Cyrax (Stranger)
10-02-01 16:05
No 219601
      Synthesis of amphetamines  Bookmark   

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
(Hive Bee)
10-02-01 22:19
No 219721
      Re: Synthesis of amphetamines  Bookmark   

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
(Hive Addict)
10-03-01 11:41
No 219920
      Re: Synthesis of amphetamines  Bookmark   

or check out Sunlights work on the Zn/HCl reduction, very exciting.

"All those memories lost like rain..."
 
 
 
 
    Cyrax
(Stranger)
10-04-01 09:24
No 220270
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-05-01 17:06
No 220778
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-06-01 12:25
No 220956
      Re: Synthesis of amphetamines
(Rated as: excellent)
 Bookmark   

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 frown
 
 
 
 
    sunlight
(Pioneer Researcher)
10-06-01 20:10
No 221101
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-07-01 03:13
No 221214
      Re: Synthesis of amphetamines  Bookmark   

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 smile
 
 
 
 
    Cyrax
(Stranger)
10-07-01 09:30
No 221272
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-07-01 10:41
No 221288
      Re: Synthesis of amphetamines  Bookmark   

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
(Hallucinogenius)
10-07-01 23:43
No 221569
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-09-01 09:14
No 222287
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-09-01 15:11
No 222397
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-11-01 15:03
No 223337
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-12-01 15:39
No 223806
      Re: Synthesis of amphetamines  Bookmark   

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
(Synaptic Cleft Mountaineer)
10-12-01 15:44
No 223808
      Re: Synthesis of amphetamines  Bookmark   

Cyrax: See the recent Zn/Hcl threads in the novel discourse, where this is discussed in detail.
 
 
 
 
    Cyrax
(Stranger)
10-13-01 06:05
No 224008
      Re: Synthesis of amphetamines  Bookmark   

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 wink
 
 
 
 
    sunlight
(Pioneer Researcher)
10-14-01 08:46
No 224410
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-17-01 09:15
No 225823
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-18-01 12:24
No 226344
      Re: Synthesis of amphetamines  Bookmark   

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.
 
 
 
 
    Cyrax
(Stranger)
10-19-01 11:10
No 226820
      Re: Synthesis of amphetamines
(Rated as: good read)
 Bookmark   

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
(Pioneer Researcher)
10-19-01 17:15
No 226966
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-20-01 01:53
No 227107
      Re: Synthesis of amphetamines  Bookmark   

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 frown.  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  mad.  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
(Chief Bee)
10-20-01 07:26
No 227154
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-20-01 08:29
No 227172
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-22-01 11:54
No 227821
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-23-01 13:56
No 228121
      Re: Synthesis of amphetamines  Bookmark   

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
(Chief Bee)
10-23-01 14:00
No 228122
      Re: Synthesis of amphetamines  Bookmark   

Nitropropenes are much less prone to dimerization under basic conditions than nitrostyrenes. I guess there is where the catch is.
 
 
 
 
    Cyrax
(Stranger)
10-24-01 05:11
No 228320
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-24-01 09:44
No 228374
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-25-01 10:09
No 228726
      Re: Synthesis of amphetamines
(Rated as: excellent)
 Bookmark   

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
(Stranger)
10-25-01 13:49
No 228779
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-25-01 17:28
No 228831
      Re: Synthesis of amphetamines  Bookmark   

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
(Stranger)
10-27-01 03:24
No 229263
      Re: Synthesis of amphetamines  Bookmark   

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
(Stoni's sexual toy)
10-27-01 17:38
No 229415
      Re: Synthesis of amphetamines  Bookmark   

That yield sucks. Al/Hg (and many other reagents) will give much better yields.
 
 
 
 
    Cyrax
(Newbee)
10-28-01 04:35
No 229572
      Re: Synthesis of amphetamines  Bookmark   

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
(Pioneer Researcher)
10-28-01 04:39
No 229573
      Re: Synthesis of amphetamines  Bookmark   

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
(Newbee)
11-29-01 09:59
No 242123
      Re: Synthesis of amphetamines
(Rated as: excellent)
 Bookmark   

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
(Chief Bee)
11-29-01 12:05
No 242180
      Re: Synthesis of amphetamines  Bookmark   

Are you thin king about the post that turned into this document: ../rhodium/chemistry /mdaoxime.html
 
 
 
 
    Cyrax
(Newbee)
11-30-01 03:44
No 242476
      Re: Synthesis of amphetamines  Bookmark   

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
 
 
 
 
    Rhodium
(Chief Bee)
11-30-01 06:11
No 242494
      Re: Synthesis of amphetamines  Bookmark   

Try to use propanol if you don't like the idea of using ethanol or butanol. Isopropanol probably reacts too slow with Na.
 
 
 
 
    Cyrax
(Newbee)
11-30-01 14:52
No 242707
      Re: Synthesis of amphetamines  Bookmark   

I have to correct myself: it seems that very pure butanol has the approximately the same price as anhydrous denaturated EtOH.  But there can be some delivery restrictions, even with DENATURATED anhydrous EtOH.  The damned gouvernment thinks that every chemist is going to give a huge cocktail party.

I found another interesting article, and it seems that it is common lab practice to use 10 eq. Na.  Just like in the ref. you gave me, Rhodium.  Now I am convinced that it is the best. 

