Rhodium (Chief Bee)
11-29-00 23:18
No 71540
      One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

Novel One Pot Amphetamine synth from BzCN, MeMgI and NaBH4

The alkylation of benzyl cyanide (phenylacetonitrile) with methylmagnesium iodide affords Phenyl-2-iminopropane, which is directly reduced with NaBH4 without isolation of the intermediate to give DL-phenyl-2-aminopropane. It is possible that the same procedure with Benzylmagnesium bromide and acetonitrile also will yield amphetamine, but rearrangement products are possible in the latter case. Of course this reaction can be extended to other amphetamines from their corresponding phenylacetonitriles.

A solution of MeMgI was prepared in the usual manner from methyl iodide (15g, 0.105 mol) and clean Mg turnings (30g) in 200ml dry THF, and the solution was added slowly with good stirring to a cooled solution of (11.7g, 0.1 mol) benzyl cyanide in 150ml dry THF in a dried 1000ml round-bottomed flask. The reaction mixture was stirred at room temp for two hours and then cooled in an ice-bath. The solution was diluted with 150ml of dry methanol and NaBH4 (9.5g, 0.25 mol) was added in portions during 30 minutes, and the reaction mixture was stirred for another hour. The reaction mixture was concentrated under vacuum and the residue dissolved in 200ml water and acidified with concentrated HCl. The solution was washed with 2x50ml DCM, made basic through the addition of 25% NaOH, and extracted with 3x75ml DCM. The pooled organic extracts was dried over MgSO4, filtered and the solvent evaporated under vacuum. The oily residue was then vacuum distilled to give DL-Amphetamine as a clear oil (bp 82-85C at 13 mmHg).

Yield 10.8g (80% of theory).

Ref: JACS 109, 3378-3387 (1987) Procedure adapted from the synthesis of #49.


http://rhodium.lycaeum.org
 
 
 
 
    uemura
(Hive Bee)
11-30-00 08:34
No 71623
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

cool
It is possible that the same procedure with Benzylmagnesium bromide and acetonitrile also will yield amphetamine, but rearrangement products are possible in the latter case.
This way looks more OTC than the other. Uemura thought of getting the P2P with this Grignard but didn't realize you can go directly to the amin. Very nice! Indeed smile

Cave Canem! latin.
 
 
 
 
    Rhodium
(Chief Bee)
11-30-00 10:36
No 71642
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

Please tell me about your results with this synth, it seems really interesting.


http://rhodium.lycaeum.org
 
 
 
 
    Dope_Amine
(Hive Bee / Eraser)
12-02-00 00:51
No 71851
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

piperonal + ? --> piperonyl cyanide

piperonyl cyanide + MeMgI --> 3,4-MD-Phenyl-2-iminopropane ?

Also Rhodium, did you read the blurb I wrote in that Rhodium Acetate thread?  I listed some journal titles you might be interested in.....



tongue


something for your mind.......
 
 
 
 
    Ritter
(Newbee)
12-23-00 15:37
No 77439
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

Hey Rhodium,
Aren't Grignard reagents usually made from nearly equal molar quantities of Mg and alkyl halide?  Your synth above calls for 1.23 mol Mg and .105 mol alkyl halide.  I have never heard of such a huge excess being called for.  Perhaps the 30g mentioned in your synth is a typo and is supposed to be 3.0g ?????  Or is the extra Mg a catalyst in combination w/ the borohydride during the reduction maybe ?????
 
 
 
 
    Drug_Phreak
(Hive Bee / Eraser)
12-25-00 04:05
No 77705
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

So is this synthesis right or what? Will the extra Mg screw up the reaction? Anyone know? 




Society exists by chemical affinity, and not otherwise.
 
 
 
 
    Rhodium
(Chief Bee)
12-27-00 00:28
No 77984
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

Yes, of course the Mg amount is wrong, I meant 3 grams (1.23 eqv).


http://rhodium.lycaeum.org
 
 
 
 
    WizardX
(Wizard Master)
12-28-00 01:49
No 78202
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

Rhodium & Ritter: 3.0 grams of Mg is CORRECT!
The atomic weight of Mg is 24.31 grams/mole. So 1 mole of Mg = 24.31 grams

Now, (3/24.31) = 0.1234 moles of Mg.
If you have 0.105 moles of methyliodide, then (0.105x24.31) = 2.553 grams of Mg is the minimum grams of Mg you need for the preparation. You should USE (0.11x24.31) = 2.674 grams of Mg, a 0.05 excess of Mg.

