N-Heterocyclic Carbene-Catalyzed Stereoselective [3 + 2] Cycloaddition of N,N′-Cyclic Azomethine Imines with Aryl Acetaldehydes

Abstract

A highly stereoselective [3 + 2] cycloaddition reaction of N,N′-cyclic azomethine imines with aryl acetaldehydes enabled by a chiral N-heterocyclic carbene catalyst is accomplished, giving efficient access to a plethora of enantioenriched N,N′-bicyclic pyrazolidinones featuring aromatic substituents at the C2 position. The current strategy can be directly conducted on a gram scale, and the product could be further reduced to bicyclic pyrazolidine without loss of enantiopurity.

Organocatalyzed cycloaddition reactions of azomethine imines—A lookback

“…Organocatalyzed cycloaddition of AMI has been widely used in the synthesis of many such biologically relevant molecules. For example, various groups have synthesized a class of molecules with proven anti-Alzheimer's properties by incorporating cycloaddition of AMI as the key step, as discussed in this review [27,28,51]. Some other compounds with similar structural motifs exhibit antibiotic, antidepressant, antiviral, anti-convulsant, and anti-inflammatory activities.…”

“…According to Zhou et al, a chiral NHC catalyst efficiently facilitated the stereoselective [3+2] cycloaddition reaction of N,N′‐ cyclic AMI with aryl acetaldehydes, resulting in enantioenriched N,N′‐ bicyclic pyrazolidinones with aromatic substituents at the C2 position (Scheme 45) [51].…”

“…AMI with different groups as N-protecting agents gave the cycloadduct in moderate to good yields. 7-Bromo-3,4-dihydroisoquinoline and the azomethine imine produced the cycloadduct in 65% yield, 4:1 dr and >99% ee.According to Zhou et al, a chiral NHC catalyst efficiently facilitated the stereoselective [3+2] cycloaddition reaction of N,N 0 -cyclic AMI with aryl acetaldehydes, resulting in enantioenriched N,N 0 -bicyclic pyrazolidinones with aromatic substituents at the C2 position (Scheme 45)[51].The oxidation followed by deprotonation of Breslow intermediate forms (Z)-enolate intermediate, whichS C H E M E 4 3 Mechanistic pathway of N-heterocyclic carbene catalyzed cycloaddition of aromatic azomethine imines with α,β-unsaturated aldehyde. S C H E M E 4 4 N-heterocyclic carbene (NHC) catalyzed [2+3] cycloaddition of α-chloroaldehydes with azomethine imines.…”