As we know, the bromosafrole route to MDMA is very attractive in its simplicity. Unfortunately, it also has certain flaws that render it less attractive than it might seem at first glance. Foremost among these flaws is the crappiness of the amination step. You need to use a huge excess of methylamine (which is not something you want to throw around like that), and typically a bomb is called for, because the boiling point of methylamine and solubility at reasonable temperatures is, well, low.
One way to overcome this problem is to use a different reagent, one that doesn't overalkylate. Azide, for example. But that's annoying and hard to get, and anyway, it'll only get you MDA from safrole. We need a better way.
Here is my highly theoretical suggestion, as a method I haven't seen any mention of at the hive:
Molecule:
benzalimine route ("c1cccccc1C=NC.c2ccccc2CC(C)Br>>c1ccccc1C=[N+](C)C(C)Cc2ccccc2.[Br-]")
This little nugget seems very interesting. I know there's at least one reference to it on Rhodium's page(
https://www.thevespiary.org/rhodium/Rhodium/chemistry/amphetamine.methylation.html
), but only for methylation...
How it works (apologies to those who already know):
Basically, a primary amine (i.e. methylamine) is stirred with benzaldehyde and dehydrated to form an imine. While other aldehydes would work, benzaldehyde is particularly preferred because it forms a stable adduct with the amine because the double bond of the resulting imine conjugates with the benzene ring, and it doesn't undergo self-aldol condensations. Once this imine adduct is formed, a stoichiometric amount of some alkylating agent is added, for example ethyl bromide, methyl iodide, or dimethyl sulfate, and the mixture is heated. Since the amine has three slots already filled up, only one more alkylation can occur, giving a quaternary iminium salt. This salt is then hydrolyzed to regenerate the benzaldehyde and give pure secondary amine. (i.e. MDMA) You could say the benzaldehyde acts as a blocker, to prevent overalkylation.
This is a very exciting general possibility, because it completely eliminates the overalkylation that would otherwise occur. It also has three other not-so-obvious advantages.
- First, the benzalimine has a VERY high boiling point, so you can heat that fucker to kingdom come without a bomb. This should speed the reaction up considerably.
- Secondly, unlike a normal alkylation reaction where HBr is evolved by displacement of the bromide by the amine, this reaction generates NOTHING. The two compounds come together and stay that way until hydrolyzed. Very handy, because there's no equilibriums to displace, no HX acids/gasses to sequester with pyridine or further excesses of amine.
- Finally, both compounds (the benzalimine and bromoalkane) are oil soluble, while the quaternary compound formed is much less so. I suspect that this will tend to help the reaction run to completion by removing the product from the mixture. If you ran it in boiling xylene, or mineral oil perhaps, I guess you could see crystals falling out of solution.
MMMMM, sounds yummy! Stoichiometric or 2x excess of amine, high yields, fast reaction, and the benzaldehyde is recyclable! That's what I like to hear! Only one problem--nobody seems to have done this reaction with a secondary haloalkane! In fact, most lit refs (and there aren't many) seem to copy the Org Syn procedures verbatim! Geez, these chemists sure are a stodgy bunch, aren't they?!
Never bothering to investigate something cool and OTC just because they already have 5 perfectly good ways of doing things already! Well, that's what we have the hive, I suppose, so we'll just have to see about such things ourselves!
So, suitably pumped up about this seeming diamond in the rough, I did some lit searching and paper abstracting, and here's what I found.
First, the procedure mentioned on Rhodium's page--N-methylation of amphetamine with dimethyl sulfate.
