Ligand-enabled methylene C(sp3)-H bond activation with a Pd(II) catalyst

Article abstract of DOI:10.1021/ja309325e

Pd(II) insertion into β-methylene C(sp³)-H bonds was enabled by a mutually repulsive and electron-rich quinoline ligand. Ligand tuning led to the development of a method that allows for installation of an aryl group on a range of acyclic and cyclic amides containing β-methylene C(sp³)-H bonds.

Full text of DOI:10.1021/ja309325e

Communication
pubs.acs.org/JACS
Ligand-Enabled Methylene C(sp3)−H Bond Activation with a Pd(II)
Catalyst
Masayuki Wasa, Kelvin S. L. Chan, Xing-Guo Zhang, Jian He, Masanori Miura, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
presence of γ-C−H bonds adjacent to the Pd center, which
ABSTRACT: Pd(II) insertion into β-methylene C(sp3)−
could outcompete the sluggish reductive elimination pathway
leading to the formation of the desired C(sp3)−C bond.
Therefore, we decided to develop a ligand to provide a solution
to this significant challenge.
Since acidic N-arylamides has been demonstrated to be
H bonds was enabled by a mutually repulsive and electron-
rich quinoline ligand. Ligand tuning led to the develop-
ment of a method that allows for installation of an aryl
group on a range of acyclic and cyclic amides containing β-
methylene C(sp3)−H bonds.
versatile auxiliaries for alkyl C(sp3)−H activation, a ligand that
strongly coordinates with the Pd(II) center and yet allows the
weakly coordinating amide moiety to bind to the same Pd
center is needed. Guided by our previous development of a
“mutually repulsive” pyridine ligand that coordinates with Pd
catalysts in a singly bound fashion and also allows the
coordination of electron-deficient arenes,9b we focused on a
pyridine-based ligand scaffold. Systematic ligand screening
using Pd(II)-catalyzed arylation with p-iodotoluene (p-Tol−I)
as a platform was carried out (Table 1). In the absence of
ligand, substrate 1 was treated with 15 mol % Pd(TFA)2, 4.0
equiv of p-Tol−I, 2.5 equiv of Ag2CO3, and 1.2 equiv of
evelopment of synthetic transformations based on
D
transition-metal-catalyzed functionalization of C(sp3)−
H bonds continues to attract intensive efforts.1,2 Our laboratory
recently demonstrated that a weakly coordinating N-arylamide
(CONHAr) moiety serves as a powerful auxiliary to effect a
diverse array of Pd-catalyzed C(sp3)−H functionalization
reactions of aliphatic acids.3 However, this auxiliary and others1
developed in our laboratory are not capable of activating
methylene C(sp3)−H bonds. Previous studies showed that Pd
insertion into inert methylene C−H bonds requires strongly
coordinating phosphine or pyridine auxiliaries (Scheme 1).4−7
a b
,
Table 1. Ligand Screening
Scheme 1. Methylene C(sp3)−H Bond Activation
Encouraged by the observed ligand acceleration in a number of
Pd(II)-catalyzed C(sp2)−H activation reactions,8 we focused
our efforts on developing ligands that can promote β-methylene
C(sp3)−H activation using the weakly coordinating N-
arylamide auxiliary. Herein we report the first example of
ligand-enabled N-arylamide-directed Pd(II)-catalyzed arylation
of acyclic and cyclic β-methylene C(sp3)−H bonds (Scheme 1).
While ligand-promoted aryl C(sp2)−H activation reactions
with Pd(II) catalysts have been developed in recent years,8,9
ligand scaffolds that facilitate C(sp3)−H activation are rare.3a,e,7
Methylene C−H bonds are significantly more resistant to Pd
insertion than primary C−H bonds because they are more
sterically hindered.1 Furthermore, following the methylene
C(sp3)−H cleavage step to form the cyclopalladation complex,
undesired β-hydride elimination could occur as a result of the
a
Conditions: 0.2 mmol of substrate, 15 mol % Pd(TFA)2, 30 mol %
ligand, 4.0 equiv of p-Tol−I, 3.0 equiv of Ag2CO3, 1.2 equiv of
b
K2HPO4, 0.5 mL of DCE, 120 °C, 24 h. The yield was determined by
1H NMR analysis of the crude product using CH2Br2 as an internal
standard, and GC/MS analysis was used to determine the mono:di
ratio.
Received: September 20, 2012
Published: November 1, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a b c
, ,
Table 2. Arylation of Methylene C(sp3)−H Bonds
K2HPO4 in 1,2-dichloroethane (DCE) at 120 °C for 24 h and
gave a <2% yield of the monoarylated product 1a based on 1H
NMR and GC/MS analyses. Interestingly, a slight increase in
the product yield to 7% was observed when 0.3 equiv of
pyridine (L2) was added to the reaction mixture. To increase
the sterics of the ligand, we screened 2,6-disubstituted pyridines
for the methylene C(sp3)−H arylation reaction. 2,6-Dimethyl-
pyridine (L3) gave a 9% yield of the monoarylated product,
while more sterically hindered L4 yielded no product.
However, we were delighted to find that 2,6-dimethoxypyridine
(L5) gave mono- and diarylated products in yields of 60 and
16%, respectively, suggesting that the electronic properties of
the pyridine are crucial. The diastereotopic ratio (dr) values of
