12-23-01 06:49
No 250067
      Amphetamine from phenylalanine
(Rated as: excellent)

Some time ago, a friendly bee (I forgot who) gave a ref. about the reduction of phenylalanine to amphetamine.  Since I am interested in peptide chemistry, I looked it up.

It goes like this:
 * reduction of the carboxylic acid with LiBH4/TMSCl
 * BOC protection of the amino group
 * conversion of the alcohol to the iodide
 * reduction of the iodide with N-Selectride (I have to look up what what this crazy molecule stands for)
 * BOC deprotection with TriFluoroAcetic acid


Efficient Procedure for the Reduction of -Amino Acids to Enantiomerically Pure -Methylamines
Quagliato, D. A.; Andrae, P. M.; Matelan, E. M.
Journal of Organic Chemistry 65(16), 5037 (2000) (../rhodium/chemistry /amphetamine.phenylalanine.html)

This is what they call a enantiomerically pure reduction of amino acids.  It means that if you start with D-phenylalanine, that you get the good stuff: dexedrine.

You will need a well equipped lab, do not try this in your kitchen: the reactions are carried out in flame-dried flasks under a dry N2 atmosphere.

Step 1: Preparation of D-Phenylalaninol

To a cold solution of LiBH4 (1.32 g, 60.54 mmol) in THF (30 ml, freshly distilled from LiAlH4) wass added trimethylsilyl chloride (15.36 ml, 121.07 mmol).  The ice/water bath was removed and the mixture was allowed to stir at room temperature for 15 min.  The mixture was recooled to 0 °C and D-phenylalanine (5 g, 30.27 mmol) was added.  The ice/water bath was removed, and the reaction mixture was stirred overnight.  The mixture was again cooled to 0 °C and MeOH (45 ml) was added dropwise, followed by 2.5 M aqueous NaOH (25 ml).  This mixture was evaporated in vacuo, and the residue extracted with chloroform (5 x).  The combined extracts were dried (Na2SO4), filtered, and evaporated in vacuo to leave 4.55 g (99%) of the product as a white cristalline solid.  M.P.: 88 - 90 °C.

Step 2: N-t-Boc-D-phenylalaninol

To a stirred, chilled (0 °C) solution of D-phenylalaninol (5 g, 33.1 mmol) in 85 ml of chloroform was added solid di-tert-butyl dicarbonate (7.22 g, 33.1 mmol).  The solution was stirred at 0 °C for 0.5 h and then stirred at room temperature overnight.  The solution was washed with 20 % phosphoric acid, a saturated NaHCO3 solution, and a saturated NaCl solution, then dried (Na2CO3) and evaporated to dryness under reduced pressure.  The resulting solid was recrystallized from a hot hexane / ethyl acetate mixture to afford 7.48 g (95 %) of the product as white fibrous crystals.  M.P.: 96°C.

Step 3: Preparation of tert-Butyl (1R)-1-Benzyl-2-iodoethyl Carbamate

To a stirred, chilled (0°C) suspension of 2.92 g of polymer-supported triphenylphosphine (8.75 mmol) in dry DCM (35 ml) was added 2.22 g of iodine (8.75 mmol), followed by 0.65 g of imidazole (9.55 mmol).  The mixture was allowed to warm to ambient temperature, and after 0.5 h a solution of 1.26 g (3.98 mmol) of N-t-Boc-D-phenylalaninol in DCM (15 ml) was added dropwise.  The mixture was then heated at reflux for 2 hours.  The cooled mixture was then filtered and the solution waswashed with dilute aqueous Na2S2O3 and water, dried (Na2SO4), and evaporated to a white crystalline solid.  Passing the residue through a short silica gel column (3:2, EtOAc:hexane) yielded the pure product which was recrystallized from hot hexane to obtain 1.09 g of product (88 %) as white crystals.  M.P.: 121-122°C

Step 4: tert-Butyl (1S)-1-Methyl-2-phenylethyl carbamate

A solution of 1.00 g (2.77 mmol) of the iodo compound in anhydrous THF (20 ml) was stirred at -15 °C as 3.04 ml (3.04 mmol) of a 1.0 M solution of N-Selectride (in THF) was added dropwise via syringe.  The mixture was allowed to warm to 5 °C over 1.5h.  Reaction progress was monitored by TLC (4:1 hexane:EtOAc).  The solution was cooled to 0°C, and the reaction was quenched by the slow addition of 1.3 ml of water. This was followed by the dropwise addition of a solution made by combining 15 ml of H20, 1.0 g of K2CO3, and 2.6 ml of 30 % H2O2.  The reaction mixture was stirred at ambient temperature for 1h.  The THF was evaporated under reduced pressure, and the product was extracted from the residue with DCM (3x).  The organic extracts were dried (Na2SO4) and the solvent evaporated to yield a white solid.  Passing this material through a short silica column (4:1 hexane:EtOAc) yields the product (0.61 g, 94 %) as a white crystalline solid.

