Sciencemadness Discussion Board - Phenethanolamine synthesis is frustrating me!

Phenethanolamine synthesis is frustrating me!

karlos³ - 25-9-2015 at 09:50

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?

CuReUS - 26-9-2015 at 02:11

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

karlos³ - 26-9-2015 at 02:30

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.

CuReUS - 26-9-2015 at 08:23

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

solo - 26-9-2015 at 12:34

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 902 times

Praxichys - 28-9-2015 at 05:47

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]

CuReUS - 28-9-2015 at 06:49

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?

Quote: Originally posted by CuReUS

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

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]

karlos³ - 29-9-2015 at 21:03

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.

byko3y - 29-9-2015 at 22:37

The Direction of Epoxide ring opening in the reaction of Styrene Oxide with Ammonia

karlos³ - 1-10-2015 at 12:30

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.

chemrox - 1-10-2015 at 16:09

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.

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.

chemrox - 1-10-2015 at 17:01

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]

byko3y - 1-10-2015 at 23:54

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.

karlos³ - 2-10-2015 at 03:25

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 :-)

CuReUS - 2-10-2015 at 06:03

Quote:

I have discovered a nice route for the latter, and when I have made some of the epoxide I will test various aminations.
care to elaborate ?
btw ,is your project related to this
http://pubs.acs.org/doi/abs/10.1021/jm00348a015?journalCode=...
flourophenethanolamine was reductively alkylated...

karlos³ - 2-10-2015 at 08:55

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.

CuReUS - 4-10-2015 at 08:19

Quote: Originally posted by CuReUS

how did you make the bromohydrin ? NBS/H₂O ? maybe the bromohydrin was contaminated with impurities from side reactions.

Quote: Originally posted by karlos³

Styrene bromohydrin was made with NSB in aqueous DMSO, foul smelling dimethylsulfide was a byproduct.

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.

according to this you will get 2-phenyl-2-aminoethanol rather than 1-phenyl-2-aminoethanol.I am confused

Darkstar - 4-10-2015 at 11:02

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]

CuReUS - 5-10-2015 at 08:49

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]

Darkstar - 5-10-2015 at 12:56

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.

karlos³ - 5-10-2015 at 23:10

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 800 times

CuReUS - 6-10-2015 at 08:18

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]

karlos³ - 6-10-2015 at 09:28

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]

byko3y - 6-10-2015 at 23:07

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 720 times

[Edited on 7-10-2015 by byko3y]

karlos³ - 7-10-2015 at 04:26

Thank you, very informative!
So the chloride ion really comes from the chloroform, and phosgene is a by-product. Thats very interesting!

CuReUS - 7-10-2015 at 06:45

A thought entered my mind today.During the decomposition of the HMTA-adduct,is there a chance of a substitution reaction between the benzylic OH and Cl- from the HCl to form chlorophenyl ethylamine ?

karlos³ - 8-10-2015 at 10:50

Well, certainly not in an aqueous environment, if you want to chlorinate such an alcohol, you would need pinch of a catalyst like ZnCl2, otherwise the chloro-compound would instantly hydrolyse back to the aminoalcohol, with chiral inversion.
In fact, this is a known route to racemise an alcohol in similiar compounds like (nor)ephedrine.

CuReUS - 9-10-2015 at 04:58

Quote: Originally posted by karlos³

Well, certainly not in an aqueous environment, if you want to chlorinate such an alcohol, you would need pinch of a catalyst like ZnCl2, otherwise the chloro-compound would instantly hydrolyse back to the aminoalcohol, with chiral inversion.
In fact, this is a known route to racemise an alcohol in similiar compounds like (nor)ephedrine.

I had this video in mind when I said that
https://www.youtube.com/watch?v=mtl-Hs66Uzo
they don't use any ZnCl₂ though

Darkstar - 10-10-2015 at 08:45

Quote: Originally posted by karlos³

I have access to a lot of chemicals...

Do you have access to tosyl chloride by any chance? If so, what about doing a Neber rearrangement on acetophenone to get 2-amino-1-phenylethanone? You could then reduce the aminoketone to the desired aminoalcohol with something like sodium borohydride. The Neber rearrangement should give pretty good yields (70-75%), and the reduction should give extremely good yields. The only thing to watch out for is dimerization since it's an alpha-aminoketone (and a primary one at that). Just protect the carbonyl group by initially reacting the intermediate azirine with acidic alcohol to form an acetal. Then when you're ready to reduce it, just hydrolyze it to the ketone. I'd also try to keep it in its salt form, too.

