Author Topic: Synthesis of amphetamines  (Read 24929 times)

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Cyrax

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Re: Synthesis of amphetamines
« Reply #20 on: October 19, 2001, 11:10:00 AM »
I have a lot of refs. for my precious reaction path

Convertion of alpha nitro alkenes to the oxime can be done with:
 * a CTH (yield: 94 % phenyl-2-oximopropane)
 Synth. Commun. (1990), 20, p 2453
 * sodium hypophosphite
 JOC (1989), 54, p 3211
 Synth. Commun. (1986), 16, p 91
 * Pb-AcOH-DMF
 Synlett (1990) p 477

NiCl2 / NaBH4 reduces 1-phenyl-3-oximo-1-butene to
1-phenyl-3-aminobutane in a 95 % yield.  Of course, it also reduces oximes if there isn't a double bond, so it should work fine for the oxime of P2P.
ref.: Chemische Berichte (1984), 117, p 856

Oximes are also reduced with Na/Hg, Na2S2O4, Na-EtOH, Al/Hg, Zn, Zn-Cu.

If you are interested, I'll give those refs another time.

I have to check out those refs myself, but I think the CTH has great potential combined with the Na-EtOH or with the NiCl2/NaBH4 reduction of the oxime. The sodium dithionite reduction looks nice (if the yields are good)

sunlight

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Re: Synthesis of amphetamines
« Reply #21 on: October 19, 2001, 05:15:00 PM »
I'm interested, yes.
In a second lecture of the path, we would use MeOH/THF, am. formate and Pd/C and then NaBH4 and NiCl2, versus the ethanol/THF and NaBH4 and am. formate and Pd/C (no NiCl2). I think is more interesting the silica NaBH4 (I hate THF) and then the CTH. But this seems still interesting.

Cyrax

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Re: Synthesis of amphetamines
« Reply #22 on: October 20, 2001, 01:53:00 AM »
I have ordered the CTH ref. with that gives the 94 % yield for the oxime of P2P.  They don't have Synth. Commun. in the library  :( .  As soon as I get my hands on the ref., I will post the procedure.

Yesterday, I wanted to look up the NiCl2/NaBH4 procedure, but they have the Chem. Ber. until 1981   >:( .  What a disappointment.  Another thing I should order.

When you get the procedures, Sunlight, could you test them so we can make sure that the procedure works in a kitchen and not only in a lab.  I 'll keep searching for easy procedures for this reaction path, it seems indeed very interesting (but it may take a while, I have a lot of other work).  We could form a great team!

Rhodium

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Re: Synthesis of amphetamines
« Reply #23 on: October 20, 2001, 07:26:00 AM »
I know that oximes can be reduced to amines with ammonium formate CTH, and if the above article says that nitroalkenes can be reduced to oximes with a CTH, then I see no reason why nitroalkenes cannot be reduced all the way to amines with a CTH in one pot.

