Improving the sustainability of the ruthenium-catalysed N-directed C–H arylation of arenes with aryl halides

Direct C–H functionalisation methodologies represent an opportunity to improve the overall ‘green’ credentials of organic coupling reactions, improving atom economy and reducing overall step count. Despite this, these reactions frequently run under reaction conditions that leave room for improved sustainability. Herein, we describe a recent advance in our ruthenium-catalysed C–H arylation methodology that aims to address some of the environmental impacts associated with this procedure, including solvent choice, reaction temperature, reaction time, and loading of the ruthenium catalyst. We believe that our findings demonstrate a reaction with improved environmental credentials and showcase it on a multi-gram scale within an industrial setting.


General information
All the reactions were set up in an argon filled glovebox with oven-dried crimp cap microwave vials (10 mL). The reactions were then capped (using PK100 20MM BUTYL SEPTA) and taken outside the glovebox to run. All starting materials were purchased from Acros (Fisher), Aldrich (Merck), Alfa Aesar (Fisher) and Fluorochem and used without further purification unless stated otherwise. Column chromatography was carried out on silica gel (particle size 40-63 µm) using flash techniques. High resolution mass spectra were performed by the School of Chemistry Mass Spectrometry Service (University of Manchester) employing a Thermo Finnigan MAT95XP spectrometer. IR spectra were recorded using a Thermo Scientific Nicolet iS5 FTIR machine, relevant bands are quoted in cm -1 . 1 H NMR, 19 F NMR and 13 C NMR spectra were all recorded on Bruker instruments in the School of Chemistry NMR service (University of Manchester). 1 H NMR are referenced to the residual solvent peak at 7.26 ppm (CDCl3), 1.94 ppm (CD3CN), or 2.05 ppm ((CD3)2CO). ppm values are quoted to 2 decimal places, with coupling constants (J) to the nearest 0.1 Hz. 13 C NMR spectra were quoted in ppm to 1 decimal place with coupling constants (J) to the nearest 0.1 Hz. The spectra were referenced to the residual solvent peak at 77.16 ppm (CDCl3), 1.32 ppm (CD3CN), or 39.52 ppm ((CD3)2CO). 19 F NMR spectra are quoted in ppm to 1 decimal place with coupling constants (J) to the nearest 0.1 Hz. Figure S1. Structure of RuBnN catalyst.

Preparation of Ruthenium Complexes
RuBnN: An oven dried 100 mL Ace pressure tube equipped with a stirring bar was transferred to a glove box, then [RuCl2(benzene)]2 (440 mg, 0.88 mmol, 0.55 equiv), NaOH (96 mg, 2.4 mmol, 1.5 equiv), KPF6 (589 mg, 3.2 mmol, 2 equiv), N,N-dimethylbenzylamine (216 mg, 1.6 mmol, 1 equiv) and MeCN (10 mL, 0.16 M) were added. The tube was sealed, transferred out of the box and placed in an oil bath at 45 °C and the reaction was stirred for 3 h. Upon completion, the reaction crude was loaded in an aluminium oxide (Al2O3, neutral) column conditioned with CH2Cl2, and quickly eluted with MeCN under N2 collecting the yellow/orange band. The solution was concentrated under reduced pressure and then quickly precipitated with Et2O affording a yellow solid/orange solid, which was promptly transferred to a glove box as it decomposes turning green/blue if exposed to air. This solid and MeCN (20 mL) were added to an oven dried 100 mL Ace pressure tube equipped with a stirring bar and the reaction was stirred for 24 h at 100 °C. After this time, the reaction mixture was filtered through a short plug of aluminium oxide, eluted with MeCN, concentrated under vacuum and precipitated with Et2O/pentane (1:1) affording RuBnN as an off-white solid (653 mg, 75%). RuBnN must be kept in a glove box as it quickly decomposes turning blue/black if exposed to air. The complexes are subjected to quantitative 1 H NMR after their synthesis. They are generally in the region of 99-100% pure by this measure. If they are of lower purity, then the complex should be dissolved in MeCN

General notes
Additives and bases were all bought from commercial suppliers, with solid reagents ground up using a pestle and mortar and dried in a vacuum oven for a minimum of 24 h prior to being transferred into the glove box for use. All solvents were bought from commercial suppliers and degassed in J Young sample flasks using the freeze-pump-thaw method, with a minimum of 3 cycles, prior to being transferred into the glove box for use.

N-directing group coupling partners
Substrates 1a, 1c, and 1e were purchased from the commercial supplier Fluorochem. Substrate 1b was prepared from the corresponding nitrile and aminoalcohol in a literature-reported procedure. 1 Substrates 1d 2 and 1g 3 were prepared by Suzuki-Miyaura coupling between phenylboronic acid and the corresponding aryl halide, in literature-reported procedures. Imine substrate 1f was prepared by a condensation reaction between the corresponding benzaldehyde and aniline substrates, in a literature reported procedure. 4 Liquid reagents were degassed using the freeze-pump-thaw method, with a minimum of 3 cycles, prior to being transferred into the glove box for use. Figure S2. N-directing group arenes.

