Mechanism of Palladium-Catalyzed C–N Coupling with 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a Base

Abstract

The mechanism of the Buchwald−Hartwig amination assisted by the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is explored with density functional theory (DFT) calculations. Whereas the previous study indicates that the tight binding of DBU to the Pd(II) center could block the desired catalytic pathways, the recent work from Buchwald and co-workers demonstrates that the bulkier ligands, such as AlPhos, can overcome the catalyst deactivation by DBU and yield the C−Ncoupled product at room temperature. The results show that the bulkier ligands sterically hinder DBU binding and enable the desired catalytic steps by improving the Pd−substrate coordination. This study confirms quantitatively and precisely how and at which step of the catalysis the steric demands engineered into the phosphine ligands improve the catalytic C−N coupling using an organic base.

Organic Superbases in Recent Synthetic Methodology Research

“…This protocol tolerates traditionally base‐sensitive functional groups, such as alkyl halides and fluoroalkylamines. The use of AlPhos ligand is critical as its electronic character and bulky adamantyl groups reduce electronic donation to the cationic Pd center, thus increasing the acidity of the N−H bond of the coordinated amine [75a] . Subsequent mechanistic studies revealed that the turnover‐limiting step is dependent on the relative nucleophilicity of the organic superbase compared to the amine nucleophile [75b] .…”

Mechanistic Studies of Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

“…1 H NMR (500 MHz, CD2Cl2) δ 7.75 (td, J = 7.3 Hz, J = 6.6 Hz, J = 1.3 Hz, 1H), 7.63 (dt, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.53 (tdd, J = 7.7 Hz, J = 2.4 Hz, J = 1.3 Hz, 1H), 7.48-7.43 (m, 1H), 5.18 (s, 1H), 5.17 (s, 1H), 2.54-2.30 (m, 1H), 1.82 (hept, J = 6.6 Hz, 2H), 1.40 (s, 9H), 1.37 (s, 9H), 1.30 (dd, J = 7.0 Hz, J = 1.3 Hz, 6H), 1.05 (dd, J = 6.7 Hz, J = 1.9 Hz, 12H) ppm. 13 X-ray quality crystals were obtained by vapor diffusion of pentane into a solution of F in CH2Cl2 at 0 °C overnight. organic phase was then dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow oil.…”

Mechanistic Studies of Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

“…We reasoned that the presence of TESCF3 inhibited the fluorination process, because fluoride anions would react preferentially with TESCF3, preventing the generation of any Pd-F species that is required for product formation. 13 It was probable that of the 30 mol% TESCF3 added at the beginning of the reaction, only a small amount participated in the formation of the active catalyst species, while the rest decomposed to either CHCF3 or CF2CF2 (observed by 19 F NMR analysis of the crude reaction mixture) under the reaction conditions. We found that approximately 30 mol% was the minimal amount of TESCF3 required to achieve the optimal regiochemical ratio of products (see the Supporting Information for details).…”

“…1 H NMR (500 MHz, CD2Cl2) δ 7.75 (td, J = 7.3 Hz, J = 6.6 Hz, J = 1.3 Hz, 1H), 7.63 (dt, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.53 (tdd, J = 7.7 Hz, J = 2.4 Hz, J = 1.3 Hz, 1H), 7.48-7.43 (m, 1H), 5.18 (s, 1H), 5.17 (s, 1H), 2.54-2.30 (m, 1H), 1.82 (hept, J = 6.6 Hz, 2H), 1.40 (s, 9H), 1.37 (s, 9H), 1.30 (dd, J = 7.0 Hz, J = 1.3 Hz, 6H), 1.05 (dd, J = 6.7 Hz, J = 1.9 Hz, 12H) ppm. 13…”

“…1 H NMR (400 MHz, CDCl3) δ 2.55 (s, 3H), 2.39-2.30 (m, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 1.73 (s, 3H), 1.33 (m, 6H), 1.17 (s, 9H), 1.14 (s, 9H), 1.01 (d, J = 6.9 Hz, 6H) ppm. 13 C NMR (101 MHz, CDCl3) δ 149.2 (ddd, J = 246.7 Hz, J = 9.6 Hz, J = 4.3 Hz), 145.5, 145.0, 139.6 (dd, J = 247.5 Hz, J = 16.6 Hz), 139.9, 139.8, 138.0 (dd, J = 6.9 Hz, J = 6.9 Hz), 137. 6…”