products 1a mono and 1a di were determined to be 4:1 and
1:1, respectively, based on 1H NMR and GC/MS analyses. The
dr values were not affected to an appreciable extent by varying
the ligand. To verify the importance of using monodentate
ligands, bidentate ligands such as N-protected amino acids and
phenanthroline (L1) were also tested and shown to give no
arylation products.
Further optimization of the 2,6-disubstituted pyridines
suggested that both the steric bulk and electron-donating
ability of the ligand are crucial for the desired reactivity. For
example, 2,6-dichloropyridine (L6), 2-methoxypyridine (L7),
and 2-isopropyl-6-methoxypyridine (L8) gave drastically
diminished yields. Highly electron-rich 2,4,6-triethoxypyridine
(L9) gave a 96% combined yield of the products (mono:di =
1.3:1). We also found 2-methoxyquinoline (L10) to be
effective, affording a 74% yield (mono:di = 5.2:1). Considering
that 2-alkoxyquinoline scaffolds are easy to prepare, we focused
on tuning this structure. Hence, we synthesized 2-isopropox-
yquinoline (L11) and 2-isobutoxyquinoline (L12), both of
which gave full conversion.
a
Conditions: 0.2 mmol of substrate, 10 mol % Pd(TFA)2, 20 mol %
ligand, 3.0 equiv of Ar−I, 2.0 equiv of Ag2CO3, 1.2 equiv of K2HPO4,
b
1.0 mL of hexane, 110 °C, 24 h. Isolated yields are shown.
c
1
Diastereomeric ratios were determined by H NMR analysis of the
crude product and verified by GC/MS analysis.
With the optimized ligand L12 in hand, we converted a
variety of commercially available carboxylic acids into the
corresponding N-arylamides to examine the scope of the
arylation protocol (Table 2). In addition, further optimization
of the reaction conditions was carried out, and hexane was
found to be the optimal solvent, as it suppressed the
homocoupling of p-Tol−I. As a result, the Pd loading and
reaction temperature could be lowered to 10 mol % and 110
°C, respectively (see the Supporting Information). Product 1a
was obtained as a mixture of mono- and diarylation products in
3:1 ratio; the monosubstituted product was isolated as a
mixture of diastereomers (dr = 4:1). Amide substrates 2 and 3
derived from butanoic and pentanoic acids were arylated to give
the products in yields of 77 and 55%, respectively. Substrate 2
could also be arylated using 1-iodo-4-methoxybenzene and 1-
fluoro-4-iodobenzene to give 2b and 2c in yields of 71 and
68%, respectively. Arylation of α-isopropyl-substituted substrate
4 gave the desired product 4a in 82% yield as a single
diastereomer, with the methine C(sp3)−H bond remaining
intact. Substrate 5 possesses benzylic and aliphatic methylene
C(sp3)−H bonds that could both be arylated. We found that
arylation of the benzylic C(sp3)−H bond took place
predominantly, giving 5a as the major product in 71% yield
(dr = 7:1). The diarylated product 5b was also isolated in 20%
yield.
more reactive,3 only an 18% yield of 6a was obtained in the
absence of L12. Cyclobutyl substrate 7 was diarylated to give 7a
as the major product as a single diastereomer. For cyclopentyl,
cyclohexyl, and pyran substrates (8−11), the corresponding
monoarylation products were isolated as the major products. 9a
was obtained as a mixture of cis- and trans-substituted products
in a 4:1 ratio; a trace amount of diarylated product was
1
observed by H NMR analysis. For substrate 10, δ-lactam 10b
as a side product was also formed in 12% yield via Pd-mediated
o-C−H amidation of the trans-arylated product. Arylation of
tetrahydro-2H-pyran-4-carboxamide 11 gave a mixture of cis-
and trans-arylated products 11a in a 6:1 ratio.
In summary, ligand-enabled methylene C(sp3)−H activation
has been achieved through systematic design of the mutually
repulsive 2,6-dialkoxypyridine and 2-alkoxyquinoline ligands.
The development of cross-coupling reactions of methylene
C(sp3)−H bonds with organoboron reagents and enantiose-
lective methylene C(sp3)−H activation reactions are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
This method was also found to be effective in activating
cyclic methylene C−H bonds (6−11). Arylation of N-
arylcyclopropanecarboxamide 6 gave the monoarylated product
6a in 86% isolated yield as a single cis-substituted diastereomer.
Although cyclopropyl C−H bonds have been shown to be
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
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dx.doi.org/10.1021/ja309325e | J. Am. Chem. Soc. 2012, 134, 18570−18572

Journal of the American Chemical Society
Communication
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS, 1 R01 GM084019-02),
and Eli Lilly for financial support. We thank Bristol-Myers
Squibb (predoctoral fellowship to M.W.); the Agency for
Science, Technology and Research (A*STAR) Singapore
(predoctoral fellowship to K.S.L.C.); and Astellas Pharma Inc.
(postdoctoral fellowship to M.M.).
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