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Author: Subject: Indole
ChemistryForever
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biggrin.gif posted on 14-12-2018 at 17:45
Indole


How can I synthesize indole ? I mean with no substituents on the rings.
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DoctorOfPhilosophy
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[*] posted on 14-12-2018 at 18:04


Can you be more specific about what starting materials and equipment you have access to? For example you could use a microwave oven: https://www.sciencedirect.com/science/article/pii/S004040390...
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Assured Fish
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[*] posted on 15-12-2018 at 13:50


The classic fischer indole synthesis is the go to really. https://en.wikipedia.org/wiki/Fischer_indole_synthesis

The reference that Doc gave is just a microwave assisted version of it as opposed to simply refluxing the acid, aldehyde, phenylhydrazine mixture which is suspect just speed up the reaction times and also decarboxylates the product.
In that paper they used pyruvic acid as the aldehyde which led to indole-2-carboxylic acid, this could be decarboxylated in a second step if you do not have access to a proper laboratory microwave.

The reaction is supposed to be quite robust and can be carried out with many different substituents of both the phenyl hydrazine ring and the aldehyde.
If you do not want to have to decarboxylate anything then acetaldehyde would get you straight to the indole however care would be needed when adding the aldehyde to the phenyl hydrazine solution as the addition is exothermic and acetaldehyde is quite volatile.




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pomegranate
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[*] posted on 15-12-2018 at 13:58


my new thread posts aren’t working, after i post them and they show up. i go to edit but the post isn’t found.

so i need to see if this post here works.

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[*] posted on 15-12-2018 at 14:08
this might work, what do you all think


let me edit this, it looks like i’m jacking your thread in the first couple sentences. this relates to your thread, i just happen to be trying to look around this same direction and skimmed off all the irrelevant data from a post i am trying to make a thread about,. the pertinent information to your thread is here as follows;


i’m looking at a benzofuran from 2-iodianisole cyclization that uses terminal acetylides. if it can be done with plain acetylene, than an unsubstituted dihydro-benzofuran

or in this case, maybe an indile could be made. the literature sources two prior attempts that use things like SMe (TMe) or NH2 inbplace if the anisole OMe, or OH.

two papers may apply, but there is an iodine that ends up on the 3-position if the dihydro-benzofuran or indole, but (i am unsure, because i am only learning) that it could be reduced off, and possibly retain the double bond in the furan or in this case indole,

some sources include::


https://pubs.acs.org/doi/10.1021/jo051299c

(https://www.google.com/amp/s/www.researchgate.net/publicatio...)
*https://www.google.com/amp/s/www.researchgate.net/publication/7445031_Synthesis_of_23-Disubstituted_Benzo_b_furans_by_the_Palladium-Catalyzed_Couplin g_of_o-_Iodoanisoles_and_Terminal_Alkynes_Followed_by_Electrophilic_Cyclization/amp*

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594699/pdf/nih...
*https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594699/pdf/nihms-445477.pdf*

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594699/)

http://www.orgsyn.org/content/pdfs/procedures/v91p0283.pdf


http://gen.lib.rus.ec


but while novel or maybe usefull for hard to substitute indoles, maybe the fischer synthesis or the other things these guys know are better of course. they could vet this perhaps


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Jackson
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[*] posted on 17-12-2018 at 08:17


React phenylhydrazine with acetaldehyde under hcl or h2so4 in a microwave.
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[*] posted on 17-12-2018 at 13:19


Quote: Originally posted by Jackson  
React phenylhydrazine with acetaldehyde under hcl or h2so4 in a microwave.

NO.
Acetaldehyde is very very volatile and flamable, a well cooled reflux condensor is mandatory, you will also need a solvent and water wont cut it, ethanol (often anhydrous) is usually used.
Also you should not be doing chemistry in a kitchen microwave, they are not the same as laboratory microwaves, you can get away with a few things here and there but your taking alot of risks.
Not to mention the fact that forming the schiff base is exothermic, i strongly advise against using a microwave for this kinda thing.

Jackson your explanation shows that you have sweet fuck all knowledge on this particular reaction, please shut up and go read about it.




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[*] posted on 17-12-2018 at 14:13


Fischer indole synthesis is nice and famous synth to run. Microwave is not necessary as it will run anyway with some heating. Find a reference as follow it. It will be doable.
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[*] posted on 17-12-2018 at 14:20


I know about Fischer indole synthesis, but for unsubstituted indole it would use acetaldehyde, not a ketone. So this is why i was asking, does this work with aldehydes?
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[*] posted on 18-12-2018 at 08:19


A few possible synthetic routes:

1. o-toluidene and chloroform via formation of an diazonium species [Fluorescent probe for detecting silver ion, its preparation method and application, Quing, et al.]

2. Dehydration of 2-aminobenzeneethanol [Iridium Catalysts for Acceptorless Dehydrogenation of Alcohols to Carboxylic Acids: Scope and Mechanism, Cherepakhin, Valeriy and Williams, Travis J. and Iridium(III)- benzoxazolyl and benzothiazolyl phosphine ligands catalyzed versatile alkylation reactions with alcohols and the synthesis of quinolines and indole, Huang et al.]

3. aniline and oxirane via zinc chloride/silver catalytic route [Process for the preparation of indoles, Xiaoqiang et al.]

4. 2-phenylamino-ethanol and a silver catalyst [also by the Xiaoqiang method above]

Realistically, given the nuisance of using silver catalysts in a home lab setting, have you considered using a ketone with a reasonably good leaving group? You could possibly do a second step to kick off the unwanted substituent. It would reduce yields but should be pretty feasible.

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[*] posted on 19-12-2018 at 07:43


Acetaldehyde is very problematical in the Fischer indole synthesis as are most aliphatic aldehydes. See Robinson's tome on the Fischer Indole Synthesis (a very big book). Despite having to add a second reaction step, Assured Fish's suggestion using pyruvic acid and phenylhydrazine followed by decarboxylation may be the most facile synthesis. I base this on the knowledge that both phenylhydrazine and pyruvic acid can be synthesized from easily available starting materials available to the hobbyist. Perhaps the best method currently would be reaction of o-nitrotoluene with dimethylformamide dimethyl acetal followed by reduction to get indole directly. This process is fully documented in "Organic Syntheses" and is a widely used method for synthesis of indoles. Either of the mentioned methods would work well and the choice would depend on availability of reagents.

At some risk, I suggest that the OP learn to do some basic literature searching to find leads for the information being asked for. The question is so basic that even wikipedia would be useful.

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