Deprotection of pinacolyl boronate esters by transesterification with polystyrene-boronic acid

Article abstract of DOI:10.1016/j.tetlet.2004.07.014

A mild, efficient method for the deprotection of pinacolyl organoboronate esters is described. Treatment of the organoboronate ester with excess polystyrene-boronic acid followed by filtration and evaporation of the solvent provides the corresponding organoboronic acid. Mild deprotection of pinacolyl boronate esters to the corresponding boronic acids was achieved in the presence of excess polystyrene-boronic acid via a transesterification process. The procedure allows for the cleavage of pinacolyl boronate esters in the presence of sensitive functional groups. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2004.07.014

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6657–6660
Deprotection of pinacolyl boronate esters by transesterification
with polystyrene–boronic acid
Thomas E. Pennington,a Cynantya Kardimanb and Craig A. Huttona,b,
*
aSchool of Chemistry, The University of Sydney, NSW 2006, Australia
bSchool of Chemistry, The University of Melbourne, VIC 3010, Australia
Received 28 May 2004; revised 23 June 2004; accepted 2 July 2004
Available online 22 July 2004
Abstract—Mild deprotection of pinacolyl boronate esters to the corresponding boronic acids was achieved in the presence of excess
polystyrene–boronic acid via a transesterification process. The procedure allows for the cleavage of pinacolyl boronate esters in the
presence of sensitive functional groups.
Crown Copyright Ó 2004 Published by Elsevier Ltd. All rights reserved.
The utility of organoboronic acids in organic synthesis
has flourished in recent years, particularly through
developments in Miyaura–Suzuki couplings,1 allylbora-
tions,2 copper-catalysed arylboronic acid–heteroatom
couplings,3 and the Petasis reaction.4 Pivotal to the
rapid advancement in organoboron chemistry has been
the accessibility of organoboron compounds under mild
conditions enabled by MiyauraÕs borylation of aryl- and
vinyl-halides in the presence of a palladium catalyst and
bis(pinacolato)diboron.5 The product pinacolyl organo-
boronate esters are themselves suitable substrates in
Miyaura–Suzuki couplings, thereby negating the need
for conversion to the corresponding boronic acids.
However, several reactions of organoboron reagents
require, or proceed most efficiently with, boronic acids.
Several general methods for the deprotection of hin-
dered organoboronate esters are known, but they often
employ harsh, acidic or oxidising conditions. Organo-
boronate esters can be converted to diethanolamine
boro- nates by treatment with diethanolamine, with sub-
sequent hydrolysis under acidic or basic conditions gen-
erating the boronic acid.9 Boronate esters can be
oxidatively cleaved by treatment with periodate.10,11
Boron tribromide has also been used to deprotect pinac-
olyl boronate esters (with concomitant cleavage of a
Boc-protected amino group).12 One of the milder meth-
ods for the conversion of pinacolyl organoboronate es-
ters is transesterification in the presence of excess
phenylboronic acid. This process is most effective under
phase-transfer conditions where the resultant organobo-
ronic acid is water soluble and is separated from the ex-
cess organic-soluble phenylboronic acid, such as in the
preparation of a-amino organoboronic acids.11 Trans-
esterification can be used under homogeneous condi-
tions, but is limited by either the difficulties in
separating large quantities of phenylboronic acid (if a
large excess is used) or incomplete conversion (if only
a moderate excess is used). An example of such an
approach was reported by Decicco et al.7 in the depro-
tection of phenylalanine- and tyrosine-derived pinacolyl
boronate esters. Typically 2equiv of phenylboronic acid
were used, with the desired organoboronic acid isolated
in ꢀ60% yield and the starting boronate ester recovered
in up to 25% yield.
The arylation of phenols and a variety of nitrogen nucleo-
philes in the presence of arylboronic acids and Cu(I) or
Cu(II) catalysts has been fine tuned over recent years to
represent one of the best methods for heteroatom aryl-
ation.3 However, these reactions proceed in very low
yields with pinacolyl boronate esters.6,7 Similarly, the
three-component coupling of an aldehyde, amine and
organoboron species (Petasis reaction) can proceed with
a pinacolyl boronate ester in some circumstances, but is
higher yielding and more general with boronic acid sub-
strates.8 Hence, the conversion of pinacolyl organobor-
onate esters to the corresponding organoboronic acids is
of much interest.
We hereby report the use of polystyrene–boronic acid
as a useful reagent for the conversion of pinacolyl boro-
nate esters to the corresponding boronic acids via
*
Corresponding author. Tel.: +61-3-8344-6482; fax: +61-3-9347-
5180; e-mail: chutton@unimelb.edu.au
0040-4039/$ - see front matter Crown Copyright Ó 2004 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.014

