Microwave-accelerated iridium-catalyzed borylation of aromatic C-H bonds

Article abstract of DOI:10.1021/ol901306m

Image Persented Microwave heating accelerates the Ir-catalyzed C-H borylation of aromatic substrates when compared with reactions carried out at the same temperature under standard heating conditions. Application to a one-pot single solvent process for ta

Full text of DOI:10.1021/ol901306m

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3586-3589
Microwave-Accelerated Iridium-Catalyzed
Borylation of Aromatic C-H Bonds
Peter Harrisson,† James Morris,‡ Todd B. Marder,*,† and Patrick G. Steel*,†
Department of Chemistry, Durham UniVersity, South Road, Durham DH1 3LE, U.K.,
and Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell,
Berkshire RG42 6EY, U.K.
todd.marder@durham.ac.uk; p.g.steel@durham.ac.uk
Received June 11, 2009
ABSTRACT
Microwave heating accelerates the Ir-catalyzed C-H borylation of aromatic substrates when compared with reactions carried out at the same
temperature under standard heating conditions. Application to a one-pot single solvent process for tandem C-H borylation/Suzuki-Miyaura
cross-coupling sequences using microwave-accelerated reactions gives fast and efficient access to a wide range of biaryl and heterobiaryl
compounds.
Aryl and heteroaryl boronates1 are very important intermedi-
ates in organic synthesis that have been deployed in many
useful transformations including the Suzuki-Miyaura cross-
coupling reactions,2 Cu-catalyzed C-O and C-N coupling
reactions,3 and Rh-catalyzed conjugate additions to carbonyl
compounds.4 As a result there is a need for efficient methods
to prepare them. Subsequent to our observation of substo-
ichiometric arene borylation during the formation of novel
[(η6-arene)Ir(Bcat)3] (cat ) 1,2-O2C6H4) complexes from
reaction of [(COD)Ir(η-indenyl)] with excess HBcat in
aromatic solvents,5 a number of groups including Ishiyama,
Miyaura, Hartwig, and Smith have developed in situ Ir
catalysts for the borylation of aromatic C-H bonds, impor-
tantly, under under mild conditions.6,7 The most widely
utilized system employs [(COD)Ir(µ-OMe)]2 (1) with 4,4′-
di-t-butyl-2,2′-bipyridine (dtbpy).8 Density functional theory
(DFT) calculations9 and experimental data10 suggest that a
sterically hindered, five-coordinate [Ir(Bpin)3L2] species
(Bpin ) B(OCMe2CMe2O)) is the active complex for C-H
activation. This sterically constrained active species accounts
for the selectivity observed, with borylation typically oc-
curring at positions remote to substituents or ring junctions.
We have used this selectivity to prepare novel pyrene-2,7-
bis(boronate) and perylene-2,5,8,11-tetra(boronate) esters
among other polycyclic aryl boronates.11
Although there have been many approaches to enhance
the potential of Ir-catalyzed C-H borylation by developing
sequential reactions, involving in situ elaboration of the
initially formed boronate ester or acid,12,13 there have been
relatively few attempts to facilitate the C-H borylation
reaction. While reactions with certain substrates are known
to proceed at room temperature, most reports describe
† Durham University.
‡ Syngenta Ltd.
(1) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005.
(2) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(3) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clarke, C. G;
Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863.
(4) (a) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571.
(b) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2881.
(5) Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder,
T. B. J. Am. Chem. Soc. 1993, 115, 9329.
(7) Mkhalid, I. A. I.; Murphy, J. M.; Barnard, J. H.; Marder, T. B.;
Hartwig, J. F. Chem. ReV. Submitted for publication.
(8) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2003, 680, 3.
(9) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem. Soc.
2003, 125, 16114.
(6) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390. (b) Ishiyama, T.; Takagi,
J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002, 41, 3056. (c)
Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III
Science 2002, 295, 305.
(10) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, I.; Miyaura,
N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263.
(11) Coventry, D. N.; Batsanov, A. S.; Goeta, A. E.; Howard, J. A. K.;
Marder, T. B.; Perutz, R. N. Chem. Commun. 2005, 217.
10.1021/ol901306m CCC: $40.75
Published on Web 07/23/2009
 2009 American Chemical Society

