Temperature-Directed in situ Generation of Fluorobenzyl Radicals: Utilization for the Complete Fluorobenzylation of Tri-, and Tetramethylbenzenes

Abstract

Organofluorine compounds have been broadly employed in the fields of pharmaceuticals, agrochemicals, and materials. Concurrently, the well-known star-shaped molecules, 1,3,5-trifunctionalized-2,4,6-trialkylbenzene, are of interest in supramolecular chemistry. For the first time, it is shown that three C-H functionalizations occur in the two-component reactions of trimethylbenzene and 2-, 3-, 4-fluorobenzyl chloride or 3-fluoro-4-methoxybenzyl chloride at 160 °C, without the use of any metals or additives. Interestingly, this reaction mixture is EPR-active, confirming the involvement of a free radical. Tri(fluorobenzyl) trimethylbenzenes are produced as the major product, with possible isolable intermediates including di(fluorobenzyl) trimethylbenzenes and mono(fluorobenzyl) trimethylbenzenes. An analogous reaction has also been observed in the case of tetramethylbenzenes. The screening involved changes in substrate ratio, temperature, and reaction time to determine the optimal conditions for achieving the maximum yield of tri(fluorobenzyl) trimethylbenzene. The addition product, 4-fluorobenzyl-TEMPO, was detected by using the HR-MS technique. Three units of 2-fluorobenzyl- or 4-fluorobenzyl in a 1,3,5-trimethylbenzene scaffold show a two-up-one-down conformation, whereas 3-fluoro-4-methoxybenzyl in a 1,3,5-trimethylbenzene scaffold displays three-up conformation in single-crystal X-ray structures. Experimental evidence indicates that these reactions may proceed through two distinct stepwise mechanisms. Firstly, three consecutive 4-fluorobenzyl radicals add to mesitylene, which subsequently undergoes three C_sp³-H bond scissions. Secondly, this process is repeated three times, involving the simultaneous addition of 4-fluorobenzyl radicals to mesitylene and the homolytic cleavage of C_sp³-H bonds, which produces mono-, and di-functionalized trimethylbenzene intermediates.