Synthesis of spirocyclic β- and γ-sultams by one-pot reductive cyclization of cyanoalkylsulfonyl fluorides.

ABSTRACT: One-pot intramolecular cyclization of novel sp³-enriched cyanoalkylsulfonyl fluorides into spirocyclic β- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH₄, NiCl₂·6H₂O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48-84%, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S-nucleophilic substitution in β-functionalized alkanenitriles or double alkylation of α-alkylthioacetonitrile, followed by oxidative chlorination with Cl₂ and further reaction with KHF₂. The title mono- and bifunctional sultams are advanced sp³-enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.

SUBMITTER: Stepannikova KO 

PROVIDER: S-EPMC8937022 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature