Author Topic: Synthesis of amphetamines  (Read 25135 times)

0 Members and 1 Guest are viewing this topic.

Cyrax

  • Guest
Synthesis of amphetamines
« on: October 02, 2001, 04:05:00 PM »
Fellow bees,

I am working out a general and easy procedure for the synthesis of aryl-2-aminopropanes.  It goes like this:
 Ar-CHO + Et-NO2 --> aryl-2-nitropropene --> aryl-2-nitropropane  --> aryl-2-aminopropane.

I have good refs. for the first 2 reaction steps.  I need a little bit of help for the last step.  First I was thinking about reducing the nitro group with aluminium amalgam.  But in 'Reductions in organic chemistry 2th ed.' Hundlicky says (p 91): "the nitro group on a tertiary carbon is reduced to amines with Al/Hg".  And in JACS (1989), 111, 5902 they did a Al/Hg on a tertiary compound with 100 % yield.  So, what about secundary nitroalkanes???  Can someone help me with this question.

Currently, I am thinking about a catalytic transfer hydrogenation to reduce the nitro, but I have to do some further research.  Has some fellow bee another user friendly method (I mean a method that doesn't require special apparatus like a Parr hydrogenator) to reduce the nitro.

Thx

jim

  • Guest
Re: Synthesis of amphetamines
« Reply #1 on: October 02, 2001, 10:19:00 PM »
This is a well covered topic.  Read Rhodium's Site.  Reduction by Al/Hg works well for the nitroALKANE, but not so well for the nitroalkENE (methinks).  My opinion on the matter is if you are going to have to reduce to the nitroalkane from the nitroalkene you might as well go the whole nine yards and try to go the the amine from the nitroalkene.  I would suggest catalytic hydrogenation.  Try Urushibara nickel catalysts, again read on rhodium's site.

Antibody2

  • Guest
Re: Synthesis of amphetamines
« Reply #2 on: October 03, 2001, 11:41:00 AM »
or check out Sunlights work on the Zn/HCl reduction, very exciting.

"All those memories lost like rain..."

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #3 on: October 04, 2001, 09:24:00 AM »
Thx for the info Jim.

I have 2 excellent refs for the conversion of aryl-2-nitrostyrenes and aryl-2-nitropropenes to the nitroalkanes with NaBH4.  Thus, my proposed reaction path is quite general and can be applied to MANY amphetamines and arylethylamines.  Here they are:

* Tetrahedron Letters (1983), 24, p 227
  This is the best: yields > 90 %

* Synthetic Communications (1985), 15(2), p 151



sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #4 on: October 05, 2001, 05:06:00 PM »
Beaker developed the route nitroalkene->nitroalkane->amine for 2,5 dimethoxy nitrostyrene, wich should work the same for arylnitropropenes, it is a very good work you can see in Rhodium's page under the entry of 2CB "New high yielding synthesis ... without LAH ". The nitrostyrene is reduced with NaBH4 in a ethanol-THF system, the nitroethane isolated and reduced to the amina with Pd/C Am. Formate with excellent yields.
I have a bit of experience with it, although my better global yield was 64 % instead of the 80+% of Beaker. It's obvious that Beaker is a very skilled chemist and he worked in the best conditions. My kitchen and my hands are not the same.
In other hand, THF is not a good thing to have around, is fucking toxic and form peroxydes and homemade Pd/C didn't work, but it worked with a good Pd/C.
It's a very interesting way, but I don't like the NaBH4 with THF, I would like to know the procedure in your references, please post or PM them.
The Zn/HCl system works, but work up is big due the amount of acid and Zn used, so probably it will be a good solution for low dose compounds in the range of domestic amounts, but not for 100 + mg dose, or only if you want to get something anecdotic. We'll see.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #5 on: October 06, 2001, 12:25:00 PM »
In Synthetic communications, they say: "Since the reaction of nitroalkenes with NaBH4 generally produces Michael adducts (especially with nitrostyrene derivatives), we decided to minimize the side reactions by slowly adding NaBH4 to the nitroalkene dissolved in THF-MeOH (10:1, v/v).  The reactions were completed within 40 min. at room temperature (the reaction could be monitored by the disappearance of the yellow color of the nitroalkene."

