Thanaset Kititheerakul, Masahito Horie, Naomasa Kirihata, Hiroaki Ichio, Masamichi Ogasawara,* and Panida Surawatanawong*

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.

Reference: Kititheerakul, T.; Horie, M.; Kirihata, N.; Ichio, H.; Ogasawara, M.; Surawatanawong, P. Unusual Regioselectivity in Palladium-Catalyzed Cyclization of 6-(Pronucleophile-tethered)-3-bromo-1,3-hexadienes: Experimental Observations and Theoretical Rationales. Organometallics 2026, 45 (10), 1132-1143. https://pubs.acs.org/doi/10.1021/acs.organomet.6c00028

Authors

Thanaset Kititheerakul − Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

Masahito Horie − Department of Natural Science, Graduate School of Science and Technology, Tokushima University, Tokushima 770-8506, Japan

Naomasa Kirihata − Department of Natural Science, Graduate School of Science and Technology, Tokushima University, Tokushima 770-8506, Japan

Hiroaki Ichio − Institute for Catalysis and Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan

Masamichi Ogasawara − Department of Natural Science, Graduate School of Science and Technology, Tokushima University, Tokushima 770-8506, Japan; Tokushima International Science Institute, Tokushima University, Tokushima 770-8501, Japan; 

Email: ogasawar@tokushima-u.ac.jp

Panida Surawatanawong − Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; 

Email: panida.sur@mahidol.ac.th