Increasing the Reactivity of Amides towards Organometallic Reagents: An Overview: An overview

Vittorio Pace, Wolfgang Holzer, Berit Olofsson

    Publications: Contribution to journalReviewPeer Reviewed

    Abstract

    The nucleophilic addition of carbon nucleophiles to amides has traditionally been a difficult task, both due to reactivity and selectivity problems. When successful, these processes would represent straightforward routes towards carbonyl-type or amine compounds, depending on the fate of the generated tetrahedral intermediate. The direct addition of nucleophiles to amides for the preparation of ketones has been studied and applied to the syntheses of several natural products. On the other hand, the addition of nucleophiles to amides to obtain substituted amines represented a major challenge, and only scattered applications on particular substrates have appeared. Initial improvements were based on the activation of amides by introduction of particular substituents, such as in N-methoxy amides (Weinreb amides) or electron-withdrawing groups able to increase the carbon nucleophilicity. Although these strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (i.e., carbonyls) are present, thus decreasing the versatility of the methods. In recent years, important advancements towards fully chemoselective methods have been realized. The capture of tetrahedral intermediates with acids generates highly electrophilic iminium species able to undergo chemoselective additions of various nucleophiles, thus accessing substituted amines. Alternatively, the in situ generation of an iminium triflate ion allows highly chemoselective additions of nucleophiles, yielding amines, ketones or ketimines. Also thioamides can be used as precursors of ketones or α-substituted amines. The success of the above methodologies is further showcased by the application in various syntheses of natural products or biologically active molecules.
    Original languageEnglish
    Pages (from-to)3697 - 3736
    Number of pages40
    JournalAdvanced Synthesis & Catalysis
    Volume356
    Issue number18
    Early online date2 Dec 2014
    DOIs
    Publication statusPublished - 2014

    Austrian Fields of Science 2012

    • 104015 Organic chemistry

    Keywords

    • Amides
    • Chemoselectivity
    • Intermediates
    • Lactams
    • Organometallics

    Cite this