Iron-Catalyzed Borrowing Hydrogen β-C(sp3)-Methylation of Alcohols

Herein we report the iron-catalyzed β-C(sp3)-methylation of primary alcohols using methanol as a C1 building block. This borrowing hydrogen approach employs a well-defined bench-stable (cyclopentadienone)iron(0) carbonyl complex as precatalyst (5 mol %) and enables a diverse selection of substituted 2-arylethanols to undergo β-C(sp3)-methylation in good isolated yields (24 examples, 65% average yield).


General information
Unless stated otherwise, all reactions were performed using oven-dried 10 mL microwave vials sealed with an aluminium crimp caps, and were stirred with Teflon-coated magnetic stirrer bars. Dry tetrahydrofuran (THF), toluene, hexanes and diethyl ether were obtained after passing these previously degassed solvents through activated alumina columns (Mbraun, SPS-800). All other solvents and commercial reagents were used as supplied without further purification unless stated otherwise. Methanol was supplied as synthesis grade from Fisher Scientific (>99.9%) and was not degassed before use.
Room temperature (rt) refers to 20-25 °C. Ice/water and CO2(s)/acetone baths were used to obtain temperatures of 0 °C and -78 °C respectively. All reactions involving heating were carried out using DrySyn blocks and a contact thermometer. In vacuo refers to reduced pressure through the use of a rotary evaporator.
Analytical thin layer chromatography was carried out using aluminium plates coated with silica (Kieselgel 60 F254 silica) and visualization was achieved using ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO4 solution. Flash chromatography used Kieselgel 60 silica in the solvent system stated.
Melting points were recorded on a Gallenkamp melting point apparatus, and corrected by linear interpolation of melting point standards benzophenone (47-49 ˚C), and benzoic acid (121-123 ˚C).

1-(4-(trifluoromethyl)phenyl)propan-1-ol
A flame dried round-bottomed flask equipped with a magnetic stirrer bar was charged with 4'-(trifluoromethyl)benzaldehyde (410 µL, 522 mg, 3.0 mmol) and THF (6 mL). The solution was cooled to 0 °C and was then charged with EtMgBr (1.2 mL, 3.6 mmol, 3M in Et2O). The mixture was then left to reach rt and was left to stir for 16h. The mixture was quenched with sat aq. NH4Cl (2 mL) and H2O (5 mL). EtOAc (25 mL) was added and the mixture was transferred to a separatory funnel. The organic layer was collected. The aqueous layer was washed with EtOAc (2 x 25 mL). The organics were

Optimization of iron-catalyzed β-C(sp 3 )-methylation
A 10 mL microwave vial equipped with a magnetic stirrer bar was charged with base (x mmol), additive (x mol %), precatalyst (x mol %), MeOH (x mL) and 2-phenylethanol (60 µL, 61.1 mg, 0.5 mmol). The vial was sealed with a cap and was left to react at the specified temperature (°C) and time (h). It was then cooled, mesitylene (70 µL, 60.1 mg, 0.5 mmol) added, EtOAc (1 mL), sat. aq. NH4Cl (0.5 mL) and H2O (0.5 mL). In some, cases brine (0.5 mL) was added to aid layer separation. The mixture was stirred for 5 minutes and left to settle for a further 5 minutes. The top layer was sampled and analysed using 1 H NMR.
The mixture was transferred to a separatory funnel filled with brine (50 mL). The organic layer was collected and the aqueous phase washed with EtOAc (2 x 50 mL). The organics were combined, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash silica chromatography (eluent S30 = 5-10% EtOAc in pet. ether, 40 x 220 mm silica) gave a colourless oil (1.02 g, 76%). Spectroscopic data in accordance with that reported previously.
The integrated peak corresponds to that stated in the literature. 20
The integrated peak corresponds to that stated in the literature. 20