Author Topic: Synthesis of amphetamines  (Read 25134 times)

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Rhodium

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Re: Synthesis of amphetamines
« Reply #80 on: December 14, 2001, 04:34:00 AM »
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...  :)

Cyrax

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Re: Synthesis of amphetamines
« Reply #81 on: December 14, 2001, 03:26:00 PM »
Whow Rhodium, I am impressed: 1 meter of refs.  I think you deserve a doctor's degree for all your chemical background knowledge  :) .  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

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Re: Synthesis of amphetamines
« Reply #82 on: December 14, 2001, 04:10:00 PM »
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

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Re: Synthesis of amphetamines
« Reply #83 on: December 14, 2001, 05:42:00 PM »
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

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Re: Synthesis of amphetamines
« Reply #84 on: December 15, 2001, 02:36:00 AM »
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.... :(

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

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Re: Synthesis of amphetamines
« Reply #85 on: December 15, 2001, 04:02:00 AM »
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  :) .  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  :) ), this is a modification of the Nef reaction.

lugh

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Re: Synthesis of amphetamines
« Reply #86 on: December 15, 2001, 04:16:00 AM »

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  :)


Rhodium

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Re: Synthesis of amphetamines
« Reply #87 on: December 15, 2001, 07:21:00 AM »
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)

(https://www.thevespiary.org/rhodium/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)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/borohydride.iodine.pdf)

Cyrax

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Re: Synthesis of amphetamines
« Reply #88 on: December 15, 2001, 09:33:00 AM »
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

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Re: Synthesis of amphetamines
« Reply #89 on: December 15, 2001, 12:13:00 PM »
Funny how the same refs seem to reappear every few months  ;)

Rhodium

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Re: Synthesis of amphetamines
« Reply #90 on: December 15, 2001, 01:12:00 PM »
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

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Re: Synthesis of amphetamines
« Reply #91 on: December 16, 2001, 08:02:00 AM »

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.