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Author: Subject: Phenethylamine from acetophenone
goldberg
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[*] posted on 25-7-2020 at 13:36
Phenethylamine from acetophenone


disclaimer: i'm not interested in making any illegal/psychoactive compounds i treat this considerations as excercise in organic chemistry. (i'm aware about application of Henry reaction for synthesising of phenethylamine and it's derivatives but this is not my goal).

Nitrosation of ketones with alkyl nitrites in acidic environment is well documented
for example http://www.orgsyn.org/demo.aspx?prep=cv2p0204
Reduction to amine is also typical reaction of oximes.

So nitrosation of acetophenone will yield 2-Nitroso-1-phenylethanone
Reduction of this compound would yield beta keto phenethylamine.
The question if it can form cyclic compound or dimer? Ketones react with amines to form imines.
So deoxygenation needs to be carried out in highly basic or acidic environment to prevent imine formation and it's reduction, right?

Would Clemmensen reduction yield phenethylamine? Or Wolff-Kishner reduction?
Amine group could be protected, but most of protecting groups for amines are not stable in highly basic and acidic environments. Monzigo reduction could be interesting route here, but let's consider less stinky alternatives.

Or maybe non selective reduction to beta hydroxy phenethylamine (no problem with dimers and cyclic compounds) and then alcohol elimination and reduction of alkene?

Substitution of OH group with halogen can also generate problem with dimers/cyclic compounds.

I also have found mention about conversion of acetophenone to ethylbenzene using Raney nickel in this conditions also oxime group should be reduced.
Is my reasoning correct?
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karlos³
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[*] posted on 25-7-2020 at 13:42


You want to make 1- or 2-PEA from it?
Because for the former the best idea is to use nickel ammine and zinc powder.
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goldberg
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[*] posted on 25-7-2020 at 13:57


I'm intrested in 2-PEA. 1-PEA would be to simple. Out of curiosity does method of reductive aminations with nickel ammine and zinc powder works only with ammonia or also with other amines, especially more complex ones?
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karlos³
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[*] posted on 25-7-2020 at 14:10


Why don't you decarboxylate cheap and available phenylalanine?
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goldberg
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[*] posted on 25-7-2020 at 14:23


If i would like practically synthesise phenethylamine this is a good route. I'm thinking about starting from acetophenone as excercise in organic chemistry. My goal excercise and learn something new.
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karlos³
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[*] posted on 25-7-2020 at 14:48


Then go via the bromoketone and react it with sodium diformylamide(Na-DFA) in DMF or MeCN, then hydrolyse to the aminoketone HCl, then NaBH4 to the alcohol and follow it up by HI/P then you're there.
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goldberg
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[*] posted on 25-7-2020 at 16:26


What is advantage of first reducing amino ketone to amino alcohol and then HI/P instead of Clemmensen/Wolff-Kishner reduction on amino ketone? It would save one step. It is interesting route but i'm curious if there are contradications to direct removal of ketone group.
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Sigmatropic
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[*] posted on 25-7-2020 at 23:48


You could also use a Neber rearrangement followed by a clemmensen reduction. Wolf kishner is not suitable because amino ketones are unstable under basic conditions.
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goldberg
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[*] posted on 26-7-2020 at 00:56


@Sigmatropic: thanks. I understand dimerization or cyclisation of amino ketone. Protonation of amino group prevents this, right?
So after amination amino ketone should be kept under acidic conditions and quickly reduced to amine, yes?
This is clear for me at one hand but at the other i was told that best pH for reductive amination is slightly acidic because this favors amine formation what is is conflict with unstability of amino ketones in basic environment. Or cause of instability of amino ketones in basic environemnt is other than imine formation?
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[*] posted on 26-7-2020 at 02:14


In reductive amination the acid speeds up the imine formation by activation of the carbonyl and elemination of water. Too strong of an or too much of an acid and the amine starting material is protonated and actually slows the reaction, or prevents it all together. For instance Amine HCl salts don't work directly in reductive aminations, but increasing the pH with a base (triethyl amine, sodium acetate, ect) does.

My understanding about the instability of amino ketones is the same, dimerization to dihydropyrazine then probably disproportionation to pyrazine and tetrahydropyrazine.
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[*] posted on 9-8-2020 at 19:18


Umm. Could produce the thioamide from either styrene or acetophenone. Via the Wilgerodt, Then reduce it to phenethylamine.

Now reduction of an amide is tough, that of a thioamide, not that terrible. Can't think of a really practical application of the pathway at this point. But, it is a thought.
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[*] posted on 10-8-2020 at 04:59


......ever consider reducing amides to amines via STAB made in situ....solo



It's better to die on your feet, than live on your knees....Emiliano Zapata.
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dextro88
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[*] posted on 12-8-2020 at 03:21


2-PEA huh, reduce the plain nitrostyrene with Zn/formic acid, this shoud work to replace the low yielding Zn/Hcl i think
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