Towards Reaction Control: An Expeditious Access to Racemic 5‐Substituted Tetramates and 5‐Substituted Tetramic Acids from Malimides

Abstract

A versatile and divergent two-step transformation of malimides to racemic tetramates and tetramic acids is described. The method consists of Grignard reagent addition with malimides to give hemiaminals and concentrated HCl-promoted chemoselective transformations of the latter. When running the reaction in CH 2 Cl 2 and in the presence of 2.5 molar equiv. of conc. HCl, 5-alkyltetramates were formed, while in neat conc. HCl, 5-alkyltetramic acids were obtained. Using this method, a variety of title compounds were prepared in good to excellent yields (82% -99%, and 76%/85%). The work also constitutes a formal racemic total synthesis of reutericyclin. On the basis of the experimental evidences and of a deuterium labeling experiment, a plausible reaction mechanism was proposed. This work thus demonstrated two new types of step economical and chemodivergent transformations starting from malic acid.

Domino Grignard Addition and Oxidation for the One-Pot Synthesis of C2-Quaternary 2-Hydroxyindoxyls

“…We propose that the reaction of 3-hydroxy-2-oxindoles 1 initiates with the formation of the intermediate A . ,, The Grignard addition to the intermediate A provides the intermediate B , which subsequently generates the indolinium ion intermediate C (Scheme ). Then aromatization-driven C3-hydrogen abstraction provides indole intermediate D that tautomerizes by capturing the proton lost during the aromatization to generate indoxyl intermediate E .…”

“…Furthermore, the 2-hydroxyindoxyl derivatives 3 bearing a C2-allyl or aryl group on reaction with sodium hydride provided the corresponding more stable 3-allyl- or aryl-3-hydroxyoxindole derivatives 7a , b in excellent yields via an α-ketol rearrangement (Scheme , c). ,, In addition, sequential treatment of the N -protected 3-hydroxy-2-oxindoles 1 with allyl or arylmagnesium bromide followed by the reaction of crude products with sodium hydride provided the corresponding oxindole derivatives 7c – e in good yields (Scheme , c; Scheme S6). Moreover, indoxyls 3 upon treatment with sodium hydride followed by methyl iodide afforded the corresponding 3-substituted 3-methoxy derivatives 8a , b in a one-pot manner (Scheme , d).…”