lowing from our earlier work,13e this was undertaken in
MTBE and required heating at 80 °C for 6 h to achieve
complete conversion. Attempts to accelerate this reaction by
undertaking an otherwise identical transformation (concentra-
tion, volume, etc.) in a microwave reactor brought about
startling benefits with complete conversion requiring only
60 min at the same reaction temperature. We sought to
ascertain whether this effect was general. Consequently, we
explored a range of substrates for which the “thermal” C-H
borylation reaction was slow, even at elevated temperatures
(Table 1).
Table 1. Comparison of Microwave Accelerated Borylation with
Standard Heating Conditions
For each substrate, reactions were carried out under both
standard heating conditions and microwave conditions in
order to provide a comparison between the different heating
methods. These experiments were carried out in identical
thick-walled glass reaction tubes with crimp top septum seals.
Conventional heating was achieved with a preheated alumi-
num block in which the depth of the tube in the block was
equal to that of the solution, and magnetic stirring was
employed in all cases. All reactions were carried out at 80
°C with 1.0 mmol of the substrate and 2.4 mL of a stock
solution containing 1.5 mol % of iridium precatalyst 1, 3
mol % of dtbpy, and 1.0 mmol of B2pin2 in MTBE.15 The
reactions were monitored at regular intervals for conversion
and product identification by GC-MS. The times stated in
Table 1 are those required to reach the given conversions.
All reactions showed acceleration compared to conven-
tional heating conditions. The borylation of m-xylene and
p-xylene (Table 1, entries 1 and 2) shows a considerable
acceleration relative to the standard reaction with comparable
isolated yields of the 5- and 2- borylated isomers being
achieved, respectively. The borylations of 2,6-dimethyl- and
2,6-dichloropyridine (Table 1, entries 3 and 4) were achieved
in 5 and 3 min, respectively, compared to 30 and 20 min
under standard heating conditions. The borylations of dim-
ethylpyrazines (Table 1, entries 5 and 6) were achieved with
high conversions in shorter reaction times compared to
classical, thermal heating conditions.
a Purified isolated yield of reaction reaching 100% conversion, unless
otherwise stated. b GC-MS conversion based on comparison of starting
material and product peak intensities. As a result of the boronate being R
to nitrogen, it was not possible to isolate the products as they are prone to
proteodeborylation. c 1:1 mixture of bis-3,6- and 3,7-pinacolboronate esters.
d 18% starting material recovered. e 16% starting material recovered. f 1.5
mmol of B2pin2 used to achieve full bis-borylation of substrate. g 58%
starting material recovered in both cases. h 85:15 mixture of 5- and
7-pinacolboronate esters. i Isolated as the 8-boronate ester along with traces
of 3 other monoborylated isomers (GC-MS). j 2.0 mmol of B2pin2 used to
achieve complete bis-borylation of substrate.
Whereas the mono-borylation of quinoline has been
reported using [(COD)Ir(µ-Cl)]2, dtbpy, and B2pin2 at 100
°C for 16 h,16 we were able to achieve the previously
unreported bis-borylation of quinoline in minutes in under
µW conditions (Table 1, entry 7). The borylation of 2,5-
substituted, five-membered heteroarenes was achieved in high
yields showing significant acceleration compared to that
achieved using conventional heating. Notably, 2,5-dibro-
mothiophene (Table 1, entry 10) was borylated in 80%
isolated yield in 1 h, compared to a time of 18 h to achieve
the same levels of product formation under standard condi-
tions. Two indole derivatives were borylated (Table 1, entries
12 and 13) to give 7- and 5-borylated isomers. Curiously,
the tetrahydrocarbazole was significantly more reactive
affording 95% conversion compared to 40% conversion for
the cyclopentylindole after a similar reaction time. Finally,
N-Boc-protected 7-azaindole (Table 1, entry 14) was bis-
borylated to achieve 3,5-borylated product in 92% isolated
yield in 20 min under microwave conditions, whereas
conditions involving reactions at elevated temperatures
(80-150 °C). We have an ongoing interest in the application
of microwave heating to facilitate various organometallic
complex catalyzed transformations,14 and in this Letter we
report that microwave (µW) irradiation considerably acceler-
ates the borylation of aromatic substrates with respect to
reactions performed using conventional heating at the same
temperature.
Initial experiments involved the C-H borylation of
m-xylene as this avoids problems of regioselectivity. Fol-
Org. Lett., Vol. 11, No. 16, 2009
3587

