Sciencemadness Discussion Board - 2-amino-3-nitrophenol synthesis - where to start??

2-amino-3-nitrophenol synthesis - where to start??

DrDevice - 12-12-2017 at 04:54

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?

CuReUS - 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 ?

zed - 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?

DrDevice - 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.

Attachment: raucher1983.pdf (600kB)
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CuReUS - 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

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 ?

DrDevice - 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.

CuReUS - 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

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.

DrDevice - 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:

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?

CuReUS - 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...

clearly_not_atara - 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)

DrDevice - 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!

Attachment: boyland1954.pdf (681kB)
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zed - 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.

clearly_not_atara - 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.

DrDevice - 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.

Attachment: raucher1983.pdf (600kB)
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CuReUS - 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

-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 ?