On monomethylation

I was looking at an old paper collection that I have, trying to find methods that enable clean monomethylation of amines (we rely on this reaction in our macrocycle work) and came across a brilliant old paper by Grieco. I have always been very fond of this reaction. As you might imagine, many studies in organocatalysis have this 1987 report as one of their cornerstones. The question of amine monomethylation may sound simple, but it is anything but trivial. Low chemoselectivity is usually quoted as the main obstacle towards high yields in this chemistry. The trouble is typical of amine transformations: the product is more reactive than the starting material. Even reductive amination cannot offer a decent monomethylation solution, which is due to the fact that the corresponding imine is not easy to isolate and that formaldehyde is quite reactive. The workaround developed by Grieco involved in situ Diels-Alder chemistry that rapidly generates the azanorbornene skeleton shown below. Once this is accomplished, the adduct can be carried through various steps and can then be cleanly reversed to the iminium ion through retro-Diels-Alder reaction. In the presence of triethylsilane as the hydride source, the desired methylated amine is generated. Temporary masking of reactive functional groups using reversible processes is a really useful trick. We need to use this process more often in our own peptide synthesis efforts.



2 thoughts on “On monomethylation

  1. I have done this azanorbornene preparation, both in solution and on solid phase (TentagelOH, ester bound peptide cleaved by methanolysis) – we were looking at it for combichem purposes actually, but seems also like a fairly sensible nitrogen protecting group. The azanorbornene formation worked best in straight trifluoroethanol as a solvent at room temperature with no catalysts but water+alcohol system is a good solvent also. The reaction scope is pretty much limited to cyclopentadiene (cyclohexadiene or 2,3-dimethylbutadiene react much slower and give incomplete conversion) and only formaldehyde and acetaldehyde from the small aldehyde set that I tested worked well. With an aminoacid derivative having alpha chiral center, one obtains 1:1 mixture of diastereomeric azanorbornane products that separate on TLC.

    Azanorbornenes are fairly stable as a free base but they are extremely sensitive to acid – 0.1% TFA in mobile phase decomposes them, even silica on TLC causes decomposition by reverse-Diels Alder. So the best method to follow the formation on TLC is to pre-develop a TLC in ammonia-containg solvent (for example chloroform-methanol-conc. NH4OH 100:10:1), dry the TLC at room temp and then spot the material and re-develop it with the same solvent system. The azanorbornane spots are nicely visualised by ninhydrin spray because azanorbornane is reversed on heating.

    (If one uses ninhydrin for detecting silica TLCs that were developed in an ammonia-containing mixture, it is necessary first to blow-dry the TLC with a hot heat gun, before ninhydrine spraying, to remove ammonia and continue this heating until all silica-absorbed ammonia is removed and ammonia is no longer perceptible on hot TLC by a sniff test. Otherwise ninhydrin would also detect the high ammonia background absorbed on silica TLC)

    • It is interesting that TFE was the solvent of choice. Yet another example where it made a difference. It is also good to know about the relative instability of azanorbornanes to mild acid (as well as visualization!). Thanks so much.

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