Abstract:

Various phenols are transformed into the corresponding phenol methyl ethers (methoxy derivates) with betaine (trimethylglycine, trimethylammoniumacetate, carboxy-N,N,N-trimethylmethanaminium) in presence of CaO.

Experimental:

The phenol (0.05-0.1 mole) is mixed with an equimolar amount of betaine (anhydrous) and CaO (50 mole%) in a round-bottomed flask equipped with a destillation unit. The reaction mixture is slowly heated with an oilbath. Below 200°C the mixture becomes clear and an increasing gas evolution indicates beginning of the reaction.

The formed ether passes over during the reaction.

The destillate is treated several times with 3N-NaOH and extracted with Et₂O. The ether is washed with H₂O, dried over Na₂SO₄ and evaporated.

Polysubstituted ethers with higher boling points are extracted several times with Et₂O from the residue in the flask and treated as described.

The byproducts of the reaction are the corresponding phenoxy-aceticacids and trimethylamine. (CAUTION: noxious gas, soluble in EtOH, H₂O; should be trapped in an acid solution).

Betaine:

Betaine hydrochloride and betaine dihydrogencitrate are OTC prescription-free medicaments (at least in the neighbour country of the authors) against liver diseases. 1 g betaine costs about ~1 US-$ as medication.

1 kg of betaine hydrochloride cost about 50 US-$ from a well-known chem supplier. Betaine is for 4times cheaper than MeI, but twice as expensive as DMS ($/mole).

Preparation of betaine (anhydrous) from betaine hydrochlorid should be done analogous to the preparation of hydroxylamin from hydroxylammonium chloride/sulfate. Dissolve in MeOH, treat with K₂CO₃, filter and evaporated MeOH. Last step might be skipped because heatin the reaction mixture as described above will get rid of MeOH.

Preparation via or from hydrochloride²

Quite useless, betaine hydrochloride is heated with H₂SO₄and then treated with a Ba-salt to precipitate the BaSO₄.

Outlook:

Although the authors didn't perform any experiments with polyphenols (e.g. hydroquinone, 2,5-dihydroxybenzaldehyde, 3,4,5-trihydroxybenzaldeyhde), one could expect similar results as even sterical hindered phenols react in good yields.

Benzoic acid was converted to benzoic acid methyl ester in 50% yield without CaO. Aliphatic alcohols didn't react until octanole, 1-methoxyoctan was prepared after 10 h reflux in 5% yield.

No other bases are mentioned by the authors. Perhaps K₂CO₃ or NaOH work, too.

Advantages:

Methylation with betaine is OTC, non-carcinogenic, requires no special equipment, proceeds fast, yields are moderate to high and work-up is easy.

[1] Monatshefte für Chemie (1966), 97(4), 1207-16.
[2] Stoltzenberg, Z. Physiol. Chem. 92, 445 (1914).