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Author: Subject: 2-amino-3-nitrophenol synthesis - where to start??
DrDevice
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[*] posted on 12-12-2017 at 04:54
2-amino-3-nitrophenol synthesis - where to start??


In the distant future I want to attempt a Meerwein arylation, and for the final structure I am aiming at, I will need to start with 2-amino-3-nitrophenol:



2-amino-3-nitrophenol.gif - 3kB

but I can't find a literature reference at any source I have access to. It's available commercially, and appears to have some history in hair dye product etc.

Any suggestions?
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CuReUS
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[*] posted on 12-12-2017 at 05:19


You can make it from 4-nitro-1,3-benzoxazole -https://www.heterocycles.jp/newlibrary/payments/form/05711/P...
if it is still available as a hair dye,that would be the most OTC way of getting it
What is the final structure you are aiming at ? Maybe an alternate starting compound could be suggested ?
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zed
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[*] posted on 12-12-2017 at 16:21


Are you certain this material can be successfully diazotized?

Somethings can be, some cannot.

And, since that phenolic hydrogen itself, might love to react with a diazonium salt, other couplings could be difficult.

Got a target molecule you might wanna share with us?
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DrDevice
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[*] posted on 13-12-2017 at 03:19


Thanks for the response @CuReUs, but unfortunately with your referenced paper the 2-amino-3-nitrophenol is an input at the start of the reaction, it is not synthesized as part of the procedure.

As far as @zed's comment, the basis for my question is the paper "Synthesis of Substituted Indoles via Meerwein Arylation" (Raucher, Koolpe, 1982 - attached). Basically reaction couples vinyl acetate to a diazo'ed substituted benzene. Then there is a cyclization reaction step described that forms an indole. With 2-amino-3-nitrophenol, the nitro part forms the -N- in the indole, and the -OH ends up in position 4 of the indole, which is tricky with Fischer. That paper describes a reaction with a methoxy ending in the 4 position; yes, an -OH is probably trickier, but a protection group could be used??

But first I have to make my 2-amino-3-nitrophenol...its a bit expensive to buy.

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CuReUS
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[*] posted on 13-12-2017 at 04:31


Quote: Originally posted by DrDevice  
unfortunately with your referenced paper the 2-amino-3-nitrophenol is an input at the start of the reaction, it is not synthesized as part of the procedure.

it is made,but the yield isn't that great.Read the entire paper:P
Quote:
the -OH ends up in position 4 of the indole, which is tricky with Fischer.

So basically you want to make 4-hydroxyindole.Why would it be tricky with fischer ?
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DrDevice
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[*] posted on 13-12-2017 at 05:20


OK, I think I see it now... The paper references other papers/methods/procedures that synthesize the 4-nitrobenzoxazole, that can then be reduced with NaBH4/EtOH to form the 2-amino-3-nitrophenol. Hmm, projected yield is not exciting me.

So with the Fischer (courtesy Wikipedia):

600px-Fischer_Indole_Reaction_Scheme.png - 6kB

any substituent meta to the phenylhydrazine almost always ends up with much higher proportion in the 6 position rather than the 4 position of the indole.

Other alternate approaches to 4-substituted indole such as "Useful synthesis of 4-substituted indoles" (Ponticello, Baldwin, 1979) also avoid the use of Fischer.

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CuReUS
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[*] posted on 13-12-2017 at 19:35


Quote: Originally posted by DrDevice  
OK, I think I see it now... The paper references other papers/methods/procedures that synthesize the 4-nitrobenzoxazole, that can then be reduced with NaBH4/EtOH to form the 2-amino-3-nitrophenol.

I am obviously not telling you to make 4-nitrobenzoxazole .What I had in mind was, you just might have some benzoxazole lying around which you could reduce.4-nitrobenzoxazole is itself made from 2-amino-3-nitrophenol:D
why don't you try some other ways to make 4-hydroxyindole.Google turns up many erowid links.The regioselectivity of 2-amino-3-nitrophenol is difficult to obtain.:(
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DrDevice
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[*] posted on 14-12-2017 at 03:39


Well, I was thinking it was getting a bit circular there...

So yes, 4-hydroxyindole by other means. But the 2-amino-3-nitrophenol becomes a challenge. I have sort-of worked out a completely impractical sequence from documented steps:
2amino3nitro_synth.gif - 8kB

  • Start with resorcinol
  • Di-Sulfonate
  • Nitrate
  • De-sulfonate (the sulfonate-nitrate-de-sulfonate process is well documented)
  • Cyclize with triethylorthoformate (US Patent 4579865) to form 4-hydroxy benzoxazole
  • Then a miracle occurs ;) Maybe tosylate/halogenate/nitrate??
  • Reduce with NaBH4/EtOH as per previous paper.
  • Et voila!

