Structurally diverse C3-alkenylbenzofurans, C3-alkenylindoles, and C4-alkenylisoquinolones are efficiently prepared by using consecutive Sonogashira and cascade Pd-catalyzed heterocyclization/oxidative Heck couplings from readily available ortho-iodosubstituted phenol, aniline, and benzamide substrates, alkynes, and functionalized olefins. The cyclization of O- and N-heteronucleophiles follows regioselective 5-endo-dig- or 6-endo-dig-cyclization modes, whereas the subsequent Heck-type coupling with both mono- and disubstituted olefins takes place stereoselectively with exclusive formation of the E isomers in most cases.
A Pd‐catalyzed 5‐exo‐selective oxycyclization/oxidative Heck coupling cascade is described, starting from readily available ortho‐alkynylbenzamides and functionalized olefins. The key to a high regioselectivity in the cyclization step is the choice of catalyst and/or additives. Thus, Pd(OAc)2 provides the desired 5‐exo products predominantly, whereas with PdCl2 or Pd(TFA)2, the corresponding 6‐endo products prevail. The subsequent oxidative Heck‐type coupling takes place stereoselectively with the very predominant formation of E isomers, leading to an effective preparation of structurally diverse carbonyl‐substituted allylideneisobenzofuranimines.
A regioselective
heterocyclization–Sonogashira coupling
cascade between 2-alkynylbenzamides and terminal alkynes is described.
The reaction proceeds under Pd(II) catalysis, with air used as a terminal
oxidant to regenerate the catalyst from the Pd(0) produced in the
C–C coupling. The cascade process provides alkynyl-substituted
isobenzofuranimine products in a single operation. These products
are the result of a 5-exo O-cyclization, while products derived from
the alternative 6-endo cyclization mode are observed in minor amounts.
Two competing mechanisms have been considered to account for the observed
results. Both involve heterocyclization, alkyne C–H activation,
and reductive elimination steps but differ in the relative order of
the first two. Control experiments using a preformed alkynylpalladium
complex have shown that a mechanism starting with alkyne C–H
activation is viable. On the other hand, DFT calculations indicate
that the alternative cyclization-first mechanism is also competitive,
particularly when PPh3 is used as ligand. Calculations
also suggest that the exo cyclization is favored over the endo mode
by the presence of PPh3 and σ-C Pd ligands in the
activated complex undergoing cyclization.
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