Pd(II)-catalyzed cross-coupling of C(sp2)h bonds and alkyl, aryl, and vinylboron reagents via Pd(II)/Pd(0) catalysis

Article abstract of DOI:10.1246/cl.2011.1004

Pd(II)-catalyzed cross-coupling of ortho-CH bonds in benzoic acid and phenylacetic acid amides with alkyl, aryl, and vinylboron reagents have been achieved via Pd(II)/Pd(0) catalysis, demonstrating the unprecedented versatility of CH activation reactions.

Full text of DOI:10.1246/cl.2011.1004

doi:10.1246/cl.2011.1004
1004
Published on the web September 5, 2011
Pd(II)-catalyzed Cross-coupling of C(sp2)-H Bonds
and Alkyl-, Aryl-, and Vinyl-Boron Reagents via Pd(II)/Pd(0) Catalysis
Masayuki Wasa, Kelvin S. L. Chan, and Jin-Quan Yu*
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, USA
(Received June 1, 2011; CL-110468; E-mail: yu200@scripps.edu)
Pd(II)-catalyzed cross-coupling of ortho-C-H bonds in
benzoic acid and phenylacetic acid amides with alkyl-, aryl-,
and vinyl-boron reagents have been achieved via Pd(II)/Pd(0)
catalysis, demonstrating the unprecedented versatility of C-H
activation reactions.
carbene (NHC) ligands to promote oxidative addition of the
organohalides and subsequent reductive elimination while
suppressing undesired side reactions;2 however, these ligands
have been incompatible in Pd(II)-catalyzed oxidative C-H
activation reactions based on our previous reports.3,4 In the
absence of appropriate ligands, each step of the catalytic cycle
could be derailed by undesired side reaction pathways such as
homocoupling and ¢-hydride elimination. Although aryl-boron
reagents have been successfully coupled to the C-H bonds in
previous reports,3,4,6 the cross-coupling of alkyl-boron reagents
has remained elusive3,4a-4c due to the following reasons: alkyl-
boron reagents are generally less stable, transmetallation
proceeds at a slower rate, and ¢-hydride elimination is a
competitive pathway upon transmetallation.2n,7
With these considerations in mind, we initiated our study on
cross-coupling of C(sp2)-H bonds with alkyl-, aryl-, and vinyl-
boron reagents using a highly versatile N-arylamide directing
group recently developed by our group (Scheme 2). Using this
directing group, we have reported a wide range of Pd(0)- and
Pd(II)-catalyzed functionalization protocols of both unactivated
C(sp3)-H and C(sp2)-H bonds, which includes arylation,
olefination, carbonylation, amination, and fluorination reac-
tions.8 Based on the remarkable versatility observed, we
conjectured that it is possible to devise reaction conditions that
enable the cross-coupling of diverse organoboron reagents with
the ortho-C(sp2)-H bonds of the synthetically and pharmaceuti-
cally valuable benzoic acid and phenylacetic acid derivatives.
We began systematic screening of the reaction conditions
using N-arylamide substrate 1 and phenylboronic acid pinacol
ester (Ph-BPin) as the coupling partner (Table 1). Gratifyingly,
we found that the cross-coupling product 1a was obtained using
Pd(OAc)2 (10 mol %) as the catalyst, Ag2CO3 as the terminal
oxidant, and NaHCO3 as the base in tAmylOH(tert-pentyl
alcohol). The use of other aryl-boron reagents such as Ph-
B(OH)2, phenylboroxine and Ph-BF3K resulted in reduced
yields. The addition of 0.5 equiv of 1,4-benzoquinone (BQ) was
crucial as a promoter for the reductive elimination to fashion the
C-C bonds: no product was obtained in its absence. Addition-
The past decade has witnessed a renaissance in Pd(II)-
catalyzed C-H activation/C-C bond forming reactions.1 Among
the various catalytic platforms such as Pd(0)/Pd(II) and Pd(II)/
Pd(IV) catalysis for forging C-C bonds via C-H activation, the
Pd(II)/Pd(0) manifold to cross-couple C-H bonds with organo-
metallic reagents is potentially one of the most versatile in terms
of scope of substrate and coupling partner. More importantly,
this catalysis mirrors the highly enabling cross-coupling
reactions using organohalides in the forging of new C-C bonds;
its potential utility in modern organic synthesis is therefore self
explanatory.2 In particular, this catalysis begins with C-H
activation by a Pd(II) catalyst (rather than oxidative addition of
the aryl, alkyl, or vinyl halide to Pd(0)) as a means of entering
the catalytic cycle (Scheme 1). Since our report on Pd(II)-
catalyzed cross-coupling of unactivated C(sp2)-H bonds with
alkyl-tin reagents in 2006,3 our group4 and others5 have sought
