Author Topic: Indole-3-acetone from indole-3-carboxaldehyde  (Read 2888 times)

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  • Guest
Indole-3-acetone from indole-3-carboxaldehyde
« on: August 14, 2002, 07:59:00 AM »
After quite some success with the Darzen´s condensation making phenylacetones, I decided to challenge some indole-3-carboxaldehyde to see what this puppy was good for.

Indole-3-carboxaldehyde, 14.5g (100mmol), ethyl 2-chloropropionate, 19.1g (140mmol), 25ml toluene and 30ml MeOH was added to a 500ml rb three-necked flask equipped with a thermometer and a magnetic stirbar. To this suspension 8.1g (150mmol) sodium methoxide (dissolved in MeOH) was added dropwise during 1 hour. This reaction was actually endothermic so no cooling was needed. After the addition was complete the reaction mixture was allowed to stir at room temp for two hours. During this time the substrate gradually dissolves and gives a orange solution from which a white precipitate separates.

10g (250mmol) Sodium hydroxide dissolved in 50ml water was then added dropwise during 10min. No cooling was applied here so the temperature reached 45 deg C. An additional 100ml water was added and the solution was stirred at 60 deg C for one hour. The toluene layer was separated from the aqueous layer (now deep red). Conc hydrochloric acid was added dropwise to the hot water solution until pH 3.5 was reached. A slightly yellowish crystalline mass fell out as the solution went acidic.  The acidic suspension was stirred at 80 deg C on a water bath for one hour to complete the decarboxylation. The mixture was extracted with 8x50ml ether and the combined organic layers washed twice with 200ml 10% sodium bicarbonate solution, twice with water and finally once with brine. The solvent was removed with a rotovap leaving slightly yellowish crystals.

Yield: 15g (87%) indole-3-acetone

I will recrystallise this and check the mp and report.

The crystals were suspended in 100ml boiling IPA, 60ml was removed by distillation and the remaining suspension was cooled to room temp and then chilled to 0 deg C for one hour. The crystals was removed by filtration and dried under vacuum at 60 deg C.

Yield: 14.1g indole-3-acetone as white crystals with a mp of 114-115.5 deg C.

Next project

indole-3-acetone --> alpha-methyltryptamine
I´ll divide the ketone in two portions and try two diffrent methods, regular reductive amination with dry NH3 and Pd/C in MeOH, and ammonium formate/Pd-C/MeOH/H2O.

Reports will follow shortly


  • Guest
The silence.....
« Reply #1 on: August 16, 2002, 02:45:00 PM »
is bone-chilling....... :(


  • Guest
Hive Law #1
« Reply #2 on: August 16, 2002, 06:00:00 PM »
The number of replies to a post is inversely proportional to its significance  ;) .


  • Guest
Don't let the silence stop ya
« Reply #3 on: August 17, 2002, 04:21:00 AM »
I'm reading, there must be others. I haven't anything to add.


  • Guest
Barium, the reaction is a real beauty from ...
« Reply #4 on: August 17, 2002, 06:32:00 AM »
Barium, the reaction is a real beauty from synthetic point of view (one pot, great).  But I have a question about the ethyl 2-chloropropionate.  Did you buy it or did you make it yourself?  Does the reaction work equally good with the ethyl 2-bromopropionate?  If it is, a possible way to make it is the Hell-Vollhard-Zelinsky reaction on propionic acid to obtain 2-bromopropionic acid & to esterify this babe.
Is ethyl 2-chloropropionate a suspicious chemical (i guess if it isn't, it will soon become one ... arg)?  Is it expensive?  Is it easy to work with?  With that halogen next to the electron sucking carboxyl, I guess it will be a lacrimator.


