C O M M U N I C A T I O N S
place, affording δ-lactam side products (5b and 6b) in 18% and
33% yields, respectively. For substrate 7, the cyclopropyl C-H
bond was selectively olefinated in the presence of an R-methyl
group to give 7a as the only product in 84% yield. Lowering the
temperature to 90 °C, we found that the cyclopropane substrates
could still be olefinated effectively without a major decline in yield
(7a, 77%).
yield. Using the CONHAr2 group, we successfully olefinated an
array of R-hydrogen-containing substrates (9, 11, 12, 13, and 14)
in good to excellent yields.
A plausible mechanism for this process involves initial amide-
directed C-H insertion by Pd(II) to generate an alkylpalladium
intermediate which reacts with the olefin via carbopalladation,
followed by ꢀ-hydride elimination to give the olefination product.
Pd(0) is reoxidized to Pd(II) by Ag(I)/Cu(II) to close the catalytic
cycle.
In summary, we have developed a Pd(II)-catalyzed reaction
protocol for the direct olefination of sp3 C-H bonds. After ꢀ-C-H
olefination, the amide products underwent 1,4-conjugate addition
to give the corresponding lactam compounds. The reaction condi-
tions could also be applied to effect olefination of cyclopropyl
methylene C-H bonds and substrates containing R-hydrogen atoms.
Studies to expand the scope to simple carboxylic acid substrates
and to develop enantioselective sp3 C-H olefination reactions of
gem-dimethyl- and cyclopropyl groups are currently underway in
our laboratory.
In our previous reports concerning sp3 C-H activation reactions
using carboxylic acids and their derivatives,11 substrates that
contained R-hydrogen atoms were unreactive. Thus, the substrate
scope was limited to compounds with quaternary R-carbon atoms.
Nevertheless, we recently established that the facile conversion of
the carboxylic acids to the corresponding CONHAr1 amides
provides a remedy to this problem, allowing access to a broad range
of substrates containing R-hydrogen atoms.9 We thus subjected
substrate 8 to the olefination conditions described above; however,
8a was obtained in only 55% yield. More complex substrates with
R-hydrogen atoms gave virtually no product. In an effort to
overcome this issue, we hypothesized that the reactivity could be
improved by exploiting the CONHAr2 directing group. Hence, we
attempted C-H olefination of substrate 9, and to our delight we
observed a considerable increase in the product yield, of 9a to 91%
Acknowledgment. We gratefully acknowledge The Scripps
Research Institute, the National Institutes of Health (NIGMS, 1 R01
GM084019-01A1) for financial support, Bristol Myers Squibb for
a predoctoral fellowship (M.W.), and the National Science Founda-
tion, the Department of Defense, and the Skaggs Oxford Scholarship
program for predoctoral fellowships (K.M.E.).
Table 2. Amide-Directed Olefination of sp3 C-H Bondsa,b
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free
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a Conditions: 0.2 mmol of substrate, 0.1 mL of benzyl acrylate, 10
mol % Pd(OAc)2, 2.0 equiv of LiCl, 1.1 equiv of Cu(OAc)2, 1.1 equiv
of AgOAc, 1 mL of DMF, 120 °C, N2, 12 h. b Isolated yield. c Obtained
as a mixture of inseparable cis/trans diastereomers (see Supporting
Information). Optically inactive starting materials were used. d Yield
1
determined by H NMR.
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