One-pot synthesis of arylboronic acids and aryl trifluoroborates by Ir-catalyzed borylation of arenes

Article abstract of DOI:10.1021/ol062903o

(Chemical Equation Presented) The synthesis of arylboronic acids and aryl trifluoroborates in a one-pot sequence by Ir-calalyzed borylation of arenes is reported. To prepare the arylboronic acids, the Ir-catalyzed borylation is followed by oxidative cleavage of the boronic ester with NaIO₄. To prepare the aryltrifluoroborate, the Ir-catalyzed borylation is followed by displacement of pinacol by KHF₂. These two-step sequences give products that are more reactive toward subsequent chemistry than the initially formed pinacol boronates.

Full text of DOI:10.1021/ol062903o

ORGANIC
LETTERS
2007
Vol. 9, No. 5
757-760
One-Pot Synthesis of Arylboronic Acids
and Aryl Trifluoroborates by Ir-Catalyzed
Borylation of Arenes
Jaclyn M. Murphy, C. Christoph Tzschucke, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520, and Department of Chemistry,
UniVersity of Illinois, 600 South Matthews AVenue, Urbana, Illinois 61801
jhartwig@uiuc.edu
Received November 30, 2006
ABSTRACT
The synthesis of arylboronic acids and aryl trifluoroborates in a one-pot sequence by Ir-catalyzed borylation of arenes is reported. To prepare
the arylboronic acids, the Ir-catalyzed borylation is followed by oxidative cleavage of the boronic ester with NaIO4. To prepare the
aryltrifluoroborate, the Ir-catalyzed borylation is followed by displacement of pinacol by KHF2. These two-step sequences give products that
are more reactive toward subsequent chemistry than the initially formed pinacol boronates.
The chemistry of arylboronic acids and aryltrifluoroborates1-3
has been developed extensively in the past decade. These
reagents are air-stable solids that can be stored for long
periods of time without decomposition.4,5 These reagents
undergo a variety of catalyzed and uncatalyzed processes.
In addition to the extensive use of arylboronic acids in the
Suzuki-Miyaura cross-coupling reaction, these reagents
undergo halogenations, oxidative aminations, metal-catalyzed
additions to imines and iminium ions, metal-catalyzed 1,2-
and 1,4-additions to aldehydes and olefins, and copper-
mediated couplings with phenols and amines.6,7
ladium-catalyzed cross coupling reactions,10 rhodium-
catalyzed 1,2- and 1,4-additions,5 and copper-catalyzed
couplings with phenols to form diaryl ethers.7,11 The stability
of organotrifluoroborates allows substrate elaboration to
precede coupling or addition reactions.8 In many cases, both
boronic acids and trifluoroborates have been shown to be
more reactive than boronic esters.
The conventional method for the synthesis of arylboronic
acids involves the use of Grignard or organolithium reagents
and starts from aryl halides.1 Addition of the metalated arene
to a trialkylborate B(OR)3, followed by hydrolysis of the
boronic ester, generates the arylboronic acid. Arylboronic
acids have also been prepared by palladium-catalyzed
coupling of an aryl halide or triflate with a boron reagent,
such as B2(OR)2 or HB(OR)2, followed by hydrolysis of the
Aryl trifluoroborates have been studied as alternatives to
boronic acids.7,8 These reagents8,9 have been used in pal-
(1) Hall, D. G., Ed. Boronic Acids; Wiley-VCH: Weinheim, 2005.
(2) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Darses, S.; Jeffery, T.; Genet, J. P.; Brayer,
J. L.; Demoute, J. P. Tetrahedron Lett. 1996, 37, 3857. (c) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11.
(3) Darses, S.; Michaud, G.; Genet, J. P. Eur. J. Org. Chem. 1999, 1875.
(4) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2005; Chapter 5.
(8) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49.
(9) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020.
(10) (a) Molander, G. A.; Yun, C. S.; Ribagorda, M.; Biolatto, B. J.
Org. Chem. 2003, 68, 5534. (b) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424.
(5) Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2003, 4313.
(6) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(7) Batey, R.; Thadani, A.; Smil, D. Org. Lett. 1999, 1, 1683.
(11) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
10.1021/ol062903o CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/03/2007

