Cu/Mn bimetallic catalysis enables carbonylative Suzuki–Miyaura coupling with unactivated alkyl electrophiles

A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C–C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones.

NMR spectra were recorded at ambient temperature using Bruker Avance DPX-400 and Bruker Avance DRX-500 spectrometers. 1 H NMR and 13 C{ 1 H} NMR chemical shifts were referenced to residual solvent. GC analysis was performed on a Shimadzu GC-2010 Plus. HRMS analyses were performed on JEOL GC-Mate II mass spectrometer with electron impact (EI).

General Procedure A: Pressurisation of reaction mixtures with carbon monoxide.
Taking carbon monoxide directly from the cylinder, the reactor was pressurised to three atmospheres whilst stirring at 300 rpm. After five minutes the pressure was released, resealed and let stir for 1 minute, after which any residual pressure was released. This process was repeated once, and then the reactor was pressurised to three atmospheres carbon monoxide, let stir under pressure for 10 minutes, after which the reaction vessel was sealed and heated to the required temperature. Note that, due to the high thermal mass of the Parr pressure reactor, around one hour was required for the internal temperature to reach 60 °C. (Table 1).

Optimisation of the formation of 4-tolylnonanone from 4-tolylboronic acid neopentylglycol ester, 1-iodooctane and carbon monoxide
To a 22-mL scintillation vial, or directly into the 3 oz glass reactor, was added the appropriate (NHC)CuCl, Na[Mn(CO)5], 4-tolylboronic acid neopentyl glycol ester, KOMe, 1-iodooctane (36 µL, 0.2 mmol), 1,3,5-trimethoxybenznene (16.8 mg, 0.1 mmol, internal standard) and THF (5 mL). The vial was capped with a septum containing lid, and the septa pierced with a needle. The vial was placed within a solid, fitted, aluminium rack within a Parr pressure reactor and pressurised according to S3 General Procedure A. The reaction was then heated at 60 °C for 16 hours. Upon completion of the reaction an aliquot of the reaction mixture was taken and filtered through a silica plug, eluting with diethyl ether, and the sample was analysed by NMR for product.

For GC or NMR yields:
To a 22-mL scintillation vial, or directly into the 3 oz glass reactor, was added KOMe (21 mg, 0.3 mmol), the appropriate (NHC)CuCl (0.03 mmol), Na[Mn(CO)5] (3.3 mg, 0.015 mmol), arylboronic acid neopentyl glycol ester (0.3 mmol), alkyl iodide (0.2 mmol) and THF (5 mL). The vial was capped with a septum containing lid, and the septa pierced with a needle. The vial was placed within a solid, fitted, aluminium rack within a Parr pressure reactor and pressurised according to General Procedure A. The reaction was then heated at 60 °C for 16 hours. Upon completion of the reaction an internal standard was added (1,3,5-trimethoxybenzene -NMR analysis, decane -GC analysis). A sample of the reaction mixture was taken and filtered through a silica plug, eluting with diethyl ether, and the sample was analysed for product.
Into the 3 oz glass reactor was added KOMe (210 mg, 3 mmol), IPrCuCl (146 mg, 0.3 mmol), Na[Mn(CO)5] (33 mg, 0.15 mmol), 4-methoxyphenylboronic acid neopentyl glycol ester (660 mg, 3 mmol), 1-iodooctane (361 µL, 2 mmol) and THF (50 mL). The reaction vessel was pressurised according to General Procedure A and heated to 60 °C in an oil bath for 16 hours. Upon completion of the reaction the solvent was removed under reduced pressure, and the crude reaction mixture taken up in hexane. This suspension was filtered through a fine grade glass frit, and concentrated under reduced pressure. The resulting yellow oil was purified by flash column chromatography (2% diethyl ether in hexanes) to give 4 as a white solid (323 mg, 65% yield). NMR data was found to match previously reported values. 10 , and THF (10 mL). The vial was capped with a septum containing lid, and the septa pierced with a needle. The vial was placed within a solid, fitted, aluminium rack within the Parr pressure reactor and pressurised according to General Procedure A. The reaction was then heated at 60 °C for 16 hours. Upon completion of the reaction the solvent was removed under reduced pressure and the resulting mixture was purified by flash column chromatography (8% diethyl ether in hexanes) to give 6 as a pale-yellow oil (104 mg, 75%).

Synthesis of 1-methyl-2-phenylpiperidine, 22 (Figure 3b).
To a 22-mL scintillation vial was added KOMe (52.5 mg, 0.75 mmol), IPrCuCl (36.5 mg, 0.075 mmol), Na[Mn(CO)5] (8.2 mg, 0.0325 mmol), phenylboronic acid neopentyl glycol ester (143 mg, 0.75 mmol), 20 (150 mg, 0.5 mmol) and THF (10 mL). The vial was capped with a septum containing lid, and the septa pierced with a needle. The vial was placed within a solid, fitted, aluminium rack within a Parr pressure reactor and pressurised according to General Procedure A. The reaction was then heated at 60 °C for 16 hours. The solvent was then removed, and purified by column chromatography (30% diethyl ether in hexanes) to give 21 as a clear oil (113 mg, 70% purity, 70% yield). The mixture containing 21 was taken up in DCM (3 mL) cooled to 0 °C, and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was maintained at 0°C with stirring for two hours, before the volatiles were removed under reduced pressure. The resulting gum was taken up in methanol (5 mL), cooled to 0°C, and sodium borohydride (76 mg, 2 mmol) was added. The reaction was allowed to warm to room temperature and stirred for one hour. 1,3,5-trimethoxybenzene (42.0 mg, 0.25 mmol, internal standard) was added and the solvent was removed under reduced pressure. The crude mixture was taken up in CDCl3 and analysed by 1 H NMR for product. 22 was found to be present in 57% yield with respect to 20. See Appendix 2 for 1 H NMR spectrum.
To a solution of IPrCuMn(CO) 5 (32.3 mg, 0.05 mmol) in THF (2 mL) was added NaOtBu (48 mg, 0.5 mmol) and 4-tolylboronic acid neopentyl glycol ester (102 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for one hour before the solvent was removed under reduced pressure.
The residue was taken up in C6D6, filtered through a plug of Celite, and analysed by 1 H NMR. IPrCu(tol) and IPrCuOtBu were found to be present in a ratio of 4.4:1. No IPrCuMn(CO)5 was detected. See Appendix 3 for 1 H NMR spectrum. Figure 4c).