I found this in JOC (1964) vol 29 p 1419:
"To 1-oximo-2-phenylcyclohexane (52 g, 0.274 mol), dissolved in warm absolute EtOH (500 ml) was  added sodium (63 g, 2.74 mol) little by little and the solution was refluxed for 1 hour.  After cooling, the mixture was acidified with concentrated HCl, whan NaCl precipitated.  After separation of the salt and the solvent, the residue was treated with water and Et2O.  The aqueous solution was made alkaline to yield the crude base which was extracted with Et2O.  The base was then submitted to distillation and a fraction of bp 133 - 136 was collected and solidified on cooling.  On recrystallisation from petroleum ether, trans-1-amino-2-phenylcyclohexane was obtained (39 g, 0.223 mol, 81 %)
 
 
 
 
    Xgoddess
(Stranger)
12-05-01 13:28
No 244566
      Re: Synthesis of amphetamines  Bookmark   

why not just Zn HCL?? that seems much simpler.
 
 
 
 
    Xgoddess
(Stranger)
12-05-01 13:42
No 244569
      Re: Synthesis of amphetamines  Bookmark   

Rhod, or anyone, I was reading a novice's procedure for 1.Mescaline and 2. amphetamine.
For #1...3,4,5-TMB + NO2CH3 were mixed in MeOH with the an equimolar amount of NaOH in H2O and stirred at 25C for thirty minutes. Rxn flooded with H2O, and then poured into acidic solution to form crystals of beta nitro styrene.  This was then reduced with Zn/HCL to give 50% yield of mescaline.  The author did this for amphetamine the exact same way except started with benzaldehyde an NO2Et. Instead of the nitrostyrene, he got a yellow oil, then upon reductin he got nothing.  The author did not specify why this would not work!! And he did not say a way that would work. The author just kept on complaining about how he hated to waste NO2Et bc his grant could barely afford it. Please helplaughsmilewink
 
 
 
 
    Rhodium
(Chief Bee)
12-05-01 15:12
No 244621
      Re: Synthesis of amphetamines  Bookmark   

What is your reference for the NaOH catalyzed nitrostyrene condensation working with benzaldehyde/nitroethane? Different aldehydes wants different catalysts to work really good. In the case of benzaldehyde/nitroethane, butylamine is said to be the best, with ammonium acetate coming on second place.

A working procedure: ../rhodium/chemistry /phenyl-2-nitropropene.html (in the first variation, you can use 10g anhydrous ammonium acetate instead of the amine).
 
 
 
 
    sunlight
(Pioneer Researcher)
12-05-01 21:02
No 244795
      Re: Synthesis of amphetamines  Bookmark   

Could you detail the 3,4,5 nitrostyrene synthesis and the reduction to the amine ? Did he use Zn/Hg or just Zn/HCl ?
 
 
 
 
    Xgoddess
(Stranger)
12-06-01 11:44
No 245008
      Re: Synthesis of amphetamines  Bookmark   

Well Sunlight, since it was your procedure, I guess I can detail it...basically, just like you said w/out isopropyl (that part just made no sense to me). anyways, thanks for the great procedure. Will the Zn/HCl redn work for the nitrostyrene for benzaldehyde and NO2Et???? Rho, do you know??
 
 
 
 
    Xgoddess
(Stranger)
12-06-01 11:51
No 245009
      Re: Synthesis of amphetamines  Bookmark   

Rho, the experiemnter never saw a procedure using NaOH. But in this rxn, all that happens is that a base removes an alpha proton from the NO2 alkane to form the "enol-type" (without the OL) molecule. Once that is formed, why would it not attack the aldehyde and dehydrate to from the nitro-styrene. Also, the yellow oil that was got after the first rxn, what do you think that was? The author said it smelled a lot like benzaldehyde still. And finally, any problem with a Zn / HCL redn of the intermediate? Thanks for all your help!!laugh
 
 
 
 
    sunlight
(Pioneer Researcher)
12-06-01 13:31
No 245049
      Re: Synthesis of amphetamines  Bookmark   

God, someone reduced 3,4,5 TMNS with Zn/HCl before me ? it was my next test...
Anyway if it is a very good new, do you confirm is has been done with success ?
I would like to know the recipe for the nitrostyrene synthesis, it seems much easier than the others with cyclohexylamine...
The alcohol is used to avoid foaming.
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 13:34
No 245051
      Re: Synthesis of amphetamines  Bookmark   

Yes, the reaction mechanism calls for just any base to do the job, but in reality both which catalyst to use, and the amount of catalyst used is VERY important to get a good yield (or any yield at all). Check the table in ../rhodium/chemistry /edda.html for various yields with different benzaldehydes and exactly the same reaction conditions - the yields fluctuate wildly between 3% and 96%.

The oil you got after the reaction was probably just a mixture of unreacted benzaldehyde and nitroethane, the intermediate nitro-alcohol along with the product phenyl-2-nitropropene. Some nitropropenes are very hard to crystallize unless they are very pure. A reason why the intermediate nitro-alcohol would not dehydrate (if that would be the case) is an excess of water in the reaction mixture. If there is a lot of water around, the molecule is less prone to give off a water molecule itself, compared to an anhydrous reaction, where the water very readily would split off in comparison.

