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PEA and mek -> NPP?

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conducter - 16-5-2007 at 03:01

i have seen a few people talking of Phenethylamine and mek could be used to make n-phenethyl-4 piperidone.

but cannot find a reference or writeup or anything..

also on the old synthetikal there was a mention of this...

"Double Mannich, using acetone, formaldehyde, & PEA" to get to NPP.

So i guess i need help if anyone has any info to hlep with.

jon - 20-5-2007 at 16:59

yeah i was looking for the same thing there's a J.A.C.S. article on it somewhere don't know where the mirrors for the hive don't exist anymore can't find it. MEK would theroretically give 3-methylsubstituted piperidones which are even better.

conducter - 20-5-2007 at 19:15

would acetone give the desired piperidone, or another substitute? if you find any article please post cuz id love to find mor einfo on this

transformer - 20-5-2007 at 20:28

This makes me wonder if it is possible to make the normal 4-piperidone using acetone in theory it should bee possible however to selectively produce the 4-piperidone one would have to bee very carefull with the rate and order of addition as there is a very big chance the main products will bee 2,2-dimethyl- and 2,2,6,6-tetramethyl-4-piperidone, then you also have the problem of the polymerization of 4-piperidone and the chances of 4-piperidone itself being reactive in the manich reaction, interesting nontheless if someone would get this working :cool:

chemrox - 20-5-2007 at 23:15

I'd like to get some basic information on these compounds first such as solubilities in some of the more common solvents. I've not yet been able to find such but am limited in my search efforts with not enough familiarity in the heterocyclic literature.

stimo-roll - 21-5-2007 at 11:19

yes i read same work (joc or jacs, cant find in cpu) - they took 1equ amine, 2equ aldehyde en 1ketone dissolved in GAA, boiled... isolated desired piperidone. As ketones used mek, acetone, but aldehyde in all cases - benzaldehyde. All piperidones are 2,6-diphenyl :-( will this methode work on formaldehyde.

conducter - 21-5-2007 at 11:24

i believe formaldehyde is the desired aldehyde.

If the amine was Phenethylamine, the ketone was Acetone, and the aldehyde is formaldehyde i believe that is when one will get N-phenethyl-4-piperidone

jon - 21-5-2007 at 13:41

how did they arrive at 2,6 substituted products? the non-enoliziable carbonyl should make the iminium ion and this add to the double bond system of the enol, it does'nt make sense.
ohh I eat my words I see.

[Edited on 22-5-2007 by jon]

stimo-roll - 21-5-2007 at 22:53

Here this article. When i downloaded him from net (maybe synthetical) he was named "4-piperidones one-pot". This JACS 70,3853,1948 - "The Preparation of Some Piperidine Derivatives by the Mannich Reaction"

Attachment: 4-piperidones-one-pot.rar (302kB)
This file has been downloaded 2498 times

jon - 22-5-2007 at 11:58

nice going I went the library no luck did'nt have beilsteins abstracts nothing.

tr41414 - 24-5-2007 at 09:13

The disscussion on the hive seemed not to give any conclusive results. But as this reaction is not mentioned anywhere else in literature, I would say that the reaction works with other aldehydes, but not the formaldehyde... So better stick with the acrylate procedure...

But regarding the use of acetone in mannich, i have heard rumors it could be used instead of acetone dicarboxylic acid in some other nice reaction

A bit off-topic: ammonia and acetone condense to tempidone - i think it is 2,2,6,6-tetramethyl-4-piperidone (?)

tr41414 - 24-5-2007 at 09:28

just an idea - what about using glyoxylic acid or it's esters instead of formaldehyde? not as readily available and would add a few steps... but it might work

jon - 24-5-2007 at 09:42

why do you say formaldehyde won't work from a mechanistic point of view?

[Edited on 24-5-2007 by jon]

tr41414 - 24-5-2007 at 09:55

sorry... have no references on that... but it would be the simplest of 4-piperidone synthesis and seems not to be in any literature i know...
hehe... but again, i might be wrong... will dig deeper and see if i can find anything interesting

jon - 24-5-2007 at 10:07

it does'nt jibe that formalin would'nt work it goes like this the aldehyde forms the aldimine this iminium carbocation adds to the electron rich double bond system of the enol formed from the ketone and you have aminomethylated product, the adduct does'nt seem to be able to react further so i don't see any complications from using an unsubstituted aldehyde like formaldehyde.

tr41414 - 24-5-2007 at 10:49

There seem to be only 3 threads on the hive regarding this way of 4-piperidone synthesis:

ning: OTC piperidone -- fentanyl

hehe... ning 's the man... he is really revolutionary about his various OTC synthesis

albert_grieves: methyl acrylate synthesis

here some thing interesting is done

hmm... divinyl ketone via mannich (acetone & formaldehyde) + elimination ... Maybe some antipolimerization agent would do the trick in our mannich synth?

Megatherium: Discussing the Mannich reaction

hmm... about a year after his otc fentanyl post he is still convinced the reaction works, but yet again he has no references to this specific rxn... I wonder if he has done the reaction....

So, maybe someone should try the reaction and report... That is the biggest drawback of the hive... usually no or very few reports of success (or attempted reactions) were posted

sadly it's now only the archive and we can't contact the original posters...

stimo-roll - 25-5-2007 at 10:43

Quote:

divinyl ketone via mannich (acetone & formaldehyde)

May you got some refs for preparation, low temp needed, may be hydroquinone as stabilizer.

divinyl ketone also known as 3-pentadienone also may used in reaction with mmm MeAm. intresting how make 3-pentadienone from cyclopentanone, any ideas.

may be anybody got access to springer, it this article is intresting?

Quote:

1. A method was found for the preparation of 2,4-dimethyl-3-pentadienone from 2,4-dimethyl-3-pentanone.
2. 1,3,5-Trimethyl-4-piperidone was synthesized from 2,4-dimethyl-3-pentadienone.

http://www.springerlink.com/content/n11x184817l13kl2/

[Edited on 25-5-2007 by stimo-roll]

jon - 25-5-2007 at 12:54

I still don't have an explanation as to why acetone formalin and pea would'nt work?

Comedy - 26-5-2007 at 02:08

I found a reference to this reaction in my merck index:
http://www.chempensoftware.com/reactions/RXN295.htm
Which is about a substituted piperidone: unfortunately I don't know how to look up the references.

tr41414 - 26-5-2007 at 12:37

Actually the reaction between acetone, methylamine and formaldehyde has been documented, and it does not produce the wanted compound

But it is interesting that diethyl ketone does react to the piperidone... Maybe MEK would then be better choice for a reactant, also acetone dicarboxylic acid derivates will probably work better... Hmm... And who knows what a pinch of hydroquinone would do

(but this again is just a speculation)

Anyway it sure can be done as a two step rxn...

