Author Topic: Monomethylation of Amphetamines  (Read 1292 times)

atara

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Re: Monomethylation of Amphetamines
« Reply #40 on: February 08, 2013, 06:24:50 AM »
Alright so the old man down the road finally decided to give this a go, heres what I witnessed:

-1.1g MDA.HCl basified, extracted twice with DCM
-DCM stripped off, the remaining base then taken up in MeOH
-To this was added 0.38ml formalin (though I screwed up the pipetting of such a small amount, inevitably this caused an excess)
-The solution of MDA formaldehyde imine was then left in a dropping funnel for ~1hr.
-in an RB, 120mg of HgCl2 (originally started with 20mg, then kept adding more to get a decent reaction rate)  and ~0.2g aluminium were amalgamated in a solution of MeOH.
-The amalgam mixture was brought to ~50°c and the MDA formaldehyde imine solution then dripped in.
-Reaction ran for ~2hrs, when most of the aluminium was used up, keeping in mind I used a decent excess of aluminium.
-Reaction volume was doubled using a solution of NaOH, then filtered to remove solids.
-The remaining liquid was extracted twice with xylene.

Yet to do the final work up to get the final result and yield (if any), will post when this is done. This is my first time witih Al/Hg and I must say I already dislike working with HgCl2, its a pain in the ass because of the precautions needed with cleaning etc. Seems like Al/Ga could be used, though im yet to find any good posts regarding its use (if anyone has any, please share).

Reference: http://www.erowid.org/archive/rhodium/chemistry/amphetamine.methylation.html

Quote
Final workup has just been completed and yielded absolutely nothing. Pretty disappointing.

Guess I might try again when I have more starting reagents to play with and up the scale a bit.

Not really sure what went wrong either, I was expecting something, even if it was a poor yield.

The problem obviously isn't in the reaction procedure. Even if we assume no reaction happened at all, the fact that your xylene xtrxn didn't give you back anything should make it clear to you that there wasn't anything in the xylene to extract: even in the total failure case, a correct work-up will give you back a decent proportion of the starting material. If I had to guess, the MDXA crashed out when you added NaOH and water to the rxn mixture, which is why none of it made it into the xylene.

Quote
Klute from memory says purification of amine can be done via distillation.
-I find this unsuitable due to working at 10 mmole scale, so instead I tried doing a mild A/B hoping it would leave behind the aldehyde and bring over the secondary amine. The indications looked good, upon basifying the acidic aqueous layer, much table salt (presumably) was visually seen and again the smell of an amine was present. A non polar extract yielded a slightly yellow solution.

"I didn't listen."

A handy tip: basify after you add the first portion of NP solvent. That way your amine doesn't end up stuck to the bottom of the glass.

Quote
Methyl bromide generated on demand for methylation. Does anything think this would not work in replacing methyl tosylate?

KI is an effective catalyst for any alkyl halide mediated methylation:

R-X + I- --> R-I + X-
R-I + R'- --> R-R' + I-

dingbow

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Re: Monomethylation of Amphetamines
« Reply #41 on: March 11, 2013, 04:24:09 AM »
...If I had to guess, the MDXA crashed out when you added NaOH and water to the rxn mixture, which is why none of it made it into the xylene.

...handy tip: basify after you add the first portion of NP solvent. That way your amine doesn't end up stuck to the bottom of the glass.
You dont always get your starting material back, if your starting material proceeded to an intermediary (whether desired or not) but did not make it to the desired end product for example. Work up was basically extraction and gassing. If whatever I extracted was not the amine, the gassing would not produce the desired salt. If there was amine present, I dont see why adding a NaOH solution would cause any issues, it would have been extracted with the non polar regardless and then given me the usual salt upon gassing.

I'll try your tip regarding extraction, though I dont think thats the issue, as I rinsed the beaker with non polar after emptying it.

dingbow

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Re: Monomethylation of Amphetamines
« Reply #42 on: March 17, 2013, 12:55:23 PM »
Reading:
http://www.mhhe.com/physsci/chemistry/carey/student/olc/ch22aldehydeskeytonesamines.html

says secondary amines react with aldehydes to form enamines. Is it possible that when the iminium salt is basified, liberating the benzaldehyde and amine, that they are reacting to form an enamine?

