Theoretical investigation on the mechanism of Cu()-catalyzed synthesis of 4-quinolones: effects of additives HOTf HOTs

A computational study with the B3LYP density functional is carried out to explore the effects of additives (HOTf vs. HOTs) on the Cu(OTf) 2 -catalyzed synthesis of 4-quinolones. The optimal reaction path includes intermolecular nucleophilic addition (Step I), a H + -transfer process (Step II), intramolecular nucleophilic cyclization (Step III) and the elimination/formation process of MeOH (Step IV). The usage of Cu(OTf) 2 as the catalyst significantly promotes Step I and Step III. More importantly, the additive HOTf can not only play the role of the proton-transfer shuttle to assist H + -shift by the stepwise proton-transport process in Step II and Step IV, but also can act as the hydrogen-bond donor to facilitate the intramolecular cyclization between C1 and C5 in Step III. Due to the assistance of HOTf, the rate-determining free energy barrier of the Cu( ii )-catalyzed reaction is greatly reduced from 167.8 to 135.0 kJ mol −1 , which explains the experimental phenomena well (0% vs. 89% in yield). Interestingly, the hydrogen-bond donor/proton-donor ability of the additives (HOTf vs. HOTs) is found to be the primary factor that critically affects the catalytic activity of the additives in the present Cu( ii )-catalyzed reactions. For the additives of sulfonic acid type HO 3 S-R (R: -CF 3 vs. -PhCH 3 ), the use of a strong electron-withdrawing group -CF 3 is advantageous for the additive-assisted reactions. In a word, the present study is expected to help one understand the influence of additives on transition metal-catalyzed reactions including the ring-closed process and the proton-transfer process. Hydrogen-bond donor/proton-donor ability is revealed to be the primary factor that controls the catalytic capability of additives (HOTf vs. HOTs).