Formaldehyde and Aluminum Amalgam¹

N-Methyl-amphetamines were prepared by the reaction of the corresponding amphetamine with formaldehyde and reduction in the absence of acid. Thus, a mixture of 1 mole amphetamine freebase (136g) and 1 mole aqueous formaldehyde (81ml 37% or 75ml 40%) in 350 ml alcohol and an excess of aluminum amalgam was reduced for several hours, water added, aluminum hydroxide filtered off, the solution acidified and evaporated, and the freebase separated by means of alkali yielding phenyl-N-methylisopropylamine, converted to the hydrochloride, mp 140°C. Similarly, 70g d-amphetamine in alcohol with aluminum and 1 mole formaldehyde gave d-methamphetamine, which was converted to the phosphate salt. 1-Phenyl-2-aminopropanol similarly yielded ephedrine.

Paraformaldehyde, Platinum Oxide and Hydrogen²

This procedure is for the methylation of 2-phenethylamine, but it can easily be adapted for use with any amphetamine.

A solution of 30.25 g (0.25 mole) of 2-phenylethylamine and 7.5 g. (0.25 mole) of paraformaldehyde (Note 1) in 50 ml of 95% ethanol was allowed to stand for a short period (Note 2). Additional ethanol (100 ml), 15 g. (0.25 mole) of glacial acetic acid (Note 3), and 0.5 g. of platinum oxide (Note 4) were added, and hydrogenation was carried out at room temperature and 3 atm. When hydrogen absorption was complete, the catalyst was removed, and the filtrate and washings concentrated to dryness. The residue was treated with sodium hydroxide solution (Note 5), extracted with ether, dried and distilled to give an 80-90% yield of N-methyl 2-phenethylamine (Note 6).

Notes:

1. Originally about 20 ml of 37% formaldehyde solution was added (0.25 mole). In view of the reported danger of dimethylation of primary amines when formaldehyde is used, it appeared safer to use paraformaldehyde, since an exact amount could be weighed.
2. When the aldehyde and base were mixed, the solution became warm. The solution was allowed to stand for 0.25-0.5 hr. for complete reaction. In some cases the mixture was allowed to stand overnight, but this gave no improvement in yield after reduction. When no heat developed in the reaction of aldehyde and amine, the mixture was warmed slightly and allowed to stand before reduction. When low boiling components are to be mixed, it is best to cool the solution of amine while the aldehyde is added to prevent loss of amine or aldehyde from the exothermic reaction. After standing, the mixture can then be hydrogenated. Hydrogen uptake was usually complete within 2 hr or less.
3. The reaction rate in this reduction was slower in the absence of acetic acid. Other acids should also be satisfactory as long a they do not cause reversal of the formation of imine. Strong acids should not be used with rhodium because they act as inhibitors of its activity. Many reductive alkylations were carried out successfully with platinum or palladium in the absence of acid. When reduction was too slow, interruption for addition of the required amount of acid did speed hydrogen uptake.
4. Palladium on carbon was not used in this experiment, but 5 g of 5% rhodium on carbon did prove satisfactory. Freifelder states there is little doubt that 5 g of 5% palladium on carbon or an equal amount of 5% platinum on carbon would work as they had in other reductive alkylations.
5. When acid is not used, addition of alkali and extraction of base are unnecessary.
6. A reaction such as this is actually a reduction of the imine in situ, a very useful procedure that may be used in alkylations with other aldehydes.

Formic acid and Lithium Aluminum Hydride³

A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no further H₂O was generated (about 20 h was sufficient, and 1.4 mL H₂O was collected). Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in 100 mL CH₂Cl₂, washed first with dilute HCl, then with dilute NaOH, and finally once again with dilute acid. The solvent was removed under vacuum giving 7.7 g of an amber oil that, on standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine. An alternate process for the synthesis of this amide involved holding at reflux for 16 h a solution of 10g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles yielded an oil that set up to white crystals, weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL anhydrous THF was added dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL anhydrous THF under an inert atmosphere. The reaction mixture was held at reflux for 4 days. After being brought to room temperature, the excess hydride was destroyed with 7.4 mL H₂O in an equal volume of THF, followed by 7.4 mL of 15% NaOH and then another 22 mL H₂O. The solids were removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in 200 mL CH₂Cl₂. This solution was extracted with 3x100 mL dilute HCl, and these extracts pooled and made basic with 25% NaOH. Extraction with 3x75 mL CH₂Cl₂ removed the product, and the pooled extracts were stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white residue which was distilled at 100-110°C at 0.4 mm/Hg to give 5.0 g of a colorless oil. This was dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the addition of sufficient anhydrous Et₂O to produce a lasting turbidity. On continued stirring, there was the deposition of fine white crystals of 3,4-methylenedioxy-N-methylamphetamine hydrochloride (MDMA) which were removed by filtration, washed with Et₂O, and air dried, giving a final weight of 4.8 g.

Benzaldehyde and Dimethylsulfate⁴

p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by stirring with conc. aq NaOH, was treated with 100 ml of benzene (toluene could be substituted) and 70 g (0.66 mole) of benzaldehyde. A mildly exothermic reaction began at once. The mixt was heated under reflux until no more H2O was present in the condensate (ca. 1 hr), then, without cooling, an attached Dean-Stark trap was removed and a soln of 82 g (0.65 mole) of Me₂SO₄⁵ in 200 ml of benzene (toluene could be substituted) was added through the condenser at such a rate as to maintain reflux (15 min). The 2-phase mixt was heated for 90 min on the steam bath, cooled slightly, treated with 200 ml of H₂O, and heated for an addn 20 min. After cooling in ice, the aqueous layer was washed twice with Et₂O to remove unreacted benzaldehyde and made strongly basic with 50% aq NaOH. Two Et₂O exts of the basic aqueous phase were added to the amine layer which separated, and the resulting solution was evacuated at the aspirator for 30 min, leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine. This material was dissolved in 500 ml of 20% abs EtOH-Et₂O and treated with 50 ml of conc HCl with swirling and cooling to yield the white, cryst hydrochloride, which was washed thoroughly with ice-cold 20% EtOH-Et₂O and dried, mp 185.5-186.5°C. The yield was 83 g (77%).

Representative Experimental Procedure

To activated powdered 4 Å molecular sieves (500 mg) in anhydrous N,N-dimethylformamide (8.3 mL), was added cesium hydroxide monohydrate (280 mg, 1.7 mmol), and then the white suspension was vigorously stirred for 10 min. After phenethylamine (0.21 mL, 1.7 mmol) was added and followed by additional 30 min of stirring, 1-bromobutane (0.21 mL, 2.0 mmol) was added into the white suspension. The reaction was stirred for 20 h, filtered to remove the molecular sieves and undissolved inorganic salts, and rinsed several times with EtOAc. After the filtrate was concentrated to a nominal volume by blowing air, the residue was taken up in 1 N NaOH, and extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography (EtOAc-EtOH, 9:1 v/v) afforded the secondary amine, N-butyl phenethylamine (260 mg, 1.5 mmol; 89%) as a colorless oil as well as tertiary amine, N,N-dibutyl phenethylamine (40 mg, 0.17 mmol; 10%) as a pale yellow oil.