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Author: Subject: 3-acetylindole
karlos³
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[*] posted on 4-9-2017 at 17:19
3-acetylindole


Hello!

I want to make this product instead of purchasing it, but after only a single attempt that wasn´t quite successful, I am very tempted to buy it, as calculating the cost of the reagents for another synthesis route to try is nearly always more expensive than the reagent.

What I´ve already did was, using an AlCl3 catalysed FC-reaction on indole, solvents being DCM and MeNO2, and Ac2O as acetylating agent. Neither the lewis acid nor the acetylating agent were a good choice, not even using friedel-crafts conditions at all.
The small amount of recoverable product was a black precipitate, confirming the bad choice of the synthesis route...

I am thinking about trying the reaction of indolylmagnesium iodide with acetylchloride(or just Ac2O?), since I am familiar forming the grignard reagent. But the reagents aren´t economical, neither is the working time involved, so I stumbled upon a much simpler method that may or may not is a cheap and viable alternative.

This would the two-step reaction of first diacetylating indole at N- and 3-, and the obtained diacetylindole can be selectively cleaved at the nitrogen with base to obtain only 3-acetylindole, the diacetylation being done using only GAA and Ac2O, and the N-deacetylation can be done using aqueous or alcoholic sodium hydroxide.
The yield isn´t that stellar, but the reagents are very cheap, also the reaction is done quite easily compared to grignard or friedel-crafts conditions.
The attached document describes said reaction.

Since I only need a few little grams of the 3-acetylindole at all, I would need just a cheap reagents using and easily perfomed synthesis route, that can beat simply buying the product.
Has anyone some useful input here?

Thank you for any reply in advance!

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CuReUS
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[*] posted on 5-9-2017 at 06:16


try acylating it with acetonitrile -http://pubs.acs.org/doi/10.1021/ol007056i
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karlos³
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[*] posted on 5-9-2017 at 06:57


Yeah thank you, I know that method...
but buying SnCl4 is more expensive than buying the needed amount of acetylindole, and I don´t have any other uses for stannous chloride :)

That is the culprit, either I can do it very cheap and/or with reagents already on hand, and if not in this case I would rather stick to buying it.

Since Ac2O and GAA are very cheap and available, this two step method of diacetylation followed by selective N-deacetylation seems very cheap, albeit not high yielding, that doesnt matter taken the price of the anhydride and acetic acid itself, also of indole, into account.
Also it does seem to be without tarry crap producing side-reactions like the metalorganic ones often do, but maybe I´m mistaken there?

Edit: Removed a few letters from a "doesn´t" to a "does" :o

[Edited on 5-9-2017 by karlos³]
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zed
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[*] posted on 8-9-2017 at 16:02


Ummm. Authors claim mild conditions, but their catalyst looks like it might be pyrophoric.
A Di-Alkyl Aluminum Chloride!

http://pubs.acs.org/doi/abs/10.1021/ol005841p


Don't know if Ketene will acetylate the three position, and Ketene requires extreme caution in its use, but it is a thought..... And, once again, it will surely acetylate the 1- position.
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karlos³
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[*] posted on 11-9-2017 at 16:59


Thank you, but I should have been much more precise, since purchasing the title compound is an option, one I´m ogling with as only few grams are needed.
So I have some conditions under which I will be attempting the synthesis, for example I would neither accept working with ketene nor buying Me2AlCl, they don´t look that comfortable compared with a simple purchase.
I´m having some reagents already that could be of help, so I would prefer if I could use some of them, or buy only substances who aren´t expensive.

The 1,3-diacetylation is worth to look further into.
Since the diacetylindole forms cleanly, and the 1N-acetyl group can clean and selective be removed too, I will try this on a small scale.
The references either reflux indole in Ac2O for 24 hours, maybe some acetic acid added too, or, Ac2O and a few drops of 85% phosphoric acid, but this variation only runs 20 minutes.
I´m lacking phosphoric acid at the moment, and couldn´t find any mention of a tried substitute for it, maybe toluenesulfonic acid will work?
Other than that little inconvenience, I am ready to try it, guess I´ll have to get concentrated H3PO4 first and be a little patient.

