Microwave-assisted synthesis of ethynylarylboronates for the construction of boronic acid-based fluorescent sensors for carbohydrates

Article abstract of DOI:10.1016/j.tetlet.2006.02.012

A reliable and operationally simple procedure for the synthesis of 2,2-dimethylpropane-1,3-diyl ethynylaryl boronates 4 was developed. The key step is microwave-facilitated selective formation of 2,2-dimethylpropane-1,3-diyl trimethylsilylethynylaryl boro

Full text of DOI:10.1016/j.tetlet.2006.02.012

Tetrahedron Letters 47 (2006) 2331–2335
Microwave-assisted synthesis of ethynylarylboronates for
the construction of boronic acid-based fluorescent sensors
for carbohydrates
Shi-Long Zheng, Suazette Reid, Na Lin and Binghe Wang*
Department of Chemistry and Centre for Biotechnology and Drug Design, Georgia State University,
Atlanta, GA 30302-4098, USA
Received 20 December 2005; revised 1 February 2006; accepted 2 February 2006
Abstract—A reliable and operationally simple procedure for the synthesis of 2,2-dimethylpropane-1,3-diyl ethynylaryl boronates 4
was developed. The key step is microwave-facilitated selective formation of 2,2-dimethylpropane-1,3-diyl trimethylsilylethynylaryl
boronates by Sonogashira reaction from the corresponding bromides. The use of microwave was found to significantly improve the
reaction yield and shorten the reaction time. The 2,2-dimethylpropane-1,3-diyl ethynylaryl boronates 4 prepared can be used in the
construction of diboronic acid libraries through [2+3] Huisgen cycloaddition for carbohydrate fluorescent sensor development.
Ó 2006 Elsevier Ltd. All rights reserved.
Boronic acids are known to form tight complexes with
compounds containing two adjacent nucleophiles. These
compounds include diols, a-hydroxyacids, a-amino-
acids, and most likely aminoalcohols.1 On the basis of this
interaction, recently, there is an increasing interest in
using boronic acids for the synthesis of sensors of carbo-
hydrates,2–10 artificial lectins (boronolectins) targeting
cell surface carbohydrates,1,11–15 and selective transport-
ers of nucleosides, saccharides, and nucleotides.16–19 In
addition, arylalkynes are interesting intermediates for
the preparation of a variety of scaffolds for various
applications. Some recent examples include fluorescent
heterocycles,20 coupling components as fluorescent
dyes,21 fluorogenic probes,22 ricin sensors,23 optically
active polymers,24,25 fluorescent materials,26–31 anti-
microbial trizoles,32 carbonic anhydrase inhibitors,33 and
natural products with antitumor or antimitotic
activity.34,35
combinatorial approaches to the synthesis of such sen-
sors.12,14,46–48 However, for this type of work, the field
is hindered by a lack of diverse monoboronic acid
monomers that are readily ‘polymerizable’ under mild
conditions. We are interested in developing a general
methods for the preparation of arylboronic acids with
a terminal alkyne group, which can be used in the
[2+3] Huisgen cycloaddition20,49–51 in library synthesis.
Herein, we describe an efficient method for the synthesis
of ethynylarylboronic acids through microwave-facili-
tated Sonogashira coupling reaction starting from
bromoaryl boronic acids.
For the synthesis of the ethynylarylboronic acids, we
envisioned using the Sonogashira coupling reaction
starting with bromoarylboronic acids (Scheme 1). For
this we needed to have the boronic acids protected for
easy purification. Therefore, bromoaryl boronic acids
1 were reacted with neopentyl glycol in refluxing toluene
with a Dean–Stark trap to give the protected 2,2-
dimethylpropane-1,3-diyl bromoaryl boronates 2 in
almost quantitative yields.
Our lab has a long-standing interest in the design and
synthesis of boronic acid-based fluorescent sensors for
carbohydrates and boronolectins.1,11,12,36–45 Along this
line, we and others have been working on developing
Although there are ample precedents showing that
Sonogashira coupling reactions give high yields in gen-
eral,52,53 their application in the synthesis of boronic
acid-containing compounds has not been well studied.
To the best of our knowledge, there is only one such
example in the synthesis of 3a reported in the literature,
Keywords: Ethynylaryl boronates; Synthesis; Sonogashira; Microwave
irradiation.
*
Corresponding author. Tel.: +1 404 651 0289; fax: +1 404 654
5827; e-mail: wang@gsu.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.012

