Methylation reaction

Methylation reaction
Brief description
In the synthesis laboratory, you will often come into contact with the methylation reaction, generally often to nitrogen, oxygen, sulfur, and carbon methylation (may also be silicon, phosphorus, etc., is not introduced here); often used methylation reagents are generally methyl iodide, dimethyl sulfate, dimethyl carbonate, dimethyl dicarbonate, methanol, diazomethane (more dangerous), dimethyl diazomethane trimethylsilane, formaldehyde, trimethyl aluminum and methylboronic acid, Methyl Grignard reagent, tetramethyltin and methylzinc reagent, etc.
Methylation Reactions
Methylation of carboxyl, hydroxyl, sulfhydryl, amine, and carbon is often carried out in synthesis and is briefly described below.

Methylation of oxygen or sulfur
Methylation of the carboxyl group is relatively common, and many reagents are used, such as iodomethane, dimethyl sulfate, dimethyl carbonate, dimethyl dicarbonate, methanol, diazomethane (dangerous), and diazomethane-trimethylsilane, etc. Some of the most commonly used ones are dimethyl sulfate, iodomethane, and methanol.
1.oxalyl chloride, DMF, DCM, 0 degree to rt, 0.5h (Preparation of chloride)
2.Methanol, rt, 12h 99% yield
WO2021151014 A1
Sulfoxide chloride, methanol, ref, 18h 78% yield
DOI:10.1016/j.bioorg.2021.105185
Examples of dimethyl sulfate, dimethyl carbonate, and dimethyl dicarbonate as methylation reagents

Diazomethane (more dangerous) and diazomethane trimethylsilane can also be used as methylation reagents. Since diazomethane is more dangerous, it is usually stored in the refrigerator in the form of a precursor, and it is usually used as it is.
For methylation of hydroxyl or sulfhydryl groups, the more commonly used reagents are iodomethane, dimethyl sulfate, dimethyl carbonate, and diazomethane, etc. Some other reagents are also used, but due to the limited use, they will not be introduced here.
Methylation of phenols and thiophenols, the reagents used are generally methyl iodide, trimethyl phosphate, dimethyl sulfate, dimethyl carbonate and diazomethane, etc. The reaction type is relatively simple, and there is generally no by-products.
Methylation of alcohols or thiols is carried out with reagents similar to those used for the methylation of phenols, and generally no by-products occur.
If nitrogen, oxygen and sulfur on the substrate can be methylated, how can only the oxygen or sulfur be methylated singly, while the nitrogen is not methylated? Since sulfur has a stronger nucleophilicity than oxygen and nitrogen, the methylation reagent will preferentially methylate sulfur; when only nitrogen and oxygen can be methylated on the substrate, the following two methods are generally used to maximize the methylation of oxygen.
Method A: Use silver carbonate in the reaction, because silver and oxygen will form a special structure, so the use of silver carbonate can maximize (not completely guaranteed) to ensure that only oxygen is methylated.
Method B: When using trimethyl tertiary oxide as a methylation reagent, only oxygen or sulfur can be methylated singly.

Methylation of Nitrogen
The most commonly used methods for methylation of nitrogen are iodomethane (and other methylation reagents), reductive amination, Eschweiler-Clarke reaction, etc. A word of caution: when methylating with iodomethane, beware of the risk of quaternary ammonium generation; Eschweiler-Clarke reaction can only methylate amino groups, hydroxyl groups and sulfur groups. The Eschweiler-Clarke reaction can only methylate the amino group, the hydroxyl group and the sulfhydryl group are not affected, but the methylation effect of this reaction is more complete, and it can only exist in the form of tertiary nitrogen, but it will not generate quaternary ammonium salt. No further examples of methylation of nitrogen will be given.
Methylation of Carbon
In order to methylate an alkyl carbon, an electron-withdrawing group is normally present on the carbon atom and hydrogen is present on the carbon atom. The bases used are generally strong bases, such as butyl lithium, sodium hydrogen, HMDSLi (Na, K) and LDA, etc. The methylation reagents used are generally methyl iodide (the most commonly used), methyl trifluoromethanesulfonate, dimethyl sulfate, etc. The methylation reaction of aryl carbons is generally carried out by the use of a methylation reagent.
Aryl ring carbon methylation reaction generally need to be coupling reaction, generally aryl halogen (iodine or bromine) and Ar-OTf involved in the coupling reaction, methylation reagents are methylboronic acid (and its derivatives), dimethyl zinc, trimethylaluminum methyl zinc reagent and methyl Grignard reagent, etc.; there are also reports in the literature that halogen on the aryl ring and butyllithium into a lithium salt, and then and the methylation reagents (dimethyl sulfate, iodomethane, etc.). and then react with methylation reagents (dimethyl sulfate, methyl iodide, etc.) to carry out the methylation method.