Another procedure for methylmagnesiumiodide preparation is Vogel, 5th Ed, Exp 5.42, page 540.
 
 
 
 
    Alphabeta121
(Hive Bee)
02-19-01 19:38
No 174323
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

I assume the same procedure could be adapted to form 2,5Dimethoxy amphetamine instead of 2-CH?

alphabeta121
 
 
 
 
    Rhodium
(Chief Bee)
02-19-01 21:26
No 174337
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH4  Bookmark   

The above procedure yields regular amphetamine.

If you want 2,5-dimethoxyamphetamine, use 2,5-dimethoxyphenylacetonitrile and MeMgI (or 2,5-dimethoxybenzylbromide and acetonitrile).

2C-H can not be made with this method, instead react 2,5-dimethoxybenzylbromide with cyanide ion to form 2,5-dimethoxyphenylacetonitrile, and reduce the nitrile directly with either LAH, Red-Al, H2/Pd or NaBH4 together with NiCl2 or CoCl2.


http://rhodium.lycaeum.org
 
 
 
 
    goiterjoe
(Hive Bee)
03-10-01 21:52
No 177725
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

for those of you that can't get sodium borohydride easily, this might help.

piperonal + HNO3 + H2SO4 ----> piperonal nitrite
piperonal nitrate + NaNO2 + HCl -----> piperonal diazonium salt
piperonal diazonium salt + KCN ----> piperonal cyanide


If pacman influenced us, we'd glide around dark rooms eating pills and listen to repetitive music.
 
 
 
 
    Osmium
(Stonium's Main Man)
03-11-01 00:20
No 177752
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

First of all nitrating piperonal produces nitropiperidine, not the nitrite or nitrate. This has to be reduced to the amine first befor you can even think about preparing the diazo compound. And the resulting benzonitril is of no use for us at all. Besides, benzaldehydes react with cyanide anyway.
 
 
 
 
    Rhodium
(Chief Bee)
03-11-01 00:53
No 177760
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

Osmium: Of course the nitration produces 6-nitropiperonal, not nitropiperidine.


http://rhodium.lycaeum.org
 
 
 
 
    goiterjoe
(Hive Bee)
03-11-01 11:05
No 177855
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

what's the difference between 6-nitropiperonal and 1-nitropiperonal?  I thought they would be the same thing, just looked at from opposite sides.



    O  //\  /NO2  
   / \//  \/ 
  /   |   ||    
  CH2  |   ||   
  \   |   ||  
   \ /\\  /         
   O  \\/ 

I could very well be wrong about this synth, but my organic lab produced bromobenzene in this fashion about 3 weeks ago from benzene, and I thought it would apply to piperonal as well.  maybe piperonal is the one I'm confused about.  does it look like this:

   O  //\ 
  / \//  \ 
 /   |   ||  
CH2  |   ||  
 \   |   ||  
  \ /\\  /         
   O  \\/           



If pacman influenced us, we'd glide around dark rooms eating pills and listen to repetitive music.
 
 
 
 
    Rhodium
(Chief Bee)
03-11-01 22:42
No 177933
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

1-Nitropiperonal does not exist, the 1-position is already occupied by the aldehyde group. Note that you have drawn 3,4-methylendioxynitrobenzene, and not any nitropiperonal. Piperonal has an aldehyde group where the nitro group is in your picture. The lower picture represents 1,3-benzodioxole (aka 1,2-methylenedioxybenzene).


http://rhodium.lycaeum.org
 
 
 
 
    goiterjoe
(Hive Bee)
03-12-01 04:20
No 178001
      Re: One Pot Amphetamine synth from BzCN/MeMgI/NaBH  Bookmark   

damn, that question about the 6 position was stupid of me to ask.  I think the methylene chloride fumes are starting to get to me.  sorry about the confusion on piperonal as well.  if 1,2 methylenedioxybenzene were available, it could be used in the synthesis I stated earlier.  I think I'll quit trying to post for a while and finish my webpage on the TMP2P synthesis via peracetic/asarone.


If pacman influenced us, we'd glide around dark rooms eating pills and listen to repetitive music.