Author Topic: Synthesis of 4-Fluoroamphetamine  (Read 19390 times)

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Rhodium

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Synthesis of 4-Fluoroamphetamine
« on: May 06, 2001, 05:25:00 PM »
I cannot seem to find any good references on the preparation of 4-fluorophenyl-2-nitropropene, is there anyone out there who could help me with a literature search?
The only ref on 4-fluorophenethylamines I can find is an article which starts with 4-fluorophenylmagnesium bromide, reacts this with ethylene oxide, brominates the resulting alcohol, and reacts the phenethylbromide with alcoholic NH3 in a bomb. I don't think that's a good route.

LAH is able to remove aromatic halogens, is this true for fluorine too? Does Red-Al have the same disadvantage?

See

http://rhodium.lycaeum.org/pharmacology/pfa.txt

for some info on 4-fluoro-amphetamine.





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Osmium

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #1 on: May 06, 2001, 08:47:00 PM »
As far as I know LAH will leave the fluorine intact.

The only fluorination reaction I can think of right now is the thermal decomosition of diazonium fluoroborates. Very ugly, very toxic, very corrosive reaction.

obituary

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #2 on: May 06, 2001, 09:15:00 PM »
surely, obit is missing something, but would sandmeyer work here?

Rhodium

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #3 on: May 07, 2001, 08:32:00 AM »
4-fluorobenzaldehyde is cheap, so that is a good starting material. But EDDA is a lousy condensation catalyst for this nitropropene, so I hoped that you had better suggestions.


http://rhodium.lycaeum.org


Lilienthal

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #4 on: May 08, 2001, 04:54:00 AM »
Maybe it's only a problem of their crystallization, not of their yield. Sometimes fluorinated compounds behave a bit strange. If I remember correctly it should be possible to use LiAlH4. For dehalogenation you usually need drastic conditions compared to nitropropene reduction.

xtaldoc

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #5 on: May 08, 2001, 07:57:00 AM »
Rodium,
I have to agree with the Mod on this one. And also, Vitride will dehalogenate as well, but I believe that this reducing agent also requires somewhat brutal conditions to pull it off. I do have a glimmer of a tid-bit for you to chew on, however. You'll have to decide if its worth chasing after...
Back in 1988 or so, Swix was working on a project that involved synthesis of 1-[2,5-dimethoxyphenyl]-1-methoxy-2-aminoethane and didn't like the method or the yeilds given for the routes suggested in the literature so far studied.
While looking around for another plan of attack, Swix noticed an interesting paper in the Canadian J. Med. Chem that illustrated an interesting variant of the well known 'Henry' rxn but with a somewhat novel catalyst employed. The catalyst in question was KF.  Odd to see this employed in a reaction usually carried out with a basic catalyst, no?  Anyhow, the fact that it was KF and you seem to bee having difficulty getting the 'Henry' to fly with your 4-Fluoro benzaldehyde in the mix makes me wonder....maybe this other catalyst would be an interesting thing to try.  Problem is, I dont recall the details of the cite, save that it was Can.J.Med.Chem. :(  I do believe that the paper was authored about circa 1974 and a little voice in my head is whispering that the author's name was Nichols, but that last notion is very 'iffy', I'm afraid.
What I can say is that the rxn itself was a real easy go: it went rapidly and generally in quite high yeilds at close to room temp and was run in alcoholic solvents, as well as neat with nearly identcal result to yeild the nitroalcohol.  This should pose no real problem in dehydration, I imagine.  As I recall; 1 mole of the aldehyde is added to 1.1 mole nitoalkane and (optional) diluted with a lower alcohol at about 1:5 to the reagent vol. KF is then added, to the extent of approx o.1 mole% and the mixture is stirred at close to room temp. No reflux is necessary. Rxn time seemed approx 15min.


No matter where you go, there you are.....

smiley_boy

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #6 on: May 12, 2001, 08:29:00 PM »
Rh,

Are you looking for references to 4-fluoroamphetamine proper, or just any 4-fluoroamphetamine?

LAH definately has the potential to chew of aromatic bromides and iodides, but chlorides and fluorides are less susceptable. If you're still worried, you can use you LAH to prepare alane, which will leave any halide alone. Shulgin uses this technique anywhere where a the Lewis acidity of LAH causes interference with electron-pair rich substituents in order to obtain better yields (e.g. - several 2C-T's.)

2LiAlH4 + H2SO4 -> 2 AlH3 + Li2SO4 + 2 H2

As would be expected, lower temps are good (O C is about right, if I remember.)