Ref: Organic Reactions (1942), Vol. 1, p. 305

jon - 26-5-2007 at 14:38

is that the ref. for the reaction between methylamine formalin and acetone?

acetone dicarboxylic acid derivatives could it seems be used and then decarboxylated, keto acids will decarboxylate pretty easily.

mono - 27-5-2007 at 17:31

Quote:

Originally posted by stimo-roll

Quote:

divinyl ketone via mannich (acetone & formaldehyde)

Quote:

1. A method was found for the preparation of 2,4-dimethyl-3-pentadienone from 2,4-dimethyl-3-pentanone.
2. 1,3,5-Trimethyl-4-piperidone was synthesized from 2,4-dimethyl-3-pentadienone.

http://www.springerlink.com/content/n11x184817l13kl2/

[Edited on 25-5-2007 by stimo-roll]

edit:
link dead.

[Edited on 9-9-2007 by mono]

stimo-roll - 28-5-2007 at 03:55

thanks mono

diethylketone is cheap, react him with 2Br2 and after dehydrobromination with di(m)ethylaniline and you got divinylketone. Another theoretical route to piperidones.

NPP

john_do - 28-5-2007 at 23:47

Once upon a time, Ning gave me a detailed writeup of the double mannich in question, along with several good relevant references. For what it's worth, he was confident that it would produce the goods as such. That is so long as a dash of HCl was added for flavour. His words not mine!

Anyhow, the archives have been sanitized since those days...

jon - 29-5-2007 at 07:00

Hcl according to one of the papers does'nt work so well because it interferes with iminium ion formation if the ph goes to low, they use acetic acid with better results.

stimo-roll - 29-5-2007 at 09:14

HCl? Ya i read some russ patents, in first unsaturated ketone - divinyl keton react with MeAm to afford piperidone, and second patent with improved procedure were chloromethyl vinyl ketone react with MeAm, yelds are adout80-90%. May be HCl added to double bond of divnyl ketone.

tr41414 - 29-5-2007 at 09:54

i think you are confusing two different reactions. one is the known-to-work divinyl ketone + MeAm, which by the way is very similiar to the acrylate method, just that here the ring is already in its position... The second one is mannich rxn, which usualy employs usage of hcl...

stimo-roll - 29-5-2007 at 10:43

Sorry, youre right this not a mannich, but some interesting:
patent RU2123495
ketone structure CH2C(CH3)COCH2CHClCH3 (obtained with Friedel-Crafts reaction chloroanhydryde metacrylic acid and propylene AlCl3 in CH2Cl2) react with 30% aqua MeAm to 1,2,5-trimethylpiperidone-4.
For F-C reaction see US2105792 and J.Chem.Soc. 1970, p2401 I.R.Owen.
too complicated for such shit like fent.

[Edited on 29-5-2007 by stimo-roll]

[Edited on 29-5-2007 by stimo-roll]

dr. nick - 29-5-2007 at 11:57

well, seems the ning is all around here somehow :)

got some pm's from him long, long ago, too, and always wanted to give it a try - at least the NPP thing, but never had all ingredients at hand. Now they are available so i'd start a little experiment, but i'm still not sure about the right mannich variation - should it be done with Formalin (i think so) or Paraformaldehyd? Does anyone have some relevant hints maybe on performing this? Of course i'd share any results :)

As far as i can remember ning said, PEA, Formaldehyd and MEK would yeild some 3-Methyl-Piperidon ... but not sure, got to look it up.

jon - 29-5-2007 at 15:19

well if you want this to condense to the intermediate formalin is used paraformaldehyde won't condense on it.
yes it seems mek would give 3-methyl piperidones which are 5X better.

dr. nick - 30-5-2007 at 12:18

thanks!

Quote:

well if you want this to condense to the intermediate formalin is used paraformaldehyde won't condense on it.
yes it seems mek would give 3-methyl piperidones which are 5X better.

In how far do you mean "5X better"?
could you explain a little, please?

thanks again!

jon - 30-5-2007 at 13:18

well the end product would be 400 X morphine depending on what your synthing.

john_do - 30-5-2007 at 20:18

Dr Nick: Do this board a favour and pretend not to be excited about what you have just learnt. Considering you claim to have spoken with Ning about this very subject, I find it hard to believe that you still need clarification from others. Find out the hard way like everybody else around here, spoonfeeding is so 90's.

dr. nick - 31-5-2007 at 12:50

@jon: thanks! i've read some somehow contradictory statements on 3-methyl-fentanyl - not so much about the strength, even if they differ there also, but on the time of action.
maybe you have some more definite information about this point?

oh dear, forgive me, great master chemist j_do - and if you want to do me a favour stop talkin silly stuff - i haven't been asking to be spoon fed here, especially not by you and i really don't care if someone like you believes me or not.

--edit: sorry if(?) being a bit harsh, i am no chemist, i'm just interested in some rather specific experiments out of privat reasons, so i really have no interest in any ego-fights, boss honcho contests or such stuff. don't take it personal.

[Edited on 1-6-2007 by dr. nick]

chemrox - 29-1-2009 at 21:42

I had another thought on 4-piperidone synthesis and dug up this old thread via the SE. My thought was this:
4-Br-pyridine + alcohol/Na --> 4-Br-piperidine + NaOH --> 4-hydroxypiperidine ---(chromic oxidation) --> 4-piperidone? This basic procedure is known for 4-pyridone .. I added the alcohol reduction at the beginning.

[Edited on 29-1-2009 by chemrox]

not_important - 29-1-2009 at 22:22

Would the bromine survive the Na/alcohol reduction?

Ebao-lu - 30-1-2009 at 01:37

i assume it would not, Na/alcohol is oftenly used for reduction of alkylhalides..
But, if you first change Br to OH(hopefully, this reaction will easily proceed), and then you can feel free to use any method of reduction. Probably, in bit more harsh conditions, the bromine could be replaced with NH-R(

) directly, and even you can try to alkylate the N atom of pyridine with b-phenylethylhalide(provided you protect the NHR group by acylation

), and then reduction(acyl may go off, but you can once again attach it)

... (:surprized that mu-opioids discussion is allowed

sparkgap - 30-1-2009 at 02:00

"But, if you first change Br to OH(hopefully, this reaction will easily proceed)"

So you're saying γ-pyridone (which is the more stable tautomer) can be reduced to 4-hydroxypiperidine with that reagent?

sparky (~_~)

[Edited on 30-1-2009 by sparkgap]

Ebao-lu - 30-1-2009 at 02:46

Well(sorry, forgot about tautomers).. not sure about sodium/EtOH, but there should be many reagents that can reduce it like this(or are there any potential problems with it? i dont see any, except the nucleophile addition in b-position of pyridone and amine elimination, causing cycle breaking))
besides chemrock written

Quote:

This basic procedure is known for 4-pyridone ..

I think that was said about reduction of 4-pyridone

[Edited on 30-1-2009 by Ebao-lu]

Tunnels - 8-2-2009 at 02:45

Nothing conclusive on the Mannich? Missed the ref but from what I gather the procedure might look something like...?

Experimental.

12.1 g of phenethylamine is dissolved in 8.9 ml 37% aq formaldehyde and 7.3 ml of acetone. Glacial acetic acid is then slowly added and solution is brought to reflux. NPP should be slightly yellow solid with a mp between 57-60 degrees.

