(----)Amphetamine from (N-Formyl)phenylalanine?

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Topic:   (----)Amphetamine from (N-Formyl)phenylalanine?

Labrat
Member
posted 05-13-98 06:51 AM
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This certainly has crossed the minds of crank-chemists not unlike myself. In my opinion, this is great and clean way to get to speed from a simple amino acid. First, read these refs:
TL 33:5517('92)[reduction of amino acids to amino alcohols by NaBH4-H2SO4]
JOC 58:3568('93)[reduction of amino acids to amino alcohols by NaBH4-I2]

Personally I like the first method (NaBH4-H2SO4) better then the second, since I2 is rather expensive, certainly compaired to H2SO4. I've also read something about borane-I2 complexes splitting ethers, so using H2SO4 is the obvious way to go. With this reductant, phenylalanine can be reduced to the aminoalcohol. This aminoalcohol is NOT the same as phenylpropanolamine(PPA). The hydroxy-group is placed at the 3 position on the isopropylamine chain, not on the 1 position. This means standard procedures for reducing benzyl alcohols as we know them (PPA ->amphetamine, ephedrine ->----) CAN NOT be applied. Benzyl alcohols are reduced a lot easier then these aminoalcohols. Now I have a question back for you: DOES ANYBODY KNOW HOW TO TRANSFORM THIS 2,3-AMINOALCOHOL INTO THE ISOPROPYLAMINE?

Ritter
Member   posted 05-13-98 01:58 PM
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This is just a shot in the dark, but I'm guessing that if the -OH is halogenated (Thionly Chloride, Phosphorous Oxychloride, Phosphorous pentachloride, Phosphorous tribromide or trichloride, ZnCl2+37%HCl, etc....) it can be removed w/ a NaBH4 reduction.... Before you flame me and say that NaBH4 wont do the trick, I recently read that it will indeed remove a halogen when used in combination w/ the proper catalyst. Don't quote me yet as I have no refs at hand but I believe NiCl2 may do the trick... Will look it up later and report back. Catalytic hydrogenation will easily remove the halogen but I'm guessing thats out of the realm of most bees.
.

Osmium
Member   posted 05-14-98 01:50 AM
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Another shot in the dark: grignard and hydrolysis.

Labrat
Member   posted 05-14-98 09:43 AM
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Thankx, Ritter, you've made me think again and then I remembered something. Good dr. Shulgin made DOB and 2C-B by simply pouring some Br2 over 2,5-dimethoxyamphetamine or 2C-H dissolved in acetic acid. I guess the amino-group can take the terror of the halogen and so the -OH group of the aminoalcohol can indeed be replaced by a halogen. Then a reductive dehalogenation will make from the halogen and H-atom and we'll have speed from phenylalanine!!! In my opinion a Grignard is not such a good idea, Os. I'm not sure (ask RatHead, he seems to be the expert), but I think the Grignard is not compatible with a hydroxyl- or an aminogroup.
Oh, I'm so curious if it really works...

Labrat
Member   posted 05-14-98 09:44 AM
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Thankx, Ritter, you've made me think again and then I remembered something. Good dr. Shulgin made DOB and 2C-B by simply pouring some Br2 over 2,5-dimethoxyamphetamine or 2C-H dissolved in acetic acid. I guess the amino-group can take the terror of the halogen and so the -OH group of the aminoalcohol can indeed be replaced by a halogen. Then a reductive dehalogenation will make from the halogen and H-atom and we'll have speed from phenylalanine!!! In my opinion a Grignard is not such a good idea, Os. I'm not sure (ask RatHead, he seems to be the expert), but I think the Grignard is not compatible with a hydroxyl- or an aminogroup.
Oh, I'm so curious if it really works...

Osmium
Member   posted 05-14-98 10:22 AM
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I meant convert the OH into Br, and then Grignard reduction to H. Don't think that amines interfere in Grignards (or am I wrong here?). Benzylic H does interfere, because it's too acidic.

Labrat
Member   posted 05-15-98 06:28 AM
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I know how to make a Grignard reagent, so I did understand what you said. Only I thought that Grignard reagents were incompatible with alcohols and amines. It's probably not the best way either with that rigourous drying and all that shit, I really hate that!!! Why can't all reactions be catalysed by water?
Anyway, I think reacting the 2,3-aminoalcohol with POCL3/SOCL2 and then a simple Al/Hg reduction to replace the -Cl with a -H would do the trick. I wonder if POCL3/SOCL2 will react with the -NH2 to produce a chloramine... Hell, that'll probably get reduced in the next step. Damn, now I'm first gonna check the Netfire on this!

