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All 44 posts   Subject: Synthesis of 4-Fluoroamphetamine   Please login to post   Down

 
    Rhodium
(Chief Bee)
05-07-01 00:25
No 189662
User Picture  		      Synthesis of 4-Fluoroamphetamine     

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.



http://rhodium.lycaeum.org 		 
 
 
 
    Osmium
(Stoni's sexual toy)
05-07-01 03:47
No 189716
       Re: Synthesis of 4-Fluoroamphetamine     

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
(Hive Addict)
05-07-01 04:15
No 189726
       Re: Synthesis of 4-Fluoroamphetamine     

surely, obit is missing something, but would sandmeyer work here? 		 
 
 
 
    Rhodium
(Chief Bee)
05-07-01 15:32
No 189827
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

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
(Moderator)
05-08-01 11:54
No 192659
       Re: Synthesis of 4-Fluoroamphetamine     

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
(Mega Meth Man)
05-08-01 14:57
No 192680
       Re: Synthesis of 4-Fluoroamphetamine     

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.frown 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
(Hive Bee)
05-13-01 03:29
No 193923
       Re: Synthesis of 4-Fluoroamphetamine     

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?wink 		 
 
 
 
    Lem2
(Stranger)
05-13-01 04:50
No 193933
       Re: Synthesis of 4-Fluoroamphetamine     

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
(Chief Bee)
05-13-01 12:38
No 194010
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

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
(Mega Meth Man)
05-13-01 15:30
No 194035
       Re: Synthesis of 4-Fluoroamphetamine     

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.cool

Sole proprietor of URANUS LABS,Inc.
Remember..."If its from URANUS, you've already tried it". 		 
 
 
 
    Rhodium
(Chief Bee)
05-13-01 15:41
No 194038
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

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.

http://rhodium.lycaeum.org 		 
 
 
 
    xtaldoc
(Mega Meth Man)
05-13-01 17:00
No 194057
       Re: Acidity of KF     

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
(Mega Meth Man)
05-13-01 21:07
No 194100
       Re: Acidity of KF     

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"

Sole proprietor of URANUS LABS,Inc.
Remember..."If its from URANUS, you've already tried it". 		 
 
 
 
    Rhodium
(Chief Bee)
05-13-01 22:44
No 194127
User Picture  		      Re: Acidity of KF     

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.

http://rhodium.lycaeum.org 		 
 
 
 
    xtaldoc
(Mega Meth Man)
05-13-01 23:39
No 194142
       Re: Acidity of KF     

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??"

Sole proprietor of URANUS LABS,Inc.
Remember..."If its from URANUS, you've already tried it". 		 
 
 
 
    foxy2
(Hive Addict)
05-22-01 08:35
No 196085
       Re: Acidity of KF     

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.



Do Your Part To Win The War 		 
 
 
 
    lugh
(Hive Bee)
05-22-01 16:59
No 196141
       Synthesis of 4-Fluoroamphetamine     

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
(Stranger)
08-03-01 20:52
No 201095
       Re: Synthesis of 4-Fluoroamphetamine     

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.smile 		 
 
 
 
    slappy
( )
08-04-01 13:01
No 201310
       Re: Synthesis of 4-Fluoroamphetamine     

What about 4-Trifluoromethylamphetamine? Does anyone have any pharmacological information on this compound? 4-tfm-benzaldehyde is also commercially available. 		 
 
 
 
    slappy
( )
08-06-01 02:16
No 201685
       Re: Synthesis of 4-Fluoroamphetamine     

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 		 
 
 
 
    Whizard
(Stranger)
08-10-01 19:28
No 203216
       Re: Synthesis of 4-Fluoroamphetamine     

My main interest in pursuing this was 4-Fluoromethamphetamine. Which is potentially a more active compound then it's unsubstituted derivative. I understand that the aldehyde is not very reactive to Nitroethane. Does anyone have data on 4-Fluoromethamphetamine activity or the aldehyde's reactivity?
I dunno, but I been told ... You never slow down, you never grow old! 		 
 
