gem‐Difluoro‐3‐azabicyclo[3.n.1]alkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

Abstract

An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks via double‐Mannich addition – deoxofluo­rination sequence is described. The scope of the method was demon­strated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced a number of bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i.e., pKa(H) and LogP).

Double Mannich reaction with ketones as a route to heterocyclic systems: A mini review

“…Thus, oxidation of N-benzyl-3-thia-7-azabicyclo[3. The synthesis of gem-difluoro-3-azabicyclo[3.3.1] alkanes (113) has been achieved through a double Mannich reaction-deoxofluorination sequence [88]. Further transformations of functional groups produced various bifunctionalized difluorinated building blocks (114).…”