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.
758
Org. Lett., Vol. 9, No. 5, 2007

Table 1. Conversion of Crude, Isolated Arylboronic Esters to
Arylboronic Acids by Aqueous NaIO4
Table 2. Conversion of Arenes to Arylboronic Acids by C-H
a
Borylation and Oxidative Hydrolysisa
a The arylboronic esters were generated by borylation of arene on a 10
mmol scale using 0.1% [Ir(COD)(OMe)]2 and 0.2% dtbpy in THF at 80
°C. NaIO4 (15.0 mmol) was added to 5 mmol of crude ArBpin in a 4:1
THF/H2O mixture. b Isolated yield.
groups. Moreover, the method tolerates functional groups,
such as esters.
a Borylation of arene was carried out on a 10 mmol scale using 0.1%
[Ir(COD)(OMe)]2 and 0.2% dtbpy in THF at 80 °C. NaIO4 (15.0 mmol)
was added to 5 mmol of crude ArBpin in a 4:1 THF/H2O mixture. b Isolated
yields on a 5 mmol scale of arene. Yields are the average of two reactions.
The compatibility of the oxidative hydrolysis with residual
iridium and a THF/water medium made it feasible to develop
a one-pot protocol for the conversions of arenes to aryl-
boronic acids without the need to remove solvent. This
sequence was evaluated starting directly with the arene. The
catalytic functionalization of the arene was conducted with
only 0.2 mol % of the combination of [Ir(COD)(OMe)]2 and
dtbpy as catalyst and B2pin2 as reagent in THF solvent.
Commercial arenes were used as received. The resulting
mixture was then diluted with water, and NaIO4 was added.
After addition of HCl and extraction into EtOAc, the crude
product was isolated. Although more than one catalyst for
the borylation of arenes has been reported,14,15,22 we note
that the IMH catalyst used in this work allows the C-H
activation to be conducted in an inert solvent, under mild
conditions, with low loadings of iridium.23
1H NMR spectroscopy. As shown in Table 2, the desired
arylboronic acids were isolated in excellent yields in most
cases. In particular, 3,5-disubstituted arylboronic acids were
selectively synthesized from the corresponding meta-
substituted arene, in most cases in high yields. This
methodology encompassed arenes containing ester and
halogen functional groups.
The major limitation of this protocol is the incompatibility
of the oxidative hydrolysis to electron-rich heteroarylboronate
esters. For example, attempts to conduct the oxidative
hydrolysis of the C-H borylation products from furan,
thiazole, N-methylimidazole, and 2,6-dimethylpyridine led
to dark reaction solutions containing mixtures of products,
A series of examples of this one-pot protocol is shown in
Table 2. The products of these reactions were isolated by
simply washing the crude boronic acids with hexanes. This
procedure provided products that were judged to be pure by
1
as determined by H NMR spectroscopy. Because of this
limitation, we also sought a nonoxidative method to convert
arylboronic esters into organoboron reagents that are more
reactive than the esters.
To this end, we studied a one-pot preparation of aryl
trifluoroborates from arenes. Vedejs reported the conversion
of arylboronic acids to the corresponding potassium aryl-
trifluoroborates by reaction of the esters with KHF2 in a 5:1
mixture of MeOH and H2O.13 A similar reaction of pinacol
boronic esters with KHF2 in a mixture of THF and H2O
(22) (a) Chen, H.; Schlect, S.; Semple, T. C.; Hartwig, J. F. Therm.,
Catal., Regiospecific Funct. Alkanes 2000, 287. (b) Cho, J.-Y.; Tse, M. K.;
Holmes, D.; Maleczka, R. E.; Smith, M. R. I. Science 2002, 295, 305. (c)
Mertins, K.; Zapf, A.; Beller, M. J. Mol. Catal. A 2004, 207, 21. (d)
Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew.
Chem., Int. Ed. 2001, 40, 2168.
(23) For examples of reactions in neat arene conducted with 0.003 mol
% and 0.02 mol % Ir, see refs 17 and 18, respectively.
Org. Lett., Vol. 9, No. 5, 2007
759

