Author Topic: Indole Grignards  (Read 5075 times)

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Lilienthal

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Indole Grignards
« on: February 14, 2002, 04:41:00 AM »
I ran across this great review article by chance:

Advances in Heterocyclic Chemistry (Academic Press NY) 10, 43 - 112 (1969)

I haven't looked up the references, but it looks like dimethyltryptamines from indole grignards (prepared from indole, alkylhalogenide, and Mg) and dimethylamino-ethyl-chloride (cheap as dirt) are possible in good yields by using anisole instead of ether as the solvent!

:)

Greensnake

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Re: Indole Grignards
« Reply #1 on: February 14, 2002, 02:24:00 PM »
>and dimethylamino-ethyl-chloride (cheap as dirt)

Cheap as dirt, but quite toxic and cancerogenic, not exactly a toy for home chemists.

Rhodium

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Re: Indole Grignards
« Reply #2 on: February 14, 2002, 04:01:00 PM »
Aren't you thinking of the bis(chloroethyl)amines now?

slappy

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Re: Indole Grignards
« Reply #3 on: February 15, 2002, 11:08:00 AM »
N,N-Dimethyl-2-Chloroethylamine is a carcinogen, although I don't believe that it's as bad as Greensnake makes it out to be.

Lilienthal

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Re: Indole Grignards
« Reply #4 on: February 15, 2002, 04:15:00 PM »
The maximum yields for that are 25% and a goo formed (dimethyltryptamine halogenide in anisole).

But the yields for the dialkyl-acetamides look promising. Later more.


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Lilienthal

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Re: Indole Grignards
« Reply #5 on: February 16, 2002, 10:05:00 AM »
Here are some references in addition to

Post 8809

(Lilienthal: "Re: maybe 4 steps from tryptophan to DMT/DET/DPT", Tryptamine Chemistry)
:

Chem. Ind. 1388 (1964) dialkyltryptamines
J. Chems. Soc. 2220 (1967) dialkyltryptamines

Patent US2692882

5-benzyloxy-indole-3-acetamides

Patent US2703325

5-benzyloxy-indole-3-acetonitriles __> 5-benzyloxy-tryptamines

Patent US2728778

5-benzyloxy-indole-3-acetonitriles

PolytheneSam

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Re: Indole Grignards
« Reply #6 on: February 16, 2002, 10:06:00 PM »
See also

Patent US1793176

(2-methyl indole MgX (grignard reagent) reacted with ClCH2CH2N(CH3)2 to get 2-methyl DMT; example 6).



http://www.geocities.com/dritte123/PSPF.html

PolytheneSam

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Re: Indole Grignards
« Reply #7 on: February 18, 2002, 03:35:00 AM »

Patent US4017513

looks interesting.  I wonder if it could work for IAA and dimethylamine.

http://www.geocities.com/dritte123/PSPF.html

terbium

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Re: Indole Grignards
« Reply #8 on: February 18, 2002, 06:00:00 AM »
Re:

Patent US4017513



I don't see what is there that is patentable.

Edit:
It seems like nothing but prior art. They use the ion exchange resin as a strong acid catalyst to form the methylester of the amino acid then they remove the resin, add ammonia and perform the ammonolysis of the ester.

Sure this should work for IAA + dimethylamine.


Greensnake

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Re: Indole Grignards
« Reply #9 on: February 18, 2002, 01:47:00 PM »
Not necessarily it should work very well for IAA/Me2NH, dimethylamine generally reacts quite sluggish with esters (if at all)

Ritter

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Re: Indole Grignards
« Reply #10 on: February 22, 2002, 10:14:00 PM »
Diethylamine practically won't even react with the methyl ester, even when refluxed for 24 hours!

PolytheneSam

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Re: Indole Grignards
« Reply #11 on: February 24, 2002, 03:52:00 AM »
Here's some interesting amide patents

Patent US6291712




In addition to the above processes, a process for producing a carboxylic acid amide has been proposed, in which the
carboxylic acid amide is produced from an ammonium carboxylate in the presence of a dehydration catalyst. In this process,
molybdenum oxide, an alkyltin catalyst, a mixture of silica gel and alumina or a titanium tetrachloride catalyst is used as the
dehydration catalyst.

In this process, the dehydration reaction can be carried out at relatively low temperatures, so that not only can the formation of
by-products such as nitrile compounds and carboxylic acid amide dimerization products be suppressed but also the reaction
time can be shortened. However, when the carboxylic acid amide is produced with the use of the catalyst, it is apprehended
that the catalyst be dissolved or otherwise contained in the obtained carboxylic acid amide and, hence, a step of separating or
otherwise removing the catalyst from the carboxylic acid amide after the completion of the reactions becomes requisite. If costs
of catalyst production and catalyst removal incurred by the use of the catalyst, etc. are taken into account, this process also
cannot be regarded as a satisfactory process.




