# Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives

## TL;DR

This paper introduces a copper-catalyzed method to create α-aminoamide compounds using a difluorocarbene intermediate, offering a safer and more versatile alternative to traditional methods.

## Contribution

A novel copper-mediated multicomponent reaction using difluorocarbene as a carbonyl source for α-aminoamide synthesis is presented.

## Key findings

- The copper-difluorocarbene intermediate is formed from BrCF2CO2K and facilitates the reaction pathway.
- The method works with a wide range of substrates, including aromatic and alkyl aldehydes.
- The approach avoids toxic cyanide salts and unstable isonitriles used in traditional reactions.

## Abstract

Difluorocarbene, an important reactive intermediate in organic synthesis, exhibits intriguing properties and synthetic versatility. However, great challenges in modulating reaction pathways limit its widespread application in synthetic chemistry. While metal-catalyzed difluorocarbene transfer offers a promising strategy but remains a formidable challenge. Herein, we disclose a copper-mediated multicomponent reaction of amine, aldehyde and BrCF2CO2K for synthesis of α- aminoamide derivatives, wherein copper-difluorocarbene serve as carbonyl source. Control experiments and DFT calculations support the pathway initiated by formation of a copper-difluorocarbene from BrCF2CO2K, followed by nucleophilic attack of the amine to produce an ammonium ylide, interception of the ylide with imine, and defluorination via carbonyl migration. This transformation demonstrates broad substrate scope, accommodating not only aromatic aldehydes but also alkyl aldehydes and drug-modified arylamines, highlighting its synthetic applicability. Furthermore, the method provides a practical and ideal alternative to classical Ugi or Strecker reactions, circumventing the need for toxic cyanide salts or unstable isonitriles.

Difluorocarbene, an important reactive intermediate in organic synthesis, exhibits intriguing properties and synthetic versatility. Herein, the authors report a copper catalyzed multicomponent reaction of amine, aldehyde and BrCF2CO2K via copper-difluorocarbene intermediate for the synthesis of multifunctional α-aminoamide derivatives.