Azlactone Reaction Developments

Abstract

Azlactones (also known as oxazolones) are heterocycles usually employed in the stereoselective synthesis of α,α-amino acids, heterocycles and natural products. The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations. This review aims to cover classical and recent applications of oxazolones, especially those involving stereoselective processes. After a short introduction on their structures and intrinsic reactivities, dynamic kinetic resolution (DKR) processes as well as reactions involving stereoselective formation of a new σ C-C bond, such as alkylation/allylation/arylation, aldol, ene, Michael and Mannich reactions will be exposed. Additionally, cycloadditions, Steglich rearrangement and sulfenylation reactions will also be discussed. Recent developments of the well-known Erlenmeyer azlactones will be described. For the most examples, the proposed mechanism, activation modes and/or key reaction intermediates will be exposed to rationalize both the final product and the observed stereochemistry. Finally, this review gives an overview of the synthetic utility of oxazolones.

Recent Advances in Azlactone Transformations

“…The Erlenmeyer azlactones (4), also known as 4-arylideno-5(4H)-oxazolones, have been prepared though an aldol-type condensation of a glycine-based azlactone (3) (usually formed in situ) with an aldehyde (Scheme 2). The general protocol usually affords the thermodynamic Z-isomer and require heating, in order to favor aldol-type condensation product over aldoltype addition.…”

“…The general protocol usually affords the thermodynamic Z-isomer and require heating, in order to favor aldol-type condensation product over aldoltype addition. Furthermore, the use of ionic liquids, such as [Et 3 4 ], was also described for the preparation of Erlenmeyer azlactones employing only hippuric acid and aldehydes, without the need of acetic anhydride to mediate the intramolecular cyclization step. Classical Erlenmeyer azlactone preparation.…”

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Azlactones, also known as oxazolones, are versatile building blocks in organic synthesis due to the presence of multiple pro-nucleophilic and electrophilic reactive sites. [4] From 2016 on, several reactions considered as challenging transformations have been carried out. Moreover, the development of one-pot, tandem and domino reactions greatly enhanced the azlactone scaffold potential.

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Base Induced Condensation of Malononitrile with Erlenmeyer Azlactones: An Unexpected Synthesis of Multi‐Substituted Δ2‐Pyrrolines and Their Cytotoxicity

“…Erlenmeyer azlactone is one of the most useful and important intermediates in organic synthesis . Erlenmeyer azlactones have been used in a wide variety of reactions as precursors for the generation of biologically active peptides, herbicides, fungicides, pesticides and agrochemical intermediates .…”

Brønsted Acid-Catalyzed Dipeptides Functionalization through Azlactones

“…[1][2][3] In this context, azlactones (also known as oxazolones) are promising substrates, since they basically consist of protected amino acids organized as five-membered rings bearing both electrophilic and pronucleophilic sites in their structure. 4,5 Due to this versatility, these heterocycles have been extensively employed in a wide scope of transformations, 6 in particular the preparation of quaternary amino acid derivatives. [7][8][9][10][11][12] Different 4-substituted oxazolones are easily available, as this moiety originates from the amino acid precursor 13 or by hydrogenation of the well-known Erlenmeyer azlactones 14 ( Figure 1).…”