Last Step: (1S)-1-Methyl-2-phenylethylamine HCl

To a stirred, cooled (0°C) solution of tert-Butyl (1S)-1-Methyl-2-phenylethyl Carbamate (2.59 g, 11.0 mmol) in DCM (20 ml) was added trifluoroacetic acid (5 ml).  The solution was stirred at ambient temperature for 18 h.  The volatile components were reduced under reduced pressure, and the residure was treated with water (10 ml), chloroform (15 ml) and an NaOH solution (2 ml, 50 %).  The mixture was shaken, and the layers were separated.  The aquous layer was extracted with chloroform (5 x) and the combined organic extracts were dried over Na2SO4 and filtered.  To this was added 6 ml of a 1.0 M HCl solution (in Et2O) and the solvents were removed to yield a yellow solid.  This was recrystallized in hot hexane/acetone to yield the product as white, needle-shaped crystalls, 1.34 g (91 %).
[α]25D = 9.21 (c 9.56, MeOH)

I find this an original synthesis.  You clearly need a lab for this, and the synthesis is a lot of work.  However, the yields are good.

What do you think about this synthesis? Let me know your opinion.
(Hive Bee)
12-24-01 12:07
No 250290
      Re: Amphetamine from phenylalanine     

Cyrax an important note is to make sure THF is used not another solvent unless the other solvent will complex the borane.......if not diborane will escape and easily kill lots of people

Johny's in the basement mixing up the medicine...I'm on the pavement
12-27-01 12:27
No 250790
      Re: Amphetamine from phenylalanine     

From ChemExper ( ):
Synonyms: -
Molecular Formula:  C12H28BNa 
Formula Weight:  206.15 
Registry number:  67276-04-4
From Sigma-Aldrich search under name:
( )
 213403 N-Selectride®
    (sodium tri-sec-butylborohydride, 1.0M solution in tetrahydrofuran) , 67276-04-4
Synonyms: (sodium tri-sec-butylborohydride, 1.0M solution in tetrahydrofuran)
Molecular Formula: NaB[CH(CH3)C2H5]3H
Molecular Weight: 206.16
CAS: 67276-04-4
MDL Number: MFCD00011709
Density: 0.893
Comments: Flash Point (°F): 5
Product Comments: (Packaged under nitrogen in Sure/SealTM bottles)
®Registered trademark of Sigma-Aldrich Co.
ELINCS/EINECS Number: 999-999-9
Miscellaneous: Label Precautions: Flammable liquid
Reacts violently with water
Harmful liquid
Handle and store under nitrogen
May develop pressure

From Certificate of Analysis on same page:

More technical details:
Quantitative Analysis of Active Metals and Metal Hydrides via Gas Buret.

You find there also that Sodium borohydride, 0.5M in diglyme ( 2-methoxyethyl ether ) and Sodium borohydride, 2.0M in triglyme ( triethylene glycol dimethyl ether ) are the latests solutes used for storage and use of borohydrides. (Hint,hint,hint, Aa, when does someone see the light?)

From Structure Image:
Literature References: Reviews: H.C. Brown, S. Krishnamurthy, Tetrahedron 35, 567 (1979); G.W. Gribble, C.F. Nutaitis, Org. Prep. Proc. Int. 17, 317 (1985); Reduction of carboxylic acid derivatives: S.R. Wann, et al., J. Org. Chem. 46, 2579 (1981); E. Santaniello, et al., ibid. 46, 4584 (1981); K. Soai, et al., Synth. Commun. 12, 463 (1982); A. Giannis, K. Sandhoff, Angew. Chem. 101, 220 (1989); Reduction of acid chlorides to aldehydes: J.H. Babler, Synth. Commun. 12, 839 (1982)

And that long post of mine about that fabulous website of that US professor about imines, you have to look that one up again. (was not the right link up there with that java script)

Here come a few very interesting ones:
Organic Syntheses via Boranes, Volume I and II, prof. H.C.Brown from Purdue Uni.

Synthetic Applications of Zinc Borohydride:
Nice piece of research, look at the references, don't forget to read nr.2, and all the ones with those funky Indian names in them. He worked 4 years with prof.H.C. Brown at Purdue University.
And then they went on in India to research further, and came up with that link I gave once in Serious Chemistry as an answer to RevDrone's question about the inner workings of the NaBH4 onepot.
(Zinc borohydride has unique properties. Unfortunately, it is also not stable long enough to be offered commercially; hence, it must be prepared in situ.)  ( METAL BOROHYDRIDES )
Read the references from Dr. Narasimhan.

