MDP2P from safrole using H2SO4 and NH4NO3

NOTE: Many people doubt the validity of this synthesis. It is possible that it does not work as advertised. Any success stories with this method is welcome in my mailbox: rhodium@ziplip.com

Introduction

This method seems to be a breakthrough in the clandestine synthesis of MDMA. For about two years, many people at the Hive have discussed back and forth the possibility of using sulfuric acid to add a water molecule across the double bond of safrole (so called acid-catalyzed hydration of alkenes) to form MDP2Pol (3,4-methylenedioxyphenyl-2-propanol). This compound is only a small oxidation step away from MDP2P (3,4-methylenedioxyphenyl-2-propanone), which is a direct precursor to MDMA and other related compounds. The problem with this approach was that the end product most people got was MDP1P, not MDP2. Investigations, mostly by the chemist Bright Star showed that this was due to the intermediate alcohol MDP2Pol (which itself was formed in quantitative yield) spontaneously rearranged itself at room temperature to the isomeric MDP1Pol, which on oxidation gave MDP1P instead of MDP2P. The rearrangement takes place in just a few hours, or even faster at elevated temperatures or vigorous oxidation conditions. What is needed is a gentle, high-yielding oxidation procedure, which is to be performed immediately after the formation of the MDP2Pol, so that it's converted to MDP2P before it has a possibility to decompose. Such a reaction is a Cu(II) catalyzed dehydrogenation in the presence of ammonium nitrate and acetic acid.

A ref for that reaction is M. Weiss & M. Appel, JACS 70, 3666-3667 (1948)

According to that ref, the reaction proceeds as follows:

R-C(OH)-R' + 2 Cu(OAc)2 R-CO-R' + 2 CuOAc + 2 AcOH

2 CuOAc + NH4NO3 + 2 AcOH 2 Cu(OAc)2 + NH4NO2 + H2O

NH4NO2 N2 + 2 H2O

And abbreviated to one line:

R-C(OH)-R' + NH4NO3 R-CO-R' + 3 H2O + N2

Experimental procedure

Experimental procedure

tBOC reads chem_wannabe's ammonium nitrate oxidation procedure, and thinks that it is rather incredible... almost unbelievable. It just so happens that tBOC loves to grow flowers, and uses NH4NO3 as fertilizer, and tBOC is also into photography and just happens to have glacial acetic acid around. Also tBOC was trying to use glacial acetic acid to get his pennies their brightest and fucked up, accidentally turning his beautiful penny collection into a nice blue powder. Well, tBOC happens to be a freak of nature (but we love him so/he's a freak of nature but we let him go) who likes to take alkenes, make ketones and then reductively aminate them (with legal ones, of course) so he decides to try this. tBOC takes all of his safr... er... alkene, and distills it off and puts it into his refrigerator. He then takes some H2SO4, 97%, and makes it into a 90% solution and puts that in the 'fridge as well. Now tBOC likes to do things right the first time so he doesn't have to do them again, so tBOC reads, asks questions, reads again, and comes to the conclusion that one should hydrate alkenes AS COLD AS POSSIBLE to ensure that the reaction occurs through an SN2 pathway, and not an SN1 pathway (i.e. cold, so one obtains the kinetic product, no carbocation rearrangements.) So tBOC takes his (not)safrole, puts 20g in a RBF with a magnetic stirrer and puts the whole thing in an ice/salt/H2O bath. He