Nucleophilic addition/ring contraction of N-substituted lactams

February 28, 2024

• Title:       

  Nucleophilic addition/ring contraction of N-substituted lactams

• Image Source:

  Sequential nucleophilic addition/1,2-rearrangement of N-iminolactam: A ring-contractive strategy for the synthesis of 2-acyl pyrrolidines

• Mark:

  Scheme 1

• Associated context:

  Our focus is on developing methods for the efficient formation  of 2-acyl pyrrolidines that would provide facial access to these compounds and allow them to be used in further synthetic applications. We recently reported the sequential nucleophilic arylation/ring-contractive rearrangement of  α-bromo N-alkoxylactams 1 (Y = OBn) with Grignard or organolithium reagents (Scheme 1). This Aza–Favorskii type rearrangement enables the nucleophilic arylation of 1 followed by the migration of the lactam carbonyl group to afford ring-contracted 2-aroyl pyrrolidines  3(Nu = Ar). When N-alkoxylactam 1 was used in the sequential reaction, various aryl and heteroaryl groups could be introduced. However, the introduction of the alkyl group is challenging because the  reaction of 1 with alkyl magnesium bromide favors halogen-metal exchange/retro-ene fragmentation (A→B) over nucleophilic alkylation to the lactam carbonyl group. To expand the range of  C-nucleophiles for this methodology, an increase in the electrophilicity at the carbonyl moiety is desired to facilitate the nucleophilic addition to the lactam over halogen–metal exchange.