That'd be not much to work with. How long is this reaction thought to take? If it takes at all, that is.

Ebao-lu - 9-2-2009 at 00:16

Are you sure treatment with Na gives ketal, not a-carbmethoxy-NPP? that should be a usual Claisen condensation.

key ref for the method

chemrox - 9-2-2009 at 00:26

The method for making NPP via PEA is in Beckett, Casy & Kirk on a&b Prodines. Here it is.

Attachment: 4-piperidones, a & b prods.pdf (1MB)
This file has been downloaded 1762 times

Nicodem - 9-2-2009 at 00:30

Quote:

Originally posted by Ebao-lu
Are you sure treatment with Na gives ketal, not a-carbmethoxy-NPP? that should be a usual Claisen condensation.

It is, it's just that Chemrox does not know the difference between a Claisen condensation and a reduction, or between a beta-ketoester or ketal... You should not take other members claims too seriously. Most people here are amateurs.

chemrox - 9-2-2009 at 00:36

oh there goes Nicodem being mean again.. anyway I posted the article for you and yeah I either didn't know or didn't remember sue me call me an amateur abuse me if this is the kind of thing that makes you feel like a bigshot professional ..

Ebao-lu - 9-2-2009 at 07:31

Quote:

12.1 g of phenethylamine is dissolved in 8.9 ml 37% aq formaldehyde and 7.3 ml of acetone. Glacial acetic acid is then slowly added and solution is brought to reflux. NPP should be slightly yellow solid with a mp between 57-60 degrees.

That'd be not much to work with. How long is this reaction thought to take? If it takes at all, that is.

If you're not sure the reaction would give NPP, you can try to do a set of small-scale experiments in test-tubes, with TLC control(you only need to identify the NPP by its Rf, and to find proper eluent, UV light ). Instead of reflux, you can keep temperature in test-tubes experiment a bit elevated in a water bath(less then boiling point). And then, if you succeed, do it in a large scale

As for Claisen condensation, i've written that only for clarification, not for abusing. It should be much easier for a one to study new information directly in the thread, instead of annoying books reading. Now chemrox probably knows, what is claisen condensation and what product is formed in the reaction

And it could take another n months for him to come accross an article in a book.
Ok, next time a will not take it too serious, less patronizing.

[Edited on 9-2-2009 by Ebao-lu]

chemrox - 9-2-2009 at 08:30

@Ebau-Lu thanks for the comment. The article I cited came from JACS btw, not a book. Where does the above experiment with formaldehyde and acetone come from?

Ebao-lu - 9-2-2009 at 09:31

That's Tunnels had written above, i quoted his post. From his words "the procedure might look something like...?" i can conclude this procedure is a proposal. But he said about some ref, so maybe the original procedure was there, ask Tunnels better. As for experiment, i think small-scale experiments(several ml) in organic chemistry are feasible, to find the proper conditions (reagents and their ratio, pH, tempereture, time) for the reaction. I've never heared of such kind of carrying out a research in professional organic chemistry, but for amateur chemists with their shortage of chemicals, it should be a good option

Quote:

The article I cited came from JACS btw, not a book.

yes, but i mean not that article, i mean the article(a paragraph) about ester and claisen condensation in a theory book

[Edited on 9-2-2009 by Ebao-lu]

chemrox - 9-2-2009 at 13:54

So the article is rather longish but reading again (last time was over a year ago) the short story was: the amine and ester are combined yielding the amine diester which undergoes internal condensation, cyclization to the ethyl ketal which is relased to the amine/ketone with acid. So wouldn't this be a Dieckmann rather than a Claisen?

Some piperidines by the Mannich Reax

chemrox - 9-2-2009 at 22:50

A member asked about this ref and I happened to have it. I also posted the Russian patent that was mentioned earlier in Refs hoping for a translation.

[Edited on 9-2-2009 by chemrox]

Attachment: piperidines by Mannich reax.pdf (349kB)
This file has been downloaded 3574 times

Nicodem - 10-2-2009 at 00:12

Quote:

Originally posted by Ebao-lu
As for experiment, i think small-scale experiments(several ml) in organic chemistry are feasible, to find the proper conditions (reagents and their ratio, pH, tempereture, time) for the reaction. I've never heared of such kind of carrying out a research in professional organic chemistry, but for amateur chemists with their shortage of chemicals, it should be a good option

In an organic synthesis research lab it is highly unusual to do any reaction above the 10 mmol scale (this has to do with avoiding dumb accidents, not wasting very expensive materials, enabling a multistep synthesis, but most importantly because the most common method of isolation is chromatography). The exception is when following a published procedure or when repeating a successful synthesis in order to prepare enough starting material for a multistep synthesis. So, I would say it is just the opposite of what you seem to believe. It is the synthesis on a scale larger than 10 mmol that is highly unusual in "professional organic chemistry". On the other hand it often seems to me that amateur chemists, understandably being more irresponsible (as well as more naive about the experiment outcome and less stingy about the chemicals they have), have this tendency to do experiments on irrationally large scales.

Quote:

Originally posted by chemrox
So the article is rather longish but reading again (last time was over a year ago) the short story was: the amine and ester are combined yielding the amine diester which undergoes internal condensation, cyclization to the ethyl ketal which is relased to the amine/ketone with acid. So wouldn't this be a Dieckmann rather than a Claisen?

Chemrox, please check what a ketal is (and what not). The expression you were seeking for "the amine and ester are combined" is Michael addition, a common reaction which uses the 1,4-conjugative addition for alkylating various nucleophiles. The Dieckmann condensation is intramolecular Claisen condensation. This is a bit confusing since it means that the Dieckmann condensation is a Claisen condensation, but a Claisen condensation is not necessarily a Dieckmann condensation. I have noticed that many chemists prefer to only call the intramolecular condensation of alpha,omega-dinitriles as Dieckmann condensation (probably just to avoid such confusion).
Anyway, I was not trying to be mean. I was only taking defence on your mistakes.

Ebao-lu - 10-2-2009 at 02:53

Nicodem, i understand, i mean that in organic chemistry they seldomly perform experiments with _set_ of reaction vesels in one experiment. I think that for amateur chemists, set of test tubes in a water bath is better then one mini- round-bottomed flask + one mini-reflux (sometimes more expensive then large ones). Besides, less paranoy with smells and parents, because most experiments are conducted in a kitchen/bathroom

chemrox - 10-2-2009 at 23:27

Nicodem please read the damned paper. As to experimental scale I agree; 10mmol is an average experiment with us except for scaleup trials and those go to 10 g yields at times.

