Action of (CH3)2SO4 on phenylalanine -Labrat

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Action of (CH3)2SO4 on phenylalanine -Labrat
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Action of (CH3)2SO4 on phenylalanine

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Labrat
Member   posted 08-05-98 10:36 AM
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When going thru some refs I noticed the following interesting piece of work:
"Degradation of alpha-methyl-3,4- dihydroxyphenylalanine (a-Me-DOPA)"
JOC 29:1424('64)

In the article there is mention of dimethylsulfate/NaOH reacting with N-acetylphenylalanine forming the methoxy compounds and a small amount of methyl ester. They mentioned that when the unprotected amine (-NH2) is used, there will be N-methylation by dimethylsulfate.

To make a long story short: the method a nobody called laborat proposed DOES NOT WORK!
He's definitely not a chemist and probably didn't understand the article one bit! I've stated it earlier, but now I think this is the article that SOB meant. You don't have to get it from microfiche, just go to the chem library, go straight to the JOC!

Thanks a lot laborat! I hope I can be of yours service anytime! Lr/

Lone Ranger
unregistered   posted 08-06-98 07:25 PM
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Good work digging up that reference, Labrat. There is on-going research on reducing the acid chloride of phenylalanine and taking the lone oxygen to CH2 in just one easy step. Work is being done to eliminate the need for LiAlH4. It is very promising. Care must be taken not to form the alcohol, of course. No yields from sodium borohydride (as expected). Kishner, Clemmensen, and Wolf methods are being explored, as I understand it. Fair yields were obtained from an exotic, expensive, LiH "replacement" reagant, with an acronym for a name.
Taking the ketone to CH2 first, and then forming the chloride for reduction, was deemed an unsuitable route by that same research team.

This could be promising reaearch, but it will not be a "one pot" method. I'll update you as I get more info, if you like.

ReFlux
Member   posted 08-07-98 01:20 AM
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Could the N-Methylation that occurs be exploited to convert MDA to MDMA?
-ReFlux

Lone Ranger
unregistered   posted 08-07-98 09:19 AM
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The product would not be N-methylated, so this experiment is no help to you.

Labrat
Member   posted 08-07-98 09:47 AM
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Lone Ranger: man, you're making me very curious! All that talk about researching makes me very excited. If you care to email with me on the subject, I'll send you my PGP key if you like.
I'm very curious what would happen if you reduced phenylalanine to the aminoalcohol with NaBH4/H2S04, then reduce the alcohol with HI/P. I know the HI isn't cheap, but suppose somebody found a bottle...

ReFlux: ofcourse you can make MDMA from MDA with dimethylsulfate! It is generally known that dimethylsulfate methylates alcohols and amines. The problem is to avoid dimethylation. This problem can be minimized by using just one molar equivalent of dimethylsulfate, but some dimethylation will occur. I guess you could use less then one equivalent of dimethylsulfate to get a product mix of MDA/MDMA. These two substances have different pharmacological profiles, so I'm very curious what this mix will be like or called. Well, I think a curious researcher will find this out one day. Lr/

neocelsis
unregistered   posted 08-07-98 11:31 AM
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About 3 (?) months ago there was an article in one of the Tetrahedron J's....on this very topic.
The amine of a phenylalaine deriv. was protected, the -COOH was reduced with NaBH4/H2SO4, and the resulting alcohol was tosylated. Then(in one pot!) the tosylate was displaced by iodide ion and the resulting primary iodide was reduced with zinc.
Particular attention was paid to stereochemistry and the protecting groups used.
A nice piece of work.
Although perhaps a bit impractical for the bathtub chemist.

Rhodium
Administrator   posted 08-08-98 06:21 PM
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Well, do you remember the ref of that article?

Lone Ranger
unregistered   posted 08-09-98 12:34 AM
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Rhodium - see:
"Synthesis of Dextroamphetamine Sulfate and methedrine HCL from D-Phenylalanine" by Repke, Bates, and Ferguson in the Journal of Pharmaceutical Sciences, Vol 67, Number 8, pp 1167-1168."

