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BENZENES VIA Pd-CATALYZED [4+2]
BENZANNULATION
Pd-CATALYZED [4+2] BENZANNUATION
REDUCTIVE COUPLING OF ALKYNES WITH ALLENES AND [4+2] BENZANNULATION REACTION
Pd-CATALYZED FORMAL [2+2+2] TRIMERIZATION OF ALKYNES
HOMO- AND
CROSSDIMERIZATION/[4+2] BENZANNULATION REACTION
HEAD-TO-HEAD DIMERIZATION OF ALKYNES
MECHANISTIC
STUDIES ON Pd-CATALYZED BENZANNULATION REACTION
Another
area of our interest is concerned with the development of highly
selective benzannulation reactions, which are efficiently
catalyzed by palladium. The palladium-catalyzed
benzannulation reaction of enynes and diynes is a useful
synthetic method for the construction of polysubstituted
benzenes, which is distinct from most known cycloaddition
reactions. Firstly, the reaction requires a specific activating
group (AG = alkenyl or alkynyl). The second feature is the
perfect regiocontrol of cycloaddition. No reaction is observed
with enynophiles which do not possess the requisite activating
group. However, if
it is present, the reaction is totally regiocontrolled with
respect to the relative orientation of coupling partners.
Different
types of mono-, di-, and trisubstituted enynes were involved
into this transformation, providing tri-, tetra-, and
pentasubstituted arylalkynes, respectively. Functional
group tolerance of this benzannulation reaction is very good,
and incorporation of various functional groups into starting
enynes and/or diynes allows for preparation of diversely
functionalized arenes.
[Synlett
2003,
2265 (review)]
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While
investigating the [4+2] benzannulation reaction, we also
explored the addition of terminal alkynes to allenes as an
attractive atom-economical method for the preparation of
conjugated enynes. We
have found that the cross-coupling of a variety of terminal
alkynes with allenylphosphine-oxides catalyzed by a Pd(OAc)2-TDMPP system provided conjugated
endo-enynes solely,
while the TCPC-catalyzed reaction of the same reagents led to
the exclusive formation of exo-isomers.
The obtained exo-enynes were successfully employed in the
synthesis of multisubstituted diarylbenzylphosphine oxides via
the Pd-catalyzed [4+2]-benzannulation reaction. [J.
Org. Chem.
2003, 68, 6251]
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As
a further extension of the highly chemo- and regioselective
palladium-catalyzed [4+2]-benzannulation reaction catalyzed by
palladium(0), we designed a sequential protocol for [2 + 2 + 2]
intermolecular trimerization of alkynes. This was accomplished
by selectively generating the enyne partner in situ, either from
two identical or different alkynes, which then reacted with the
enynophile in [4+2] fashion to produce a multisubstituted
benzene ring.
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Most
importantly, sequential [2+2+2] trimerization afforded tetra-
and pentasubstituted benzenes as single reaction products
without formation of any regio- or chemoisomers. A
significant acceleration of the sequential trimerization
reaction was observed in the presence of Lewis acid/phosphine
combined system. Studies
to elucidate the role of Lewis acid are underway in our
laboratories. [J.
Org. Chem, 2001, 66, 2835]
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We
have also explored in detail the Pd-catalyzed dimerization of
terminal alkynes as the first step of the benzannulation
sequence. This led
us to discover unusual highly regioselective palladium-catalyzed
dimerization of terminal arylalkynes to produce E-head-to-head
enynes in the presence of a palladium(II) catalyst with a bulky,
electron-rich phosphine ligand, and amine additive. We found
this transformation very interesting from a mechanistic point of
view, as Pd(II) and Pd(0) complexes normally catalyzes reductive
coupling of alkynes affording head-to-tail enynes exclusively.
However,
efficient formation of an anti-Markovnikov product was observed
only in the reaction with terminal arylacetylenes possessing at
least one ortho-hydrogen
atom. It was
proposed that agostic interaction between the transition metal
and ortho-protons of
aromatic ring in the substrate is responsible for the observed
unusual regioselectivity of the reaction.
Kinetic isotope effect studies supported involvement of
agostic interaction at the carbopalladation step. [J.
Am. Chem. Soc. 2001, 123, 11107]
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Motivated by the importance of developing a more efficient [4+2] cyclization methodology, and intrigued by the acceleration effect observed in the presence of a Lewis acid, we performed systematic studies on the Lewis acid-assisted benzannulation reaction. It was found that dramatic acceleration of the Pd-catalyzed benzannulation reaction was achieved in the presence of MAO/TDMPP additives. It was also found that tertiary amines exhibit an even more pronounced accelerating effect on this reaction. These novel sets of conditions not only significantly facilitated the Pd-catalyzed [4+2] benzannulation reaction, but also improved the yields and, most remarkably, widened the scope of tetra- and pentasubstituted benzenes which can now be efficiently obtained by this methodology.
[J. Am. Chem.
Soc. 2006, 128, 5818-5827].
A detailed investigation of the observed effects suggested that the real nature of the acceleration lies not only in assisting the E/Z isomerization of starting enynes, but also in promoting one of the key steps of the [4+2] benzannulation, the formal [1,3]-hydrogen migration.
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