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    Speculation or insight on novel amphetamine substitutions? 
    #1
    I was wondering if any research has been done or if anyone could speculate as to the activities of meth/amphetamine analogs where either an allyl bridge is used with or without an alpha substitution or if the bridge can be reversed to have the extra carbon closer to the alpha position in place of the standard propyl or i Also can't locate [anything] on 1-halophenethylamines which i thought was surprising. I was thinking alpha-chloro or fluoro
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    #2
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    I've never heard about a single compound with a halogen and NH2 on same carbon, if that's what you mean by alpha-chlorophenethylamine.
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    #3
    Here's one...
    http://www.chemspider.com/Chemical-S....10709144.html

    I was also thing of other alpha subs such as a carbonyl or ethenyl

    Or silanyl
    Last edited by S.J.P.; 08-11-2018 at 22:51.
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    #4
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    Alpha-chloroamines are too reactive to exist; presumably they'd eliminate or polymerize too easily. You might be able to produce alpha-fluoro-amphetamine but I'd imagine it'd be difficult installing the tertiary fluoride without elimination to an alkene.

    "Alpha-carbonyl" means you'd form phenylacetamide, which is inactive.

    an allyl bridge is used with or without an alpha substitution
    Allyl bridge?
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    #5
    And also wondering what replacing the amine with an imine or N-carbonyl would do?

    Alkyl bridge between the phenyl and amine being an allyl(propenyl)
    2-phenylallylamine and the n-methyl and a-methyl counterparts exist

    Why does it form acetamide may i ask? Does the exposed carbon react with oxygen or something?

    Maybe i have my _yls wrong, i thought carbonyl was just simply carbon as in alpha-carbon where the carbon is only attached by 1 hydrogen
    Last edited by S.J.P.; 09-11-2018 at 20:47.
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    #6
    Quote Originally Posted by (zonk) View Post
    Maybe i have my _yls wrong, i thought carbonyl was just simply carbon as in alpha-carbon where the carbon is only attached by 1 hydrogen
    Carbonyl = carbon that's connected to oxygen via a double bond, and to two other substituents via single bonds.

    Examples include ketones (the 2 bonds are to other carbons), aldehydes (one of the bonds is to hydrogen), carboxylic acids (one of the bonds is to -OH) and amides (one of the bonds is to NH2).

    Thus, if you made the alpha-carbon in amphetamine into a carbonyl, you would, by definition, have an amide, namely phenylacetamide.
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    #7
    The -F analogues have been around for at least a decade. Solubility appears to be adversely affected since they snort like powdered glass (and yes, we tried a number of different addition salts). Metabolism is questionable and at least some appear to possess MAOI activity which is what I think finally stopped them. The market, as one, said 'fuck that' and the matter was dropped.
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    #8
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    Fun to learn about a new kind of compounds. Here's a patent where they actually seem to attach two fluorines on the carbon alpha of an amine, and in some cases replace the fluorines with some other halogen. https://patents.google.com/patent/EP1813596A1/en
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    #9
    For mephedrone, the toluene is alkylated with 3-fluoropropanoyl chloride instead of propanoyl chloride and the rest of the synthesis continues with the same molar amounts.

    Why look for complicated answers when the simple ones work. Having tried the above, all I can say is that the HCl isn't too soluble - it's like snorting powdered glass. The sulphate & phosphate work but of course, the workup is a bit more work which is apparently enough to put the Chinese off making it.
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    #10
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    Quote Originally Posted by (zonk) View Post
    And also wondering what replacing the amine with an imine or N-carbonyl would do?
    You would kill the activity.

    Alkyl bridge between the phenyl and amine being an allyl(propenyl) 2-phenylallylamine and the n-methyl and a-methyl counterparts exist
    I'm still not sure what you mean here. Is it possible to link to a picture of an example?

    Quote Originally Posted by clubcard View Post
    For mephedrone, the toluene is alkylated with 3-fluoropropanoyl chloride instead of propanoyl chloride and the rest of the synthesis continues with the same molar amounts.
    That would give the alpha-fluoromethyl compound, not the alpha-fluoro.
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    #11
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    If you are wondering about 1-phenyl-2-amino-prop-2-ene ("alpha-methylene-phenethylamine"), that's actually an imine/enamine (the two species above can interconvert) which will decompose to phenylacetone and ammonia in aqueous environments. Same with the methyl and ethyl imines. The whole family of compounds is just a quick borohydride reduction away from amphetamines tho.
    Last edited by sekio; 10-11-2018 at 07:09.
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    #13
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    The first one would be more correctly called beta-methylene-phenethylamine and that second one is beta-methylene-amphetamine. Presumably beta methylene amphetamine would be active as a stimulant; beta-methyl-amphetamine is AFAICT, as is beta-methyl-phenethylamine.
    Last edited by sekio; 10-11-2018 at 07:11.
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    #14
    (Zonk) those are likely be active just like a cathinone, but will be very unstable in (weak) acid and light/air
    In first case it can isomerize to the enamine position (exomethylene isnt quite favorable form) then the enamine will hydrolyze to ammonia and a p2p.
    And in both case they will autopolymerize with air/light just like styrene monomer, albeit should be faster.