2332
S.-L. Zheng et al. / Tetrahedron Letters 47 (2006) 2331–2335
O
O
HO
OH
B(OH)2
Ar
Br
B
Ar
Br
toluene, reflux
2
1
O
O
Si(CH3)3
(H3C)3Si
Ar
B
PdCl2(PPh3)2, CuI, PPh3, Microwave
3
+
[2 3] Huisgen
cyclization
N
K2CO3, MeOH
rt
O
O
N
B(OH)2
Ar
B
Ar
N
R
4
Scheme 1. Synthesis of 2,2-dimethylpropane-1,3-diyl ethynylaryl boronates.
which involved long reaction time and an excess of the
expensive reagent trimethylsilylacetylene.24,25 For our
purpose, we need an efficient synthesis, which gives high
yield, uses near stoichiometric amount of trimethylsilyl-
acetylene, and allows for the ready synthesis of a large
number of such boronic acids. Therefore, we undertook
an effort to search for optimal conditions for the Sono-
gashira reaction. The optimization studies had to take
into consideration the presence of a boronic acid group,
which is prone to cleavage under acidic, basic, and oxi-
dative conditions. In addition, Suzuki coupling reaction
is one possible side reaction in such Sonogashira reac-
tions when a boronic acid is present on one of the start-
ing materials. For this part of the study, we used 2,2-
dimethylpropane-1,3-diyl 4-bromophenyl boronate 2a
as the model because it has been used for the synthesis
of 3a.24
the reaction at 130 °C in a sealed tube. In this case (entry
3), the product was obtained in 60% yield, which is a sig-
nificant improvement over the existing method. Such
results indicate that elevated temperature facilitates the
reaction if it does not lead to the escape of reaction com-
ponents. With this in mind, we became interested in
studying the effect of microwave, since its primary func-
tion in facilitating organic reactions is to heat up the
reaction under very well controlled conditions.
In the microwave reaction54,55 using a sealed tube, we
maintained the reaction temperature at 120 °C. Reac-
tion for 25 min gave 98% isolated yield of the desired
product (entry 4). At the same time, the deprotected free
boronic acid product was obtained in 1.5% yield. Com-
bined together, these two products gave quantitative
conversions of the Sonogashira coupling reaction.
Our initial optimization efforts focused on reaction tem-
perature. When the reaction was carried out at room
temperature, as is the case with most Sonogashira reac-
tions, the product was obtained only in 23% yield after
reaction for 48 h (Table 1, entry 1). This was clearly
unacceptable to us. When the reaction was conducted
in refluxing DMF (entry 2), no desired product was ob-
tained. Therefore, it seems that high temperature did not
help the reaction. However, this could also be due to the
evaporation of some essential components in the reac-
tion mixture such as diethylamine or trimethylsilylacetyl-
ene at elevated temperature. Therefore, we conducted
We were interested in examining the scope of applica-
tion in using microwave to facilitate such reactions. In
doing so, we studied the reaction using the less reactive
chlorophenylboronic acid instead of the bromo analog
(entry 5). In this case, no product was observed. This
is understandable since the chloro substitution is less
reactive. The results also indicate that chloro substitu-
tion can probably be tolerated on the boronic acid moi-
ety because of the reactivity differences with the bromo
substitution. Such functional group compatibility infor-
mation is very important for our future design of new
boronic acid analogs.
Table 1. Optimization of Sonogashira reaction conditions
O
O
O
O
Si(CH3)3 (1.1 equiv.)
B
B
X
(H3C)3Si
PdCl2(PPh3)2, CuI, PPh3, Et2NH, DMF
3a
Catalyst
Entry
X
Temperature (°C)
Time
Heating method
Yielda (%)
1
2
3
4
5
Br
Br
Br
Br
Cl
rt
48 h
6 h
0.5 h
25 min
25 min
Traditional
Traditional
Traditional
Microwave
Microwave
5% PdCl2(PPh3)2, 5% CuI
5% PdCl2(PPh3)2, 5% CuI
5% PdCl2(PPh3)2, 5% CuI
5% PdCl2(PPh3)2, 5% CuI
5% PdCl2(PPh3)2, 5% CuI
23
b
Refluxing
130 (Oil bath)c
120
60
98
b
120
a Isolated yield.
b No product was found by TLC and GC–MS.
c The reaction was performed in a sealed vessel.

