N-Methylation of Boc amino acids

In this procedure, A Boc-protected amino acid is N-methylated. This is our preferred procedure for trideuteromethylation of amino acids. The Boc amino acid is doubly deprotonated by NaH at the carboxylic acid and the N-H in the presence of iodomethane. The carboxylic acid associates with Na+ ions in aprotic solvent (THF), and depending on the order of addition of reagents, only the nitrogen is methylated. The dianion, although insoluble, is consumed rapidly by reaction with iodomethane and should not precipitate. Upon acidification, the N-Boc-N-methyl-amino acid is obtained as the free carboxylic acid.

Quick Summary

First, the Boc amino acid is dissolved in THF.
Then, after cooling the solution on an ice bath, the iodomethane is added.
Then, the sodium hydride is added in portions, spaced out over a few hours.
Once the sodium hydride is added, remove the ice bath and stir overnight.


A gross excess of iodomethane and sodium hydride is used. The original procedure uses 10 equivalents of each. I have had a complete reaction with 5 equivalents of each. Starting Boc amino acid may be difficult to remove from the product. However, 10 equivalents of sodium hydride takes a long time to add (due to plentiful bubbling) and may cause the reaction slurry to thicken (requiring more THF). At least two equivalents of sodium hydride is needed to form the sodium carboxylate complex. This is the theoretical minimum. I wouldn't go below 4 or 5 equivalents of sodium hydride and iodomethane.

Amateur Tip: Don't forget your sodium hydride contains 40% mineral oil by mass. When you calculate how much sodium hydride you'll need, divide that mass by 0.6 to obtain the mass you'll actually need.


The solvent for this reaction is dry THF. I would recommend at least 20mL per gram of sodium hydride.

Sodium hydride

Sodium hydride (NaH) is supplied as a 60% w/w emusion in mineral oil. Sodium hydride reacts with water and alcohols to release hydrogen gas and heat. It is stored in a desiccator. When exposed to the atmosphere, NaH will go stale due to humidity. Sodium hydride comes in a plastic bag inside a metal can. When you are weighing out the NaH, work quickly. You may find there is a layer of white stuff covering the gray stuff. The gray stuff is the good stuff. Just brush aside the white stuff. Don't worry about getting it exact, just work quickly. Everyone has to use this sodium hydride. Once you have weighed your NaH into a screw-cap vial (to protect from atmospheric moisture), retie the bag with the twist tie. Then, with the lid cracked, discharge an argon balloon into the container. Once done, quickly close the container and tap down the metal lid with a wrench (or other reasonably sized tool) lightly but thoroughly.


Dry your round-bottom flask with stirbar in the oven for an hour or so. After removing, allow to cool in a desiccator or other dry environment. Dryness is not as important for this reaction as one might think. Once cooled, flush the flask with argon before adding dry THF. Then, add your Boc amino acid and your iodomethane. Flush with argon, stir everything together, and cool on an ice bath until you think it's cold (maybe 20 minutes). In the meantime, weigh your NaH into a screw-top vial. Once your rxn mix is cool, start adding your NaH in small portions. You'll notice vigorous bubbling. Reattach balloon/septum after each addition. Do not seal the flask without a balloon because gas needs to escape. Wait for this to subside before adding the next portion. Stirring should be rapid. If the slurry becomes too thick to stir, this is a problem. If the sodium hydride is just sitting on top, this is a problem. Either of these could lead to a sudden violent reaction. The addition of NaH will probably take a few hours. You may need to replenish the ice bath. When your NaH is all added, remove the ice bath and allow reaction to stir at room temperature overnight.

Amateur Tip: Use a flask with a 24/40 ground-glass joint (rather than a smaller joint). You'll want to use the largest egg-shaped stirbar possible because you're going to have a thick slurry once most of the NaH has been added. Also, there's going to be a lot of bubbling, and a wider joint will allow more effective escape of hydrogen gas and easier addition of NaH. Plan to fill your flask to no more than 1/3 capacity (e.g. if you plan to use 60mL of THF, use a 250mL RBF).

Amateur Tip: If your reaction should become unstirrable and you need to add more THF and maybe even move to a larger flask, do so. This reaction is really not that air-sensitive. If sodium hydride accumulates on the surface, that's a much bigger problem.

Time Management: This reaction takes several hours to set up and add NaH, especially if it's your first time. Start early in the afternoon if you want to go home in the early evening.

The Quench

Sodium hydride is hazardous. It must be carefully quenched before proceeding with workup. First, cool your reaction on an ice bath. After 20 minutes, add isopropyl alcohol dropwise. You will get some bubbling. When adding iPrOH no longer produces bubbling, add a few mL water dropwise. If there's no bubbling, go ahead and rotavap to maybe 1/5 the original reaction volume (no need to evaporate to dryness). This will make workup a bit easier.


Next, transfer to a separatory funnel using small portions of water (maybe 25mL water per gram of Boc amino acid - divided into maybe 3 portions to rinse contents of reaction flask into separatory funnel thoroughly). You'll need to use the stirbar retriever - if the stir bar ends up in the sep funnel it's irritating. Let the first portion of water sit in the flask for a minute to be sure it's quenched. Wash the aqueous three times with diethyl ether to remove mineral oil (1/2 volume of aqueous for each washing - rinse flask with each portion before transferring to sep funnel). By now, the reaction flask should be pretty much clean - requiring only a quick rinse with diH2O followed by a quick rinse with acetone before placing in the drying rack. Next, acidify the aqueous with 1M HCl (or your preferred acid - the original reference uses 20% citric acid) to a pH betwen 1 and 2. This will convert the carboxylate salt to the neutral (organic-soluble) carboxylic acid. You need to be well below the carboxylic acid pKa but not way too acidic. It should become persistently cloudy. The Boc group is really not that delicate and it should be pretty hard to get the pH below 1 (this would require overshooting by over 1/10 your original aqueous volume with 1M HCl). Once sufficiently acidic to pH paper, do not delay. Pour it into the sep funnel. Extract the aqueous with three portions of ethyl acetate (each ~1/2 volume of aqueous). Use each portion of EtOAc to rinse the flask that previously held the aqueous into the sep funnel. I like to wash my combined ethyl acetate extracts with acidified brine (brine containing 0.1M HCl). Normal brine will probably work fine though. Now, dry your ethyl acetate extracts over sodium sulfate. Drying takes several minutes and if you need to take a break, now's the time. Filter your ethyl acetate through cotton and rotavap. The resultant solid (or perhaps oil) should be sufficiently pure to move on to the next step in your synthesis.


Boc-L-Leu monohydrate: 2.50g, 10mmol
CD3I: 3.12mL, 50mmol
NaH (60% w/w): 2.01g, 50mmol
THF: 60mL (run reaction in a 250mL RBF)

As for the workup:
Transfer to sep funnel using 60mL diH2O
Wash 3X with 30mL ether
After acidification, extract 3X with 40mL ethyl acetate. You may wish to rotavap ethyl acetate out of a 500mL RBF to avoid bumping, but that's ok.

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