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Dr.SAM
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Morpholine derivate from secondary amine/alcohol
Hello folks, this is my first post.
I apolagize in advance if it's against the rules to open a topic at the first post.
I need little help with a reaction i theorized.
Basically i want to form a morpholine derivate from a secondary alcohol and amine.
The reaction I came up with was:
R1-CHOH-CH2-NH-R2 + Br-CH2-CH2-Br -->
R1-Morpholine-R2 + Br2
Is it better to use dibromoethane or diiodoethane?
Is this reaction possible?
Could someone help me on this please.
Thanks
[Edited on 5-9-2008 by Dr.SAM]
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ScienceSquirrel
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That should be 2HBr.
In principle it may work.
Your biggest problem may be the much greater nucleophilicty of an amine group compared with an alcohol.
The size of your R1 and R2 groups could pose problems as well due to steric hindrance.
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smuv
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I have vaguely seen it refrenced as working with EtX2; but no reaction conditions were given. The more classic method is via ethlene oxide to form
the corresponding ethanolamine which can be cyclicised with acid catalysis.
If you try with EtX2 post the results as I think many would be interested.
P.S. Don't worry about aziridine formation it doesn't work under 'various conditions' as one paper stated. I guess the major conceivable side products
would be substituted ethylene diamines or over-alkylation of the amine.
[Edited on 9-5-2008 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Dr.SAM
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Thanks for replying.
I was planning to dissolve the compound as a free base in absolute ethanol and then gently add EtBr2 while heating at 50 'C. Would it be good? Should
I add some acid?
Would Diodoethane work better than EtBr2?
What sideproducts might this reaction give?
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smuv
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I covered side products in my above post...
I would stick with whatever is cheaper (probably dibromoethane). You might have to experiment with the reaction conditions. Definitely acid would
not help; you would want a non-nucleophilic base. Alkylating the amine is easy but I am not sure how easily the intramolecular cyclization will
occur; it is entropically favored of course but I do not know if it would still require a reagent that can quantitativly deprotonate the alcohol (as
in a Williamson ether synth) or if it is so favorable that a weakish base would work.
I would experiment with things; I am not sure enough about what conditions are required to make a good suggestion. Does anyone else on these forums
have an idea/experience?
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Dr.SAM
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After some reserch I came out with a promising synthesis.
The reaction involves making and ether of a secondary alcohol and alkylating a secondary amine. In order to complete the ether bond, according to the
williamson ether synthesis, a polar aprotic solvent should be used to speed the reaction and get higher yields.
So i would chose the very common acetone as a solvent.
the reaction takes place under basic conditions but unfortunately sodium hydroxide is insoluble in acetone, so is sodium carbonate i think. on the
other hand amines are soluble in organic solvents and the molecule we're speaking of has got already an amine group, so i don't think its necessary to
add another organic base, plus i dont really have any available organic base. Adding a concentrated solution of ammonia would make the solvent more
protic so i dont know if i should consider it a wise thing to do.
A soluble iodide could be used as a catalyst in this reaction.
Alkyl iodides have practically no polarity, they are good leaving groups but they are unable to polarize the carbon to C+ so i think dibromoethane
would be more effective.
The reaction should be carried to 60-100 'C.
Am I doing anything wrong?
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smuv
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Yes. If you don't add any base some of your unreacted substrate will be converted to the non-nucleophilic hydrobromide (or iodide depending on your
alkylating agent) and kill your yields.
I dont really understand what you are trying to describe; why not post the paper.
Maybe a starting point would be to mix 1eq dibromoethane (or whatever you want to use), excess K2CO3 with the amino alcohol in acetone or butan-2-one
and reflux it for a while. The potassium carbonate will not dissolve but it will eat up some acid and to a very small extent detonate the alcohol. I
would worry about using stronger basses as it may possible to eliminate a halide from the dihaloethane to produce a vinyl halide.
Don't use nucleophilic bases like ammonia...
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Dr.SAM
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So the full yhtesys would be.
Boiling absolute ethanol in conc. sulphuric acid in a reflux apparatus to give ethene gas.
The gasses escaping the reflux column are going to be bubbled into a cold solution of sodium hydroxide to remove SO2 and ethanol vapors.
the gas will be then going through a sodium hydroxyde/copper chloride column to remove humidity and any probable alcohol traces.
