Comprehensive perspectives of metal and metal-free C–H activation approaches in pyrimidines and related heteroarenes: scope, mechanistic insights, and synthetic utility

Pyrimidines, fundamental constituents of nucleic acids, pharmaceuticals, and agrochemicals, represent crucial scaffolds in organic synthesis owing to their electron-deficient aromatic character and multifaceted reactivity. This review meticulously assesses three distinct methodologies for the direct activation of C-H bonds in pyrimidines and associated heteroarenes bearing a pyrimidine moiety: transition-metal-catalyzed processes, metal-free techniques, and photochemical approaches. Metal-catalyzed strategies, utilizing catalysts such as palladium, nickel, or copper, facilitate the formation of C-C and C-N bonds with high regioselectivity, exemplified by the C(5)-arylation of 2-amino pyrimidines and the C(7)-H activation in pyrazolo[1,5-<i>a</i>]pyrimidines. Metal-free methodologies, which exploit Minisci-type radical reactions involving persulfates or phosphonium intermediates, provide sustainable functionalization pathways under mild reaction conditions. Photochemical methodologies, incorporating visible-light-driven photocatalysts such as eosin-Y or iridium complexes, facilitate radical-mediated arylations while offering environmental advantages. Through a comprehensive analysis of efficiency, regioselectivity, and scalability, this review also highlights significant progress in the synthesis of bioactive heterocycles, addresses pertinent challenges in green chemistry, and delineates avenues for future advancements in pyrimidine-centric therapeutics and innovative materials.