Aryl halide coupling partners
Substrates 2a-Cl, 2b-Cl, 2c-Cl, 2a-Br, 2b-Br, 2c-Br, 2a-I, 2b-I, and 2c-I were all purchased from the commercial suppliers Fluorochem, Merck, Acros and Alfa Aesar. Liquid reagents were degassed using the freeze-pump-thaw method, with a minimum of 3 cycles, prior to being transferred into the glove box for use.

Aryl halide coupling partners from complex molecules
Substrates 2d, 2e, and 2f were all purchased from commercial suppliers and used as supplied. Figure S4. Bioactive aryl halide coupling partners.

Late-stage functionalisation coupling partners containing N-directing groups
Substrates 1h and 1i were purchased from Merck and Fluorochem respectively. Substrate 1j was prepared via a Suzuki-Miyaura coupling reaction between 6-chloropurine riboside and phenylboronic acid, in a literature reported procedure. 5 Figure S5. Late-stage functionalisation coupling partners.

General Procedures
General Procedure A: Ru-catalyzed arylation of DG-containing arenes with aryl halides Scheme S1. Reaction scheme for General Procedure A.
All liquid reagents were degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use. The ruthenium catalyst (RuBnN) was prepared using the procedure described above, and stored in the glove box for its lifetime. Potassium carbonate (K2CO3) and tetrabutylammonium acetate (TBAOAc) were ground using a pestle and mortar and dried in the vacuum oven for a minimum of 24 h, prior to being transferred into the glove box and stored there.
Unless otherwise stated, all reactions were set up in the glove box using 10 mL crimp-cap microwave vials, to which were added: RuBnN (10.8 mg, 0.02 mmol, 5 mol %), TBAOAc (36.2 mg, 0.12 mmol, 30 mol %), and K2CO3 (165.9 mg, 1.2 mmol, 3 equiv). The appropriate directing-group-containing arene (0.4 mmol, 1 equiv) and aryl halide (0.8 mmol, 2 equiv) were then added by weight (for solids) or by volume (for liquids -using an appropriate volume micro-syringe), followed by dimethyl carbonate (0.4 mL). The vials were then crimp-capped and transferred outside the glove box to be stirred on a hotplate at 35 °C for 24 hours. Upon completion, these reactions were opened to air and filtered through a small silica pad, using Et2O as the eluent. The crude reaction mixture was then loaded onto silica gel to be purified by flash column chromatography.

General Procedure B:
Ru-catalyzed arylation of DG-containing arenes with aryl halide coupling partners involving bioactive and complex substrates Scheme S2. Reaction scheme for General Procedure B.
All liquid reagents were degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use. The ruthenium catalyst (RuBnN) was prepared using the procedure described above, and stored in the glove box for its lifetime. Potassium carbonate (K2CO3) and tetrabutylammonium acetate (TBAOAc) were ground using a pestle and mortar and dried in the vacuum oven for a minimum of 24 h, prior to being transferred into the glove box and stored there.
Unless otherwise stated, all reactions were set up in the glove box using 10 mL crimp-cap microwave vials, to which were added: RuBnN (10.8 mg, 0.02 mmol, 10 mol %), TBAOAc (18.1 mg, 0.06 mmol, 30 mol %), and K2CO3 (83.0 mg, 0.6 mmol, 3 equiv). The appropriate directing-group-containing arene (0.2 mmol, 1 equiv) and aryl halide (0.2 mmol, 1 equiv) were then added by weight (for solids) or by volume (for liquids -using an appropriate volume micro-syringe), followed by acetone (0.4 mL). The vials were then crimp-capped and transferred outside the glove box to be stirred on a hotplate at 50 °C for 24 hours. Upon completion, these reactions were loaded directly onto silica gel to be purified by flash column chromatography.
The crude reaction mixture was purified by column chromatography (eluent: Hexane:EtOAc with gradient from 100:0 to 95:

Reaction Optimization
The reactions below were set up in the glove box using 10 mL crimp-cap microwave vials, to which were added: RuBnN, TBAOAc, and K2CO3 in the quantities described. The directing-group-containing arene 2-phenylpyridine 1a (1 equiv) and aryl halide 1-bromo-3,5-dimethylbenzene 2a (2 equiv) were then added by using an appropriate volume syringe, followed by the solvent DMC. The vials were then crimp-capped and transferred outside the glove box to be stirred on a hotplate at the desired temperature for a set time period. Upon completion, the reactions were opened to air and quenched by the addition of the internal standard, hexadecane, in 2% Pyridine in Et2O. After thorough mixing, a portion of the reaction mixture was filtered through a silica plug into a vial suitable for GC-FID, using Et2O as the eluent. The samples were then run on the GC-FID to determine the distribution of products, which are as reported below.