sunlight

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Re: Synthesis of amphetamines
« Reply #24 on: October 20, 2001, 08:29:00 AM »
All procedures that work in a lab work in a kitchen, but I wouldn't make Grignard reagents or things that are hazardous if not in absolute anhydrous conditions. LAH can be used. I've done CTH and NiCl2/NaBH4 at home, Beaker procedure yielded 65 % instead of 80%+, and NiCL2/NaBH4 directly with 25DMNS 20 % of amine. There are not big differences beween a lab and a kitchen if you have the minimum glassware, reagents, solvents and a hot plate stirrer. There are a lot of things in a labe that are not strictly necessary.
My main problem is that I've not air conditioned system, and I live in a humid and hot place, so anhydrous conditions are possible some days, but not usually. Other things I've observed is that the IudexK procedure for condensation of aldehydes with nitromethane yield less in summer than in winter, it seems that this rxn works better < 20 C.
You have the kitchen fume hood and if you need more, you can apply some plastics to it to make a similar lab fume hood. And some inventions are useful, a 1 or 2 or more liters sep funnel can be made with a glass bottle and a two hole rubber stopper, you put a glass tube from the out of stopper to near bottom of the bottle, and the other from out till the end of stopper, the end of tubes are joined to small pieces of rubber tube that are close with a crocodile, so you can put the solution and solvent, a current rubber stopper, shake and then substitute the stopper for the two hole, invert the bottle, open the vent tube, let separate the layers and open the exit tube to recover what you want. Separation is not completely good, but is enough for washes, and the definitive separation is made decanting over a 250 cc sep funnel. Sorry for my horrible english.
When we talk about kitchen chemistry we are more talking about easy procedures with common chemicals and generic glassware and better with OTC solventes or even reagents, and doesn't need complicated conditions as pressure, anhydrous etc ... So I understand kitchen chemistry like rxns like are almost the same to cook your dinner. You cook for after dinner.
Post the references, I'll probably try it or if not me other bee. I want to explore now more things with Zn, it seems practically the best procedure in the field of kitchen chemistry and modest amounts. It could make accessible for home a lot of active and interesting compounds you could not make if not with NaBH4, LAH ...
I've had n idea that could resolve the question of solvents in your CHCl3 IPA NaBH4 rdxn (something similar was posted by KrZ), use the same amount of solvents and reagents, and after 30 minutes make another adition, and so on. Theoretically it will work the same, saving solvents. See this and compare with your reference and with my idea:
Sodium borohydride (2.8 g) was added portionwise over 10 minutes to a stirred suspension of the nitrostyrene (b.1) (5.6 g) and silica gel (Fluka 60) (28 g) in chloroform (200
ml) and isopropanol (50 ml). The suspension was stirred at 20.degree. for 16 hours. The silica gel was removed by filtration and the solvent evaporated to dryness to give the
intermediate nitroethane as a pale yellow oil.

The rxn works in a suspension too, so why not add more reagents after first batch ?
You are a promising bee.

Cyrax

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Re: Synthesis of amphetamines
« Reply #25 on: October 22, 2001, 11:54:00 AM »
Rhodium, I was also dreaming about a one pot reaction but I think it is too good to be true.  I haven't found any ref. about a CTH on the oxime (and I searched hard).

What I found in JOC (1989), 54, p. 3213-3215 is this:
 In the article, they did a CTH on a nitropropene that is attatched to a imidazole ring (whatever) with NaH2PO2 as hydrogen donor.  They got the oxime (83 % yield) and the target molecule was the amine.  So they had to do a Parr hydrogenation on 10 g of the oxime with 5 !!! g of 10 % Pd / C and this during 20 h at 50 °C with 50 psi H2 pressure. 
And the yield was only 70 %.  What a crappy yield for a Parr hydrogenation and what a waste of so much Pd / C.
It seems that the oxime is hard to reduce.  If you have a good procedure for the CTH of the oxime, I am very interested.

sunlight

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Re: Synthesis of amphetamines
« Reply #26 on: October 23, 2001, 01:56:00 PM »
There are two supposedly good procedures that works, this is one and the other, posted by dreamer too, is a direct CTH rdxn with Pd/C, am. formate and acetic and solvent. I've tried both with 2,5 DMNS and didn't work at all.
Acording with your reference, the CTH rdxn produces the oxime, no amine. I didn't see the amine anyway.
I tried the direct Pd/C NaBH4 rdxn, and probably my best design was to make the first Beaker NaBH4 rdxn to the nitroalkene, and then Pd/C was added, and more NaBH4. Just tar. I can't say they don't work as an absolute truth, it didn't work for me, and I use to get something when a rxn works even a little, even a 5 %.
May be they work with nitropropenes (as dreamer posted) and not with nitrostyrenes.
There's another rdxn I tried, Pd/C and NaBH4 in THF, that reduces the nitroalkanes, and got nothing.
May be silica gel could aid...

Rhodium

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Re: Synthesis of amphetamines
« Reply #27 on: October 23, 2001, 02:00:00 PM »
Nitropropenes are much less prone to dimerization under basic conditions than nitrostyrenes. I guess there is where the catch is.

Cyrax

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Re: Synthesis of amphetamines
« Reply #28 on: October 24, 2001, 05:11:00 AM »
I am convinced that you will not have problems with the silica gel, in the article they are very proud that they got nitroalkanes FREE OF DIMERS in near quantitative yield.  You should try it.

Rhodium, the problem with doing a NaBH4 reduction on the oxime in one pot  (thus after the CTH) is that NaBH4 will react with the ammonium formate.  This will give a lot of H2.  I guess that we will have to crystallize the oxime and  then do the NaBH4 - Pd/C reduction or the NaBH4 - NiCl2 reduction.