Labrat, so far the experiments I was refering to have not had any promising results, but some methods have been abandoned. The DMSO/Sodium borohydride reduction of the Chloro compound derived from SOCl2 treatment of the alcohol (derived from NaBH3 reduction of phenylaniline) was shelved due to the formation of undesirable by-products. The Clemmensen reduction of phenylalinine to the alcohol was also shelved, due to difficulties in extracting the product from the zinc chloride mess. The Clemmensen reduction of the acid chloride, followed by Rosenmund reduction (if needed - if the chlorine atill hangs on) is being investigated presently.

Progress is slow. My Grandma (the DEA licensed research chemist) would like to investigate the Clemmensen, Wolf, and Kishner methods first, before trying the borane/THF system. But this system will also be tried, as will any other reasonable suggestions. She welcomes any other ideas for experiments that you may like her to try. b

If there are reasons why any of these methods are a waste of time, I will tell her to skip that method. As it is now, we both feel that any one of these (and some others), could be THE ONE.

Of course I will share details of any positive results she may have. So far only reduction of the Chloro compound derived from SOCl2 treatment of the alcohol (derived from reduction of phenylaniline) with LiAlH4 or NaALH2(OCH2CH2OCH3)2 have had any positive results. The first reducing agent is much too unavailable to be useful, the second is obscure enough to be of potential value. It is a process that will be revisited if the other methods fail.

neocelsis
unregistered   posted 08-09-98 03:01 PM
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That issue may be at the bindry at the moment. Looked for it couldn't find it. The chemistry wan't that interesting to me so didn't copy. As I remember the article more fully it was on the conversion of tyrosine to PMA. A fast glance at the PMA section in PIHKAL will point out why one should stay far away from it. And there are much better things to make from tyrosine.

Labrat
Member   posted 08-10-98 10:39 AM
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Neocelsis: can you give us an exact reference? Thanks a lot!
LR: thanks for the tips man! This saves us a lot of experimenting. It's pretty shitty the DMF/NaBH4 reduction of the chlorocompound doesn't give good results. What kinda byproducts are ya talking about?

If you're interested we can continue this conversation with PGP encryption. Lr/

Lone Ranger
unregistered   posted 08-11-98 04:50 PM
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The DMSO/NaBH4 experiment liberated a huge quantity of unbelievably putrid sewer gas. There was product formed, but it was rendered unpalatable.
The thought of stinking up her lab againg has my Grandma pretty well set against repeating this. The fume hood had to be wiped down with ammonia to kill the lingering oders!

neocelsis
unregistered   posted 08-12-98 09:49 AM
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Terribly sorry.....wrong journal.
The procedure is in Syn. Comm.
vol. 28 No.11 pgs.1935-45.
So many journals - so little time.

Labrat
Member   posted 08-12-98 10:41 AM
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Lone: so the DMSO/NaBH4 reduction evolved some sewer gas eh? And it had to be wiped down with ammonia? Very odd. I'd expected some HCl would evolve, but "sewer gas"? Probably some ammonia derivative. Have you tried to wash the product or was the stench enough to abandon the project? Keep up the good work!
Neocelsis: thanx! I've been cruising the Beilstein to find that ref, but since you mentioned TL I've only searched this journal and found nothing. This helps alot! Lr/

Lone Ranger
unregistered   posted 08-12-98 07:14 PM
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The DMSO reduction products were washed, and some small amount product was obtained. The stench makes this an unlikely experiment to be repeated. Likely the gases were ammonia compounds.
The Clemmensen reduction of the acid chloride in a two phase system gave excellent yields of a black tar! This tar does not form a salt with HCl, and is probably not a nitrogen containing compound (speculation). It seems that the unprotected amide is not surviving reducyive efforts very well. Perhaps it should be methylated prior to reduction? This would form some less desirable dimethyl compound, but the price would be right.

