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karlos³
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Phenethanolamine synthesis is frustrating me!
Hi!
I am looking for a good synthesis of Phenethanolamine (CAS 7568-93-6), I´ve already tried to make it via the nitroalcohol, which worked ok with low
yield and tedious workup when reduced with Zn/HCOOH (all the Zn salts after basification!).
Recently I tried to reduce it with Pd/C and HCOOK (my first CTH reduction) which worked not much, very frustrating. I guess I have to optimise that
reduction. Maybe the Pd/C was not good, I dont know.
I tried to monitor the reaction with TLC, but the nitroalcohol has´nt disappeared even after 24 hours! So I decided to work it up, cause some amine
was there, even if it was less than a 5% yield...
I have also tried once to react styrene bromohydrin with hexamine, and subsequently hydrolysis, which worked also not very well. I have only reacted
it on reflux for a half day and then let the reaction sit for a few days, but the yield was also frustrating.
Styrene seems as a good precursor with this end product in mind, as I have read about its epoxide being reacted with ammonium, or in a microwave with
ammonium acetate, etc.
I have access to a lot of chemicals and it would be very appreciated if someone could give me some advice from personal experience.
I guess it´s possible to reduce the nitroalcohol with Red-Al?
How much hydride must one use to get acceptable yield? I know for nitrostyrenes it has to be an eight molar equivalent, to reduce unwanted
sidereactions. Even if only four equivalents are theoretically needed.
So should four equivalents suffice to reduce the nitrogroup without unwanted side reactions?
I have never reduced a nitroalcohol with Red-Al, indoleglyoxylamides, yes, nitrostyrenes, yes, but never a nitroalcohol.
Can someone give me please some advice from personal experience?
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Nicodem
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Thread Moved
25-9-2015 at 15:24 |
CuReUS
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see this paper(80% yield of phenethanolamine from stryene epoxide)
http://www.sciencedirect.com/science/article/pii/S0040403912...
another method could be hydration of cinnamic acid,followed by a hoffman bromamide to get the desired product,but I don't have a reference for that
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karlos³
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It´s an indian paper, I have problems with their general trustworthiness (is this even a word?).
But thank you anyway.
Have you made phenethanolamine from cinnamic acid? Sounds interesting, which reagents and conditions have you used to get there?
I have thought about something similiar but couldn´t dig up any reference on that.
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CuReUS
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see this paper,you won't need cinnamic acid after all
http://pubs.acs.org/doi/abs/10.1021/jo100828c
this followed by a schimdt reaction should give your product in 2 steps 
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solo
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Reference Information
Acetic Acid Aldol Reactions in the Presence of Trimethylsilyl Trifluoromethanesulfonate
C. Wade Downey, Miles W. Johnson
J. Org. Chem.
2010, 75 (15), pp 5351–5354
DOI: 10.1021/jo100828c
Abstract
In the presence of TMSOTf and a trialkylamine base, acetic acid undergoes aldol addition to non-enolizable aldehydes under exceptionally mild
conditions. Acidic workup yields the β-hydroxy carboxylic acid. The reaction appears to proceed via a three-step, one-pot process, including in situ
trimethylsilyl ester formation, bis-silyl ketene acetal formation, and TMSOTf-catalyzed Mukaiyama aldol addition. Independently synthesized TMSOAc
also undergoes aldol additions under similar conditions.
Attachment: Acetic Acid Aldol Reactions in the Presence of Trimethylsilyl Trifluoromethanesulfonate.pdf (416kB)
This file has been downloaded 646 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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Praxichys
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LiAlH4 reduction of benzoyl cyanide?
A. Burger and E. D. Hornbacker (1952). "Reduction of acyl cyanides with lithium aluminum hydride." J. Am. Chem. Soc. 74 5514.
http://pubs.acs.org/doi/abs/10.1021/ja01141a501
The paper mentions that hydrogenation can also be used, albeit with a tedious workup.
[Edited on 28-9-2015 by Praxichys]
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CuReUS
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Quote: Originally posted by karlos³  |
I have some questions if you don't mind
Phenethanolamine (CAS 7568-93-6), I´ve already tried to make it via the nitroalcohol, which worked ok |
karlos,how did you know you had made nitroalcohol ? did you follow an something similar to an ephedrine synthesis?
https://www.erowid.org/archive/rhodium/chemistry/nor-pseudo-...
| Quote: | | with low yield and tedious workup when reduced with Zn/HCOOH (all the Zn salts after basification!). |
from the ephedrine link
" Presumably many of the ordinary metal-acid reducing agents can be used provided the temperature is kept sufficiently low to prevent dehydration.
