chemrox
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proposed synthesis
My partner and I think this might be a worthwhile framework to sandwich metal ions. Here's the proposed procedure to make, N,
N'-diphenethylpiperazine. We're aware one of the starting ingrediants is on a hot list but we obtained some before the listing and have a mtg
scheduled with a DEA rep.
(0.1 mol.) N-benzylpiperazine is dissolved in DCM under Ar atmosphere*. To this is added (0.1) phenylacetaldhyde and (0.2 mol) acetic acid. The
mixture is stirred for a half hour after which (0.15 mol) STAB was added and the whole is stirred for 24 hours. The expected product is
N, N'-diphenethylpiperazine.
*[procedure-pump out the air until the solvent starts to boil and let Ar on. Repeat nine times and maintain slight pressure with an oil bubbler or
baloon]
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not_important
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If you mean the attached, then consider catalysed hydroamination of styrene with piperazine. Following are articles on the general class of reaction
doi:10.1016/S0045-6535(00)00319-2
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi...
doi:10.1016/S0040-4039(03)00008-X
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi...
http://www3.interscience.wiley.com/journal/55002646/abstract
http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2000/122/i39...
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chemrox
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No, I hadn't seen these. Thanks! I also pulled up a couple of JOC articles. Nobody is doing it quite the way we propose.
[Edited on 30-5-2008 by chemrox]
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Nicodem
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| Quote: | Originally posted by chemrox
(0.1 mol.) N-benzylpiperazine is dissolved in DCM under Ar atmosphere*. To this is added (0.1) phenylacetaldhyde and (0.2 mol) acetic acid. The
mixture is stirred for a half hour after which (0.15 mol) STAB was added and the whole is stirred for 24 hours. The expected product is
N, N'-diphenethylpiperazine.
*[procedure-pump out the air until the solvent starts to boil and let Ar on. Repeat nine times and maintain slight pressure with an oil bubbler or
baloon] |
That would give you 1-benzyl-4-(2-phenylethyl)-piperazine and not N, N'-diphenethylpiperazine (assuming that stands for
1,4-bis(2-phenylethyl)piperazine)! If you want to prepare that using STAB, then why not using the cheap piperazine hexahydrate and phenylacetaldehyde?
Though it sounds a bit exaggerated that you actually want to prepare such a simple product using a relatively expensive reagent like STAB. Even
hydrogenation of phenylacetaldehyde and piperazine with Pd-C would be way cheaper. The synthesis from styrene like not_important suggested is the most
economically reasonable one though it would require anhydrous piperazine.
Also, why do you want to use inert atmosphere? Reductive aminations using STAB do not require any protection from air and phenylacetaldehyde certainly
does not react with oxygen at room temperature so rapidly for this to be an issue.
It is also suggested to use 1,2-dichloroethane as solvent. Though I don't know if this is because STAB is soluble in it or if there are other reasons.
I seem to remember reading somewhere that methanol and 1,2-dichloroethane as solvents influence the imine equilibrium most optimally, so perhaps that
is the reason rather than solubility issues.
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Klute
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With the benzylpiperazine, you are one carbon short compared to the other chain afetr reductive amination with phenylacetaldehdyes...
You would get: N-benzyl-N`-phenethylpiperazine this way.
How did the other reductive aminations with STAB go BTW?
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chemrox
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extra C there
Crap, you're right. It could be done with benzaldehyde, maybe. Two reasons for inert conditions here. One the paper I posted last year in the
reductive ams thread I have re-posted here. See method IV. Also, the cautions on the reagent bottle for N-benzylpiperazine say it has to be opened
and used under inert. Carbonates? Anyway, I think you overtated it. Sometimes N2 is required using STAB as in the attached. Example was reax
between piperidine and 2-heptanone.. others. You and discussed one I was working on that failed last year from lack of adequate air removal. See the
method I proposed above for clearing the air and subbing in the Ar; it made the other finally work. (It wasn't very interesting otherwise.)
And anyway it would be a lot cheaper ad easier to make the product with benzyl halide. Phenthyl halide would be the alternative to what I wrote and
would also go easier and cheaper. It would be too floppy though and we'd lose the symmetry we we're going to have.
[Edited on 31-5-2008 by chemrox]
Attachment: Reductive Amination of Aldehydes and Ketones with STAB_copy.pdf (412kB)
This file has been downloaded 602 times
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Nicodem
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No, with benzaldehyde or benzyl halides you would get 1,4-dibenzylpiperazine. Actually, there is no way you could get 1,4-bis(2-phenylethyl)piperazine
out of 1-benzylpiperazine without debenzylating at one point. But surely you can obtain piperazine, so you can start from there given you have both
phenylacetaldehyde and STAB.
At my job I had to do a couple of reductive aminations of some ketones with anilines and amines using STAB and I never used inert atmosphere. And
still I had no problems and the yields were good. In preparative chemistry you only use inert atmosphere when the reactants are sensitive to O2, H2O,
CO2... or if you simply don't have enough self confidence and knowledge about the atmospheric effects on the reaction. The only cases where inert
atmosphere is commonly used even when unnecessary is when you do basic research (kinetic and mechanistic studies, reaction optimizations, etc.) where
it is important to have controlled and reproducible conditions (like some of the examples cited in that review). But you don't seem to be into this
kind of research, so that is why I asked what is the argon for. Inert atmosphere surely does not hurt your reaction - I was just curious about why you
mention it.
PS: That paper was already uploaded in the STAB thread. It would be more convenient to post a link there rather than upload it as an attachment again
- in the sense of forum bandwidth & server space economy.
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unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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chemrox
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"No, with benzaldehyde or benzyl halides you would get 1,4-dibenzylpiperazine." Actually, this si where I was headed to start with and got confused
about the number of C's. The ph-et moiety is too floppy for what I want but thanks. I'm bothered by what you're telling me although I don't doubt
you in the least. Re-reading the paper, all the methods cited, and this is the genreal method as far as I know, employ inert conditions. Why? Do
you suppose it was habit the workers were into as a general precaution? When I first used STAB my amine was difunctional and that could have been a
different kind of cat to skin. In the paper, the Method I example uses hexamethylenimine .. any air sensitivty there? I've been going through the
book, "Enamines" and haven't found an explanation there either. I have also seen other writeups using anilines with naBH4 and in those the reax were
run in normal atm. as you said but you were using STAB so that's not it. [point about bandwidth appreciated]
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Klute
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Working in a research lab, we always use inert atmospher, eevn in the case were the reaction could do without it. As Nicodem suggested, this is to
minimalize the variables, and offer reproducible results. Sometimes, even if the use of inert atmospher isn't mandatory, O2 can cause a slight color
change, a little humidity can cause a certain type of crystallization, etc etc
If the use of inert atmospher is problematic, you could try without an dsee how it works. Otherwise, you cna start with it, see hwo the reaction goes
excluding the impact of atmospheric O2 and H2O, and then try the reaction again (if you need to) without the inert atmospher and se how it goes.
Luckily, there won't be any difference. I fthere is, you can try and see what else was cganged (rate of addition, scale,e tc) to see if it was really
the atmospher that caused the change.
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