Anyway, just something to consider if you're not having much luck with any of the other synthesis routes you've tried.

thingy22.bmp - 410kB

Neber rearrangement from OrgSyn using 4-Acetylpyridine instead of acetophenone

clearly_not_atara - 12-10-2015 at 22:57

Delépine reaction on acetophenone? Phenacyl bromide should be an optimal substrate for the reaction... but it is a tear gas so do be careful if you go that route. The ketone can be reduced with any number of chemicals; Al(OiPr)3 is an obvious choice, but Na2S2O4 or NaBH4 should work fine.

I'm surprised the Pd/C didn't work out for you. Maybe give it another go with a different solvent? The papers use MeOH/THF but you could try MeOH/EtOAc or just EtOAc.

byko3y - 13-10-2015 at 07:57

Once again I don't understand the goal of the discussion. There's no way to make 2-amino-phenylethanol easier than by reaction of epoxide with amine/imine/imide. Unless you prove me wrong, but I see no arguments.
4 steps route is cool, but it's a fucking pain in the ass with tosyl chloride, sodium ethoxide and sodium borohydride.
I propose to react glyoxalic acid with benzene, then separate mandelic acid, convert to amide, and finally reduce the amide with LAH.

karlos³ - 13-10-2015 at 12:40

Those contributions are very worthful, thank you all very much!

@CuReUS: Thats because benzyl alcohol is a primary one, those get easier halogenated without a catalyst than secondary alcohols like phenethanolamine is one.

@Darkstar: Well thats an interesting route, but I would probably more likely reduce isonitrosoacetophenone for that matter, I know dimerisation would be a big problem even then, don´t want any dihydropyrazine dimer into it. That´s why I stay away for the moment from acetophenone as a precursor. But if I wanted any specific isomer, then it would be the educt/starting material of my choice.

@clearly_not_atara: I am wondering too about my Pd/C, I am planning another try with another substrate and another solvent system, but I am not sure if it maybe is of lesser quality than advertised. I bought it cheap from someone I know, not in a shop, not originally packed, so who knows? Another experiment will show.
Delepine on Phenacyl halide sounds also good, I know its a bad lachrymatory, as if have already encountered bromopropiophenone

It would be interesting to know if this reaction also have to be made in CHCl3 like for styrene oxide/styrene halohydrin and if the hexamine adduct also contains "crystal-chloroform"?

I am unsure if the delepine on styrene oxide would also work in DCM, as it is much cheaper than CHCl3? That would be a lot more supportive for this experiment.
I have tried the reaction already in EtOH but like every paper confirms it does not work well if anything. What also goes along with my experience.
Now I know that the chloroform is essential for this reaction, but it would be much better if it can be substituted with another solvent.
Of course I will try it with chloroform first, it is maybe a bit more expensive, but I will follow the literature exactly for my next attempt.

clearly_not_atara - 13-10-2015 at 13:26

Quote: Originally posted by byko3y

Once again I don't understand the goal of the discussion. There's no way to make 2-amino-phenylethanol easier than by reaction of epoxide with amine/imine/imide. Unless you prove me wrong, but I see no arguments.

I think the problems with the epoxide route are the lability of styrene epoxide, the inaccessibility of styrene monomer (depolymerization is a pita), and the difficulty in obtaining reagents used to form the epoxide, preferably mCPBA, which isn't too hard to make (it's on orgsyn) but it's not the sort of thing you can buy at the store.

Actually I've always wondered if you can make mCPBA from benzoic acid. Orgsyn uses the acyl chloride, but there is a difference in solubility in DCM between the acid and peracid that might allow you to shift the equilibrium in the presence of H2O2.

zed - 13-10-2015 at 17:57

Looks to me that synthesis via hydrogenation of Benzaldehyde Cyanohydrin is promising.

Working with cyanide isn't fun, but it looks like Benzaldehyde Cyanohydrin, may be commercially available.

https://books.google.com/books?id=nacWAAAAQBAJ&pg=PA613&...

There is also some prep information available via erowid: https://www.erowid.org/archive/rhodium/chemistry/mandelic.ht...

[Edited on 14-10-2015 by zed]

Praxichys - 14-10-2015 at 08:45

@zed -

I posted a good reference for the prep you speak of. See above, 5th reply in this thread.

It is confusing because of nomenclature. Benzoyl cyanide = benzaldehyde cyanohydrin.