then loads up a dropping flask with 20mL of his chilled 90% H2SO4 solution and begins to add it to the alkene at the rate of 1 drop per second. Once all the acid is added, he lets it stir for another five minutes or so, then he loads up that dropping flask with 80 mL cold water (about 3C) and adds this to the H2SO4/alkene at the rate of 1 drop per second. When all the water was added, tBOC throws the whole thing in a separatory funnel and waits until it's separated. tBOC then pours out the water into a beaker, and pours the top layer into a RBF with a magnetic stirrer, then weighs it. Minus the tare weight, tBOC has 22g of his alcohol. Now, theoretical yield on this process should have been 22.222g. Goddamn it, tBOC is pissed that he didn't get that last 0.222g out of the reaction. Oh well. To 20 grams of this alcohol tBOC adds 1.2 molar equivalents of ammonium nitrate fertilizer, 4 mL glacial acetic acid, 1 mL H2O and a dash of cupric acetate for flavoring. tBOC then heats gently on his heating mantle (about 25 out of 120) with a reflux apparatus in place, and takes 60mL water and adds 60mL NaOH to it. Once this solution is made and cooled to room temperature, tBOC removes the heat from the now yellow reaction mixture and cools this by first running cold water over the outside of the flask and then by setting it in an ice bath for about five minutes. At this point tBOC notices A LOT of white solid at the bottom. tBOC wonders about this, wondering if perhaps he had added too much NH4NO3 to the reaction. Oh well, he thinks, and filters it off, takes the remaining reddish-yellow liquid, and puts it into a sep funnel and adds a total of 9.3mL of his NaOH solution to the yellow stuff dropwise. Two layers are clearly evident: a bottom black yucky layer and a top yellow layer with just the slightest tinge of red. tBOC pours off the bottom layer, then pours the top layer onto some silica sand in a Hirsch funnel (carefully) and pulls it through with his aspirator. The shit that comes out is nice yellow beautiful and smells like cardamon. tBOC hates vac distillation, so he checks the solution with a TLC analysis using an 80/20 Et2O/hexanes mixture with 3 spots made on the same plate, a product spot, a rxn mixture spot, and a product/rxn mixture co-spot. The rxn mixture spot is homogenous, and the co-spot reveals that it is definitely not the starting material. tBOC is happy now that he knows he can make a ketone from a terminal alkene in a little less than an hour. But the final score isn't in. tBOC weighs his product and sees that he has 19g. Goddamn it. tBOC didn't get 100% theoretical yield-- again. tBOC is pissed. tBOC consoles himself with the knowledge that he doesn't have to vac distill and that 20g of his alkene becomes 19g of his ketone in about an hour. tBOC guesses it isn't all THAT bad. Oh yeah, tBOC took that white crystalline stuff, smelled it, tasted it (smelled like vinegar and ammonia and burned like a motherfucker) and threw some in some NaOH solution. Ammonia gas boiled out of the solution... tBOC thinks that maybe this impurity is ammonium acetate. tBOC finds this quite interesting since he has some sodium cyanoborohydride lying around and just might want to make a primary amine from a ketone someday. tBOC need to take melting point next time and analyze to make sure white crap is ammonium acetate.

