Cobalt‐Catalyzed Suzuki Biaryl Coupling of Aryl Halides

Abstract Readily accessed cobalt pre‐catalysts with N‐heterocyclic carbene ligands catalyze the Suzuki cross‐coupling of aryl chlorides and bromides with alkyllithium‐activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt species is reduced to Co0 during the reaction.


General Information
Unless otherwise indicated, all experiments were performed under a dry and inert atmosphere (N2 or Ar) using standard Schlenk-line and glovebox techniques. Anhydrous solvents were obtained using an S2 Anhydrous Engineering double alumina column drying system. Commercial grade solvents were used for chromatography and work-up procedures. Column chromatography was performed using technical grade silica gel, pore size 60 Å, 230-400 mesh particle size. TLC analyses were performed using aluminium plates covered with SiO2 (Merck 60, F-254) and visualized by UV detection (254 or 365 nm). Benzene-d6 was degassed and dried over activated molecular sieves (4 Å). 1,3-Bis(2,6-di-isopropylphenyl)imidazolidin-2-ylidene (SIPr) was synthesised according to literature procedure. [S1] 1 H, 13 C and 19 F NMR spectra were recorded in CDCl3 on Varian 400-MR, Bruker Nano 400, Jeol ECS 400 or Bruker Advance III HD 500 Cryo spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) referenced to the solvent residual peak. Coupling constants (J) are given in Hz and multiplicities being abbreviated as: br (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Infrared spectra were recorded using a Perkin Elmer Spectrum Two FT-IR spectrometer.
Absorption spectra were recorded with an Ocean Optics USB2000+UV-VIS spectrometer. The method for determining magnetic moments originally described by Evans was followed. [S2] Mass spectrometry was performed by the University of Bristol mass spectrometry service by electrospray ionisation (ESI + ) using a Bruker Daltonics MicroTOF II. GC-FID/MS analysis was conducted using an Agilent 7820A GC system and 5977B MSD.

Preparation of activated boronate nucleophiles, Li[(Ar)( n Bu)Bpin], 1.
The appropriate arylboronic acid pinacol ester, 3, (1.5 mmol) was dissolved in THF (3.8 ml) in a Schlenk flask. To this, was added a solution of 2.5 M n-butyl lithium in hexanes (1,5 mmol) in one portion at -40 °C. The mixture was stirred at -40 °C for 30 minutes, allowed to warm to 0 °C and then stirred for another 30 minutes. This resultant solution of 1 was used immediately after preparation. [S3]

Optimisation of the Reaction Conditions
A Schlenk flask was charged with the appropriate amount of CoCl2 (2 -10 mol%) SIPr·HCl (2 -10 mol%) and dry THF (1 ml) was added. The solution was stirred at room temperature for 1 hour. A solution of the appropriate borate, 1 (0.5 -0.75 mmol) and then chlorotoluene (30 µl, 0.25 mmol) were added, the mixture was stirred at the appropriate temperature for 12-48 h, and then cooled to room temperature. The reaction mixture was quenched with HCl(aq) (1 M, 2 ml) and the organics were extracted using CH2Cl2 (3 x 10 ml) and dried over anhydrous Na2SO4. The organic extracts were S3 filtered and the solvent removed under reduced pressure to afford the crude product, 2a. The product was dissolved in CDCl3, 1,3,5-trimethoxybenzene (42.0 mg, 0.25 mmol, internal standard) and the conversion to 2a was determined by 1 H NMR spectroscopy. The variations to components or conditions summarised in tables 1 and S1 -S3.

General Procedure for Cobalt-Catalyzed Suzuki Cross-Coupling of Aryl Halides
A Schlenk flask was charged with CoCl2 (6.5 mg, 0.05 mmol, 10 mol%), SIPr·HCl (21.4 mg, 0.05 mmol, 10 mol%) and dry THF (1 ml) was added. The solution was stirred at room temperature for 1 hour. Freshly prepared borate 1 (1.5 mmol in THF 3.8 ml) and then aryl halide (0.5 mmol) were added, the mixture was stirred at 60 °C for 48 h and then cooled to room temperature. The reaction mixture was quenched with HCl(aq) (1 M, 2 ml) and the organics were extracted using CH2Cl2 (3 x 10 ml) and dried over anhydrous Na2SO4. The organic extracts were filtered and the solvent removed under reduced pressure to afford the crude product. Spectroscopic yields were determined by 1 H NMR spectroscopy (1,3,5-trimethoxybenzene internal standard). The crude product was purified by column chromatography (silica gel).

1-Phenylnaphthalene (Table 2, Entry 15)
The general procedure was followed using 1-chloronaphthalene and 1a. Purification by column chromatography (hexanes) gave the title compound as a colorless oil (74 mg, 73% Spectroscopic data in agreement with the literature. [S12]

(b) Using 1a as a reducing agent
A mixture of CoCl2 (0.013 g, 0.1 mmol) and SIPr (0.039 g, 0.1 mmol) were stirred in THF (1 ml) for 1 hour. To the resulting blue solution, dvtms (0.023 mL, 0.1 mmol) was added. A THF solution of 1a (0.75 mmol), prepared as described above, was transferred to the reaction mixture. The reaction was stirred at room temperature for 1 hour and a green solution formed. The solution was filtered, the solvent removed under reduced pressure and a sample of the crude product was analysed by 1 H NMR spectroscopy, see Figure S2.

Preparation of [Co(SIPr)(norbornene)2], 6b.
CoCl2 (0.083 g, 0.64 mmol) and SIPr (0.250 g, 0.64 mmol) were stirred in THF (4 ml) for 1 hour at room temperature to form a blue solution. Norbornene (0.121 g, 1.28 mmol) was added and the solution was stirred for a further 5 minutes, after which, a slurry of KC8 (0.174 g, 1.30 mmol) in THF (2 ml) was transferred to via cannula. A green mixture was observed and the reaction was stirred at room temperature for 20 hours. The reaction mixture was then filtered through Celite, concentrated under vacuum to give a yellow-green solid that was washed with hexane (1 ml) and dried under vacuum to afford 6b as a yellow-green powder (0.309 g, 76 %  Figure S3.

Cross-coupling using 6a as a pre-catalyst
To a THF (2 m) solution of 6a (0.0159 g, 0.025 mmol), 4-chlorotoluene (0.0296 ml, 0.25 mmol) was added, followed by the transfer of 1a (0.75 mmol). The reaction was stirred at 60 C for 20 hours and then quenched with HCl (1 M in H2O, 2 ml). 1,3,5-trimethoxybenzene (0.042 g, 0.25 mmol) was added as an internal standard. The work-up stated in the general procedure for cross-coupling reactions was followed. No cross-coupled product 2a was observed.