6658
T. E. Pennington et al. / Tetrahedron Letters 45 (2004) 6657–6660
transesterification. The advantages of solid-phase rea-
gents in synthetic transformations are well established:
primarily the ability to use a large excess of reagent
due to the ease of removal of excess reagent by filtra-
tion.13 We envisaged that the use of a polymer-sup-
ported arylboronic acid would allow an excess of
reagent to be used in a boronate transesterification reac-
tion, thereby driving the reaction towards complete con-
version while also enabling simple removal of the
reagent and isolation of the product boronic acid.
nitrile/1M HCl, at room temperature in the presence of
ꢀ5equiv of polystyrene boronic acid (Scheme 1).
Various aryl pinacolyl boronate esters 1 were then de-
protected using these conditions, as shown in Table 2.
In general higher yields were obtained using the aceto-
nitrile/1M HCl method, in many cases giving the boronic
acids 2 in >90% yield. In such cases chromatography
was unnecessary, and simple removal of the solvent after
filtration provided the near-pure boronic acid with only
a trace of the pinacolyl boronate ester detectable. It
should be noted that the lower yields using the acetonit-
rile/TFA method represent lower conversions, with the
remainder of the boronate ester being recovered.
Polystyrene–boronic acid is available commercially
(Lancaster) or from bromopolystyrene according to
the methods of Farral and Frechet14 and Hodge
et al.15 Initial attempts to prepare polystyrene–boronic
acid using n-butyllithium/trimethylborate according to
the conditions of Hodge et al. did not provide a high
loading of boronic acid functionality. However, using
triisopropyl borate in place of trimethyl borate gave
polystyrene–boronic acid with higher loading and with
greater reproducibility. Whereas Hodge et al. deter-
mined the loading by boron elemental analysis, we
employed a titration-type procedure, which can be per-
formed in the laboratory, is cost effective, and we believe
gives a more accurate reflection of ÔavailableÕ boronic
acid functionality. The polystyrene–boronic acid is trea-
ted with 2–3equiv of pinacol in THF for 16h such that
available boronic acid groups are converted to pinacolyl
boronate esters. The polymer is removed by filtration
and the solvent is evaporated to leave the excess pinacol.
Simple calculation of the amount of pinacol retained by
the polymer then provides a measure of the loading,
which was typically ꢀ2mmol/g.
The results shown in Table 2 indicate that functional
groups such as nitro groups, ketones, carbamates, esters
and alkenes tolerate these conditions. Of note is that the
Boc-group of a protected aniline derivative was stable
under these conditions, with the protected arylboronic
acid isolated in 78% yield after chromatography (entry
12). The procedure is also applicable to the deprotection
of more complex pinacolyl boronate esters such as a
protected tyrosine-3-boronate derivative16 (entry 14).
Treatment of the boronate ester with 5equiv of polystyr-
ene–boronic acid in acetonitrile/1M HCl (9:1) for 18h
yielded 99% of the corresponding boronic acid. Vinyl
pinacolyl boronate esters can also be deprotected under
these conditions (entry 13) (Scheme 2).
As a large excess of polymer-supported reagent is used,
the recovered reagent can be used several times without
drastic loss of activity. For example, the resin recovered
from the deprotection of the m-tolyl and p-methoxyphen-
ylboronates (entries 3 and 5, method B) was reused in
identical reactions and still gave good yields of the cor-
responding boronic acids (second run yields in brack-
ets), the yields of the second runs being ꢀ90% of the
first run. Ultimately, though, regeneration of the poly-
styrene–boronic acid was deemed necessary to make this
Deprotection of phenyl pinacolyl boronate 1a was inves-
tigated in various solvents in the presence of acid cata-
lysts. Two procedures emerged as being most suitable.
Acetonitrile appeared to be the best solvent, with either
trifluoroacetic acid or aqueous hydrochloric acid as
additives. The acetonitrile/TFA procedure was initially
optimised for the deprotection of phenyl pinacolyl
boronate 1a (see Table 1). Acetonitrile was a superior
solvent to dichloromethane and chloroform (entries 1–
3), and concentrations of TFA greater than 2% did
not improve yields (entries 4–6). The use of ꢀ9equiv
of polystyrene–boronic acid in refluxing conditions re-
sulted in virtually complete deprotection of the pinacolyl
boronate ester in 6h (entry 9). Optimised conditions for
the HCl/acetonitrile procedure were the use of 9:1 aceto-
OH
OH
B
O
B
B
OH
excess
O
OH
1a
2a
Scheme 1.
Table 1. Optimisation of deprotection of phenyl pinacolyl boronate ester in acetonitrile/TFA
Entry
Polystyrene–boronic acid
Solvent
Temp
Time
Conv. (%)
1
2
3equiv
3equiv
3equiv
3equiv
3equiv
3equiv
9equiv
9equiv
9equiv
9equiv
CH2Cl2/1%TFA
CHCl3/1%TFA
CH3CN/1%TFA
CH3CN/1%TFA
CH3CN/2%TFA
CH3CN/5%TFA
CH3CN/2%TFA
CH3CN/2%TFA
CH3CN/2%TFA
CH3CN/2%TFA
25°C
25°C
25°C
25°C
25°C
25°C
25°C
Reflux
Reflux
Reflux
14d
14d
14d
5d
13
36
98
27
3
4
5
5d
5d
37
36
6
7
5d
3h
97
78
8
9
10
6h
18h
98
100

