Palladium-Catalyzed Dual Ligand-Enabled Alkylation of Silyl Enol Ether and Enamide under Irradiation: Scope, Mechanism, and Theoretical Elucidation of Hybrid Alkyl Pd(I)-Radical Species

Abstract

We report herein that a palladium catalyst in combination with a dual phosphine ligand system catalyzes alkylation of silyl enol ether and enamide with a broad scope of tertiary, secondary, and primary alkyl bromides under mild irradiation conditions by blue light-emitting diodes. The reactions effectively deliver α-alkylated ketones and α-alkylated N-acyl ketimines, and it is difficult to prepare the latter by other methods in a stereoselective manner. The α-alkylated N-acyl ketimine products can be further subjected to chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester to deliver chiral N-acyl-protected α-arylated aliphatic amines in high enantioselectivity up to 99% ee, thus providing a method for facile synthesis of chiral α-arylated aliphatic amines, which are of importance in medicinal chemistry research. The N-acetyl ketimine product also reacted smoothly with various types of Grignard reagents to afford sterically bulky N-acetyl α-tertiary amines in high yields. Theoretical studies in combination with experimental investigation provide understanding of the reaction mechanism with respect to the dual ligand effect and the irradiation effect in the catalytic cycle. The reaction is suggested to proceed via a hybrid alkyl Pd­(I)-radical species generated by inner-sphere electron transfer of phosphine-coordinated Pd(0) species with alkyl bromide. This intriguing hybrid alkyl Pd­(I)-radical species is elucidated by theoretical calculation to be a triplet species coordinated by three phosphine atoms with a distorted tetrahedral geometry, and spin prohibition rather than metal-to-ligand charge transfer contributes to the kinetic stability of the hybrid alkyl Pd­(I)-radical species to impede alkyl recombination to generate Pd­(II) alkyl intermediate.

Pd-catalyzed formal Mizoroki–Heck coupling of unactivated alkyl chlorides

“…Mechanistic investigations. To examine the reaction mechanism, it was first attempted to confirm that the reaction indeed proceeds through a radical pathway involving a Pd(I)/alkyl radical hybrid, as previously reported 20,21,31 . First, when a control experiment with a radical scavenger was performed, complete shutdown of reactivity was observed with the addition of 1 equiv of (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) to the standard reaction conditions (Fig.…”

“…By applying this strategy, the Gevorgyan group reported the first visible light-induced Pd-catalyzed Mizoroki–Heck reaction of alkyl bromides and iodides 30 . Subsequently, the Fu group reported the first Pd-catalyzed Mizoroki–Heck coupling of tertiary alkyl bromides, which are highly susceptible to β-hydride elimination 9 , expanding the reactivity to silyl enol ethers and enamides 31 . Similar reactions have also been reported by using other alkyl electrophiles, including N-hydroxyphthalimide esters or tertiary alkyl iodides, by Fu 32 , and Glorius 33 , and Gevorgyan 34 groups.…”

Visible-light-driven palladium-catalyzed Dowd–Beckwith ring expansion/C–C bond formation cascade

“…Based on the above results and literature, 11 a plausible mechanism for this ring-expansion/alkenylation reaction is proposed ( Scheme 2 ). Firstly, the L n Pd 0 complex is photoexcited to form an excited state L n Pd 0 * species upon irradiation, which promotes a single-electron transfer event with 1a to generate the putative Pd I species and a primary alkyl radical I .…”

“…Inspired by the pioneering works on visible-light induced Pd-catalyzed alkyl-Heck coupling reactions, 11 we envisioned that photoirradiation might facilitate the SET event between Pd(0) complex and Dowd–Beckwith halides to initiate the ring expansion process. The interaction of the tertiary radical species and Pd( i ) complex generated in situ would provide opportunities for further transformation ( Scheme 1 , eqn b).…”

Acid‐Acid‐Catalyzed Tandem Reactions Driven by an Additive‐Like Component

“…1,4-Dihydropyridine esters, also named as Hantzsch esters (HEH), as a special type of biomimetic transfer hydrogenation agents, are frequently applied in the reduction of unsaturated bonds such as carbon-carbon, carbon-nitrogen and carbonoxygen double bonds to construct structurally diverse molecules thanks to their excellent reducing ability under different catalytic conditions (Figure 3). [64,65] Because of its intrinsic affinity with organic species, and also the weak basicity of its oxidization pyridine, the combined use of Hantzsch ester and organocatalyst or chiral Brønsted acids has been well adopted by chemists, and many expedient and efficient tandem catalytic systems for enantioselective synthesis were developed. Some excellent review already summarized this chemistry.…”