Solvent-Free Mechanoradical-Mediated Minisci-Type C–H Alkylation of N-Heteroarenes

Abstract

An environmentally friendly new C−H alkylation method of N-heteroarenes facilitated by mechanochemistry is described. Under solvent-free ball-milling, mechanoradicals (SO 4•− ) were generated from persulfate via in situ homolysis in the solid state, at as low as −50 °C. These highly oxidizing radicals readily transform alkyl trifluoroborate salts to their corresponding carbon-based radicals for subsequent C−C bond formation with N-heterocycles. Mechanistic studies unambiguously confirmed the involvement of both oxygen-and alkyl-radical-based intermediates.R adical reactions are generally initialized by heat, light, and chemical approaches (Scheme 1a). 1 Due to the harsh conditions often needed to form these open shell species, radical reactions were once considered too reactive and unselective. In the past 15 years, methodologies deriving from drastically mild conditions have been developed, notably through visible light photoredox catalysis 2 and electrocatalysis, 3 unleashing the unique synthetic values in radical chemistry, and they have now become a powerful tool in modern organic synthesis.Mechanochemistry, more specifically ball-milling, has gained renewed interests in polymer chemistry and organic synthesis. 4,5 Being solvent-free, solvent screening and other solvent-required operations in solvent-phase reactions are avoided to save time and cost and enhance sustainability. Mechanical force can also be applied to generate free radicals, known as mechanoradicals. Since a century ago, Staudinger, Sohma, and others had discovered that polymers undergo chain scission upon mechanical stimulation through homolytic pathways. 6,7 Recently, using this strategy, the formation of fluorescent polymers from commodity polymers was reported. 7d,8 Given the widespread applications in both radical chemistry and mechanochemistry, we strive to develop processes merging these two areas together, more specifically, to investigate how a radical is generated in the solid state and if new types of bondformation/-breaking reactions and/or reaction mechanisms (distinct from solution-phase reactions) can be discovered. Despite the long history of mechanoradicals, implementing this force-directed concept in organic synthesis, especially in C−H activation and C−C bond-formation reactions, is relatively unexplored. 9,10 Recently, Ito 9b and Bolm 9f elegantly demon-