In order to produce bromine gas I was planning to bubble Cl2 gas made from conc. HCL and NaOCl in a saturated solution of potassium bromide kept in an
ice bath to dimish the bromine-water solubility. The bromine under cold conditions should separate easily from the water layer especially if the water
is saturated by potassium chloride.
The pure bromine, still kept under ice cold conditions is ging to be poured into a bubbling apparatus.
Later I'm going bubble the previsously made ethene gas into pure bromine until the liquid becomes prefectly clear meaning that all the bromine reacted
with ethene to give pure 1,2 dibromomethane.
Then I'm plnning to dissolve the hydroxyamine base in acetone and ad an excess of anhydrous potssium carbonate and then obviously the 1,2
dibromoethane.
However since the base form of the molecule is a sticky, oily liquid i would prefer dissolving the hydrochloride salt in hot acetone wich would then
be neutralized back to a base by the potassium carbonate.
I'm planning to reflux the mixture at 60 to 90'C with occaional swirling. Probably i'm going to ad a tiny iodine chrystal to act as a catalyst
according to the Williamson ether synthesys route.
The reflux will last 6 to 8 hours and once complete I'm goin to slowly add conc. hydrochlorid acid to turn the compound into its hydrochloride form
again.
The acetone is goin to be gently evaporated and the resulting chrystals are going to be purified with an acid freebase extraction.
Am I missing anything?
[Edited on 6-9-2008 by Dr.SAM]
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smuv
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If you have to make the ethylene dibromide; you would be better off making ethylene oxide and sticking to well known procedures to making morpholine
derivatives.
There are some things wrong...
-On a small scale that is a crappy way of producing bromine...you might as well just use ethylene dichloride; it could likely get the job done.
-I wouldn't bother washing the gasses. Sulfur dioxide wont be much of a problem; it may reduce some Br2 to HBr, but this is trivial. Just fractionate
your product after synthesis to remove the very little amount of halohydrin and monohaloethane that may be produced. Remember with relatively cheep
reagents yields can be sacrificed for an easier procedure.
-I think making the freebase in situ is a bad idea; it complicates things and because of the low solubility of potsassium carbonate it might not work
so well.
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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not_important
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Consider treating ethylene glycol with excess hydrobromic acid, simpler than the EtOH => ethylene, + Br2 => C2H4Br2
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Dr.SAM
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Unfortunately i dont know where to get ethylene glycol, neither hydrobromic acid.
Although i know how to get conc. sulphuric acid, absolute ethanol, and potassium bromate.
It's much easier for me to reflux absolute ethanol in conc sulphuric acid and then filter the gasses escaping from the condenser in a solution of cold
NaOH.
By the way, do you guys think that the reaction i posted above is practically possible?
what could i add to increase the yield?
Are 5 hours of refluxing enough or should i wait a day or so?
Another question: could traces of water in my acetone mixture mess up my reaction?
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ScienceSquirrel
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To be honest it might work, on the other hand it might not.
With a proper lab, NMR spectroscopy etc these things can be far from simple.
It is possible that a competent postgraduate could make a range of these compounds in a few months but there could be some huge pitfall in your
proposed route and without the proper gear you just will not find out what is going wrong.
The old style chemists were brilliant at doing a lot with very little but the price they paid was years of painstaking work and a lot of deductive
reasoning.
The structure of benzene is obvious to the modern chemist armed with instrumental techniques, it was a near impenetrable puzzle to Kekule's
generation!
Making ethylene dibromide at home on a preparative scale by reacting ethylene with home made bromine is going to be far from a walk in the park and
that is only the foothills of your project.
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smuv
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And considering he will be consuming the product (phenmetrazine)....better be damn sure it is the desired product. Although Mp and TLC are good ways
of checking approx. purity.
IMO if you have to be spoon-fed you are not ready to successfully do it.
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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ScienceSquirrel
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Now the squirrel can see the hazelnut 
I would follow the classic route.
I do not know where you are going to get the phenylpropanolamine from in sufficient quantity.
But I would react it with 2-bromoethanol to form the N-hydroxyethylaminopropanolamine and then cyclise this with acid. That answers your main problem
about reaction centre specificity.
The ether will be be formed in a facile manner due to the adjacent phenyl group that will promote the easy formation of a carbocation by loss of
water. Nucleophilic attack by the primary alcohol will then result in the formation of the six membered ring which will be entropically preferred to
intermolecular reaction.