There are, however, several byproducts of the reduction".
| Quote: | | Recently I tried to reduce it with Pd/C and HCOOK (my first CTH reduction) which worked not much, very frustrating. I guess I have to optimise that
reduction. Maybe the Pd/C was not good, I dont know. |
from the paper-" When catalytic hydrogenation was selected as the method, N-ethylbenzylamine was a by-product"
| Quote: | | I have also tried once to react styrene bromohydrin with hexamine, and subsequently hydrolysis, which worked also not very well. I have only reacted
it on reflux for a half day and then let the reaction sit for a few days, but the yield was also frustrating. |
how did you make the bromohydrin ? NBS/H2O ? maybe the bromohydrin was contaminated with impurities from side reactions.
use NH3.hexamine won't work.it will just form a stubborn adduct.
| Quote: | | Styrene seems as a good precursor with this end product in mind, as I have read about its epoxide being reacted with ammonium, or in a microwave with
ammonium acetate, etc. |
this is the best method for the amateur chemist,IMHO.why didn't you try it out.
another thing that is bothering me is that phenylethanolamine will have stereoisomers.Do you want a specific one?
In the two step method I suggested,will the OH of 3-hydroxy,3-phenylpropanoic acid survive schmidt reaction conditions or will it get dehydrated ?
Will the dehydration be reversible ? What if the temp is carefully controlled ( <90'C)
| Quote: | | I have never reduced a nitroalcohol with Red-Al, indoleglyoxylamides, yes, nitrostyrenes, yes, but never a nitroalcohol. |
I had another idea.Why not make mandelonitrile and then reduce that to the target compound using Red-Al?
[Edited on 29-9-2015 by CuReUS]
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karlos³
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Yes I did use this route, MeNO2/EtNO2 with Et3N catalysis, then reduced it to the Aminoalcohol.
For norephedrine it works better.
Styrene bromohydrin was made with NSB in aqueous DMSO, foul smelling dimethylsulfide was a byproduct.
The adducct of hexamine to it was reacted with HCl to cleave it to the amine.
Also tried to aminate it with ammonia with the chlorohydrin made with TCCA.
I do not want a specific isomer, the racemate is fine enough.
I will probably try out the reduction of the nitroalcohol with Red-Al, this seems to work good even if its expensive.
Because I also want to make p-Fluorophenethanolamine this route should be it, I dont want to waste precious nitroalcohol that can´t be made as easily
from styrene.
For unsubstituted phenethanolamine I will probably try again with styrene, make the epoxide and the halohydrin and try both the delepine reaction
again and ammonolysis of the epoxide under various conditions.
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byko3y
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The Direction of Epoxide ring opening in the reaction of Styrene Oxide with Ammonia
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karlos³
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So, I have made some 1-(4-fluoro)phenyl-2-nitroethan-1-ol, and reduced the nitroalcohol with Red-Al. And, as always with halogenated substances, added
the Red-Al to the nitroalcohol, not the other, usual way around. It was a batch of 0,05 mol, so I used 0,2 mol Red-Al.
Will report back to the yield of 4-fluorophenethanolamine then.
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chemrox
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| Quote: Originally posted by karlos³ | It´s an indian paper, I have problems with their general trustworthiness (is this even a word?).
But thank you anyway.
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Me too. I've seen a few Indian "dry lab" reports. Seems not much in the way of peer review. My professor reviewed for OrgSyn by following the
reactions exactly. If he and a few others were successful the method was published. Ortherwise not.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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chemrox
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You haven't been able to use the Henry reaction approach? The synthesis of phenylpropanolamine would be easier. However you might be able to use the
Henry. The synthesis of the desired isomer of Ppropanolamine was enhanced by the use of 0.2 eq of diethylamine. You could give that a whirl..check the
Erowid article: copy of a eu patent
I believe there's a way from acetophenone. Try GB1513110A
[Edited on 2-10-2015 by chemrox]
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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byko3y
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I don't really understand whether your want to have a fun trying different techniques and test henry catalysts, or just obtain the aminoethanol?
