Unusual Regioselectivity in Palladium-Catalyzed Cyclization of 6-(Pronucleophile-tethered)-3-bromo-1,3-hexadienes: Experimental Observations and Theoretical Rationales

A palladium-catalyzed reaction of a series of 6-(pronucleophile-tethered)-3-bromo-1,3-hexadiene substrates 1, in which a bromodiene unit and a pronucleophile moiety are connected with a –(CH2)2– linker, was investigated. Under optimized conditions, intramolecular nucleophilic substitution and cyclization predominantly took place to give the corresponding vinylcyclopentene derivatives 2 in good to excellent yields. The reaction proceeded through the alkylidene-π-allylpalladium intermediate M2, and the tethered soft nucleophile moiety attacked at the internal sp2-carbon in the alkylidene-π-allylpalladium moiety. This is an unprecedented “reverse” regioselectivity in the palladium-catalyzed substitution of 2-bromo-1,3-dienes with a soft nucleophile. According to our density functional theory calculations, alkylidene-π-allylpalladium generally favors nucleophilic attack at the terminal sp3-C1 carbon due to the weaker Pd–C1 bond and a favorable obtuse attack angle. However, bearing a short –(CH2)2– tether, M2 necessarily imposes an acute attack angle at the terminal sp3-C1, and this also leads to an unfavorable ring strain in the seven-membered endocyclic allene product. As a result, the intramolecular nucleophilic attack at the internal sp2-C3 becomes predominant, accounting for the observed “reverse” regioselectivity.