Chalcones, a Privileged Scaffold: Highly Versatile Molecules in [4+2] Cycloadditions

Abstract

Chalcones are aromatic ketones found in nature as the central core of many biological compounds. They have a wide range of biological activity and are biogenetic precursors of other important molecules such as flavonoids. Their pharmacological relevance makes them a privileged scaffold, advantageous for seeking alternative therapies in medicinal chemistry. Due to their structural diversity and ease of synthesis, they are often employed as building blocks for chemical transformations. Chalcones have a carbonyl conjugated system with two electrophilic centers that are commonly used for nucleophilic additions, as described in numerous articles. They can also participate in Diels-Alder reactions, which are [4 + 2] cycloadditions between a diene and a dienophile. This microreview presents a chronological survey of studies on chalcones as dienes and dienophiles in Diels-Alder cycloadditions. Although these reactions occur in nature, isolation of chalcones from plants yields very small quantities. Contrarily, synthesis leads to large quantities at a low cost. Hence, novel methodologies have been developed for [4 + 2] cycloadditions, with chalcones serving as a 2π or 4π electron system.

Synthesis, reactions and application of chalcones: a systematic review

“…The aza-Michael reaction is one of the most important synthesis routes for forming a C-N bond between an accessible NH-nucleophile and an unsaturated electrophile to generate useful intermediates for the synthesis of natural product analogues and active pharmaceutical ingredients. 122 The synthesis of biologically active azaheterocycles such pyrroles, isoxazoles, pyrazoles, benzodiazepines, triazoles, and pyrimidines is frequently carried out using chalcones [123][124][125][126] (Scheme 35).…”

“…192 Dibromochalcones 131 are produced using a variety of brominating agents, including bromine in various organic solvents, bromine vapour, pyridinium hydrobromide perbromide, phenyl trimethylammonium bromide, (bromodimethyl)-sulfonium bromide, tetrabutylammonium tribromide, and boric acid in potassium bromide solution, [192][193][194][195][196][197] as seen in Scheme 44. . 123 Chalcone can function as a heterodiene in a [4 + 2] cycloaddition as well as a dienophile in a Diels-Alder cycloaddition. This duality is recorded.…”

“…This duality is recorded. 123 Quantitative yields were obtained for the Diels-Alder annulation between 2′-hydroxychalcone 31 and diene 134 utilizing reusable catalysts that supported AgNPs in silica gel under solvent-free conditions, producing endo/exo product 135 199 (Scheme 46). It was reported that chalcones 137 and allenoates 136 experienced a hetero-Diels-Alder and isomerization process that was catalyzed by N-heterocyclic carbenes (NHCs), yielding highly functionalized multisubstituted pyranyl carboxylates 138 200 (Scheme 47).…”

Chalcone Scaffold: A masterpiece for medicinal chemistry recent biological insights

“…Chalcone is known by its commonly accepted consistent IUPAC name, 1,3-diphenyl-2-propen-1-one, which is also known as phenyl styryl ketone [9]. The numbering of positions between the flavonoid structure and the chalcone nucleus differs significantly.…”

Additivity of Diene Substituent Gibbs Free Energy Contributions for Diels–Alder Reactions between Me2C═CMe2and Substituted Cyclopentadienes

“…Early studies , that involved questions of orbital matching, radical vs closed-shell electronic interactions, and steric congestion have evolved to consider more complicated issues such as diradical mechanisms, , Pauli repulsion, and catastrophe theory . Aspects and applications of the Diels–Alder reactions are reviewed regularly; recent reviews examined the role of the reaction in natural/biochemical systems, , polymer synthesis, , and click chemistry. , Computational studies involving inverse electron demand, energy decomposition analysis, and molecular dynamics of the reaction have provided considerable insight into the fine details of cyclization.…”