Here are a few references citing fluorinated nitrostyrenes being reduced to phenethylamines. The second one in the list explicitly includes 4-fluoroamphetamine using LAH, though the yields are not so impressive (52%.)

J.Med.Chem.; EN; 11; 4; 1968; 814-819;
J.Med.Chem.; EN; 33; 7; 1990; 2015-2019;
J.Med.Chem.; EN; 35; 16; 1992; 2970-2978;
J.Med.Chem.; EN; 33; 9; 1990; 2408-2412;
J.Med.Chem.; EN; 29; 11; 1986; 2250-2256;
Synth.Commun.; EN; 24; 3; 1994; 417-426;
Farmaco Ed.Sci.; EN; 43; 1; 1988; 49-60;
J.Med.Chem.; EN; 38; 25; 1995; 4929-4936;
J.Fluorine Chem.; EN; 74; 2; 1995; 303-306;
Med.Chem.Res.; EN; 6; 5; 1996; 318 - 332;
J.Med.Chem.; EN; 39; 21; 1996; 4261-4274;
Eur.J.Med.Chem.Chim.Ther.; EN; 34; 2; 1999; 137 - 152;

Alternatively, if you're still paranoid that LAH will do bad things to your fluoride, you can use borane/diborane complexes as your hydride source. BH3*THF is cheap and reasonably available, and is especially mild in this regard. The yields are generally good using that too.

So now that I've answered the question, tell me what's interesting about 4-fluoroamphetamine? Do you know something the rest of us don't? ;)

Lem2

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #7 on: May 12, 2001, 09:50:00 PM »
I don't mean to sound like an ass, but I just wanted to say that KF is a salt of a strong base and a weak acid, which would make it basic.

Rhodium

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #8 on: May 13, 2001, 05:38:00 AM »
As I have read that 4-fluoroamphetamines aren't neurotoxic like the other haloamphetamines, and that the effects are very close to that of regular amph/meth but more mellow, and because of the fact that they are legal in most of the civilized world (except the US of course), I feel they should be explored in more detail as stimulants.


http://rhodium.lycaeum.org


xtaldoc

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #9 on: May 13, 2001, 08:30:00 AM »
Re: I dont mean to sound like an ass...

Dont worry about sounding like an ass or questioning anything from anybody.  Anyone who cant handle being questioned is an 'ass', IMHO.

To answer; according to the Merck Index, anhydrous HF is one of the most acidic substances known; its Hammett acidity function (Ho) being -10.98. 8)


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Remember..."If its from URANUS, you've already tried it".

Rhodium

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #10 on: May 13, 2001, 08:41:00 AM »
Yes, but the acidity of HF in aqueous solution is not that great (due to the poor hydration of fluoride ion). It all depends on what kind of solvent and reaction you are talking about.


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xtaldoc

  • Guest
Re: Acidity of KF
« Reply #11 on: May 13, 2001, 10:00:00 AM »
Yes indeed. If it was a snake I'd bee bit!
Thank you very much, Rhodium: I will ammend my thinking to comply with obvious reality hereafter.... Thanks also to Lem2, without who's comments I'd bee less clear.
Best regards to all!

"If ignorance was bliss, I wouldn't need drugs"


Sole proprietor of URANUS LABS,Inc.
Remember..."If its from URANUS, you've already tried it".

xtaldoc

  • Guest
Re: Acidity of KF
« Reply #12 on: May 13, 2001, 02:07:00 PM »
You know, in my 1st post to this thread I mentioned KF and quoted the original work without really doing any of my own thinking.  It was all part of a past dream, as it were.  But the question of KF's relative acidity being solvent dependant, having been nicely answered by Rhodium, still leaves me wondering, since the paper that reported KF as a catalyst for this reaction was using it in two different solvent systems.  Actually, EtOH and no solvent. What is the answer under these conditions?  I would think this would imply less basicity, no?

"Only users lose drugs"


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Remember..."If its from URANUS, you've already tried it".

Rhodium

  • Guest
Re: Acidity of KF
« Reply #13 on: May 13, 2001, 03:44:00 PM »
I guess it was me expressing it clumsy. In solution in protic solvents (like water, and also alcohols) the fluoride anion is poorly solvated (not specifically hydrated as I wrote) because of its small size (not many hydrogen bonds can form with it). Bromide and iodide are larger, and are therefore more easily stabilized in solution, through forming hydrogen bonds with many solvent molecules, and therefore HI and HBr more easily gives up a proton than HF, and in protic solvents HF is therefore less dissociated, and hence a weaker acid.

In the case of the reaction being run with no solvent, I am not sure about what happens.



