Decarboxylative stereoretentive C-N coupling by harnessing aminating reagent.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Transition-metal catalysis is key for C-C and C-heteroatom bond formation.
• Decarboxylative C-N bond formation is vital for synthesizing pharmacologically relevant amines.
• Existing methods struggle with stereospecific synthesis of chiral amines due to radical intermediates.

Purpose of the Study:

• To develop a stereoretentive decarboxylative amidation method.
• To utilize 1,4,2-dioxazol-5-one as a robust amidating reagent.
• To provide access to α-chiral amines under transition-metal-free conditions.

Main Methods:

• Base-mediated reaction of carboxylic acids with 1,4,2-dioxazol-5-one.
• Transition-metal-free conditions at ambient temperature.
• Experimental and computational mechanistic studies.

Main Results:

• Stereoretentive synthesis of α-chiral amines from primary, secondary, and tertiary carboxylic acids.
• High functional group tolerance and scalability.
• Successful ¹⁵N-isotope labeling demonstrated.

Conclusions:

• The developed method offers a versatile and efficient route to chiral amines.
• The transition-metal-free, stereoretentive approach overcomes limitations of prior methods.
• The reaction proceeds via a Lossen-type rearrangement mechanism.