LiAlH4 or hydrogenation can be used, but the hydrogenation workup is going to suck.

CuReUS - 14-10-2015 at 09:49

Quote: Originally posted by byko3y

I propose to react glyoxalic acid with benzene, then separate mandelic acid, convert to amide, and finally reduce the amide with LAH.

how will you make mandelic acid from glyoxalic acid and benzene? don't tell me you have a FC-acylation followed by an intramolecular cannizaro in mind

Quote: Originally posted by karlos³

@CuReUS: Thats because benzyl alcohol is a primary one, those get easier halogenated without a catalyst than secondary alcohols like phenethanolamine is one.

But I thought that secondary alcohols undergo faster substitution without catalyst than primary alcohols.Also the -I effect of the NH₂ group should speed up the reaction,shouldn't it ?

Quote: Originally posted by karlos³

That´s why I stay away for the moment from acetophenone as a precursor. But if I wanted any specific isomer, then it would be the educt/starting material of my choice.

Karlos,how do you plan to do the enantioselective synthesis ? will you use a chiral reagent ?

Quote:

Now I know that the chloroform is essential for this reaction, but it would be much better if it can be substituted with another solvent.

I suggested using DMF in the previous page.

Quote: Originally posted by clearly_not_atara

I think the problems with the epoxide route are the inaccessibility of styrene monomer (depolymerization is a pita),

styrene is available OTC as fibreglass resin

Quote:

the difficulty in obtaining reagents used to form the epoxide, preferably mCPBA, which isn't too hard to make (it's on orgsyn) but it's not the sort of thing you can buy at the store.

yes you are right.But karlos is not going to use mCPBA in the first place.There are many alternate,amateur friendly and OTC reagents to make the epoxide.

Quote:

Actually I've always wondered if you can make mCPBA from benzoic acid. Orgsyn uses the acyl chloride, but there is a difference in solubility in DCM between the acid and peracid that might allow you to shift the equilibrium in the presence of H2O2.

I don't see why not.It is well known that performic and peracetic acid can be made from the acids itself.And benzoic acid is stronger than acetic acid.IIRC perbenzoic acid can be made from benzoic acid.But you need methane sulphonic acid and 70% H₂O₂

Quote: Originally posted by Praxichys

@zed -

I posted a good reference for the prep you speak of. See above, 5th reply in this thread.

I already suggested this "prep" in my post just below the one you have linked.Read the last line

Quote:

It is confusing because of nomenclature. Benzoyl cyanide = benzaldehyde cyanohydrin.

I am sorry to say,but they are not the same.The latter is the semi-reduced form of the former.

Quote:

LiAlH4 or hydrogenation can be used, but the hydrogenation workup is going to suck.

It would be better if Red-Al is used for the reduction,since karlos is an expert with it.

Quote: Originally posted by zed

Working with cyanide isn't fun, but it looks like Benzaldehyde Cyanohydrin, may be commercially available

I had an idea yesterday.could mandelonitrile be obtained from amygdalin ,or even better,from prunasin ?.I remember a member talking about the extraction of amygdalin from apple seeds.
see this http://chemistry.stackexchange.com/questions/24528/how-do-i-...

and this http://eprints.whiterose.ac.uk/83873/2/Bolarinwa.pdf

[Edited on 15-10-2015 by CuReUS]

karlos³ - 17-10-2015 at 07:58

First of all, I would like to thank all of you for the great ideas thrown in, the useful references and your contributions in general! It really gave me a lot of inspirations, very appreciated.

Quote:

That´s why I stay away for the moment from acetophenone as a precursor. But if I wanted any specific isomer, then it would be the educt/starting material of my choice.

Quote:

Karlos,how do you plan to do the enantioselective synthesis ? will you use a chiral reagent ?

I would like to use yeast, more specific their ADH enzyme, on it, the reduction of halo- or azidoacetophenone is reported in the literature. Also, I really like working with yeast, except of the messy workup.
I really like the smell of yeast, its non-toxic, and a cheap reagent. Too bad that other microorganism for reduction of alcohols are so hard to get, e.g. Rhodococcus and Candida species which are useful here.
Maybe I will try it with an chiral borane reagent derived from an aminoacid?

Quote:

Now I know that the chloroform is essential for this reaction, but it would be much better if it can be substituted with another solvent.

Quote:

I suggested using DMF in the previous page.

Would it work, I would guess the needed chloride for the hexaminium chloride would be missing?
Do you have a reference for that, that would be great?
Thank you in advance!