Nicodem - 10-2-2009 at 23:46

I did not read it, I just skimmed trough it, but I could find nothing relevant about ketals being formed during their synthesis which uses the Michael addition of ethyl acrylate, the intramolecular Claisen condensation (Dieckmann condensation), C-alkylation, and finally the hydrolysis/decarboxylation of the beta-ketoester. Nothing unusual here. The only mention of ketals in the paper is in that they observed that some of their 4-piperidones formed the hydrochlorides of the coresponding ketals (instead of the original ketones) in their attempts to make the hydrochlorides using ethanolic HCl (which is how ketals are made anyway). However, this was not part of their synthetic route and I don't know how this observation could be relevant. If you, by a thorough reading, noticed any ketals as synthetic intermediates, please let us know.

chemrox - 11-2-2009 at 14:34

I'm glad you noticed the reaction was intramolecular. When you chastised me earlier you had somehwo missed that calling it a Claisen. I missed the whole thing the first time around calling it a reduction so I don't claim superior virtue. What I object to is this trigger happy urge to attack people for what you perceive to be as their chemical shortcomings. As you said, you decide to get offended and act on that basis. I had a guy like you working for me a few years ago and he resisted all my efforts to develop him into a competent manager. I had to fire him or lose other employees I had a lot of time invested in. Learn the art of correcting people in a way that makes them appreciative rather than defensive. After all this is all voluntary. Back to the ketals, they're in the intermediates under experimental in the middle of the article. If you're saying they're not important that's an opinion I guess, the authors found them, reported them and so did I by paraphrasing the experimental rundown.

chemrox - 11-2-2009 at 14:54

On another subject in this thread, I worked with piperidones for about a year and one thing that came up whenever I combined a 4-piperidone with another compound was red impurities. I'm wondering if anyone has a guess as to what might be involved. I don't have a GC-MS and the stuff doesn't give a consistent IR picture that I can detect. At first I thought a halide might be the culprit because I was using an organo bromide but the same color showed up with other transformations not involving halides. It's not a major issue but I'm curious.

Nicodem - 12-2-2009 at 00:20

Quote:

Originally posted by chemrox
I'm glad you noticed the reaction was intramolecular. When you chastised me earlier you had somehwo missed that calling it a Claisen.

It is a Claisen condensation. Read the replies again. You have been told this several times. "Intramolecular" is not the name of a reaction, it only means the reaction occurs inside the same molecule.

Quote:

What I object to is this trigger happy urge to attack people for what you perceive to be as their chemical shortcomings.

This has nothing to do with "chemical shortcomings". It is a personality thing (not just my personality though).

Quote:

Back to the ketals, they're in the intermediates under experimental in the middle of the article. If you're saying they're not important that's an opinion I guess, the authors found them, reported them and so did I by paraphrasing the experimental rundown.

Where? I can't find anything about them being synthesis intermediates. They report the very classical synthetic route to 4-piperidones with the scheme depicted. There are no ketals besides the only obtained from the 4-piperidones with ethanolic HCl. Please post a graphic with a route where ketals are intermediates, or at least your interpretation of the reaction scheme. Maybe this will clear the issue as pictures say much more than words.

Quote:

On another subject in this thread, I worked with piperidones for about a year and one thing that came up whenever I combined a 4-piperidone with another compound was red impurities.

When a ketone turns red it usually means the red products is some crap (technically called "tarry materials"). They generally give consistent IR spectra.

chemrox - 12-2-2009 at 01:19

"S-2‘-phenylethyl-4-piperidone e t hylketal [in italics] (35 g) as a pale yellow oil
which could not be distilled. Found: equiv., 279; calcd. for
*‘ Melting points are uncorrected. t Analyses are by Mr. G. S. Crouch, School of Pharmacy, University of London;
equivalent weights of bases and salts mere determinod by titration in non-aqueous
media.
(p. 50)
C17H27O2N equiv., 277). It gave a hydrochloride. needles from
ethanol, m.p. 178-179" dec."
(p. 51)
look harder next time, bottom of page 50 to top of page 51 in the article btw it didn't copy and paste very well

[Edited on 12-2-2009 by chemrox]

Nicodem - 12-2-2009 at 02:05

Is this some weird way of saying "I was wrong"? Because what you did was copy-pasting from the experimental section where they describe the preparation of the ketal from the ketone, that is from N-2'-phenylethyl-4-piperidone. So, how can the ketal be an intermediate step in the synthesis of the N-2'-phenylethyl-4-piperidone when it is prepared from N-2'-phenylethyl-4-piperidone? Probably I'm just stupid, but to me this appears against all logic.

kmno4 - 12-2-2009 at 02:34

All stupidity lies on chemrox's side (and not for the first and not for the last time).
Chemrox is/are not partner for discussions.

chemrox - 12-2-2009 at 03:11

Look again:
(KMNO4- shoo!)
"A mixture of N-2'-phenylethyl-
4-piperidone ethylketal (20 g) and dilute aqueous hydrochloric
acid (150 ml) was refluxed for 2 h. cooled aid washed with ether.
The free base was liberated with aqueous ammonia and extracted
with ether. After drying (Na2,SO4), the ether was evaporated
and the residue (13.0 g) crystallized from light petroleum (b.p.
80-100) to give N-2'-phenylethyl-4-piperidone"

I don't know what you're reading. Right there the last step is to refulx the ketal with acid and work it up with ammonia to give the to give the NPP. Now please apologize and let's move on.

[Edited on 12-2-2009 by chemrox]

Nicodem - 12-2-2009 at 03:34

Oh my god! You just cited the experimental where they recover N-phenylethyl-4-piperidone from its ketal which was made from N-phenylethyl-4-piperidone in the first place. That is not part of the synthetic route. You confused a characterization/derivatization chemical acrobatics with being part of the preparation itself. What are you thinking about, if about anything at all, when reading papers?

Edit: OK, I think I know what got you confused. You probably missed or did not understood the explanation on page 38 where they explained that during their attempt at forming the hydrochloride from N-phenylethyl-4-piperidone in ethanol (experimental on lower half of page 50), an incidental ketalization occurred with the solvent. They explain this probably happened to previous researchers as well since their EA were not in good agreement with the expected hydrochloride. That's why they characterized the hydrochloride of the ketal, the ketal itself, as well as recover the ketone by the hydrolysis procedure you posted above. This acrobatics was only to prove a concept and correct the results of older researchers.
When reading scientific papers it is best to first read the discussion and then the experimental, by reading just the experimental like you seem to have done you only get more confused.

[Edited on 12/2/2009 by Nicodem]

chemrox - 12-2-2009 at 10:25

If that's the case I wholeheartedly apologize for all my remarks. Let's be sure. I shall re-read the whole thing-it's a long sucker and I'm into triazines now. (Too much crossover with med chem related issues in the piperidones.) I will shout "Oops" and push a peanut with my nose around my building three times if you're right about this not being part of the experimental procedure.

Globey - 12-2-2009 at 12:06

based solely on the formally low price for multi Kg quantities of NPP, one might guess the synthesis was indeed simple (2-pea, dmk, CH3O), one pot, etc. the higher current price is probably more a reflection of additional administrative requirements now attached to the chemical.
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"The taboo of“Trolling” is the modern online equivalent of McCarthyism. It is all too frequently invoked (regardless of merit), whenever someone of authority perceives a threat. Ironically, those who cry “trolling” the most (you know who they are…they often have fancy, esoteric quotes added to their posts, in an attempt to demonstrate to everyone just how sophisticated they think they are), usually abuse their power of moderation to troll the most. Having blanket license to troll (as moderator) makes one’s intellect dull, as instead of defending one’s wit with the mighty pen (or keyboard), a dictator can just execute all threats, and cleanse/falsify the record.

