cabal
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N-Monomethylation of Primary Amines using Elemental Zinc and Formaldehyde
While researching the topic of N-monomethylation of primary amines, I stumbled upon the following thread:
http://www.sciencemadness.org/talk/viewthread.php?tid=8375
This is a fascinating topic and I wonder why it is getting so little attention. Klute, who unfortunately does not seem to frequent this board anymore,
has made some really nice contributions trying to reproduce what Silva et al published in their 2007 paper on the topic (Tetrahedron Letters 48 7680–7682, og. uploaded by Mush).
Then I found another paper by Giovenzana et al, published in 2011, concerning the same topic, but applying a slightly different methodology. (see
attachment for paper)
Silva et al (2007) used 1 mmol amine, 1,5 mmol HCHO, 2 mmol zinc and either acetic acid or a neutral phosphate buffer.
They note that "an aqueous acidic medium is not only needed to solubilize all reagents and products and to catalyze the reversible condensation,
but is also necessary as a proton source when zinc is used in the reduction step. In the case of cyclic amines and the lower dialkyl amines (Table 1,
entries 1–6), aqueous acetic acid revealed to be the best compromise to guarantee sufficient reactivity in the electron transfer and, on the other
side, to avoid unnecessary consumption of metal by hydrogen evolution."
Giovenzana et al (2011), however, use 5 mmol amine, 5 mmol aldehyde and 15 eq, i.e. 37,5 mmol zinc (did I calculate that corectly? it seems excessive)
in a 5% KOH solution.
That strikes me as rather odd - Silva et al pointing out the need of an acidic medium while Giovenzana et al use an alkaline medium, also the excess
of zinc dust. I should add that Giovenzana et al did not write about methylation per se, but rather reductive amination - they prepared the imine
beforehand and then reduced it, while Silva et al reduced the imine that was created in situ in a one-pot-reaction.
Another, older, paper by Tsukinoki et al (Tetahedron Letters 39 8873-8876, og. uploaded by Mush) used practically the same process as Giovenzana et al, except they used NaOH. However, just
as with the later paper, their experimental data does not include an imine formed using formaldehyde.
If anyone is interested, I will try both routes within the next weeks at different scales and post the results here. My goal is to find out whether
zinc could be a viable, non-toxic and environmentally agreeable alternative when N-methylating primary amines outside a 1-10 mmol range. I'd love to
get some assistance, should problems occur. Does anyone here have some experience with the reactions or has an idea why they differ so fundamentally
from each other?
Would the reaction also work with an amine salt? I figure that it wouldn't as protonated amines are not nucleophilic, as Sandmeyer has pointed out in
the linked thread. But the Giovenzana route uses an alkaline medium, so maybe here using a salt is feasible.
Attachment: Beilstein_J_Org_Chem-07-1095.pdf (188kB)
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Giovanni Roviello
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monomethylation of primary amines
Hi! I am very interested in your topic. I have to monomethylate a primary amine and I was wondering how the procedure of Silva et al. with Zn dust in
aqueous buffer worked in your hands. Can you give me your procedure (in case it worked)?
Really thank you!
Giovanni
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cabal
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Hey Giovanni,
I'm sorry, I almost forgot about this thread because it had garnered rather little interest when I last checked.
I was testing the procedure with 8,4 mmol amine and twice that molar amount of phosphate buffer and, as described, with 100% excess of zinc dust and
37% HCHO.
First, I understand why Klute was frustrated with the workup if he did not have a vacuum pump. I guess it would be hard to work with the sludge that
is produced after basification without some kind of suction. However, I do have good vacuum equipment and I'm glad to say: workup was a breeze. The
liquid drained beautifully and, to be sure, I extracted it twice with toluene. The sludge dried up to a solid little crystal cake within a minute or
so of vacuum filtration.
However - and now comes the important part - I understand why Klute forewent this seemingly promising approach so early: yields are godawful. After
bubbling HCl into the combined extracts, I was left with an almost negligible amount of secondary amine. It wasn't even the ~10% yield that Klute
described. So I repeated the procedure and let the reaction proceed overnight. Yields were better than before, but even then never significantly
exceeded the yields reported by Klute, and repeatedly fell short of them. I changed different reaction parameters (like additive and pH), but to no
avail.
I cannot say whether Silva et al actually had almost quantitative yields at 1 mmol, because the 50 ml FBF that I used is too large to properly stir
such a small amount (the zinc would splash on the walls of the flask, making it hard for a reaction to occur). But if they had, then I can just
confirm what Klute wrote, namely that the procedure is practically useless as soon as it is upped to a preparatory scale. I can only guess what the
yields would be like if you upped the scale even more.
So I guess if you have loads of the primary amine you want to methylate and only need a few couple grams of secondary amine for another reaction that
you absolutely cannot procure any other way, then this simple reaction might be an emergency solution. In any other case, at any other scale, you
better place your efforts into looking for an alternative. Like Klute, I have been looking into catalytic hydrogenation in the past weeks, and it
looks very promising.
Hope that helped,
cabal
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