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Author: Subject: 5-Bromoindole preparation
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[*] posted on 23-3-2015 at 00:44


Karlos is correct. Further in the example is a reduction of the chlorindole. It is the preceding annulation that is difficult, but once that is accomplished, there seems to be additional leeway. Gassman indole synthesis should have good examples of halogenated indoles surviving reductions.
There is a pretty simple possibility in the classics.
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CuReUS
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[*] posted on 23-3-2015 at 01:35


I thought NBS might work because of this reaction
https://www.erowid.org/archive/rhodium/chemistry/safrole.htm...
upon close examination of the amide reduction given in the textbook using Zn,I saw that above the arrow between the product(mescaline) and the reactant(the corresponding amide) its given -"Zn/HCl" but under the arrow there is [H]
before I thought that the [H] referred to the nascent hydrogen produced due to the metal/HCl reduction but now I think it means that H2 gas must be pumped in:(
but yesterday I found a good reaction using Zn,methanol and POCl3
http://link.springer.com/article/10.1007%2FBF01936778
instead of POCl3, maybe oxalyl chloride could be used.

[Edited on 23-3-2015 by CuReUS]
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[*] posted on 23-3-2015 at 01:56


You have been close to something that would work, in kind of a roundabout way. I feel confident if you were looking through more primary literature, you would find a very reasonable solution. I have one sitting in front of me.
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[*] posted on 23-3-2015 at 03:12


Quote: Originally posted by CuReUS  

you could try nitrating 3-bromobenzaldehyde using H2SO4/HNO3 at room temp for 4 hours to get the 5-bromo-2-nitrobenzaldehyde

it suddenly struck my mind that this reaction might be wrong.Shouldn't the meta directing property of CHO dominate over the o,p directing nature of Br ?
Quote: Originally posted by Chemosynthesis  

Quote:
I had another reaction in mind.Suppose you started of with o-toulidine.reacting this with Br2 in CS2 or any other non polar solvent should give you the 5-bromo-toulidine easily,due to the activating nature of NH2
then you could oxidise the NH2 to NO2 using H2O2 and do the resseirt indole synthesis

Doubtful. Giving you the benefit of the doubt on cleanliness of a peroxide oxidation of the given substrate,.

this might be my lucky day,just found another beauty:D .Maybe DMDO could be used as well
so I guess my idea is back on the table;)
Attachment: A Mild Oxidation of Aromatic Amines with Oxone.pdf (114kB)
This file has been downloaded 397 times

[Edited on 23-3-2015 by CuReUS]
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[*] posted on 23-3-2015 at 04:14


You are going about things the wrong way.
For aromatic directors, the most activating group takes directional precedence.
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karlos³
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[*] posted on 23-3-2015 at 10:00


I cant think of all the indole i have readily, and just seem unable to put an acetyl-group on the nitrogen!
Its just a so simple procedure, I dont have to form the indole first, and simply just making the 2-sodium indoline sulfonate, then the n-acetyl derivative of this, brominating and just base hydrolysis to get rid of all the unwanted groups!

What about a transesterification maybe? I find my lack of acetic anhydride so disturbing, it would be so simple with it, or another way to put an acetylgroup to deactivate the nitrogen on it...
That is very annoying, despite all your brilliant suggestions, i have indole, it bothers me just to put the bromine on the right position, to form the ring all the way myself.

If i could just heat the sodium indoline sulfonate with ethylacetate, to N-acetylate it...
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[*] posted on 23-3-2015 at 13:32


You don't need an anhydride for what you are trying to do. You don't necessarily need to work through an acetamide either.
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[*] posted on 23-3-2015 at 17:37


Nowadays, you would probably have to make those "Nasty" mustard gas precursors too.

And, even that, might present difficulties. Thionyl Chloride is no longer an easy buy. At least, it is hard to obtain for many of us. Some members have corporate or university ties, which allow them fairly easy access to such reagents. Others do not.

Recalling my ancient days at the U.... an odd purchase, even then, might elicit a call from a curious control agent.