T. E. Pennington et al. / Tetrahedron Letters 45 (2004) 6657–6660
6659
conditions. The yield of p-methoxyphenylboronic acid
was 91%, indicating that the regenerated resin had
>90% activity of the fresh resin.
OH
OH
B
OH
B
O
B
R
OH
R
O
excess
1
2
The development of an efficient, mild method for the de-
protection of pinacolyl boronate esters enables this
group to be used as a true protecting group, rather than
simply as a blocking group introduced during the prep-
aration of the organoboron species. Accordingly, we
have utilised our method in the synthesis of the polyaryl-
ether 9 (Scheme 3).
Scheme 2.
Table 2. Deprotection of pinacolyl organoboronate esters
Entry Substrate (R) Yield of boronic Yield of boronic
acid (method A)a acid (method B)b
1
98
78
94
94
m-Benzyloxyphenyl pinacolyl boronate ester 3 was con-
verted to either the phenol 5 (by hydrogenolysis of the
benzyl ether) or the boronic acid 4 (by employing the
polystyrene–boronic acid deprotection procedure de-
scribed above). Coupling of the phenol 5 and boronic
acid 4 in the presence of Cu(OAc)2 gave the biaryl ether
6 in 89% yield. Samples of the biarylether 6 were likewise
converted to the corresponding phenol 8 (by hydrogeno-
lysis) and boronic acid 7 (by polystyrene–boronic acid
deprotection of the pinacolyl boronate) in good yields.
Subsequent Cu(II)-catalysed coupling of compounds 7
and 8 gave the tris(biaryl ether) 9. The pinacolyl boro-
nate ester group is used as a true protecting group in this
sequence, being both orthogonal to the benzyl ether group
and preventing reactivity of the boron substituent in
the Cu-catalysed phenol–boronic acid coupling reactions.
2
Me
Me
3
85
90
95 (87)c
Me
4
90
5
88
98
99 (90)c
90
MeO
MeO
6
OMe
7
92
85
95
95
MeO
8
In conclusion, the use of polystyrene–boronic acid resin
in acidic acetontrile provides a mild, high-yielding meth-
od for the deprotection of pinacolyl boronate esters.
This method allows for the simple isolation of the prod-
uct boronic acid and tolerates numerous functional and
protecting groups.
MeO
OH
9
82
99
80
95
96
88
O
Me
10
O
O2N
BnO
B(OH)2
B
O
11
CH3CN, 1M HCl
3
H2, Pd/C
93%
95%
12
13
37
67
78
94
BocHN
OH
O
B
BnO
B
HO
OH
O
Cu(OAc)2
CbzHN
BnO2C
5
4
89%
NEt3
O
B
14
52
99
BnO
O
O
OBn
B(OH)2
CH3CN, 1M HCl
86%
6
a CH3CN/2% TFA, 9equiv polystyrene boronic acid, reflux, 18h.
b 9:1 CH3CN/1M HCl, 5equiv polystyrene–boronic acid, room temp,
18h.
H2, Pd/C
96%
OH
O
B
c Second run.
BnO
O
B
HO
O
OH
O
method cost effective. Accordingly, used resin was trea-
ted with excess diethanolamine in THF, followed by
treatment with 1M HCl/acetonitrile, in order to convert
resin-bound pinacolyl boronate ester groups to free
boronic acid groups. The used resin recovered after
two rounds of deprotection of p-methoxyphenyl pinaco-
lyl boronate (entry 5) was regenerated using this proce-
dure, then resubjected to the deprotection reaction
7
8
Cu(OAc)2
NEt3
50%
O
B
BnO
O
O
O
O
9
Scheme 3.

6660
T. E. Pennington et al. / Tetrahedron Letters 45 (2004) 6657–6660
8. Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron
Lett. 2002, 43, 5965.
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