Time to stop crying “trolling, troll!” every time a nobody (in your book), has out witted you."

[Edited on 12-2-2009 by Globey]

ketals article

chemrox - 12-2-2009 at 13:40

@Nicodem:- I feel we both bear responsibility. You for not reading the experimental section thoroughly before jumping all over me and me for not reading the text before reporting the experimental content. You hadn't either I saw. As an interesting footnote the patent document also mentioned the ketal as an intermediate product. The intermediate ketal formation was the cause of a lot of consternation over melting points while this chemistry was being developed and a paper was published addressing the issue. I have attached it. If anybody want to compare the patent with the paper it is British patent (GB?) 832491. After reviewing all three papers I am not pushing a peanut around my building. Although the intermediate ketal was not intended and when the authors wanted to characterize it further they made it from the piperidone, nevertheless it was reported in the sequence I stated; in both the paper and the patent.

[Edited on 12-2-2009 by chemrox]

Attachment: Ready Formation of Ketals by 4-Piperidones.pdf (316kB)
This file has been downloaded 1220 times

Nicodem - 13-2-2009 at 01:10

That is a more thorough explanation on the issue of the unusual ease of 4-piperidones reacting with alcohols in acidic. Yes, I admit I only read the page 38 the first time you mentioned ketals and I told you about them not being reaction intermediates already in my first reply to your objection, but you did not bother checking. I did not read the experimental before yesterday when you still insisted about them being intermediates on the route N-phenylethyl-4-piperidone. I have limited free time, you know.
As an interesting note, this reactivity of the carbonyl group in protonated 4-piperidones is otherwise general. For example, even plain 4-piperidone hydrochloride forms a stable hydrate with water, probably due to the electron withdrawing effect of the ammonium group. Essentially they behave as electron poor ketones, of which chloral is one such textbook example.

chemrox - 13-2-2009 at 10:04

That's fine as far as it goes but this started out with you telling everyone I didn'y know what a Claisen condensation is, when it was in fact a Dieckmann, that I didn't know what a ketal was and all before you'd read any of the source material. I suggest if you have limited time you might limit your attacks too. Indeed, way do you attack? It's not at all helpful and just makes the forum a less pleasant place to be. Let us both go forward and try to do a little better in future.

BobHawson - 26-2-2009 at 13:49

Does anyone have access to these?

(1) Scott, Robbins and Chen, Science, 104,587 (1946).

(2) Jensen, Lindquist. Rekling and Wolffbrandt, Dansk ~Tidsskr.
Farm., 17, 173 (1943): C. A.. 39, 2506 (1945); Lee and co-workers.
J. Org. Chem., 12, 894, 904, 911 (1947).

(3) Blicke, “The Mannich Reaction,” “Organic Reactions,” 1,
303 (1942).

(4) Kuhn, Badstabner and Grundmann, Ber., 69, 98 (1936).

Taken from: http://www.sciencemadness.org/talk/viewthread.php?action=att...

They haven't been mentioned yet and I think they're quite relevant:

"
A number of piperidones have been prepared by
the Mannich reaction[3]. It should be possible to
extend the use of this reaction for the synthesis of
a large variety of 4-piperidones with different substituents
in the 1,2,3,5 and 6 positions.
"
I think this has the implication that the Mannich reaction worked with making unsubstituted piperidones like npp.

I'd know for sure if someone could find the articles, particularly number 3.

Polverone - 26-2-2009 at 14:22

Organic Reactions Volume 1 was scanned by S.C. Wack and has been in the library for a while now.

Edit: I should add that almost all of the information published about synthetic analgesics based on substituted piperidones and the Mannich reaction post-dates the review in Organic Reactions.

[Edited on 2-26-2009 by Polverone]

chemrox - 27-2-2009 at 20:26

Thanks SC Wack, Polverone and the text gods for a non-volatile upload. It is too bloody frustrating to go to a journal that is on an expired &-shared site or is a multi-volume set where each volume takes 5 minuted to start the dl and you're limited to two a day for 34 volume set. Oh and it's compressed too. @ Polverone- ahem, I have seen articles from McElvain, Rice and some others since 1942.. quite a few into the early 50's. They're not Mannich condensations though. Seems like Mansfield and Schmidle did some Mannich condensations and double Mannichs to make piperidines.

[Edited on 27-2-2009 by chemrox]

Attachment: Derivs XVIII-Mcelvain & Rorig.pdf (769kB)
This file has been downloaded 1671 times

N-Phenethyl2-6biphenylpiperidone > NPP

BobHawson - 2-3-2009 at 20:46

How would one convert N-Phenethyl2-6biphenylpiperidone into NPP?

N-Phenethyl2-6biphenylpiperidone synthesis is here: http://www.sciencemadness.org/talk/viewthread.php?action=att...

not_important - 2-3-2009 at 22:39

I would not do the conversion for two reasons

1. SFAIK it is not easy to remove an aromatic substitute from the piperidone ring, the ring is very likely to be destroyed.

2. NNP is Official Disapproved of in a number of countries, having possession is reason for various and vigorous treatments by LEAs.

BobHawson - 4-3-2009 at 09:00

Is a reaction possible with n,n-dimethylphenethylamine and acetone to give NPP?

chemchemical - 14-3-2009 at 09:21

I thought this article sounds interesting as a possible starting point to making NPP from PEA, unfortunately the online articles for 1998 do not include the first two volumes.

"Fentanyl of a potent anilidopiperidine analgesic has been synthesized from a simple phenylethylamine by four step sequence. The key part of this synthesis involves an efficient construction of phenylethylpiperidone skeleton via aminomethano desilyltion-cyclization followed by Swern oxidation.

Arch Pharm Res. 1998 Feb;21(1):70-2."

BobHawson - 14-3-2009 at 12:12

Also, would a reaction between N,N,-diethylphenethylamine and formaldehyde produce NPP?

I don't know what such a reaction would be called, if there is one.

4-Piperidone Synthesis

BobHawson - 14-3-2009 at 12:16

Anyone know of routes to piperidone not starting with piperidine?

I have utse and know of no posts on this chem btw.

Sauron - 15-3-2009 at 00:15

Probably because drug cookery is discouraged here, and 4-piperidone has little use other than making opioids.

Furthermore spoonfeeding requests are also frowned upon.

You cite no literature and show no evidence of having a clue.

There are quite a few preps of piperidine which have been discussed, one very recently from pentamethylenediamine (cadaverine). It ought to be clear that a carbonyl group in the appropriate position in the acyclic precursor will be unaffected by the ring closure and that 4-piperidone would result. My point is, have you searched for analogous preps of piperidine that can be modified? Apparently not.

Just asking for this information on a platter is asking for spoonfeeding.