Labrat
Member   posted 05-15-98 06:43 AM
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I think I found something on the reduction of aminoalcohols. It seems Na/EtOH can be used to effect the transformation. The refs:
Tetrahedron 46:6859-6868('90)
Arch. Pharm. 326:171-180('89)

Labrat
Member   posted 05-15-98 06:43 AM
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I think I found something on the reduction of aminoalcohols. It seems Na/EtOH can be used to effect the transformation. The refs:
Tetrahedron 46:6859-6868('90)
Arch. Pharm. 326:171-180('89)

Ritter
Member   posted 05-15-98 08:48 AM
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Don't worry about the chlorinating agents making chloroamines or any funky shit like that.. What will happen is the amine group will suck up the molecule of acid liberated to make the salt of the amine. If SOCl2 is used, I believe some hydrochloric acid along w/ some sort of sulfuric acid will be produced in the main reaction and be scavanged by the -NH2 group floating around on your aminoalcohol. Some pyridine, triethylamine, random tertiary amine can be included in the reaction to scavange the free acid and the product of this will be a water soluble salt of the amine(tertiary halogen scavenger) which is easily removed from product w/ a simple water wash. If you dream about any ideas like this, please post them!!!!! BTW have you ever seen that german paper which converts D-phenylalanine into amphetamine? I believe its cited in the Merck under amphetamine. Uses all kinds of hydrides and shit so its pretty much useless (well in this realm of honey suckers anyway!)
Hope this helps.
Later,
Ritter

Rhodium
Administrator   posted 05-15-98 10:35 AM
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Na/EtOH is always used when reducing something with Na - would Na in IPA or MeOH work, they are much easier to find anhydrous.

Labrat
Member   posted 05-18-98 09:31 AM
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Ritter: thanx for the right answer. This is what I wanted to know. When the SOCl2 reacts with an -OH group, HCL will be freed, which indeed will be neutralized by the -NH2 group.
No sulfuric acid is produced, only SO2 is liberated (which could react with water to form H2SO3). I think no extra amine is necessary, cuz most of the SO2 will escape as a gas and the HCl that is formed, can be neutralized by the -NH2 group. Yes, I've seen that German paper. They used LiAlH4 there to reduce the shit. But I think using sodium borohydride to do the reaction is certainly a better way, since it's so easily purchased. You've been a great help, Ritter, don't hesitate to ask a favor back. Lr.
Rhod: sorry man, I've got the ref from the Netfire, searching for REDUCTION and AMINOALCOHOL. I thought I found a reduction to reduce the alcohol group of the aminoalcohol, but no, when I checked the ref it was something completely else. But thanx to Ritter I know the right way: react the aminoalchol with SOCL2, then reductive dehalogenation and voila, perfectly good speed.

ReFlux
Member   posted 05-23-98 02:11 PM
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Labrat, have you thought about sorting out stereoisomerism of the phenylalanine before converting it into amphetamine?
That is if you start with DLPA (DL-Phenylalanine) you end up with DL-amphetamine.
Also, any thoughts on going from amphetamine to -----amphetamine?

ReFlux
Member   posted 05-23-98 02:11 PM
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Labrat, have you thought about sorting out stereoisomerism of the phenylalanine before converting it into amphetamine?
That is if you start with DLPA (DL-Phenylalanine) you end up with DL-amphetamine.
Also, any thoughts on going from amphetamine to -----amphetamine?

Fan of Shulgin
Member   posted 05-24-98 03:03 PM
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If you want to separate the D and L isomers , then all you have to do is esterify the phenylalanine with an optically pure alcohol...hmmn, im trying to think of one.... anyway - I suppose that this wouldnt be practicle for most bees!
There is also chromatography - stuff for this can be bought/made quite easily without raising any suspicions!

Labrat
Member   posted 05-25-98 09:55 AM
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Reflux - I think that if you start with D-phenylalanine you get D----- eventually. The reduction I mentioned is not so harsh that stereochemistry is thwarted. So this is a method to get pure ---- with the right stereochemistry. I told you this was good, didn't I. Going from pep to ---- you said? I think reacting amphetamine with benzaldehyde and some acid to make the Schiff base. Reacting this Schiff base with dimethylsulfate and then hydrolysing to get about 85-90% yield of ----. The original article can be looked up. The author is Woodruff. Hope this helps you.
Fan of Shulgin - it seems to me that buying pure D-phenylalanine is a better way then buying a complete chromatographic column & accessoires to do the separation. Lr/

Lone Ranger
unregistered   posted 05-25-98 11:32 AM
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All of the reductions from cold pills require either -ephedrine or +pseudo, which are also different using the D,L notation system. Yet stereochemistry is preserved in these reductions. It is no simple matter determining which phenylalinine isomer to start with. How a molecule will bend light is immpossible to predict, how it will lay flat on a piece of virtual paper is only extrodinarily difficult to predict! If I were going to dream of this one, I would hedge my bet by buying the other isomer also!

