Manganese(I)‐Catalyzed β‐Methylation of Alcohols Using Methanol as C1 Source

Abstract Highly selective β‐methylation of alcohols was achieved using an earth‐abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)2Br[HN(C2H4PiPr2)2]] 1 ([HN(C2H4PiPr2)2]=MACHO‐iPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β‐methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β‐position, opening a pathway to “biohybrid” molecules constructed entirely from non‐fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn‐pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C−C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules


General Experimental
All catalytic and stoichiometric reactions were performed under argon atmosphere using a combination of Schlenk and glove box techniques. Chemicals were purchased from Sigma-Aldrich, Alfa-Aesar, TCI chemicals and used without further purification. Dry solvents were prepared according to standard procedures. Glasswares were dried under vacuum at high temperatures, evacuated, and refilled with argon at least three times. 1 H, 13 C, and 31 P NMR spectra were recorded with spectrometers Bruker AV300 or AV400 at room temperature. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3  t, triplet; q, quartet; sext, sextet; m, multiplet; br, broad.
Catalytic reactions involving high pressure gases were carried out in home built stainless steel reactors equipped with pressure transducer and external electrical heating.
Safety advice: High-pressure experiments represent a significant risk and must be conducted with appropriate safety procedures and in conjunction with the use of suitable equipment.

General procedure for screening of Mn-catalysts
Mn-precursor and NaOMe (108.04 mg, 2 mmol) were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was closed with a septum and transferred into the bottom part of the 10 mL steel autoclave, where it was opened under a stream of argon. After sealing, the autoclave was purged with argon three times. 2-phenyl ethanol 6a (122.2 mg, 1 mmol) and methanol (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and heated to at certain temperature. After 24 h, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy.

General procedure for the catalytic selective -methylation of 2-aryl ethanols
Mn-MACHO 1 (2.48 mg, 0.5 mol%) and NaOMe (108.04 mg, 2 mmol) were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was closed with a septum and transferred into the bottom part of the 10 mL steel autoclave, where it was opened under a stream of argon. After sealing, the autoclave was purged with argon three times. 2-aryl ethanol (1 mmol) and methanol (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and heated to 150 o C temperature for 24 h. After completion of the reaction, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy. The isolation of pure product was carried out using column chromatography over silica gel (100-200 mesh) using ethyl acetate/petroleum ether (12 : 88) mixture as eluent.

General procedure for the catalytic selective  -methylation of secondary alcohols
Mn-MACHO 1 (2.48 mg, 0.5 mol%) and NaOMe (216.08 mg, 4 mmol) were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was closed with a septum and transferred into the bottom part of the 10 mL steel autoclave, where it was opened under a stream of argon. After sealing, the autoclave was purged with argon three times. Secondary alcohol (1 mmol) and methanol (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and heated to 150 o C temperature. After 36 h, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy. The isolation of pure product was carried out using column chromatography over silica gel (100-200 mesh) using ethyl acetate/petroleum ether (12 : 88) mixture as eluent.

2-methyl-3-phenylpropan-1-ol (11a):
Prepared by following the general experimental procedure with:  analytical data is consistent with those previously reported in the literature. [19] 2-methyl-5-phenylpentan-1-ol (11d): Prepared by following the general experimental procedure with: analytical data is consistent with those previously reported in the literature. [20] 2-methylpropan-1-ol (11e): Prepared by following the general experimental procedure with: Hz, CH 3 ) ppm. The obtained analytical data is consistent with those previously reported in the literature. [21] 2-methylbutan-1-ol (11f): Prepared by following the general experimental procedure with:

General procedure for the catalytic selective -methylation of diols
Mn-MACHO 1 (2.48 mg, 0.5 mol%) and NaOMe were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was closed with a septum and transferred into the bottom part of the 10 mL steel autoclave, where it was opened under a stream of argon. After sealing, the autoclave was purged with argon three times. Diol (1 mmol) and methanol (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and heated to 150 o C temperature.
After the desired reaction time, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene was added as an internal standard to the reaction mixture which was further analyzed by NMR spectroscopy.     Mesitylene (120 mg, 1 mmol) was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy. Yield was determined by 1 H NMR spectrum using mesitylene as an internal standard (δ Mesitylene(standard) = 6.98 (s, 3H), δ product = 3.80-3.84 (m, 2H)).

Procedure for  -methylation of 6a with paraformaldehyde and H 2
Mn-MACHO 1 (2.48 mg, 0.5 mol%), NaO t Bu (192.3 mg, 2 mmol) and paraformaldehyde (150.1 mg, 5 mmol) were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was transferred to a 10 mL stainless autoclave that was evacuated and refilled with argon at least three times. 6a (122.1 mg, 1 mmol) and toluene (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and pressurized with 10 bar of hydrogen. The autoclave was heated to 150 o C temperature for 24 h. After 24 h, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene (120 mg, 1 mmol) was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy. Yield was determined by 1 H NMR spectrum using mesitylene as an internal standard (δ Mesitylene(standard) =6.84 (s, 3H), δ product = 3.71 (d, 2H)).

Procedure for  -methylation of Acetophenone (14) with methanol
Mn-MACHO 1 (2.48 mg, 0.5 mol%) and NaOMe (216.08 mg, 4 mmol) were measured into a glass inlet equipped with a stirring bar inside a glovebox. The glass inlet was closed with a septum and transferred into the bottom part of the 10 mL steel autoclave, where it was opened under a stream of argon. After sealing, the autoclave was purged with argon three times. Acetophenone 14 (120.2 mg, 1 mmol) and methanol (1 mL) were added at room temperature through a valve under argon. The autoclave was sealed and heated to 150 o C temperature. After 24 h, the autoclave was cooled to room temperature and slowly vented while stirring continued. Mesitylene was added as an internal standard to the reaction mixture that was then passed through a short path of acidic alumina before the composition was analyzed by NMR spectroscopy.