Quote:

the difficulty in obtaining reagents used to form the epoxide, preferably mCPBA, which isn't too hard to make (it's on orgsyn) but it's not the sort of thing you can buy at the store.

Quote:

yes you are right.But karlos is not going to use mCPBA in the first place.There are many alternate,amateur friendly and OTC reagents to make the epoxide.

Well yes, I wanted to use H2O2 with MeCN, but it turned out I hadn´t any MeCN, I thought I had, but looking through my chemical cabinet I found there was not any.
So unfortunately the epoxide synthesis has to wait...

Quote:

LiAlH4 or hydrogenation can be used, but the hydrogenation workup is going to suck.

Quote:

It would be better if Red-Al is used for the reduction,since karlos is an expert with it.

I think Red-Al is interchangeable in most reductions that can be performed with LiAlH4.
Also, my answer to this is probably off topic, but thank you for calling me an expert with Red-Al, I think of myself just as a novice in working with this stuff

But thank you for the compliment!

Quote: Originally posted by zed

Working with cyanide isn't fun, but it looks like Benzaldehyde Cyanohydrin, may be commercially available[/rquote]
I had an idea yesterday.could mandelonitrile be obtained from amygdalin ,or even better,from prunasin ?.I remember a member talking about the extraction of amygdalin from apple seeds.
see this.

Well, it is commercially available but not that cheap.
But then again, phenethanolamine is also commercially available and cheaper.

I made recently a bit 2-nitrophenylethanol from benzaldehyde and nitromethan, catalysed with triethylamine. It was an 0,2mol (of benzaldehyde) batch, and it gave after Zn/HCOOH reduction only 12g of phenethanolamine as HCl salt.
But anyway, I would like to try other methods out so I will continue my experiments.

Another idea came to my mind: I am a bit bankrupt at the time, so when I searched through my chemicals (when i was looking for the MeCN/acetonitril for styrene epoxide synthesis) I stumbled over NaN3 and thought it would be a good reagent for use here.
I would like to make the halohydrin, bromo, or chloro, and then react it with the sodium azide to give the azidoalcohols which can be reduced with NaBH4 to phenethanolamine.
That would be an option, wouldn´t it?

(Also, sorry for fucking up the quotation, I hope it is still readable and clear who said what?)

CuReUS - 18-10-2015 at 05:27

Quote:

no need of MeCN,see this thread
http://www.sciencemadness.org/talk/viewthread.php?tid=7641
nicodem talked a lot about OTC methods for making the epoxide
http://www.sciencemadness.org/talk/viewthread.php?tid=15284#...
The TCCA method he posted goes via the chlorohydrin,but I think the oxone/acetone method is more interesting.

Quote:

I stumbled over NaN3 and thought it would be a good reagent for use here.
I would like to make the halohydrin, bromo, or chloro, and then react it with the sodium azide to give the azidoalcohols which can be reduced with NaBH4 to phenethanolamine.That would be an option, wouldn´t it?

I think it will.Azide ion is a better nucleophile than amine without the inherent naughtiness of giving tri-alkylated products. Read the chapter on azides in "total synthesis 2" by strike.Its seems the azide can be reduced to amine just by adding Mg or Ca to it.

as for DMF,I suggested it because it was found that the yield for a gabriel reaction could be increased if DMF was used.Since you talked about wanting to use pthalimide(from the german paper),I thought it would be helpful if I mentioned it.

[Edited on 18-10-2015 by CuReUS]

Praxichys - 19-10-2015 at 06:22

Quote: Originally posted by CuReUS

Quote: Originally posted by Praxichys

It is confusing because of nomenclature. Benzoyl cyanide = benzaldehyde cyanohydrin.

I am sorry to say,but they are not the same.The latter is the semi-reduced form of the former.

*facepalm* Bad day at the library. I stand corrected. Carry on, gentlemen.

byko3y - 19-10-2015 at 08:14

Ethane-yl — ethyl.
Ethanoic-yl — ethanoyl.
Benzoic-yl — benzoyl.
Product of condensation of benzaldehyde with cyanide is benzaldehyde cyanohydrin.

karlos³ - 20-10-2015 at 09:18

Ok CuReUS, I thougt you´ve meant DMF for the Delepine, not Gabriel synthesis. Thank you for clearing that up.
I guess I will order some succinimide and try that too.

I tried the TCCA route to the chlorohydrin too, and it worked well enough.
But I will make the azide from the bromohydrin I think, more expensive but a better leaving group for making the azide(which itself is not that cheap).