 
 
    Rhodium
(Chief Bee)
08-10-01 20:05
No 203228
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

From the JMC reference given above:

4-fluorobenzaldehyde (24.8g, 0.2 mol), nitroethane (30g, 0.4 mol), 20ml of isopropanol and 1 ml butylamine were heated under reflux for 5h. The reaction mixture was allowed to cool to room temperature overnight while crystallization occured. The crude yellow product was filtered and recrystallized from methanol to afford 20g (55%, 0.11 mol) of pale yellow crystals (mp 64-66°C). 		 
 
 
 
    obituary
(Hive Addict)
08-10-01 22:09
No 203255
       Re: Synthesis of 4-Fluoroamphetamine     

is the sub. bz.aldehyde watched at all? 

is there any pharma info for 4-F-Meth? 		 
 
 
 
    Rhodium
(Chief Bee)
08-10-01 23:08
No 203279
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

The aldehyde is completely unwatched. Pharmacological information can be found in Eur.J.Pharmacol., EN, 287:2, 1995, p105-114, which largely says it is a stimulant similar to amphetamine, and is not similar to serotonergic agents like MDMA, and therefore is not toxic to serotonergic neurons like the other 4-haloamphetamines.

A subjective test by Mobius can be read at https://www.rhodium.ws/pharmacology/pfa.txt 		 
 
 
 
    Whizard
(Stranger)
08-11-01 06:08
No 203383
       Re: Synthesis of 4-Fluoroamphetamine     

Thanks for the details of the JMC citation. Your write up "Ethylenediammonium diacetate - a mild and effective Henry reaction catalyst" led me to have little hope of this aldehyde's cooperative nature.
BTW is JMC available to online?smile
I dunno, but I been told ... You never slow down, you never grow old! 		 
 
 
 
    Rhodium
(Chief Bee)
08-11-01 17:30
No 203498
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

JMC is available online, but you will have to pay per credit card for all articles you want to access. 		 
 
 
 
    Whizard
(Stranger)
08-13-01 05:28
No 204010
       Re: Synthesis of 4-Fluoroamphetamine     

So are you offering me the use of your credit card (OFOM!). Seriously, I started my quest investigating the preparation and (possible) activity of 4-fluoromethampetamine after the citation in "Future Synthetic Drugs of Abuse" which I believe you are familiar with...

Alternatively, the use of 1-(4-fluorophenyl)propan-2-one, in place of P2P, would almost certainly give a product with adrenomimetic properties, and may in fact be considerably more potent than methamphetamine.

The underlying question is: Is there a compound which is stronger (as a stimulant as defined LOC CIT) than Methamphetamine?

I dunno, but I been told ... You never slow down, you never grow old! 		 
 
 
 
    Rhodium
(Chief Bee)
08-13-01 14:00
No 204081
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

I really don't know, and I have asked this myself earlier. I think slappy had a QSAR on stimulants, and I hope he will be posting the reference soon. 		 
 
 
 
    slappy
(Hive Bee)
08-14-01 11:20
No 204388
       Re: Synthesis of 4-Fluoroamphetamine     

Rhod, I am currently away from all of my ref's, and will remain so for the rest of the month. When I get access to a local university library, and Beistien & CAS I can find it for you.

I seem to recall them mentioning that electron injecting substituents maintained or (rarely) increased potency, and electron withdrawing substituents usually decresed potency (especially -NO2). Electron density at the aromatic ring is also important along with even electron distrobution, and unreactivity. Replacment of the benzene ring with similar aromatic heterocycles resulted in reduced potency. The furan, thiophene, pyrrole, pyridine, and pyrimidine analouges were explored. 		 
 
