N‐Atom Deletion in Nitrogen Heterocycles

Abstract

Excising the nitrogen in secondary amines, and coupling the two residual fragments is a skeletal editing strategy that can be used to construct molecules with new skeletons, but which has been largely unexplored. Here we report a versatile method of N‐atom excision from N‐heterocycles. The process uses readily available N‐heterocycles as substrates, and proceeds by N‐sulfonylazidonation followed by the rearrangement of sulfamoyl azide intermediates, providing various cyclic products. Examples are provided of deletion of nitrogen from natural products, synthesis of chiral O‐heterocycles from commercially available chiral β‐amino alcohols, formal inert C−H functionalization through a sequence of N‐directed C−H functionalization and N‐atom deletion reactions in which the N‐atom can serve as a traceless directing group.

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

“…Another nitrogen-deletion protocol of secondary amines featuring a Curtius-type rearrangement/nitrogen extrusion was reported by Lu’s group very recently. 27 , 28 Electrophilic nitrogen transfer using in situ generated iodonitrene has been an emerging research area 29 − 34 ( Figure 1 C).…”

“…In 2021, Levin’s group disclosed the nitrogen deletion of secondary amines using an N -anomeric amide, postulating the concept of skeletal editing of organic molecules. , An N -anomeric amide acts as a nitrogen transfer reagent to a secondary amine to produce a 1,1-diazene, which generates a biradical via nitrogen extrusion, affording cyclobutane. Another nitrogen-deletion protocol of secondary amines featuring a Curtius-type rearrangement/nitrogen extrusion was reported by Lu’s group very recently. , Electrophilic nitrogen transfer using in situ generated iodonitrene has been an emerging research area − (Figure C).…”

Direct Deamination of Primary Amines via Isodiazene Intermediates

“…We hypothesized that anomeric amides would undergo an analogous substitution with primary amines to generate primary isodiazene intermediates (Figure C). However, unlike secondary isodiazenes, which have been well-studied and even spectroscopically characterized at cryogenic temperatures, − primary isodiazenes are almost entirely unprecedented, suggesting an opportunity to leverage a novel reactive intermediate. − …”

Substituted pyridines from isoxazoles: scope and mechanism

“…1,2 In a recent example, one can "delete" a nitrogen atom from a heterocyclic structure. 3,4 This type of core structure editing, or "scaffold hopping", is an intriguing method for taking biologically active compounds and switching out the core while leaving the substituents the same or adding complexity. [5][6][7][8][9] This type of "hopping" is often discussed as a conceptual or in silico method for drug design, but synthetic methods for leaving peripheral substituents more or less in place and changing the core are an intriguing synthetic area.…”