Sciencemadness Discussion Board

4-Amino-1-phenethylpiperidine | CAS: 51448-56-7

chemrox - 15-3-2016 at 16:57

I plan to make the desired intermediate by dissolving the N-phenethyl-4-pieridone from an earlier synthesis in ethanol and adding hydroxylamine HCl in water to the mixture. After refluxing the above for an hour needles of the oxime should pcpt. Reducion with Na/ethanol should yield the desired amino piperidine. This is after Lindwall and Harper & Chignell, '64.

Attachment: The Chemistry and Pharmacology of Some 4-Aminopiperidines and Their Derivatives.pdf (506kB)
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prettypolymer - 16-3-2016 at 06:04

Would you like some propionic anhydride along with that, my good sir?

solo - 16-3-2016 at 06:58

" Would you like some propionic anhydride along with that, my good sir? "......prettypolymer


.......? when all you need is aniline and a reduction and Propionyl Chloride......as a theoretical synthesis ...solo

chemrox - 16-3-2016 at 10:20

No thanks and Solo is correct if you want to make the propionamide.. I don't. Not for this one. Nor aniline thank you Solo.. different compound.. another route.

clearly_not_atara - 16-3-2016 at 10:22

This is one of those syntheses that worries me because it might really kill the person who tries it. Anyway you might be able to do it by making 4-aminopyridine from 4-pyridylpyridinium as in the preparation of 4-DMAP.

http://en.wikipedia.org/wiki/4-dimethylaminopyridine#Prepara...

Protecting the amine terminus, 1-alkylation with phenethyl bromide, and hydrogenation gives the target compound. Please be safe and don't make any chemical weapons.

solo - 16-3-2016 at 10:53

......a very nice approach Atara,....say bye to the 4-piperidone and all the acrylates .......solo

chemrox - 16-3-2016 at 11:12

Thanks for the info. Since I already have N-phenethyl-4-piperidone I probably won't go this route but I'm interested as an alternative for making N-phenethyl-4-piperidine. I don't generally like working with Cl2 and couldn't find any details on the first step. Do you have a ref for that?
Anyway was looking for comments on the hydrazine reaction and conditions. I know the NPP would dissolve in alcohol and was also thinking of running it in MeOH with reduction using EtOH (denatured)/Na

Or maybe do the reduction with MeOH/Na and avoid any issues with EtOAc in the mix. (I'm really short on anhydrous undenatured EtOH)

[Edited on 16-3-2016 by chemrox]

CuReUS - 17-3-2016 at 06:00

Quote: Originally posted by solo  
......a very nice approach Atara

but isn't it wasteful, one mole of product in exchange of 3 moles of reagent
Quote: Originally posted by chemrox  
I'm interested as an alternative for making N-phenethyl-4-piperidine.

do you mean N-phenethyl-4-aminopiperidine ? In that case I have some ideas
1. from phenethylamine and divinylketone :
read the 19th post of nicodem in this thread
http://chemistry.mdma.ch/hiveboard/newbee/000480940.html

reduce the piperidone to amine using leukart reaction http://cccc.uochb.cas.cz/55/5/1297/ pg 1305
Quote:
A mixture of 11·4 g I-benzyl-4-piperidone, 40'5 g formamide, and 8'5 g formic acid was stirred for 30 min at l00-125°C and 5 h at 170°C(bath temperature 190°C). It was evaporated under reduced pressure (bath temperature until 145°C), the residue was dissolved in 70 ml benzene, the solution was washed with water, IM-NaOH, and water, dried, and evaporated; 9'6 g (73%) 'of crude l-benzyl-4-(formamido)piperidine. It did crystalline neither in the form of the base, nor
as the oxalate. The crude intermediate (6'7 g) was disolved in 15 ml ethanol, 14 g KOH were added and the mixture was stirred and refluxed for 4 h. After cooling the mixture was diluted with 50 ml water and extracted with ether. Processing of the extract gave 5·7 g (97%) of crude
4-amino-I-benzylpiperidine which was distilled, b.p. 93-95°cj40 Pa. Ref. 17 , b.p. 113-116°C/80 Pa (different method).