 
 
    randolph_carter
(Hive Bee / Eraser)
08-28-01 13:07
No 207995
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

well well ..
hey now....
ye bee a talkin about my ole favourite da fluorinated amphez...
i've did a lil research in this arena and i can most certainly comment on the READY availablity of 2 fluoro p2p (think acros...sig/flu/ald...)which i can assure you is a MUCH more pleasant dream than the 4 fluoro varietal...a lil pricey tho i.e. $3-$6/g but it is "puriss" grade...
neurotoxicity is lower than other halogens by a mile....
although on perusing da sig catalog i find 4 cl MeAmp available uncontrolled and served neat @ $150/g also noted some 4-fluoro cmpds as well...
they do taste great and they are much less filling...
R_C
"remember little ones, love is real,not fade away, so pass some ammo on today......" 		 
 
 
 
    Rhodium
(Chief Bee)
08-28-01 15:22
No 208021
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

Are you saying you have actually tried any fluoroamphetamines? In that case I would be VERY interested in hearing about your syntheses and bioassays.

Do you have any pharmacological/chemical references pertaining to other fluorinated (meth)amphetamines than 4-fluoroamphetamine?

4-Chloroamphetamines are serotonergic neurotoxins and are not stimulants. 		 
 
 
 
    randolph_carter
(Hive Bee / Eraser)
08-28-01 23:10
No 208121
User Picture  		      Re: Synthesis of 4-Fluoroamphetamine     

WELL OF COURSE!!!
i wuz a inquirin around here about 2 years ago about said compounds and really didn't get much except some old nichols quotes and some sasha redux...
so as they say inquirin m indz have GOT to know...
so on europa's farthest shore lizards obtained 2-fluoro-P2P neat via sigmoidz for some experiments...a lil leucart wallach with a dash of everyones fave n-methylformamide and voila..
what ya seek..
MUCH longer cycle to metabolize to nada than the non sub....

more raves to come later....
gotta go get some lilith bootie now....
hope to bee back soon.....


"remember little ones, love is real,not fade away, so pass some ammo on today......" 		 
 
 
 
    Bwiti
(PVC-Analog Taste-Tester)
08-15-02 12:51
No 345653
User Picture  		      Flourine + Amphetamine?     

  Rather than synthing it from 4-fluorophenyl-2-nitropropene: Dissolve freebase amphetamine in ether and gas it with flourine?? I'm probably completely off base, but it doesn't hurt to ask. Peace!cool
Love my country, fear my government. 		 
 
 
 
    Cyrax
(Hive Bee)
08-15-02 15:26
No 345666
       Bwitti, fluorine gas is very, very, very ...     

Bwiti, that yellow fluorine gas is very, very, very reactive.  It is one of the most vicious chemicals I know (if you do not take phosgene into account).  Trust me: you do not want to mess with it.  There is no way to get a regioselective reaction (mabey just a regioselective death of all the dudes that stand in the vicinity of the reaction vessel).

This comes from Advanced Inorganic Chemistry, 5th ed, Cotton F.A. p 546:  "Fluorine is the chemically most reactive of all the elements and combines directly at ordinary or elevated temperatures with all the elements other than nitrogen, oxygen, and the lighter noble gases, often with extreme vigor (whow !!!).  It also attacks many other compounds, particulary organic compounds, breaking them down to fluorides; organic materials often inflame and burn in the gas."

If some laboratory operator is broken down to fluorides, he must have been working with F2 gas crazy. 		 
 
 
 
    SPISSHAK
(Hive Bee)
08-15-02 21:03
No 345747
       What I want to know is     

where that guy that posted in novel forum on catalytic transfer hydrogenation of p2p's got that 4-fluorophenylacetone from? 		 
 
 
 
    Dr_Heckyll
(Hive Bee)
08-16-02 02:27
No 345871
       CAS#: 459-03-0     

4-FLUOROPHENYLACETONE
CAS#: 459-03-0

Available from ACROS and Lancaster. Cost ~ $10/g

DrH


http://lyricsdomain.com/lyrics/26021/ 		 
 
 
 
    Barium
(Hive Bee)
08-16-02 13:32
No 345967
       I guess that guy would be me..     