I am still waiting on the article I ordered.  Then things will become clearer.

sunlight

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Re: Synthesis of amphetamines
« Reply #29 on: October 24, 2001, 09:44:00 AM »
I've tried once more time a direct rdxn of 2,5 DMNS with NaBH4 and Pd/C, still fresh:
To 50 ml of IPA where added 10 grams of silica gel without indicator powdered with a coffee grinder, 3 grams of NaBH4 and then 150 mg. of Pd/C (best stuff), and immediatly started to drop 3 grams of 2,5 DMNS dissolved in 30 ml of DCM. The rxn flask was in a water bath, and temp was controlled around 25 C, addition time 1 hour. 12 hours later where added 50 cc of 15% HCl, pH very acidic, filtered, filter washed with water and DCM, more water was added to allow the DCM go to bottom, DCM wash separated and backextracted with 2x20 ml of water. Then the acidic solution was basified with NaOH 25 %, IPA removed with the aspirator. There was not amine on top and no amine smell.
The basic solution (125 ml) extracted with 3x15 ml of toluene. Toluene was wahed with 25 % NaOH and then with brine. pH of toluene was not basic. Addition of a bit of H2SO4 in IPA (very familiar procedure that works fine) gave nothing. 0 %.
The idea was to make a one pot rxn, making the nitroethane with the NaBH4/silica and reducing the nitroethane to the amine with NaBH4 and Pd/C. The rxn was slightly effervescent and the addition of the nitro produced a bit of foam, so it was done slowly. Excess of H2 was 3:1.
Silica gel was not of chromatography, and chloroform was substituted with DCM, but if it works with good silica and chloroform it should work may be less with this test. I have had to get something, a 5 or 10 %, whatever.
I've tried the same with THF and ethanol without silica and other variations, several times, and no one worked at all. I won't waste my time and reagents with this way anymore.

What seems to work fine is the nitrostyrene nitroethane rdxn, color disappear almost immediatly when a drop goes to the silica/IPA/NaBH4 solution, and it could be a good way to reduce solvents. It's more or less Beaker's procedure, but with DCM or chloroform instead of THF, and IPA instead of ethanol, these chemicals are more friendly and easier to get. We'll try it and we'll check the TLC having made first your reference procedure, and if it works as it seems, isolating the nitroethane we'll be easier than with Beaker's and then a CTH ... It sounds perfect. But slowly, we don't have all the time for it.
For me this can be the perfect way to process things like 3,4,5 TMNS, and the Zn rdxn for modest aspirations.

Cyrax

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Re: Synthesis of amphetamines
« Reply #30 on: October 25, 2001, 10:09:00 AM »
In Synthetic Communications (1990), vol 20, p 2453 we find a method to convert aryl-2-nitropropenes to
aryl-2-oximopropanes.

The reaction does NOT work for aryl-2-nitrostyrenes because it yields a complex mixture of products.  And there is a side reaction, they say: 'Ketone formation was observed as a side reaction presumably involving hydrogenolysis of the ketoxime to an imine followed by hydrolysis to the corresponding ketone.'

Now the good news: the yields are quite good!
* P2NP --> phenyl-2-oximopropane
 reaction time: 0,33 h.
 yield: 94 %
* 3,4-dimethoxyphenyl-2-nitropropene
        --> 3,4-dimethoxyphenyl-2-oximopropane
 reaction time: 0,50 h.
 yield: 86 %

This is the general procedure:
 "Dry ammonium formate (315 mg; 5 mmol) was added to a solution of nitroalkene (1 mmol) in a mixture of THF and MeOH (8 ml, 1:1, v:v).  5 % Palladium on carbon (236 mg, 10 mole-% Pd) was added to the solution, and the resulting mixture stirred at rt. until all the starting material had been consumed (TLC).  The catalyst was removed by filtration and washed with DCM (10 ml) followed by absolute EtOH (10 ml).  The solvent was removed under reduced pressure and the residue was washed with H20 (10 ml) and the product sas extracted into DCM (2 x 20 ml).  The crude product was purified by chromatography on a silica gel column using DCM to elute the ketone and absolute EtOH to elute the oxime."

