Pd(II)-catalyzed cross-coupling of sp3 C-H bonds with sp 2 and sp3 boronic acids using air as the oxidant

Article abstract of DOI:10.1021/ja801355s

O-Methyl hydroxamic acids, readily available from carboxylic acids, are found to be extremely reactive for β-C-H activation by Pd(OAc)₂. This reactivity is exploited to develop the first example of cross-coupling sp³ C-H bonds with sp³ boronic acids. Air was shown to be a suitable stoichiometric oxidant for the catalytic oxidative coupling reaction. A biologically active natural product is readily converted to its novel analogues through this coupling reaction. Copyright

Full text of DOI:10.1021/ja801355s

Published on Web 05/14/2008
Pd(II)-Catalyzed Cross-Coupling of sp3 C-H Bonds with sp2 and sp3 Boronic
Acids Using Air as the Oxidant
Dong-Hui Wang, Masayuki Wasa, Ramesh Giri, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received February 26, 2008; E-mail: yu200@scripps.edu
Table 1. ꢀ-Arylation of O-Methyl Hydroxamic Acidsa
Palladium-catalyzed cross-coupling reactions using organohalides
and other surrogates1 are among the most powerful and versatile tools
for forming carbon-carbon bonds.2 Recently, feasibility of oxidative
coupling of C-H bonds with organometallic reagents has also been
demonstrated via Pd(II)/Pd(0) catalysis.3,4 Upon further improvement
of the substrate scope and catalytic system, these C-H activation/
C-C coupling reactions5 could serve as a complementary tool for
cross-couplings when the regioselective introduction of halides in a
particular synthetic intermediate is problematic or requires multistep
operation. We have recently reported the coupling of ꢀ-C-H bonds
in carboxylic acids with organoboron reagents.3c However, major
limitations of the current protocol for C-H activation/C-C coupling
reactions remain to be addressed. First, the C-H activation/C-C
coupling reactions of carboxylic acid substrates only work with aryl
boronic esters and methylboronic acids. Second, the coupling of sp3
C-H bonds with sp3 boron reagents has not been achieved to date
despite the remarkable progress made in sp3-sp3 cross-coupling
reactions.6 Third, the use of Ag2CO3 or Ag2O as the stoichiometric
oxidant is not practical. To overcome these limitations, we here report
a new protocol using readily accessible and synthetically useful methyl
hydroxamic acids as substrates (eq 1).
We previously found that the formation of sodium salts of carboxylic
acids is crucial for the C-H activation and subsequent coupling with
phenyl boronic ester and MeB(OH)2.3c We hypothesize that the failure
a Reaction conditions: O-methyl hydroxamic acid (0.5 mmol),
arylboronic acid (0.8 mmol), Pd(OAc)2 (0.05 mmol, 10 mol %), Ag2O
(1 mmol), benzoquinone (BQ, 0.25 mmol), K2CO3 (1 mmol), t-BuOH (3
in using PhB(OH)2 and other alkyl boronic acids as coupling partners
is largely due to undesired homocoupling or ꢀ-hydride elimination
from the alkyl fragments of the sp3 boronic acids. We therefore decided
mL), 70 °C, 18 h. Reactions were carried out in a Teflon cap-sealed
tube. b t-BuOH:DMF ) 4:1 as solvent.
to derivatize carboxylic acids to structurally analogous and stronger
binding O-methyl hydroxamic acids.7 Since CONHOMe groups can
be readily converted to esters8a and amides8b or reduced to alkane
fragments,8b C-H activation using this functionality will be syntheti-
cally useful. Thus, we began to screen various reaction conditions using
our previous coupling protocol (see Supporting Information). We found
stirring substrate 1 with 0.5 equiv of benzoquinone, 2 equiv of Ag2O,
2 equiv of K2CO3, 1.5 equiv of PhB(OH)2, and 10 mol % of Pd(OAc)2
in tert-BuOH at 70 °C for 18 h afforded ꢀ-phenylated product 1a in
85% isolated yield (Table 1, entry 1). The presence of K2CO3 is critical
for the reaction to proceed. Other bases used for the coupling of
carboxylic acid substrates are not effective in this case. We were
pleased to find that substituted aryl boronic acids are also suitable
coupling partners, albeit giving lower yields (entries 3 and 4). Notably,