I have made my 2- and 4-FP-2-P myself of course.

They are quite easily made from the benzaldehydes and nitroethane, then reducing/hydrolysing the nitropropene by any of the routes I´ve also suggested in the novel forum.

Or, they can very easily be made by the Darzen route, also in the novel forum.

UTFSE 		 
 
 
 
    randolph_carter
10-15-02 13:58
       2 f p2p sources...
(Rated as: no sources!) 		    
 
 
 
    randolph_carter
(Hive Bee / Eraser)
10-18-02 14:08
No 369927
User Picture  		      whooops!!!!     

I forgot about that dudez...
just tryin to bee too helpful i guess....
an earnest search will locate sources suffice it to say....


"remember little ones, love is real,not fade away, so pass some ammo on today......" 		 
 
 
 
    Antoncho
(Official Hive Translator)
01-27-03 07:19
No 401822
       Fluorinated BA's - in the kitchen?     

This is certainly very very intriguing... All these funny fluoro-substituted stims.... Fluorinated 4-MAR also has to bee worthwhile...

So decided i'd dig up smth for the OTCbees like me so that they have a hope of making some at some very verysmile distant future...


Here goes:

Patent US5227531

175 g (1 mol) of 2,4-dichlorobenzaldehyde were heated together with 1,000 g of sulfolane and 151 g (2.6 mol) of potassium fluoride for 15 h at 210 DEG-215 DEG C. The reaction mixture was thoroughly mixed during the entire duration of the reaction by a powerful stirring mechanism in order to prevent the insoluble salts settling. Cooling was then carried out to room temperature and the inorganic constituents were separated off by means of a suction filter covered with a blanket of nitrogen. Rinsing was carried out twice using 100 g of fresh sulfolane in each case. From the filtrate 96.6 g=68% of theory of 2,4-difluorobenzaldehyde with a boiling point of 70.5 DEG C. (40 mbar) was obtained by rectification under reduced pressure in a column containing approx. 20 theoretical trays. Solidification point: approximately 2 DEG C.



Sulfolane ain't exactly OTC, but they also say that:


The reaction is able to proceed in a wide temperature range. Expediently, temperatures between about 120 DEG and 250 DEG C., in particular between about 180 DEG and 230 DEG C., are employed.

Suitable as solvents for the reaction are in principle all the possible dipolar aprotic solvents, preferably tertiary carboxylic acid amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N,N,N',N'-tetramethylurea, N,N'-dimethylimidazolidin-2-one, sulfoxides such as dimethylsulfoxide and sulfones such as dimethylsulfone, diphenylsulfone and sulfolane. Particularly preferred are N-methylpyrrolidone, dimethylsulfoxide and dimethylsulfone, in particular, however, sulfolane.



And there's also diethylacetamide (bp 185 C) which can bee easily made from next-to-OTC materials.



Antoncho 		 
 
 
 
    Rhodium
(Chief Bee)
01-27-03 08:14
No 401834
User Picture  		      4-Fluoroamphetamine     

Good, that complements Post 380478 (pHarmacist: "p-F-benzaldehyde from p-Cl-benzaldehyde", Methods Discourse) nicely.

I have also uploaded a 4-Fluoroamphetamine pharmacology article to my page: Eur. J. Pharmacol. 287, 105-113 (1995) (https://www.rhodium.ws/pdf/4-fluoroamphetamine.pdf) 		 
 
 
 
    Chimimanie
(Newbee)
01-29-03 23:16
No 402453
User Picture  		      kick ass synthesis of fluoro-amphetamine
(Rated as: excellent) 		    

Synthesis of N-(beta-haloalkyl)-N-alpha-dimethyl-arylethylamines and their conversion into aziridium salts, E. Zara-Kaczian, Gy Deak, J. Hasko-Breuer and A. Neszmelyi., Acta Chimica Academiae Scientiarum Hungaricae, Tomus 79 (4), pp. 433-447 (1973)

Chimimanie's voice:
This article is one of those from foreign countries that is a true pearl for us Clan'Chimist; I like those unknown journals whose contributors chose to do so many great reactions and combine them in their article, really the less subside the chemists have the greatest their work!

