Aryl trihydroxyborates: Easily isolated discrete species convenient for direct application in coupling reactions

Article abstract of DOI:10.1021/ol061564w

A conceptually and practically simple alternative approach to the use of arylboron species as the organometallic component in cross-coupling processes is described whereby trihydroxyborate salts are isolated and directly employed. The protocol derives practical benefit from the ease and convenience of the isolation and subsequent use of the discrete borate salts, eliminates the need for additional base, and aids the use of correct reaction stoichiometry.

Full text of DOI:10.1021/ol061564w

ORGANIC
LETTERS
2
006
Vol. 8, No. 18
071-4074
Aryl Trihydroxyborates: Easily Isolated
Discrete Species Convenient for Direct
Application in Coupling Reactions
4
Andrew N. Cammidge,*,† Victoria H. M. Goddard, Hemant Gopee,
†
†
†
†
†
‡
Nicola L. Harrison, David L. Hughes, Christopher J. Schubert,
Benjamin M. Sutton, Gary L. Watts, and Andrew J. Whitehead
†
†
School of Chemical Sciences and Pharmacy, UniVersity of East Anglia,
Norwich NR4 7TJ, U.K., and GSK Pharmaceuticals, Gunnels Wood Road,
SteVenage SG1 2NY, U.K.
a.cammidge@uea.ac.uk
Received June 26, 2006
ABSTRACT
A conceptually and practically simple alternative approach to the use of arylboron species as the organometallic component in cross-coupling
processes is described whereby trihydroxyborate salts are isolated and directly employed. The protocol derives practical benefit from the
ease and convenience of the isolation and subsequent use of the discrete borate salts, eliminates the need for additional base, and aids the
use of correct reaction stoichiometry.
The use of aryl boronic acids as cross-coupling partners in
palladium and other transition metal catalyzed (e.g., Suzuki-
Miyaura) reactions has received enormous interest particu-
transfer of the second aryl residue from aryl boronic acid to
the arylpalladium intermediate. Aryl boronic acids do not
themselves participate in such transmetalation processes. To
transmetalate, the boronic acid (or boronate ester) needs to
be activated by reaction with a nucleophile to form the
1
larly over the last 10-20 years. The mechanisms of these
2
reactions can vary subtly. In a conventional Suzuki-
3
Miyaura cross-coupling reaction (Scheme 1), aryl halide (or
triflate) can be considered to undergo oxidative addition to
Pd(0). The second key step in the catalytic cycle involves
corresponding borate complex. Conventionally, this occurs
in situ with addition of a suitable base/nucleophile to the
(2) See, for example: (a) Goossen, L. J.; Koley, D.; Hermann, H. L.;
Thiel, W. Organometallics 2006, 25, 54. (b) Goossen, L. J.; Koley, D.;
Hermann, H.; Thiel, W. Chem. Commun. 2004, 2141. (c) Armatore, C.;
Jutand, A. Acc. Chem. Res. 2000, 33, 314. (d) Armatore, C.; Jutand, A. J.
Organomet. Chem. 1999, 576, 254. (e) Cammidge, A. N.; Crepy, K. V. L.
J. Org. Chem. 2003, 68, 6832.
(3) Braga, A. A. C.; Morgen, N. H.; Ujaque, G.; Maseras, F. J. Am.
Chem. Soc. 2005, 127, 9298.
†
University of East Anglia.
GSK.
‡
(1) Reviews on the Suzuki reaction include: (a) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457. (b) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (c) Bellina, F.; Carpita, A.; Rossi, R. Synthesis
004, 2419.
2
1
0.1021/ol061564w CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/01/2006

