Author Topic: Bromomethylation of indole  (Read 2767 times)

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Bandil

  • Guest
Bromomethylation of indole
« on: January 09, 2004, 06:34:00 AM »
Hi!

After reading and drooling over

Post 475109

(Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse)
. Swim decided to test the procedure. The only currently available substrate was indole, but swim decided that it probably would work with this as it is activated at the correct sites and also reacts with the Villsmeyer complex in the same manner as the other substrates(dimethoxytoluene etc).

Thus the procedure w/o HBr was tried out. Because the substrate was indole(which is a solid) and not benzene(liquid) 5X the amount of GAA was used in order to dissolve most of the sludge. Everything turned very purple immediately and the reaction was allowed to commence as described in the procedure.

Was it correct to assume that indole would react in the same manner as benzene? I'd say that it would be even more reactive than benzene because of the more activated site. If it works, it sure is an slick'n'easy route to AMT...

Feedback appreciated!

Regards
Bandil


Rhodium

  • Guest
Indole is more reactive than most benzenes
« Reply #1 on: January 09, 2004, 12:31:00 PM »
I'd assume that indole was too reactive for a bromomethylation, so that you would end up with the dimer bis(3-indolyl)methane instead of 3-(bromomethyl)-indole. This is just a hunch though.


Nicodem

  • Guest
Gramine is better
« Reply #2 on: January 11, 2004, 10:13:00 AM »
There is no point in trying to make something like a 3-halogenomethyl-indole. Even if it is stabile at all (I don't know) it is nevertheless probably impossible to get it with a halogenomethylation (as Rhodium pointed out).
It is much better to use gramines as the alkylating agents for the nitroacetic acid esters:

Lyttle and Weisblat. The Chemistry of Nitroacetic Acid and its esters. I. The alkylation of Alkylnitroacetates with Gramine. J. Amer. Chem. Soc. 69 (1947), 2118-2119.

Lyttle and Weisblat. The Chemistry of Nitroacetic Acid and its esters. II. The Synthesis of Ethyl-alpha-Nitro-betta-(3-indole)-propionate from Gramine and Ethyl Nitromalonate. J. Amer. Chem. Soc. 71 (1949), 3079-3081.

Gramines themselves are easily made by the aminomethylation of indoles. But unless the appropriate gramines are more easily accessible than their indole counterparts I don't see much value in this route.
Firstly, because I'm not so sure how smoothly the decarboxylation of the product goes (it probably does well but I saw no such example in the above papers as they were up to tryptophan more than anything else).
Secondly, because the 2-(3-indolyl)-nitroethanes can be prepared more easily by the electrophylic substitution on the indoles with nitroethene (NO2-CH=CH2) or 2-nitropropene (for the alpha-Me-tryptamines).
Even easier would be trying to react formaldehide, 2-nitropropane and an indole to end up with an alpha, alpha-dimethyl-tryptamine. Or one could use 2,2-dimethyl-2-nitro-ethanol instead of formaldehide+2-nitropropane. In any case it would be a cheap 2-step preparation. But who knows which ones of these tryptamines, if any, are active and interesting (though I suspect many are).


Nicodem

  • Guest
The papers mentioned in the above post
« Reply #3 on: March 18, 2004, 10:36:00 AM »
...and also referenced in

Post 304144

(Aengus: "Alkylation of nitroalkanes", Methods Discourse)
:

The Chemistry of Nitroacetic Acid and its esters. I. The alkylation of Alkylnitroacetates with Gramine.
Lyttle and Weisblat.
J. Amer. Chem. Soc. 69 (1947), 2118-2119.


Abstract: A new synthesis of dl-tryptophan which consists of the alkylation of ethyl nitroacetate by gramme, reduction of the resulting ethyl a-nitro-beta-(3-indole)-propionate, and hydrolysis of ethyl dl-tryptophan is presented. An investigation of the chemistry of nitro acetic acid and its esters is being undertaken.

The Chemistry of Nitroacetic Acid and its esters. II. The Synthesis of Ethyl-alpha-Nitro-betta-(3-indole)-propionate from Gramine and Ethyl Nitromalonate.
Lyttle and Weisblat.
J. Amer. Chem. Soc. 71 (1949), 3079-3081.


Abstract:
1. A new synthesis of dl-tryptophan employing ethyl nitromalonate and gramine is reported.
2. An improved method for preparing and stabilizing esters of nitromalonic acid is described.