Catalytic Asymmetric Electrochemical α‐Arylation of Cyclic β‐Ketocarbonyls with Anodic Benzyne Intermediates

Abstract

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine‐benzyne protocol provides a concise method for the construction of diverse α‐aryl (α‐cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.

Recent Applications of Homogeneous Catalysis in Electrochemical Organic Synthesis

“…132 Using enamine chemistry, Luo and co-workers also achieved enantioselective -arylation reactions between -ketoesters 31-15 and benzyne (31-H, generated in situ from amino triazole 31-16) by using the TfOH salt of diamine 31-18 as a chiral catalyst (Figure 31g). 133 In 2020, He and co-workers reported a method for highly enantioselective direct synthesis of C2-quaternary indolin-3-ones 31-21 from 2-phenylindole 31-19 and cyclohexanone (31-20) via anodic oxidation with inexpensive and readily available L-proline as an organocatalyst and TEMPO as a mediator (Figure 31h). Chiral nitroxyl compounds have been used as both redox catalysts and chiral catalysts in asymmetric electrochemical organocatalysis.…”

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“…As will be discussed later in this review, an elegant catalytic asymmetric variant of this methodology has subsequently been developed. 120 …”

“… 142 − 144 We highlight three key studies in this emerging field involving the synthesis of helicenes (axial chirality) 145 , 146 and the introduction of quaternary stereocenters (point chirality). 120 …”

“…Also in 2020, the Luo group reported a pioneering study in the catalytic asymmetric trapping of arynes and related strained intermediates. 120 Their methodology strategically blends organocatalysis and electrochemistry to achieve the α-functionalization of 1,3-dicarbonyl substrates and establish point chiral stereochemistry. For example, treatment of ketoester 61 with 1-aminobenzotriazole ( 87 ) and amine catalyst 88 , under their optimal electrochemical oxidation conditions, afforded α-arylated ketoester 63 in 71% yield and 94% ee ( Figure 16 ).…”

Asymmetric Electrochemical Arylation in the Formal Synthesis of (+)-Amurensinine

“…[32][33][34][35] However, enantioselective electrochemical transformation [36][37][38] for the architectural assembly of the unique core in combination with the stereoselective installation of the requisite α,α-diaryl carbonyl-containing functional groups to pursue the total synthesis of bioactive molecules presents significant challenges. [39][40][41][42][43][44][45] Given the pharmacological importance of isopavine alkaloids, direct asymmetric electrolysis [46][47][48][49][50][51][52][53][54][55][56][57] to access enantiopure analogs in the context of total synthesis via a sustainable process is highly desirable. Recently, the Meggers group 58 and our group 59 established the enantioselective α-functionalization of carbonyl compounds enabled by Lewis acid catalysis in a range of unique asymmetric bond constructions.…”