I don't know so much about the Zn/HCl reduction, I think Sunlight is the authority on that reduction method. But as a general rule, any reduction method that works for nitrostyrenes also work for phenylnitropropenes.
 
 
 
 
    hest
(Hive Bee)
12-06-01 14:04
No 245066
      Re: Synthesis of amphetamines  Bookmark   

My personal exp. with the synth of 3,4,5-TMNS is that the Shulgin way is the absolut best one. The use of edda was a disaster (<30%).
The red. of the dubble bond with NaBH4 goes smooth (and the nitro alkan is a nice solid).
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 14:09
No 245075
      Re: Synthesis of amphetamines  Bookmark   

What is the melting point of that nitroalkane?
 
 
 
 
    Xgoddess
(Stranger)
12-06-01 16:58
No 245132
      Re: Synthesis of amphetamines  Bookmark   

Sunny -D, the redn, according to the author, couldnt be any simpler...solution starts yellow...after much addition of Zn/HCl over a couple hours, almost all yellow is replaced by a transparent solution. temp kept cool, arount 15-20. workup was a slight bitch bc of all the precipitate when base is added. upon HCL gas, the author got 2.5 grams of pure white crystals.  No GC/MS, NMR, IR, or HPLC was run, but he did a biological assay at 250 mg. It was the real deal.  However, the author did run an IR of his nitro styrene before reduction...It showed perfect evidence (no carbonyl peak, strong alkene peak, etc).
  Like the author wrote, the NaOH works fine for this nitro styrene.
  Now I have a question for you...what is all the hype about 2 C H...PIKAL says its not even active???
  Finally, since your the pioneer of the Zn/HCl redn, go ahead and try it for the product of benzaldehyde and NO2Et and let me know how it works. Dont wait too long or I'll be writing up the authors results before you.tongue
 
 
 
 
    Xgoddess
(Stranger)
12-06-01 17:02
No 245134
      Re: Synthesis of amphetamines  Bookmark   

Nope...the shulgin way is only the best way if you want to spend more time and use more exotic chemicals.  most researchers prefer to keep it as simple as possible when that gives the best yields (NaOH,H20, 25C, 30 min, stirring).  As for your two step redn, thats even worse. why not just do a one-pot, and not even deal w/ NaBH4???crazy
 
 
 
 
    Xgoddess
(Stranger)
12-06-01 17:10
No 245137
      Re: Synthesis of amphetamines  Bookmark   

Rho,in your opinion, what is the best phenethylamine...also, is there a phenethylamine that somewhat resembles MDA? 
Also, is 2CH active?
Can 2CB be prepared from the aldehyde that is already brominated(ie: from 2,5-dimethoxy-4bromo benzaldehyde) , or does bromination have to be done after the reduction?
Finally, in you opinion, what is the best phenyl -2-amino propane?? Sorry for all the questions, but you seem to really know you chemistry.  Thanks a lot.
 
 
 
 
    sunlight
(Pioneer Researcher)
12-06-01 18:04
No 245150
      Re: Synthesis of amphetamines  Bookmark   

I'm very happy that a bee have tried with success the Zn/HCl rdxn, as he saw it's very simple, just first course of psychedelic chemistry, and probably we can make almost all PIHKAL.
About nitropropenes I tried in a small test a rdxn of 345TMPNP, the rdxn went perfect, with the tipical change of color of this reation, and when basifying I saw the oil floating and a clear amine smell, my impression is that it worked fine. Other test was made with 34MDPNP and it seemed to work, but I was not there in the workup and may be the other person fucked the essay (or may be not).
We have a lot of products to test, but now the question is if as we think the nitropropenes can be reduced as well with this procedure. I wan't try P2NP but I'll try others compounds, may be other can bee the job.
I'll try the NaOH for 345TMB.
I've tested the procedure for nitrostyrenes that is in a new entry of Rhodium's page, 19.5 gr of 3,4,5 TMB, 7.8 gr of am. acetate, 10 ml of nitromethane and 70 cc of acetic acid refluxed 2 h 15 minutes, then 50 gr of ice was added and the precipitate filtered and wash with cold IPA. It gave 14.8 gr of a crystalline product that was greenish instead of yellow, I made a TLC and showed one spot and the mp was 118-120, in a recent uemura reference the mp was reported as 120-121, so it was the nitrostyrene but probably with a small contamination that gave the greenish color.
 
 
 
 
    Rhodium
(Chief Bee)
12-06-01 22:09
No 245204
      Re: Synthesis of amphetamines  Bookmark   

2C-H is not active in itself, but as it is used as a precursor for 2C-B, it is widely discussed there. The bromination may be done in forehand on the benzaldehyde, but some reduction agents like LAH may hurt the bromine, something like diborane or alane could work.
 
 
 
 
    Xgoddess
(Stranger)
12-07-01 10:58
No 245352
      Re: Synthesis of amphetamines  Bookmark   

Rho, the researcher appreciated your advice for using ammonium acetate...unfortunately, he will never be able to get that. He has Na acetate. can you think of any reason why that would/ or would not work?
He also has propyl amine, di isopropyl amine,  1,2-phenylene diamine,ethylenediamine, and pyridine.  Would any of those work?
Sorry, no melting point was reported in the paper for 345 TMNS.
 