permits convenient isolation of the discrete “active” borate
salt suitable for direct use in cross-coupling reactions. The
boronic acid is prepared in the usual manner, from 4-bromo-
Scheme 1. Suzuki-Miyaura Coupling Reaction and
Simplified Catalytic Cycle
1
-hexylbenzene via formation of the Grignard reagent
followed by quenching with trimethylborate. The reaction
mixture is subjected to normal aqueous workup and con-
centrated. The residue is dissolved in toluene and treated
with a concentrated solution of sodium hydroxide. A
precipitate of the corresponding sodium trihydroxyarylborate
salt forms immediately (sodium hydroxide is added dropwise
until no further precipitate forms) and can be isolated by
filtration as a free-flowing, pure colorless powder (Scheme
1
2
). The H NMR spectrum clearly indicated that a single,
Scheme 2. Preparation and Isolation of “Activated” Boratesa
4
reaction mixture. An alternative strategy has been occasion-
ally employed whereby the “activated” boronate ester is
formed, typically by quenching an organolithium intermedi-
a
After preparation of boronic acid by conventional procedures,
5
the crude product is taken up in toluene. Concentrated NaOH is
added until no further precipitate is formed. The pure borate salt is
isolated by filtration.
ate with trialkyl borate, and used. Recent innovations involve
6
7
the use of trifluoroborate and tetraarylborate salts as the
coupling partners in such reactions.
In most cases, particularly on a laboratory scale, these
conventional reaction sequences (formation and isolation of
boronic acid and subsequent reaction with an added base
nucleophile) pose few problems. However, this sequence can
present well-known problems, especially when more elabo-
rate (often precious) aryl boronic acid derivatives are required
for use. Hydrophobic boronic acids can be difficult to isolate,
usually requiring chromatography. The materials tend to form
waxy solids comprising a variable and unpredictable mixture
of the parent boronic acid and anhydrides. Formation of the
latter does not affect subsequent reactions but prohibits
convenient, reproducible calculation of the reaction stoichi-
ometry, important for large/production scale applications.
The above drawbacks were routinely encountered in our
laboratories and led us to investigate a conceptually and
practically simple solution based on isolation and direct use
of trihydroxy borate salts. Hexylphenylboronic acid/boronate
was selected as the substrate for this investigation. This
boronic acid can be easily prepared, but its isolation is not
convenient due to its hydrophobic/amphiphilic character.
However, a simple modification to the experimental protocol
discrete species was formed. Further evidence for formation
11
of the borate salt came from B NMR which shows a single
resonance at 5.89 ppm, characteristic of tetrahedral boron
8
species.
The general applicability of this protocol for isolation of
related borate salts has been investigated using a series of
prepared and commercially available boronic acids. In all
cases, the sodium trihydroxyarylborate salts (shown in Table
1
and in Supporting Information) were easily and con-
veniently isolated as described above in near quantitative
yield. Crystals were grown (from water) of the sodium
4
(
[
-methoxyphenylborate salt, and the X-ray crystal structure
the first of such a species) is shown in Figure 1. The
Na(H O) units are linked in hydrogen-bonded sheets in
B(OH) units form links
2
5 n
]
the crystal. The anionic p-MeOC
H
6 4
3
between the sheets, with the borate groups forming part of
the hydrogen-bonding network in one sheet and the methoxy
O atom acting as an acceptor group in the neighboring sheet.
The sodium atom is coordinated by six water molecules in
an approximately octahedral pattern. Every hydrogen of the
water molecules is involved in an O-H‚‚‚O hydrogen bond.
Two of the borate OH groups are also hydrogen-bond donors,
and the three borate O atoms are acceptors. Other salts, as
prepared, are similarly isolated as hydrates. Their water
content is easily determined using NMR spectroscopy in
(4) Formation of trihydroxyboronates in solution has been accepted for
many years, but the species have been only rarely isolated: Fields, C. L.;
Doyle, J. R. Thermochim. Acta 1974, 8, 239.
(5) (a) Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59, 6501. (b)
Frohn, H.-J.; Adonin, N. Y.; Bardin, V. V.; Starichenko, V. F. J. Fluorine
Chem. 2003, 122, 195.
3
CD OD by integration. Alternatively, anhydrous salts were
obtained by drying in a desiccator overnight.
(
6) (a) Darses, S.; Michaud, G.; Gen eˆ t, J.-P. Tetrahedron Lett. 1998,
3
9, 5045. (b) Molander, G. A.; Figueroa, R. Aldrichchimica Acta 2005, 38,
4
9. (c) Darses, S.; Gen eˆ t, J.-P. Eur. J. Org. Chem. 2003, 4313.
(7) Lu, G.; Franzen, R.; Zhang, Q.; Xu, Y. J. Tetrahedron Lett. 2005,
(8) Nakazawa, I.; Suda, S.; Masuda, M.; Asai, M.; Shimizu, T. Chem.
Commun. 2000, 879.
4
6, 4255.
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Org. Lett., Vol. 8, No. 18, 2006