  • Guest
What Cyrax said...
« Reply #5 on: August 17, 2002, 08:22:00 AM »
I was wondering the same about ethyl 2-chloropropionate, as it is quite expensive. Can methyl 2-chloropropionate not be used instead, as you used this making phenylacetones from benzaldehydes? Methyl 2-chloropropionate is much cheaper, and available in kg quantities.
Excellent procedure by the way, just I (and probably many others) do not really have much else to contribute. :-[


  • Guest
It's a nice synth, but what exactly is the ...
« Reply #6 on: August 17, 2002, 08:53:00 AM »
It's a nice synth,  but what exactly is the advantage over
the way Shulgin does it (as described in TiHKAL #48)?

(Shulgin forms the nitropropene from indole-3-carboxaldehyde and nitroethane, and then reduces it with LAH to AMT)


  • Guest
>It's a nice synth, but what exactly is the ...
« Reply #7 on: August 17, 2002, 10:35:00 AM »
>It's a nice synth,  but what exactly is the advantage over
>the way Shulgin does it (as described in TiHKAL #48)?

Maybe that you can easily make N-substituted derivatives? Alpha-methyl and alpha-ethyl, N-substituted tryptamines could be interesting compounds.


  • Guest
Maybe I'm missing something, but shulgin makes ...
« Reply #8 on: August 17, 2002, 11:25:00 AM »
Maybe I'm missing something, but shulgin makes a-MT from
indole-3-carboxaldehyde and nitroethane, and a-ET from indole-3-carboxaldehyde and nitropropane.

Of course, if you can't find nitroethane or nitropropane, this route is just as good (yields are equivalent).


  • Guest
What you might be missing are the N-substituents: ...
« Reply #9 on: August 17, 2002, 01:02:00 PM »
What you might be missing are the N-substituents: reduction of the nitroalkene always leads to the primary amine. You could alkylate it, yes, but that's an additional step, maybe two for secondary amines. The ketone can be reductively aminated with any suitable amine.


  • Guest
Our friends Carl, Jacob & Nicolai
« Reply #10 on: August 17, 2002, 04:58:00 PM »
Here 's some literature on the HVZ reaction:

Org. Synth. (1941), vol 21, p 74
J. Am. Chem. Soc. (1948), vol 70, p 3626
J. Am. Chem. Soc. (1964), vol 86, p 5496

For those who want to go back to the roots & read about it from the chemists who invented this reaction, there is:

Carl M. Hell (German dude from the university of Stuttgart, 1849 - 1926), Ber. (1881), vol 14, p 891
Jacob Volhard (also a German but from  uni. of Halle, 1834 - 1910), Ann. (1887), vol 242, p 141
Nicolai D. Zelinsky (Russian professor from the uni. of Moscou, 1861 - 1953), Ber.(1887), vol 20, p 2026

Whow, that Zelinsky dude must have been a smart motherfucker: he was only 16 years old when he published his article in Chemische Berichte.  Naughty, naughty boy: playing with phosphorus and bromine instead of with the girlies ...


  • Guest
Cyrax: Ethyl 2-chloropropionate is cheaper and, ...
« Reply #11 on: August 18, 2002, 05:01:00 AM »
Ethyl 2-chloropropionate is cheaper and, in my opinion, better to use than the methyl ester.
It has a lower vapor pressure and hence, stinks less.
I buy it from a major chem supplier for less than $100/L. In bulk it´s really cheap.
It is not bad at all to work with. Non-watched until now I guess, or very soon.

In some of the articles is quickly scanned trough before I started with this route
I remember seeing something about the chloro being better than the bromo or iodo.
This was due to some strange side reactions which could occur wiht the heavier haloesters.
But under the mild reaction conditions I´ve had I don´t see any problems with the bromoester.

From Vogel 5:th ed.