Because if the latter is true, than I'm sure the way via styrene oxide is the easiest one, until you can't purchase the styrene.
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karlos³
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I used the henry reaction to obtain the nitroalcohol for p-fluorophenethanolamine, with triethylamine as catalyst.
However, for unsubstituted phenethanolamine styrene is a bit cheaper than benzaldehyde, also no reductions have to be used, so for unsubstituted
phenethanolamine I will go via styrene epoxide.
I have discovered a nice route for the latter, and when I have made some of the epoxide I will test various aminations.
Has anybody some personal experience with the synthesis of this particular molecule?
Before I forget it, thanks to all of you who have contributed!
Its really nice to have the option to ask here :-)
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CuReUS
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karlos³
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Related to some methadone analogue? No, not the tiniest bit.
Yes, the method for styrene epoxide consists of reacting styrene dissolved in alcohol and acetonitril in the presence of Na2HPO4 with H2O2, because I
have a lot H2O2 and styrene, this seems like the best method.
Reference is here available: http://forum.lambdasyn.org/index.php/topic,1181.0.html
The discussion about the synthesis mentions with NH3 one can have nearly quantitative yields of triphenylethanolamin... This is definitely not what I
want!
But anyway, I will give it a try.
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CuReUS
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| Quote: Originally posted by CuReUS |
how did you make the bromohydrin ? NBS/H2O ? maybe the bromohydrin was contaminated with impurities from side reactions.
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what I meant by side reactions was the formation of the diol and dibromo compound along with the bromohydrin. | Quote: Originally posted by karlos³ |
The discussion about the synthesis mentions with NH3 one can have nearly quantitative yields of triphenylethanolamin... This is definitely not what I
want!
But anyway, I will give it a try. |
maybe if the phenoxirane was slowly dripped into a flask of NH3,formation of triphenylethanolamine could be prevented.
but I saw something funny on wiki
https://en.wikipedia.org/wiki/Styrene_oxide
| Quote: | | In addition, nucleophiles always attack the secondary carbon of the oxirane ring because of stability of the intermediate and steric hindrance.
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according to this you will get 2-phenyl-2-aminoethanol rather than 1-phenyl-2-aminoethanol.I am confused
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Darkstar
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| Quote: Originally posted by CuReUS | but I saw something funny on wiki
https://en.wikipedia.org/wiki/Styrene_oxide
| Quote: | | In addition, nucleophiles always attack the secondary carbon of the oxirane ring because of stability of the intermediate and steric hindrance.
|
according to this you will get 2-phenyl-2-aminoethanol rather than 1-phenyl-2-aminoethanol.I am confused |
I'm not really following this thread, but what's so confusing about that statement? The nucleophile adds to the secondary carbon because it gives an
extremely stable benzylic carbocation intermediate which is stablized by the adjacent phenyl ring through resonance. The oxygen gets protonated first
and leaves as a hydroxyl group, forming the stable benzylic carbocation and opening the oxirane ring, giving the primary alcohol. The nucleophile then
attacks the carbocation intermediate at the benzylic position.
Edit: The above was obviously under acidic conditions only. Under basic conditions, I'd imagine the oxygen and carbon first disassociate at the benzyl
position (which is easy since the benzylic carbocation is very stable), opening the oxirane ring and giving the 2-phenylethoxide intermediate
(positive charge at benzylic position, negative charge on oxygen). The nucleophile then adds to benzylic position and a proton is transferred to
oxygen (or abstracted from solvent/other proton source).
[Edited on 10-4-2015 by Darkstar]
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CuReUS
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| Quote: | | I'm not really following this thread, but what's so confusing about that statement? |
because this statement contradicts the paper byko posted above.And karlos won't get the product he thought he would get.
[Edited on 5-10-2015 by CuReUS]
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Darkstar
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| Quote: Originally posted by CuReUS | | Quote: | | I'm not really following this thread, but what's so confusing about that statement? |
because this statement contradicts the paper byko posted above.And karlos won't get the product he thought he would get.
[Edited on 5-10-2015 by CuReUS] |
According to the paper, it does seem that both pathways are possible, with attack at the primary carbon being preferred. Perhaps the Wiki statement
was only meant for attack under acidic conditions, as that would indeed allow a very stable benzylic carbocation to form?