reactions under standard heating conditions required 6 h to
provide a similar yield.
of different Ir sources including IrCl3, [(COD)Ir(µ-OMe)]2,
[(COD)Ir(µ-Cl)]2, and [Ir(Cp*)Cl2]2. Each metal source was
examined in the presence and absence of dtbpy. Reactions
were carried out using 1 and 3 mol % Ir with, where used,
1.0 equiv (to [Ir]) of dtbpy at 100 and 150 °C in MTBE.
However, all such attempts to find an alternative iridium
source to access the same chemistry were unsuccessful,
suggesting that the known active species for this reaction
remains intact during the µW accelerated reaction.
While this work was in progress, Gaunt et al. reported
the use of µW irradiation for the aromatic C-H borylation
of an N-protected pyrrole using [(COD)Ir(µ-Cl)]2, dtbpy, and
B2pin2 in hexanes, followed by Suzuki-Miyaura cross-
coupling.20 Although efficient, the reported conditions
involved elevated temperatures (100 °C) for extended reac-
tion times (1 h) for the borylation step. Applying our
methodology to this substrate provided significant advantage
with both much reduced reaction times and increased
efficiencies, (Figure 1). The µW borylation reaction was
Although microwave irradiation in organic synthesis has
been in use for many years, the mode of action is not yet
fully understood.17 Microwave heating has been used in
many cases as a means to attain elevated temperatures leading
to enhancements of reactions rates and thus shorter reaction
times. Microwave radiation also offers a more direct heating
mode, reducing the effects of convection and thus removing
hot and cold spots in a reaction vessel.
However, there are examples in which reactions are
accelerated at the same reaction temperature as for standard
heating conditions; this is termed “non-thermal effects”.17,18
From the results given in Table 1, it could be seen that
the borylations of these aromatic substrates show marked
acceleration when performed under µW conditions relative
to standard reaction conditions.
As both conventional and µW heating modes were
employed at the same temperature, we wanted to probe the
cause of this acceleration. Since the solvent used, MTBE,13e
is not predicted to be a strong microwave absorber, we
focused on the roles of catalyst and substrate. The latter
seems unlikely to be the sole cause as although the
heterocyclic substrates have a significant dipole moment and
can be expected to be efficiently activated under microwave
conditions, the simple nonpolar arenes (entries 1 and 2) also
show effective promotion. Maguire et al. have recently
described a protocol in which benzene and other simple
aromatics were borylated using Ir(0) nanoparticles in ionic
liquids under µW conditions in moderate to good yields.19
Speculating that, under the µW reaction conditions, Ir
nanoparticles might be generated, we explored a selection
Figure 1
irradiation.
. C-H borylation of N-Boc pyrrole using microwave
monitored by GC-MS, which showed 100% conversion after
3 min at 80 °C and led to an isolated yield of 98% of the
3-borylated product (Figure 1).
(12) (a) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III
J. Am. Chem. Soc. 2003, 125, 7792. (b) Shi, F.; Smith, M. R., III; Maleczka,
R. E., Jr. Org. Lett. 2006, 8, 1411. (c) Murphy, J. M.; Liao, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 15434. (d) Murphy, J. M.; Tzschucke,
C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757. (e) Tzschucke, C. C.; Murphy,
J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761. (f) Holmes, D.; Chotana,
G. A.; Maleczka, R. E., Jr.; Smith, M. R., III Org. Lett. 2006, 8, 1407. (g)
Having demonstrated that the borylation of a wide range
of aromatic and heteroaromatic substrates can be achieved
with reaction times vastly reduced from those previously
reported in the literature and in comparison to conventional
heating conditions, we then sought to extend this methodol-
ogy to include functionalization of the boronate ester.
Consequently we thus employed a rapid, single solvent, two-
step, one-pot C-H borylation/Suzuki-Miyaura cross-
coupling sequence in which the purified biaryl products were
isolated in quantitative yields after reaction times of minutes
without the need for changing solvent or removal of reactant
or catalyst following the borylation step. Following complete
conversion of the initial arene to the boronate ester (GC-MS),
the microwave vessel was successively charged with water
(1.0 mL) and then 2 mol % Pd(dppf)Cl2, KOH (5.0 equiv)
and methyl 4-iodobenzoate (1.1 equiv). Simply heating this
mixture in the microwave reactor at 80 °C for 5 min afforded
the biaryl product in quantitative conversions (Table 2).
As previously described,13e we observed, by GC-MS,
biaryl products that arose from the homocoupling of the aryl
boronate, in amounts consistent with the reduction of the
Pd(II) catalyst precursor to the active Pd(0) catalyst. This
Boebel, T. A.; Hartwig, J. F. Tetrahedron 2008, 64, 6824
.
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Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2006, 128, 15552.
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.
(15) Typically, 25 mL of catalyst stock solution was prepared, which
was enough to carry out 10 reactions when 2.4 mL of the solution was
used per reaction. Thus, 1 (104 mg), dtbpy (83 mg), and B2pin2 (2642 mg)
were added to a volumetric flask, and the stock solution was diluted to 25
mL with MTBE.
(16) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.
Tetrahedron Lett. 2002, 43, 5649
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3588
Org. Lett., Vol. 11, No. 16, 2009

