Synthesis and studies on gem-fluorinated 2-azabicyclo[n.1.0]alkanes

•The substances obtained via direct difluorocyclopropanation of corresponding ene-carbamates.•Deprotected substances possess different stability.•Fragmentation occurs by either intramolecular or intermolecular cyclopropane opening.•The free amines undergo acid–base transition at neutral pH values.•CF2-fusion gives only minute impact on lipophilicity (slight increase).

Three novel amines all possessing gem-difluorocyclopropane, secondary amino group and a fused aliphatic cycle were synthesized by difluorocyclopropanation of N-Boc protected enamides. The compounds were stable when amino group was blocked by protonation or acylation, but otherwise underwent fragmentation already at the room temperature. Chemical structure, physico-chemical properties and fragmentation mechanisms of the fluorinated amines are studied in details.

Graphical abstractThe paper describes three novel amines – analogs of pyrrolidine, piperidine and azepane – in terms of their stability, integral properties and structure. The amines have their pKa around neutral values, and the transition to the basic form triggers their quick fragmentation. In addition, we discuss the lipophilicity impact of the difluorocyclopropane moiety and structural features.Figure optionsDownload full-size imageDownload as PowerPoint slide