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Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents

Nadia Hirbawi, Patricia C. Lin and Elizabeth R. Jarvo*

*Department of Chemistry, University of California, Irvine, California 92697-2025, United States, Email:

N. Hirbawi, P. C. Lin, E. R. Jarvo, J. Org. Chem., 2022, 87, 12352-12369.

DOI: 10.1021/acs.joc.2c01590

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Grignard reagents can act as halide nucleophiles to form alkyl iodides and bromides from alkyl mesylates. Grignard reagents can also be employed in a one-pot halogenation reaction starting from alcohols, which proceeds through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and also runs on multi-gram scale.

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Preparation of MeMgI

Under a N2 atmosphere, a three-neck round-bottom flask equipped with a stir bar, a reflux condenser, and a Schlenk filtration apparatus was charged with magnesium turnings (4.3 g, 180 mmol, 1.5 equiv). The flask and magnesium turnings were placed under vacuum and flame-dried and then back-filled with N2. A crystal of iodine (ca. 2 mg) was added to the flask, followed by anhydrous Et2O (30 mL). Freshly distilled iodomethane (7.5 mL, 120 mmol, 1.0 equiv) was added dropwise until the reaction initiated, and then the reaction mixture was cooled to 0 °C and the remaining iodomethane was added slowly over 30 min to maintain a gentle reflux. The mixture was stirred for 2 h at rt and then filtered through the fritted Schlenk filter into a pear-shaped flask under a N2 atmosphere. The pear-shaped flask was capped with a septum, sealed with parafilm, and stored either in the glovebox under a N2 atmosphere for up to 8 weeks or in a −20 °C freezer for up to 4 weeks. The resulting methyl Grignard reagent was typically between 2.9 and 3.1 M, as titrated by Knochel’s method.

One-Pot Reaction of Alcohols to Form Iodides

A flame-dried round-bottom flask equipped with a stir bar was charged with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N2. Et3N (1.5 equiv) was added, and the reaction mixture was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and the reaction mixture was allowed to stir at rt for 1 h. PhMe (0.20 M in alcohol) was added, the reaction mixture was cooled to 0 °C, and then MeMgI (2.0 equiv, 2.4–3.2 M in Et2O) was added dropwise. The reaction mixture was allowed to stir at 0 °C for 5 min. If commercial MeMgI was employed, the reaction mixture was allowed to stir for 1 h. Then, the reaction mixture was warmed to rt for 5 min. MeOH was added dropwise to quench the reaction, and then the mixture was filtered through a plug of silica gel eluting with Et2O and concentrated in vacuo. The reaction mixture was purified by column chromatography. If the reaction scale was 0.40 mmol or greater, then an extraction workup was carried out, instead of the silica gel plug, as follows. After warming up the reaction for 5 min, sat. aqueous NH4Cl was added dropwise. The layers were separated, and then the aqueous layer was extracted with DCM (×3). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. For the optimization reactions, phenyltrimethylsilane (PhTMS; 8.6 μL, 50. μmol) was added before purification and the yield was determined by 1H NMR based on comparison to PhTMS as the internal standard.

Key Words


ID: J42-Y2022