Scholars help scholars who get stuck but have little time for the terminally indolent.

And that goes double for those just trying to squeeze a little joyjuice out of chemistry.

The appropiate compound would be 1,5-diamino-3-pentaneone.

H2N-CH2CH2-C(=O)-CH2CH2-NH2

See the cadaverine thread for that cyclization.

I do not know if the ketone stinks like cadaverine, let's hope not.

How to get to the intermediate?

Figure out how to make the corresponding glycol:

HO-CH2CH2-C(=O)-CH2CH2-OH

and chlorinate it or brominate it then treat it with conc NH4OH.

An obvious precursor to the keto glycol would be the trihydroxy compound 1,3,5-trihydroxypentane which you can selectively oxidize to the keto glycol with TCCA. The primary hydroxyls are unaffected.

That keto glycol looks vaguely like a citric acid derivative.

[Edited on 15-3-2009 by Sauron]

Ebao-lu - 15-3-2009 at 02:16

Starting with citric acid, you can apparently make its triamide, then dehydrate it into trinitrile, then eliminate the mid. CN group with KOH to get a useful byproduct KCN, the ketone is reduced by LAH to 1,5-diamino-3-pentanol and oxidized to corresponding ketone (then it is treated like cadaverine).

Sauron - 15-3-2009 at 02:37

Got any lit. on that?

Or is this old rhodium stuff?

The dehydration of the triamide, how? P2O5, POCl3, PCl5 if so this will be out of reach for most. Almost certainly for the thread author.

LAH is also a deal killer for many.

How about going directly from citric acid to acetonedicarboxylic acid (3-ketoglutaric acid) and reducing that to the trihydroxy compound (catalytically most likely) which gets you the starting material and then proceeding as I outlined above?

1. TCCA to the keto glycol
2. Chlorinate to the keto dichloride (bromination may be better)
3. Aminate w/ conc NH4OH

No restricted phosphorus reagents, no restricted LAH.

Acetonedicarboxylic acid is easy to make if you can get oleum. Just watch out for all that CO formed. Hood, or outside.

[Edited on 15-3-2009 by Sauron]

Ebao-lu - 15-3-2009 at 06:13

What lit? It must be a very kewl person who attempted this pathway, usual chemists haven't ever done it i believe.

Quote:

1. TCCA to the keto glycol
2. Chlorinate to the keto dichloride (bromination may be better)
3. Aminate w/ conc NH4OH

now its your turn (lit)

Sauron - 15-3-2009 at 09:24

For formation of acetonedicarboxylic acid from oleum, smartass, try my thread on things to do with citric acid; also axt's thread on DINA which is made from the same intermediate (ADCA) and both of us posted many papers on the reactions of citric acid with conc H2SO4 or (better) 15-20% oleum, UTFSE. Also see Org.Syn for prep of acetonedicarboxylic acid and references therein. All this was posted long before you ever joined this forum, but still.

Also a thread I did on prep of citrazinic acid which bears similarities to your proposal.

Org.Syn. also has prep of the di-ester (methyl or ethyl) of ADCA and I or someone else posted the prep of its cyclic anhydride which is prepared from ADCA and Ac2).

It does not take lit. to envision the catalytic hydrogenation of ADCA to the trihydroxy-3-pentanone, the TCCA selective oxidation of sec. hydroxyls has been posted here before, the halogenation of the keto glycol is trivial and so is its aminolysis.

It would be a good idea to do a literature search to pin down (hopefully) atm. or low pressure conditions and catalyst for hydrogenation of ADCA. I have a pressure reactorr but not many do, so a 60 spi procedure that could be done in a stirred Parr bottle would be more convenient for most.

Some people like conc HBr for alkyl bromide preps, I favor TCT/DMF/KBr. The lit. on that one has been posted several times.

Since I have zero interest in 4-piperidone I am never going to prepare it and so I will leave it to somneone who is more motivated to dig out the as yet unearthed lit. ADCA etc are a different story, been there, done that, posted already.

And yes it can be done with conc H2SO4 but the yields are shit compared to using oleum.

[Edited on 16-3-2009 by Sauron]

Ebao-lu - 15-3-2009 at 09:53

Ok, you won. You have provided literature so thats fine. Just let BobHawson to have a go (still, maybe try with cadaverine first to work out the procedure and not to flunk the last step with diaminoketone).

Sauron - 15-3-2009 at 10:31

It wasn't my stinky corpse juice. That was someone else who wanted to dry-distill it from lysine, see his thread. Ugh. He claimed he was just doing it out of curiosity, uh-huh. Cadaverine is a well known precursor to piperidine, so I guess we all know what that guy had in mind.

Master Hawson framed the question, how to make 4-piperidone from other than piperidine.

I merely wanted to demonstrate to him how chemists think. His problem was tractible. He's just not a chemist. I offered him an object lesson, not a spoonfeeding. I doubt he can make use of my route any more than he could get PCl5 and LAH to essay yours.

If I WANTED 4-piperidone I would probably start with pyridine and go from there, with a nuclear reduction in between maybe to a hydroxyypiperidine that can be mildly oxidized. A 5 minute review of pyridine chemistry in Ullmann's would probably tell all.'

But I do not have any use for it. I am past get rich quick schemes and certainly have no desire for instant incurable acute Parkinson's.

[Edited on 16-3-2009 by Sauron]

Sandmeyer - 15-3-2009 at 19:18

Parkinson's? Is the discussion about the synthesis of MPPP which under certain reaction conditions leads to the side-product MPTP (to be consumed)? No, it is not. It is interesting that you first take a "moral" stance against the "drug cookery" thread only to become the most active contributor in it. hahaha...

[Edited on 16-3-2009 by Sandmeyer]

chemrox - 15-3-2009 at 21:23

There is a lot of literature available through ACS on synthesis of piperidones. It's mostly done by the Dieckmann route. The intermediate compounds are alos covered in papers by McElvain and others, Baty, Jones & Moore and Beckett, Casey and others to name a few. Do some homework. When you have iden tified a specific paper ask for help getting it in refs if you don't have journal or library access. I don't see how you missed the rather too much discussion here if you searched. At least one of the papers was posted in a thread on piperidones. As Sauron says, they're mostly used in medicinal chemistry. I like them for other reasons and spent some time with them last year.

Sauron - 15-3-2009 at 21:23

Sandmeyer, as usual, I couldn't give a damn about what you think is "interesting".

What you characterize as a "moral" stance is nothing more or less than the current forum policy, no cook threads and no spoonfeeding.

The thread author exhibited neither interest in the chemistry of piperidones nor any scholarly effort to ferret out the literature on same beyond an obviously superficial and unsuccesful search. This is the sort of thread Nicodem loves to close precisely on those grounds. The thread author was doing nothing but asking for a synthesis - in effect a recipe.

So you see, "morality" has nothing to do with it. If you don't like the policy, take it up with the management, not with me.

BobHawson's other threads are revealing. Have a look. PEA -> NPP so I don't think it is inappropriate to conclude he is after opioids such as the infamous super-demerol.