With these data in hand, we combined the borylation of
the arene in THF catalyzed by the [Ir(COD)(OMe)]2/dtbpy
system with conversion of the arylboronic ester to the
corresponding trifluoroborate with 6 equiv of KHF2 in a 1:3
mixture of H2O and THF. Removal of the solvent under
vacuum, extraction into acetone, and evaporation of the
acetone gave a mixture of pinacol and the desired aryltri-
fluoroborate product.
Table 3. Conversion of Arenes to Potassium
Aryltrifluoroborates by C-H Borylation and Displacement of
Pinacol by Fluoridea
It was difficult to find one solvent system that would
separate the pinacol byproduct from the aryltrifluoroborates.
The aryl trifluoroborates are typically purified by recrystal-
lization from acetonitrile or mixtures of acetone and hex-
anes.13 However, some of the pinacol crystallized together
with the trifluoroborate from these media. Although solvents
that separated the two materials could be found, the identity
of the solvent depended on the identity of the aryltrifluoro-
borate. A more general procedure involved sublimation of
the pinacol from the crude mixture at 60 °C, and the products
from studies on reaction scope were isolated by this method.
The scope of this synthesis of aryl trifluoroborates from
arenes by C-H borylation and conversion of the ester to
the resulting trifluoroborate is summarized in Table 3. Like
our studies on the reactions to form arylboronic acids, our
studies on the reactions to form trifluoroborates focused on
the synthesis of 3,5-disubstituted products that are lengthy
to generate by classical methods. The reactions occurred with
the more electron-rich and electron-poor meta-substituted
arenes. Like the reactions to form arylboronic acids, they
tolerated the presence of halogens on the arene and occurred
in high yield with an arene bearing a carbethoxy group.
Because of the absence of any oxidant in the conversion
of the boronic esters to the trifluoroborates, this protocol also
allowed for the synthesis of heteroaryl trifluoroborates. As
shown in entries 10 and 11, the reaction of benzofuran and
benzothiophene selectively formed the 2-substituted hetero-
aryl trifluoroborates in good to excellent yield.
To summarize, a synthesis of arylboronic acids and
potassium aryltrifluoroborates starting from arenes has been
developed. This one-pot methodology alleviates the need to
initiate the synthesis of boronic acids from halogenated
arenes and to use Grignard or organolithium reagents. More-
over, this sequence generates boronic acids with substitution
patterns that complement the types of substitution patterns
that can be generated from the sequence beginning with the
haloarenes. The commercial availability of [Ir(COD)(OMe)]2,
dtbpy, and a large number of arenes allows for easy access
to a wide range of new arylboronic acids and trifluoroborates.
a Borylation of arene was carried out on a 10 mmol scale using 0.1%
[Ir(COD)(OMe)]2 and 0.2% dtbpy in THF at 80 °C. KHF2 (5.7 mmol) was
added to 5 mmol of crude ArBpin in a 4:1 THF/H2O mixture. b Isolated
yields on a 5 mmol scale of arene.
would allow a one-pot synthesis of the aryl trifluoroborate.
However, conversion of a stable aryl pinacolboronate ester
to the trifluoroborate was not known.24
To test if the pinacolate group would be displaced to form
a trifluoroborate in a mixture of THF and water, we treated
a solution of PhBpin in THF with an aqueous solution of
KHF2. Complete conversion to the PhBF3 anion was
observed, as determined by 11B NMR spectroscopy.
Acknowledgment. We thank the NSF for support of this
work. C.C.T. thanks the German academic exchange service
(DAAD) for a postdoctoral fellowship. We thank Frontier
Science for a gift of bis-pinacolatodiboron.
Supporting Information Available: Experimental pro-
cedures and spectral data for reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(24) For an example starting with a different type of boronic ester, see:
Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153.
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