 
 
 
    Rhodium
(Chief Bee)
12-07-01 11:25
No 245355
      Re: Synthesis of amphetamines  Bookmark   

I don't think sodium acetate would work. Propylamine and isopropylamine are probably good butylamine substitutes. However, I really advise you to use that ethylenediamine and make the acetate salt of it with acetic acid and use that for your condensation reactions, see ../rhodium/chemistry /edda.html for the preparation and use.

Someone said that it is not good for 3,4,5-trimethoxybenzaldehyde though, I believe your propylamine would be much better there.

What is the paper/article you are referring to?
 
 
 
 
    Osmium
(Stoni's sexual toy)
12-07-01 11:27
No 245357
      Re: Synthesis of amphetamines  Bookmark   

Ethylene diamine diacetate will work in about 60% yield.
../rhodium/chemistry /edda.html

I'm sure at least one or two of the others will work too, maybe even with better yields. UTFSE. All the info is here, and all you have to do is digging it up.

And what did you try to say when you mentioned

> ammonium acetate...unfortunately, he will never be able
> to get that.

If you really can't buy it (very unlikely), then simply prepare your own! That's not exactly rocket science...
 
 
 
 
    Osmium
(Stoni's sexual toy)
12-07-01 11:30
No 245358
      Re: Synthesis of amphetamines  Bookmark   

Oooops!
 
 
 
 
    uemura
(Hive Bee)
12-07-01 14:45
No 245409
      Re: Synthesis of amphetamines  Bookmark   


Sorry, no melting point was reported in the paper for 345 TMNS.



This may help: 345TMNS, strong yellow plates, mp 120-121. From Slotta, Ber. 1933


Carpe Diem
 
 
 
 
    Rhodium
(Chief Bee)
12-07-01 15:56
No 245444
      Re: Synthesis of amphetamines
(Rated as: excellent)
 Bookmark   

I wondered about the melting point of the phenylnitroethane, not the phenylnitroethene. But it seems like I found the data I was looking for in Chem Pharm Bull 34, 1628 (1986), the mp of the nitroethane is 82-83C.


3,4,5-Trimethoxyphenyl-2-nitroethene

The following components were placed in a one-necked 1000ml conical flask equipped with a Dean-Stark water trap (capacity about 30ml): 3,4,5-trimethoxybenzaldehyde (98.1 g, 0.5 mol), dimethylammonium chloride (81.5 g. 1 mol), nitromethane (300ml), toluene (300ml) and anhydrous potassium fluoride (4.36 g, 75 mmol). This mixture was vigorously refluxed with stirring for 5 h. The reaction flask was cooled down, then fitted to a rotary evaporator to order to remove the volatiles by gradual heating under reduced pressure. To the tepid residue (~55C), chloroform (125 ml) and 0.2 M HCl (400 ml) were added. The mixture was heated on the water bath until complete dissolution. Then the flask was stored overnight in a refrigerator (-5C). A crystalline solid was filtered out by suction, carefully rinsed with water and thoroughly dried in a vacuum oven. The filtrate was poured into a separatory funnel, the layers were separated and the aqueous phase was extracted with chloroform (3x100 ml). The organic extracts were combined then evaporated to give a crude oily material, which was chromatographed over silica gel (400g, eluent dichloromethane-ethyl acetate, 95:5). After removal of the solvent, the resulting solid and the previously separated product were recrystallized together from isopropanol: yield 99.2g (83%); mp 125.5-126.5C (allotropic change at 121-121.5C).

3,4,5-Trimethoxyphenyl-2-nitroethane

The following components were placed in a 6000ml wide-mouthed reaction flask provided with an efficient mechanical stirrer: isopropanol (750 ml), chloroform (2500ml) and the above nitrostyrene (47.8 g, 0.2mol). When the crystals had dissolved completely, silica gel 200-400 mesh ASTM (400g) was poured into the flask whilst the mixture was continuously stirred vigorously. Sodium borohydride (33.25 g, 0.88 mol) was then added portionwise over a period of 15 min. The slurry was stirred for an additional 2 h, and acetic acid (~50 ml) was carefully added. The insoluble material was separated by suction and the filtrate was evaporated in vacuo (the recovered solvents were used to rinse the silica gel thoroughly). The resulting crude material was taken up with dichloromethane (500 ml) and water (300 ml). The organic layer was separated, and the aqueous phase was extracted with dichloromethane (3x100ml). The combined extracts were dried with magnesium sulfate, filtered, then evaporated to dryness. The residue was chromatographed on a silica gel column (400g, eluent dichloromethane-ethyl acetate, 95:5) to give 3,4,5-Trimethoxyphenyl-2-nitroethane (46g), which was further purified by recrystallization (benzene-cyclohexane) to yield 44.6g (92.5%) as colorless crystals, mp 82-83C.
 
 
 
 
    Cyrax
(Newbee)
12-08-01 02:13
No 245574
      Re: Synthesis of amphetamines  Bookmark   

Rhodium, you just made my day.

I am extremely happy to see that my silica gel assisted reduction of nitrostyrenes in CHCl3 / i-PrOH [Tetrahedron letters (1983) vol. 24, p 227] can be scaled up with great succes.

Great work Rhodium!!! You are the best.
 