I am still open to any other suggestion, thank you for the help already!
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[*] posted on 11-9-2017 at 17:42


Well, I've seen references to acetylating indoles via phosphoric acid, but yield were not impressive.

Another possibility is acetylating indole via a Villsmeyer-Haak type reagent, prepared from Dimethylacetamide and Phosphorus Oxychloride. The reaction has been commonly used, to produce Indole 3 carboxaldehyde from Dimethylformamide and POCl3. Phosphorus Oxychloride could be tough to buy, but it is easily prepared from Phosphorus Pentoxide, which can often be purchased without undue difficulty. Seems to me, the procedure is layed out in Scheme 20.


http://www.academia.edu/10574900/3-Acetylindoles_Synthesis_R...

http://pubs.acs.org/doi/abs/10.1021/jo01081a615?journalCode=...

http://orgsyn.org/demo.aspx?prep=cv4p0539

I include the procedure for indole 3 carboxaldehyde, because there may be a limited number of examples for the creation of ketones. And I have not seen the rest of the Anthony paper. I don't have access from this computer.

[Edited on 12-9-2017 by zed]

[Edited on 12-9-2017 by zed]

[Edited on 12-9-2017 by zed]
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[*] posted on 12-9-2017 at 17:09


The simple 1,3-diacylation and then deprotection makes sense, plus for many reactions, you would need to leave the indole protected anyway. Using Me2AlCl sounds like a great way to burn your lab down, I've used some alkylaluminum's and I would like to never use them again.

But acylating indole is doable, haven't done that exact method, but done similar ones, all on protected indoles.
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karlos³
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[*] posted on 6-10-2017 at 07:01


Thanks for all the input given, more or less helpful but always very nice and welcome, I appreciate your help very much :)

I agree on dialkylaluminium chlorides, being pyrophoric is definitely a disadvantage, and the vilsmeier-haack with acetamide is interesting, too, but not very viable for me(I don´t have any [dialkyl]acetamide).
It is simply not very economical for me to use such expensive reagents like POCl3 if the same results can be achieved using something a magnitude cheaper.

The first paper zed posted is very comprehensive and useful on that subject, I have read it extensively before I started this thread.

In the meantime, I´ve purified my first attempt with the AlCl3 catalysed friedel-crafts acylation, using acetic anhydride, and tried the diacetylation using Ac2O as well.
Both reactions were tried at 25mmol scale, which corresponds to 2,9g indole, and the F-C resulted in a disappointing final yield of 550mg or 14%theoretical yield(expected, shitty catalysts and acetylating reagent, even with the here very suitable solvent system DCM/nitromethane[25/15ml used]).

The Ac2O diacetylation was done in 22ml acetic anhydride, 1,5ml GAA, and refluxed for 24 hours, cooled a little, and while a sample was taken for tlc, I tried an idea I had out in practice.
So, I´ve added a few dozen milligrams of p-toluenesulfonic acid(50mg exactly) and heated the mixture gently for further thirty minutes, then worked it up, the 1,3-diacetylindole was obtained in 81% and used for the next reaction after a single recrystallisation.

Reason I added a bit tosic acid was the procedure using Ac2O with a few drops of 85% H3PO4, resulting in a much shorter reaction time, so I somehow assumed that tosic acid would have some beneficiai effect here as well.
I can´t say if it really did, the starting material was almost gone when I added the p-TsOH monohydrate, probably should´ve added it at the beginning instead, that could have shortened the reaction time.
The yield was very good anyway, at least compared to the references used.

The 1,3-diacetyl-indole in 20ml EtOH was then reacted with 40ml of 10% aqueous KOH and heated gently until everything went into solution(ca.20-30 minutes), then cooled down, poured on a 250 milliliter cold water, and the precipitated product was filtered out.
Washed with lots of water, then aq. EtOH, recrystallisation from EtOH, and the so obtained, slightly yellow 3-acetylindole was weighing 2,98 gram, melting at 186-188°C, a 75% yield of the theory starting from indole.