Ehh, read this one too:  Magtrieve superoxidant ( CrO2 ).
Ehh, threw this one also in, can't resist:
Aldrich Techware LaBNoteBook, lots of interesting toys:  and then look at this baby:
Newly designed to stir high volumes of
liquid (up to 5 gallons) with ease
• One year warranty
• 120 volt; 100 to 1,100rpm stir range
• Rugged ABS top, 11 x 11 inch.

(Chief Bee)
12-27-01 13:21
No 250801
      Re: Amphetamine from phenylalanine     

LT: I'm interested in those glyme solutions. Exactly at what URL did you find that information? Your hints on this are referring to easier addition of NaBH4 to your reductive amination, right?
12-29-01 03:27
No 251092
      Re: Amphetamine from phenylalanine     

You 're right.  Diborane is toxic as hell, I find it a good practice to follow articles and not to make modifications because the chemists that publish the articles give - in the most of the cases - an optimised procedure that will work.

Thanks for the information about N-Selectride. How much does N-Selectride cost?

I think that the previous reaction where they substitute the alcohol for the iodide, is the Mitsunobu reaction.  But it seems that they have used imidazole instead of diethyl azodicarboxylate to activate the triphenylphosphine toward nucleophilic attack by the alcohol.
(Chief Bee)
12-29-01 09:09
No 251118
      Re: Amphetamine from phenylalanine     

Thanks for typing that one in Cyrax, I have illustrated it and archived it at my page now:
../rhodium/chemistry /amphetamine.phenylalanine.html

N-Selectride goes for about $40 for 100ml 1.0 M solution in THF (and $200 for 800ml) from Aldrich.

I think the synthesis is a pretty elegant one, even though it is not exactly optimized for economy and common chemicals. But as it is indeed a novel synthesis, it makes it much more interesting. I believe there were only Repke's LAH/SOCl2/LAH route that had been published on the reduction of Phenylalanine to Amphetamine until now.
12-29-01 15:07
No 251170
      Re: Amphetamine from phenylalanine     

Rhodium, you have made a nice HTML page out of it.  I was glad to type it.  I totally aggree with you: since this is a rather unusual reaction path to get dexedrine, it is very interesting.  And if you want to be original, this is the way to do it.  I like creative reactions very much.

I do not think that this is a good procedure for large scale productions.  However, this procedure can be good for 'recreational' organic chemists smile
(Chief Bee)
05-10-04 09:19
No 506236
      D-Amphetamine from L-Phenylalanine
(Rated as: excellent)

In addition to the above procedure, phenylalanine (or tyrosine, 4-methoxyphenylalanine) has been reduced to amphetamine (or 4-methoxyamphetamine) via the methods below.

If you "cut and paste" different steps from the different procedures, you can come up with rather simple protocols for the preparation of dextro-amphetamine from L-Phenylalanine. I especially like the possible reduction of the N-protected phenylaninol tosyl ester to the corresponding N-protected amphetamine with NaI/Zinc in over 80% yield.

The sodium borohydride reduction of phenylalanine to phenylalaninol has been covered before in Post 459611 (Rhodium: "Reduction of Phenylalanine to Phenylalaninol", Stimulants) and in Post 459750 (Rhodium: "Phenylalaninol, exact procedure", Stimulants). The nitrogen has to be protected before the tosylate ester is formed, or the product will just be an unusable dimer.

Synthesis of Dextroamphetamine Sulfate and Methamphetamine Hydrochloride from D-Phenylalanine
Repke, DB, Bates, DK, Ferguson, WJ
Journal of Pharmaceutical Sciences 67, 1167-1168 (1978) (../rhodium/chemistry /amph.phenylalanine.html)
____ ___ __ _

Synthesis of Optically Active 4-Methoxyamphetamine from Tyrosine
Harumichi Kohno, Takeo Iwakuma and Koichiro Yamada
Synthetic Communications, 28(11), 1935–1945 (1998) (../rhodium/chemistry /tyrosine2pma.html)

Optically active 4-methoxy-α-methylphenylethylamine (1), a useful chiral building block in medicinal chemistry, was synthesized from L- or D-tyrosine by using a simple and efficient procedure via one-pot zinc reduction of the corresponding O-tosylate (4) in the presence of H2O and Nal in pure form.

This article has also been referenced in Post 375675 (GC_MS: "this...", Novel Discourse) and Post 108462 (dormouse: "Action of (CH3)2SO4 on phenylalanine  -Labrat", Novel Discourse)
____ ___ __ _

Conversion of chiral amino acids to enantiomerically pure α-methylamines
B. G. Donner
Tetrahedron Letters, 36(8), 1223-1226 (1995) (../rhodium/pdf /phenylalanine2boc-amphetamine.ra-ni.pdf)

Enantiomerically enriched α-methylamines are obtained in high yield by Raney nickel reduction of N-Boc-protected, amino acid-derived thioethers.

The Hive - Clandestine Chemists Without Borders