Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp³)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

Abstract

Enantioselective functionalizations of unbiased methylene C(sp3)−H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)‐catalyzed enantioselective arylation of unbiased methylene β‐C(sp3)−H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non‐C2‐symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β‐arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)‐catalyzed enantioselective C−H activation with less reactive and cost‐effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C−H palladation step.

Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds

“…In our previous work, the enantioselective C—H palladation of β‐methylene of PIP‐derived carboxamide 1 with 3,3’‐substituted BINOLs or BINOL‐derived phosphoric acids (CPAs) as ligands could give a chiral palladacycle Int‐A . Oxidative addition of aryl iodide gives a Pd(IV) species Int‐B , which could undergo a C—C reductive elimination (RE) to form the arylation product in good enantioselectivity (Scheme , path a, up to 90% ee) [14a] .…”

“…In our previous work, the enantioselective C—H palladation of β‐methylene of PIP‐derived carboxamide 1 with 3,3’‐substituted BINOLs or BINOL‐derived phosphoric acids (CPAs) as ligands could give a chiral palladacycle Int‐A . Oxidative addition of aryl iodide gives a Pd(IV) species Int‐B , which could undergo a C—C reductive elimination (RE) to form the arylation product in good enantioselectivity (Scheme , path a, up to 90% ee) [14a] . Inspired by Wu's reports, [8b,c] we anticipated that if a competitive C—N RE from Int‐B could occur by tuning the steric and electronic effects of aryl iodide, asymmetric synthesis of β‐lactam 2 might be possible (path b).…”

“…3,3’‐Dimethyl‐BINOL L2 gave a slightly improved yield and ee value (entry 2). Encouraged by our previous findings that BINOLs bearing electron‐withdrawing groups at 3,3’‐positions could significantly enhance both the reactivity and selectivity, [14b,16] a series of BINOLs bearing F‐, Cl‐, Br‐, CN‐, and NO 2 ‐ at the 3,3’‐positions were investigated (entries 3—8). Fortunately, 2a was obtained in 75% isolated yield with 92% ee when 3,3’‐chlorinated‐BINOL ( L6 ) was used (entry 6).…”

“…Enantioselective functionalization of unbiased methylene C(sp 3 )–H bonds is achieved only recently (Scheme 1e). In 2016, the Yu group reported the Pd(II)‐catalyzed arylation of unbiased methylene C(sp 3 )−H bonds in high enantioselectivity taking advantage of weakly coordinating monodentate DG with a bidenate acetyl‐protected aminoethyl quinolone ligand (up to 96% ee) . Our group successfully developed Pd(II)‐catalyzed enantioselective arylation and alkynylation of unbiased methylene C—H bonds enabled by the strong bidentate PIP auxiliary with chiral phosphoric acids (CPAs) (up to 90% ee) or chiral 3,3’‐F 2 ‐BINOL (up to 96% ee), respectively .…”

Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds Enabled by a 2‐Pyridylisopropyl Auxiliary†

“…Based on our previous research on PIP, we hypothesized that the steric communication between gem ‐dimethyl group in our PIP auxiliary and backbone of a monodentate chiral C 2 ‐symmetric ligand may limit the free rotation to create a rigid and stronger chiral environment around the substrate (Scheme c, int‐A ). Fortunately, our group successfully developed a Pd(II)‐catalyzed enantioselective arylation and alkynylation of unbiased methylene C—H bonds enabled by the combination of PIP auxiliary with chiral phosphoric acids (CPAs) (up to 90% ee) or chiral 3,3’‐F 2 ‐BINOL (up to 96% ee), respectively (Scheme c) …”