 
 
 
    sunlight
(Pioneer Researcher)
12-08-01 04:07
No 245588
      Re: Synthesis of amphetamines  Bookmark   

There's no doubt, Rhodium is the best ...
 
 
 
 
    hest
(Hive Bee)
12-08-01 05:01
No 245592
      Re: Synthesis of amphetamines  Bookmark   

Thats a reasonabel yeald, not the two times 50 I'm fooling around with.
Thanks
 
 
 
 
    Rhodium
(Chief Bee)
12-08-01 08:42
No 245616
      Re: Synthesis of amphetamines  Bookmark   

Oh, nice to see that you like my posts so much. I have been doing alittle cleaning in my large pile of copied references, and I have scanned and OCR'd the most interesting parts for you all. There is a good chance much of this will end up in a larger mescaline synthesis document at my page, with about at least five different routes.
 
 
 
 
    sunlight
(Pioneer Researcher)
12-08-01 12:31
No 245663
      Re: Synthesis of amphetamines  Bookmark   

One more time, let me say thanks.
 
 
 
 
    Xgoddess
(Stranger)
12-08-01 12:49
No 245671
      Re: Synthesis of amphetamines  Bookmark   

Thanks a lot Rhodium and Osmium...in the words of sunlight, you two are the best. When the paper is published, I will let you know the yields and the best catalyst for the condensation reaction for phenyl-2-nitropropene...
The only problem I saw with using propylamine in place of butyl amine is its low BP..48...However, if refluxing is not necessary, then I'll recommned that the professor try that.
 
 
 
 
    Cyrax
(Newbee)
12-08-01 17:03
No 245723
      Re: Synthesis of amphetamines  Bookmark   

In a previous post i showed how you can convert an aryl-2-nitropropene to an aryl-2-oximopropane.  However, if you want the aryl-2-propanone to do something usefull like a catalytic hydrogenation with Adams' catalyst & MeNH2 in EtOH, that's no problem because you can convert the oxime in the ketone in a quantitative yield.

In JOC (1989) vol 54 p 3211, they do the reation on some imidazole-2-oximopropane:
 " To a solution of 30 g (0.12 mol) of 1-[5-methyl-1-(phenylmethyl)-1H-imidazol-4-yl]propane-2-one oxime in 300 ml of 20 % (v/v) sulfuric acid at 0C was added a solution of 18 g (0.26 mol) of sodium nitrite in 50 ml of water, the temperature being maintained at < 5 C.  After stirring for 0.5 h at 0 C, the reaction mixture was made basic wint 20 % K2CO3 and extracted with two 700 ml portions of DCM.  The combined extracts were dried over MgSO4 and charcoal treated, and the solvent was removed under vacuum to give 28 g (99 %) of the ketone as an oil."

I dare say that aryl-2-nitropropenes and aryl-2-nitrostyrenes are versatile compounds smile
 
 
 
 
    Cyrax
(Newbee)
12-09-01 04:36
No 245817
      Re: Synthesis of amphetamines  Bookmark   

Xgoddess: for the preparation of phenyl-2-nitropropene, the best method is to reflux benzaldehyde and nitroethane in toluene with a n-butylamine catalyst.  It is important to reflux and to use a Dean-Stark water trap, because you will azeotropicially remove the water (toluene and water for a azeotrope and when you distill it out of the reaction mixture, the equilibrium of the reaction will shift towards the phenyl-2-nitropropene).

For an example, check out Organic Syntheses, CV 4, 573.
They make o-methoxyphenyl-2-nitropropene.

"A 1 L RBF is fitted with an electric heating mantle, a Dean and Stark water separator and a reflux condenser.  To the flask are added in this order 200 mL of reagent-grade toluene, 136 g (1 mole) of o-methoxybenzaldehyde, 90 g (1.1 moles) of commercial nitroethane and 20 mL of n-butylamine [It is desirable to swirl the flask after each addition to prevent the formation of layers].  The solution is heated to produce a rapid reflux until the separation of water ceases.  The pure nitroolefin can be obtained by removing the toluene on the steam bath at water-pump pressure and recrystallizing the resulting oil from ethanol.  The yield is 150 - 175 g (80 - 90 %).  The crystals melt at 51-52 C when pure."
 
 
 
 
    Cyrax
(Newbee)
12-09-01 05:40
No 245826
      Re: Synthesis of amphetamines  Bookmark   

If you do not have a Dean-Stark water trap or if you do not like toluene, you can follow the following user friendly procedure:

"One mole of benzaldehyde, one mole of nitroethane, 5 mL of n-butylamine and 100 mL of absolute ethanol (no water!) were refluxed for 8 hours in a 1000 mL round bottom flask.  When the contents were cooled and stirred a heavy, yellow, crystalline mass formed immediately.  After recrystallization from absolute ethanol, the 1-phenyl-2-nitropropene weighed 105 g.  Yield: 64 %. M.P.: 65 C"

Ref.: JOC (1950) vol 15 p 8
 
 
 
 
    BieneMaja
(Hive Bee)
12-09-01 14:28
No 245935
      Re: Synthesis of amphetamines  Bookmark   

two days swib did a run with 1 mole benzaldehyde + 1 mole nitroethane and 12ml butylamin. mxtr was refluxed on the waterbath for about 1.5 hrs. then flushed with 75ml dh2o and removed most of the water. after 2 min crystalisation starts and the beaker was placed in the freezer for 0.5 h. the so obtained crystals were washed with ice cold denatured etOH losing most of there orange color. after drying the yield was at least 120g (yield could have been higher, some crystals falled out of the washing alc. but swib was to lazy to work them up, she just want to finish her work cause some of the p2np get on her face *argh*)
now she don't know how to reduce them. maybe again Zn/HCl or Pd/C...

