[Safe methylating agent]


Unfortunately product 3m requires cesium carbonate. However, noting the efficiency of the bases used, KOH may be a better choice if it could be somehow used in a microwave (perhaps by a judicious choice of the reaction vessel). All the reactions occur at a maximum scale of 80 mL, but I think that this method will probably scale up successfully. [Edit by Enkidu - the authors had trouble with the scale up.]


Reference information:

Microwave-assisted methylation of phenols with tetramethylammonium chloride in the presence of K2CO3 or Cs2CO3
Nenad Maraš, Slovenko Polanc and Marijan Ko?evar
Tetrahedron Volume 64, Issue 51, 15 December 2008, Pages 11618-11624 doi:10.1016/j.tet.2008.10.024

We have evaluated the potential of using tetramethylammonium chloride (Me4NCl) as an alternative methylating agent for phenols under microwave-assisted conditions. Its chemical behavior was tested in a reaction with 2-naphthol in the presence of various bases and solvents. The method was then applied in 1,2-dimethoxyethane or toluene under heterogeneous conditions for the O-methylation of a series of phenolic compounds. We found that many simple phenols can be methylated in the presence of K2CO3, whereas some other less-reactive phenols require the presence of the more reactive Cs2CO3.  

Tetramethylammonium cation can methylate phenols, as seen in the first attachment. [Removed: it was the Acta Chim Slov article uploaded in the above post - Enkidu] This requires high temperatures and base, but it's totally workable.

Glycine betaine aka trimethylglycine is a popular nutritional supplement. It looks like this:

http://its.goofyti.me/u/http://en.wikipedia.org/wiki/File:Betain2.svg

The decarboxylation of this yields tetramethylammonium cation directly. I am not sure, however, precisely which conditions would lead to decarboxylation; it seems as though heat and acid should be sufficient, as a partial negative charge on the relevant carbon is stabilized as an ylid, allowing decarboxylation to proceed. The presence of acid serves to prevent decomposition of the ylid to trimethylamine. Betaines do tend to decarboxylate easily:

http://its.goofyti.me/u/http://www.nrcresearchpress.com/doi/abs/10.1139/v72-480

"the methyl betaine of picolinic acid decarboxylates 200 times faster than the anion" -- picolinic acid is aromatic, so the situation is not precisely analogous.

It is also totally plausible that betaine could be used directly in methylations. I'm guessing the methyl groups will transfer easier than the glycolyl.

It is further plausible, though sort of unlikely, that tetramethylamine could carry out the holy grail -- methylating tryptamine to DMT without quaternization. Methyl transfer occurs between amines in aqueous solution at high temperatures, but favors secondary amines:

http://pubs.acs.org/doi/abs/10.1021/ja021212u

The glycine betaine methylation of phenols is here: http://designer-drug.com/pte/12.162.180.114/dcd/chemistry/betaine.html

It is further plausible, though sort of unlikely, that tetramethylamine could carry out the holy grail -- methylating tryptamine to DMT without quaternization. Methyl transfer occurs between amines in aqueous solution at high temperatures, but favors secondary amines

you might think it obvious but for the record one would do best to keep that reaction away from air as well as possible

edit - also if aqueous solution allows transmethylation perhaps an ionic fluid would to more or less a degree. now I don't know if tetramethylammonium salts work too or glycine even, but eutectics are known with choline. http://en.wikipedia.org/wiki/Deep_eutectic_solvent

and on the subject of choline I think there was something about (quaternary) N-demethylation with aminoethanol? I'll have a look.