Solvent Screen
The reactions were set up in the glove box using 10 mL crimp-cap microwave vials, to which were added: RuBnN (

Reaction Comparisons
For the following reactions, liquid reagents 1a and 2a were degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use. The ruthenium catalyst (RuBnN) was prepared using the procedure described in section 2 and stored in the glove box for use. Potassium carbonate (K2CO3) and tetrabutylammonium acetate (TBAOAc) were ground using a pestle and mortar and dried in the vacuum oven for a minimum of 24 h, prior to being transferred into the glove box and stored there for use. Dry DMC solvent was purchased from Merck and degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use. Scheme S3. Scheme of reaction conditions for rate comparison.
Additive TBAOAc (36.2 mg, 0.12 mmol, 30 mol %) and base K2CO3 (165.9 mg, 1.2 mmol, 3 equiv) were weighed out in the glovebox into 3 x 10 mL microwave vials. Stock solutions in NMP or Acetone were prepared for 2-phenylpyridine 1a, 1-bromo-3,5-dimethylbenzene 2a, and internal standard hexadecane, and these were added to the vial using the appropriate volume microsyringe. NMP or Acetone was then added to make the volume to 0.7 mL and the vial was capped with a B14 suba-seal.
The reaction was then heated at 40 °C inside the glove box for 20 min with a stirring rate of 500 rpm, before a solution of RuBnN in NMP or Acetone (100 µL) was added at 0 min to start the reaction.
Aliquots of approximately 20 µL were then taken throughout the reaction at specified time points.
Each aliquot was added to approximately 0.5 mL of a solution of 2% pyridine in EtOAc (v/v), before being removed from the glove box to be passed through a short plug of silica into a GC vial ready for analysis. The samples were then analysed by GC-FID, using hexadecane as the internal standard.

Improved Reaction conditions
For the following reactions, liquid reagents 1a and 2a were degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use. The ruthenium catalyst (RuBnN) was prepared using the procedure described in section 2 and stored in the glove box for use. Potassium carbonate (K2CO3) and tetrabutylammonium acetate (TBAOAc) were ground using a pestle and mortar and dried in the vacuum oven for a minimum of 24 h, prior to being transferred into the glove box and stored there for use. Dry DMC solvent was purchased from Merck and degassed using the freeze-pump-thaw method, with a minimum of three cycles, prior to being transferred into the glove box for use.

Part 1. Low catalyst loading
Scheme S4. Reaction conditions for low-catalyst loading reaction.
The reaction was set up in the glove box using a 10 mL crimp-cap microwave vial, to which was added:  Figure S13 and S14).  Figure S13. 1 H NMR spectrum of batch 1 crude reaction product 4ab for purity calculation (CDCl3, 500 MHz).

Part 3. Room temperature reactivity
Scheme S6. Reaction conditions for room-temperature reaction.
The reaction was set up in the glove box using a 10 mL crimp-cap microwave vial, to which was added: RuBnN (10.8 mg, 0.02 mmol, 5 mol %), TBAOAc (36.2 mg, 0.12 mmol, 30 mol %), and K2CO3 (165.9 mg, 1.2 mmol, 3 equiv). The directing-group-containing arene 2-phenylpyridine 1a (64.1 mg, 0.4 mmol, 1 equiv) and aryl halide 1-bromo-3,5-dimethylbenzene 2a (148.1 mg, 0.8 mmol, 2 equiv) were then added by using an appropriate volume syringe, followed by dimethyl carbonate (0.4 mL). The vial was then crimp-capped and transferred outside the glove box to be stirred on a hotplate at 25 °C for 24 hours. Upon completion, the reaction was opened to air and filtered through a small silica pad, using Et2O as the eluent. The crude reaction mixture was then loaded onto silica gel to be purified by flash column chromatography, to give product 4aa as a white solid (140.6 mg, 97%).

Part 4. Fast reaction time
Scheme S7. Reaction conditions for fast reaction time.
The reaction was set up in the glove box using a 10 mL crimp-cap microwave vial, to which was added: RuBnN (10.8 mg, 0.02 mmol, 5 mol %), TBAOAc (36.2 mg, 0.12 mmol, 30 mol %), and K2CO3 (165.9 mg, 1.2 mmol, 3 equiv). The directing-group-containing arene 2-phenylpyridine 1a (64.1 mg, 0.4 mmol, 1 equiv) and aryl halide 1-bromo-3,5-dimethylbenzene 2a (148.1 mg, 0.8 mmol, 2 equiv) were then added by using an appropriate volume syringe, followed by dimethyl carbonate (0.4 mL). The vial was then crimp-capped and transferred outside the glove box to be stirred on a hotplate at 70 °C for 30 mins. Upon completion, the reaction was opened to air and filtered through a small silica pad, using Et2O as the eluent. The crude reaction mixture was then loaded onto silica gel to be purified by flash column chromatography, to give product 4aa as a white solid (134.4 mg, 92%).