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.
A three-component, one-pot, stepwise Sonogashiraheterocyclization-Heck-coupling process was developed starting from either haloarenecarboxamides, halophenols or haloanilines, terminal alkynes and electron-deficient alkenes. Cyclic imidate-, benzofuran-, or indole-type products are obtained, respectively, in useful yields, being typically better than those obtained with isolation of the intermediate Sonogashira adducts. Very high 6-endo selectivity is maintained with imidate-type coupling products despite the presence of copper salts carried over from the Sonogashira coupling.
A Practical Protocol for Three-Component, One-Pot, Stepwise Sonogashira--Heterocyclization-Heck Couplings. -A stepwise protocol is developed for the three-component process using halobenzamides, alkynes, and ethyl acrylate. The cyclization-intermolecular Heck coupling cascade of the initially formed 2-alkynylbenzamides with ethyl acrylate provides cyclic amidates in a 6-endo-selective manner. The extension of this protocol to phenol and aniline type substrates allows the preparation of benzofurane and indole derivatives. -(MADICH, Y.; DENIS, J. G.; ORTEGA, A.; MARTINEZ, C.; MATRANE, A.; BELACHEMI, L.; DE LERA, A. R.; ALVAREZ, R.; AURRECOECHEA*, J. M.; Synthesis 45 (
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