T-cowboy

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Re: Monomethylation of Amphetamines
« Reply #43 on: April 03, 2013, 02:41:16 PM »
are you going for another attempt dingbow`?

dingbow

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Re: Monomethylation of Amphetamines
« Reply #44 on: April 11, 2013, 01:48:09 PM »
I would like to, I still have a small yield from the last batch I want to bio-assay. Its difficult working these days, I dont get much opportunity. Sometime in the future I will

atara

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Re: Monomethylation of Amphetamines
« Reply #45 on: April 18, 2013, 06:29:36 PM »
The attached paper describes the reaction of organocuprates with amines. Usually organocuprates are prepared from [pyrophoric!] organolithium reagents, but the methyl cuprate can be had via a methyl Grignard.

The reaction is:

MeMgCl + CuI --> [MeCu]
MeCu + RR'NH --> RR'NCuMe
RR'NCuMe + O2 --> RR'NMe

Typical solvent is THF; the reaction is selective for monomethylation. Reaction conditions are given in the paper.

no1uno

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Re: Monomethylation of Amphetamines
« Reply #46 on: April 28, 2013, 06:56:41 AM »
Chloral (http://www.erowid.org/archive/rhodium/chemistry/chloralhydrate.html) will form the n-formyl derivative (+CHCl3), might be useful
« Last Edit: April 28, 2013, 06:58:53 AM by no1uno »
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uchiacon

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Re: Monomethylation of Amphetamines
« Reply #47 on: May 26, 2013, 04:34:44 AM »
Alright so the old man down the road finally decided to give this a go, heres what I witnessed:

-1.1g MDA.HCl basified, extracted twice with DCM
-DCM stripped off, the remaining base then taken up in MeOH
-To this was added 0.38ml formalin (though I screwed up the pipetting of such a small amount, inevitably this caused an excess)
-The solution of MDA formaldehyde imine was then left in a dropping funnel for ~1hr.
-in an RB, 120mg of HgCl2 (originally started with 20mg, then kept adding more to get a decent reaction rate)  and ~0.2g aluminium were amalgamated in a solution of MeOH.
-The amalgam mixture was brought to ~50°c and the MDA formaldehyde imine solution then dripped in.
-Reaction ran for ~2hrs, when most of the aluminium was used up, keeping in mind I used a decent excess of aluminium.
-Reaction volume was doubled using a solution of NaOH, then filtered to remove solids.
-The remaining liquid was extracted twice with xylene.

Yet to do the final work up to get the final result and yield (if any), will post when this is done. This is my first time witih Al/Hg and I must say I already dislike working with HgCl2, its a pain in the ass because of the precautions needed with cleaning etc. Seems like Al/Ga could be used, though im yet to find any good posts regarding its use (if anyone has any, please share).

Reference: http://www.erowid.org/archive/rhodium/chemistry/amphetamine.methylation.html

Quote
Final workup has just been completed and yielded absolutely nothing. Pretty disappointing.

Guess I might try again when I have more starting reagents to play with and up the scale a bit.

Not really sure what went wrong either, I was expecting something, even if it was a poor yield.

The problem obviously isn't in the reaction procedure. Even if we assume no reaction happened at all, the fact that your xylene xtrxn didn't give you back anything should make it clear to you that there wasn't anything in the xylene to extract: even in the total failure case, a correct work-up will give you back a decent proportion of the starting material. If I had to guess, the MDXA crashed out when you added NaOH and water to the rxn mixture, which is why none of it made it into the xylene.

Quote
Klute from memory says purification of amine can be done via distillation.
-I find this unsuitable due to working at 10 mmole scale, so instead I tried doing a mild A/B hoping it would leave behind the aldehyde and bring over the secondary amine. The indications looked good, upon basifying the acidic aqueous layer, much table salt (presumably) was visually seen and again the smell of an amine was present. A non polar extract yielded a slightly yellow solution.

"I didn't listen."

A handy tip: basify after you add the first portion of NP solvent. That way your amine doesn't end up stuck to the bottom of the glass.