"A Rapid, Convenient Preparative Procedure for Phenethylamines", JMC 1972, 214
p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by stirring with concentrated aq NaOH, was treated with 100 ml benzene and 70 g (0.66 mole) of benzaldehyde. A mildly exothermic reaction began at once. The mixture was heated under reflux until no more water was present in the condensate (circa 1 hour), then, without cooling, an attached Dean-Stark trap was removed and a solution of 82 g (0.65 mole) of DMS in 200 ml of benzene was added through the condenser at such a rate as to maintain reflux (15 min). The 2-phase mixture was heated for 90 min on the steam bath, cooled slightly, treated with 200 ml water, and heated for an additional 20 min. After cooling in ice, the aqueous layer was washed twice with ether to remove unreacted benzaldehyde and made strongly basic with 50% NaOH. Two ether extracts of the basic aqueous phase were added to the amine layer which separated, and the resulting solution was evaporated under aspirator vacuum for 30 min, leaving 90 g (102%) crude N-methyl-p-methoxyphenethylamine. This material was dissolved in 500 ml of 20% anhydrous ethanol-ether and treated with 50 ml of concentrated HCl with swirling and cooling to yield the white, crystalline hydrochloride, which was washed thoroughly with ice-cold ethanol-ether and dried. Yield: 83 g (77%)
JOC 1989, 2448
: Methyl(trideuteriomethyl)amine
N-benzylidenemethylamine (3.58 g, 30 mmol) and CD3I (5 g, 34 mmol) were pipetted into a small (40 ml) stainless steel pressure cylinder, sealed, and heated to 100 C for 24 h. After cooling, to 45 C (not lower, to prevent the contents from solidifying), the cylinder was opened cautiously in a fume hood and the contents were poured into a 100-ml flask, along with the rinsings of the cylinder (10% HCl, twice 5 ml). The reddish brown slurry was refluxed for 2 h and the resultant mixture placed in an addition funnel and dropped slowly onto NaOH pellets to liberate gaseous Me(CD3)NH. [...] An 83% yield of Me(CD3)NH.HCl was obtained.
Here's a fun one--they use methyl BROMIDE for the alkylation...freaky.
JACS 1992, 5091
: n-hexadecylmethylamine
To a solution of n-hexadecylamine (3.0 g, 12 mmol) in 100 ml toluene was added 1.32 g of benzaldehyde (12 mmol). This solution was heated at reflux for 2 h and the water formed during the reaction removed by means of a Dean-Stark trap. After the solution cooled at room temperature, the organic solvent was distilled under reduced pressure, leaving quantitatively the imine derivative. This material (4.02 g, 12 mmol) dissolved in 100 ml of methylene chloride was poured in a screw-top pressure tube and cooled to -78 C. After the addition of 3.3 ml of methyl bromide (60 mmol), the tube was sealed and kept at 70 C in an oil bath for 48 h. The solvent was then evaporated and the residue treated with 100 ml of 0.1 M NaOH and extracted with chloroform. The evaporation of the dried organic layer (Na2SO4) afforded a crude material that was purified by dissolving it in acetone and precipitating the HCl salt of the amine upon addition of concentrated HCl. The white solid n-hexadecylmethylamine HCl, 3.18 g (91%), was collected and washed several times with acetone.
Also, please see Org Syn CV 5, 736 and 758, N-methylbutylamine and N-methylethylamine.
Finally, there is a paper in French which does the same thing. Maybe someone skilled in the language could translate the relevant parts--Journal of Fluorine Chemistry 93 (1999), 145
They seem to also reduce imines to amines with sodium dithionite in there. Perhaps this too could be useful? Hmmm...
So what's the point? The point, my friends, is this: If you can alkylate amphetamine with methyl iodide, or some bromide in high yield by this method, why could you not instead alkylate methylamine with bromosafrole or 2-bromo phenylpropane?
I have seen:
: all kinds of things alkylated with methyl iodide
: something alkylated with alkyl bromides (somewhere...)
All in high yields!
Yes, I'm sure it would be slower, but the steric hindrance is roughly the same, and you wouldn't need sealed tube or anything because the boiling point of both components would be high enough. Just a little dry acetone or DMSO, a pinch of NaI perhaps, and away you go! I wouldn't be too surprised if yields in excess of 70% could be realized, without needing the vast excesses of methylamine that haunt the normal bromosafrole method. Probably a 2x would be more than enough.
Thoughts?