Patent US4379928




Alkyl amides have been synthesized from cyclic anhydrides, carboxyl acids and their esters by contacting them with an amine carbamic acid salt.





The amine carbamic acid salts can be prepared by the interaction, e.g., of an alkylamine and carbon dioxide. A suitable
procedure is described in U.S. Pat. No. 2,927,128 by H. A. Lindahl et al. assignors to Pure Oil Co.

Alternately the amine carbamic acid salts can be generated in situ by the reaction of carbon dioxide with an amine. In the simple
case where the amine is dimethyl amine, the equation for the reaction is: ##STR7##




Patent US6313294




Many conventional synthetic pathways exist for preparing amide compounds. For instance, the reaction of an amine and an
ester in a solvent, a well-known basic organic reaction, can be used to form an amide. In particular, it is known that the
formation of an amide linkage by the reaction of a primary amine with an ester in a solvent under heating is possible. Moreover,
the formation of an amide by reacting a secondary amine and an ester, can require not only a solvent, but also a catalyst, such
as Lewis acid, strong base, or enzyme.




Patent US3763234

Lewis acid catalysts

Patent US2478114

hydrosulfite catalyst

Patent US1954433

carboxylic acid, amine and xylene or amylbenzene distilled

Patent US3288794

dimethylamides using alkali metals/alkoxide catalysts

Patent US4139557

dimethylacetamide, MoO3 catalyst

Patent US1582675

formamide



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zed

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Indole Grignard's
« Reply #12 on: April 20, 2002, 04:21:00 AM »
Zed has seen this reaction performed. It does produce a one pot DMT synthesis. And, yes, the yield is actually about 25%. I don't have the paperwork. But, as I recall, Ethyl Bromide or Iodide is added dropwise to Magnesium in Diethyl Ether, to form the Grignard reagent. Indole is then added slowly to to the reaction mixture to form a 1-Indole Magnesium complex, Which there after, is reacted with Dimethyl-Amino-Ethylchloride, to produce DMT. This Reaction, unlike many you find in Chemical Literature, actually works pretty well!

The Downside was, that at that time, Indole was a pretty tough acquisition. And, Dimethylaminoethylchloride wasn't easy either, seems folks were using it in some opioid synthesis. There were not as many Phychoactive substances, and the Feds could focus a lot of attention, on just a few precursers. So, the ones they did focus on, they could squeeze pretty tight.

That being said, the difficult part of this synthesis is in the execution. Ordinary stirring will not do for most proceedures. The additional solvents employed, and the cold temperatures we used, created a thick peanutbutter-like reaction mass. No ordinary stirrer can move this stuff. You must employ a powerful, explosion proof DC Motor to provide the required stirring. Also note, that a fair volume of ethane gas is released, don't be surprised.

Anyway, that was the old way, thanks for the great references, I'll cruise for improvements.

PolytheneSam

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Pd/C
« Reply #13 on: May 14, 2002, 01:28:00 AM »
In

Patent US2692882

column 2 it says you can use Pd/C hydrogenation of an IAA amide at one atmosphere pressure.  I found an example of atmospheric pressure hydrogenation here. 

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0586


It looks like you need very little Pd/C catalyst relative to the reactants and products.  Would 15-20 year old unopened Pd/C still be good for a reaction like this?


http://www.geocities.com/dritte123/PSPF.html
The hardest thing to explain is the obvious

zed

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Amine via Pt/H2?
« Reply #14 on: May 16, 2002, 01:04:00 AM »
Saw patent. The Pd-C/H2..... Seemed it was being used to remove a 5-Benzyloxy-group.

They did make a claim, that the amide could be reduced to amine via Pt/H2. But, this is a pretty tough reduction. I haven't seen it done via Pt/H2. LAlH4...yes, NaBH4-AlCl3....yes, Pt/H2......? I would like to believe..........tell me more.

zed

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2-Methyl-DMT
« Reply #15 on: May 16, 2002, 01:42:00 AM »
Funny you should mention that. I once synthesised a bunch of 2-Methyl-DET, via the Fischer Indole Synthesis, unfortunatly it seemed quite inactive.

Likewise, my hopeful comrades, made the 2-Methyl-DIPT, by another method... also inactive. Shulgin's findings were similar.