The reaction mixture was heated for at most 15 minutes. It ran very clean and you could watch your alcohol turning color to that of the ketone. The color change was complete within 5 minutes, so at most 10 minutes seem to be needed. The only reason I kept heating was that there was a lot of white solid on the bottom of the flask that wasn't dissolving. I thought that this might be unreacted ammonium nitrate so I kept heating to see if anymore dissolved, or any color change occurred.

As soon as the alcohol was made and weighed, it was kept cold (very near to 0C) while adding the rest of the reactants. Reaction appeared to begin almost immediately (i.e. evolution of a gas.) Gentle heat, not even really to reflux. If you want to be picky you can monitor the progress with TLC, but I have had no problems with this reaction going too far and getting too much bad shit. Last rxn went so clean that after the 50% w/w NaOH soln wash spot was homogenous to TLC, and it was NOT the same as the alcohol used, as evidenced by co-spot of starting materials.

tBOC knows that ammonium nitrate can be used to make many secondary alcohols into ketones (tBOC has oxidized many alcohols in this way in good yields, but of course never MDP2Pol.) What tBOC (and maybe a couple other bees out there) wants to know is if this can be used with the Al/Hg in situ MeNH2 production method of recutive amination. Well tBOC found out, and maybe found out something else interesting. tBOC made 5g of a ketone. tBOC used the same procedure he's used before, not-safrole to not-MDP2Pol and then 1.2mol NH4NO3, 1mol not-MDP2Pol, a couple milliliters of acetic acid (80%) and a spatula tip of cupric acetate. Gentle heating for about 15 minutes, followed by cooling under cold running water then in ice bath followed by filtration of the solid and a single wash with 5mL 50% NaOH solution yielded a yellow oil smelling sweeeeet like a ketone should. tBOC starts amalgamating aluminum, puts his 5g of ketone in a sep funnel with 21g 35%nitromethane content racing fuel (as is, straight from package, no purification of any kind) and shakes the two. Once the aluminum had amalgamated well, tBOC pours off water, rinses the sizzzling aluminum with some distilled water, and reaches for some ethanol to put it in. Unfortunately tBOC doesn't have any. The only alcohol tBOC has is n-BuOH (n-butyl alcohol, 1-butanol) so tBOC pour 75mL of this over the aluminum in a 1L beaker and adds the racing fuel/ketone mix over the course of about 35 seconds. The reaction starts going crazy, so tBOC throws a wet rag over the top of it and sets it in a spare bedroom an takes off to work. tBOC comes back, finds the aluminum all dissolved, and throws in 300mL 50%NaOH and dumps the whole thing in a sep funnel. Next morning tBOC pours out the bottom layer and pours in another 300mL 50%NaOH solution and goes off to work. tBOC comes back, pours out the bottom again, and filters the top layer (about 70mL of liquid) on a buchner funnel. tBOC then figures he'll do an acid base extraction on it then crystallize so he checks pH (slightly alkaline: ~9-10) and starts to add 30% HCl. A white solid started to crash out of solution almost immediately, but tBOC keeps adding HCl until the pH is about 4, then filters off the white crap and puts it in the oven to dry while tBOC separates off the bottom layer of water from the n-BuOH and then smokes a cigarette. tBOC comes back to find one solid chunk of white crystal in the oven, so he weighs it. 4.1g. "Damn, that sucks. Should've been a whole hell of a lot more, especially since I was soooo careful with monitoring this process," thinks tBOC. Now tBOC has no way of taking a melting point, so he figures he'll just see what a dab tastes like. tBOC puts a little on his finger and tastes it. Hmmmmm.... salty. BUT tBOC's fingers ALWAYS taste salty to him for some odd reason (don't ask...please...) so he tastes it again. Yup, definitely salty. But it's not all that salty tasting and it doesn't look like any salt he's ever seen. So tBOC takes a decent chunk (about 50mg, maybe 70-80... not sure) and pops it on his tongue. Yup, definitely tastes rather salty. tBOC sets it aside, looks up properties of his amine-HCl salt and finds that it is supposedly soluble in alcohol. Ahhhhhhh, maybe it's in the n-BuOH still, thinks tBOC. Or it could be in the aqueous phase he just separated. tBOC pours the water phase on a plate and sets it on top of his oven, which is cooking up some po... er... brownies and tBOC smokes another cigarette while pondering what to do and decides to distill off some nitromethane for next time while he tests a small aliquot of the alcohol for the presence of amine by adding some CH2Cl2 and seeing if anything falls out. So tBOC sets up his distillation apparatus, which for some reason is a lot more difficult than he remembers it to be. He puts the distillation head on backwards, plugs his mantle directly into the wall socket (without a variable transformer in place) and wonders how that little elf on his coffee table got into his house. By the time tBOC gets the distillation apparatus set up he realizes he is actually quite intoxicated and decides that playing with nitromethane wouldn't be a good idea, so tBOC closes up shop and takes off for a very wonderful stroll in the middle of the night, making it back to his place just in time to crawl onto his roof and watch the most beautiful sunrise of his life. tBOC goes inside and sees the plate has been sitting on his warm oven for a long time, and has completely dried out, leaving behind a bunch of crap that looks like table salt, laced with some kind of white powder. tBOC smiles to himself, thinking that as soon as tBOC gets some more absolute EtOH he can dissolve the white stuff in it, leaving behind the (supposed) table salt then add some Et2O or CH2Cl2 or maybe even some n-hexanes to the alcohol to get out some more of that wonderful little elf dust. Success, thinks tBOC. And it's all OTC.

Notes

Alright. Since I FINALLY got a usable end product out of the whole

not-safrolenot-MDP2PolNOT-MDP2PMOST-DEFINITELY-NOT-MDMA thing, my faith in the mechanism of Strike's whole H2SO4 hydration recipe is restored. But a whole hell of a lot of things DID NOT WORK in the alcohol-->ketone stage. Here's my thoughts on the matter, FWIW.

[1] Cold is the key thing to keep in mind here. The colder the better. Remember that little bit about kinetic vs. thermodynamic product? It's fucking true. Keep your shit cold with salt/ice/water bath, add your concentrated H2SO4 (I prefer 90%) COLD and SLOWLY and then add your water COLD and DROPWISE with GOOD STIRRING. Since I started using this procedure, I've noticed that my yields went way up from about 80% with just dumping hot water in to almost 100% when adding water fresh from the fridge dropwise followed by a couple grams of salt to break up the emulsion. Which brings me to my second point:

[2] Any oxidation done on the alcohol, in order to have half a chance of success must happen fast and cold. Numerous attempts with refluxing sodium dichromate in aqueous H2SO4 resulted in only 20-30% yield, and longer reaction times resulted in lower yields. In fact, everything that I tried at over 0C that had a reaction time longer than 10-15 minutes had horrible yields. So right now I'm scouring through references to cold oxidation methods to find something that will work on this lovely compound, preferably with a minimal investment. 3) The ammonium nitrate oxidation works, and works well. But it took SEVERAL tries to find the right proportions and work-up conditions. Also I personally have no intention whatsoever of scaling up the reaction to anything above 20g of ketone at a time. So something better has to be found. BTW: I found the original reference to this procedure: JACS Vol 70, page 3666 (1948). 4) A common problem is over-oxidation, i.e. the oxidizer used is too reactive and tears apart the O-CH2-O ring. Milder reagants need to be found. This actually makes research into new methods easier, as one can reasonably focus on only methods that are used to convert primary alcohols to aldehydes in good yields (MILD OXIDIZING CONDITIONS!!!) 5) Finally, a note on reactivity. The alcohol in question has a horrible tendency to migrate to carbon 1 due to electronic factors introduced by the substituents on the benzene ring. This thorn in my proverbial side actually turns out to be to my advantage when doing oxidations at cold temperatures because that same electronic influence makes the oxidation of this alcohol go a lot faster than it otherwise would.

[3] The ammonium nitrate oxidation works, and works well. But it took SEVERAL tries to find the right proportions and work-up conditions. Also I personally have no intention whatsoever of scaling up the reaction to anything above 20g of ketone at a time. So something better has to be found. BTW: I found the original reference to this procedure: JACS Vol 70, page 3666 (1948).

[4] A common problem is over-oxidation, i.e. the oxidizer used is too reactive and tears apart the O-CH2-O ring. Milder reagants need to be found. This actually makes research into new methods easier, as one can reasonably focus on only methods that are used to convert primary alcohols to aldehydes in good yields (MILD OXIDIZING CONDITIONS!!!) 5) Finally, a note on reactivity. The alcohol in question has a horrible tendency to migrate to carbon 1 due to electronic factors introduced by the substituents on the benzene ring. This thorn in my proverbial side actually turns out to be to my advantage when doing oxidations at cold temperatures because that same electronic influence makes the oxidation of this alcohol go a lot faster than it otherwise would.

[5] Finally, a note on reactivity. The alcohol in question has a horrible tendency to migrate to carbon 1 due to electronic factors introduced by the substituents on the benzene ring. This thorn in my proverbial side actually turns out to be to my advantage when doing oxidations at cold temperatures because that same electronic influence makes the oxidation of this alcohol go a lot faster than it otherwise would.

First of all, let me congratulate piglet on his astute observation that one can just use an excess of AcOH and not worry about the exact amount. You da man, Piglet. When done this way, the ketone is just sitting pretty at the top of the acid, and the whole reaction mixture is ready for a quick toss in the ol' sep funnel. Then you just pour out the bottom and save the top. Pure to TLC analysis and definitely suitable for most any further reaction you choose.

Now on to the fuckups:

tBOC was using 90% H2SO4 to hydrate the olefin to make his alcohol, and kept ending up with a purple gunk that just sat there when he tried to hydrolyze it. At most 10% of the olefin converted to the alcohol. After a couple failures, tBOC thought it just might have been caused by the fact that his acid was old and impure since it was slightly discolored, but decided to dilute down to 80% and try once more. Even though his now 80% acid had a slight pink tinge to it, when he added it to his olefin cold, he got a quantitative yield. Actually 100% (+/- 1%) conversion to the alcohol. So from the several 90% acid attempts that failed, and the two 80% attempts that got 100% yields, tBOC concludes that 80% H2SO4 is the ideal concentration of the acid. 90% seems to be too harsh too our precious MD-ring.

So, quick review: 90%- bad 80%- good.

Now on to the oxidation. tBOC, once he FINALLY got some alcohol made, weighs out 10g (not bothering to wash or purify in any way) and weighs out 10g of NH4NO3 (a rather large molar excess, about 2 mol NH4NO3/mol alcohol) and combines these two in a RBF in an ice bath. tBOC adds a pinch of Cu(AcO)2 and 30ml glacial acetic acid (aldrich, guaranteed 99+%) and 5mL water straight from the sink. The alcohol is now sitting on top of the acid and not much is happening, so tBOC starts with the gentle heating. After about 10 minutes there is a definite yellow tint to the top layer and acid phase which had initially turned slightly brown is now entirely bluish-green. tBOC decides to let it run for an hour or so and see what happens while he goes off to get laid.