So many roads to phenethanolamine, that is really some fun in the lab!

@Praxichys: You can remember it more easy by thinking about the -hydrin as an addition product of water and cyanide/halogen, two carbons apart from each other.

CuReUS - 21-10-2015 at 00:27

Quote: Originally posted by karlos³

But I will make the azide from the bromohydrin I think, more expensive but a better leaving group for making the azide(which itself is not that cheap).

Yes,I was going to suggest the same thing.All the papers I have read till now use the bromo compound to make the azide.

But I have one question. Is there a chance of any intramolecular cyclization between the azide ion and the adjacent OH ?
(I don't think so,since azide ion has negative charges on both the terminal N atoms,but still ? )

DrMethyl - 2-12-2015 at 12:28

Hello,

I want to dig up this thread because the discussion is very interesting. I myslef had biiiig problems to reduce nitroalcohol with metal/H+ or CTH !!! I think the main problem can comes from dehydration to nitrostyrene in acidic environement.

I think you can open the styrene oxide on the right side with a strongly basic nucleophile such as NaNH2. The azide will also attack to the right side and is naturally easy to convert to amine by any method. Azide can also do the SN2 behind the bromo of the NBS oxydation product of styrene in water.

I know the oxyamination but requires the exceedingly dangerous Os+8 compound.

You can start with protected glycine, then friedel craft acylation (one pot after chlorination), after reduction of carbonyl with NaBH4 the amino is deprotected. The special part is choosing the most suitable protecting group :TFA support strong lewis acid and is easily cleaved with weak base, carbamate are well known protecting groups but I dont know whether they survive AlCl3, maybe weaker lewis acid such as SnCl4 ? Any idee ?

You can also condense commercial mandelic acid or mandelate with ammonia and reduce the amide to target.

Other ideas are welcome.

byko3y - 2-12-2015 at 14:24

It's just interesting to watch that few people actualy have read the thread and papers in it (because every question is already answered here).

karlos³ - 16-12-2015 at 13:05

I have the urge to report back about how it is going.
Actually I have decided to use gabriel/delepine like reactions and have purchased succhinimide, hexamine, and saccharin. I still have to wait for one or two reagents for each route to arrive, but I was successfull in synthesising the epoxide(H2O2 in EtOH and MeCN). Also I prepared a few grams of the bromohydrin (with NBS in DMSO) of styrene.

When the reagents I am awaiting come to my door, I will try to post a writeup about the synthesis of the adduct which synthesis works best.
I have abadoned the idea of using the azide, I mean, it´s convenient, but I would really prefer to make the title compound without any reduction.

At the moment I had much fun with this synthesis, actually I am cleaning a batch of my last HCOOH/Zn reduction. I hate this crap that is also produced and lowers the yield!
But it is easy to clean the final salt.
Anyone who would like to attempt the synthesis of this compound via nitroalcohol, please use another reducing agent as Zn and formic acid!
I would like to try sodium amalgam as reducing agent once, have anything to make it, but I think it is a bit dangerous for me.
Don´t know if thats realistic.

But for know, styrene is intriguing me the most. As soon as my reagents arrive, I will report back.

Mandelic acid is something I don´t consider useful for that synthesis.
Maybe R-Mandelonitrile made with HCN from benzaldehyde with the oxynitrilase from almond meal, but any other way, no, not really. Reducing agents are expensive and even if I have access to many of them, I would like to prepare this simple compound without any reduction.

Thanks to everyone who parcipitated here! I appreciate it very much, you all gave me very helpful ideas and other input!
Thats why I like this community so much

byko3y - 16-12-2015 at 18:15

I can't understand whether Zn-HCCOH is a nice way to reduce the nitroalcohol or a messy one.

karlos³ - 17-12-2015 at 05:30

Well, it is a messy one, but easy to carry out and the reagents are very cheap.

CuReUS - 18-12-2015 at 04:49

Quote: Originally posted by byko3y

I can't understand whether Zn-HCCOH is a nice way to reduce the nitroalcohol or a messy one.

Quote: Originally posted by karlos³

Well, it is a messy one,

Is it ?
http://www.sciencemadness.org/talk/viewthread.php?tid=34833#...

karlos³ - 18-12-2015 at 08:53

Yes, in a larger, preparative scale it certainly is.
Mostly because of the large solvent volumes needed, and also the Zn salts, which can be vac-filtered, or, (some substrates are not suited for this) with large amounts of NaOH you can prepare the soluble sodium zincate salt, which eats a lot of NaOH and consequently increases the volume.
Otherwise, the reagents are quite cheap, but the solvents needed are not.'
Have you done a Zn/HCOOH reduction in a scale of like a mole? It sucks to work with this mess.
I would likely have another option.

