Methylation reagents in organic synthesis

Methylation reagents in organic synthesis
Today we will talk about a very simple organic synthesis reaction: methylation. Friends engaged in CRO should have more or less contact with this kind of reaction, but the methylation reagent can not just know methyl iodide (MeI), there are some other useful methylation reagents we must also know and skillful use.
Next, I will talk about some common methylation reagents and the precautions for their use:

1, iodomethane
Iodomethane is a colorless and odorless liquid with strong toxicity and a boiling point of only 40 degrees, so use it or take precautions.
Iodomethane can methylate carboxylic acids, phenols, alcohols, amides, amines. The following picture is the molecule I made up as I went along, I think the molecule in the picture below, due to the strong acidity of carboxylic acid’s phenol, under the action of potassium carbonate, it can selectively methylate carboxylic acid and phenol, but the weak acidity of alcohol naturally won’t react; however, if you choose to use a strong base, such as sodium hydroxide, then the carboxylic acid, alcohol, as well as the phenol, can all take part in the reaction.
For methylation reactions of amides, they are often accompanied by the production of isomers. As shown in the picture below, both the N and O of the amide may react with MeI to produce isomers, which generally need to be analyzed by 2D spectroscopy.
In order to avoid the generation of isomers, a solution is to choose to use silver such as AgO or Ag2CO3 instead of a base, which in many cases can be methylated exclusively on oxygen.
For the following methylation of sulfur carbonyls, there is generally no need to worry about isomerization, as sulfur is much more nucleophilic than nitrogen and oxygen.
2, Methanol or sodium methanol
As a methylation reagent, sodium methanol must be reacted with the corresponding halogen. The benzyl alcohol below usually needs to be chlorinated by SOCl2 or COCl2 first, and then reacted with sodium methanol.
Methanol as a methylation reagent is most often used in carboxylic acid, generally through the following 2 routes: 1) methanol as a solvent, add catalytic amount of sulfuric acid can be; 2) first convert carboxylic acid to chlorine chloride, and then add methanol. Those who do synthesis know that sometimes methanol is added to test whether the acyl chloride is made or not, in order to verify that the acyl chloride is made.

3, Dimethyl sulfate or dimethyl carbonate
Dimethyl sulfate is a very strong methylation reagent, it can methylate carboxylic acids, phenols, alcohols, amides and so on, but due to its high toxicity, its use is sometimes restricted.
Dimethyl carbonate is much less toxic and can also methylate carboxylic acids, phenols, alcohols, amides and thioamides.
4, TMSCHN2 (TMS Diazomethane)
We won’t discuss diazomethane, there is no need to take a risk with so many methylation reagents. But TMSCHN2 is still commercially available and safe.
Generally, TMSCHN2 is used more for methylation of carboxylic acids or phenols, and should not be very effective for other functional groups. The commercially available TMSCHN2 is usually stored in n-heptane and is light yellow in color. Doing this reaction is very simple: you keep adding TMSCHN2 solution, at first the reaction solution is colorless, and you should stop adding it when the reaction solution is yellow.

5, Trimethyloxonium tetrafluoroborate
This reagent generally performs a methylation reaction on the hydroxyl group. As shown in the picture below
If the methylation reaction is performed on amide, generally this reagent will tend to methylate on oxygen.
6, Formaldehyde or paraformaldehyde
Formaldehyde or paraformaldehyde generally methylate amine, but the following picture of the reduction of amination reaction, generally get the dimethylation product, mainly because the methyl site resistance is too small, it is easy to go up to 2 methyl, as for how to eliminate this thing, is not the scope of this article. (Generally, this method is not used for monomethylation of primary amines)
7, DMF-DMA
It is estimated that many partners do not know that DMF-DMA can also be used as a methylation reagent.
DMF-DMA can methylate carboxylic acids, phenols, amides. No problem.
8, Methylboronic acid, tetramethyltin, trimethylaluminum, dimethylzinc, methylformat reagent, lithium methylketone reagent
Obviously, methylboronic acid, tetramethyltin, trimethylaluminum, dimethylzinc, methylformat reagent, methylketolithium reagent, all of these reagents are metal-coupled methylation reagents.

Translated with DeepL.com (free version)