Author Topic: Oxalic acid leuckart reaction  (Read 10434 times)

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  • Guest
Oxalic acid leuckart reaction
« on: March 25, 2004, 08:32:00 PM »
This one's for Tengo 8)

It must be a dream: Reductive amination with oxalic acid

As seen in Synthetic Communications vol.32, pg. 457, 2002

"A Solvent-Free and Formalin-Free Eschweiler-Clarke Methylation for Amines"


Primary and secondary amines are N-methylated by a mixture of paraformaldehyde and oxalic acid dihydrate in good to excellent yields. The reaction proceeds without involvement of organic solvents and toxic formalin. Reaction temperatures of 100 C are required for the decomposition of oxalic acid into the intermediate formic acid which acts as the actual reductant. The reaction conditions have been optimized, and the mechanism has been elucidated by means of deuteration experiments.

The good stuff:

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.


- 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?


  • Guest
No comments?
« Reply #1 on: April 04, 2004, 12:57:00 AM »
Or is it just too shiny to touch?

Maybe the leuckart went out of vogue in the seventies... ;D


  • Guest
First try with Tryptamine
« Reply #2 on: April 04, 2004, 04:36:00 AM »
As swim saw this, he instantly had to try this with Tryptamine.HCl as he had some lying around.

10  mmol Tryptamine.HCl (2.0g)
100 mmol Oxalic acid dihydrate (12.6g)
20  mmol Paraformaldehyde (0.6g)

was heated for one hour at 100°C and 10 min. at 120°C. A few minutes after heating started, the mixture turned first brown, then a bit later it was black.

The flask was cooled, 100ml of Water was added, filtered,  made basic with NaOH and extracted with EtOAc. Evaporation of the solvent gave NOTHING!

Maybe swim should try again with the freebase?

more experiments will follow...


  • Guest
As swim saw this, he instantly had to try this
« Reply #3 on: April 04, 2004, 05:08:00 AM »
As swim saw this, he instantly had to try this with Tryptamine.HCl as he had some lying around.

You surely can't expect a Leucart to work on tryptamine?
Tryptamine reacts with HCHO to form tetrahydro-beta-carbolines even in only slightly acidic medium. If you did not get any product from the reaction it probably means that tryptamine got oxidased or the amine group formed a neutral amide (a formamide?).


  • Guest
Plain amine
« Reply #4 on: April 04, 2004, 09:11:00 AM »
They use plain amine, not amine HCl. It seems important.


  • Guest
« Reply #5 on: April 04, 2004, 12:41:00 PM »
If it would work on P2P or for example on amphetamine, wouldn't this reaction scheme always give dimethylated amphetamines then?


  • Guest
Oh, I'm sorry!
« Reply #6 on: April 04, 2004, 01:54:00 PM »
Your tryptamine! Such a waste! How to do?

If you look at the paper, the last case they did actually use an HCl salt, I imagine because it's boiling point was too low as freebase. And it worked.

In the case of P2P, I was just fantasizing the extension of this technique beyond just methylation. In that case, the oxalic acid would be replacing formic acid in the leuckart reaction, with methylamine or ammonia.

hongito, if you're not too discouraged, maybe you have some other not-so-delicate amine lying around?
Ning appreciates your sacrifice for the cause!! 8)


  • Guest
is that lilienthal i hear?
« Reply #7 on: April 06, 2004, 01:05:00 PM »
It’s echoing in from the distance…..”Picket-Spengler……..Picket-Spengler……..Picket-Spengler” 

Any way, hell yea hongito, we all appreciates your sacrifice, try the free base! Who knows..Cool find ning.


  • Guest
« Reply #8 on: April 06, 2004, 02:09:00 PM »
”Pictet-Spengler……..Pictet-Spengler……..Pictet-Spengler”  :)


  • Guest
Tryp phans will be interested in example 27 on
« Reply #9 on: May 09, 2004, 03:38:00 PM »
Tryp phans will be interested in example 27 on the 26th page of WO02079153 (also see example 32 on the 27th page).

Patent WO02079153