Amphetamine From Solvents: NO Reducing Agents!

[PrimoPyro]

MUWAHAHAHAHAHAHAHA  

At last, the final piece to an idea I've had for awhile now, the synthesis of amphetamine from solvent, namely toluene, without going through a P2P intermediate, and with one major requirement: No reducing agents/reactions are allowed!  

Now that I know you can halogenate 2-butanone at the 3-position, I can finally piece together the idea.  

1.Preparation of Benzyl Iodide From Toluene:

Chlorinate toluene with calcium hypochlorite to form benzyl chloride, and then use sodium iodide to swap the halogens, formind sodium chloride and benzyl iodide.

2.Preparation of 3-Iodobutan-2-one:

Chlorinate MEK with calcium hypochlorite + hydrochloric acid, and then use sodium iodide to swap the halogens, forming the 3-Iodobutan-2-one.

3.Coupling The Two Aforementioned Reagents:

Use the Ullmann Reaction, with the two reagents above, and copper, to couple them together, forming Phenyl-isopropyl Methyl Ketone.  

4.The Haloform Reaction:

Use more calcium hypochlorite to induce the haloform reaction, trichlorinating the lone methyl, then ripping it off, to form 2-methyl-phenylpropanoic acid.

5.Make Our Beloved Amine:

Distill from ammonia, or dissolve in ammonia solution and boil all water solution away, forming the amide of the acid. Then, you guessed it: use even more calcium hypochlorite to perform the Hoffmann rearrangement, ripping off the carbonyl this time, forming.....

........Amphetamine!  

The theme is to not use any reducing agents, nor any exotic reactions like the Grignard Reaction, Pseudonitrosites, and no exotic chemicals like acetic anhydride or methylamine hydrochloride.

Usage of a few main reagents, with the continued use of calcium hypochlorite, makes for a very simple reaction scheme. Perhaps this is more suited for the individual who wishes to make DOB, not amphetamine, as usage of p-MNT and P2O5 + MeOH as a methylatine agent, would certainly make a nice conversion from nitrotoluene to 2,5-dimethoxytoluene.

Another note, the only reason for the halogen switching is because the example I had seen for the coupling did not say RX, it said RI and copper, so I thought it was probably specific to iodine. If however, that reaction can be done with chlorides, then that would be even more economical.

If someone will do me the large favor of telling me where I can get a piece of software that will let me convert *.skc files into jpgs, I would gladly post shitloads of pictures for you. I use ISIS Draw to make molecular sketches, but I cannot turn them into jpgs without rendering them. I don't have photoshop.

                                                     PrimoPyro
Wir pumpen..... (Klatschen) Sie oben!

[Sunlight]

Very creative !!!

[PrimoPyro]

What about reacting bromobenzodioxole with bromoacetone and copper? That would form MDP2P if it worked, and if excess bromoacetone was used, you would form lots of hexan-2,5-dione as byproduct.

haloform + distill from ammonia --> succinimide. Bromination gives a wonderful reagent for turning benzodioxole into bromobenzodioxole.  

Efficiency, efficiency, I love it!  

                                                    PrimoPyro
Wir pumpen..... (Klatschen) Sie oben!

[PolytheneSam]

See this post

Post 222968

(PolytheneSam: "Re: The Meerwein Reaction", Serious Chemistry) in this thread

Post 222804

(PEYOTE: "The Meerwein Reaction", Serious Chemistry) .
http://www.geocities.com/dritte123/PSPF.html

[PrimoPyro]

Yes, Ive seen those threads before. They were a small part of what made me look to creating a large chain and using reactions to shorten it to get amphetamine, instead of the normal working the other way around.  

Thanks.  

                                                PrimoPyro
Wir pumpen..... (Klatschen) Sie oben!

[menthol_man]

Cool... how bout a write up?  Anybee tried this yet?
I would love to get in on this  
Seig Heil Uber Allies !

[PrimoPyro]

Mr mentol_man: I'm sorry to say, but PrimoPyro is only a theorist and thinker, not an active clandestine chemist, or a dreamer.

Any writeups will be from other bees/handles.

                                                   PrimoPyro
Wir pumpen..... (Klatschen) Sie oben!

[psychokitty]

One of the main problems with your scheme is that many of the intermediates are lachrymatory.  Benzyl chloride and probably bromide and iodide are stinky if not so much lacrymatory.  However, chloro-, bromo-, and probably even iodo- MEK are probable war-gasses.  The reason I say this is because halogeno acetones ARE war-gasses.  But who knows?  Look up the 3-chloro or 3-iodo MEK in the Merck index.  I'm sure you'll find something about the dangers in handling it.

Anyway, the 3-iodo butanone can probably be had by simply reacting I2 directly with MEK.  This would make the process more simple to operate as no isolation of intermediates would be required.  I2 can be had OTC by reacting NaI or KI with oxone.  I'll see if I can find some information on the synthesis of 3-iodo-2-butanone.

As for the formation of the amide, I seriously doubt that simple evaporation of the ammonia solution will yield it (BTW, chlorination of the acid to form the acid chloride WILL react with ammonia to form the amide directly, but chlorinating agents aren't, to my knowledge, OTC).  The ionic ammonium salt can be formed from reaction of the acid with ammonia, but the amide will take a bit more work.  This probably isn't as difficult as one might think.  Formation of N-formyl amphetamine (N-formyl amide), according to one U.S. Patent that I have laying around somewhere, can be had by first reacting amphetamine free base with formic acid.  The salt thus formed is refluxed using a dean-stark trap in toluene for, like, 24 hours or something.  The formation of the amide is slow, but does occur to completion with the azeotropic removal of the water in solution to form a high yield of the N-formyl amide.  Work-up is standard.

As for the Hoffman rearrangement, yields are reported to be somewhat low (but this was for substituted amphetamines).  I have a paper detailing the synthesis starting from cinnimaldehyes of something like that.  For clarification on this issue, refer to Rhodium's page under that review of MDA and its analogues and homologues (sp?) and their manufacture.  The Hoffman degredation reaction is listed there as an alternative to common MDA manufacturing methods.  It also contains the references to the original papers.

I'll see about getting you some of this infomation soon.

[Lem2]

perhaps to avoid trouble, you could do the chlorination/iodine swap on both toluene and MEK at the same time, then do the ullmann in the same pot.
He who makes a beast of himself gets rid of the pain of being a man.

[halfapint]

My new old book arrived, Jerry March's 3rd edition of Advanced Organic Chemistry. This lunatic notion of PrimoPyro's naturally made me a little curious, it's so similar to the way I think sometimes, in the way it approaches possibilities by working completely around the way folks are thinking about the problem.

March mentions the Ullmann coupling only as an aryl-aryl coupling procedure. No mention is made of any possibility of an alkyl-aryl coupling made with copper.    
n.b. --- I have no reason to think alkyl-aryl coupling of the iodides (best of the halides, which all work for Ullmann coupling) won't work; but my bet is, it might make a mess to separate.
1. Would use of copper amalgam soup up the rxn rate?
2. What are the conditions of the Ullmann reaction?

If we find such a reaction, of alkyl-aryl coupling as selective as Ullmann coupling, we must call it the PrimoPyro coupling. >>>>/||\<<<<
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