Ethyl 2-bromopropionate

In a 1L two-necked round-bottomed flask, equipped with a dropping funnel and a double surface reflux condenser to which is attached a gas absorbation trap, place 220g (135ml, 1.86mol) of redistilled thionyl chloride, and heat to boiling. Add 125g (126ml, 1.69mol) of pure propanoic acid at such rate that the mixture refluxes gently (1 hour). Reflux the mixture for a further 30 minutes to expel the dissolved sulphur dioxide, allow to cool and add 0.5g purified red phosphorus. Introduce 310g (100ml, 1.93mol) of dry bromine during 5-7 hours to the gently boiling propanoyl chloride, and then reflux the mixture for 7 hours, by which time the evolution of hydrogen bromide almost ceases.
Add the crude 2-bromopropanoyl chloride during 2 hours to 250ml absolute ethanol (note 1) contained in a three-necked round-bottomed flask, equipped with a mechanical stirrer and a reflux condenser. Complete the reaction by heating on a water bath for 4 hours, when hydrogen chloride is slowly evolved. Filter the reraction liquid into 500ml distilled water, separate the oil and wash it successively with water, sodium bicarbonate solution and water. Dry over calcium sulphate and distill at normal pressure to remove the low boiling fraction (largely ethyl bromide: 75g) and the at diminished pressure. Collect the ethyl 2-bromopropionate as a colourless liquid at 69-70 deg C @ 25mm Hg; the yield is 221g (72%)

Note 1. Substitute for methanol or another alcohol if you´d like.



  • Guest
Yellium: it´s a novel route to a whole shitload ...
« Reply #12 on: August 18, 2002, 05:23:00 AM »

it´s a novel route to a whole shitload of tryptamines

Indole-3-carboxaldehyde and ethyl 2-chloropropionate gives indole-3-acetone.
From indole-3-acetone and
ammonia                      alpha-methyltryptamine
methylamine              alpha,N-dimethyltryptamine
ethylamine                N-ethyl-alpha-methyltryptamine
propylamine              alpha-methyl-N-propyltryptamine
isopropylamine        N-isopropyl-alpha-methyltryptamine
allylamine           N-allyl-alpha-methyltryptamine
dimethylamine         alpha,N,N-trimethyltryptamine
diethylamine          N,N-diethyl-alpha-methyltryptamine
dipropylamine      N,N-dipropyl-alpha-methyltryptamine
diisopropylamine N,N-diisopropyl-alpha-methyltryptamine
diallylamine     N,N-diallyl-alpha-methyltryptamine

Indole-3-carboxaldehyde and ethyl chloroacetate gives indole-3-acetaldehyde
From indole-3-acetaldehyde and
ammonia                         tryptamine
methylamine             N-methyltryptamine
ethylamine               N-ethyltryptamine
propylamine             N-propyltryptamine
isopropylamine       N-isopropyltryptamine
allylamine               N-allyltryptamine
dimethylamine       N-N-dimethyltryptamine
diethylamine         N,N-diethyltryptamine
dipropylamine       N,N-dipropyltryptamine
diisopropylamine N,N-diisopropyltryptamine
diallylamine        N,N-dilallyltryptamine

5-methoxyindole-3-carboxaldehyde......I´m sure you get the picture by now.


  • Guest
Some of the tryptamines I mentioned in my ...
« Reply #13 on: August 18, 2002, 05:29:00 AM »
Some of the tryptamines I mentioned in my previous post are illegal to manufacture and posesss without license. If you don´t have such a license, please, don´t make them or handle them i any way.

My post was not ment to encurage anyone to break the law. It was just meant for academic information.


  • Guest
But under the mild reaction conditions I´ve had I ...
« Reply #14 on: August 18, 2002, 06:26:00 AM »
But under the mild reaction conditions I´ve had I don´t see any problems with the bromoester

Did you actually try the reaction with the ethyl 2-bromopropionate or do you just suspect that the reaction will run equally well.
I mean, this could be important if the narcs consider ethyl 2-chloropropionate as a precursor.  Then you can make the bromo analog from scratch.
If you could report results about a little test reaction with the ethyl 2-bromopropionate, this would be great.

I really appreciate this reaction.  Good work, Barium.