I don't know if any claims are made for 2-Methyl-DMT, but the rest of the series wasn't impressive. Something to consider before investing a lot of time and energy.

Also, Shulgin's Tikal reports on oral effects being...zippo. Effects via smoking also seem to be....zippo!

PolytheneSam

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hydrogenolysis
« Reply #16 on: May 16, 2002, 02:18:00 AM »
After looking at that patent again I think they're using the Pd/C hydrogenation to remove the benzoyl group and not reducing the amide part.  See also example 4 on page 13 in

Patent US5192770



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The hardest thing to explain is the obvious

Rhodium

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2-Methyl-DMT
« Reply #17 on: May 16, 2002, 06:52:00 AM »
Zed: 2-Methyl-DMT gets an unusual review in Tihkal:


(with 120 mg, orally) "There is as much to be said for what didn't happen as for what did. No visual changes. No cloudiness of the thought processes. No motor impairment what-so-ever. There was some down-shifting of music, with some distortion, which was overall more annoying than interesting. But I am glad I am alone because I cannot wear clothing. Anything touching the skin makes all my hair stand on end. The erection of my nipples is almost painful. Exploring sexual stimulation is seemed a little dangerous but explored anyway. The climax was disappointing. Too much activity of a slightly scary sort. Never again at this level.

zed

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2-Methyl-DMT
« Reply #18 on: May 16, 2002, 11:33:00 AM »
Sounds very similiar to my early experiences with Catholicism.....Not fun!

Also, sounds like the several ounces now in existance, will be sufficient to meet world demand for the next hundred years or so. Too bad! Easy to make! The Fischer is a cakewalk.

Rhodium

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Indole grignards
« Reply #19 on: January 13, 2003, 11:49:00 PM »

Post 397806 (missing)

(Aurelius: "US patent 1793176  Tryptamines through grignards", General Discourse)

Rhodium

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DMT by alkylation of Indole Grignards
« Reply #20 on: September 26, 2003, 03:56:00 PM »
Preparation of DMT by alkylation of Indole Grignard reagent, referenced in 

Post 270360

(Lilienthal: "Re: Indole Grignards", Tryptamine Chemistry)


A New Route to Tryptamine Derivatives
C. R. Ganellin and H. F. Ridley

Chemistry and Industry 1388-89 (1964)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/dmt.indole.grignard.html)

Rhodium

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Propynylindole and 3-Indolylacetone
« Reply #21 on: January 15, 2004, 06:17:00 AM »
3-Prop-2'-ynylindole
W. R. N. Williamson
J. Chem. Soc. 2834 (1962)

Brown, Henbest, and Jones1 reported their failure to prepare 3-prop-2'-ynylindole by treating 3-indolylmagnesium bromide with prop-2-ynyl bromide, "chiefly because the Grignard reagent reacted first with the active acetylenic hydrogen atom to regenerate indole". They do not report the solvent used, but it was presumably diethyl ether. According to Majima and Kotake2 anisole is a superior solvent for the preparation and subsequent reaction with carbonyl compounds of indolyl Grignard reagents. This apparently cannot be attributed to the higher boiling point of anisole, since in this solvent ethylmagnesium iodide evolves ethane on treatment with indole in the cold, while in ether no gas is evolved at room temperature and heat is required. When we used anisole in the preparation of 3-indolylmagnesium iodide from ethylmagnesium iodide, with subsequent reaction with prop-2-ynyl bromide, a 39.5% yield of 3-prop-2'-ynylindole was obtained. The compound, which was a pale yellow oil slowly becoming darker, was characterised by conversion into 3-indolylacetone2 by heating it with acidic mercuric sulphate.

Experimental

3-Prop-2'-ynylindole

Ethylmagnesium iodide [from magnesium (4.8 g.) and ethyl iodide (32 g.)] in dry anisole (20 ml.) was cooled in ice, and indole (15.6 g.) in anisole (20 ml.) was added dropwise. After being stirred (0.5 h) at 20°C it was treated at 0°C with prop-2-ynyl bromide (20 ml) in anisole (10 ml) during 15-20 min, stirring continued at 0°C for 11 h, and the mixture then stored at 20°C overnight. It was cooled to 0°C and treated with ether (100 ml), water (200 ml), acetic acid (12 ml), and more water (100 ml), and then extracted with ether (5x25 ml.). The extract was washed with sodium bicarbonate solution and water and dried (MgSO4 and charcoal), the solvents were removed under reduced pressure, and the 3-prop-2'-ynylindole (8.17 g) was distilled as a pale yellow oil, bp 143-145°C/2mmHg, which solidified when cooled below 20°C.