you can also reduce the oxime using LiAlH4
http://pubs.acs.org/doi/abs/10.1021/jm00123a028
in this paper they also mention that the diamine(4-amino phenethylpiperidine) is sensitive to air oxidation,so keep that in mind

2. from isonicotinic acid :
similar to atara's method,isonicotinic acid is reacted with phenethylbromide,hydrogenated and finally a schmidt reaction is done to get 4-aminophenethylpiperidine.In case there is a chance of the phenethylbromide reacting with the COOH to form an ester(which I doubt),then isonicotinamide has to used which can be converted to the amine using bleach
Quote:
I don't generally like working with Cl2

I think TCCA or bleach can be used instead of Cl2 but I may be wrong
Quote:
Anyway was looking for comments on the hydrazine reaction and conditions. I know the NPP would dissolve in alcohol and was also thinking of running it in MeOH with reduction using EtOH (denatured)/Na
Or maybe do the reduction with MeOH/Na and avoid any issues with EtOAc in the mix. (I'm really short on anhydrous undenatured EtOH)

http://cccc.uochb.cas.cz/55/5/1297/
on pg 1299,they talk about hydrazine hydrate reduction.I didn't read it so go through it if interested
on pg 1298,they talk about Na/ethanol reduction
Quote:
4-amino-l-benzylpiperidine has been prepared not only by the methods described (reduction of I-benzyl-4-piperidone oxime(22) with sodium and ethano1(23) or with lithium aluminium hydride 16 ,17) but also by making use of the Leuckart reaction(24)


[Edited on 18-3-2016 by CuReUS]

zed - 17-3-2016 at 14:19

Some have suggested the oxime may be reduced via Aluminum Amalgam.

skip - 17-3-2016 at 16:07

Chemrox,Have you experience with sodium in etOH ? I tried it one time with pyridine and failed. I believe algamated sodium in etOH is what really works. I no longer care about piperidine. The point I wanted to make was that the whole time I was adding sodium I was a nervous wreck , scared that the anhydrous etOH wasn't dry. The sodium was cut into pea size chunks and it was skimming on top and etOH was boiling like hell. I would add a small chunk and get away until it was about gone, the whole time I thought it was going to turn into a fire ball. If you have done it then I appoligize. Honestly I think the sodium in etOH cited in literature is bull, I may be wrong.

PEA-4-piperidone etc

spankyetal - 24-7-2017 at 14:49

the newer reactions involving the tried and true amine/acrylate additions and subsequent Dieckmann cyclization with Na sand in toluene have major improvements. One pot reactions with 91% yields of the target biesters and 58%+ yields of the 2-PE- 4-piperidone and beyond are very impressive. Nanosulfuric acid catalyst without any solvent is awesome. No microwaves either. Having hands-on experience I can relate the literature on Dieckmann cyclizations leads to failure or dismal yields. Major critical details are left out of the older literature as the authors ASSUME the readers are up on a-prior-art. Like using a Helium cloud instead of N2. Alkaline pyrogallol scrubbing of O2 from that cloud. etc. Producing Na sand and accurately weighing it. etc.

PEA-4-piperidone etc

spankyetal - 24-7-2017 at 14:54

Na sand can easily be made by rapidly stirring molten sodium in toluene just above the melting point of Na and then cooling the mixture to keep the sand in particle form. The faster the stirrer the smaller and more effective is the sodium sand in the next cyclization Rx. The sand is made alone and not in situ during the cyclization rx. It will stay in particle form as the reaction is maintained at 80 C or so and sodium doesn't melt until 97 C.



[Edited on 7/24/2017 by spankyetal]

spankyetal - 24-8-2017 at 17:38

Quote: Originally posted by clearly_not_atara  
This is one of those syntheses that worries me because it might really kill the person who tries it. Anyway you might be able to do it by making 4-aminopyridine from 4-pyridylpyridinium as in the preparation of 4-DMAP.

http://en.wikipedia.org/wiki/4-dimethylaminopyridine#Prepara...

Protecting the amine terminus, 1-alkylation with phenethyl bromide, and hydrogenation gives the target compound. Please be safe and don't make any chemical weapons.

these analogs did injure aa significant number of people in central california. DOJ labs traced it back to imperfect hydrogenation step yielding severe neurotoxins. carefull what ya wish for