Nickel-catalyzed C–N bond activation: activated primary amines as alkylating reagents in reductive cross-coupling† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c9sc00783k

The reductive cross coupling of pyridinium salts derived from readily available primary alkyl amines with aryl halides has been achieved under mild reaction conditions using a nickel catalyst.


Copies of NMR Spectra
Electronic Supplementary Material (ESI) for Chemical Science. This journal is © The Royal Society of Chemistry 2019

General Information
Unless otherwise noted, all commercially available compounds were used as provided without further purification. Solvents for chromatography were technical grade and freshly distilled prior to use. DMA used in reactions was purchased from J&K, bubbled for 30 min with Ar, and stored at room temperature.
All other solvent used in reaction optimization were acquired from SPS. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminium plates with F-254 indicator, visualized by irradiation with UV light, in some cases stained with PMA. Column chromatography was performed using silica gel (Macherey Nagel, particle size 0.040-0.063 mm). 1 H-NMR and 13 C-NMR were recorded on a Varian AV300, AV400 or AV600 spectrometer in CDCl 3 and are reported relative to the solvent residual peaks. Data are reported in the following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet), bs (broad singlet), d (doublet), t (triplet), m (multiplet); coupling constants (J) are in Hertz (Hz). IR spectra were recorded on a Perkin Elmer-100 spectrometer and are reported in terms of frequency of absorption (cm -1 ). Mass spectra (EI-MS, 70 eV) were conducted on a Finnigan SSQ 7000 spectrometer. HRMS were recorded on a Thermo Scientific LTQ Orbitrap XL spectrometer. Gas chromatography (GC) was performed on a Shimadzu GC-2010 chromatograph.

Substrates Synthesis General Procedure for Preparation of Pyridinium Salts from Ammonium Salts
The Katritzky pyridinium salts were synthesized according to the procedure described previously in the literature. 1-11 2,4,6-Triphenylpyrylium tetrafluoroborate (4.0 mmol, 1.0 equiv.) was suspended in absolute EtOH (4 mL). Subsequently, primary amine (4.8 mmol, 1.2 equiv.) was added and the reaction mixture was refluxed at 88 °C for 4 h. After this time, the mixture was cooled to room temperature and diluted with Et 2 O (20 mL). The resulting precipitate was filtered off, washed with Et 2 O, and dried under vacuum to afford the Katritzky salt. If the product failed to precipitate after addition of Et 2 O, the reaction mixture was concentrated in vacuo and purified by column chromatography (acetone/CH 2 Cl 2 ).

1-cyclohexyl-4-methoxybenzene (3j)
According to the general procedure, the title compound was isolated as a white solid after flash chromatography on silica gel (eluent: hexane) in 64% yield (24.3 mg

(4-cyclohexylphenyl)(methyl)sulfane (3k)
According to the general procedure, the title compound was isolated as a white solid after flash chromatography on silica gel (eluent: hexane) in 77% yield (31.7 mg

4-cyclohexylpicolinonitrile (3s)
According to the general procedure, the title compound was isolated as a colorless oil after flash chromatography on silica gel (eluent: 50:1 to 10:

4-cyclohexylphenyl 4-(N, N-dipropylsulfamoyl)benzoate (5c)
According to the general procedure, the title compound was isolated as a white solid after flash chromatography on silica gel

Cyclic Voltammetry Measurement of Katritzky Salt
Cyclic voltammograms were taken on PGSTAT101 from Metrohm Autolab using a platinum working electrode, a Ag + (0.01 M AgNO 3 , 0.1 M NBu 4 PF 6 , CH 3 CN)/Ag as reference electrode, a platinum wire counter electrode and 0.1 M NBu 4 PF 6 as supporting electrolyte. The solution was prepared in CH 3 CN and degassed with argon bubbling for 20 min prior to voltammetric studies. The scan rate was 50 mV/s. The potentials were given relative to the Fc/Fc + redox couple with ferrocene as internal standard. For conversion to SCE as reference, it is known that SCE is 400 mV more negative than Fc/Fc + in MeCN with NBu 4 PF 6 as supporting electrolyte. 32 We chose 1-cyclohexyl-2,4,6-triphenylpyridin-1-ium tetrafluoroborate salt as model Katritzky salt. The concentration of it was 10 mM. The scan direction was negative. We first measured the CV of our substrate alone, then measured the CV of our substrate together with internal standard ferrocene.

Computational methods
All DFT-calculations were performed using Gaussian 09, Revision D.01. 33 The geometry optimization and frequency analysis were performed using meta-hybrid-GGA DFT functional ωB97xD. 34 The split-valence plus one polarization function Def2-SVP basis set was used for non-metal atoms and the triple-ζ basis set Def2-TZVP was used for metals (Ni and Mn). 35 In all cases, the default integral grid (Fine Grid) was employed. Frequency calculations were performed in order to obtain thermal corrections (298 K) and to confirm the nature of the stationary points (minima with no imaginary frequency or transition states with one imaginary frequency). All transition states were optimized using the default Berny algorithm implemented in the Gaussian 09 code. 33 For transition state structures, IRC calculations were undertaken to confirm that the transition states were connected to the correct minima. For further validation of energetics, single-point calculations were performed on the ωB97xD/Def2-SVP optimized geometries using meta-hybrid GGA functional M06 36 employing a valence quadruple-ζ-type of basis set Def2-QZVPP 35 for all atoms. The solvent effects (n,n-DiMethylAcetamide (DMA): ε=37.781) were evaluated implicitly by a self-consistent reaction field (SCRF) approach for all the intermediates and transition states, using the SMD continuum solvation model. 37 Unless specified otherwise, ΔG was used throughout the text. The ΔG value was obtained by augmenting the E el energy terms at M06(SMD-DMA)/Def2-QZVPP with the respective free energy corrections at the ωB97xD/Def2-TZVP(Ni,Mn)/Def2-SVP(non-metal) level in gas phase. The wavefunction analysis were performed using Multiwfn 3.6 dev.b. 38 VMD was used to visualize the orbitals. 39 The geometries were realized using CYLview, 1.0b. 40

Generation of Ni 0 active catalyst B
In this reaction, Ni II pre-catalyst NiCl 2 ·glyme was used. First, it complexes with ligand bpy and glyme is liberated with a free energy gain of 30.7 kcal/mol. Next, the Ni II complex is reduced by Mn to form the Ni 0 active catalyst H3 with a free energy gain of 58.0 kcal/mol.
Scheme S1: Generation of Ni 0 active catalyst B

SET reduction of Katritzky salt
Two possible mechanisms were initially proposed (Scheme S2).

Scheme S2: Two possible catalytic cycles
The main difference was the SET reduction of Katritzky salt. In order to figure out this process, DFT calculations were performed for both possible pathways (Scheme S3). The results showed that the SET reduction of Katritzky salt by Ni I -aryl is clearly favored.