Quote
Methyl bromide generated on demand for methylation. Does anything think this would not work in replacing methyl tosylate?

KI is an effective catalyst for any alkyl halide mediated methylation:

R-X + I- --> R-I + X-
R-I + R'- --> R-R' + I-

So there just happens to be several hundred mL of methyl iodide lying around in the neighbours garage. He is a retired chemist.

Did anyone happen to have a source for that methyl iodide methylation of the primary amine?

lugh

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Re: Monomethylation of Amphetamines
« Reply #48 on: May 26, 2013, 05:32:01 AM »
Rhodium stated in the first paragraph from:

http://www.erowid.org/archive/rhodium/chemistry/amphetamine.methylation.html

that:

There are many procedures out there for the production of N-methyl-amphetamines (methamphetamines) from various starting materials, such as phenyl-2-propanone (P2P) or ephedrine, but what if you already have an amphetamine (or phenethylamine) and wanted to add a methyl group to the nitrogen atom? If you would use the first reaction that comes to mind for the conversion, to alkylate the amphetamine with methyl iodide or dimethylsulfate, you would be disappointed, as you would get a mixture of products, most important the N,N-dimethyl-amphetamine (of very low activity), as once the amphetamine has been methylated to methamphetamine, the molecule is much more succeptible to another alkylation, and thus the dimethyl- amphetamine is formed much faster than the remaining amphetamine is alkylated to methamphetamine. Actually, in the reaction mix you would find unreacted amphetamine, N-methylamphetamine, N,N-dimethyl- amphetamine and even some of a quaternary N,N,N-trimethylamphetammonium salt.

you would get mostly N,N-dimethyl amphetamine  ::)  Studying this thread and that web page should answer most if not all questions pertaining to N monomethylation  8)
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uchiacon

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Re: Monomethylation of Amphetamines
« Reply #49 on: May 26, 2013, 05:37:06 AM »
Bugger.

So I suppose

"Another way is to react the amine with benzaldehyde to form an imine, which then can safely be alkylated with methyl iodide or dimethyl sulfate, and after hydrolysis of the resulting compound, N-Methylamphetamine is formed."

Would be the only practical way? Using MeI of course.

carl_nnabis

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Re: Monomethylation of Amphetamines
« Reply #50 on: May 26, 2013, 06:59:37 AM »
But what about this one? From doktor Shulgin himself?
His route can only monomethylate:

Quote from: pihkal
SYNTHESIS: (from MDA) A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no further H2O was generated (about 20 h was sufficient, and 1.4 mL H2O was collected).
Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in 100 mL CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally once again with dilute acid.
The solvent was removed under vacuum giving 7.7 g of an amber oil that, on standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine.
An alternate process for the synthesis of this amide involved holding at reflux for 16 h a solution of 10 g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles yielded an oil that set up to white crystals, weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL anhydrous THF was added dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL anhydrous THF under an inert atmosphere.
The reaction mixture was held at reflux for 4 days.
After being brought to room temperature, the excess hydride was destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4 mL of 15% NaOH and then another 22 mL H2O.
The solids were removed by filtration, and the filter cake washed with additional THF.
The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in 200 mL CH2Cl2.
This solution was extracted with 3x100 mL dilute HCl, and these extracts pooled and made basic with 25% NaOH.
Extraction with 3x75 mL CH2Cl2 removed the product, and the pooled extracts were stripped of solvent under vacuum.
There was obtained 6.5 g of a nearly white residue which was distilled at 100-110 ° C at 0.4 mm/Hg to give 5.0 g of a colorless oil.
This was dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the addition of sufficient anhydrous Et2O to produce a lasting turbidity.
On continued stirring, there was the deposition of fine white crystals of 3,4-methylenedioxy-N-methylamphetamine hydrochloride (MDMA) which were removed by filtration, washed with Et2O, and air dried, giving a final weight of 4.8 g.
Oh, now I see...
Nobodys talking about this routes because it REQUIRES lithium aluminum hydride and nothing else can faciliate an amide to amine reduction, that must be the reason  :-\

So I suppose

"Another way is to react the amine with benzaldehyde to form an imine, which then can safely be alkylated with methyl iodide or dimethyl sulfate, and after hydrolysis of the resulting compound, N-Methylamphetamine is formed."

