A manganese(i)tricarbonyl-catalyst for near room temperature alkene and alkyne hydroarylation

Developing more efficient catalytic processes using abundant and low toxicity transition metals is key to enable their mainstream use in synthetic chemistry. We have rationally designed a new Mn(i)-catalyst for hydroarylation reactions that displays much improved catalytic activity over the commonly used MnBr(CO)5. Our catalyst, MnBr(CO)3(MeCN)2, avoids the formation of the off-cycle manganacycle-(CO)4 species responsible for low catalyst activity, allowing near room temperature hydroarylation of alkenes and alkynes with broad functional group tolerance including late stage functionalisation and diversification of bioactive molecules.


General Experimental Details
All reagents and starting materials were purchased from commercial sources and were used without further purification. MnBr(CO)5 was purchased from alfa aesar. Mn(I) complexes were prepared as described in literature. 1-4 MnBr(CO)3(MeCN)2 was prepared in absence of light under inert conditions, and stored in an argon-filled glovebox. All hydroarylation reactions were set up inside an argon-filled glovebox. All liquid reagents and solvents were dried over 4 Å molecular sieves and degassed with 3 freeze-pump-thaw cycles. Purification of crude was carried out using silica gel based flash chromatography. 1 H NMR, 19 F NMR and 13 C NMR spectra were recorded at 400 or 500 MHz on Bruker instruments. 1 H NMR are referenced to the residual solvent peak at 7.26 ppm (CDCl3) or 2.50 ppm DMSO-d6 ppm values are quoted to 2 decimal places, with coupling constants (J) to the nearest 0.1 Hz. 13 C NMR spectra were recorded at 126 or 101 MHz and 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) or 39.52 ppm DMSO-d6. 19 F NMR spectra recorded at 376 MHz in CDCl3 and quoted in ppm to 1 decimal place with coupling constants (J) to the nearest 0.1 Hz. 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 Bruker alpha platinum ATR machine; relevant bands are quoted in cm -1 .

A. Ester formation from acrylic acid and alcohol
In a round bottom flask, the corresponding alcohol (1.0 equiv), EDC (1.5 equiv) and DMAP (10 mol%) were dissolved in CH2Cl2 (0.5 M). To the reaction mixture, a solution of acrylic acid (1.1 equiv) in CH2Cl2 (2 M) was added slowly and stirred overnight at room temperature. After completion the reaction was diluted with water and extracted with CH2Cl2 (3 × 5.0 mL/mmol). The organic extracts were combined and washed with brine (5.0 mL/mmol), dried over Na2SO4 and concentrated in vacuo. This residue was purified using silica gel chromatography.

B. Hydroarylation of alkenes and terminal alkynes
In an argon-filled glove box, MnBr(CO)3(MeCN)2 (10 mol %, 9.0 mg) catalyst was added to an oven dried microwave vial containing a magnetic stirrer bar, followed by addition of N-directing group arene 1 (1.5 equiv), electrophile 2a-h, or 4a-j (0.3 mmol), and Cy2NH (20 mol %) dissolved in Et2O (1 M). The vial was sealed, taken out of the glove box and the reaction stirred at 35 °C for 24 h. After completion the reaction mixture was filtered through a cotton plug, washed with Et2O and concentrated in vacuo. This material was purified using silica gel chromatography to obtain the desired product.

Competition experiments between electron-rich and poor aromatics
In an argon-filled glove box, [MnBr(CO)3(MeCN)2] (9.0 mg, 10 mol%) catalyst was weighed and transferred to an oven dried microwave vial containing magnetic stirrer bar, followed by addition of 1f (100.4 mg, 0.45 mmol), 1b (83.25 mg,0.45 mmol), n-butyl acrylate (43.2 μL, 0.3 mmol), and Cy2NH (11.9 μL, 20 mol%) dissolved in diethyl ether (0.3 mL, 1 M).The vial was sealed, taken out of the glove box and the reaction stirred at 35 °C for 16 h. After this time, 1 mL of a stock solution with internal standard (1,3,5-trimethoxybenzene (0.1 M in Et2O)) was added to the reaction. The reaction was then filtered through a short pad of silica into an NMR tube. Analysis of the crude using 1 H NMR, with reference to the spectra of pure compounds, showed the formation of 3fa (25%) and 3ba (75%).

Kinetic Concentration Sensitivity Experiments
General procedure employing 2-phenylpyridine 1a and butylacrylate 2a: In an argon-filled glove box, MnBr(CO)3(MeCN)2 catalyst was weighed and transferred to an oven dried microwave vial containing a magnetic stirrer bar, followed by addition of 2-phenylpyridine 1a. Stock solutions of n-butyl acrylate 2a and Cy2NH in Et2O were prepared, these were added to the vial via microsyringe. The vial was sealed, taken out of the glove box and the reaction stirred at 35 °C for 4 h. After the time duration, a stock solution of internal standard hexadecane was added and the reaction mixture was filtered through a short plug of silica into a GC vial ready for analysis.  Table 6. Results of kinetic order. Yields determined by GC-FID using hexadecane as an internal standard.

Kinetic Experiments for determination of orders
7.3.1 General procedure for kinetic experiments employing 2-phenylpyridine 1a and butylacrylate 2a: In an argon-filled glove box, MnBr(CO)3(MeCN)2 catalyst was weighed and transferred to an oven dried microwave vial containing a magnetic stirrer bar. Stock solutions in Et2O were prepared for n-butyl acrylate 2a and Cy2NH, and internal standard hexadecane, these were added to the vial. The vial was capped with a rubber stopper and the reaction was then heated at 35 °C inside the glove box, before a solution of 2-phenylpyridine 1a in Et2O was added at 0 min to start the reaction.
Aliquots of approximately 20 µL were then taken throughout the first 4 h of the reaction at specified time points. Each aliquot was added to approximately 0.5 mL of a solution of 1% pyridine in EtOAc (v/v), before being passed through a short plug of silica into a GC vial ready for analysis. The reaction was then monitored by GC-FID, using hexadecane as the internal standard.

Determination of Order in Catalyst
The order in catalyst has been determined using normalized time scale analysis. Reactions were carried out with different concentrations of catalyst and their temporal profiles were normalized according to the catalyst loading raised to the power of the order in the catalyst. All the resulting curves were plotted together and the correct order in catalyst is the one that causes the curves to overlay. The overlap between the temporal reaction profiles with catalyst loadings of 10 and 15 mol % suggests that the order in [MnBr(CO)3(MeCN)2] is 1.0 at these concentrations. The overlap between the temporal reaction profiles with 10 and 20 mol % of additive suggests that the order in Cy2NH is 0.3 at these concentrations.

Determination of Orders in Reagents
Determination of order in 1a The overlap between normalised time scale reaction profiles for these two reactions with differing concentrations of 1a shows an order of 1. This strongly suggests the C-H activation step of 1a is kinetically relevant.