You can not do a one pot reaction (reduction of the oxime using NaBH4 / Pd-C) because of the ammonium formate.

I read 'High yielding synthesis of MDA using MDP2P by Sonson' on Rhodium's site where they crystallize the oxime.

In retrospect, I think that is a better idea to reduce the double bond of P2NP with NaBH4 and to do afterwards a CTH on the nitro.  Do you agree?

Cyrax

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Re: Synthesis of amphetamines
« Reply #31 on: October 25, 2001, 01:49:00 PM »
I 'll try to explain why the reduction of nitrostyrenes with NaBH4 in the presence of silica gel in a mixture of CHCl3 and Isopropanol will work.

Nitrostyrenes are prone to form dimers.  WHY???  Well, when a hydride ion attacks the beta carbon of a nitrostyrene molecule, it will generate a resonance stabilized alpha carbanion.  This carbanion (the Michael donor) will attack the beta carbon of another nitrostyrene (the Michael acceptor), forming the damned dimer.

If we do the reaction in the presence of a NONPOLAR aprotic solvent (CHCl3) and a insoluble protic phase (the silica gel), the POLAR carbanion will not go in solution but it will be formed on the POLAR silica surface and consequently will accept a proton to give the nitroalkane before it has a chance to act as a Michael donor.

Trust me and do not use DCM instead of CHCl3: CHCl3 - isopropanol is the most effective to prevent dimer formation.

If you want to read a good article before going to bed, check out the ref.  IT IS THE BEST and it will explain the hole problem clearer than I can.

sunlight

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Re: Synthesis of amphetamines
« Reply #32 on: October 25, 2001, 05:28:00 PM »
I trust you about the CHCl3, and yes, I agree with you about the NaBH4 and then CTH. And chloroform/IPA with silica seems more attractive than THF.
Thanks for your explanations. It makes me think that dripping the nitrostyrene in CH3Cl3 in an IPA/silica/NaBH4 suspension could not work the same that having all in the system.
My test was not about this topic, was about a direct rdxn nitrostyrene - amine with NaBH4 and Pd/C that sometimes I've heard it's possible, and may be it is, but I've not found the way. As this post is almost a conversation between us, we may use PM for more details, questions and designing procedures.

Cyrax

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Re: Synthesis of amphetamines
« Reply #33 on: October 27, 2001, 03:24:00 AM »
Sunlight, I have found a nice article in Synthesis (1987), p 713.  It goes about the reduction of aliphatic and aromatic nitro compounds with NaBH4 in THF using 10 % Pd on C as catalyst.

First you have to reduce the double bound and then you should reduce the nitro (I think it is best if you don't do the 2 reactions in one step).  The yield  (70 - 90 %)is not as good as a CTH reaction .

They did the reaction on para-methylphenyl-2-nitroethane. Yield: 75 %, reaction time: 50 min.

Procedure:
 "A 100 ml two-necked flask equipped with reflux condenser and stirrer is charged with the nitro compound (10 mmol) in THF (40 ml).  The solution is cooled by an ice bath and 10 % Pd on C (0,4 g) is added.  NaBH4 (25 mmol) is then added in three portions over 10 min., the ice bath is removed, and stirring is continued at room temp. for 20 - 30 min.  Excess NaBH4 is decomposed with 2 normal HCl (till pH = 6) and Et20 (70 ml) is added.  The solid is filtered off and the filtrate is washed with H20 (2 x 15 ml) and dried (MgSO4).  The solvent is evaporated to give pure amine."

Osmium

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Re: Synthesis of amphetamines
« Reply #34 on: October 27, 2001, 05:38:00 PM »
That yield sucks. Al/Hg (and many other reagents) will give much better yields.

Cyrax

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Re: Synthesis of amphetamines
« Reply #35 on: October 28, 2001, 04:35:00 AM »
Osmium, do you have refferences for the Al/Hg reduction of primary or secundary nitroalkanes.  I did a litterature research and found only procedures for tertiary nitroalkanes and nitrobenzenes.  So, my question is: What is the problem for primary or secundary nitroalkanes?

