Regioselective Nitrosocarbonyl Aldol Reaction of Deconjugated Butyrolactams: Synthesis of γ‐Heterosubstituted α,β‐Unsaturated γ‐Lactams

Abstract

The nitrosocarbonyl aldol reaction of deconjugated butyrolactams is developed employing quinidine as organocatalyst. The nitrosocarbonyl species generated in situ from hydroxamic acids react with a variety of deconjugated butyrolactams at room temperature, offering valuable α,β-unsaturated γ-lactams bearing heterosubstituted quaternary carbon center in very high yields. This nitrosocarbonyl aldol reaction is O-selective and proceeds exclusively at the γ-center of deconjugated butyrolactams. The reaction is scalable, accommodates diverse functional groups, and is also effective with azodicarboxylates.γ-Lactams and derivatives thereof, particularly those encompass unsaturation in the ring framework and quaternary carbon center at the γ-position, constitute an important class of heterocycles with eminence in medicinal and pharmaceutical chemistry. [1,2] They represent the core structure of many natural products and biologically significant molecules (Figure 1). [2] They are also widely used as versatile building blocks in organic synthesis towards complex targets. [3] Consequently, devising straightforward strategies to access functionally rich unsaturated γ-lactams remains in the limelight of organic synthesis. [4] In this scenario, among the diverse synthetic endeavours, exploration of nucleophilic reactivity of γ-monosubstituted deconjugated butyrolactams have fetched considerable impetus as they are accessible in diverse substitution patterns from readily available precursors. [5] However, this strategy results in dienolate intermediate which could react with electrophile either through the αor γ-position, leading to a mixture of regioisomeric products (Scheme 1a). Further, such reactivity of deconjugated butyrolactams has majorly been investigated for carbon-carbon bond forming reactions and exploration in carbon-heteroatom bond forming reactions are scarce. In 2017, Mukherjee et al. reported sulfenylation and selenylation of γ-monosubstituted deconjugated butyrolac-[a

A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams

“…It should be noticed that while numerous synthetic approaches to 5-hydroxy-3-pyrrolin-2-one derivatives have been reported [ 7 , 8 , 9 , 10 , 11 , 12 ], to our best knowledge, to date, there are just a few methods leading to 3,5-diaryl substituted γ-hydroxy butyrolactams 1 [ 1 , 13 , 14 ], and none that would afford the herein-described 3,5-di-aryl/heteroaryl-4-benzyl pattern. Thus, the developed procedures greatly expand the chemical space [ 15 ] of available 5-hydroxy 3-pyrrolin-2-ones which, in turn, could be used among other things for a convenient access to other heterocyclic systems [ 16 ].…”