Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals

Abstract

Here we report the development of a C(sp³)-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp³)-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidation, leads to elimination of a chlorine radical in what amounts to the sequential capture of two photons. Arylations of a benzylic C(sp³)-H bond of toluene and a completely unactivated C(sp³)-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp³)-H bond functionalizations under exceptionally mild conditions.

Figure 1

(A) Interfacing chlorine radical C(sp³)–H bond activation and cross coupling. (B) Chlorine radical generation via photolysis of high-valent nickel chloride complexes.

Figure 2

Proposed catalytic cycle. 3 = Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆; dF(CF₃)ppy = 2 (2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine.

Figure 3

(A) Halide additive studies. See Table S6 for additional experiments. (B) Deuterium labeling experiments. Ar = 2-(4-halophenyl)-6-methyl-pyridine. ^aYields determined by GC-FID or ¹H NMR using 1-fluoronaphthalene as an external standard. ^bYields determined by ²H NMR using DMF-d₇ as an external standard.

Figure 4

(A) Emission quenching of *Ir(III) 4. Ni complex 33 (Ar = 2-methylphenyl) gives a similar quenching rate to the reaction mixture consisting of Ni(dtbbpy)(cod) and 2-chlorotoluene. Additional data, controls, and statistics may be found in the SI. (B) Stoichiometric studies with Ni(II) complex 34 (Ar = 4-methylphenyl). See Table S13 for additional experiments. ^adtbbpy (1 equiv), K₃PO₄ (2 equiv), 2 mM THF. ^bYields determined by GC-FID using 1-fluoronaphthalene as an external standard. ^c1 mM THF.

Figure 5

Preliminary demonstration of reaction generality. ^aYield determined by ¹H NMR using 1-fluoronaphthalene as an external standard. ^bReaction was carried out using toluene as a solvent. ^cYield determined by GC-FID using 1-fluoronaphthalene as an external standard.