred for 1 h, and treated with N-
methyl-N-phenethylamine (0.305 mL, 2.1 mmol). After 1 h, Dowex
50WX2-400 resin (1 g) was added and the mixture was stirred for 1
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Synlett 2004, No. 5, 892–894 © Thieme Stuttgart · New York