New Entries toward 3,3-Difluoropiperidines

Abstract

Difluoropiperidines attract considerable interest from organic and medicinal chemists, but their synthesis is often problematic. This paper describes a new synthetic pathway toward valuable 3,3-difluoropiperidines starting from suitable delta-chloro-alpha,alpha-difluoroimines. The latter imines can be synthesized via electrophilic fluorination of the corresponding delta-chloroimines using NFSI (N-fluorodibenzenesulfonimide) in acetonitrile. After hydride reduction of the imino bond and subsequent intramolecular substitution of the chloride atom, new 3,3-difluoropiperidines were obtained in good yields. In addition, this methodology was applied to establish the first synthesis of N-protected 3,3-difluoropipecolic acid, a new fluorinated amino acid.

A General Approach to Various Five‐ and Six‐Membered gem‐Difluoroheterocycles: Application to the Synthesis of Fluorinated Analogues of Sedamine

“…Another example is the NR2B NMDA antagonist (MK‐0657, VI ), while the difluoropiperidine VII acts as an antagonist of the dopamine receptor 4 (Figure ) . In that case, various elegant approaches have already been developed by several groups toward piperidines with a gem ‐difluoro substitution on positions β or γ of the heterocycle …”

Recent Advances in the Synthesis of Fluorinated Amino Acids

“…In 2008, the first synthesis of the N-protected 3,3-difluoropipecolic acid 259 (Scheme 29) was accomplished, in straightforward fashion, by De Kimpe's group. [72] The synthesis commenced with conversion of the N-(1-arylethylidene)alkylamine 253 into the δ-chloroimine 254 by deprotonation with LDA at 100°C and subsequent treatment with 1-bromo-3-chloropropane. Treatment of the crude imine 254 with NFSI (3.0 equiv., dried prior to use) in dry CH 3 CN in the presence of K 2 CO 3 and molecular sieves provided the difluoroimine 255.…”

Synthesis of 3-Aminomethyl-3-fluoropiperidines

“…Only a limited number of synthetic routes toward these interesting 3-fluoropiperidines are available. 11 One method proceeds via a-fluorination of 4-piperidone 12 followed by TfOH-catalyzed double electrophilic substitution to ben-zene resulting in 3-fluoro-2,2-diphenylpiperidine. 13 Recently, the synthesis of a wide range of optically active 3fluoropiperidines was developed starting from prolinols by treatment with DAST or Deoxo-Fluor TM .…”