C-N Cross-Coupling via Photoexcitation of Nickel-Amine Complexes

Abstract

C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C-N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr₂·3H₂O), is oxygen tolerant, and proceeds through direct irradiation of the nickel-amine complex. This operationally robust process was employed for the synthesis of diverse C-N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr₂·3H₂O with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C-N cross-coupling reactivity.

Figure 1

Synthetic applications and mechanistic studies. (A) Light-driven sequential C–S and C–N cross-couplings to construct molecular complexity. For the synthesis of 37, 1.0 equiv of 4′-bromoacetophenone and 1.5 equiv of 3-bromothiophenol were used; for the synthesis of 38, 1.5 equiv of 3-aminopyridine and 1.5 equiv of quinuclidine base were used. DMSO = dimethyl sulfoxide. (B) Synthesis of flibanserin and two structurally related derivatives; the yields of 19, 9, and 22 are shown in Scheme 2. Using 19, 9, and 22 as the reagents, 39, 40, and 41 were obtained in the yields of 50%, 40%, and 70%, respectively. (C) UV–vis spectra of NiBr₂·3H₂O and NiBr₂·3H₂O + morpholine in DMAc; 70 equiv of morpholine was added with respect to NiBr₂·3H₂O in accordance to our standard reaction conditions. Photographs showing the teal color of NiBr₂·3H₂O solution in DMAc transformed to brownish yellow upon morpholine addition. (D) Proposed C–N cross-coupling mechanism derived from density functional theory (DFT) calculations for n = 3. Reported free energies (in kcal/mol at 298 K and 1 M in solution) were computed at uM06/6-311+G(d,p)//uM06/6-31+G(d,p) level of theory with CPCM-described solvation in DMAc solvent. (E) Computed transition state structures for steps DE and DF (for n = 3). morph = morpholine, PhCF₃Br = 4-bromobenzotrifluoride, CPCM = conductor-like polarizable continuum model; λ_max is the maximum absorption wavelength and ε the molar absorptivity.

Figure 2

Kinetic Isotopic Effect (KIE) Experiment. The rate of C–N cross-coupling was compared between piperidine and piperidine-d₁₁ using 4-bromobenzotrifluoride as the coupling partner. Reactions conditions: 1.0 equiv of 4-bromobenzotrifluoride (0.4 mmol), 3.5 equiv of piperidine (H or D), 5 mol% NiBr₂·3H₂O, and irradiation at 365 nm. The observed rate constant (k_obs) was determined by solving a second-order rate equation model via numerical integration (RK4 method, Figures S23 and S24); inhibition periods of 6 and 52 min were included in the model fitting of piperidine and piperidine-d₁₁, respectively.

Scheme 1

Historical Development of the C–N Cross-Coupling Reaction

Scheme 2

C–N Cross-Coupling via Photoexcitation of Nickel–Amine Complexes: Amine and Aryl Halide Scope Unless otherwise specified the reaction was conducted at 0.4 mmol scale and aryl bromide was used as the coupling partner. Percent isolated yield is reported next to the product’s boldface number. A photograph depicts the 3D-printed photoreactor equipped with the 365 nm LED used in this study (Figures S8 and S9). The LED consumes 13 W with 3.3 W radiant flux at 700 mA and 15.5 V (top right). Abbreviations: DMAc, N,N-dimethylacetamide; rt, room temperature; LED, light-emitting diode; Boc, tert-butyloxycarbonyl. ^a3.5 equiv amine used with no added base. ^b6.4 mmol scale reaction. ^cDimethyl sulfoxide (DMSO) used as solvent. ^d1.5 equiv amine used with 1.5 equiv quinuclidine base. See Supporting Information for further details.