Angewandte
Chemie
DOI: 10.1002/anie.201207770
C–H Activation
Ether-Directed ortho-C–H Olefination with a Palladium(II)/
Monoprotected Amino Acid Catalyst**
Gang Li, Dasheng Leow, Li Wan, and Jin-Quan Yu*
Cyclopalladation reactions promoted by strong s-chelation
have served as a fruitful platform for studying and developing
redox chemistry to establish catalytic cycles for C–H func-
tionalization processes.[1] However, these well-established
C–H activation reactivities have several limitations from the
viewpoint of both catalysis and synthetic applications.[1f] First,
the cyclopalladated intermediates are thermodynamically
stable and less reactive in the subsequent functionalization
step, thereby making early discovery of suitable conditions for
a diverse range of catalytic reactions difficult. Second, the
substrates are typically limited to molecules containing
nitrogen-, sulfur-, or phosphorus-chelating groups.[1a] Third,
the strongly coordinating directing groups either outcompete
ligands for vacant coordination sites or dominate the elec-
tronic properties of the metal centers, both of which are not
desirable for developing ligand-controlled reactions. In
response to these challenges, we and others have recently
established weak coordination as a powerful means for
directing catalytic C–H activation with PdII, RhIII, and RuII
catalysts.[2–3] The interplay between a suitable ligand and these
types of weak coordination on PdII centers was also shown to
accelerate C–H activation.[4] Herein, we demonstrate for the
first time that monoprotected amino acid ligands (MPAA)
promote ether-directed C–H olefination,[1e] which provides
a method to functionalize readily available arylethyl ethers to
afford novel cinnamate derivatives.
example of using arylether directing groups to promote
À
activation of benzylic C H bonds, the use of simple alkyl-
ethers to direct aryl C–H activation via a six-membered
cyclopalladation represents a distinct and unanswered chal-
lenge. Since alkylethers are widespread in natural products
and drug molecules,[5] we set out to develop C–H activation
reactions using a combination of weak coordination of the
alkylether moiety and ligand acceleration[2h] to provide a new
method for the functionalization of a major class of ethers,
namely arylethyl ethers [Eq. (2)].
Arylether-directed benzylic C–H activation:[6a]
Alkylether-directed aryl C–H activation:
Ether is one of the most common functional groups in
natural products and drug molecules.[5] The development of
ether directed C–H functionalization reactions would be very
useful and important. However, such reports are very rare in
literature,[6,7] presumably owing to the poor coordination of
ethers to late transition metal centers. To our knowledge, only
one example of ether-directed C–H functionalization with
a PdII catalyst is documented to date, and it is arylether-
directed benzylic C–H amidation reported by ꢀlvarez and
MuÇiz et al. [Eq. (1)].[6a] While this reaction is an intriguing
Taking into consideration the weakly coordinating ability
of the ether moiety, we began to develop the olefination of
ether 1a using a weakly coordinating solvent hexafluoroiso-
propanol (HFIP).[2h] Thus a mixture of ether 1a (0.2 mmol),
ethyl acrylate 2a (0.3 mmol), Pd(OAc)2 (10 mol%), and
Ag2CO3 (0.4 mmol) was stirred in HFIP (2 mL) under 908C
for 24 h (Table 1, entry 1). 1H NMR analysis detected the
formation of the mono-olefinated product 3a in 11% yield.
Guided by previous studies on PdII-catalyzed C–H activation
using MPAA ligands,[2h,4] we screened these ligands and
observed significant improvement of the reaction with several
ligands (Table 1, entries 2–4).[8] The olefinated products were
formed in 92% total yield (mono/di = 1.9/1) when Ac-Gly-
OH was used (Table 1, entry 4). Other solvents except
CF3CH2OH drastically decreased the yields (Table 1,
entries 5–7). Among the oxidants tested, Ag2CO3 was shown
to be the most effective one, which was consistent with our
previous report on PdII/Pd0 catalysis (Table 1, entries 8–11).[9]
Notably, the use of O2 as the terminal oxidant was also
possible with a catalytic amount of Cu(OAc)2 (Table 1,
entry 12). To improve the mono-selectivity, reaction condi-
tions were further optimized (Table 1, entries 13–16). Either
lowering the reaction temperature or stopping the reaction at
lower conversion led to improved mono-selectivity while
[*] Dr. G. Li, Dr. D. Leow, L. Wan, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[**] We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS, 1 R01 GM084019-04),
Amgen, Novartis, and Eli Lilly for financial support. We also thank
the Agency for Science, Technology and Research (A*STAR)
Singapore for a postdoctoral fellowship (D.L.). L.W. is a visiting
student from Nanjing University of Science and Technology,
sponsored by the China Scholarship Council.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1245 –1247
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1245
Li, Gang
