COMMUNICATION
DOI: 10.1002/chem.201201806
Palladium-Catalyzed Cross-Coupling of Unactivated Alkenes with Acrylates:
Application to the Synthesis of the C13–C21 Fragment of Palmerolide A
Zhen-Kang Wen,[a] Yun-He Xu,[a, b] and Teck-Peng Loh*[a, b]
À
Functionalized butadienes are ubiquitous structural motifs
in natural products, and they are also useful building blocks
in modern organic synthesis.[1] The construction of butadiene
scaffolds is frequently accomplished using the Horner–
Wadsworth–Emmons olefination reaction.[2] In recent years,
with the development of transition-metal-catalyzed coupling
reactions, butadiene synthesis that involves the use of either
palladium,[3] rhodium,[4] or ruthenium[5] complexes as cata-
lysts have been reported. However, for these reactions, the
need for prefunctionalizing the reactants and the undesired
formation of stoichiometric amounts of waste make them
neither atom economical nor environmentally benign.[6]
Consequently, the establishment of catalytic reactions that
involve the formation of a Csp2–Csp2 bond between two olefin
1,3-butadiene.[12] A rhodium-catalyzed oxidative C H olefi-
nation of functionalized alkenes was also developed by Glo-
rious and co-workers.[13] Despite the success in our initial
report on the palladium-catalyzed cross-coupling of two ole-
fins to form dienes, the reaction of more elaborate aliphatic
olefins did not afford the desired products.[14] Thus as part
of an effort to synthesize the natural product, palmeroli-
de A, which contains a complex diene motif, we needed to
find reaction conditions that would allow alkyl-substituted
alkenes to couple with acrylates. Accordingly, we report
herein a new method for the coupling of alkyl-substituted
alkenes with acrylates along with its application toward the
synthesis of the C13–C21 fragment of palmerolide A.
Initially, using our previously reported reaction conditions,
the model reaction of 1a (1 equivalent) with n-butyl acrylate
(2 equivalent) did not afford any desired product.[14] To
obtain the product, different bidentate ligands were used to
increase the catalytic activity of the palladium catalyst
(Table 1, entries 1–4). The results showed that, among the
ligand tested, 1,10-phenanthroline was the most efficient in
promoting the cross-coupling reaction (Table 1, entry 4).
Unfortunately, the reaction was not selective, the E and Z
products being obtained in equal amounts (50:50). To in-
crease the selectivity, a series of protected homoallylic alco-
hols were employed. To our delight, with the TIPS-protect-
ed substrate, the E and Z isomers were obtained in a ratio
of 75:25, albeit the reaction yield was low (Table 1, entry 9)
To further improve the reaction yield and stereoselectivity,
the catalyst loading, temperature, and choice of solvent
were varied. Ultimately, we found that the following reac-
À
substrates through direct C H bond functionalization, thus
giving butadienes, are necessary. Pioneering work on stoi-
chiometric palladium-mediated oxidative coupling of arenes
with electron-deficient olefins, as well as a catalytic variant
thereof, was first reported by the research group of Fuji-
wara.[7] Building on those results, palladium-catalyzed direct
À
C H bond functionalization reactions are now employed in
the synthesis of complex organic molecules.[8] To date, de-
À
spite the efficiency of direct (hetero)aryl C H bond func-
tionalization reactions,[9] direct alkene–alkene coupling reac-
À
tions involving alkenyl C H bond activation are rarely re-
ported. This paucity is primarily due to the inertness of the
À
C H bond in simple olefins, and the difficulties in promot-
ing the desired cross-coupling while avoiding homocou-
pling.[10] To date, a number of successful examples of such
cross-coupling reactions have been reported. Ishii and co-
workers reported the cross-coupling reaction of vinyl car-
boxylates with acrylates as catalyzed by PdII with vanadomo-
lybdophosphoric acid.[11] Yu and co-workers reported cross-
coupling reactions of activated alkenes and functionalized
tion conditions were the most effective: 10 mol% Pd
12 mol% 1,10-phenanthroline, 12 mol% AgSbF6 as an addi-
tive, and 2 equivalents of Cu(OAc)2 as an oxidant in NMP/
PivOH (v/v, 1:1) at 1208C for 24 hours. When using these re-
action conditions, the desired coupling product was obtained
in 82% yield with an E/Z ratio of 75:25 (Table 1, entry 17).
ACHTUNGTRENNUNG(OAc)2,
AHCTUNGTRENNUNG
[a] Z.-K. Wen, Y.-H. Xu, Prof. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371
1
Moreover, the H NMR analysis of the crude reaction mix-
ture indicated that neither products derived from a homo-
coupling reaction of alcohol 1a nor those derived from the
dimerization of butyl acrylate 2 were observed under the
optimized reaction conditions. Other oxidants, such as
AgOAc, Ag2O, and benzoquinone, gave relatively poor
yields of the cross-coupling product.
With optimized coupling reaction conditions established,
we expanded the scope of the reaction by examining the
cross-coupling between a dozen structurally diverse TIPS-
[b] Y.-H. Xu, Prof. T.-P. Loh
Hefei National Laboratory for Physical Sciences at the Microscale
and
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P. R. China)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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