I am sure that you will find a synthesis of 2-bromoethanol somewhere on the net.
Are Italian prisons particularly comfortable? 
[Edited on 9-9-2008 by ScienceSquirrel]
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kolpak
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Once I've faced with the same problem. I needed to convert amino ethanol PhCH(NH2)CH2OH into corresponding morpholine. I find out from the literature
that treatment with dibromoethane leads basically to bis products: HOCH2CH(Ph)NHCH2CH2NHCH(Ph)CH2OH - the obvious result 
The simple and reliabale method I used is treatment with chloroacetylchloride - gave corresponding amide from amino-group acylation, then its
cycization into correspodning 2-oxomorpholine and reduction with lithium aluminium hydride.
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Ketone
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Well, it seems pretty obvious you're going to make (Well, try to make) Phenmetrazine. Those unnamed substituents (sp??) is C6H5 and CH3 aren't they?
You should just level with the people here you know, if anything it could save you alot of frustation when they start discussing all that boring
chemistry instead of just telling you "Yes, you can make drugs this way" or "no, you can't make drugs that way." 
I don't think you can make it this way btw. Don't got (any) experience with "substituted morpholines" but if this reaction works..
Then I think the CH3 would be in the wrong position.
Though, it might make you high all the same..
But as I said, I don't think it will work, it just seems.. wrong. Way wrong.
| Quote: | Originally posted by ScienceSquirrel
Are Italian prisons particularly comfortable? |
Lol..
| Quote: | Originally posted by Dr.SAM
i dont know where to get ethylene glycol |
Lol.... try a gas station maybe?
[Edited on 16-9-2008 by Ketone]
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ScienceSquirrel
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I think he just made a mess of his original formula, I think he means;
PhCH(OH)CH(NH2)CH3
which would give you phenmetrazine.
Notice that he eliminates bromine in the reaction which is nonsense.
I think he has just given up now anyway.
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Nicodem
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Phenmetrazine can not be made by reacting any of the 2-amino-1-phenylpropanols with 1,2-dibromoethane as far as I know. The reaction of an primary
amine with 1,2-dibromoethane would not stop at the R-NH-CH2CH2-Br stage since these compounds only exist untill the amine is protonated. In neutral
and basic conditions they they form the coresponding aziridines (R-N=(CH2CH2)) which are electrophilic enough to alkylate amines. Hence the results
Kolpak described above. This is essencially inevitable, hence the method used to produce phenmetrazine from 2-amino-1-phenylpropanol involves the use
of chloroacetyl chloride, cyclisation and amide reduction, though there is a way simpler method used by the pharm industry which however does not
start from any 2-amino-1-phenylpropanol stereoisomer.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
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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smuv
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| Quote: | | In neutral and basic conditions they they form the coresponding aziridines (R-N=(CH2CH2)) |
The formation of a 6 membered ring interferes with the synthesis of aziridines (as I previously posted)...
See: Eur. J. Org. Chem. 2007, 3281–3291
DOI: 10.1002/ejoc.200700041
[Edited on 9-17-2008 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Nicodem
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| Quote: | Originally posted by smuv
| Quote: | | In neutral and basic conditions they they form the coresponding aziridines (R-N=(CH2CH2)) |
The formation of a 6 membered ring interferes with the synthesis of aziridines (as I previously posted)...
See: Eur. J. Org. Chem. 2007, 3281–3291
DOI: 10.1002/ejoc.200700041
[Edited on 9-17-2008 by smuv] |
Aziridines generally can not be prepared using 1,2-dibromoethane since they are often more reactive than 1,2-dibromoethane itself therefore leading to
R-NH-CH2CH2-NH-R products. Here aziridines are just intermediates allowing for what is called neighbouring group assisted nucleophilic substitution
(though, there are exceptions where some aziridines can also be isolated). Probably I did not made this clear enough in my previous post.
I would be a bit sceptical about these claims in the paper where the formation of the morpholine ring is considered only a side note without any
experimental date. Also, they do not say unambiguously that they used 1,2-dibromoethane while the "various conditions" say close to nothing. I guess
one could always email to the authors and ask for more information if particularly interested.
