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.