A General Copper-Catalyzed Radical Cross-Coupling of Unactivated Alkyl Halides

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• First-row transition metal catalysis is crucial for C(sp3)-carbon/heteroatom cross-coupling of unactivated alkyl halides.
• Copper catalysts excel in C(sp3)-N cross-coupling due to facile reductive elimination.
• Limitations exist in copper's reducing capability for challenging substrates like alkyl chlorides.

Purpose of the Study:

• To develop a general copper-catalyzed C(sp3)-C/N cross-coupling reaction for unactivated alkyl halides.
• To overcome the limitations of copper catalysts in activating less reactive alkyl halides.
• To enable the synthesis of diverse molecular frameworks via late-stage functionalization.

Main Methods:

• Utilized copper(I) catalysts with anionic N,N,N-ligands.
• Employed mild thermal conditions for the cross-coupling reactions.
• Investigated the coupling of various alkyl halides (bromides, chlorides, iodides) with diverse nucleophiles.

Main Results:

• Achieved general copper-catalyzed C(sp3)-C/N cross-coupling of unactivated alkyl halides.
• Demonstrated enhanced reducing capability of Cu(I) catalysts using anionic N,N,N-ligands.
• Showcased broad substrate scope including primary to tertiary alkyl halides and various nucleophiles (amines, indoles, amides, alkynes).
• Confirmed good functional group compatibility and applicability in late-stage functionalization.

Conclusions:

• Developed a versatile copper-catalyzed protocol for C(sp3)-C/N cross-coupling.
• The use of anionic N,N,N-ligands is key to enhancing catalyst performance.
• The method offers a powerful platform for synthesizing complex molecules and late-stage functionalization.