Synthesis of Aryl Glycines by the α Arylation of Weinreb Amides

Abstract

Wenige Beispiele für die Umpolung von Enolaten sind bekannt, doch ein solcher Prozess liegt der Titelreaktion zugrunde: Aus einem Weinreb‐Amid wird durch Umsetzung mit einer Base zunächst ein Iminiumion gebildet, an das anschließend ein Grignard‐Reagens addieren kann (siehe Schema). Chirale Amide führten zu hoch diastereoselektiven nucleophilen Additionen. LDA = Lithiumdiisopropylamid.

Chemoselective Synthesis of N‐Substituted α‐Amino‐α′‐chloro Ketones via Chloromethylation of Glycine‐Derived Weinreb Amides

“…results, probably due to the good coordination with the organolithium reagent. In addition, neither side products resulting from the known organolithium-mediated demethoxylation of Weinreb amides [50] nor self-condensation products resulting from a-deprotonation of the Weinreb amide were detected. On the other hand, more apolar media such as toluene (entry 16), pentane (entry 17) or Trapp mixture (THF/Et 2 O/pentane = 4:4:1) (entry 18), which is often used for reactions at very low temperatures, [46] led to less satisfactory results.…”

“…Evidently, the Li/I exchange is faster than the competing attack of MeLi to the carbonyl moiety. In addition, neither side products resulting from the known organolithium‐mediated demethoxylation of Weinreb amides50 nor self‐condensation products resulting from α‐deprotonation of the Weinreb amide were detected. All these aspects are pointing to a surprisingly selective transformation with large potential for the synthesis of a variety of α‐amino‐α′‐chloro ketones.…”

Iron‐Catalyzed Three‐Component Synthesis of α‐Amino Acid Derivatives

“…With water as the only byproduct, these reactions also meet the requirements of modern, sustainable organic synthesis 12. However, these reactions are in general limited to very reactive (hetero)arenes,6e and often stoichiometric amounts of strong Lewis or Brønstedt acids have to be employed 13. Therefore, the scope of these reactions is rather limited, and considerable amounts of waste can be generated in these processes.…”