Yield with phenyl-2-nitrostyrene: 64 %
           phenyl-2-nitropropene: 82 %

In Tetrahedron Letters, they have solved the problem of the side reaction that produces those damned dimeric compounds.  They say: "Reduction of a variety of nitrostyrenes with NaBH4 in the presence of silica gel in a mixture of chloroform and 2-propanol furnished the corresponding nitroalkanes free of dimers in near quantitative yields.  The amount of silica gel required to suppress the formation of dimeric product completely varied but was in the range of 1 - 3 g / mmol of nitrostyrene.
Example: To an efficiently stirred mixture of 2,3-dimethoxyphenyl-2-nitrostyrene (209 mg, 1 mmol), silica gel (2 g, column chromatography grade), 2-propanol (3 ml), chloroform (16 ml) was added NaBH4 (156 mg, 4,1 mmol) in 40 mg portions over a period of 15 min at 25 °C.  The mixture was stirred for additional 15 min, by which time the yellow color due to the nitrostyrene has completely disappeard.  Excess NaBH4 was decomposed with dilute HCl and the mixture was filtered.  The filter was washed with CH2Cl2 and the combined filtrates were washed with brine, dried (Na2SO4) and then evaporated in vacuo to dryness to give 199 mg (94%) of the nitroethane as a colorless oil.
Purity: 1 spot on TLC."

If you do this with P2NP, use 1 g silica gel / mmol nitropropene.  Reaction time: 45 min, yield: 93 %

In comparison with Beaker's procedure: the described method has 2 advantages. 1) It uses 2 eq. NaBH4 instead of 4.  2) There is no dimer formation.  Therefore, if this procedure can be scaled up, and if you combine this with Beaker's CTH reaction, you will have a kickass reaction path.

Could someone test and scale up this procedure with 2,5-dimethoxynitrostyrene of P2NP?  For the moment, I am just a damned theoretical organic chemist  :(

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #6 on: October 06, 2001, 08:10:00 PM »
The second one is very interesting, and something similar was posted in the Hive, but the problem, what seems a usual thing, is the huge amounts of solvents, 16 liters of chloroform per mol. Ff it could be solved it would be a fantastic way. Thank you.
I think with the Zn HCl we could get at least a 60 %, but with big volumes of solvents, it seems that for good yields, the rxn needs big excess of Zn, so a big amount of alkaline solution to extract.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #7 on: October 07, 2001, 03:13:00 AM »
You are right.  The problem for large scale reactions is the big amount of chloroform.  Therefore I suggest that if some friendly bee tries to scale up the reaction, that he / she gives it a try with less of the chloroform - propanol solvent system.

In the article they do the reaction with
phenyl-2-nitrostyrene;1,5 g silica gel / mmol nitro; Reaction time: 25 min; yield: 93 %
phenyl-2-nitropropene; 1 g / mmol; 45 min.; 93 %
2-methoxyphenyl-2-nitrostyrene; 1 g / mmol; 50 min.; 92 %
4-methoxyphenyl-2-nitrostyrene; 3 g / mmol; 25 min.; 94 %
2,3-dimethoxyphenyl-2-nitrostyrene; 2 g / mmol; 30 min.; 94 %
4,5-dimethoxyphenyl-2-nitrostyrene; 3 g / mmol; 30 min.; 92 %
3,5-dimethoxyphenyl-2-nitrostyrene; 2 g / mmol; 15 min.; 90 %
3,4,5-trimethoxyphenyl-2-nitrostyrene; 2 g / mmol; 35 min.; 94 %
2,4,5-trimethoxyphenyl-2-nitrostyrene; 2,5 g / mmol; 40 min.; 94 %

So, I dare say that the reaction is quite general  :)

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #8 on: October 07, 2001, 09:30:00 AM »
In retrospect, I don't think that my method is good for large scale productions (chemically and economically speaking.  If you want to make a few 100 g of amphetamines, you 'd better convert the phenyl-2-nitropropene into phenylacetone.  A good way to convert benzaldehyde into P2P without isolating the P2NP is outlined in

Patent US2557051

(1951). However, you will need better lab equipment & skills.

But hey, if you are a kitchen chemist and if you want to be original, you can further explore the route of Beaker with my little improvement.  Remember: if you make 1 g of 2C-B, you still can do 50 trips.

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #9 on: October 07, 2001, 10:41:00 AM »
I'll do it, sure. I'm not interested in 50 doses, more in 500, if not you are always working in the lab, alone and breathing toxic fumes and with a lot of things in your head you can't share with the people . It's better to work time to time.
An optimization of the chloroform IPA silica gel system could be the way to make mescaline and MDA in moderate amounts.

KrZ

  • Guest
Re: Synthesis of amphetamines
« Reply #10 on: October 07, 2001, 11:43:00 PM »
Check out

Patent GB360266

.  They have some interesting tidbits in there, quite neat, although the batards didn't give yields.

