Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Flow Chemistry

Background:

• N-arylation of chiral amino acid esters is challenging due to α-stereocenter sensitivity.
• Maintaining enantiopurity during N-arylation requires careful control of reaction conditions.

Purpose of the Study:

• To develop a versatile and efficient synthetic method for N-arylated amino acid esters.
• To achieve N-arylation with minimal racemization using a continuous-flow system.

Main Methods:

• Utilized cyclohexanones as aryl sources for N-arylation.
• Employed a continuous-flow system with a coil reactor and a packed-bed reactor.
• Incorporated a Palladium hydroxide on carbon (Pd(OH)₂ /C) catalyst.

Main Results:

• Successfully synthesized N-arylated amino acid esters with minimal racemization.
• Achieved high yields and enantiopurity of the desired products.
• Demonstrated high space-time yield (74.1 g L^-1 h^-1) and turnover frequency (5.9 h^-1) over 3 days.

Conclusions:

• The developed continuous-flow method is robust and efficient for N-arylation of chiral amino acid esters.
• This approach offers a scalable and sustainable route to enantiopure N-arylated amino acids.
• The method effectively minimizes racemization and co-product formation.