On the other hand, 1,2-dibromoethane does react with ortho-aminophenols to yield the corresponding benzomorpholines without problems and generally in
good yield, but this is expected since the phenols are easily deprotonated hence the aziridine intermediate reacts more easily intramolecularly or
alternatively the reaction starts with O-alklyation since the phenoxide is a good nuclephile and gives the same product. But to simulate such a
condition on aliphatic aminoalcohols one would need to react 1,2-dibromoethane with the O-deprotonated aminoalcohol (for example by using NaH on the
aminoalcohol in THF followed by 1,2-dibromoethane addition). However, I never saw any such example so I have doubts about it working.
Besides, I still don't full understand the practical aspects of this thread. In which way would be using 1,2-dibromoethane more practical than the
classical synthesis employing the cyclisation of N-(2-hydroxyethyl)aminoalcohols in acidic media? I understand the unattractiveness of the route
employing chloroacetyl chloride since it is based on the reduction of the amide, but preparing the N-(2-hydroxyethyl)aminoalcohols is hardly a
difficult task giving that just about any reagent able to form vinyl oxide in situ can be used (like 2-chloro or 2-bromoethanol).
The paper referred by Smuv is attached in case someone wants to read it more thoroughly (I just check the paragraph mentioning the discussed reaction
so perhaps I missed something):
Attachment: An Approach to Enantioselective 5-endo Halo-Lactonization Reactions.pdf (216kB)
This file has been downloaded 1200 times
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
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)
Read the The ScienceMadness Guidelines!
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smuv
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Nicodem,
You did not miss anything; reaction conditions were not given, however the writers state "all our attempts (to make the aziridine) led to the
exclusive formation of the cyclic amine (morpholine)." If one were sufficiently interested in making these morpholines from 1,2-dihaloethanes some
experimentation in this area could be fruitful.
Admittedly I know little about aziridine chemistry; I would expect the formation of ethylenediamines as a side reaction to be entropically unfavorable
as opposed to intramolecular cyclization though. Although I suppose under the conditions I proposed kinetics would probably trump energetics... I was
also hoping that this cyclization would be so strongly favored that quantitative deprotonation of the alcohol would not be required.
I agree with you though, if you don't care about experimentation and just want to make the morpholine, might as well stick to known routes involving
ethylene oxide and halohydrin.
[Edited on 9-18-2008 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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sonogashira
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| Quote: | | Originally posted by smuvmight as well stick to known routes involving ethylene oxide and halohydrin. |
Would you mind sharing these references and papers (if you have them)?
I had a look in the Merck index and the patents mentioned there only discussed routes starting from a-bromopropiophenone or the chloroacetyl chloride
route mentioned.. But no mention of this "well known" 2-bromoethanol method?
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Nicodem
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It is the most common route to morpholines and there are lot's of references (even plain morpholine is made this way!). For the synthesis of
2-phenylmorpholines you can just check the reference given in the paper I uploaded in my previous post. I think it was the reference number 11, an old
JMC paper, if I remember correctly. I would guess the only reason it was not used in the industry for the phentermines synthesis (or was it?) is
simply because it is not so rational and economic as the simple process starting from propiophenone.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
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)
Read the The ScienceMadness Guidelines!
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ScienceSquirrel
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The original synthesis of phenmetrazine from 2-amino-1-phenylpropanol.
Otto, W. G., Angew. Chem. 68, 181 (1956)
[Edited on 19-9-2008 by ScienceSquirrel]
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jon
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right, that's what he's driving at, 2-iodoethanol, k2co3, ephedrine, and methanol reflux it.
but why bother? that's a shit compound you want phenmetrazine the routes are cloroacetylchloride to phenylpropanolamine, followed by cyclization with
koh and reduction with LAH.
or oxalyl choride and ppa and lah reduction.
or you could get *creative* and react iodo ethanol with ppa in dmf with CsOH to suppress dialkylation distill the hydroxyethylamine and cyclizize with
conc. h2so4 via the concerted reaction they talk about.
i don't think the haloethanols form vinylic oxides in situ how? the conditions are'nt basic enough in the literature reactions??
am i just some dumb redneck or am i missing something here?.
i've never seen iodoethanol reacted with primary amino alcohols like this in any literature examples. for the suspected reason that they react the
classic sn2 way any halo alkane and amine would giving rise to predominately tertiary amines.
oh and why bother with otc haloethanol synthesis you can buy from science supply houses no questions aked
[Edited on 13-1-2009 by jon]
[Edited on 13-1-2009 by jon]
[Edited on 13-1-2009 by jon]
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