This article describe two quick ways to this compound, one of those is based on the 'Oh so speaked but not so tried' reaction of chloroacetone on a grignard reagent (made from the cheap p-bromo-fluoro-benzene) and the second one start from the cheap fluorobenzene and react it with allyl chloride to make the fluoro-phenyl-chloropropane derivative. I think these two methods (especially the second) are kicking ass, they make p-fluoro-amphetamine in 3 steps from unwatched and cheap precursors in not too bad yield.

Anyway 'Felicitation Mr Zara-Kaczian!'


This is an excerpt of the text:

For the grignard reaction with chloroacetone:

Reproduction of the procedure in the litterature gave the yield specified (40%), and its improvement was attempted by varying the reaction conditions.(...) It was found, however, that under certain conditions - when the reaction was carried out at 0°C in 5h - a product other than the expected one formed. It proved to be an alcohol, probably 1-chloro-2-(p-fluorophenyl)-2-propanol, that is, the addition process became the predominating reaction.

(...)

By Friedel-Crafts reaction, about the chloropropane derivative:

Another reaction path was also considered for the preparation of metamphetamine derivatives halogenated in the nucleus. The Friedel-Crafts reaction of fluoro- or chlorobenzene (Chimimanie's voice: not chlorobenzene for our purpose!) in the presence of iron (III) chloride gives a 1-aryl-2-chloropropane[6] carrying a halogen atom in the benzene ring. This product yield with methylamine the corresponding halogenated metamphetamine; when methylaminoethanol is used, the N-beta-hydroxyethyl derivative is obtained; the latter reaction has not been achived previously. (Chimimanie's voice: they give a ref with methylamine in ethanol solution in a bomb, same ref I give below, the hydroyethyl is made with a bad yield (8.7%) with methylaminoethanol as solvent, this is better to swap with azide and reduct)

(...)

When fluorobenzene was used in the reaction, the product obtained in 48% yield proved to be a mixture of ortho and para isomers (72% para, 28% ortho).


Experimental:

N,alpha-dimethyl-p-fluorophenetylamine

A mixture of p-fluorobenzyl methyl ketone (41.1 g; 0.26 mol), N-methylformamide (95.5g; 1.62 mole) and 100% formic acid (12.5 g; 0.27 mole) was refluxed in a rbf, equipped with a reflux condenser, for 12 hrs. After cooling, the solution was diluted with water (140 ml) and extracted with ether (3x140 ml). The ether was evaporated from the combined extract and the residue refluxed with conc. HCl (200 ml) for 12 hrs. After cooling, the mixture was shaken with ether (3x140 ml), the aqueous phase was made alkaline (pH 8) with 30% NaOH (about 120 ml) while cooling, then saturated with Na2CO3. An oil separated which was extracted with ether (5x140 ml) and dried over anhydrous Na2SO4. The ether was evaporated and the residue was distilled in vacuum to give a colourless liquid (26.15g; 58%) bp 86°C/4.5 torr; n20=1.4887; lit bp 87-89°C/10 torr n20=1.4922

