Photocatalysis and Kinetic Resolution by Lithiation to Give Enantioenriched 2-Arylpiperazines

Abstract

Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3β inhibitor activity with potential for treating Alzheimer’s disease.

Synthesis of enantioenriched spirocyclic 2-arylpiperidines via kinetic resolution

“…Instead, we opted to carry out dichlorocyclopropanation with chloroform and sodium hydroxide on the parent piperidine 3 followed by reduction with lithium metal in tert-BuOH. Subsequent proton abstraction and carboxylation gave the acid 4 that was subjected to metallaphotoredox catalysis 16,17 with coupling to 1-chloro-4-iodobenzene to give the piperidine 5. This chemistry provides an alternative approach to the preparation of such 2-aryl substituted compounds.…”

“…This chemistry provides an alternative approach to the preparation of such 2-aryl substituted compounds. In the same way, the piperidine 6 was subjected to proton abstraction and carboxylation to give the acid 7 , followed by photocatalysis with coupling to 1-chloro-4-iodobenzene to give the piperidine 8 (other aryl derivatives should also be accessible 16 ).…”

α‐Amino Acids: An Emerging Versatile Synthon in Visible Light‐Driven Decarboxylative Transformations

“…In 2020, the Hopskins group developed a metalla‐photoredox strategy for the synthesis of benzyl amines 90 g – j via a radical coupling of aryl bromides with N ‐electron‐deficient α‐amino acids (Scheme 31A) [50] . Very recently, Coldham and coworkers optimized MacMillan's strategy into an more applicable fashion (Scheme 31B) [51] . A kinetic resolution protocol based on cascade photredox/nickel dual catalysis and have been described.…”

“…[50] Very recently, Coldham and coworkers optimized MacMillan's strategy into an more applicable fashion (Scheme 31B). [51] A kinetic resolution protocol based on cascade photredox/nickel dual catalysis and have been described. In this work, a piperazine derivative α-amino acid was employed, two sets of chiral compounds were obtained by virtue of kinetic resolution which are assisted by (À )-sparteine under n-BuLi-involved conditions.…”

Ligand effect of cyclometallated iridium(iii) complexes on N-alkylation of amines in hydrogen borrowing reactions

“…N-Alkylation is an important process in the chemical and pharmaceutical industries because nitrogen-containing organic moieties are important building blocks that play crucial roles in bioactive compounds. [1][2][3] To date, alkylation of amines with alkyl halides has been widely used industrially to produce target molecules with nitrogen backbones. [4][5][6][7][8] This reaction is generally fast but also has signicant disadvantages such as the introduction of tedious purication procedures, the use of toxic reagents that are harmful to human health, and environmentally unfriendly stoichiometric waste.…”