If you are in the U.S., and you have an itch that you just have to scratch, maybe a "handlers license" will be required.

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[*] posted on 23-3-2015 at 22:19


Good thing I live in good old europe, have SOCl2, and can have more whenever i want!
A problem is, i am a private person, so its somehow comical what chemicals I can order, and which ones are forbidden to sent by standard post, university and others can use conveyance ordering for chemicals which arent allowed to sent (like MeOH, Oxalylchloride, some Hydrides, etc), but thats very expensive for private persons.
I even had to pick my oxalylchloride up in person, because its one of these chemicals.
They even want to put benzoic acid and concentrated formic acid on the list of toxic substances, so those cannot be mail ordered soon anymore in my country.

@chemosynthesis, ive found a reference where they use 2,3-dihydroindoline to brominate at 5-, do you refer to that?
Or using AcCl for that? I have Propionylchloride on hand, I wanted to use it on other pet projects, but if it would work here too, and the propionylgroup can be as easily cleaved as an acetyl after bromination, well, then I will use this.
If I dont have to use Ac2O for acetylating, that would be great.
In what solvent would this reaction be done, pyridine i guess?
If not, can you please elaborate more about what you are meaning?

Unrelated, but this night ive dreamed about 5-bromo homotryptophol, it disturbed me so much, i mumbled about too much carbon in my native language when i was fully awake as i havent seen that homotryptophol is one carbon too long...



[Edited on 24-3-2015 by karlos³]
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[*] posted on 24-3-2015 at 18:23


There are some citations available which utilize the carboxylic acid, much less an acyl halide or anhydride. They don't all acylate the same atom, depending on conditions, which is why your current method requires sulfonation. I didn't check yields... but I did notice that not all acylations require a protecting group at a 2 or 3 position.
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[*] posted on 25-3-2015 at 01:49


Quote: Originally posted by karlos³  

Ive read a paper about using NBS on tryptophol and indole acetic acid, and they dont produce the 5-bromo derivative, i think it was the double bond on the pyrrole ring which directs them to position 3- or 2, cannot remember, but sadly nothing what i want.

I had a crazy idea,maybe instead of trying to protect the N atom,we could try a different approach by removing/protecting the pyrrole ring double bond.Then I think normal halogenation should give the 5-bromo product,after which the double bond can be formed again.
http://www.scripps.edu/baran/images/pdf/pdf41.pdf
if you desperately need to acylate,why not just use good old ketene(I know its toxic,but if you take the right precautions...).there are many threads on SM about making a simple ketene generator.
Quote: Originally posted by karlos³  

@Waffles SS:
The first reaction directly from Indole you mentioned, using sodium hydrogensulfite, sounds similiar to the route i found on erowid, but without adding an acetyl-group to the nitrogen before bromination.
That sounds pretty interesting, thats what I was looking for, i am going to ask for the paper in the references thread to get a look at the conditions, but that sounds very compromising and short.
Maybe the sulfonate is just bulky enough to inactivate the whole pyrrole ring, and allows direct bromination of the aromatic ring on position 5-.

looks can be deceiving,dont weigh your ppt before it dries,read the article first:(
Quote:
, 5-bromoindole (1b) was prepared from
indole (1a) in the presence of ethanol and 27% aqueous sodium bisulfite, followed by reaction with acetic anhydride and bromine


[Edited on 25-3-2015 by CuReUS]

[Edited on 25-3-2015 by CuReUS]
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[*] posted on 26-3-2015 at 05:24


sorry for my stupid post.I realised that later that sulphite was being used to remove the double bond:D
aside from making amides to protect amines,you could also make carbamates(and they can be removed much more easily compared to amides).see this for synthesis of some alkyl carbonates
http://en.wikipedia.org/wiki/Carbonate_ester#Experimental_ro...
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[*] posted on 26-3-2015 at 11:04


Well, thank you all for your input. I think I am going to make a gram of 2-sodium indoline sulfonate, and they divide the yielded substance in two parts, and try to acetylate it using refluxing ethyl acetate and also refluxing in glacial acetic acid.
I guess TLC and melting point will show me what comes out then, if its of any use.
Or maybe I should divide the indoline sulfonate by three and do the third reaction with a mixture of dry AcOH in EtOAc?

