A practical catalytic reductive amination of carboxylic acids

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Catalysis

Background:

• Reductive alkylation is a crucial transformation in organic synthesis.
• Existing methods often require harsh conditions or specialized reagents.
• Developing efficient and versatile routes for amine functionalization remains an active area of research.

Purpose of the Study:

• To develop a novel reductive alkylation protocol for amines utilizing carboxylic acids as electrophiles.
• To explore the utility of phenylsilane's dual reactivity in a two-step amidation-reduction sequence.
• To demonstrate the broad applicability and scalability of the developed method.

Main Methods:

• A two-step reaction sequence involving silane-mediated amidation followed by zinc acetate-catalyzed amide reduction.
• Utilizing phenylsilane for both amidation and subsequent reduction steps.
• Optimization of reaction conditions and catalyst loading for efficient amide reduction.

Main Results:

• Successful reductive alkylation of a diverse range of amines and carboxylic acids.
• Demonstration of scalability with a 305 mmol amine reaction.
• Efficient synthesis of the antiretroviral drug maraviroc, showcasing the method's utility in complex molecule synthesis.
• Mechanistic insights revealing the role of residual carboxylic acid in enhancing silane reductant reactivity.

Conclusions:

• The developed method provides a novel and efficient route for reductive alkylation of amines.
• The reaction's applicability to secondary amides, previously unreactive, broadens its synthetic scope.
• This methodology offers a valuable tool for accessing functionalized amines in organic synthesis and drug discovery.