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Difluorometilación bencílica C-H catalizada por cobre y dirigida por cloroamida

Xiaojun Zeng^1,2,3, Wenhao Yan¹, Matthew Paeth¹

¹Department of Chemistry and Biochemistry , Miami University , Oxford , Ohio 45056 , United States.

Journal of the American Chemical Society

|November 23, 2019

Resumen

Este estudio introduce un nuevo método catalizado por cobre que utiliza N-cloroamidas para formar enlaces C-C, lo que permite la primera difluorometilación bencílica catalítica de C-H de varias moléculas.

Área de la Ciencia:

Química orgánica
Catálisis
La Química Radical

Sus antecedentes:

Los radicales amidil son intermediarios versátiles en la síntesis orgánica.
La funcionalización catalítica C-H ofrece rutas sintéticas eficientes.
La difluorometilación es crucial para modificar las propiedades moleculares.

Objetivo del estudio:

Desarrollar una estrategia catalítica para la generación de radicales amidil a partir de las N-cloroamidas.
Para lograr la primera difluorometilación bencílica de C-H.
Explorar el alcance y las limitaciones de esta nueva metodología.

Principales métodos:

Reacciones catalizadas por el cobre que utilizan N-cloroamidas y una fuente de difluorometilo nucleofílica.
Condiciones de reacción a temperatura ambiente.
La activación intramolecular de C-H seguida de una transferencia de grupo difluorometilo mediada por cobre.

Principales resultados:

Difluorometilación bencílica catalítica exitosa de diversos sustratos.
Amplio alcance del sustrato y tolerancia del grupo funcional demostrada.
Protocolo escalable que permite la difluorometilación en fase avanzada de las moléculas bioactivas.
Extensión de la estrategia a la pentafluoroetilación y a la trifluorometilación.

Conclusiones:

Se ha establecido un nuevo y eficiente sistema catalítico para la generación de radicales amídicos y la formación de enlaces C-C.
Este método proporciona una herramienta poderosa para la introducción de grupos difluorometílicos en posiciones bencílicas.
El protocolo desarrollado es aplicable para la funcionalización en etapas avanzadas en el descubrimiento y desarrollo de fármacos.

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