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.
