Fluorine, the most abundant halogen in the earth's crust. Owing to the distinctive physical and biological properties of fluorine atoms, fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. However, naturally occurring organic fluorine compounds are extremely scarcely found. Thus, novel methodologies and reagents for the efficient synthesis of organofluorine compounds have been intensely developed over the recent few decades. Nowadays, organofluorine compounds have become abundant and readily accessible, which makes them attractive as functional moieties as well as building blocks for further organic synthesis. However, the chemical transformation of fluorinated moieties to other functional groups is a considerable challenge because the C–F bond possesses the highest bond dissociation energy compared to other C–X (X = H/D, C, N, O, Si, S, etc.) bonds. To overcome this challenge, new methodologies are urgently needed to be developed to make the selectively defluorinative functionalization of fluorinated moieties mildly realized, specifically finely adjusting the structure of fluorinated part according to related requirements or transforming fluorine-contain industry wastes (for example PFAS) into valuable feedstocks and recovering F resource.
Initially successful transformation of organic fluorides to organic silanes via defluorosilylation1 in the presence of silylboronates (such as Et3SiBpin) and KOtBu encouraged us to explore more possibilities of this defluorinative functionalization reactions. Therefore, a catalyst-free and regioselective carbosilylation of alkenes under room temperature has been disclosed as a useful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups (from organic fluorides) across an alkene double bond.2 Further mechanism control experiments revealed that this carbosilylation might involve a single-electron transfer (SET)/radical-mediated process.
Although the most reliable preparation methods of aromatic tertiary amines are the transition-metal-catalyzed C(sp2)–N cross-couplings of aryl (pseudo)halides with amine nucleophiles, a better concept of green chemistry requires the development of transition-metal-free systems. As a continuation of our studies regarding selective defluorinative C–F bond functionalization, we wondered whether the fundamentally important C–N bond cross-coupling could be accessed to bypass the traditional protocols involving transition-metal-catalyst and/or high temperature. Fortunately, nitrogen-centered radicals could be efficiently generated from corresponding secondary amines through a SET process.3 Surprisingly, the solvent effect is outstanding observed in this defluoroamination. For example, when the reaction was carried out in THF rather than in triglyme, the yield significantly decreased, while increased in the presence of 18-crown-6. Because it is known that the potassium cation could be capsuled by glymes and also by 18-crown-6, which results in the formation of naked, reactive −OtBu. Therefore, the cooperation of Et3SiBpin and KOtBu once again enables the cross-coupling of C–F and N–H bonds under very mild conditions, effectively avoiding the high barriers associated with thermally induced SN2 or SN1 amination. Additionally, the selective activation of the C–F bond of the organic fluorides in this system remarkably tolerant potentially cleavable C–O, C–Cl, C–Br, heteroaryl C–H, C–N bonds, and CF3 groups. Tertiary amines with aromatic, heteroaromatic, and/or aliphatic groups were efficiently synthesized in a single step using electronically and sterically varying organic fluorides and N-alkylanilines or secondary amines. This mild protocol also extended to the late-stage synthesis of drug candidates, including their deuterium-labeled analogs.
For more findings of this defluorinative functionalization of the C–F bond in organic fluorides, please also refer to the just-published article on the silylboronate-mediated radical cross-coupling of aryl fluorides with arylalkanes.4 Corresponding control experiments such as the addition of TEMPO, radical ring-opening and radical cyclization experiments, and ESR experiments all support our proposed reaction mechanism.
- Cui, B., Jia, S., Tokunaga, E. & Shibata, N. Defluorosilylation of fluoroarenes and fluoroalkanes. Nat. Commun. 9, 4393 (2018).
- Zhou, J. et al. Catalyst-free carbosilylation of alkenes using silylboronates and organic fluorides via selective C–F bond activation. Nat. Commun. 12, 3749 (2021).
- Pratley, C., Fenner, S. & Murphy, J. A. Nitrogen-centered radicals in functionalization of sp2 systems: generation, reactivity, and applications in synthesis. Chem. Rev. 122, 8181–8260 (2022).
- Zhou, J. et al. Synthesis of triarylmethanes by silyl radical-mediated cross-coupling of aryl fluorides and arylmethanes. Chem. Sci. 14, (2023) doi:10.1039/d3sc00154g.