Methylation reagents in organic synthesis

Methylation reagents in organic synthesis
1, Iodomethane
Iodomethane is a colorless and odorless liquid with strong toxicity and a boiling point of only 40 degrees, so it is better to use it with good protection.
Iodomethane can methylate carboxylic acids, phenols, alcohols, amides and amines. The following figure is the molecule that I made up as I went along, I think the molecule in the figure below, due to the strong acidity of the phenol of carboxylic acid, under the action of potassium carbonate, it can selectively methylate carboxylic acid and phenol, but the weak acidity of the alcohol naturally won’t react; however, if you choose to use a strong base, such as sodium hydroxide, the carboxylic acid, the 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 figure below, both the N and O of the amide may react with MeI to produce isomers, which generally need to be analyzed by two-dimensional spectroscopy.
One way to avoid the generation of isomers is to choose to use silver such as AgO or Ag2CO3 instead of a base, which in many cases will methylate exclusively on the oxygen.
For the following sulfur carbonyl methylation reaction, generally do not have to worry about the isomer problem, because the nucleophilicity of sulfur is too much stronger than nitrogen and oxygen.

2, Methanol or sodium methanol
Sodium methanol as a methylation reagent, must be and the corresponding halogen to react, the following benzyl alcohol generally need to be chlorinated by SOCl2 or COCl2 first, and then react with sodium methanol.
Methanol as a methylation reagent is most often used in carboxylic acids, generally through the following two paths: 1) methanol as a solvent, add a catalytic amount of sulfuric acid can be; 2) carboxylic acids into chloric acid first, then add methanol. Friends who do synthesis know that sometimes, in order to verify whether the acyl chloride is made, add methanol to test.
3, dimethyl sulfate or dimethyl carbonate
Dimethyl sulfate is a very strong methylation reagent, can be carboxylic acids, phenols, alcohols, amides and other methylation reaction, but because of its high toxicity will sometimes limit its use.
Dimethyl carbonate is much less toxic, and similarly, it can methylate carboxylic acids, phenols, alcohols, amides, thioamides, and so on.
4, TMSCHN2 (TMS diazomethane)
We will not discuss diazomethane, so many methylation reagents do not need to risk. However, 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. Commercially available TMSCHN2 is usually stored in n-heptane, light yellow, do this reaction is very simple: you have been adding TMSCHN2 solution, at first the reaction solution is colorless, when your reaction solution is yellow, you should stop adding.

5、Trimethyloxonium tetrafluoroborate
This reagent is generally a methylation reaction to the hydroxyl group. As shown in the figure 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 general methylation reaction on amine, but the following figure of the reduction of amination reaction, generally obtained is dimethylated product, mainly because the methyl site resistance is too small, it is easy to 2 methyl, as to how to eliminate this thing, is not the scope of this article. (Generally do not use this method for primary amine monomethylation)
7, DMF-DMA
It is estimated that many partners do not know 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, methyl format reagent, lithium methyl ketone reagent
Obviously, methylboronic acid, tetramethyltin, trimethylaluminum, dimethylzinc, methylformat reagent, methylketolithium reagent, these reagents are metal-coupled methylation reagents.