Angewandte
Communications
Chemie
Reaction Cascades Hot Paper
An Iron-Catalyzed Bond-Making/Bond-Breaking Cascade Merges
Cycloisomerization and Cross-Coupling Chemistry
Pierre-Georges Echeverria and Alois Fꢀrstner*
Abstract: Treatment of readily available enynes with alkyl-
Grignard reagents in the presence of catalytic amounts of
Fe(acac) engenders a remarkably facile and efficient reaction
3
cascade that results in the net formation of two new CꢀC bonds
while a CꢀZ bond in the substrate backbone is broken. Not
only does this new manifold lend itself to the extrusion of
heteroelements (Z = O, NR), but it can even be used for the
cleavage of activated CꢀC bonds. The reaction likely proceeds
via metallacyclic intermediates, the iron center of which gains
ate character before reductive elimination occurs. The overall
transformation represents a previously unknown merger of
cycloisomerization and cross-coupling chemistry. It provides
ready access to highly functionalized 1,3-dienes comprising
a stereodefined tetrasubstituted alkene unit, which are difficult
to make by conventional means.
Scheme 1. A possible new way of harnessing the reactivity of metalla-
cycles; the proposed scenario merges the ability of low-valent iron to
catalyze cycloisomerization and cross-coupling reactions.
[
14,15]
atom at the bridgehead position from occurring.
Rather,
T
he growing awareness of the many favorable attributes of
homogeneous iron catalysis fertilizes, amongst other things,
the alignment of the electron-rich [M]ꢀC bond and the
s*-orbital of the adjacent CꢀZ entity should lead to ring
opening. This manifold might allow one to extrude hetero-
elements and could even lend itself to the cleavage of
the development of new methodology for the selective
[
1–6]
formation of CꢀC bonds.
In this context, early work by
[16]
our group has helped to demonstrate that this cheap, benign,
readily available, and—for a surprisingly long time—under-
utilized element can serve as a substitute for palladium in
(activated) CꢀC bonds. The challenge in reducing this plan
to practice, however, lies in the downstream chemistry:
whereas any conventional decomposition of a metallacycle
by b-hydride elimination forms a reactive metal hydride
species that ultimately safeguards catalyst turnover (compare
C!D), a separate reaction has to juxtapose with the
envisaged ring opening to ensure regeneration of the active
principle [M]. We conjectured that iron catalysis is adequate
for this purpose, in that the envisaged cycloisomerization
could be merged with cross-coupling; in so doing, function-
alized 1,3-diene products of type F come into reach. It is
[
7]
various cross-coupling reactions. In addition to this “noble
task”, its use allows the scope to be extended, since catalysts
generated in situ from simple iron salts and Grignard reagents
are capable of engaging certain electrophilic partners into
cross-coupling that fail to react under conventional
[
8]
conditions.
Along similar lines, the ability of low-valent iron to induce
a host of cycloisomerization or cycloaddition reactions
becomes increasingly apparent, which are otherwise also
tempting to assume that the ability of iron to form ate
[
9–12]
[17,18]
dominated by the use of noble-metal catalysts.
Once
complexes
provides further assistance, since alkylation of
again, it is reasonable to assume that this metal cannot only
emulate well-established reactivity patterns, but might
provide opportunities for innovation.
the ferracycle B (M = Fe) primarily formed will facilitate the
ring opening through the increased electron density of the
reacting site in E; at the same time, the escorting cation might
engage with the leaving group, relieve possible geometric
constraints in the transition state, and hence lower the
barriers along the reaction coordinate.
Under the proviso that many such reactions proceed via
[
9–13]
metallacyclic intermediates,
we envisaged an unorthodox
reaction mode (Scheme 1). Thus, it seems unlikely that
a reactive intermediate of type B comprising a potential
leaving group Z within the bicyclic core will evolve by
canonical b-hydride elimination, since the fairly rigid frame-
work prevents efficient orbital overlap with the hydrogen
[
19]
The readily available enyne 1a
was deemed an
adequate model compound to test this hypothesis
(Scheme 2). The electron-deficient alkene unit of 1a will
favor oxidative cyclization with formation of a metallacycle
2
a, which in turn should benefit from the partial enolate
character that the ester imposes. At the same time, this
functional group will report whether the projected iron-
catalyzed manifold is fast enough to outperform competing
attack of the Grignard reagent at the electrophilic sites of the
substrate. Finally, the good leaving group properties of
[
*] Dr. P.-G. Echeverria, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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