Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF 3 I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.medicinal chemistry | C-H functionalization | synthetic methodology T he trifluoromethyl group is becoming an increasingly common trait among molecules found in billion-dollar pharmaceuticals, agrochemicals, liquid crystals, dyes, and polymers (1-6). The inclusion of this motif and the unique properties its presence elicits is a testament to the success of chemical synthesis, as it is notably absent in Nature. Methodologies for the trifluoromethylation of arenes can be divided into two general categories (Fig. 1A): those that functionalize the inherently reactive positions of the substrate ("innate trifluoromethylation") and those that utilize substrate prefunctionalization or a directing group ("programmed trifluoromethylation"). For most applications, "programmed" aryl trifluoromethylation holds a distinct advantage because it can selectively functionalize positions that are not naturally reactive. Indeed, incredibly powerful methods have recently emerged in this arena (10-18). On the other hand, methods that capitalize on innate reactivity avoid the complication of preparing prefunctionalized substrates. We became interested in exploring "innate" aryl trifluoromethylation during our recent studies in the area of direct C-H arylation of heterocycles (19) and quinones (20) using radicals derived from boronic acid precursors. Aromatic heterocycles containing the trifluoromethyl group represent an important subsection of molecules of practical interest, particularly for pharmaceuticals, and therefore previously undescribed methods for their rapid assembly are in high demand. Our goal was to identify a reagent that would circumvent the use of gaseous CF 3 I (21), a reagent that is often avoided in pharmaceutical settings. At the start of our work, the task of replacing this reagent for the innate trifluormethylation of nitrogen containing heterocycles remained an unmet challenge.As briefly illustrated in Fig. 1, we evaluated numerous reagents for the trifluoromethylation of 4-t-butylpyridine as a model compound, with the aim of exploring those that might p...