Actually the F-C may has potential here, but not like I did, better with acetyl chloride, catalysed by SnCl4 or similar, even MeCN and SnCl4 is much better than Ac2O and AlCl3, the latter are seemingly both the worst acetylation agent as well as catalyst for this reaction...

But the diacetylation followed by base hydrolysis, that can´t be beat if one has access to Ac2O, in terms of yield, ease of the reaction, and of course the expenses.

What are your thoughts on the tosic acid?
Since the two diacetylation procedures I used are very similar, the major difference is the reaction time, with phosphoric acid added the reflux time in total was just 20 minutes, but without 24 hours.
I can only assume the H3PO4 is responsible, being the only different reagent in both procedures, and I also assume this is due to it being a reasonably strong acid and thus somehow catalysing the reaction.
But actually I have no idea and am just guessing to be honest.

Not that it matters anymore, the quantity now prepared is enough for my needs(probably) :D
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[*] posted on 6-10-2017 at 17:32


I would guess that adding any acid may form some form of mixed anhydride, some of which are better acylating agents than the symmetrical one. But that is just a guess, or just acting as a general Lewis acid.

But that sounds like a great overall solution.
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karlos³
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[*] posted on 6-10-2017 at 19:24


Thanks Dr.Bob!
That seems plausible, regarding tosic acid being a good leaving group, as is phosphate, but acetanhydride not so much compared to the former, also the formation of a mixed anhydride is a likely reaction.

I guess, to be certain about this, I have to do another batch with tosic acid added from the beginning, and follow the reaction progress on TLC.
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[*] posted on 11-4-2018 at 11:02


karlos³

I have been trying to prepare 3-acetylindole using the widely cited acetic anhydride/acetic acid reaction [1] with consistently poor results. I have varied temperture and reaction times with little variability in the result. The product I initially isolate from this reaction is quite impure. The purification of this product is very complex and is not adequately described in the cited paper[1]. The reference you cited in your initial post is in part a rehash of the Saxton paper and does not provide any additional insight. How did you purify your initially isolated products? Did you check your products (1,3-diacetyl and 3-acetyl derivatives) by melting point and/or tlc? I find that a fair amount of unreacted indole carries through the purification process.

You mentioned a procedure using Ac2O with a few drops of 85% H3PO4 which apparently is in the literature. Can you provide a citation? I have not been able to find such a reference after considerable searching.

Following one of your comments above, I tried reacting indole with Ac2O + a few crystals of p-TosOH with slow warming to about 75C with a total reaction time of about 30 minutes. This produced a black tar which in acetone solution had the color of potassium permanganate. I am contemplating making separately the mixed anhydride of acetic acid and p-TosOH which is known to be a very powerful acylating agent but I do not hold much hope for this.

I will appreciate any information and insight that you may be able to provide.

[1] J.E. Saxton, J. Chem. Soc. 1952, 3592.

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[*] posted on 11-4-2018 at 22:24


AvBaeyer,

I worry that in all the failed attempts here the strongly acidic environment combined with air exposure is causing rapid oxidation and degradation of the indole. All of the papers I see in the literature for the direct acylation of indole use some form of inert atmosphere (sealed vessel, Schlenk technique, N2 atmosphere). For example, see [-1]

However, it seems to me that the acylation should proceed without issue as long as the indolic nitrogen is protected. Thus, I propose the following: 1) form n-tosylindole from indole and tosyl chloride under PTC conditions [0,1]. 2) Acylate the protected indole using your favorite Friedel-Crafts system [1] 3) Deprotect the indolic nitrogen with aqueous base; the references I saw were using fairly exotic things like KF/alumina, but K2CO3 solution should work fine for this. Alternatively, do whatever chemistry you were planning to do with the 3-acetyl, and deprotect at whatever step is most convenient later on.


