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.
The Pd(0)-catalyzed cyclization-allylation reactions of 2-alkynylbenzamides proceed with high regioselectivity to afford the 6-endo-cyclization-derived products 4-allyl-isochromen-1-imines. DFT calculations have been performed on this and the related arylation reaction, that has been reported to afford the products corresponding to an exo-cyclization under similarly Pd(0)-catalyzed conditions. Under the reaction conditions, these cyclizations are presumed to be triggered by activation of the C-C triple bond with either an allyl- or an aryl palladium complex, generated by oxidative addition of an allyl- or aryl halide to the Pd(0) catalyst. For reactions promoted by allylpalladium species, calculations predict a reversible cyclization, followed by a regioselectivity-determining endo-selective reductive elimination. In contrast, according to calculations, the corresponding arylations would proceed through irreversible exo-selective cyclization and reductive elimination steps. These predictions are consistent with the experimental observations. The divergent regiochemical outcome appears to have its origin in the differences caused on the intermediate palladium complexes by the groups derived from the coupling agents (allyl or aryl) and by the reaction conditions (solvent and ligands) through a subtle interplay of polarity and coordinative effects.
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