It is starting to look like this will not be within the reach of most people. The hope is that it can be.

Well there is still reduction under basic conditions, and the Labrat borane methods to be tried!

Labrat
Member   posted 08-13-98 10:43 AM
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It seems the amine group of phenylalanine is not stable enough to survive the reaction conditions you've tried so far. A solution to this problem would be protecting-deprotecting the amine, but this adds 2 steps to the rxn scheme. This is definitely not what we want.
I've a good feeling about making benzedrine by the route I mentioned, that is reduction of Phe-Ala by NaBH4/H2SO4, then HI/P reduction of the intermediate alcohol. This is a 2-step process with not-to-hard-to-get chemicals. The last process is already practiced a few decades in the US, so this won't be prob.

Personally I'm very interested in a completely different route to amphetamine from phenylalanine:
phenylalanine is reacted with KOCN to produce the oxazolidine, the latter compound is methylated at the alpha position and then the oxazolidone is hydrolysed to get the a-Me phenylalanine. Decarboxylating this gives amphetamine. This is a 4-step process, but the chems are pretty easy to get and yields are good. If you want I'll keep you posted on this. Lr/

Lone Ranger
unregistered   posted 08-13-98 07:58 PM
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Would reacting with MeI (methylating and dimethylating N) provide enough protection so that the compound could survive?

Rhodium
Administrator   posted 08-14-98 04:40 AM
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The "sewer gas" couldn't be some kind of product from the reduction of DMSO, like dimethylsulfide or the like?

Labrat
Member   posted 08-14-98 10:53 AM
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Lone: methylating the amine will certainly protect it, but do you have any idea to remove those groups afterwards? Protecting it as the acetate may be a better way.
Rhodium: do you think that NaBH4 is strong enough to reduce DMSO? Even NaBH4/TMSCl is not strong enough to reduce DMSO quantitatively to dimethylsulfide. Lr/

Lone Ranger
unregistered   posted 08-16-98 01:43 PM
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Rhodium - The experiment with the DMSO was repeated with only DMSO/NaBH4 (no substrate). Holy Shit! Does this stink! I quess it is a DMSO break down product that smells.
Then the pugsley DMSO/NaI/H2SO4 method of generating anhydrous HI was tried. It makes HI and more - a very similar, divorce-inducing, gut-turning, "sewer gas" was genereated. This is a problem that people should bear in mind when reacting in DMSO. Start small and be sure you can take this stench!

Due to the above problems, evaporating "used" DMSO, with or without vacuum, is out of the question. How else would one recover a product from this solvent?

Labrat
Member   posted 08-17-98 09:58 AM
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Lone: if DMSO is the cause of the sewer gas generation, why not substitute this dipolar aprotic solvent for another one? Have you tried DMF or acetonitrile as substitutes for DMSO? I don't think NaBH4 is strong enough to reduce a formamide or a nitrile to something smelly, but you never know until you try. Lr/

Shaft
Junior Member   posted 08-28-98 12:32 AM
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LR: Ever think of heating the acid with
soda lime (mix of NaHO and CaHO) to
give off the carboxyl group as methane gas?
Maybe oxidizing the acid first, and then
proceeding as follows would work?

Tonto
unregistered   posted 08-28-98 05:51 PM
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At our last conversation Lone Ranger was waiting for some new dipolar aprotonic solvents. I did get the feeling that he was no longer very hopeful, though. What are the 'popular' methods of reducing a carboxylic acid to a hydrocarbon? I cannot find any methods of doing this that are less than 3 steps.
Shaft - any thoughs are welcome on this difficult task, but this highly oxidized
COOH group will not oxidize further, and is far to stable to give off methane by merely treating with a base. I would love to be wrong on this, of course.

