α,ß-Desaturation and Formal ß-C(sp3)-H Fluorination of N-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry.
J Am Chem Soc
; 146(33): 22982-22992, 2024 Aug 21.
Article
em En
| MEDLINE
| ID: mdl-39132893
ABSTRACT
Incorporation of C(sp3)-F bonds in biologically active compounds is a common strategy employed in medicinal and agricultural chemistry to tune pharmacokinetic and pharmacodynamic properties. Due to the limited number of robust strategies for C(sp3)-H fluorination of complex molecules, time-consuming de novo syntheses of such fluorinated analogs are typically required, representing a major bottleneck in the drug discovery process. In this work, we present a general and operationally simple strategy for site-specific ß-C(sp3)-H fluorination of amine derivatives including carbamates, amides, and sulfonamides, which is compatible with a wide range of functional groups including N-heteroarenes. In this approach, an improved electrochemical Shono oxidation is used to set the site of functionalization via net α,ß-desaturation to access enamine derivatives. We further developed a series of new transformations of these enamine intermediates to synthesize a variety of ß-fluoro-α-functionalized structures, allowing efficient access to pertinent targets to accelerate drug discovery campaigns.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Halogenação
/
Aminas
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article