sequence giving cross-coupled biaryl products from an
unactivated arene with reaction times of minutes. Impor-
tantly, this is achieved without need for change of solvent
or removal of reactant following the borylation step.
In conclusion, we have shown that iridium-catalyzed
borylation of aromatic C-H bonds can be accelerated by
the use of microwave heating. This methodology can also
be applied to a one-pot single solvent C-H borylation/
Suzuki-Miyaura cross-coupling sequence. This process
provides access to substituted and structurally diverse biaryls
from unactivated arenes in high yields in minutes, and
represents a powerful method for the generation of compound
libraries.
Table 2. One-Pot Borylation/Suzuki-Miyaura Cross-Coupling
Sequence
Acknowledgment. We thank the EPSRC and Syngenta
(CASE award to P.H.) for financial support of this work,
AllyChem Co. Ltd. for a generous gift of B2pin2, Dr. A. M.
Kenwright (Durham University) for assistance with NMR
experiments, and Dr. M. Jones (Durham University) and the
EPSRC National Mass Spectrometry Service in Swansea for
mass spectra.
a Borylation carried out under µW irradiation at 80 °C. b Suzuki-Miyaura
cross-coupling carried out under µW irradiation at 80 °C, with 2 mol %
Pd(dppf)Cl2, KOH (5.0 equiv), methyl 4-iodobenzoate (1.1 equiv), and H2O
(1.0 mL). c Purified, isolated yield.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
was further confirmed by the isolation of a maximum of 96%
yield of cross-coupled biaryl following column chromatog-
raphy.
OL901306M
Although µW-assisted Suzuki-Miyaura reactions are well
documented,21 these are the first examples of a one-pot
(21) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.
Org. Lett., Vol. 11, No. 16, 2009
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