    They both, still, should be still stable enough for synthesis and isolation, but i am unsure about safety due to the reactivity reasons.
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    #15
    And what about replacement of amine with an imine(n-carbon amine)
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    #16
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    Replacing amine with imine nets you 1-phenyl-2-imino-propane, which is unstable in aqueous environments and will decompose to ammonia and phenylacetone.


    If you mean adding an imine on the other side, that will simply degrade back to amphetamine and e.g. formaldehyde, for N-methylene-amphetamine ("methamphetimine"?).

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    #17
    Quote Originally Posted by S.J.P. View Post
    That would give the alpha-fluoromethyl compound, not the alpha-fluoro.
    Well obviously - but try reading it IN CONTEXT. If people simply want to bypass legal control (and I see no other reason would seek to make it) then it is, as I said, simple, answer is known and tested.
    Last edited by S.J.P.; 11-11-2018 at 17:40. Reason: Removed personal attack from "Reason for Editing" line.
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    #18
    "Amphetimines" (amphetschiffbases?)) already occur as intermediates during the reductive amination of phenylacetone in the production of (meth-)amphetamine, but as sekio said, these are pretty unstable in an aqueous solution.
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    #19
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    Quote Originally Posted by clubcard View Post
    Well obviously - but try reading it IN CONTEXT. If people simply want to bypass legal control (and I see no other reason would seek to make it) then it is, as I said, simple, answer is known and tested.
    The original poster was asking about alpha-halo amphetamines and there was nothing to indicate that you weren't discussing the alpha-fluoro amphetamine until you posted the precursor. I know that you know what compound you were talking about but for those who might not have the synthesis background I was clarifying. Cheers.
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    #20
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    I remember seeing some formulae of non-amine dopamine reuptake inhibitors, one of them was like a methylphenidate molecule but with an ether oxygen in the place of the ordinary amine nitrogen. This is probably a more interesting line of development.
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    #21
    Quote Originally Posted by polymath View Post
    I remember seeing some formulae of non-amine dopamine reuptake inhibitors, one of them was like a methylphenidate molecule but with an ether oxygen in the place of the ordinary amine nitrogen. This is probably a more interesting line of development.
    Potency way, way lower. They were made to compare O: & N: and I'm kind of surprised that the phenyl(piperidin-2-yl)methanones haven't shown up. By tweaking the cyclic amine you can move that N: quite a lot. My only tip on this one is don't trust Reaxys. Their reference is WRONG.
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    #22
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    https://www.ncbi.nlm.nih.gov/pubmed/14612136

    It's surprising that the atom replacing the nitrogen doesn't even need to have an unshared pair of electrons, as a methylene substitution also retains some activity.

    It would be an interesting but tedious exercise to draw structures for this kind of derivatives from many different stimulants (e.g. desoxypipradrol and others with a nitrogen heterocycle) and try to find whether those compounds already exist in nature (maybe in some plant of fungus).

    Edit: In the case of desoxypipradrol, it looks like some 2-(diphenylmethyl)tetrahydropyrans have already been found to be monoamine (including dopamine) reuptake inhibitors, but the ones with data available also seem to have a nitrogen atom somewhere else in the molecule. https://patents.google.com/patent/US7915433

    NSFW:
    Last edited by polymath; 26-11-2018 at 16:12.
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    #23
    O-2172 is an analogue of methylphenidate that is approximately 1/3rd the potency of regular MPH, despite lacking the piperidine nitrogen.

    At first glance, this may seem impressive, but not so much so once you consider that it is more specifically an analogue of 3,4-Dichloromethylphenidate (3,4-CTMP), which is approximately 10 times as potent as plain ritalin. So as clubcard already said, we're talking about a pretty drastic decrease in activity.

    Then again, even if it is only 1/30th of the potency of 3,4-CTMP, the fact that O-2172 is even active *at all* despite the absence of a lone pair on the ring is pretty fascinating.
    Last edited by Hodor; 27-11-2018 at 07:36.
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    #24
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    Quote Originally Posted by Hodor View Post
    Then again, even if it is only 1/30th of the potency of 3,4-CTMP, the fact that O-2172 is even active *at all* despite the absence of a lone pair on the ring is pretty fascinating.
    So, with both chlorines and the nitrogen removed, the compound would cause some effects for a non-tolerant person when taken in an estimated 300-500 mg dose.

    There didn't seem to be any info about sulfur or selenium replacements of the nitrogen in MPH.
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    #25
    It'd be a good idea, if those were to be assayed, to test the sulfurous analog first, since there could be the potential for toxicity in seleniuretted compounds.

    If that ether is cleaved off metabolically, then one would end up with methanol in vivo, no? although probably in doses the human body could get rid of, but methanethiol would be most unpleasant to have as a metabolite.

    And methyl selenomercaptan? no THANKS
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