Edit: Full text available in

Post 481878

(Aurelius: "GB 360266  trialkoxyphenethylamines", Methods Discourse)

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #11 on: October 09, 2001, 09:14:00 AM »
About the NaBH4, I believe that heating a bit the solvent, say 40 C, it could dissolve more product and economize volumes and solvents. This is something I am thinking about some months, and it's waiting for an appropiate moment.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #12 on: October 09, 2001, 03:11:00 PM »
Experimentation is the only way to master organic chemistry. But a little warning: chloroform is toxic for your precious liver, so don't inhale the vapors. I think it is also a carcinogen: watch out!!!

Now, I am totally convinced that the best way for a kitchen chemist to reduce the nitroalkane to the amine is catalytic transfer hydrogenation.  It will work for primary nitroalkanes (see Beaker) and for secundary nitroalkanes (see Tetrahedron Letters, 1988, vol 29, p 5733-5734).  For example, they do a CTH on phenyl-1-hydroxy-2-nitropropane.

They say: "A typical procedure is as follows.  To a solution of phenyl-1-hydroxy-2-nitrobutane (0,219 g; 1,1 mmol) is THF and MeOH (50:50, 10 mL) was added 10 % Pd on C (50 mg) followed by ammonium formate (0,35 g; 5 eq.).  The mixture was stirred at room temperature until all the starting nitro alcohol had been consumed (TLC).  The mixture was diluted with Et20 (100 mL), filtered and the filtrate was evaporated in vacuo to yield the crude amine.  Flash column chromatography (SiO2, methanol chloroform, 2:98 v/v) gave the amine (0,16 g; 87 %).

Personally, I dislike flash chromatography because it is tedious.  If you do the reduction on a larger scale, you can do a crystallisation: that sounds better.

If you want to increase the buzz for buck ratio, why not making DOB with this method: 1 g = 500 trips.

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #13 on: October 11, 2001, 03:03:00 PM »
I agree with you about the NaBH4 and Am Formate Pd/C method, it seems the best for medium amounts of product or for high dose compounds like mescaline. For low dose, the Zn reduction seems much more workable at home. In both cases we have to find a shorcut that minimizes the use of solvents.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #14 on: October 12, 2001, 03:39:00 PM »
I can be mistaking, but I thought that they used the Zn HCl reduction usually for the reduction of nitro groups on benzene rings.  Can you please type in your kitchen procedure for the reduction of aliphatic nitro compounds.  I am VERY, VERY interested.

Thx

Rhodium

  • Guest
Re: Synthesis of amphetamines
« Reply #15 on: October 12, 2001, 03:44:00 PM »
Cyrax: See the recent Zn/Hcl threads in the novel discourse, where this is discussed in detail.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #16 on: October 13, 2001, 06:05:00 AM »
Sunlight, you are the best !!!

I have read your Zn / HCl reduction and I have to say that your procedure is certainly more user friendly.

Great work  ;)

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #17 on: October 14, 2001, 08:46:00 AM »
I'm trying to find something more efficient in order to use less Zn and less HCl to don't have a work up with big extractions and lots of solvent for llttel product. It is not so easy as I though first. Anyway ther's not doubt that the rxn works, I've done it with work up four times and without much more, and always I've seen the evident rdxn of nitrostyrene, and always the workup yielded tha amine. No doubts, dead dure, its indredible.

Cyrax

  • Guest
Re: Synthesis of amphetamines
« Reply #18 on: October 17, 2001, 09:15:00 AM »
Now I am looking into the possibility to follow a completely different reaction path with approximately the same reagents.

First we do a catalytic transfer hydrogenation in MeOH / THF to convert P2NP into phenyl-2-oximopropane (yield 94 %).  There are other methods, but the CTH ref. uses P2NP.
Then we reduce the oxime to the amine.  You can use Na in EtOH or NiCl2/NaBH4 (yield > 90 %) or hell, why not try the Zn/HCl reaction of Sunlight.  The oxime should reduce more easily than the nitropropene.

Q: Is the oxime of P2P stable?  If it is, this is probably an interesting route.

I 'll check out the refs.

sunlight

  • Guest
Re: Synthesis of amphetamines
« Reply #19 on: October 18, 2001, 12:24:00 PM »
Cyrax, if the nitrostyrene is converted to the oxime and then we use NiCl2 NaBH4 it can be very very interesting. The Ni2B is easily filtered. In 2 tests, direct reduction of the nitrostyrene with NiCl2/NaBH4 yielded a 20 %, if you are sure about the 2 rxn (the references ...) it can be a good way having all the chemicals.