[44124-85-8] · C3H10OSe · Trimethylselenonium Hydroxide · (MW 141.09)
(methylating agent for relatively nonnucleophilic heteroatoms1)
Solubility: sol H2O, MeOH.
Form Supplied in: not commercially available.
Analysis of Reagent Purity: solution concentration can be determined by titration with 0.1 N hydrochloric acid.
Preparative Method: a solution in methanol-water can be generated by addition of Silver(I) Oxide (1 equiv) to a solution of trimethylselenonium iodide (1.3 equiv).1 Typical concentrations of ~0.7 N are obtained.
Handling, Storage, and Precautions: the solution is stable at temperatures below 10 °C, undergoing ~5% decomposition after 1 month. The solution is alkaline, and therefore would not be compatible with acidic solvents. Since one of the byproducts of the reaction is dimethyl selenide, reactions should be carried out in a fume hood.
Trimethylselenonium hydroxide is a mild methylating agent, reacting with carboxylic acids, thiols, phenols, and other weakly basic heteroatoms.1 The reactions are typically performed by adding the substrate (1.0 equiv) to a solution of the electrophile (1.1 equiv) in methanol-water and concentrating the mixture on a rotary evaporator.1 The reaction flask is then equipped with a distillation head and heated with stirring. In the case of solid nucleophiles, DMF is added prior to heating the reaction mixture.1 The dimethyl selenide (bp 56-57 °C) produced in the reaction is collected in the distillation, and could be reused by regeneration of trimethylselenonium iodide with Iodomethane.2 The pure methylated products could then be purified by direct distillation or recrystallization of the crude residue.
The reactions with carboxylic acids (eq 1), phenols (eq 2), and thiols (eq 3) are complete within 15 min and progress in quantitative yield.1 Ring amines in aromatic heterocycles are also smoothly converted to the methylated derivatives as well (eq 4).1 Alcohols and both aliphatic and aromatic amines do not react under these conditions. Selective methylations can thus be readily performed (eq 5).1 Multiple methylations can be effected in a single pot, as in the synthesis of caffeine (eq 6).1 Trimethylselenonium hydroxide and triethylselenonium hydroxide can also be used to quantitatively alkylate fatty acids on a GC (eq 7).3
Trimethylselenonium hydroxide is the most reactive of the onium hydroxides, which generally follow the reactivity order of Me3SeOH > Me3SOH > Me3SO2H > PhMe3NOH (see also Trimethylsulfonium Hydroxide).1 Trimethylselenonium hydroxide has several advantages over more conventional methylating agents. Purification is facilitated as compared with MeI or Dimethyl Sulfate because no inorganic salts are generated. Due to the carcinogenicity of Diazomethane, as well as its N-nitroso precursors, trimethylselenonium hydroxide should be considered as a safer alternative. Finally, since the dimethyl selenide can be recovered and reused, the relatively high cost of this starting material is less of a deterrent.
James W. Leahy
University of California, Berkeley, CA, USA