Would be the only practical way? Using MeI of course.
Seems feasible, taken into account that in a basic milieu an imine will form which in an acidic milieu will cleave the aminogroup...
But on the other hand, amphetamine is more likely to add two N-benzylimino groups than only one, so what lugh has quoted applies in this case here too.
You have to seperate the full alkylated imino dibenzylimino and the unalkylated virgin-amines from your wanted monoalkylated benzyliminoamphetamin and all that even before it gets really nasty with the MeI-alkylation, wont be easy.
« Last Edit: May 26, 2013, 07:13:44 AM by carl_nnabis »
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uchiacon

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Re: Monomethylation of Amphetamines
« Reply #51 on: May 26, 2013, 07:32:04 AM »
looks like LAH is the only way to go.

:(

lugh

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Re: Monomethylation of Amphetamines
« Reply #52 on: May 26, 2013, 04:27:57 PM »
The attached patent filed by Doctors Keil and Dobke describes how to reduce the imine with al-hg  ;)  You all need to start reading long enough to understand the subject before touching a keyboard  ::) Comprehension takes time, otherwise nothing is accomplished   :P The end really does result from the effort applied  8)
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no1uno

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Re: Monomethylation of Amphetamines
« Reply #53 on: June 06, 2013, 12:27:50 PM »
I wonder, just hypothetically, from something Atara mentioned in another thread, a weak alkylating agent like ammonium methyl sulfate might work, it is probably going to take forever (which would stop a lot of dimethyl and trimethylation), but it might be worth a shot.

Dingbow, if you run an AB on benzaldehyde you are going to get benzoic acid (and benzyl alcohol). You may have the amide, more likely the benzoate salt, depends how hard you pushed it I suppose.
« Last Edit: June 06, 2013, 12:30:26 PM by no1uno »
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uchiacon

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Re: Monomethylation of Amphetamines
« Reply #54 on: June 06, 2013, 12:54:40 PM »
The attached patent filed by Doctors Keil and Dobke describes how to reduce the imine with al-hg  ;)  You all need to start reading long enough to understand the subject before touching a keyboard  ::) Comprehension takes time, otherwise nothing is accomplished   :P The end really does result from the effort applied  8)

My guess lugh, that for the next generation of bees, the quick gratification of the internet has ruined our patience to search extensively for resources. As always, the input it appreciated.

I wonder how many times you have said "the end really does result from the effort applied"

Keen to try the benzaldehyde route.

atara

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Re: Monomethylation of Amphetamines
« Reply #55 on: June 06, 2013, 01:53:04 PM »
I wonder, just hypothetically, from something Atara mentioned in another thread, a weak alkylating agent like ammonium methyl sulfate might work, it is probably going to take forever (which would stop a lot of dimethyl and trimethylation), but it might be worth a shot.

Dingbow, if you run an AB on benzaldehyde you are going to get benzoic acid (and benzyl alcohol). You may have the amide, more likely the benzoate salt, depends how hard you pushed it I suppose.

My guess would be to try to prepare the amphetamine methylsulfate, perhaps by Le Chatelier trickery:

NaMeSO4 + RNH3Cl --> RNH3SO4Me + NaCl (precip.)  [in EtOH ?]

or

NH4MeSO4 + RNH3Cl + CuCl2 --> RNH3SO4Me + Cu(NH3)2Cl4(2-) + 2 H+ [turns blue] [in anything that dissolves CuCl2]

and in both cases

RNH3SO4Me --> RNMeH3SO4...

The resulting rearrangement could even be as easy as it looks. More generally, using metal ammine complexes to activate AMS may be a fruitful and simple route to stronger methylating agents.

Quote
Nobodys talking about this routes because it REQUIRES lithium aluminum hydride and nothing else can faciliate an amide to amine reduction, that must be the reason

http://bitnest.ca/Rhodium/chemistry/amide2amine.zn-borohydride.html
« Last Edit: June 06, 2013, 01:58:43 PM by atara »