Copper(I)-catalyzed asymmetric decarboxylative Mannich reaction enabled by acidic activation of 2H-azirines

Abstract

Chiral aziridines are structure units found in many biologically active compounds and are important building blocks in organic synthesis. Herein, by merging nucleophilic generation through copper(I)-catalyzed decarboxylation and activation of poorly electrophilic 2 H -azirines through protonation with carboxylic acids, an asymmetric decarboxylative Mannich reaction between α,α-disubstituted cyanoacetic acids and 2 H -azirines is uncovered, which leads to generation of chiral aziridines containing vicinal tetrasubstituted and acyclic quaternary stereogenic carbon centers in good to excellent diastereo- and enantioselectivities. At last, transformations of the produced chiral aziridine are successfully carried out to deliver synthetically useful compounds.

Asymmetric Catalytic Ketimine Mannich Reactions and Related Transformations

“…This method employed racemic 2-H-azirines; one enantiomer of which preferentially reacted with a chiral Cu-enolate complex, affording the aziridines bearing three contiguous stereogenic centers in 65-99% yields with 45:55-91:9 diastereoselectivities and 32-94% ee. In 2019, Yin and coworkers reported a copper(I)-catalyzed asymmet decarboxylative Mannich reaction of 2H-azirines (Scheme 14) [70]. This method utilized 2H-azirine not only as an electrophile but also as a base to deprotonate a cyanoacetic ac to induce its decarboxylation (i.e., decarboxylative enolization).…”

“…As such, a reacti electrophile was a protonated 2H-azirine whose electrophilicity was enhance Importance of this "proton transfer" strategy was successfully demonstrated by showi that a nonprotonated 2H-azirine did not react with a corresponding nucleophile under t otherwise identical reaction condition. The reaction scope was very broad and tolerat various substituents on both nucleophiles and electrophiles, affording various enant enriched aziridines in 73-99% yields with 2.4:1->20:1 diastereoselectivities and 91-98% In 2019, Yin and coworkers reported a copper(I)-catalyzed asymmetric decarboxylative Mannich reaction of 2H-azirines (Scheme 14) [70]. This method utilized a 2H-azirine not only as an electrophile but also as a base to deprotonate a cyanoacetic acid to induce its decarboxylation (i.e., decarboxylative enolization).…”

Carboxylic Acids as Building Blocks in Catalytic Asymmetric Reactions

“…66,67 In 2019, Yin and co-workers reported a Mannich reaction between an α,α-disubstituted cyanoacetic acid and 2H-azirines in an asymmetric manner to prepare chiral aziridines (Scheme 80). 68 In this method, the nucleophile is generated from the cyanoacetic acids via Cu(I)-catalyzed decarboxylation. On the other hand, 2H-azirine's electrophilicity is enhanced by forming iminium species via protonation by cyanocarboxylic acid.…”

Enantioselective Reaction of 2H-Azirines with Oxazol-5-(4H)-ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts

“…The group of Lin and Feng reported the asymmetric addition of β-ketoamides with racemic 2,3-diaryl-2 H -azirines using chiral N , N′ -oxide/Cu­(II) complexes; the reaction gave products bearing vicinal tetrasubstituted stereogenic centers with good diastereoselectivity and high enantioselectivity (dr = 91:9–70:30, 83–92% ee) . The enantioselective decarboxylative Mannich reaction of cyanoacetic acids with 2 H -azirines using diphosphine–Cu­(I) catalysts was reported by Yin and co-workers, and Adrio and Carretero reported the enantioselective 1,3-dipolar cycloaddition of α-substituted iminoesters with 2 H -azirines to afford products with good enantioselectivity . Recently, Trost and co-worker reported the enantioselective Mannich reaction of alkynyl ketones to 2 H -azirines using Zn–prophenol catalysts .…”