magstirrer (Stranger)
06-13-04 14:50
No 513202
       p-methoxy-PEA     

Hello Bees,

SWIM was recently (theoretically!) considering the possibility of making (di)bromo/iodo derivatives of the p-methoxyphenethylamine. These compounds are relatively unknown with a little info available here on Hive (...) and seem a worthy synthetic target. The chemist-wanna-bee envisioned the synthesis like this:

1) Oxidize anethole to anisaldehyde. As might bee seen in Anise oil as para-methoxyamphetamine (PMA) precursor (../rhodium/pdf /forensic/anethole.pma.precursor.pdf), anethole doesn't have to bee isolated from anise oil which is exactly what SWIM is gonna do. The only problem is whether he should use the bichromate method from above (ca 50%, looks straightforward but K2Cr2O7 is toxic/suspicious) or the great-looking permanganate on alumina method (like here: Post 237918 (jim: "Simple KMnO4 method of benzaldehyde formation", Chemistry Discourse) Post 293705 (otto: "using permanganate", Chemistry Discourse) Post 511939 (Kinetic: "Cinnamic acid to benzaldehyde", Newbee Forum)). The KMnO4 procedure would bee ridiculously cheap, excellent yielding (ca 95%), and easy to work up. The obvious problem is gargantuic amounts of solvent and oxidizer. SWIM has an impression this could be reduced substantially, good stirring warranted, as anethole is easily soluble in DCM and wonders whether someone here has tried this. If not, he is going to experiment on this himself with like 3-5x less solvent/oxidizer and hope it works.
2) Condense anisaldehyde with nitromethane under Henry rxn conditions. He is definitely gonna use the ethylenediamine/EtOH method (Post 508451 (azole: "ethylenediamine as a catalyst", Methods Discourse), yield 97%).
3) Reduce the nitrostyrene to p-MeO-PEA. SWIM is a little stuck on this too. He is aware of the beautiful nitrostyrene reduction method of Leminger (Post 245040 (Rhodium: "O Leminger's Phenethylamines - posted by Karel", Novel Discourse)) but was unable to find any published specifics on p-MeO-nitrostyrene Anyone? If this fails, he is gonna try Urushibara type catalyst like ../rhodium /amph.urushibara.html. If this fails, in a fit of despair he will try to use the well-known Al/Hg method and/or Clemmensen conditions 9(Post 507331 (Rhodium: "Clemmensen reduction of nitrostyrenes", Methods Discourse)). Again, no specifics were found on p-methoxynitrostyrene. Would bee glad to hear your comments on that.
4) Brominate/iodinate the PEA. There is a lot of possibilities here, the UHP/iodine method (Post 488372 (Rhodium: "Aromatic Iodination with I2 and Urea-H2O2 (UHP)", Chemistry Discourse)) looks promising, then we have oxone/KI (Post 428701 (Barium: "Can it be true?", Novel Discourse) and ../rhodium /oxone.aromatic.iodination.html, BTW is the formation of 2C-I under these conditions confirmed?), oxone/KBr (../rhodium /oxone.aromatic.bromination.html), iodine/KNO3, plain old Br2/AcOH, HBr/H2O2, iodine/silver sulfate etc... Hell, KI/persulfate should work also... SWIM is gonna try the above methods more or less in the order listed. Any advices?
5) Workup and isolate as sulfate from DCM or acetone solution

The project is starting in at most month, the literature is gathered and read, most reagents waiting on the shelf... SWIM will keep you informed on this for sure!

Thank you for any and all comments. 		 
 
 
 
    Antibody2
(LinguisticBee)
06-14-04 18:33
No 513423
       keep it simple     

anise oil is very cheap ($15/litre) don't worry about the oxidation yeild.  It can be done with KMnO4 alone in 50% yeilds and saves messing around with alumina. For the condensation MeNO2 and NaOH in MeOH works great, no need for fancy catalysts or reflux (look on Rhodiums site) and for the reduction lemingers synth works fine so long as everything is kept very cold.

good luck
We are all just witnesses. 		 
 
 
 
    GC_MS
(Hive Addict)
06-14-04 22:18
No 513471
       halogenation     

The halogenations of phenethylamines employing KX and oxone have not been confirmed to my knowledge. I have tried the oxone halogenation method posted on this board for the chlorination (KCl) and iodination (KI) of 2C-H, and both trials failed (yield: 0%). Maybe the procedure works, but at least not in the way it is advertised. Notice that Shulgin synthesizes 2C-C from 2C-H and chlorine, while chlorinations of methoxybenzenes with KCl/oxone go via HOCl (I think).

I tell you this as a warning in case you wanted to make the 3.5-dihalo-4-methoxyphenethylamine. You might end up with your precursor again and ingest it as the dihalo analogue. 4-Methoxyphenethylamine is likely metabolized to tyramine, so be careful with your assays. It might not be a bad idea to take dietary precautions.
Aztecunnilingus Maximus 		 
 
 
 
    magstirrer
(Stranger)
06-16-04 14:07
No 513833
       synthesis economy     

Strange thing is in SWIM's homeland (Oz, I think you heard about it before) anise oil is quite expensive, contrary to all other chems required in this envisioned synthesis, including ethylenediamine, so my friend thinks it would be a good thing to keep high yield throughout. Btw, MeNO2/ethylenediamine/EtOH is simple as well, several days left alone in a cold place and gives excellent yield so is a unquestionable winner.

Do you have any specifics on the KMnO4 oxidation? SWIM thinks that's not as easy as putting things together in a solvent and mixing - overoxidation would surely result. The alumina method is equally easy, the permanganate is bound by the Al2O3 and deactivated and works exactly fine for aldehyde synthesis.

And the Leminger part, do you have it on good ground it would work here or is it just a guesstimate?

GC_MS: thank you for the tyramine info, SWIM has been warned, he would never have thought that himself :) Btw, the halogenated counterpart should pass the metabolic pathway with aromatic ring untouched, right? Was so long ago I seen any pharmacology text...

Thank you for your comments again and keep your fingers crossed! 		 
 
 
 
    Antibody2
(LinguisticBee)
06-16-04 19:43
No 513887
       for what it is worth . . .     

Post 173322 (uemura: "TMA2-P2NP: an alternative approach", Novel Discourse)
Post 348662 (Antibody2: "2,3-dimethoxy-4,5-methylenedioxyphenylethylamine", Methods Discourse)

MeNO2/ethylenediamine/EtOH is simple as well,  but you can't purchase ethylenediamine in a hardware storewink
We are all just witnesses. 		 
 
 
 
    neukz
(Stranger)
08-17-04 13:03
No 525945
       Is there any specific reason that you just...     

Is there any specific reason that you just don't buy the p-MeO-PEA? I've seen it available online recently.

What is the easiest way to halogenate this compound?