When he comes back 1.5h later, tBOC cuts the power, cools down the mixture and throws it into a sep funnel. After the layers have been sitting for a while (two bong bowls and a cigarette) tBOC separates the two and does TLC analysis on the top layer. THE SHIT COMES OUT AS ONE SPOT ON THE TLC. tBOC weighs it (10g, qualitative... nice!!!) chucks it into the freezer (set to -10C, and it DID NOT FREEZE, btw) and takes the acid layer, which is now the color of dirty pennies, and tries to use it on a second batch of alcohol.

10g of alcohol and 10g NH4NO3 are added to the old acid solution, and the flask is heated again. After 0.5h the whole thing is one dirty black color. FUCK!! tBOC thinks this shit is screwed and tBOC is right. No pretty yellow layer on top and tBOC has to resort to extractions with CCl4 to get out his yellow ketone. Stripping off the solvent tBOC is left with that yellow solid everyone almost had tBOC convinced he made the LAST time he tried this.

So, first time with the acid in excess, and second time with excess NH4O3: good . Second time: bad . Got it? Good.

Reductive amination with Al/Hg + MeOH/BuOH +MDP2P + Nitromethane

Now on to the fuckups with reductive aminations. tBOC sets up two simultaneous reactions, both with n-BuOH as the solvent using nitromethane reduced as the in-situ amine source. Same scales with both, 0.25mol ketone with 0.40mol nitromethane added to 40gAl/Hg in 650mL n-BuOH, only one is with 5g ketone, the other with 15g. (tBOC forgets the actual weight amounts but knows he calculated and weighed out these same proportions in each batch.)

The 5g batch runs smooth and clean, no problems. Adding 300ml 50%NaOH and washing with water results in a nice clear top layer that spits out 4.6g white crystals when acidified to pH 4 with 30% HCl. The 15g batch, however, instead of having the yellow color of the ketone disappearing as the reaction proceeds, starts to turn red and when the 50%NaOH is added after it cools, turns into a black mess. No amount of washing, A/B extractions, etc, yields any product at all. tBOC thinks for a minute, reads Shulgin's add-the-amine-in-yourself method and notices one little phrase: Keep the reaction below 60C....

Well, goddamn. Maybe the 15g batch got a tad too toasty, thinks tBOC. So tBOC takes another 10g ketone and instead of using straight nBuOH, he mixes it 50/50 with MeOH (with a much lower boiling point, should keep it cool enough, thinks tBOC....)

And he was right. 10g ketone, same proportions of other reagants (with the alcohol called for being 50/50 MeOH/nBuOH), dumped in shitloads 50% NaOH after the reaction was done and it had returned to room temperature, washed with water, titrated to pH 4 with 30%HCl and out drops 8.2g product.

So, tBOC has learned that once he has his safrole pure, he can put in about 3h of work and get out up at least 8.2g (likely more) sweet honey crystals as long as he keeps the following in mind:

At least 1.2 mol NH4NO3/mol alcohol and as much as an equal w/w amount. This oxidation is actually a catalytic dehydrogenation with CuO as the active reagant being generated in situ on demand by the NH4NO3.

Excess of AcOH: about 35mL of around 80% AcOH works great for 10g not-MDP2Pol. Ya just gotta love the generosity of this reaction towards lazy people who hate measuring shit out .

Keep final reaction cool. Use 50/50 mix MeOH/nBuOH and you should be fine. tBOC SHOULD have known this, it's been repeated over and over again on this board. But tBOC has a tendency to make the same stupid mistakes over and over again without learning from them.

Separate the not-MDP2P directly from the 80% AcOH. If you dilute with water, you will find that it tends to diminish the top layer, making separation a bitch, requiring extraction, filtration, distillation, etc.

In the not-safrolenot-MDP2Pol stage, the H2SO4 is added at 80% concentration direct from the freezer at the rate of about 3 drops/sec to the not-safrole which is being magnetically stirred in a ice-water/salt bath chilled to -5 ° C or less. Then chilled dH2O is added dropwise at the same or a slightly faster rate to the sulfate as soon as the H2SO4 is all in. Normally I just use a sep funnel and as soon as the H2SO4 is all added just pour my water in the top then go smoke a cigarette or two. Once all the dH2O is added, some salt is then stirred in to help break up the emulsion. Yields are consistently 100%.

M. Weiss & M. Appel, JACS 70, 3666-3667 (1948)