Metal‐Free N–H/C–H Coupling for Efficient Asymmetric Synthesis of Chiral Dihydroquinoxalinones from Readily Available α‐Amino Acids

Abstract

We have developed a method for the synthesis of dihydroquinoxalinones via intramolecular N–H/C–H coupling using hypervalent iodine. The starting materials were prepared from inexpensive and readily available aniline and amino acid derivatives. Various functional groups were tolerated to give multisubstituted dihydroquinoxalinones in moderate to excellent yields. The chirality of the amino acid was transferred to the desired target compound without a loss of enantiomeric excess. Preliminary mechanistic studies indicated that the reaction proceeds via an ionic mechanism.

Recent Advances in Intramolecular Metal‐Free Oxidative C–H Bond Aminations Using Hypervalent Iodine(III) Reagents

“…Shibata group developed a method for the synthesis of chiral dihydroquinoxalinones 130 starting from amino acid derived compounds ( N ‐aryl propanamides, 129 ) via intramolecular N–H/C–H coupling using PIDA ( 1 ) in good yields with retension of chirality (Scheme ) …”

Nitrenium Ions from Amine‐Iodine(III) Combinations

“…Very recently, Kanyiva and Shibata utilized the iodine(III)‐enabled nitrenium ion cyclization protocol for the synthesis of chiral dihydroquinaxolinones 85 from readily available amino acids (Figure ) . The dihydroquinaxolinones were readily formed in good to excellent yields with retention of configuration from the starting material to the product.…”

Iron‐ or Zinc‐Mediated Synthetic Approach to Enantiopure Dihydroquinoxalinones

“…[9] Also, the fact that the ligands were expensive or not commercially available and the reaction required inert atmosphere or produced toxic waste made these methods problematic. The fourth method emerged in recent years involving asymmetric catalysis using rhodium, [1,8z] Lewis bases, [7b,8aa] Brønsted acids [8y] and Lewis acids [7a] as catalysts (Scheme 1d).…”

“…[1] Non-nucleoside HIV-1 reverse transcriptase inhibitor GW420867X [2] is a good example of chiral drugs with the dihydroquinoxalinone core. [9] Also, the fact that the ligands were expensive or not commercially available and the reaction required inert atmosphere or produced toxic waste made these methods problematic. [6] Hence, the synthesis of dihydroquinoxalinones has attracted considerable attention in the past decades and remains of great interest today.…”