Lone Ranger
unregistered   posted 05-25-98 11:40 AM
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I quess I can save some money now:
"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."

Thanks to P.G.

ReFlux
Member   posted 05-25-98 12:21 PM
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Labrat- Hypothetically speaking, isn't D-phenylalanine hard to come by. I mean that the L-form is sold as a nutritional supliment and occurs naturally, the DL form is also sold as a supplement and is synthesized, but I have not seen just the D form offered from any source, (except obvious science / chem sources i,e fisher, etc.) Do you know what uses D-phenylalanine have?

Fan of Shulgin
Member   posted 05-25-98 02:13 PM
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As I have said in another thread, reacting phenylalanine racemate with an alkaloid such as quinine produces two physically distinct enantiomers (ie mp).

Labrat
Member   posted 05-26-98 10:11 AM
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Lone Ranger: I don't think you can save some money. Have you seen the yields and the reagents they use to come to their final products? I guess overall yield from phenylalanine is 20%. Phenylalanine is relatively not cheap, there are MANY cheaper ---- precursors. There are better ways.
Reflux: I thought natural amino acids are almost always the D-form. Are you really sure L-Phe is the natural form? And if you're gonna make ----, why bother to just get D-----. I think the racemate is potent enough, just a sniff keeps me up all night.
Fan of Shulgin: I know that a racemic mixture can be separated by creating diastereomers with different physical properties. But it's laborious, expensive and no fun to do. I'm just pointing out the easiest way. Lr/

laborat
unregistered   posted 05-26-98 10:31 AM
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Yesterday i'v found a paper with the following info on it.
DL-Phenylalanine and DimethylSulphate(carefull!) stirred for 3 hrs, wash with dH2O, extr. with CH2CL2 evap, and Xtall. Gives ~80 % Benz.

Interrested? someone. Than the story will continuated. Greetings from europe.

ReFlux
Member   posted 05-26-98 01:24 PM
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Labrat- All naturally occuring Amino acids are not in the Dextro form. Phenylalanine occurs as L-Phenylalanine : that's the kind your body needs and uses. Synthetic Phe. is in the raecemic DL form. Hypothetically speaking, D----- is something on an order of magnitude or more (10 to 15X) more potent than its optical isomer L-----. I guess one could leave it in as a sort of cut, but I feel that's sloppy. Also, processing DL form wastes other chems along the way since your processing for twice the yeild of actual D-----. No, hypothetically speaking, I would think that resolution into D-phe before further processing was in order. Also, DLPA is very cheap, and completeley legal and available in EVERY health food store / vitamin store on the planet. This makes it, hypothetically, a very valuable precursor.

Lone Ranger
unregistered   posted 05-26-98 03:14 PM
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In regards to SOCl2, it must be used under anhydrous conditions, so no H2SO4 will be formed. The beauty of this reagant is that the by products (SO2 and HCl) are all gaseous. If anyhdrous conditions are not used, all the SOCl2 reacts with trace water present. It acn halogenate benzl/phenyl rings, but under aggressive conditions. Don't heat it. I like this approach a lot.....

Fan of Shulgin
Member   posted 05-26-98 05:26 PM
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Im not being funny, but I really dont understand what you are trying to say Lone Ranger !
Could you repeat that in a slightly more coherent fashion ?

Peace, Love and Empathy

Fan of Shulgin!

Lone Ranger
unregistered   posted 05-26-98 06:16 PM
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I'll try. SOCl2 + CHCl3, RT, for a couple of hours is a selective way to replace OH with Cl. No solid by-products. It is SN2 and stereochemistry is reversed. High yield intermediate producing method.
Also PBr3, PCl5 - but some solid waste products form with these. Not as nice.

Minereal acid method sucks. Non selective.

I am not addressing what to do with these halo intermediates until I have an equally beautiful way of removing the halogen....But there are ways (Rosenmund, ect)

Was that more or less coherant? I'm not sure

ReFlux
Member   posted 05-26-98 07:45 PM
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Lone- If you add some pyridine to an aqueous soln of SOCl2, the pyridine will absorb the HCl that is formed and most of the SO2 is liberated as a gas. Therefore none of the need for the rigors of anhydrous chemistry!! What are your thoughts on that?

Rhodium
Administrator   posted 05-26-98 08:12 PM
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Laborat: Yes, please continue the DLPA+Me2SO4 story...

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Labrat
Member
posted 08-05-98 10:36 AM

Re:Action of (CH3)2SO4 on phenylalanine

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.