Thx

sunlight

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Re: Synthesis of amphetamines
« Reply #36 on: October 28, 2001, 04:39:00 AM »
Of course, if you make the two rxns separatedly, probably it works. I knew this reference. But if you have to isolate the nitroalkane, then it's better and cheaper to make a CTH. The only sense of trying to reduce everything with NaBH4 and Pd/C is to have a one pot rxn, clean, easy, fast and with good yields. But I'm convinced now that there's no way. I think I got a 2 % yield with methanol versus a 20 % (two times) with NiCl2, and 0 % in the other tests (direct rdxns) with THF ethanol, silica and THF ethanol, silica , IPA and chlrorform... something like that. May be it works in certain conditions, but I believe I have enough experience and success to have so many fiascos if the rxn yields something, whatever.
For me or Zn or NaBH4 and Pd/C, it's the best I've seen.

Cyrax

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Re: Synthesis of amphetamines
« Reply #37 on: November 29, 2001, 09:59:00 AM »
I checked out the Synlett (1990) p 477 ref. and found something nice.  It is a method to reduce nitroalkenes by means of lead powder in an acetic acid - DMF solvent to give the corresponding aldoximes and ketoximes in high yields.

You can do the reaction with:
 * arylnitrostyrenes, reaction time: 0.5 h, yield: 94 %
 * arylnitropropenes, reaction time: 2h, yield 92 %

Standard procedure:
 "A nitroalkene (0.1 mol) was dissolved in a mixture of acetic acid (5 mL) and DMF (75 mL), and lead powder (2 eq.) was added.  The mixture was stirred at ambient temperature for a period given in the table.  The mixture was poured into ice-water, and extractedd with Et2O.  The ether solution was washed successively with an aq. NaHCO3 solution and an aq. NaCl solution, and then dried over MgSO4.  The solvent was evaporated off and the resultant crude oxime was purified by chromatography (silica gel / DCM)."

If you dislike chromatography, I found in Chem. Ber. (1981) 114;12 p 3813 - 3830 that you can crystallize phenyl-2-oximopropane in hexane.

I was thinking about reducing the oxime with a Na / EtOH reducing system.  However, some friendly bee told me that on the hive there is a post where they do the reduction in n-propyl alcohol or n-butyl alcohol, and that it requires then only one eq. of oxime to do the reduction in a 90 % yield.

Can someone help me to find this post?  Thx.

Rhodium

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Re: Synthesis of amphetamines
« Reply #38 on: November 29, 2001, 12:05:00 PM »
Are you thin king about the post that turned into this document:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdaoxime.html


Cyrax

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Re: Synthesis of amphetamines
« Reply #39 on: November 30, 2001, 03:44:00 AM »
Because I think that absolute EtOH is more expensive than n-BuOH, I was wondering if the reaction in n-BuOH gave the same good results.  But after doing some research, I have to say that the procedure with Na in EtOH is better.  I found this in the Journal of the American Society (1934) vol. 56 p 487 about the reduction of methyl alkyl ketoximes with sodium and n-butyl alcohol:

* the yields are only 69 - 86 %

* they use SEVEN (!) eq. of Na

* I think that there can be some problem with the reaction workup because you have to distill a water / n-BuOH / amphetamine mixture.  Is this a steam distillation?  Is the bp. of amphetamine sufficiently low to distill over?

For general information, I will give the procedure, so you can see what I am talking about.

Procedure: "A solution of 1 mole of oxime in 2300 mL of n-BuOH in a 5 liter two-necked flask fitted with a 2,5x100 cm Pyrex condenser was heated to boiling and 161 g. (7 moles) of sodium added in 10-20 g. pieces at short intervals through the large neck of the flask.  This required 15 minutes.  After the reacdtion had moderated the mixture was refluxed until practically all of the sodium had dissolved.  The reaction mixture was allowed to cool, 1.5 liters of water added and the mixture distilled to remove the amine and alcohol.  More water was added as necessary.  The distillate was made slightly acidic with HCl and distilled to a volume of 300 ml., 500 ml of water added and distillation continued until no more alcohol came over.  The water solution of amine HCl was saturated with NaOH, the uper layer of amine separated and further dried over NaOH and then over Na.  The amine was now distilled from sodium in a 250 ml special Claisen flask.

I am disappointed because the workup is troublesome and they use 7 eq. of sodium.  So I reject the idea of doing the reaction in n-BuOH.  Rhodium, you are right, let's stick to the Na / EtOH reduction