Bench‐Stable N‐Heterocyclic Carbene Nickel Precatalysts for C−C and C−N Bond‐Forming Reactions

Abstract Herein, we introduce a new class of bench‐stable N‐heterocyclic carbene (NHC) nickel‐precatalysts for homogeneous nickel‐catalysis. The nickel(II) complexes are readily activated to Ni0 in situ under mild conditions, via a proposed Heck‐type mechanism. The precatalysts are shown to facilitate carbonyl‐ene, hydroalkenylation, and amination reactions.


I. General Information
Unless otherwise indicated, all reactions were performed in flame-or oven-dried glassware under rigid exclusion of air, either in a nitrogen-filled glove box or using standard Schlenk techniques.
Tetrahydrofuran, dichloromethane, acetonitrile, triethylamine and 1,4-dioxane were degassed by sparging with argon and dried by passing through a column of activated alumina on an SG water solvent purification system. Bis-(1,5-cyclooctadiene)nickel(0) [Ni(cod)2] purchased from Strem Chemicals appeared as yellow crystals and was stored in the glovebox at -30 °C. PCl3 was purified via distillation prior to use. Triethylsilyl triflate (TESOTf) and styrene were distilled over CaH2 prior to use. Liquid olefins were passed through a column of activated MgSiO4 (Florisil) or activated basic alumina and sparged with argon prior to use. 1,3-Bis(2,6diisopropylphenyl)imidazol-2-ylidene (IPr) was prepared according to a literature procedure [1] and stored in the glove box. Other carbene ligands were used as received from Strem Chemicals.
Thin layer chromatography (TLC) was carried out on EMD Millipore 60 F254 glass-backed plates (silica or neutral alumina). Spots were visualized using UV light (254 nm) or a basic potassium permanganate stain. Flash chromatography was carried out on a Biotage Isolera automated column chromatography system using silica (SNAP Ultra), NH-capped silica (SNAP-NH) or alumina (neutral, activated) columns.

Amine-Derived Nickel-NHC Precatalysts
General procedure: N-(2-chlorobenzyl)amines were prepared from 2-chlorobenzyl chloride and the corresponding amine according to the known literature procedure with spectral data matching those described in the literature. [6] In the glove box, a solution of the N-(2-chlorophenyl)amine (0.6 mmol, 1.2 equiv) in THF (3 mL) was charged to a solution of Ni(cod)2 (138 mg, 0.5 mmol, 1.0 equiv) in THF (8 mL) at -35 °C. After stirring for 1 min, a solution of IPr (189 mg, 0.5 mmol, 1.0 equiv) was added and the mixture was warmed to room temperature and stirred for 2 h. The vial was opened to air and stirred for an additional 10 min. The solution was filtered through celite and concentrated in vacuo. The red-brown residue was purified by flash chromatography on neutral alumina (100% hexanes, then 0% to 100% CH2Cl2/hexanes).

Olefin Tethered Amine-Derived Nickel-NHC Precatalysts
General procedure: To a suspension of magnesium powder (1.82 g, 75.0 mmol, 3.0 equiv) in THF (30 mL) was added a small amount of the (n+2)-bromo-1-alkene or 1-bromopropane. After initiation of the Grignard reaction was observed through gentle heating of the solution, the remaining (n+2)-bromo-1-alkene or 1-bromopropane (37.5 mmol, 1.50 equiv) was added dropwise. The solution was then heated to reflux and stirred for 2 h. After cooling to room temperature, the prepared Grignard reagent was added dropwise to a solution of 2-chlorobenzaldehyde (3.51 g, 25.0 mmol, 1.0 equiv) in THF (80 mL). After 2 h, sat. NH4Cl solution was added slowly until all of the formed magnesium salts had dissolved. The resulting alcohol product was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were dried over MgSO4, concentrated in vacuo and purified by flash chromatography on silica (10% ethyl acetate / hexanes).
To a stirred solution of the respective benzylic alcohol (5.0 mmol, 1.0 equiv) and triethylamine (3.5 mL, 25.0 mmol, 5.0 equiv) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (475 µL, 6.0 mmol, 1.2 equiv) dropwise at 0 °C. After stirring at 0 °C for 2 h, water (25 mL) was added and the product was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The respective benzyl mesylate was used without further purification.
The respective amine (25.0 mmol, 5.0 equiv) was added to a solution of the benzyl mesylate in acetonitrile (25 mL). The mixture was stirred at room temperature for 12 h. After concentration in vacuo, the residue was purified via flash chromatography on NH-capped silica (100% hexanes, followed by 20% EtOAc/hexanes).    General procedure: In the glovebox, a solution of IPr (189 mg, 0.5 mmol, 1.0 equiv) and the ligand precursor (0.6 mmol, 1.2 equiv) in THF (3 mL) was charged to a slurry of Ni(cod)2 (138 mg, 0.5 mmol, 1.0 equiv) in THF (8 mL) at -35 °C. The mixture was warmed room temperature and stirred overnight. The vial was then opened to air and stirred for 10 min. The solution was filtered through celite and concentrated in vacuo. The red-brown residue was purified by flash chromatography on alumina (neutral, activated) (100% hexanes, then 0% to 100% CH2Cl2/hexanes).