In situ copper photocatalysts triggering halide atom transfer of unactivated alkyl halides for general C(sp3)-N couplings

Abstract

Direct reduction of unactivated alkyl halides for C(sp3)-N couplings under mild conditions presents a significant challenge in organic synthesis due to their low reduction potential. Herein, we introduce an in situ formed pyridyl-carbene-ligated copper (I) catalyst that is capable of abstracting halide atom and generating alkyl radicals for general C(sp3)-N couplings under visible light. Control experiments confirmed that the mono-pyridyl-carbene-ligated copper complex is the active species responsible for catalysis. Mechanistic investigations using transient absorption spectroscopy across multiple decades of timescales revealed ultrafast intersystem crossing (260 ps) of the photoexcited copper (I) complexes into their long-lived triplet excited states (>2 μs). The non-Stern-Volmer quenching dynamics of the triplets by unactivated alkyl halides suggests an association between copper (I) complexes and alkyl halides, thereby facilitating the abstraction of halide atoms via inner-sphere single electron transfer (SET), rather than outer-sphere SET, for the formation of alkyl radicals for subsequent cross couplings.

Fig. 1. Different strategies to achieve copper-catalyzed C-N couplings with unactivated alkyl halides.

a Diverse strategies for copper-catalysed C(sp3)-N couplings. b Photo-induced pyridyl-carbene-ligated copper (I) catalyst for general C-N couplings. SET single electron transfer. XAT halide atom transfer.

Fig. 2. The substrate scope of N-nucleophiles and alkyl iodides.

The reactions were run using N-nucleophiles (0.1 mmol), alkyl iodides (0.15 mmol). ^atBuOLi instead of MTBD, ^bUsing MTBD (0.28 mmol).

Fig. 3. Extended application of pyridyl-carbene copper catalysis.

a The substrate scope of amination of alkyl bromides. b Late-stage modification of complex molecules and the scale-up reaction. The reactions were run using N-nucleophiles (0.1 mmol) and alkyl bromides/iodides (0.15 mmol) under standard conditions unless otherwise noted. ^ausing DMF/CH₃CN = 9/1 as the solvent, ^busing PhCF₃/CH₃CN = 9/1 as the solvent, ^c18 h.

Fig. 4. Exploration of the active copper species.

a UV-vis spectra and emission spectra of LED light. b Cu(Py-NHC)₂PF₆ complex in solution. c ¹H NMR spectra of copper complexes. d Investigation into the active Cu^I species involved in the photochemical process.

Fig. 5. Investigation of radical process of C-N couplings.

a Radical trapping experiments. b EPR spectra (X-band, 9.4 GHz, 100 K). Black trace: spectrum of mixture of Cu(OAc)₂, L1, and MTBD. Red trace: spectrum of mixture of modified catalytic condition without p-toluidine 2. Blue trace: spectrum of mixture of modified catalytic condition. c Investigation of Cu^II intermediate for C-N coupling. d The lowest unoccupied molecular orbitals and singly occupied molecular orbitals of Cu^II(Py-NHC)(OAc)(NH-p-Tol), with isovalues of 0.04 a.u.

Fig. 6. Time-resolved spectroscopy studies.

a Two-dimensional pseudo-color femtosecond TA spectra of the in-situ generated Cu-1 complex (λ_pump = 400 nm). b Time-slicing TA spectra at selected pump-probe delays. c Single-wavelength TA (ΔA) kinetics probed at 460 nm (upper panel) and at 380 nm (lower). The kinetics at 460 nm in the presence of varying concentrations of quencher (iodocydohexane) are also shown for comparison. d Two-dimensional pseudo-color nanosecond TA spectra of the in-situ generated Cu-1 complex (λ_pump = 355 nm). e Steady-state emission spectra of the in-situ generated Cu-1 complex (excitation at 375 nm, 80 K). f Long-lived luminescence decay for the in-situ generated Cu-1 complex measured at 80 K (excitation at 375 nm). g TA kinetics at 380 nm of the in-situ generated Cu-1 complex (gray line). TA kinetics in the presence of quencher (red), MTBD (blue) and quencher plus MTBD (green) are also shown for comparison. h TA lifetime plotted as a function of the quencher concentration. i Proposed scheme for the intersystem crossing of the Cu-1 complex and its inner-sphere SET to attached alkyl halide.

Fig. 7. Plausible Mechanism.

The generation of various species or intermediates in the proposed catalytic cycle.