[-1] Acylation of Indole under Friedel−Crafts Conditions: An Improved Method To Obtain 3-Acylindoles Regioselectively. Olı via Ottoni,* Amarı ́lis de V. F. Neder, Ana K. B. Dias, Rosimeire P. A. Cruz, and
Lıgia B. Aquino


[0] Ke Wang & Zhanzhu Liu (2009) Synthesis of Arcyriarubin A and Arcyriaflavin
A via Cross-Coupling of Indolylboronic Acid with Dibromomaleimides, Synthetic Communications,
40:1, 144-150,

[1] Stereoselective Synthesis of cis‐2,6‐Disubstituted Morpholines and 1,4‐Oxathianes by Intramolecular Reductive Etherification of 1,5‐Diketones Santosh J. Gharpure, Dandela Anuradha, Jonnalagadda V. K. Prasad, Pidugu Srinivasa Rao. See supporting information.


If you are having trouble accessing anything, let me know and I can attach it.

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[*] posted on 12-4-2018 at 18:30


Cryolite,

I generally agree with you regarding reaction conditions if one is using a Friedel-Crafts type of approach. However, there is significant older (non-F/C) literature which describes the 3-acylation of indole with acetic anhydride under various but similar conditions. I do not think that these earlier workers worried too much about inert atmosphere. The reference I cited above is the main one cited by other workers although there are several other references at much earlier dates describing similar reactions.

Finally, I do not have the resources to run inert atmosphere reactions and I am not a big fan of F-C chemistry. I will have more to say about all this later as I finish up a number of experiments.

Thanks for the comments, always appreciated.

AvB
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[*] posted on 10-5-2018 at 22:48


AvBaeyer,

Sorry for my late reply, just have seen your post.

I can only tell you, that I have checked the melting point of both the diacetyl and monoacetyl product, and according to my notes, did few recrystallisations using ethanol as solvent.
Also I have followed the diacetylation using tlc.
I can't quite remember exactly how I have done all of this from memory now, but when I lastly saw the monoacetyl product in my storage, it was still of a rather good looking, of a little tan colour still(looking to the brown glass container).
I have not proceeded to react this stuff further yet.

However, due to the experiment being somewhat ago, and me doing a lot of different experiments at the time, I can't properly tell from my memory.

But I have not experienced a lot of polymerisation, unlike using other processes to prepare the title compound.

I will try to find the original reference, I have it somewhere on my computer, but the only one I could find readily was a bit of text copied from the reference into my notes.
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[*] posted on 11-5-2018 at 18:35


karlos³,

Thanks for getting back to this post. As I mentioned above, the Saxton procedure produces a rather complex reaction mixture in my hands. In order to sort some of this out I did an independent synthesis of 1-acetylindole [1]. It is produced in very good yield using acetic anhydride, DMAP, and triethylamine and is isolated as a distillable liquid. It is the only compound produced in the reaction. Having 1-acetylindole in hand I was able to see by tlc (silica, benzene) that the major product in the Saxton procedure in my hands is in fact 1-acetylindole. 1-Acetylindole is inert to further acetylation at the 3-position using the Saxton procedure so its formation in the reaction is a dead end. (It is well established that attempts to acylate 1-acetylindole under Friedel-Crafts conditions results in reaction only on the benzene ring.) I see two other products in the Saxton reaction which I presume are 3-acetylindole and the 1,3-diacetyl derivative. The latter compound would derive from N-acetylation of the 3-acetylindole. I am able to isolate a poor yield (ca 15%) of a crystalline material which melts broadly near the expected mp of 1,3-diacetylindole. TLC shows 2 spots. Attempts to hydrolyze this material to 3-acetylindole using Saxton's procedure resulted in a complex mixture. It looks like there is a lot of competing chemistry going on in the pot! I also isolated a fair amount of unreacted indole.

I have not been able to work too much on this lately but I plan to get back to it. It is an interesting challenge.

[1]. K. Nickisch, et al,, Chem. Ber. 113, 2036 (1980).

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[*] posted on 15-5-2018 at 03:37


Might be better to protect the indole NH with a alkylprotecting group, like benzyl. But even with a tosyl group there, I think I have seen acylation at the 3 position before, might have been harsher conditions, however.
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