The guy appears clueless, so let's not paint him as some world class medivinal chemist all of a sudden.

[Edited on 16-3-2009 by Sauron]

Nicodem - 15-3-2009 at 23:55

These latest thread was anything but informative and all it gives to this forum is one more opioid thread. One such thread would be more than enough, this is why I'm merging it with the longest one. No more new threads regarding piperidin-4-one and opiods in general - use the existing ones!

Sauron - 16-3-2009 at 02:48

The decarboxylation of lysine to produce cadaverine was described in Ber. 18, 2956 (1885), and I think the same procedure would apply to the diamino-3-pentanone prepared from citric acid.

The Dieckmann condensation of a suitable diester would require Na or preferably K metal or freshly opened potassium alkoxide. Na metal is not too hard to come by, potassium is rather dear, I have 6 Kg Na but only 250 g K.

Nicodem, I have a use for dilute solns of piperidine in Fmoc-streyegy peptide synthesis as a deprotection reagent, and buying piperidine is a pain in the ass everywhere because of the anti-PCP regimes. So making my own is attractive. I do not, as stated above, have any use for 4-piperidone, but chemrox does and he is no drug cook. No one is discussing how to make opioids per se. (Well not in this piperidone thread anyway. I think NPP is closer to the mark.)

Nicodem - 16-3-2009 at 03:27

Quote:

Originally posted by Sauron
Nicodem, I have a use for dilute solns of piperidine in Fmoc-streyegy peptide synthesis as a deprotection reagent, and buying piperidine is a pain in the ass everywhere because of the anti-PCP regimes. So making my own is attractive.

Those who are too annoyed by the paper signing when buying piperidine for Fmoc deprotection are now using piperazine for this purpose, at least that is what I have been recently told by a biochemist. I bet morpholine or pyrrolidine would work just as well. There is no need to stick to piperidine just because historically it is the reagent of choice for this deprotection.

Quote:

No one is discussing how to make opioids per se. (Well not in this piperidone thread anyway. I think NPP is closer to the mark.)

Already using such drug cook acronyms like "NPP" says more than enough about the intentions of the original poster and others involved in this thread. Not to mention the kewlish discourse used here, or the asocial form of posting of members like BobHawson and the like. For some reason most members that ask about opioids synthesis just have this need to shout to the whole world about their intentions.

Sauron - 16-3-2009 at 03:39

Oh, I absolutely agree about conducter and BobHawser and their ilk, I would think I make that perfectly clear. I agree that they broadcast their intentions about as effectively as the Goodyear Blimp over a packed stadium with an electronic signboard.

But BobHawser vanished like a vampire at the sight of the True Cross as soon as a few of us took over this thread. And conducter is nowhere around either.

Peptide chemists are rather conservative about reagents and often loathe to switch. I understand your reasoning that any old 5 or 6 membered secondary N-heterocycle ought to do as well as piperidine. But peptide chemists will turn up their noses at the suggestion. This personality trait has been remarked upon in the literature of peptide synthesis.

Piperazine itself is anyway under DEA scrutiny because of abuse of N-benzylpiperazine (horse cathartics if I recall) as rave drugs or some such. So that one is likely to be a problem in the future if not already.

I have never tried to buy piperidine here but a friend is a professor of molecular biology at a med school in Lausanne and he has been kicked upstairs into admin and described to me the paperwork the Swiss antidrug agency makes the university do to buy 5% solutions of piperidine for their peptide work. Next time I see him I will ask him about piperazine. Recently he was complaining about the shortage of acetonitrile worldwide.

[Edited on 16-3-2009 by Sauron]

BobHawson - 18-3-2009 at 17:31

Thanks for your replies folks!

I was waiting to post until some people had responded.

Now, anyone know of routes to piperidone that DO start with piperidine?

I have uts engines and know of no posts or literature on the conversion of piperidine to piperidone, though wikipedia says that piperidone is a derivative of piperidine. I don't know if this could be done on a lab scale, or wouldn't be practical.

[Edited on 18-3-2009 by BobHawson]

ergoamide - 18-3-2009 at 18:37

Just because something is a derivative of something doesn't mean it can be made from that something (easily anyway).

chemrox - 18-3-2009 at 21:43

Again, as Nicodem implies, there are already many posts on the subject here and if one looked a lot of the relevant literature has also been posted. Did you not hear the part about spoonfeeding? Having devoted the better part of a year and half to 4-piperidones (but not opioids thank you) I can tell you that pyridines and piperidines are not very good ways to make them. Cyclizations and addition reactions are employed. Even that old friend of yours and mine the Diels Alder has been utilized. FYI: in the opioid literature piperidones are gateways to piperidinyl moieties. Starting from piperidine would be backwards. Maybe it would be worthwhile for you to pick up one of those guides to chemical research. Not searching the literature as far as you are able will only earn you resentment and contempt. Moreover, there's a mod that waxes indecorous when this subject comes up. Maybe you should peruse the thread and send out a few pms after a search through the refs and a trip to the library. Pay heed to the words just posted by ergoamide. Also, out of his innate compassion, our friend Sauron did pretty much spoon feed you the general synthetic approach. Thank him and do some homework.

[Edited on 18-3-2009 by chemrox]

Sauron - 19-3-2009 at 00:18

I am very preoccupied with downloading 110 years of JACS volumes at present and after that I have a couple dozen large chemistry books to scan so I am afraid I have little time to help with this. Sorry.

By the way I regard any sentence starting with "According to Wilkepedia..." as epistomologically invalid. And if you do not know what epistomology is, look it up. It is a term the Jesuits pounded into me.

chemrox - 8-5-2009 at 21:14

This thread is long finished except that I felt I had to weigh in on the Wikipedia question. Wikipedia articles are written by volunteers and often carry the hope with them that another volunteer author will come along and correct the one first offered. That indeed makes them epistemologically invalid or suspect which ammounts to the same thing. Than k you Sauron.

Sedit - 8-5-2009 at 21:31

Ill have to go check Wikipedia to see if I can find out what epistomologically means.

Sauron - 8-5-2009 at 21:39

Try the OED instead. Wiki is for pinheads.

chemrox - 6-4-2010 at 16:31

I thought I'd follow up on this discussion with some experimental results. The PEA method works but the yields aren't great. Since that experiment I started making esters of various phenethyl cmpds; alcohol, halides, aldehyde. The results with acids including oxalic, anthranillic, propionic, acetic, citric yielded rosy flavors ranging from fruity and sharp to musky and bergamot like. I've been wondering if the method of using 4-piperidone HCl·H2O, Na2CO3 and phenethyl Br fails because the phenethyl compounds are too acidic. Maybe stronger base would have worked as suggested in a patent on ANNP (Indian). The esterifications mentioned above are *very* easy. The Indian patent is easily found for those wanting it and I shan't post it here for two reasons; bandwidth and I don't really want to encourage further delving into this area. However, the problem of failure of the N-alkylation by way of the halide bothers me. Maybe I'll try it with 4N NaOH sometime to see how it works. Also using the Cl rather than the Br cmpd. If I get around to it I'll write back with some details.

majortom - 8-5-2010 at 08:33

Could someone give me a link to an explanation of this reaction? I am not quite understanding the mechanism of this reaction, what is it called?

mongler - 30-3-2011 at 00:14

I apologize for this being my first post, for diggin it up from the depths, and for making it so "TL;DR"

I noticed this thread while thinking about this topic, mostly for fun (because who is honestly going to undertake this and ruin their career in chemistry).