But for the moment I´ve decided I will do reduction-free synthesis routes.
Even if they are not as high yielding, the delepine like reactions are very charming in my opinion. Very clean, small solvent volume, easy recycling of the solvents and cheap reagents (succinimide, saccharine, hexamine are so cheap! The disadvantages are, hexamine needs TCM, saccharin DMF, but only a tiny amount, but succinimide does not, only some alcohol and pyridine which are both cheap).

I guess my Pd/C is of a very bad quality. Otherwise I would go this way. I don´t want to waste my MeNO2 for this stuff at the moment, so I am going the styrene routes.

zed - 20-12-2015 at 16:54

Didn't catch where you had problems with your Pd/C. Nitriles do poison some Catalysts.

Also, freshly prepared Catalysts are usually more active.

karlos³ - 21-12-2015 at 12:13

Well, zed, I think it is because of the quality of the Pd/C.
I bought it from a well known auction site, without an original package, without any guarantee, just because it was cheap.
As I am a bit short of money, and have too many projects running around, I haven´t tried another substrate with this catalyst yet.
Because I am not sure if it is worth it, maybe another substrate will do fine, but maybe the catalyst is bad and it will be frustrating.
I wish I had prepared it myself... just a bit NaBH4, active charcoal and PdCl2. Then I would have at least known it would work.

But for the nitriles, I recently found out that mandelonitrile is dirt-cheap, and can even be reduced with Na in alcohol, preferably n-BuOH.
So if everything else is not satisfying, I will buy like 25ml of mandelonitrile and work with this.
Sodium alkoxides are very cheap and good reducing agents and this route looks also very appealing to me.
I like working with sodium as reducing agent, that is a very neat one if it can be used.
Also cheap and easy to prepare and work-up afterwards.

So many options, so little time. But everyone here helped me a great deal with it, so I´ll have a lot to do and try out, and hopefully a lot of personal experience to add here soon!
With good results I hope(crossing my fingers/pressing my thumb/any gesture else to hope for luck).

Chemi Pharma - 8-5-2016 at 07:54

Karlos, you'd better try Nickel Boride made in situ reacting not expensive NaBH4 with NiCl2.6H2O in methanol to reduce 2-nitrophenylethanol. See the paper below:

Attachment: Reduction Of Aliphatic Nitro Compounds To Amines Using NaBH4_NiCl2 and Ultrasound.pdf (157kB)
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Attachment: sodium borohydride-nicl2.pdf (399kB)
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karlos³ - 11-5-2016 at 10:39

I did it now using the epoxide of styrene and with succinimide, the yield was as expected lousy, but it was very pure then after cleavage. A second run using the epoxide and hexamine was much better, but took a longer time and the solvents were more expensive.

But thank you for your suggestion, it will be worthwhile when I am doing it with the para-fluoro substituted nitroalcohol.

Sadly, when I tried to prepare more epoxide and wanted to pour out the styrene into a beaker, nothing came out... I shook the can, nothing happened... no sound of liquid in there... banged on the can, still nothing :-D
So now I have a can full of glass-like polymer, it happened very fast, suprisingly fast even!
Maybe the stabilisator was out of capacity to inhibit any polymerisation? (The monostyrene was like 2-3 years old)

Organikum - 24-2-2023 at 12:40

Two Efficient Enantioselective Syntheses of 2-Amino-1-phenylethanol.

Tanielyan, S. K., Marin, N., Alvez, G., & Augustine, R. L.
Organic Process Research & Development, 10(5), 893–898. (2006).
doi:10.1021/op060122x

The article discloses also a superior way to hydrolyze the succinimido alcohol (compared to the German article where the this compound is derived from styrene oxide and succinimide) with excellent yields.

The reaction of succinimide and styrene oxide can for sure also be optimized and together with the better hydrolysis it seems the method of choice for Phenylethanolamine.

Also in the article: Resolution of the stereoisomeres can be done by di-O-toluoyltartaric acid or dehydroabietic acid.

[Edited on 24-2-2023 by Organikum]

Attachment: Two Efficient Enantioselective Syntheses of 2-Amino-1-phenylethanol.pdf (121kB)
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