Nickel-catalyzed C–H alkylation of indoles with unactivated alkyl chlorides: evidence of a Ni(i)/Ni(iii) pathway† †Electronic supplementary information (ESI) available: Full experimental procedures and characterization data, including 1H and 13C NMR of all compounds. See DOI: 10.1039/c9sc01446b

A mild and efficient nickel-catalyzed method for the chemo and regioselective coupling of unactivated alkyl chlorides with the C–H bond of indoles and pyrroles at 60 °C is described.


2.
Reaction optimization  i Using LiOtBu or NaOtBu as base. j Using Na 2 CO 3 , NaOAc, K 2 CO 3 or Cs 2 CO 3 as base.

3.
Representative procedure for alkylation

Procedure for NMR tube experiment
To a J-Young NMR tube, the ligand bpy (0.006 g, 0.04 mmol) was introduced, and 4-MeO-C 6 H 5 -Me (0.005 mL, 0.04 mmol, internal standard) and toluene-d 8 (0.5 mL) was added into it. The 1 H NMR analysis shows the expected signals for the bpy compound ( Figure S4A).
To the NMR tube, (thf) 2 NiBr 2 (0.015 g, 0.04 mmol) and LiHMDS (0.027 g, 0.16 mmol) were added and the reaction mixture was heated at 60 o C for 15 min. The 1 H NMR analysis shows a broad signal at 10.69 ppm for all the bpy protons (coordinated to Ni) and a signal at 0.08 ppm for the unreacted LiHMDS ( Figure S4B). In addition, de-coordinated THF protons are visible. This suggests the probable formation of a paramagnetic bpy-coordinated nickel species during the reaction. To the same NMR tube, indole 1a (0.008 g, 0.04 mmol) and 1-chlorooctane (2a; 0.006 g, 0.04 mmol) were added and the reaction was further heated at 60 o C for 15 min in a preheated oil bath. The 1 H NMR analysis of the reaction mixture shows peaks for product 3aa, however, the peak corresponding to the (bpy)Ni was disappeared ( Figure S4C). This strongly suggests the existence of a paramagnetic (bpy)Ni species during the reaction.  Procedure: The representative procedure of the alkylation reaction was followed, using indole 1a (0.039 g, 0.20 mmol), 6-chloro-1-hexene (2u; 0.047 g, 0.40 mmol) and the reaction mixture was stirred for 16 h. Purification by column chromatography on neutral alumina S47 (petroleum ether/EtOAc 50/1) yielded 3au (0.043 g, 78%) and direct coupled product 2-(hex-5en-1-yl)-1-(pyridin-2-yl)-1H-indole (0.005 g, 9% (GC yield)). The data of the concentration of the product vs time (min) plot was drawn (Table S2 and Figure   S5) with Origin Pro 8. The data's were taken from the average of two independent experiments.  Figure S5. Time-dependent formation of 3aa using (thf) 2 NiBr 2 /bpy system (shown up to 120 min).

Procedure for kinetic experiment (using isolated complex):
Representative procedure of kinetic experiment (Sec 12.1.1) was followed using (bpy)NiBr 2 (0.0037 g, 0.01 mmol, 0.01 M), LiHMDS (0.067 g, 0.40 mmol), indole 1a (0.039 g, 0.20 mmol, 0.2 M) and 1chlorooctane (0.059 g, 0.40 mmol, 0.4 M) and n-hexadecane (0.025 mL, 0.085 mmol, 0.085 M, internal standard). An aliquot of sample was withdrawn to the GC vial at regular intervals (10, 20, 30, 40, 50, 60, 90, 120 min, etc.). The data of the concentration of the product vs time (min) plot was drawn (Table S3 and Figure S6(B)) and fitted linear with Origin Pro 8, and the rate was determined by the initial rate method (up to 360 minutes). The slope of the linear fitting represents the reaction rate. These data were taken from the average of two independent experiments.  was drawn ( Figure S9) and fitted linear with Origin Pro 8, and the rate was determined by initial rate method (up to 120 minutes). The slope of the linear fitting represents the reaction rate.  ( Figure S11). This experiment in the absence of nickel catalyst (thf) 2 NiBr 2 /bpy also shows the same result.

Procedure for EPR study
Representative procedure: To a flame-dried screw-cap tube equipped with magnetic stir bar were introduced 1-(pyridin-2-yl)-1H-indole (1a; 0.019 g, 0.10 mmol), 1-chlorooctane (2a; 0.030 g, 0.20 mmol), (thf) 2 NiBr 2 (0.011 g, 0.03 mmol, 30.0 mol %), bpy (0.005 g, 0.03 mmol, 30.0 mol %) and LiHMDS (0.033 g, 0.20 mmol) inside the glove box. To the above mixture in the tube was added toluene (1.0 mL) and the resultant reaction mixture was immersed in a preheated oil bath at 60 °C and stirred for 30 min. At ambient temperature, the reaction tube was transferred to the glove box, and the reaction mixture was transferred to an EPR tube and frozen at 100 K, which was then subjected to EPR measurement.
The intensity of the EPR spectrum obtained from the mixture (thf) 2 NiBr 2 + bpy + LiHMDS

Procedure for XPS analysis
Representative procedure: To a flame-dried screw-cap tube equipped with magnetic stir bar were introduced 1-(pyridin-2-yl)-1H-indole (1a; 0.019 g, 0.10 mmol), 1-chlorooctane (2a; 0.030 g, 0.20 mmol), (thf) 2 NiBr 2 (0.009 g, 0.025 mmol), bpy (0.004 g, 0.025 mol) and LiHMDS (0.033 g, 0.2 mmol) inside the glove box. To the above mixture in tube was added toluene (0.5 mL). The resultant reaction mixture in the tube was immersed in a preheated oil bath at 60 o C and stirred for 30 min. At ambient temperature, the reaction tube was transferred to the glove box. The sample for XPS analysis was prepared inside the glove box. After sample preparation, the sample was transferred to a vacuum transfer module which was subsequently evacuated in the antechamber of the glove box. The samples were loaded onto the spectrometer using this vacuum transfer module and subsequently pumped down by turbo molecular pumps connected to the load lock chamber. This allowed efficient transfer of the samples without being exposed to the atmosphere. The spectra were collected using Thermo Kalpha + spectrometer with a mono chromated Al Kα X-ray source with energy 1486.6 eV. The pass energy for the acquisition was S58 50 eV for the individual core-level. All the spectral acquisition was done in the presence of ultralow energy co-axial electron gun for charge compensation. The peak fitting of the individual core-levels were done using Avantage software with a Shirley type background.

The geometry of intermediate A (X = Br) is optimized under the framework of Density
Functional Theory (DFT) using a linear combination of Gaussian orbitals as implemented in deMon 5.0 code. S16 For all the calculations, PBE exchange correlation functional was used. S17 Atomic orbitals of Ni are described through effective core potentials with ECP SD basis set for the valence orbitals. S18 The