Synthesis of (diarylmethyl)amines using Ni-catalyzed arylation of C(sp3)–H bonds

The first nickel catalyzed deprotonative cross coupling between C(sp3)–H bonds and aryl chlorides is reported, allowing the challenging arylation of benzylimines in the absence of directing group or stoichiometric metal activation.


I. General considerations
 Aryl chlorides were used as received. Anhydrous, oxygen-free solvents (DMAc, tetrahydrofuran (THF), dimethoxyethane (DME), Dioxane and toluene) and the bases (NaOtBu, KOtBu, KHMDS, LiHMDS, NaHMDS) were stored in a glovebox and used as received. N-Benzylidene-N-(diphenylmethyl)amine (1d) was purchased from Sigma Aldrich and used as received. The well defined Ni complexes 1 and the benzylimine substrates 2 were prepared according to previously reported procedures.  Flash chromatography was performed on silica gel 60 Å pore diameter and 40-63 μm particle size.  1 H, 13 C and 19 F Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker-300, 400 or 500 MHz spectrometer at ambient temperature in CD 3 OD or CDCl 3 . Chemical shifts (δ) are reported in ppm, relative to the solvent residual proton peak CD 3 OD (3.31 ppm for 1 H and 49.0 ppm for 13 C) and CDCl 3 (7.26 ppm for 1 H and 77.00 ppm for 13 C). For 19 F NMR, chemical shifts refer to an external calibration using CFCl 3 (δ = 0.00 ppm). Data for 1 H NMR are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, br = broad signal, m = multiplet), coupling constants (J) in Hz and integration.  HRMS analysis were performed at the EPSRC UK National Mass Spectrometry Facility (NMSF), Swansea.  All isolated yields are an average of two runs.

IV. Experimental procedures
General procedure for the arylation of imines. Inside a glovebox, [Ni(COD) 2 ] (0.0125 mmol,), IPr (10 or 15 mg, 2 equiv. with respect of Ni) the selected imine (0.5 mmol, 2 equiv.), KHMDS (100 mg, 0.5 mmol) were weighted in a screw cap vial equipped with a stirring bar. The aryl chloride (0.25 mmol, 1 equiv.) was added at this stage, if solid. The vial was sealed and carried out from the glovebox, where and the aryl chloride, if liquid, and the dry, degassed solvent (toluene, 1.5 ml) were added. The reaction was then stirred for 16 hours at 45°C. The reaction was then quenched adding some drops of water and filtered through Mg 2 SO 4 . After checking the NMR, the crude was absorbed on silica previously basified (stirring it overnight with 2% triethylamine in pentane) and purified by flash chromatography (typically with a pentane / diethyl ether = 95 / 5 eluent mixture) to afford the desired product.
Procedure for the hydrolysis of 3k. HCl 1N in diethyl ether (1 mL) was added to the solution of imine 3k (39.7 mg, 0.1 mmol) in THF (1 mL) at 0°C. The solution was warmed to room temperature, stirred at room temperature and monitored by TLC until all the imine was consumed. The THF was evaporated under vacuum. Another 1 mL HCl (1N) was added and a white precipitate was observed. The white solid was filtered and washed with cold Et 2 O (1.0 mL×3). After drying under vacuum for 12 h, the hydrochloride salt was obtained as a white solid (25.4 mg, 99% yield). of 1a (table2, entries 1-3). Inside a glovebox, 1a (54 mg, 0.2 mmol, 1.0 equiv.) and the base (2.0 equiv.) were weighted in a screw cap vial equipped with a stirring bar. Outside the glovebox, toluene (0.6 mL) and benzyl chloride (0.25 μL, 2.4 mmol, 1.2 equiv.) were added, and the reaction was then stirred at 45 °C for 3 hours. The reaction was then quenched with 2 drops of water, filtered thru MgSO 4 and dried under vacuum. The yield was then assessed via quantitative 1 H-NMR, using diethylmalonate as internal standard.

Procedure for the bases test (table 2, entries 4-6)
. Inside a glovebox, 1a (54 mg, 0.2 mmol, 1.0 equiv.) and the base (0.5 equiv.) were weighted in a screw cap vial equipped with a stirring bar. Outside the glovebox, dry degassed toluene (0.6 mL) was added using a syringe thru the septum, and the reaction was then stirred at 45 °C for 3 hours.
The reaction was then quenched with 2 drops of water, filtered thru MgSO 4 , dried under vacuum and analyzed via 1 H-NMR.