Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water

Abstract

Hydroxypyridinone (3,4-HOPO) is a vital metal-chelating pharmacophore. However, the efficient synthesis has been a long-standing problem in drug development. In this paper, we report an efficient electrophilic activation of unprotected maltols via reversible covalent bonds between boronic acid and 3hydroxyl/4-carbonyl. This one-pot reaction proceeded well on a gram scale in water with excellent efficiencies up to 97%. Moreover, taking advantage of the covalent interactions via the transient boronate, most of the previously tough amine donors, including sterically hindered amines, aromatic amines, and amino acids and amino alcohols, were well-tolerated. Importantly, the potential of this strategy in the pharmaceutical industry was highlighted with a successful synthesis of 3,4-HOPOs containing ironchelating active pharmaceutical ingredients on 10 g and kilogram scales.

Synthesis of γ-Pyrones and N-Methyl-4-pyridones via the Au Nanoparticle-Catalyzed Cyclization of Skipped Diynones in the Presence of Water or Aqueous Methylamine

“…As the core skeleton of 4-pyridone appears in a series of bioactive compounds, several synthetic approaches for the synthesis of this class of compounds have been developed so far. The most prominent include the treatment of γ-pyrones with amines, which is a slow process but can be promoted on certain types of pyrones (maltols) by boronic acids, via 4-alkoxy pyridinium salts under basic conditions; the Cu­(I)-catalyzed reaction of 4-hydroxypyridines with propargylic acetates, via the dehydrogenation of 2,3-dihydro-4-pyridones; the three-component cascade reaction of anilines, ethoxymethyl enemalonates, and acetylenedicarboxylates; the [4 + 2] cycloaddition between 3-aminocyclobutenones and electron-deficient alkynes; and the transition-metal-catalyzed N -allylation of parent 4-pyridone with allenes . We emphasize that the catalyzed approach for the synthesis of 4-pyridones using skipped diynones as precursors is practically underexamined.…”