Table 1. Suzuki-Miyaura Couplings Employing Isolated
Borate Salts
Figure 1. First X-ray crystal structure of an aryl trihydroxyborate
salt (p-MeOC B(OH) Na).
6
H
4
3
cleanly under standard conditions, and (unoptimized) yields
are very good (typically >90% by NMR spectroscopy of
the crude reaction product). Representative examples, shown
in Table 1 (further examples in Supporting Information),
demonstrate that this “base-free” protocol is widely ap-
plicable. Extension to alkylborates is straightforward (n-hexyl
is shown as an example) providing a shelf-stable, solid alkyl
anion equivalent for cross-couplings. It can be seen that
electron-rich and heteroaromatic borates are readily employed
in this protocol, and the reaction between thiophenylborate
and bromobenzonitrile further demonstrates the potential to
expand substrate tolerance to include examples with base-
sensitive functional groups. The reactions shown in the table
were performed using the salts as isolated (1.5-2 equiv).
However, a distinct advantage to isolating and employing
discrete borate salts stems from the ability to calculate and
use more precise stoichiometry (boronic acids themselves
are typically contaminated with varying proportions of their
respective anhydrides). The sodium borate salt was formed
from 2-methoxyphenylboronic acid, as described above, and
dried in a desiccator overnight to give the anhydrous salt.
This salt (1.1 equiv) was employed in a standard Suzuki-
Miyaura coupling with 4-bromotoluene and gave >95%
conversion to the corresponding biphenyl. Sodium salts have
been investigated most extensively, but preliminary experi-
ments indicate that the corresponding potassium and barium
salts can be similarly prepared and employed (Supporting
Information).
Activated boronic acids/borates are finding application in
transition metal catalyzed reactions beyond Suzuki-Miyaura
cross couplings. To prove the broader application of these
isolated, active borates, we selected the rhodium-catalyzed
a
Yields are of isolated material.
9
conjugate addition reaction between the boronate salt
10
prepared from 4-tolylboronic acid and cyclohexenone. Once
again, the direct reaction proceeded cleanly and smoothly
to give a good yield of the conjugate addition product
The main motivation for isolating these borate salts was,
however, their subsequent direct use in Suzuki-Miyaura (and
other) reactions. It became immediately apparent that the
borate salts can indeed be used directly and conveniently in
Suzuki-Miyaura coupling reactions. As expected, the reac-
tions do not require addition of further base/nucleophile,
which is itself a significant advantage. The reactions proceed
(Scheme 3).
(
9) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(10) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000.
Org. Lett., Vol. 8, No. 18, 2006
4073

use of the borate salts. Elimination of the base from the
catalyzed reaction has both economic benefits and the
potential to expand substrate tolerance.
Scheme 3. Rhodium-Catalyzed Conjugate Addition
Employing an Isolated Boronate Salt
Acknowledgment. We would like to thank EPSRC, GSK,
and Merck Ltd. for financial support and the EPSRC National
Mass Spectrometry Service Center (Swansea).
Supporting Information Available: X-ray structural
data, experimental procedures, and compound characteriza-
tion data (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, a conceptually and practically simple
alternative approach to the use of arylboron species as the
organometallic component in catalyzed processes has been
demonstrated.11 The protocol derives practical benefit from
the ease and convenience of the isolation and subsequent
OL061564W
(11) Patent applied for.
4074
Org. Lett., Vol. 8, No. 18, 2006