Strike
Administrator   posted 08-28-98 09:37 PM
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Maybe ya'll can help Strike out with this one. Strike has found a lot of methods that remove the COOH of the amino acid down to an OH. A lot of ya'll have emailed Strike more methods on doing that.
But that does not do anyone any good unless there is a way to effectively get rid of the OH to get final amphetamine. And that is what Strike has very little clue about. How can that be done?

A primary carbon OH is one of the most difficult species to reduce. What's the story?

Tonto
unregistered   posted 08-28-98 10:22 PM
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OH can be swapped out for easily reduced Cl or Br with some available non-watched reagants. How to get from COOH to good ole OH is where Ranger and I are stuck.
Secondary (yea I know, this one is primary) alcohols can be reduced to H in one pot, primary alcohols will require isolating the intermediate.

Shaft
Junior Member   posted 08-29-98 02:34 PM
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The addition on NaOH with phenylalanine
doesn't produce methane gas and the product.
However, aluminum chloride can be easily
made from 2x hydrogen chloride as aluminum
foil. Also, H gas is formed. Maybe
making the AlCL and adding the phenylalanine
to a sealed container, and then a catalyst
(Ni), you could reduce the cooh to H
in one pot. I know for fact that AlCL
works to reduce to the Cl, but I'm uncertain
of utilizing the H present, with a catalyst.
Any thoughts?

Tonto
unregistered   posted 08-29-98 06:06 PM
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N-Bromosuccimimide can take carboxylic acids directly to the halogen with loss of CO2. But this is not a general reaction. I am saving it for a last ditch effort. How else can CO2 be removed from COOH?? Or, second best, what are these great ways to convert COOH to OH that Strike hints at?? I'll post 3 ways of taking alcohols to hydrocarbons for every way posted that takes COOH to OH. Clemmensen and Wolf or Kishner methods don't count. That's three for one - what a deal!
Here's a freebe (a popular method):
The most general reducing agent for cabinols is a combination of red phosphorous and hydriodic acid. The combination is used under mild conditions to reduce hydroxyl groups, sealed tube and 190deg to reduce phenolic groups (even carboxyl groups, in some cases). As a rule, any carbinol that converts to a carbonium ion in boiling formic acid will be reduced to a hydrocarbon.
This method might even work with phenylalinine, but I don't want to mess with heating sealed tubes.

Labrat
Member   posted 08-31-98 09:57 AM
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Labrat has already proposed a method to reduce that -OH to an alkane by a known method: HI/red P reduction. This reagent is
used in the literature to reduce carbonyl, nitrite, halide and ALCOHOL groups.
For those who like literature:

"Reagents for Organic Synthesis" vol 1: p.449 ('67)
"Survey of Organic Synthesis" vol 7 .332 ('70)

Thanks Stony for the refs!~ Lr/

Shaft
Junior Member   posted 08-31-98 11:26 AM
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Labrat: Are you saying that RP/I can reduce
the phenylalanine to amphetamine, without further steps? The implications and savings
would be havok-wreaking!

Labrat
Member   posted 09-01-98 09:36 AM
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OK, I'll give a general outline how to make benzedrine from phenylalanine:
1)reduce phenylalanine to phenylalaninol.
You can use NaBH4/H2SO4 to do this in one step, or you can make the acid chloride, which can be reduced to the alcohol.

2)reduce the phenylalaninol to benzedrine.
There are many ways, but in my opinion, the HI/red P reduction COULD be the way to go. The alcohol should be reduced in one step to the alkane, like described in the literature I gave in an earlier post. The amine is known to be stable, since ephedrine is reduced by HI/red P too.

Other ways to make benzedrine from phenylalaninol usually transform the alcohol to an halide, which is then reduced. But usually the amine needs to be protected for this, adding 2 steps to the sequence. These last steps are unnecessary if HI/red P is used. Lr/

Shaft
Junior Member   posted 09-01-98 12:14 PM
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LR: Thanks for the info. I'll try to post
hypothetical results.