the coupling of amino acid derivative 4 provides a novel route to a
wide range of amino acid analogues (entry 6). The coupling of amide
5 derivatized from the corresponding acid (Gemfibrozil, a lipid
regulating agent) demonstrates the potential utility to access biologically
active compounds in medicinal chemistry (entry 7).
However, the coupling of substrate 1 with phenylethyl- and
butylboronic acids using this protocol did not give any desired product,
presumably due to ꢀ-hydride elimination. Previous studies on sp3-sp3
cross-coupling reactions suggest that this undesired pathway could be
suppressed by using a sterically hindered ligand and careful choice of
solvents.6 While the presence of sterically hindered ligands prevented
C-H activation, the use of 2,2,5,5-tetramethyltetrahydrofuran as the
solvent allows the coupling of sp3 C-H bonds with alkylboronic acids
(Table 2). We believe that this solvent serves as a sterically bulky
ligand preventing homocoupling and ꢀ-hydride elimination. Substrates
1, 2, and 5-7 were coupled with phenylethyl-, n-butyl-, i-butyl-, ethyl-,
and cyclopropylboronic acids to give the alkylated products in moderate
yields (Table 2, entries 1-8 and 10). An ester group in substrate 8
was also tolerated, and the coupling product cyclized in situ to give
the imide derivative 8a (entry 9).
From the viewpoint of catalysis, the replacement of Ag(I) salt
by an inexpensive and environmentally friendly oxidant such as
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7190 J. AM. CHEM. SOC. 2008, 130, 7190–7191
10.1021/ja801355s CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Functionalization of Dehydroabietic Acid
Table 2. ꢀ-Alkylation of O-Methyl Hydroxamic Acidsa
air9 will significantly improve the practicality of C-H coupling
reactions. In the current study, we found that air could serve as an
efficient stoichiometric oxidant for the newly developed C-H
activation/C-C coupling reaction of substrates 1-7 (Table 3).
The potential utility of these types of C-H activation/C-C
coupling reactions was further demonstrated by the alkylation of
substrate 9 derived from dehydroabietic acid (Scheme 1), a natural
product identified as an efficient BK channel opener.10 Compounds
exhibiting such activity could lead to useful treatments for diseases
such as acute stroke, epilepsy, and asthma. Typically, diversification
of such structures is difficult due to the general unreactivity of these
molecules aside from the carboxylic acid moiety, which is essential
for biological activity of the molecule. Masking the carboxylic acid
as the hydroxamic acid allows for functionalization at the methyl
C-H bond, affording a novel class of analogues that may display
improved pharmacokinetic properties.
In summary, we have developed the first protocol for the coupling
of sp3 C-H bonds with both sp2 and sp3 boronic acids. The
feasibility of using air as the oxidant is also demonstrated. Since
the CONHOMe group can be readily converted to esters, amides,
or hydrogens, this reaction is likely to find broad synthetic utility.
Acknowledgment. We thank The Scripps Research Institute for
financial support, and A. P. Sloan Foundation for a Fellowship (J.-Q.Y.).
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: O-methyl hydroxamic acid (0.5 mmol),
alkylboronic acid (0.8 mmol), Pd(OAc)2 (0.05 mmol, 10 mol%), Ag2O
(1 mmol), K2CO3 (1 mmol), benzoquinone (BQ, 0.25 mmol),
2,2,5,5-tetramethylTHF (3 mL, inhibitor free, anhydrous), 70 °C, 18 h.
Reactions were carried out in a Teflon cap-sealed tube.
References
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a Reaction conditions: O-methyl hydroxamic acid (0.5 mmol), boronic
acid (0.8 mmol), Pd(OAc)2 (0.05 mmol, 10 mol %), K2CO3 (1 mmol),
benzoquinone (BQ, 0.25 mmol), 20 atm air and 20 atm N2, 80 °C, 48 h.
Solvent for arylation: t-BuOH (3 mL). Solvent for alkylation:
2,2,5,5-tetramethylTHF (3 mL). Reactions were carried out in a high
pressure vessel. b 20 atm air. c 20 atm air and 60 atm N2.
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