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xtaldoc

  • Guest
Re: Acidity of KF
« Reply #14 on: May 13, 2001, 04:39:00 PM »
Thanks again, Rhodium. Your response was both rapid and complete! Now - if Swix could just get all his reactions to bee like that.....(LOL!)
As far as relative acidity in a non hydroxylic solvent or no solvent (except the reactants themselves) at all; could it be that, since the definition of acidity changes with context (we swap models), there isn't always a perfect way to describe that relative quality when the example falls between the contextural cracks in the models we've set up?

" Whutta ya mean 'it'll make me go blind -- can't I just go til I need glasses??"


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Remember..."If its from URANUS, you've already tried it".

foxy2

  • Guest
Re: Acidity of KF
« Reply #15 on: May 22, 2001, 01:35:00 AM »
Here is an idea Rhodium, possibly use this procedure on para-amino P2P or para-amino phenylnitropropene(HF might react with the unsaturated bond??) or para-amino phenyl nitropropane to get the para-fluoro derivative.  Just after a quick glance the procedure seems fairly straight forward, just need HF.
Foxy

United States Patent  4,487,969 
Boudakian  December 11, 1984 
--------------------------------------------------------------------------------
Production of m-fluoroacetophenone

Abstract
A process for the production of m-fluoroacetophenone comprises reacting m-aminoacetophenone with a diazotization agent in the presence of hydrogen fluoride. The diazonium fluoride compound produced is decomposed by heating to produce highly pure m-fluoroacetophenone in good yields.

What is claimed is:

1. A process for the production of m-fluoroacetophenone which comprises reacting m-aminoacetophenone with a diazotization agent and hydrogen fluoride to produce a corresponding diazonium fluoride; and decomposing the diazonium fluoride to produce m-fluoroacetophenone.

2. The process of claim 1 in which said diazotization agent is selected from the group consisting of sodium nitrite, potassium nitrite, nitrous anhydride, nitrous acid, nitrosyl halide, and a complex of a nitrosyl halide with hydrogen fluoride.

3. The process of claim 2 wherein ammonium ions are also provided by adding to the hydrogen fluoride an ammonium ion generating compound selected from the group of anhydrous ammonia, aqueous ammonia, ammonium fluoride, ammonium bifluoride, a solvate of ammonium fluoride with hydrogen fluoride, a soluble non-fluoride ammonium salt, and combinations thereof.

4. The process of claim 3 in which said diazonium fluoride is decomposed by heating at a temperature in the range of from about 15.degree. C. to about 100.degree. C.

5. The process of claim 4 wherein said diazotization and decomposition steps are conducted in a solution of hydrogen fluoride containing from about 2.5 to about 15 mole percent of ammonium ion, and from about 7.5 to about 25 moles of hydrogen fluoride are present per one mole of said m-aminoacetophenone.

6. The process of claim 5 wherein said ammonium ions are formed by adding ammonium bifluoride to said hydrogen fluoride.





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lugh

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Synthesis of 4-Fluoroamphetamine
« Reply #16 on: May 22, 2001, 09:59:00 AM »
Lithium Aluminum Hydride doesn't displace the fluorine in saturated fluorocarbons, and can reduce chlorine, bromine and iodine while leaving the fluorine group intact according to JCS 61, (1955). The authors suggest that using ether is essential as RX-OEt2 complexes aid in halide displacement reactions, and that the hydride ion is able to overcome the flourine shielding. Also see JCS 1251 & 4695, (1951);  4426, (1954);1749, (1955); 148, (1959); 3198, (1961); & 4828, (1963).

Whizard

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #17 on: August 03, 2001, 01:52:00 PM »
This is my first post so bear with me. 4-flourobenzaldehyde is available commercially and the standard rxn with nitroethane should work. Alternately would a reaction of 4-bromobenzaldehyde with KF in DMF give the first compound? The bromo synthesis is in Vogel. :)

slappy

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #18 on: August 04, 2001, 06:01:00 AM »
What about 4-Trifluoromethylamphetamine? Does anyone have any pharmacological information on this compound? 4-tfm-benzaldehyde is also commercially available.

slappy

  • Guest
Re: Synthesis of 4-Fluoroamphetamine
« Reply #19 on: August 05, 2001, 07:16:00 PM »
Just in case anyone is interested, here are a couple ref's on p-Fluoroamphetamine. The second one includes pharmacolgical data.

J.Med.Chem., EN, 33:7, 1990, p2015-2019
Eur.J.Pharmacol., EN, 287:2, 1995, p105-114