Isomerization-Arylation of 2,3-Epoxycyclohexanone
dium,21 we decided to investigate this heating method
under otherwise identical PPh3-stabilized aqueous DMF
conditions. Disappointingly, all attempts to carry out the
isomerization-arylation reaction with 2f at 150-180 °C
with otherwise classical conditions resulted in low yields
and problematic purification of 3a due to aryl scrambling
(p-Tol-Pd(PPh3)2X f Ph-Pd[P(p-Tol)Ph2](PPh3)X)22-25 and
accommodating problematic purifications.
SCHEME 1
A number of protocols for the utilization of aryl
bromides in Heck couplings have recently been identified
by using ligand-free reaction cocktails and only trace or
homeopathic amounts of palladium.26-30 From a prepara-
tive standpoint a phosphine-free catalyst is highly ben-
eficial since aryl scrambling is avoided and triarylphos-
phines are difficult to remove.31 Among available solvent
alternatives, poly(ethylene glycol) (PEG) is known to
promote Heck vinylation of various aryl bromides under
phosphine-free conditions.32 PEG has also been recog-
nized as a particularly green solvent33 and has been
suggested to act as a phase transfer catalyst in Heck
reactions with inorganic bases.34 To invent a high-speed
microwave promoted protocol for arylation of 1 allowing
a low catalytic loading, aqueous poly(ethylene glycol)
(PEG 200) was in initial experiments found to be a
promising reaction medium.
We selected the rearrangement-arylation of 1 with 2a
using only 0.05 mol % of Pd(OAc)2 and 20 min of
microwave heating at 150 °C as an appropriate PEG
model reaction for preparative optimization (Table 2). All
reactions were performed in 1.0 mmol scale utilizing
septum-sealed and microwave-transparent Pyrex vials.
The highest yields of product 3a resulted when 50%
aqueous PEG 200 (entries 4 and 9-11) was used. It
should also be noted that use of pure water or pure PEG
afforded inefficient reactions. An additional advantage
with aqueous PEG 200 concerned the convenient puri-
fication method. A rapid filtration of the cool reaction
mixture through a short silica plug removed unreacted
2a along with dehalogenated and homocoupled biaryl
compounds, permitting pure 3a to be separately eluated.
The reaction showed good productivity with catalyst
loadings as low as 0.05 mol %, although yields dropped
tions, the potentially chelating 1,3-diketone would be
present only in small amounts during the course of the
reaction, avoiding efficient trapping and deactivation of
catalytic metal. To our surprise, starting from 1 and with
an excess of bromobenzene (2a), only the isomeric 3-phen-
yl-1,2-cyclohexanedione (3a) was formed under the em-
ployed Heck conditions (Scheme 1). This finding encour-
aged us to investigate the synthetic value and the
reaction route of this novel transformation.
Results
The isomerization-C3-arylation protocol initially em-
ployed for the 1 to 3 interconversion was similar to the
earlier reported protocol for the Heck arylation3 of 1,2-
diketone 4: 5.0 mol % of Pd(OAc)2, 12.0 mol % of PPh3
(triphenylphosphine), 1.0 equiv of 1, 4.0 equiv of 2, and
4.0 equiv of DIEA (diisopropylethylamine) in aqueous
DMF. When applying these palladium(0) conditions with
nonhindered electron-rich or neutral aryl bromides and
classical oil bath heating at 100 °C for 17-41 h in sealed
vessels, the resulting product mixture comprised pre-
dominantly C3-arylated 3 (Table 1, classical conditions).
In fact, the DMF-based classical protocol enabled isola-
tion of 3a,d-g, in useful (45-72%) yields, although
p-anisyl bromide (2c) delivered no arylated product
whatsoever. Reacting electron-deficient aryl bromides led
only to low (3k) or no yields and an extensive formation
of dehalogenated arenes and biaryl side products. In this
preparative attempt, as well as in the previously reported
direct arylation of 4, sterically hindered 2l,m provided
only very low yields (entries 12 and 13). Important from
a mechanistic point of view, small amounts of intermedi-
ate 4 could be detected by GC-MS in most isomerization-
arylation entries during the reaction progress. Overall,
the yields of isolated 3 were comparable with the results
previously obtained starting with pure 4.3 Attempts to
substitute the aryl bromides for iodides or triflates under
classical reaction conditions were unsuccessful. In the
case of aryl triflates, no significant conversions took place,
and with aryl iodides, a rapid conversion into biaryl
structures immediately consumed the arylating agent.
Since rapid single-mode microwave heating19,20 to high
temperatures is known to decomplex trapped palla-
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