3-Indolylacetone

2N Sulphuric acid (10 ml) was treated with mercuric sulphate (0.05 g)3, stirred and heated on a steam-bath, and the propynylindole (1.5 g) in ethanol (10 ml) added. Stirring and heating was maintained for 2 hr. Pouring the solution into water and treatment with sodium hydrogen carbonate produced a brown gum (1.42 g.), mp 95°C (softening at 75°C). Crystallisation from benzene (charcoal) gave the ketone as brownish rhombs (0.28 g), mp 112-115°C. The mp of a mixture with authentic 3-indolylacetone was 112-115°C.

References
[1] Brown, Henbest, and Jones, J. Chem. Soc. 3172 (1952)
[2] Majima and Kotake, Chem. Ber. 55B, 3859-3865 (1922); cf. Kharasch and Reinmuth, "Grignard Reactions of Nonmetallic Substances", 1954, Prentice-Hall, Inc., New York, p. 81.
[3] Thomas, Campbell, and Hennion, J. Amer. Chem. Soc. 60, 718 (1938)


Rhodium

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Scaleable Route to Chiral alpha-Methyltryptamines
« Reply #22 on: May 13, 2004, 01:57:00 AM »
Process Development of a Scaleable Route to [chiral alpha-methyltryptamines]
Hiroshi Harada, Akihito Fujii, Osamu Odai, and Shiro Kato
Organic Process Research & Development 8, 238-245 (2004)





Several different routes are discussed in the article, weighing pros and cons, not just the nifty one in the picture. Note the NaBH4 reduction of a beta-keto-tryptamine, a topic recently discussed.


Rhodium

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3-Indolylacetaldehyde and 3-Indolylacetone
« Reply #23 on: June 05, 2004, 03:18:00 AM »
This is reference #1 from the article in

Post 482491

(Rhodium: "Propynylindole and 3-Indolylacetone", Tryptamine Chemistry)


3-Indolylacetaldehyde and 3-Indolylacetone
J. B. Brown, H. B. Henbest, and E. R. H. Jones

J. Chem. Soc. 3172-3175 (1952)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/3-indolylacetone.pdf)

Abstract
3-Indolylacetaldehyde (I), the aldehyde corresponding with heteroauxin, which has been claimed to have been detected in some plant sources, has been prepared for the first time, and has been fully characterized. The related 3-indolylacetone (VI) has also been prepared.


Offline sophie7

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Re: Indole Grignards
« Reply #24 on: January 29, 2017, 03:55:41 PM »
Is 4 benzyloxy indole useless?
The creating to make start from 2benzyloxy 6 nitrotoluene condensated with tpm(piperidine+triethyl ortho formate),j.org.chem . or tris nn dimethylamino methane 1.5 eq with heat 110C and under vacum  aspirator ,for 4Hours yield  B piperidine o nitrostyrine
The crude nitrostyryne disolved in minimal amt asceton and 6,2 eq of 20% soln Ticl3 and twice the vol of that  Ticl3 of 4M ammacetatete buffer
Mix  for at least 10minutes and extracted several times with diethyl ether, this also can be do for another ,chloro and another benzyloxy ,methoxy,cyano from voresponding o-nitrotoluene if had any chance or maybe some better than its describe, (more friendly) i think this not too friendly using any nn tris chemcal.  But why not , , around 62 % yield


« Last Edit: January 29, 2017, 04:36:45 PM by sophie7 »
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Offline Tsathoggua

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Re: Indole Grignards
« Reply #25 on: February 05, 2017, 04:46:59 AM »
If the corresponding n,n-dimethyltryptamine were the intended target, it could serve as a precursor for psilocin, methinks, via catalytic removal of the benzyl group to give psilocin, and subsequent esterification would be a good idea, due to the instability of 4-OH tryptamines.
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Offline Beard

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Re: Indole Grignards
« Reply #26 on: February 15, 2017, 06:14:27 PM »
If the corresponding n,n-dimethyltryptamine were the intended target, it could serve as a precursor for psilocin, methinks, via catalytic removal of the benzyl group to give psilocin, and subsequent esterification would be a good idea, due to the instability of 4-OH tryptamines.


David E. Nichols does exactly ALL of that starting with 4-benzoyloxy-indole (and goes directly from 4-benzoyloxy-DMT -> 4-Acetoxy-DMT) here: https://www.erowid.org/archive/rhodium/pdf/nichols/nichols-psilocin.pdf
« Last Edit: February 15, 2017, 06:19:19 PM by Beard »