kallos kai agatos
 
 
 
 
    Xgoddess
(Stranger)
12-12-01 13:22
No 246870
      Re: Synthesis of amphetamines  Bookmark   

Rho, thanks for the advice on ED-di actetae. would the synth for ethylenediammonium diacete work w/ toluene solvent also, or must Et2O be used.  frowncrazycoolblush
 
 
 
 
    Xgoddess
(Stranger)
12-12-01 13:34
No 246871
      Re: Synthesis of amphetamines  Bookmark   

Cryax--thanks for the advice. the only problem is that refluxing is just an extra hassel. Rho suggested that one should use ethylenediammonium diacetate stirred with benzaldehyde and NO2Et AT ROOM TEMP!! Could it get any simpler. Also, I know that 345 Tri methoxy BA + NOCH3 forms the nitro styrene in good yield with NaOH as catalyst!! Now , the question is "will this catalyst work for 245 TMA and 246 TMA?? Now that would be simple!! Finally, the Zn/HCL reduction is documented in March's "Advanced Organic Chemistry"--1994 for reducing all NO2 and most alkene groups.  Someone please let me know if the Pd/C reduction is a simple.  -XXblush
 
 
 
 
    Cyrax
(Newbee)
12-12-01 14:26
No 246878
      Re: Synthesis of amphetamines  Bookmark   

Yes, the NaOH catalyst will also work for the TMA analogs.

The basic catalyst (this can also be n-BuNH2) abstracts a proton from nitromethane and the resulting anion attacks the carbonyl group of benzaldehyde.  Then, there is an elimination of H20.  This gives the nitrostyrene.

So, it doesn't matter which kind of base you use.
 
 
 
 
    Rhodium
(Chief Bee)
12-12-01 14:43
No 246881
      Re: Synthesis of amphetamines  Bookmark   

The choice of base is very important to get the best yield possible. Raising a bad yield fourfold is possible by choosing the right base and solvent.
 
 
 
 
    Cyrax
(Newbee)
12-14-01 03:30
No 247461
      Re: Synthesis of amphetamines
(Rated as: good read)
 Bookmark   

If you don't believe me that nitroalkenes are versatile compounds, you have to read the article in Tetrahedron Letters (1990) p 7443.  There, I found a kick-ass reaction.

Reduction of unsaturated nitroalkenes with BH3-THF and NaBH4 (catalytic amounts)

Phenyl-2-nitrostyrene -->  Phenylethylamine  (88%)
Phenyl-2-nitropropene  -->  Amphetamine (91%)
3,4-diethoxyphenyl-2-nitropropene  -->  3,4-diethoxyphenyl-2-aminopropane (87%)

Method
------

"The synthesis of phenylethylamine is representative.  A flame-dried, nitrogen-flushed, 100 mL flask, equipped with a septum inlet, magnetic stirring bar and reflux condenser was cooled to 0 C.  A BH3-THF solution (16 mmol, 9.5 ml, 1.7 M) was injected into the reaction flask via a syringe, followed by the slow addition of nitrostyrene in THF (4 mmol, 0.6 g in 6 mL THF).  After the addition, the ice-bath was removed and a catalytic amount (~ 40 mg) of NaBH4 was added to the stirred reaction mixture by means of a spatula.  A moderately exothermic reaction ensued.  The reaction was then allowed to proceed for 6 days at 25 C.  The reaction mixture was poured on to ice-water mixture (50 mL), acidified with 10 % HCl (~ 20 mL) and then stirred at 60-65 C for 2 h.  After cooling to room temperature, the acid layer was washed with ether (2 x 50 mL), and then the phenylethylamine was liberated via the addition of aqueous sodium hydroxide.  Solid NaCl was added and the product extracted into ether (3 x 50 mL).  The combined ethereal extracts were dried over anhydrous MgSO4, and the solvent reduced under reduced pressure to yield 0.43 g (88 %) of phenylethylamine."
 
 
 
 
    Rhodium
(Chief Bee)
12-14-01 03:43
No 247467
      Re: Synthesis of amphetamines  Bookmark   

That is by Varma & Kabalka, right? Those two chemists has done nearly as much improvements to nitroalkene chemistry during the last two decades as the combined efforts by the Hive Collective the last few years. The only problem is that they have not optimized their procedures for clandestine chemistry ease, but rather improved old methods, and extended the range of reagents that can be used to effect various functional group transformations.
 
 
 
 
    sunlight
(Pioneer Researcher)
12-14-01 04:25
No 247474
      Re: Synthesis of amphetamines  Bookmark   

It is in TSII. Someone told in the Hive that BH3-THF could be done with H2SO4 and NaBH4 in THF. Well, I made a single trial and got nothing. Probably I didn't make a good BH3 solution, so I would like to know a method to make it.
 