I was thinking about how to make the dominant structural features for a convergent synthetic scheme by utilizing the absolute bare minimum of watched precursors (because it is absolutely impossible to achieve this synthesis by avoiding the use of chemicals watched by LEO). I realized that the main structural elements do indeed have synthons that are readily preparable from ubiquitous materials, and possibly even utilizing several multi step 1-pot reactions (without intervening purifications, just "add this, heat, add this, heat, etc")

Obviously the main core unit is the PEA, but like most of the posters here, I realized that construction of 4-piperidone might be possible and did the same googling and Scifinder-ing that everyone else did (Still have VPN access to my old institution's network, so I still have journal access and I have the Scifinder 2007 application installed, as opposed to the we based utility which sucks in comparison).

anyway, I stumbled upon that same intermolecular mannich followed by intramollecular mannich: amine+2xaldehyde+ketone prep.

The question of will formaldehyde work instead of benzaldehyde? my guess is yes, but the reaction conditions would have to be amended to optimize the yield of the target material. With formaldehyde, the imine/iminium ion intermediate (imine because either PEA or ammonia can be deprotonated to the neutral imine) is wildly reactive and will react with literally anything in solution, be it solvent or unreacted (or completely reacted target material) ketone or amine or impurity.

on the other hand, the benzaldehyde intermediate: phenyl-CH=N-R,H (where R is ethyl amine if you used PEA or H if you used ammonia, and I have written the structure as the deprotonated, neutral imine, not the iminium formed by a 2ndary amine mannich.) is very stable, with a large amount of resonance stabilization energy. why is this important? it means that the intermediate persists long enough for the ketone to diffuse through the solvent and encounter the intermediate with the right energy and orientation, which depends (as usual) on a Boltzmann distribution (as usual for encounter pairs in solution.... just like the old days of the Marcus Cross relation and the Eigen Fuos mechanism for inorganic electron transfer reactions, lol)

furthermore, in the NEXT mannich (on the "other side" of the carbonyl, so to speak), the intermediate Is, yet again, stabilized by the phenyl conjugation (though the effect is less significant, because this reaction is intramolecular, so the free energy stabilization is not as pronounced, due to a major entropic consideration). basically, if you ran the reaction with formaldehyde, the initial imine intermediate would react so quickly that the target material would be formed in precipitously low yield. but then again, who cares... its just formaldehyde.... if you run the reaction with ammonia and formaldehyde... who cares, that stuff is cheap and LEO really cannot fault you for buying paraformaldehyde and ammonia. you are just cleaning your floors and acting as an amateur entymologist (the formaldehyde)

and for the sake of completion....

the question is, what is the absolute bare minimum of "watched" chemicals?
if you can get a borane, PCC (pyridinium chlorochromate), H2, Pd/C (palladium adsorbed on carbon), styrene, aniline, various solvents, glassware, electronics (oil baths, mantle, stir plate, etc), tools (syringes, septums, etc), silica gel, celite, etc. and SOME synthetic equivalent for propionic acid.... molecular sieves (3-4 Angstrom) would be ideal as well

example:

styrene + 9-BBN ---> PCC ----> (1 pot, sequential) 2-phenyl-ethanal

no need for alkaline hydrogen peroxide, the PCC oxidizes the trialkylborane directly to the aldehyde (yes I have the reference, it is in my Advanced Organic texbook, by Zweifel, as an example with the reference which is from 1980)

2-pheny-ethanal + 4-piperidone ----> N-styryl-4-piperidone (enamine) + freshly distilled aniline ----> the imine adduct...

this is a 1 pot sequential reaction. no isolation, no change in solvent or reagent conditions.

H2, Pd/C (helps to be run under ~30 atmosphere) will reduce the imine and enamine but leave the phenyl groups. yes. I have references for this. remember, the reaction WILL proceed at ~1 psi guage pressure, but it will take forever (like weeks of stirring under H2). high pressure just speeds it up, nothing more.

the question is how to add the synthetic equivalent for propionic acid without using propionic anhydride or propionyl chloride or getting DCC or other activating agent. my advice would be to make propionaldehyde from propene (propylene) using the same synthetic methodolgy employed above with styrene.

form the simple aldol with reduced diamine listed above, but prevent the reaction from proceeding further to the ene-amine (prevent dehydration), and oxidize the amino alcohol intermediate with the "already obtained" PCC to the amide.

this, again, is theoretically a 1 pot, sequential addition reaction with no intervening isolation/purification. there are some concerns about formation of Chloro-amines, but in the presence of the pyridine itself, I think this would be fairly limited.

this exact concept (amidation of an aldehyde synthon) is actually a currently pursued area of research... many researchers have found various catalytic systems employing copper salts or other peroxides to furnish the intended amide (usually in the form of an amino-aldol, followed by alkoxy oxidation of the amino alcohol).

the absolute final step would be chromatography. each reaction listed above can be run using a filtered crude reaction mixture from the previous step. even the oxidation of the alkylborane will produce a filterable precipitate, and the side product can come along for the ride. the only genuine "isolation" steps would be filtration of any soldids, then drying over sodium sulfate and evaporation of the solvent. the biggest issue would be the use of any high BP solvents like DMSO, which requires long duo-seal vacuum pump time, or lyopholization.

I should note, I mentioned above that you might use the acetone dicarboxylic acid. here are some useful Decarboxylation methodologies:

1) the usual strong acid, high concentration, high heat
2) catalytic Cu2O in a polar-aprotic solvent at high (but not super high temp)... think MeCN at 90 C
3) DMAP in pH 7 buffered H2O/toluene at 90 C
4) LiI in H2O/DMSO or H2O/Collidine at reflux
5) Heating with Boric Acid

[Edited on 30-3-2011 by mongler]

jon - 30-3-2011 at 18:01

Petrenko-Kritschenko synth of piperidones
put this under your cap.

http://en.wikipedia.org/wiki/Petrenko-Kritschenko_piperidone...

sauron i remember you ranting on about the jesuits long ago they must have done something to shape your thinking.
i know they are some strict teachers.

it looks like if unsubstituted piperidones could be made this way they would have been already.

nope nope it is double micheal addition of methylacrylate to phenylethylamine followed by diekmann condensation and, saponification

phenylethylpiperidone can also be made from methyl piperidone by exhaustive methylation with MeI then heating in an excess of phenylethylamine if anyone wants that reference pm me.

[Edited on 31-3-2011 by jon]

[Edited on 31-3-2011 by jon]

[Edited on 31-3-2011 by jon]

[Edited on 31-3-2011 by jon]

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