  • Guest
Ifn you animate with one or the other chiral ...
« Reply #15 on: August 22, 2002, 10:39:00 PM »
Ifn you animate with one or the other chiral alphamethylbenzylamine, and deprotect, as per JMC 1986, 29, 10, 2014 both AMT stereoisomers would be available, pure, although this I would not advise, unless you have a license, and know how to do it properly, and have a signed note from your Mum


  • Guest
Ethyl 2-chloropropionate
« Reply #16 on: November 21, 2002, 12:29:00 AM »
Sandmeyer reaction to get the 2-halo propionate from alanine might be easier and more otc than Hell Volhard Zelinsky reaction on propionic acid -

Post 221895

(lugh: "(R)-2-Bromopropionic Acid from D-Alanine", Methods Discourse)
. assuming the choice was not to purchase.


  • Guest
Sorry for bringing up this old thread...
« Reply #17 on: May 21, 2004, 11:52:00 AM »
High Bees!

Swim tried the procedure on Indole-3-carboxaldehyde, but instead of Ethyl-2-Chloropropinoate Methyl-2-Chloropropinoate was used, and the sodium methylate was made by dissolving sodium in MeOH.

The reaction went exactly as Barium described it, and SWIM recovered ~14g of product which was recrystallised from IPA. It had still a pale orange colour.

Today Swim ran an HPLC on it and found out that it was absolurtly pure indole-3-carboxaldehyde  ::)  Melting product test confirmed that the reaction didn´t go right.

Does this method only work with ethyl-2-chloropropionate?? (Many other benaldehyde substrates were converted to their corresponding P2Ps with the methyl ester by Barium)

Best wishes,


  • Guest
« Reply #18 on: May 21, 2004, 12:34:00 PM »
Did you really perform the reaction as I described it? Because I can't understand how indole-3-carboxaldehyde can stay dissolved in the aqueous alkaline solution you get after removing the toluene after the hydrolysis has been performed.

The methyl and ethyl esters are interchangable. Just use a ethoxide to the ethyl ester and a methoxide to the methyl ester.


  • Guest
High Barium! So here is the writeup, exactly...
« Reply #19 on: May 21, 2004, 12:48:00 PM »
High Barium!

So here is the writeup, exactly as it went:

Indole-3-carboxaldehyde, 30ml of MeOH and 25ml Toluene were added to a 500ml RBF. A stir bar was added, and 15,2ml of Methyl-2-chloropropionate was added. 3,6g of Na were dissolved in 40ml of MeOH, and this (slightly yellow) solution was added dropwise to the reaction mixture during  ~50 minutes.

On addition the solution became more orangish and all substrate dissolved. The solution was stirred for 2 hours - a relatively small amount of precipiate was seen during this time.

Then 10g NaOH in 50ml were added dropwise. The temp reached ~38°C. 100ml water was added, and the solution was heated to 60-65°C for one our. The solution turned from dark orange to a very deep red.

Then the mixture was poured into a sep funnel and the toluene (which was way darker then the aqueous solution) was drained off. The aqueous layer was acidified with conc. hydrochloric acid. - This caused a lot of orange solids to precipiate out (but no vigorous CO2 evolution was noted, only slight bubbling). This was heated again to 80°C for a good hour.

Then swim wanted to extract the goods with DCM, but he found out that the product wasnt soluble in DCM... so the DCM was drained off again, and the mixture was extracted with ether. - The solubility in ether was also very poor, so swim filtered the crytals and washed them with a lot of cold water.

The ether phase was washed with bicarbonate solution (bicarb-solution turned orange too!), then with water, and finally the solvent was removed on the rotary evaporator.

The combined crystals were dried, and then recrystallized from ~80ml of IPA to yield a pale orange solid with the same rentention time on HPLC as Indole-3-carboxaldehyde (eluent: methanole, column: nucleosil 5C-18), and also the same melting point of about ~195°C.

Does anybee have some ideas what went wrong?

I dont wanna waste any more precoursor until i know what caused the failure....  :(

...everything looked that good during the reaction!

best wishes,