Theoretical Study On C1-vs. C3-regioselectivity In Pd(?)-catalyzed Olefination/dearomatization Of 2-naphthyl Ureas

Due to its atom-economical and environmentally friendly properties,C-H direct functionalization has received increasing attention as a method for efficiently constructing complex molecules.In particular,transition metal-catalyzed C-H direct functionalization has become one of the most important reactions in modern synthetic organic chemistry with its unique regioselective features.The regioselectivity in Pd(II)-catalyzed C-H direct functionalization of C2-substituted naphthalene has been a long-term issue in synthetic organic chemistry exactly due to its existence of multiple competitive reaction sites,including C1-,C3-and even C4-sites.A recent achievement in Pd(II)-catalyzed C1-dearomatization of 2-naphthyl ureas encouraged us to find out the key factors for determining the C1-and C3-regioselectivity of 2-naphthyl ureas by density functional theory(DFT)and wavefunction analysis.In this work,we have studied two reactions.One was Pd(II)-catalyzed C1-dearomatization of 2-naphthyl ureas and the other was Pd(II)-catalyzed C3-arylation of 2-naphthyl aniline.For Pd(II)-catalyzed C1-dearomatization of 2-naphthyl ureas,we identified a plausible reaction pathway,which led to the experimental C1-functionalized product with a reasonable energy profile.A homologous pathway giving C3-spirocycle was also calculated to investigate the nature of C1-regioselectivity in this reaction.According to the calculated results,we found that in the reaction C-H cleavage was the regioselectivity-determining step,and that C1 was the kinetically favorable site in this step due to electronic effect which makes C1 a more vulnerable site to electrophiles compared to C3,as reflected by the condensed Fukui function and its larger proportion of the highest occupied molecular orbital.Energy decomposition analyses and electronic structure analyses were further performed,of which the results were in good accordance with our conclusion but indicated C1 was a more sterically hindered site.This result provided us with the inspiration that steric hindrance may play an important role in frequently reported transition metal-catalyzed C3-arylation in the literature.We then studied by DFT calculations the reaction mechanism of the C3-arylation reaction mentioned before,which had been recently reported.The result was in line with our assumption that in C3-arylation of 2-naphthyl aniline the preferential functionalization of C3-site is due to its less steric hindrance than C1-site.This work is thus instructive for understanding the regioselectivity in Pd(II)-catalyzed C-H direct functionalization of C2-substituted naphthalene.