So like I said, maybe impractical :(

But is there perhaps another starting phenol but with a different substituent in the 2- position that would still be di-sulfonated, driving the subsequent nitration to the desired position, then de-sulfonated?

Followed by reduction of of the nitro to an amine, then convert substituent to nitro?

OR is there a feasible methodology to substitute/protect just one of the -OH in the 2-nitroresorcinol?




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CuReUS
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[*] posted on 15-12-2017 at 21:32


you could make O-acetylamino nitrophenol from aspirin
1.schimdt reaction on aspirin to get O-acetylamino phenol
2.o-nitration using amyl nitrate(pg 2977) -http://pubs.rsc.org/en/Content/ArticleLanding/1954/JR/jr9540...

amino nitrophenol2.png - 3kB
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clearly_not_atara
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[*] posted on 19-12-2017 at 09:25


Retrosynth:

Elbs persulfate oxidation of 2-nitroaniline:

http://en.wikipedia.org/wiki/Elbs_oxidation

Ullmann reaction of 2-chloronitrobenzene and ammonia; nitration of chlorobenzene and separation of isomers. Or nitrodecarboxylation of 2-chlorobenzoic acid from rxn of hypochlorite with sodium benzoate (alkaline conditions give 2-isomer)




[Edited on 04-20-1969 by clearly_not_atara]
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DrDevice
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[*] posted on 20-12-2017 at 01:07


I think you've solved it :)

Following the references to the Elbs oxidation, I found references to the Boyland-Sims oxidation and the paper "The Oxidation of Some Aromatic Amines with Persulphates" (Boyland, Sims, 1954, copy attached) with the desired 3-nitro-o-aminophenol as one of the examples.

And I have all the required reagents, so a project for over Christmas holidays.

Thanks again for the pointers!

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[*] posted on 20-12-2017 at 17:48


Ummmm. Them little mushrooms are native to my area. And, we consider them legal. More or less. Pop-up on the lawns, at Reed College.

So a walk in the park, seems more practical, than a trip to the lab.

That being said, a few years back, some fellas concocted a lab synthesis, that was pretty straightforward looking.

https://erowid.org/archive/rhodium/chemistry/psilocin_synthe...

Instead of starting from an exotic ring structure, they convert ordinary indole into its 3-aldehyde. Which seems to activate the 4 position... Etc.
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clearly_not_atara
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[*] posted on 20-12-2017 at 22:04


So I just read the threadstarter -- do Meerwein arylations work on o-hydroxyanilines? It seems like you'd get some weird diazo-quinone thing. You might want to make an O-protected version -- luckily the phenol should be much more reactive towards substitution than the aniline, so I think you'd get a good yield with stoichiometric benzyl chloride at low temps.



[Edited on 04-20-1969 by clearly_not_atara]
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DrDevice
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[*] posted on 21-12-2017 at 00:01


O-protection thoughts were next on the agenda.

The source paper for the approach is "Synthesis of Substituted Indoles via Meerwein Arylation" (Raucher, Koolpe, 1983, attached). There were only a limited number of substituents attempted, and -OH wasn't one of them.

Using this approach, it would need to be a fairly funky substituted alkene to end up with an ethylamine in the right place for this reaction to end up with anything, um, dodgy.

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CuReUS
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[*] posted on 21-12-2017 at 07:44


Quote: Originally posted by clearly_not_atara  
So I just read the threadstarter -- do Meerwein arylations work on o-hydroxyanilines? It seems like you'd get some weird diazo-quinone thing. You might want to make an O-protected version
Quote: Originally posted by DrDevice  
O-protection thoughts were next on the agenda.

hence my aspirin approach :D -http://www.sciencemadness.org/talk/viewthread.php?tid=78901#...
In case you successfully make the vinyl nitrophenol ,here is another ref for the cyclisation -http://pubs.acs.org/doi/10.1021/jo970516%2B
Quote: Originally posted by zed  
Instead of starting from an exotic ring structure, they convert ordinary indole into its 3-aldehyde. Which seems to activate the 4 position... Etc.

That's what even I suggested upthread, since there is a way to convert indole directly to 4-hydroxyindole.But maybe the OP has a problem procuring indole ?:(
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