A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

Abstract

A new way of developing novel synthesis strategies for the construction of monocyclic rings found in organic molecules is presented. The method is based on the visual application of integer partitioning to chemical structures. Two problems are addressed: (1) the determination of the total number of possible ways to construct a given ring by 2-, 3-, and 4-component couplings; and (2) the systematic enumeration of those possibilities. The results of the method are illustrated using cyclohexanone, pyrazole, and the Biginelli adduct as target ring systems with a view to discover new and greener strategies for their construction using multicomponent reactions. The application of the method is also extended to various heterocycles found in many natural products and pharmaceuticals.

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups

“…A prime example of this selectivity is the site-selective Pdcatalyzed C−F arylation of polyfluoroarenes that was demonstrated by Zhang and coworkers (Scheme 6). 67 This methodology involved the treatment of various polyfluoroarenes (10) with a diverse array of arylboronic acids and an in situ generated Pd(0) catalyst to synthesize monoarylated crosscoupled products. These reactions proceeded in accordance with their known S N Ar selectivity, where cross-coupling occurred para to a nonfluorine R substituent to provide monoarylated products 11a−d.…”

“…Functionalized arenes and heteroarenes (collectively, (hetero)­arenes) occur in a diverse array of secondary metabolites (i.e., natural products), drug candidates, ligands (e.g., those employed in transition-metal-catalyzed reactions), polymers, and electronic materials. − Given the ubiquity of these structural motifs, synthetic chemists continue to seek efficient, generalizable syntheses to prepare these scaffolds. − Two approaches have primarily been pursued. In the first approach, the core (hetero)­arene is assembled from acyclic precursors already bearing key substituents that will reside on the periphery of the (hetero)­arene. − A second approach focuses on functionalizing the periphery of a preformed (hetero)­arene core through sequential functionalizations . Of the two approaches, the latter has become more commonly employed due to the widespread availability of the unfunctionalized (hetero)­arene precursors and the broad range of functionalization strategies that currently exist, including aromatic substitution reactions, − metal-mediated halogen-exchange reactions, , C–H functionalization processes, cross-coupling reactions, and the more recently developed photoredox catalysis …”