C O M M U N I C A T I O N S
Table 2
Broad scope with respect to the carboxylic acid component was
also noted. Arylated 3,5-dinitrobenzoate and 2-bromoacetate allylic
esters such as 10 and 12 (entries 9 and 11, Table 1) may be further
elaborated via asymmetric Pd(0)-π-allyl substitution reactions and
enolate-type Claisen rearrangements, respectively.7,8 Arylated p-
nitrobenzoate allylic esters such as 11 may be readily hydrolyzed
during workup to afford the corresponding arylated allylic alcohols
(eq 3). Significantly, yields for the tandem sequence were observed
to be higher with excess carboxylic acid.9
The ability to use inexpensive and abundant hydrocarbon starting
materials to rapidly generate densely functionalized fragments for
complex molecule synthesis is a significant feature of this meth-
odology. Medicinally relevant arylated N-Boc glycine allylic esters
13 and 14 are accessible in isomerically enriched form (E:Z ) >20:
1; internal:terminal olefin ) >20:1) and in one step from com-
mercial hydrocarbon, amino acid, and aryl boronic acid reagents
(entry 12, Table 1, eq 2). Compounds related to 14 have been trans-
formed to medicinally important dipeptidyl peptidase IV inhibitors
via a series of steps that feature enolate-Claisen rearrangement of
the N-Boc glycine allylic ester to γ,δ-unsaturated amino acids,
Suzuki cross-coupling of the aryl bromide to biaryls, and ozonolysis/
oxidation of the olefin to a carboxylic acid moiety (eq 2).10
We have described a new one-pot transformation that converts
R-olefin hydrocarbons to E-arylated allylic esters with high regio-
and E:Z selectivities. The ease with which densely functionalized
building blocks are constructed from robust, commercial starting
materials makes this method well-suited for high-throughput
applications. The demonstrated ability of Pd(OAc)2/bis-sulfoxide
1 to effect vinylic C-H arylation under acidic, oxidative conditions
provides a new reaction manifold that is complementary to the
standard basic, reductive one, for generating Pd-aryl intermediates
for cross-coupling reactions.
Acknowledgment. M.C.W. acknowledges the NSF (CAREER
CHE-0548173) and Merck for financial support. J.H.D. is a Pytosh
Fellow. M. S. Chen confirmed eq 3.
Supporting Information Available: Experimental procedures, full
characterization, and a complete list of authors for ref 10. This material
References
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yields of 15 were obtained when the reaction was run under an O2
(1 atm) rather than the standard air atmosphere. The cinnamyl
alcohol unit may be further elaborated via enantioselective epoxi-
dation/resolutions, and the meta-substituted anisyl ring may be
transformed via Birch reduction/ozonolysis to a â-keto ester.11 Using
these transformations followed by selective reduction reactions, 15
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natural products such as bryostatin 1.11
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for allylic oxidation (entries 6-11, Table 2).
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Butylethylene (lacking an allylic hydrogen) is an excellent substrate for
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Vinylic C-H arylation most likely proceeds via an electrophilic
Pd(II)-promoted transmetalation/CdC bond insertion mechanism.
Consistent with this, substrates bearing allylic acetoxy and small
alkoxy substituents undergo highly regioselective vinylic C-H
arylation to yield internal olefin products,12 whereas substrates with
small allylic alkyl substituents yield mixtures of internal and
terminal olefins (Table 2, entries 1a-c vs 1d).13 Steric bulk in the
allylic position also furnishes product in high regioselectivities and
yields (Table 2, entry 1e).13 Catalyst 1 and BQ and carboxylic acid
reagents were needed for efficient vinylic C-H arylation. Although
Pd(OAc)2 has been shown to undergo transmetalation with boronic
acids under stoichiometric conditions in the absence of activating
agents,14 the bis-sulfoxide ligand was found to be critical for
efficient catalysis (entries 1 vs 2, Table 2). In support of a Pd(II)
cycle, in the absence of BQ oxidant, the reaction furnished only
trace amounts of 17, corresponding to one turnover of the catalyst
(entry 3, Table 2).15 Consistent with the noted increase in overall
yields with excess carboxylic acid, increased reactivity for the
arylation reaction was observed in the presence of AcOH (entry 1
and 5 vs 4, Table 2). Carboxylic acid may facilitate generation of
the electrophilic Pd(II) complex needed for efficient catalysis.16
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J. AM. CHEM. SOC. VOL. 128, NO. 47, 2006 15077