Really, I have to thank you all very much for participating in this discussion, there were many good ideas and opinions thrown in.
So I will go the way mad scientist do... experiment is king, so I will report what results I got(or if I figure it out, why results lacked).
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[*] posted on 26-3-2015 at 15:10


I think you're missing a catalyst and possibly a different solvent for that second reaction, based on what I was looking at.
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[*] posted on 26-3-2015 at 21:21


Ah, thank you, Zinc acetate should it be then, in the microwave :D.


Attachment: acetylation of amines in acetic acid under MW radiation.pdf (111kB)
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[*] posted on 4-5-2015 at 05:02


I apologise for not doing any experiments for making 5-Bromoindole, because I was fucking lazy and simply bought a few grams for my experiments. Will do then Anthony-Speeter Tryptamine Synthesis then with it, using diethyl- and 2-butylamine if anyone is interested in this, I will post about this instead.
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[*] posted on 7-5-2015 at 00:53


are you going to extract the diethylamine from DEET ?
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[*] posted on 7-5-2015 at 09:16


No, why? Its very cheap. Also, I cant source DEET.
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[*] posted on 23-5-2015 at 01:10


this paper looks very promising for carrying out the bromination using NaBr .Unfortunately I can't access it.could someone get it ?
http://www.ingentaconnect.com/content/stl/jcr/2006/00002006/...
karlos,could you explain why you need to protect the N before brominating ?
also,could you post a write-up about a Red-Al reduction please ?
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[*] posted on 6-6-2015 at 04:58


So, I did the glyoxylamide Preparation.
Ive prepared the Gloxylamide of 5-Bromo-Diethyltryptamine, an analogue of the marine Alkaloid 5-Br-DMT.
Still need to reduce it, but here is an photo-essay on how it was done:
5-Bromoindole
http://www.xup.in/dl,14021715/br_indol.JPG/
Oxalylchloride:
http://www.xup.in/dl,13524228/cocl2.JPG/

2g 5-Bromoindole were dissolved in 40ml MTBE, and 2,2g of Oxalylchloride were added in three portions, over 10 minutes, to a good stirred erlenmeyer flask sitting in an ice/salt bath.
After the first portion of (COCl)2 was added:
http://www.xup.in/dl,12940741/saeurechlorid.JPG/
After the addition was complete, sitting in the ice/salt bath on the stirrer:
http://www.xup.in/dl,16219134/eisbad.JPG/

After 30 minutes, the solid, yellow acid chloride was filtered and washed with ice cold MTBE:
http://www.xup.in/dl,21160994/festes_saeurechlorid.JPG/

It was added to 8ml cooled Diethylamine in two portions, 5 minutes between the first and last addition, while the Et2NH was allowed to come to RT and after 30 minutes, the solution with the suspended yellow flakes became all white.
There were added about 20ml dH2O and enough 7% HCl solution to make the solution weakly acidic, and no Diethylamine smell could be observed.
The precipitating glyoxylamide after addition of water and HCl:
http://www.xup.in/dl,17998806/amid_nach_reaktion.JPG/

And the dried, in EtOH recrystallised, fine Needles of the 5-Bromoindol-3-yl-N,N-diethylglyoxylamide:
http://www.xup.in/dl,14596823/dasendprodukt.JPG/

The yield was lousy, only 840mg of amide from 2g 5-Bromoindole.
But at least, i did it successfully.

@Cureus:
There are a lot of described reductions with Red-Al, some are even in Tihkal, some are on Erowid, very easy to find!

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[*] posted on 8-6-2015 at 03:57


Very interesting, thanks for sharing Karlos!
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[*] posted on 8-6-2015 at 21:43


Agreed. Now that you have graciously shared your work, I will point towards an area that would be applicable for a chloro derivative (likely bromo too) in NMDA antagonists.
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