 
 
 
    Rhodium
(Chief Bee)
12-14-01 04:34
No 247476
      Re: Synthesis of amphetamines  Bookmark   

BH3 is formed by the action of I2, H2SO4, CH3SO2H and a few other reagents upon sodium borohydride, making it active enough to reduce carboxylic acids to alcohols, which in my opinion is good enough to reduce nitroalkenes to amines. I can probably gather some writeups on this when I have the time, I have recently sorted all of my photocopied journal references (which was a pile of papers over 1 meter high) into different subject areas, now making it at all possible to find something in there... smile
 
 
 
 
    Cyrax
(Newbee)
12-14-01 15:26
No 247665
      Re: Synthesis of amphetamines  Bookmark   

Whow Rhodium, I am impressed: 1 meter of refs.  I think you deserve a doctor's degree for all your chemical background knowledge smile.  You are right, the ref is from Kabalka and I agree: the procedure is not exactly for kitchen chemistry.  Kabalka has also a procedure for the NaBH4 reduction of the double bound in nitroalkenes, but I found that the procedure with silica gel is much better. 

I think that a very interesting reaction with aryl-2-nitropropenes is the conversion to the ketone with HCl / Fe.  I have done some research, so I will post the refs. when I have the time.
 
 
 
 
    Ritter
(Master Whacker)
12-14-01 16:10
No 247683
      Re: Synthesis of amphetamines
(Rated as: good read)
 Bookmark   

Here is a procedure for reducing carboxyl groups to alcohols using NaBH4/H2SO4

Tet. Lett. 33, 5517-18 (1992)  :  An Improved, Convenient Procedure for Reduction of Amino Acids to Aminoalcohols:  Use of NaBH4-H2SO4

To a stirred suspension of NaBH4 (100g, 2.5mol) in THF (1 Liter, reagent grade) was added D-phenylglycine (151g, 1.0mol).  The flask was immersed in an ice bath and a solution of fresh conc. H2SO4 (66ml, 1.25mol) in ether (total volume 200ml) was added at such a rate to keep the temp below 20'C (addition time approx 3hr).  Stirring of the reaction mixture was continued at room temp overnight and MeOH (100ml) was added carefully to destroy excess BH3. The mixture was concentrated to ca. 500ml and 5N NaOH (1Liter) was added.  After stripping the solvent below 100'C, the mixture was heated at reflux for 3hr.  The turbid mixture was cooled and filtered through celite which was washed with water.  The filtrate and washes were combined and diluted with add. water to ca. 1Liter.  The CH2Cl2 extraction (4 x 500ml) followed by evaporation of the solvent left solid phenylglycinol to yield 115g (84% yield)


Now my question is can this procedure possibly be used to convert benzoic acids to benzyl alcohols such as the acid formed by methylation of gallic acid?  If so, this may be an excellent method for producing 3,4,5 trimethoxy benzylchloride!
 
 
 
 
    Rhodium
(Chief Bee)
12-14-01 17:42
No 247706
      Re: Synthesis of amphetamines  Bookmark   

Sounds interesting! It should not be too hard to try that reaction out on some plain o'l benzoic acid to see if there is any good yield of product benzyl alcohol.
 
 
 
 
    uemura
(Hive Bee)
12-15-01 02:36
No 247810
      Re: Synthesis of amphetamines  Bookmark   

Hi Ritter,
Uemura digged out a table on the reduction of carbonylcompounds with complex metal hydrides [1]. It says:
R-COCl, R-COH, R-COR' are reduced by NaBH4 to the alcohol,
R-COOR may or may not be reduced to the alcohol (in MeOH)
R-COOH, R-CN and R-CONR2 are not reduced by NaBH4 but by LiAlH4.
It's a pitty thsat it's not clear if acid esthers are reduced. They are easy to get from the acids....frown

BTW: Long me ago when SWIM had access to LiAlH4 and DMS, the preparation of the 345TMbenzylalcohol from
Gallusacid --> 345 TM-benzylmethylester --> 345 TM-benzylalcohol
worked easy and high yielding.

Uemura further remembers that some time ago he read an article where acids are reduced to their alcohols with NaBH4 using iodine as part of the rxn. If there is some interest Uemura could seek in his pile of papers this one out.
Carpe Diem
 

[1] Organikum, page 548
 
 
 
 
    Cyrax
(Newbee)
12-15-01 04:02
No 247817
      Re: Synthesis of amphetamines  Bookmark   

OK, I know it: this is not the most interesting method to prepare phenylacetone (chemically and economically speaking).  But for those who want to be original, I 'll give it anyway smile.  It's from our friends Kabalka & Varma (same ref. as in my previous post).

"Lithium tri-sec-butylborohydride (11 mL of a 1 M solution in THF) was placed in a flame-dried, nitrogen-flushed, 100 mL flask equipped with a septum inlet and a magnetic stirring bar.  A solution of 2-nitro-1-phenylpropene (1.63 g, 10 mmol) in THF (10 mL) was added dropwise to the stirred solution of the trialkylborohydride at room temperature.  A mildly exothermic reaction ensued with the disappearance of yellow coloration (nitroalkene).  The mixture was stirred for 30 minutes and then poured onto cold (-10 C) 4 normal sulfuric acid (50 mL).  Ice / water was carefully added to the mixture which was stirred for 10 minutes.  The product was extracted with ether (3 x 50 mL).  The combined ether extracts were washed with water (2 x 50 mL), dried with MgSO4, and evaporated under reduced pressure.  The crude product was purified by column chromatography (silica gel; 4 % ether / petroleum ether eluant) to give the phenylacetone as an oil.  Yield: 1.1 g (80 %)."

