boronic ester to the boronic acid.12 The corresponding
trifluoroborates have been synthesized by treating the aryl-
boronic acid or the arylboronic ester with potassium hydro-
gen difluoride.13 Aryltrifluoroborates can also be synthesized
in a one-pot fashion by lithiation of an aryl halide, followed
by trapping with a trialkylborate and addition of an aqueous
KHF2 solution.5
Although these routes to arylboronic acids and aryl
trifluoroborates have been used many times, they have
several limitations. First, the use of organometallic interme-
diates can limit the tolerance toward functional groups.
Second, the synthesis is limited by the substitution patterns
of haloarenes. This substitution pattern is typically controlled
by the regioselectivity of electrophilic aromatic substitution.
Thus, few 3,5-disubstituted boronic acids are commercially
available.
from the unfavorable hydrolysis of the pinacolboronates to
boronic acids.
Thus, a convenient method to directly convert the arenes
to arylboronic acids or to aryltrifluoroborates would enhance
the utility of this C-H activation chemistry. We report a
one-pot method to convert arenes to arylboronic acids and a
similar one-pot method to convert arenes to aryl trifluoro-
borates (Scheme 1). These transformations occur by C-H
Scheme 1
We have studied the direct, catalytic functionalization of
C-H bonds to form boronate esters.14 With Ishiyama and
Miyaura, we have published the most active catalysts for
the conversion of arenes to arylboronic esters.15-17 This
catalyst, herein called the IMH catalyst, is based on the
combination of [Ir(COD)(OMe)]2 and di-tert-butylbipyridine
(dtbpy), and it catalyzes the borylation of both electron-rich
and electron-deficient arenes and heteroarenes with bis-
pinacolatodiboron (B2pin2) as the boron source. Smith has
published catalysts containing bisphosphine ligands that
operate at higher temperatures.18 The C-H borylation
processes with both catalysts tolerate a variety of functional
groups, such as alkoxides, nitriles, esters, and halogens, and
the regioselectivity of the borylation processes complements
that of electrophilic substitutions. The regioselectivity of the
arene borylation is largely determined by steric factors rather
than by the electron distribution in the arene.15,19
bond activation with pinacolboronates, followed by conver-
sion of the esters to acids and trifluoroborates in situ using
aqueous sodium periodate and potassium hydrogen difluo-
ride, respectively.
To develop a route to arylboronic acids by C-H activation
of arenes, it was necessary to find a method that would
convert the arylboronic esters to arylboronic acids in the
presence of the iridium catalyst and in the solvent of the
catalytic process. Arylboronic esters have been shown to be
converted to the arylboronic acids by an oxidative cleavage
of the pinacol group by NaIO4.21 This oxidative process
drives the equilibrium for hydrolysis to the boronic acid by
oxidation of the pinacol to acetone, and this oxidant does
not convert the boronic acid to the corresponding phenol.
Thus, a protocol based on this conversion of the pinacol ester
to the acid should involve a C-H activation step with low
loadings of iridium and a solvent that is both inert to the
C-H activation chemistry and suitable for the oxidation step.
Because the arene borylations are known to be efficient in
THF,19 we tested this medium for the hydrolysis of pinaco-
latoboronic esters.
Unfortunately, the C-H borylation processes have re-
quired the use of pinacol-substituted boron reagents and form
pinacol-substituted boronic esters. These products are con-
venient to handle, but they are often less reactive than boronic
acids or trifluoroborates in the transformations described in
the first paragraph.7,20 This lower reactivity results, in part,
(12) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447. (c) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001,
57, 9813. (d) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997,
62, 6458. (e) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 2000, 65, 164. (f) Euzenat, L.; Horhant, D.; Ribourdouille, Y.; Duriez,
C.; Alcaraz, G.; Vaultier, M. Chem. Commun. 2003, 2280.
(13) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M.
R. J. Org. Chem. 1995, 60, 3020.
(14) (a) Chen, H.; Hartwig, J. F. Angew. Chem., Int. Ed. 1999, 38, 3391.
(b) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995.
(15) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390.
(16) (a) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew.
Chem., Int. Ed. 2002, 41, 3056. (b) Takagi, J.; Sato, K.; Hartwig, J. F.;
Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. (c) Ishiyama,
T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924.
(d) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
AdV. Synth. Catal. 2003, 345, 1103.
(17) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura,
N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263.
(18) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R.
Science 2002, 295, 305.
The compatibility of the oxidation and C-H activation
methods to the remaining iridium catalyst and the THF
medium was first tested using crude arylboronic esters
produced by arene borylation in the presence of the IMH
catalyst and evaporation of all of the THF solvent. The crude
arylboronic esters were subjected to the oxidative hydrolysis
procedure with NaIO4 as oxidant in a 4:1 mixture of THF/
H2O. The boronic acids were isolated after the reaction by
addition of aqueous HCl solution and extraction of the
boronic acid into ethyl acetate. As shown in Table 1, the
conversion of the crude boronic ester to the acid occurs with
systems containing electron-rich and electron-poor aryl
(20) (a) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.;
Giralt, E. J. Org. Chem. 2004, 69, 6812. (b) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829.
(21) (a) Falck, J. R.; Bondlela, M.; Venkataraman, S. K.; Srinivas, D. J.
Org. Chem. 2001, 66, 7148. (b) Coutts, S. J.; Adams, J.; Krolikowski, D.;
Snow, R. J. Tetrahedron Lett. 1994, 35, 5109.
(19) Chotana, G. A. R.; Michael, A.; Smith, M., III. J. Am. Chem. Soc.
2005, 127, 10539.
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Org. Lett., Vol. 9, No. 5, 2007