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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

  1. Dissolve the Boc amino acid in THF.
  2. Cool the solution on an ice bath, then add iodomethane.
  3. Add sodium hydride in portions, spaced out over a few hours.
  4. Once all sodium hydride is added, remove the ice bath and stir overnight.

Stoichiometry

A gross excess of iodomethane and sodium hydride is used. The original procedure uses 10 equivalents of each. Complete reaction has been achieved 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 (the theoretical minimum). Do not go below 4 or 5 equivalents of sodium hydride and iodomethane.

Don't forget the mineral oil

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.

Solvent

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

Sodium Hydride

Sodium Hydride Safety

Sodium hydride (NaH) reacts with water and alcohols to release hydrogen gas and heat. It must be stored in a desiccator. When exposed to the atmosphere, NaH will go stale due to humidity. Work quickly when weighing.

Sodium hydride is supplied as a 60% w/w emulsion in mineral oil. It comes in a plastic bag inside a metal can. When 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.

Setup

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 reaction mixture 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

Gas needs to escape. If the slurry becomes too thick to stir, or if the sodium hydride is just sitting on top, this is a problem. Either of these could lead to a sudden violent reaction.

Wait for bubbling to subside before adding the next portion. Stirring should be rapid. 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 the reaction to stir at room temperature overnight.

Flask selection

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. There will 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 60 mL of THF, use a 250 mL RBF).

If the reaction becomes unstirrable

If your reaction becomes 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

Quench carefully

Sodium hydride is hazardous. It must be carefully quenched before proceeding with workup.

  1. Cool your reaction on an ice bath.
  2. After 20 minutes, add isopropyl alcohol dropwise. You will get some bubbling.
  3. When adding iPrOH no longer produces bubbling, add a few mL water dropwise.
  4. 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.

Workup

  1. Transfer to a separatory funnel using small portions of water (maybe 25 mL water per gram of Boc amino acid, divided into ~3 portions to rinse contents of reaction flask into the sep funnel thoroughly). 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.
  2. Wash the aqueous layer three times with diethyl ether to remove mineral oil (1/2 volume of aqueous for each wash — 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 deionized water followed by a quick rinse with acetone before placing in the drying rack.
  3. Acidify the aqueous with 1 M HCl (or your preferred acid — the original reference uses 20% citric acid) to a pH between 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 extremely acidic. It should become persistently cloudy. The Boc group is not that delicate and it should be hard to get the pH below 1 (this would require overshooting by over 1/10 your original aqueous volume with 1 M HCl). Once sufficiently acidic by pH paper, do not delay.
  4. Pour 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.
  5. Wash combined ethyl acetate extracts with acidified brine (brine containing 0.1 M HCl). Normal brine will probably work fine though.
  6. Dry your ethyl acetate extracts over sodium sulfate. Drying takes several minutes — if you need to take a break, now's the time.
  7. Filter your ethyl acetate through cotton and rotavap. The resultant solid (or oil) should be sufficiently pure to move on to the next step in your synthesis.

Example

Reagent Amount
Boc-L-Leu monohydrate 2.50 g, 10 mmol
CD3I 3.12 mL, 50 mmol
NaH (60% w/w) 2.01 g, 50 mmol
THF 60 mL

Run the reaction in a 250 mL RBF.

Workup for this example:

  • Transfer to sep funnel using 60 mL deionized water
  • Wash 3x with 30 mL diethyl ether
  • After acidification, extract 3x with 40 mL ethyl acetate (you may wish to rotavap ethyl acetate out of a 500 mL RBF to avoid bumping)