S.-L. Zheng et al. / Tetrahedron Letters 47 (2006) 2331–2335
2333
Table 2. Synthesis of the ethynylaryl boronates
Si(CH3)3
O
O
K2CO3, MeOH
rt
O
O
O
(H3C)3Si
Ar
B
B
Ar
B
Ar
Br
PdCl2(PPh3)2, CuI,
Ph3P, Et2NH, DMF
O
4
2
3
Entry
1
Product 3
Yielda (%) of 3
Product 4
Yielda (%) of 4
O
O
O
B
O
B
98
78
Si(CH3)3
4b
3b
O
O
B
B
O
O
2
90
75
Si(CH3)3
3c
4c
O
O
B
O
B
Si(CH3)3
3
4
93
97
77
80
O
4d
3d
O
O
O
O
B
B
Si(CH3)3
3e
4e
Si(CH3)3
O
B
O
5
6
96
94
79
O
B
O
O
O
Cl
Cl
4f
OH
3f
HO
B
O
O
B
OMe
31c
OMe
4g
(H3C)3Si
3g
OH
B
OMe
O
OMe
Si(CH3)3
HO
B
30c
O
7
95
4h
3h
deborylation
position
d
d
d
d
d
d
8
9
S
82b
76b
73b
(H3C)3Si
(H3C)3Si
3i
deborylation
position
S
3j
(H3C)3Si
10
deborylation
position
N
H
3k
a Isolated yield.
b Yield of the deborylated product.
c Yield of boronic acid.
d Not available.

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S.-L. Zheng et al. / Tetrahedron Letters 47 (2006) 2331–2335
The deprotection of the trimethylsilyl group of 3a was
achieved by reaction with potassium carbonate in meth-
anol to give 80% of the desired product 4a. This com-
pared favorably with the 50% yield obtained in the
literature procedures using tetrabutylammonium fluo-
ride in tetrahydrofuran.24
Supplementary data
Supplementary data (including experimental procedures
and spectroscopic data for all compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.02.012.
With the initial success of the microwave-facilitated
reaction, we were interested in examining the scope of
application with analogous arylboronic acids. These
boronic acids include positional isomers (Table 2,
entries 1 and 2), a biphenylboronic acid (entry 3), a
naphthaleneboronic acid (entry 4), arylboronic acids
that have an additional electron-donating substituent
(methoxy) in different positions (entries 6 and 7), and
cases where the boronic acid group is on a different aryl
group as the alkyne group (entries 3 and 5). In all those
cases, the desired Sonogashira coupling product was
obtained in over 90% yield. The cleavage of the trimeth-
ylsilyl group was accomplished in over 75% isolated
yields except with entries 6 and 7, which have an addi-
tional electron-donating substituent. In the latter two
cases, the deprotection yields were about 30% and the
product was the free boronic acids. The more difficult
purification of the free boronic acid compared with the
protected esters could be part of the reason for the
low isolated yields in entries 6 and 7. The results of entry
5 (Table 2) also show that chloro substitution can be tol-
erated, which is consistent with the relative reactivity
(R–Cl < R–Br) of organic halides in palladium-cata-
lyzed reactions52 and the result obtained is presented
in Table 1 (entry 5).
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