starting amine product amine yield (%)
------------------ ------------------------------ --------
Morpholine N-methyl morpholine 100(!)
2-aminoethanol 2-dimethylaminoethanol 93
Aniline N,N-dimethylaniline 100(!)
Ethylene diamine Ethylene di(N,N-dimethylamine) 96
Dimethylamine.HCl Triethylamine.HCl 84
The reaction conditions for all these runs was the following:
- Stoichiometric ratio of formaldehyde to amine (2:1 for 1' amines, 1:1 for 2' amines).
- 5:1 molar ratio of oxalic acid *dihydrate* to formaldehyde (if you use anhydrous, it has to be doubled to 10:1 cuz the bound H2O acts as a hydrogen donor!)
- Reaction temperature must be at 100 C or greater. They used 120 C. Reactions run at 80 C lost ~40% yield.
Experimental procedure:
A flask was charged with primary amine (10 mmol), paraformaldehyde (20 mmol) and oxalic acid dihydrate(100 mmol), and briefly flushed with nitrogen. In the case of secondary amines, 10 mmol of formaldehyde and 50 mmol oxalic acid were used. For amines with multiple amino functions, 10 mmol of formaldehyde and 50 mmol oxalic acid were applied per methyl group to be introduced. The vessel was closed and heated to 100 C for 1 h, and to 120 C for 10 min. The reaction mixture was cooled to room temperature. The white, crystalline mass obtained was crushed, and calcium oxide (100 mmol) suspended in 50 ml ethanol was added. The mixture was stirred vigorously for 30 min, solids were removed by filtration, and the solvent was removed in vacuo to produce the pure amine.
For volatile amines, the crystalline reaction product was crushed and dissolved in water (100 ml). The solution was adjusted to a pH of 10 by 10% aqueous NaOH and twice extracted with ethyl acetate (10 ml). The combined organic phases were dried over Na2SO4 (?), the desiccant was removed, and a 2 M solution of HCl in ethyl ether (8 ml) was added. The resulting precipitate, the corresponding aminium hydrochloride, was separated by filtration, washed with ethyl acetate (5 ml) and liberated from residual solvent in vacuo.
Notes:
- The "flask" was "closed". Does this mean a sealed tube or what? How tightly can you close a flask when your reaction moves forward by evolving CO2? Methinks some experimentation on this point would be very useful.
- The insanely good yields given depend much on stoichiometry. 10% extra paraformaldehyde caused scuzzification of the reaction mixture due to polymerization. Don't skimp on the oxalic acid either.
- The workup no doubt takes advantage of calcium oxalate's insolubility to remove all non-products by filtration, leaving only alcohol to evaporate. Too easy!
- Formalin doesn't really work very well with this procedure. I wonder why?
- This reaction doesn't produce quaternary ammonium salts. How handy. For tryptamines!
- It appears that this reaction somehow operates differently from the normal Eschweiler-Clarke reductive alkylation. When N-alkylating with mono- or di-deuterated formaldehyde, the normal method exchanges the formaldehyde's methylene hydrogens around. However, this method does not, suggesting a different mechanism of operation. The authors suggest either a hydride transfer, or a proton followed by two electrons. A hydride transfer!? Also, the presence of water reducing the amount of oxalic acid necessary for the reaction to operate well is rather confounding. Didn't we usually use a Dean-Stark trap to *remove* water from the average Leuckart-Wallach reaction? Perhaps this method should be tried on imines and other, more interesting compounds to probe its potential. If it indeed works by hydride transfer, or by hydrogen transfer from a donor like water, than it could perhaps substitute for borohydride, or a dissolving metal reduction (Al-Hg?). I hope someone does a stereochemical and mechanistic study on this reaction to test it further.
The question is, how well does it work for P2P?
Any volunteers?
Patent WO02079153 (http://l2.espacenet.com/dips/viewer?PN=WO02079153&CY=gb&LG=en&DB=EPD)