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Grignard Synthesis of Methamphetamine

Methyl Grignard Addition to Phenylacetaldehyde Methylimine

Written by Labrat

HTML by Rhodium

Grignard reagents add to aldimines (Schiff bases) to give amines, in which the hydrocarbon residue of the Grignard is attached to the carbon atom. In the case of methamphetamine, this means that that methyl Grignard reagent adds to the Schiff base between phenylacetaldehyde and methamphetamine. The first step in the synthesis is the preparation of the Schiff base, which is exemplified below:


Phenylacetaldehyde Methylimine (Method 1)1

A solution of 45.7 g (0.38 mole) of freshly distilled (Note 1) phenylacetaldehyde in 100 ml benzene was cooled to 0C and a solution of 15.5 g (0.5 mole) of anhydrous methylamine in benzene (Note 2) was added. An exothermic reaction occured with separation of water; start refluxing with a Dean-Stark trap attached to the reflux condenser to collect the water that is generated in the reaction. When no more water separates, distill off the solvent and distill the aldimine. Yield ~47 g (~90%).

Note 1: The phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer on distillation.
Note 2: According to the Merck Index, a saturated solution of methylamine in benzene is 10.5 g MeNH2 in 100 ml benzene at room temp. Prepare the benzene/methylamine solution by bubbling methylamine gas into benzene at 0C.

Phenylacetaldehyde Methylimine (Method 2)2

Bubble methylamine gas (prepared by dripping 50% aqueous NaOH on methylamine hydrochloride crystals and drying the gas by passing it through a gas wash bottle with NaOH pellets) into cooled phenylacetaldehyde (45.7 g, 0.38 mole) while stirring until the solution has gained about 15 g (0.5 mole) of methylamine. Let stand for 1-2 hrs under cooling and stirring. Extract the mixture with dry ether, dry the ether and evaporate the solvent to get about 80-90% yield of aldimine.

With the aldimine in hand, it's important to proceed directly to the next step: the preparation of a methyl Grignard solution in ether.

Methamphetamine by Methyl Grignard Alkylation of the Above Imine1,2

Methyl Grignard reagent is prepared by adding 71 g (0.5 mole) of methyl iodide to a suspension of 12.2 g (0.5 mole) of Mg turnings in 150 ml dry ether. Adding a crystal of iodine speeds up the reaction. After about ½ hour standing, cool the Grignard reagent to 0C and add dropwise the aldimine obtained in the previous step (this better be ~0.32 mole!) dissolved in the minimum amount of dry ether. After the addition, remove the ice-bath and start refluxing the solution (I guess for about 2 hours). Afterwards, decompose the excess Grignard reagent by adding dilute (15%) ice cold HCl until the pH <2. Separate the ether layer and discard this. Bring the aqueous solution to pH >10, extract with 3x250 ml ether and dry the ether. Bubble HCl gas through the solution to get [an unspecified yield of] methamphetamine hydrochloride.

Note by Rhodium: Another synthesis of methamphetamine by the Grignard addition to an imine has been reported by the italian researcher V. Emdokimoff3. The reaction of 2 eq. of benzylmagnesium chloride with acetaldehyde methylimine in diethyl ether followed by reflux and aqueous hydrolysis gave the desired amine in 40% yield (calculated on the imine).


  1. J. Am. Chem. Soc. 69, 1792 (1947)
  2. J. Am. Chem. Soc. 70, 3868 (1948)
  3. Vera Emdokimoff, Gazz. Chim. Ital. 77, 320-323 (1947)