1-o-Fluoro and 1-p-fluoro-2-chloropropane

Anhydrous iron(III) chloride (16.2g; 0.1 mole) was added to fluorobenzene (192.2g; 2.0 mole), the mixture was cooled to -21°C and allyl chloride (38.25g; 0.5 mole) was added to it dropwise during about 2hrs, with continuous cooling and stirring. Stirring was aplied for 3 hours more at -16°C, then the reaction mixture was poured into a mixture of ice (500 g) and conc. HCl (50 ml); the organic phase was washed with 1:1 HCl (3x70ml), with saturated NaHCO3 solution (2x70ml) and finally with saturated NaCl solution (2x100ml) until free from acid, then dried over anydrous Na2SO4. After evaporation of the fluorobenzene, the residue was fractionated in vacuum; the product collected at 14 torr pressure and 90-94°C temperature (41.7g; 48.4%) was a mixture of the o- and p-isomers.
The isomeric mixture was separated by means of a preparative gas chromatograph of type Carlo-Erba Fractovap Mod P , on a column packed with 6% Apieson L/Chromosorb 6 (6m in lenght, 25mm diam); H2 carrier gas and 150°C column temperature applied. blush

A blunt of ortho and para isomers is sufficiant for me...cool

The chlorine atom can be swapped with sodium azide and then reducted to the amine by various methods, UTFSE.

p-fluoro-phenylacetone From [5]

A grignard reagent was prepared from 35g (0.2 mole) of p-fluorobromobenzene and 4.6g (0.19 mole) of magnesium. To this was added 18.5 g (0.2 mole) of chl oroacetone in 50ml of ether as rapidly as the refluxing of the reaction mixture would allow. The ether was removed by heating the reaction flask in an oil-bath and at 100°C the residue foamed with formation of a gel from which ether was removed slowly by heating at 135-140°C for forty-five minutes. The flask was cooled, ice and dilute acid were added, the heavy oil which separated was removed with ether and the ether solution dried and fractionated. There was obtained 11.2g (37%) of practically pure ketone distilling at 106-107°C (18mm)

A variation of this procedure in which the reaction mixture was not heated above 100°C gave a product that could not be satisfactorily fractionated. Substantially pure ketone was finally obtained by conversion to the sodium bisulfite addition compound followed by regeneration with dilute sodium carbonate. It distilled at 108°C (18 mm) as a light yellow oil with n20d 1.4965, d20 4 1.107, Md calcd 40.07, obsd 40.17. After a few days of standing, crystals of p-fluorobenzoic acid were deposited. Carbon and hydrogen analyses gave low results even with material kept in a sealed ampoule. A solid derivative was therefore prepared. The dinitrophenylhydrazone did not form but the semicarbazone mp 200.5-201.5° separated readily. Analysis by the Jamieson method of titrating with potassium iodate gave only fair results.

alpha-Methyl-p-fluorophenetylamine ibid

A mixture of 8.7g (0.057 mole) of p-fluorobenzyl methyl ketone and 16g (0.36 mole) of formamide was heated in a 100ml rbf attached to an air condenser for twelve hours at a temperature where vigorous bubbling occured. The amide was hydrolyzed by refluxing for eleven hours, and the amine layer separated. Distillation gave 3.6g (41% yield) of pure amine, bp 95-96°c (17 mm) The amine rapidly took up CO2 from the air forming a solid salt. The hydrochloride salt melt at 156-157°C

ref:
[5]: Suter and Weston, JACS 63, 602, 1941
[6]: Patrick, F M, JACS 68, 1009 (1946) 		 
 
 
 
    pHarmacist
(Hive Addict)
02-03-03 06:38
No 403885
User Picture  		      Chimimanie     

Nice Nice, advancement indeed! Thank you friend! wink To bad that post office fucks with us eh? frown
Accept No Imitations, There Can Only Bee One; www.the-hive.ws 		 
 
 
 
    lugh
(Moderator)
06-29-04 20:50
No 516374
       Fluorination Articles     

There is no way to get a regioselective reaction



The authors of these articles seem to disagree with that statement wink

JOC 34 1387-91 (1968)



JOC 34 2835-9 (1969)



JOC 35 723-7 (1970)




cool

Chemistry is our Covalent Bond 		 
 

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