Anyway, under basic conditions with ammonia, it does seem like Sn2 would be preferred, with attack at the primary position being preferable due to
steric hindrance at the benzylic position.
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karlos³
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I found this interesting paper, it gives yield and reaction times for the ammonolysis of styrene epoxide with various amines.
The last amines in the chart are very interesting, hexamethylentetramine, succinimide and phthalimide. They would give access to the primary amine
without di- or trisubstitution, via delepine/gabriel synthesis.
So, delepine should it be then for me!
The cleavage of phthalimide/succinimide adducts is harder than the cleavage of hexamine adduct in the delepine synthesis, but the reaction time is
much longer (5 days at 50°C, compared to 10 hours at reflux).
Attachment: Uber-die-Aminolyse-von-Styroloxyd.pdf (764kB)
This file has been downloaded 564 times
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CuReUS
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| Quote: Originally posted by Darkstar |
Perhaps the Wiki statement was only meant for attack under acidic conditions, as that would indeed allow a very stable benzylic carbocation to form?
|
perhaps you are right, but if you read the wiki statement more carefully
"nucleophiles always attack the secondary carbon"...
| Quote: Originally posted by karlos³ | I found this interesting paper, it gives yield and reaction times for the ammonolysis of styrene epoxide with various amines.
The last amines in the chart are very interesting, hexamethylentetramine, succinimide and phthalimide. They would give access to the primary amine
without di- or trisubstitution, via delepine/gabriel synthesis.
So, delepine should it be then for me! |
since I can't read german,I may be wrong,but the paper only makes the HMTA adduct.It gives no info whether or not a primary amine would be formed on
decomposition.
also the yield of the adduct is only 54%.Surely the primary amine formed will be even less.
| Quote: | | The cleavage of phthalimide/succinimide adducts is harder than the cleavage of hexamine adduct in the delepine synthesis, but the reaction time is
much longer (5 days at 50°C, compared to 10 hours at reflux). |
you could always hammer it out with hydrazine hydrate/HCl .
also you could try using DMF to get a better yield instead of CHCl3(which was used in the german paper).
[Edited on 6-10-2015 by CuReUS]
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karlos³
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Well, yeah hydrazine would be an idea for gabriel synthesis of phthalimide, or even HCl for the succinimide (that is even, without given yield,
described in that paper).
There will form a primary amine on decomposition of the HMTA-adduct. It even gives some as a byproduct before cleaving in ethanolic HCl in the
chloroformic solution after the adduct is filtered!
This is why I still prefer the delepine synthesis, even if the yield of the adduct is low, and the yield of its cleavage not so great, it still is a
cleaner route since the hexamine adduct can easily be recrystallised, there is absolutely no isomeric by-product, and the educts/reagents are
dirt-cheap.
I could run a 1-2mol batch starting with styrene and then I dont have to worry about a low yield since a bigger batch would still give me plenty of
the aminoalcohol.
My attempt at reducing the nitroalcohol p-fluorophenyl-2-nitroethan-1-ol with Red-Al (4-fold excess) did worked good, not for a Red-Al reduction, but
with a solid yield of around 30%.
Considered the price, it was not worth it.
I will go back to Zn/HCOOH reductions for nitroalcohols, the yield was comparable to the attempt with Red-Al. But cheaper.
Edit: The paper states the product of the reaction of styrene oxide with hexamine is a hexaminium chloride? I wonder where the chloride ion comes
from, certainly not from the chloroform?
[Edited on 7-10-2015 by karlos³]
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byko3y
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The Synthesis of Aminoalcohols from Epoxides and Ammonia
karlos already posted one papper, i'm adding another from the same researcher:
Eine neue Methode zur Herstellung von 1-Amino-2-hydroxy-Verbindungen ohne Bildung von Di- und Tri-(oxyalkyl)-aminen als Nebenprodukte Mitteilung:
Aminolyse von Epoxyden
Attachment: Oxirane aminolysis - 10.1002@ardp.19592920205.pdf (345kB)
This file has been downloaded 496 times
[Edited on 7-10-2015 by byko3y]
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karlos³
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Thank you, very informative!
So the chloride ion really comes from the chloroform, and phosgene is a by-product. Thats very interesting!
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