to expand the synthetic utility of the C-C cross-coupling
reactions via C-H activation by exploiting synthetically useful
directing groups, and nontoxic and abundant organoboron and
organosilane reagents as the coupling partners. It is worth noting
that early studies by the groups of Oi and Murai have
independently demonstrated C(sp2)-H activation/C-C cross-
coupling reactions catalyzed by Rh and Ru, respectively,5
although Pd-catalyzed C-H/R-M coupling represent a distinct
challenge involving completely different redox chemistry.
Despite these efforts, the development in Pd(II)-catalyzed
C-H activation/C-C cross-coupling reactions still remains at an
early stage compared to the state of the art in cross-coupling
reactions using organohalides. Modern cross-coupling reactions
rely upon bulky, electron-rich phosphine and N-heterocyclic
Scheme 1. General cross-coupling catalytic cycles.
Scheme 2. Proposed transformation.
Chem. Lett. 2011, 40, 1004-1006
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1005
Table 1. Cross-coupling of Ph-BPin and C(sp2)-H bondsa,b
Scheme 3. Alkylation and vinylation of C(sp2)-H bonds.13
Scheme 4. Amide hydrolysis.13
Subsequently, we also established the ortho-vinylation protocol
of substrate 1 using cyclohexene-1-boronic acid pinacol ester. To
our delight, we obtained the vinylation product 1c in 70% yield.
The product was isolated as a ¤-lactam formed via a tandem
intramolecular Pd-mediated oxidative amination between the
amide directing group and the newly installed olefin: a mixture
of 1c and the uncyclized product was obtained with a shorter
reaction time. To our knowledge, this is the first example of
Pd(II)-catalyzed cross-coupling of vinyl-boron reagents and
C(sp2)-H bonds.11,12
To summarize, we have developed a versatile Pd(II)-
catalyzed protocol for the cross-coupling of C(sp2)-H bonds
with a diverse range of organoboron reagents including aryl-,
alkyl-, and vinyl-boron reagents. The N-arylamide directing
group could be hydrolyzed under basic conditions to give the
corresponding carboxylic acid in excellent yield (Scheme 4).
Studies to expand the scope of the cross-coupling protocol to
aliphatic acid amide substrates are underway in our laboratory.
aReaction conditions: 0.2 mmol of substrate, 10 mol %
Pd(OAc)2, 1.5 equiv of Ph-BPin, 3 equiv of NaHCO3, 1.5
equiv of Ag2CO3, 0.5 equiv of BQ, 5 equiv of H2O, 0.4 equiv
DMSO, 1 mL tAmylOH, 100 °C, N2, 12 h.13 bIsolated yields.
1
cFormation of diarylated product was observed by H NMR.
ally, the introduction of 5 equiv of H2O to the reaction improves
conversion (15-20%) by facilitating transmetallation of Ph-
BPin.9 The addition of DMSO stabilizes the Pd(0) species by
suppressing catalyst decomposition, thus further improving the
yield by 5-10%.10 Substrates 2, 3, 6, and 7 provide a mixture of
mono- and diarylation products under the optimized reaction
conditions, however, substitution in the meta position with
an electron-withdrawing group (4 and 5) provides selective
arylation in the para position respective to the halide. The amide
derivatives of commercial drugs ibuprofen 7 and naproxen 8
were also functionalized in good yields. For the Ibuprofen
derivative 7, ¢-C(sp3)-H arylation also takes place to provide 7b
as a minor side product.
Encouraged by the successful development of the arylation
protocol, we further investigated the cross-coupling of alkyl-
and vinyl-boron reagents (Scheme 3). The successful develop-
ment of the alkylation protocol relied on utilizing alkyl-
trifluoroborates as the coupling partner as they undergo facile
transmetallation relative to the other alkyl-boron reagents and
display better stability under the reaction conditions.2n Under the
optimized conditions, 74% of the n-butylation product 1b was
obtained using n-Bu-BF3K as the coupling partner. The use of
Li2CO3 as the base and THF as solvent was found to be optimal.
We gratefully acknowledge The Scripps Research Institute,
and the National Institutes of Health (NIGMS,
1 R01
GM084019-02) for financial support. We thank Bristol Myers
Squibb for a predoctoral fellowship (M.W.), and the Agency for
Science, Technology and Research (A*STAR) Singapore for a
predoctoral fellowship (K.C.).
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
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Chem. Lett. 2011, 40, 1004-1006
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/