As a side note for the theoretical chemists (like me smile), this is a modification of the Nef reaction.
 
 
 
 
    lugh
(Hive Bee)
12-15-01 04:16
No 247820
      Re: Synthesis of amphetamines  Bookmark   


It's a pitty thsat it's not clear if acid esthers are reduced. They are easy to get from the acids....




Esters can be reduced to alcohols by LAH, globally:

2 RCOOR' + LiAlH4 ---> (RCH2O)2(R'O)2LiAl ---->H2O + 2 RCH2OH + 2 R'OH + LiAlO2

Carbinol esters have been reduced to the parent carbinols by sodium borohydride, for example, 3-carboethoxypropionyl chloride has been reduced to butyrlactone in 40% yield, see JACS 71 122 (1949) for details. What would be interesting to look into would be using sodium borohydride and nickel chloride etc, one would think the number of functional groups reduced would be greater smile

 
 
 
 
    Rhodium
(Chief Bee)
12-15-01 07:21
No 247847
      Re: Synthesis of amphetamines
(Rated as: good read)
 Bookmark   

Uemura: The NaBH4/I2 papers are JOC 58 3568-3571 (1993) and Tetrahedron 48(22), 4623-2628 (1992)

Addendum: latest addition (10-19-04):

A Convenient Reduction of Amino Acids and Their Derivatives
Marc J. McKennon and A. I. Meyers
J. Org. Chem. 58, 3568-3571 (1993) (../rhodium/pdf /borohydride-iodine.pdf)
____ ___ __ _

Convenient Methods for the Reduction of Amides, Nitriles, Carboxylic Esters, Acids and Hydroboration of Alkenes using the NaBH4/I2 System
A. S. Bhanu Prasad, J. V. Bhaskar Kanth, M. Periasamy
Tetrahedron 48(22), 4623-4628 (1992) (../rhodium/pdf /borohydride.iodine.pdf)
 
 
 
 
    Cyrax
(Newbee)
12-15-01 09:33
No 247864
      Re: Synthesis of amphetamines
(Rated as: excellent)
 Bookmark   

I have a lot of articles about the Fe/HCl reduction of phenyl-2-nitropropene to the oxime and the subsequent hydrolysis.  However, in my eyes, Patent US2557051 gives the most convenient procedure.

Example 1

200 grams of o-methoxybenzaldehyde, 150 grams of nitroethane and 40 mL of n-butylamine were dissolved in 400 mL of toluene in a flask equipped with a reflux condenser and a suitable water seperation trap and the mixture heated under reflux until the collection of water ceased.
The water trap was removed from the system and a stirrer introduced into the flask.  750 grams of finely-divided iron, 1500 mL of water and 7 grams of ferric chloride were then added.  The mixture was then heated to boiling and, while stirring vigorously, 750 mL of concentrated HCl was added dropwise over a period of 4 hours.  The reaction mixture was subjected to steam distillation, 18 liters of distillate being collected.  The toluene layer was removed  and the aqueous layer was extracted with fresh toluene.  The combined toluene extracts were fractionally distilled, yielding 247 grams of o-methoxyphenylacetone boiling at 126-132 C / 14 mm Hg.  Yield: 75.5 %


Example 3

In the same manner as given for Example 3, approximately equimolar proportions of benzaldehyde and nitroethane are condensed in toluene in the presence of n-butylamine at about reflux temperature, the distillate collected, water removed, and the toluene removed to the reaction zone.  After about 6 hours the calculated quantity of water has been removed from the reaction zone and iron, water and ferric chloride are added thereto.  Concentrated HCl is then adde dropwise to the mixture at about reflux temperature with vigorous agitation over a period of 6 hours.  Upon steam distillation of the product and the removal of the toluene, extraction of the aqueous layer with fresh toluene, and fractional distillation of the extracts, approximately 75 percent of the theoretical yield of desired phenylactone is obtained.

IMHO, this is THE method for the preparation of P2P. 
The next step will be something like:
P2P + MeNH2  -->  meth
I suggest a Parr hydrogenation with PtO2 as catalyst.
 
 
 
 
    Osmium
(Stoni's sexual toy)
12-15-01 12:13
No 247892
      Re: Synthesis of amphetamines  Bookmark   

Funny how the same refs seem to reappear every few months wink
 
 
 
 
    Rhodium
(Chief Bee)
12-15-01 13:12
No 247912
      Re: Synthesis of amphetamines  Bookmark   

The ones talking about NaBH4 plus an "enhancing reagent", Os? I know, some day someone out there will try it out and we will have the method permanented into our repertoire.
 
 
 
 
    lugh
(Hive Bee)
12-16-01 08:02
No 248161
      Re: Synthesis of amphetamines  Bookmark   


It's a pitty thsat it's not clear if acid esthers are reduced. They are easy to get from the acids....




Carboxylic acids and esters have been reduced to alcohols by sodium borohydride/titanium(IV) chloride, see JACS 78 2586 (1956), Curr Sci 30 218 (1961) & J Sci Ind Res 20B 318 (1961) for details.