Abstract
Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann-Löffler-Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)–H bonds. Here we report an amidyl radical-triggered site-selective remote C(sp3)–H heteroarylation of amides under organic photoredox conditions. This approach provides a mild and highly regioselective reaction affording remote C(sp3)–H heteroarylated amides at room temperature under transition-metal free, weakly basic, and redox-neutral conditions. Non-prefunctionalized heteroarenes, such as purines, thiazolopyridines, benzoxazole, benzothiazoles, benzothiophene, benzofuran, thiazoles and quinoxalines, can be alkylated directly. Sequential and orthogonal C–H functionalization of different heteroarenes by taking advantage pH value or polarity of radicals has also been achieved. DFT calculations explain and can predict the site-selectivity and reactivity of this reaction. This strategy expands the scope of the Minisci reaction and serves as its alternative and potential complement.
Highlights
Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann–Löffler–Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)–H bonds[15,16,17,18,19]
Zhu et al.[39] reported a hypervalent iodine-promoted remote C(sp3)–H heteroarylation of amides. Inspired by these reports on remote C(sp3)–H arylation, here, we report an amidyl radical-triggered, transition metal free and site-selective remote C(sp3)–H heteroarylation with non-prefunctionalized heteroarenes under photoredox conditions (Fig. 1b)
Details of the optimization of the reaction conditions are in the Supplementary Tables 1–6
Summary
The C6 alkylated purine (3) was isolated in 89% yield as a single regioisomer (Table 1, entry 1). When the reaction proceeds without the photocatalyst, product 3 can be obtained in 65% isolated yield (Table 1, entry 5). Basic conditions and visible light irradiation Transition metal and oxidant-free. None Without light Air instead of N2 Without K2CO3 Without 3CzClIPN Ir(ppy)[3] instead of 3CzClIPN Ru(bpy)3Cl2 instead of 3CzClIPN Eosin Y instead of 3CzClIPN 4CzIPN instead of 3CzClIPN Na2HPO4 instead of K2CO3 DIPEA instead of K2CO3 CH3CN instead of DMSO MeOH instead of DMSO 45 W CFL instead of 90 W blue LEDs 2′a instead of 2a aReaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.5 mmol), base (0.2 mmol), photocatalyst (2 mol%), solvent (1.0 mL), rt, 90 W blue LEDs bIsolated yield CTogether with 8% yield of C8-alkylated regioisomer.
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