(Chief Bee)
11-07-02 20:12
No 377548
      Solid-Phase Synthesis of 5-MeO-DMT (or DMT)
(Rated as: excellent)

Solid-Phase Synthesis of 5-MeO-DMT (or DMT) [1]

Our approach starts with the synthesis of different tryptamine scaffolds (Scheme 1) in three facile steps using previously reported protocols [2]. Commercially available indoles 1 were reacted with oxalyl chloride in refluxing ether. The resulting indole oxalyl chlorides were filtered and treated with ammonia in dioxane to give the corresponding indole oxalyl amides. These were again filtered and reduced to the corresponding tryptamines using lithium aluminum hydride in refluxing THF. After aqueous workup, the crude tryptamines were directly mixed with vinylsulfonylmethyl polystyrene resin (Novabiochem) [3]. This also served as a purification step, as only the fully reduced tryptamines were captured onto the resin. Activation of the safety catch linker can be achieved by treatment with excess methyl iodide to form the quaternary ammonium salt, though other alkylating agents have been used in the past [3]. A Hoffman elimination using N,N-diisopropylethylamine releases the N,N-dimethyltryptamine from the resin. The yield of the cleaved products ranged from 10% to 20% overall, based on the resin-loading level. A variety of commercially available indoles with either electron-donating or electron-withdrawing functional groups on the benzo ring as well as alkyl and aryl groups at the C-2 position are compatible with this scheme.

5-MeO-indole -> 5-MeO-indolyl-3-oxalyl chloride -> 5-MeO-indolyl-3-oxalylamide -> 5-MeO-Tryptamine [1]

5-Methoxyindole (1.0 g, 6.8 mmol) was suspended in ether (25 mL) and treated with oxalyl chloride (1.78 mL, 20.4 mmol) and stirred at reflux for 6h. The reaction was cooled to ambient temperature and the solids were filtered. The solids were treated with 0.5 M ammonia in dioxane (25 mL) and stirred at ambient temperature for 8h. The solids were filtered, suspended in THF and treated with lithium aluminum hydride (1.3 g, 34 mmol) followed by heating at reflux for 8h. The reaction was cooled to ambient temperature followed by slow addition of 1 mL 3N KOH, 2 mL H2O, and then 3 mL 3N KOH sequentially. The reaction mixture was stirred at ambient temperature for 1h. The salts were filtered and the organic layer was removed. The aqueous layer was extracted with EtOAc and the combined organic layers were evaporated in vacuo (weight of crude = 1.44 g).

5-MeO-Tryptamine -> (resin-bound) 5-MeO-Tryptamine [1]

Crude 5-methoxytryptamine was dissolved in DMF (35 mL) and added to 1.8 g vinylsulfonylmethyl polystyrene resin (2 mmol, 1.12 mmol/g) with stirring at ambient temperature for 16h. The resin was then washed with 10 mL of CH2Cl2, DMF, H2O, and MeOH. The washing procedure was repeated four times and the resin was dried overnight in vacuo.

(resin-bound) 5-MeO-Tryptamine -> 5-MeO-DMT [1]

Resin-bound 5-MeO-tryptamine (150 mg, 0.15 mmol, ~1 mmol/g) was then suspended in DMF (2.0 mL), treated with MeI (96µL 1.5mmol) and agitated at ambient temperature for 8h. The resin was then washed with 10 mL of CH2Cl2, DMF, H2O, and MeOH four times. The resin was again suspended in DCM (2.0 mL), treated with diisopropylethylamine (392 µL, 2.25 mmol) and agitated at ambient temperature for 24h. The resin was filtered and washed with 1 mL DCM twice. The filtrate and washings were concentrated in vacuo to give the product 5-MeO-N,N-dimethyltryptamine in 88% yield.

[1]: Organic Letters 4 (23), 4033-4036 (2002)
../rhodium/pdf /dmt.synthesis.solid-phase.article.pdf
../rhodium/pdf /dmt.synthesis.solid-phase.data.pdf
[2]: Bioorg. Med. Chem. Lett. 10, 1707-1709 (2000)
../rhodium/pdf /dmt.synthesis.solid-phase.resin1.pdf
[3]: Tetrahedron Lett. 38, 8573-8576 (1997)
../rhodium/pdf /dmt.synthesis.solid-phase.resin2.pdf
(Hive Bee)
11-11-02 07:54
No 378707
      You deserve a Noble price (If it works)  Bookmark   

You deserve a Noble price (If it works)
(Hive Bee)
11-11-02 10:46
No 378738
      Merrifield won the nobel prize for his work on ...  Bookmark   

Merrifield won the nobel prize for his work on the solid phase synthesis of peptides.

What about a nobel prize for the solid phase synthesis of DMT? smile

This is indeed a very elegant procedure for the dimethylation of DMT.  Nice work.  The main advantage of a solid phase synthesis is that the workup is very simple.  You can use a large excess of reagents to drive the reaction to completion & all the junk can simply be washed away when you filter the end product that is bound to the beads.  Then cleave the product off the beads and voilŕ, you 've got the pure product.

Flipper, since the procedures are taken from literature, you can bet it will work.
(Hive Bee)
11-11-02 13:23
No 378764
      could diisopropylethylamine be synthesised from ...  Bookmark   

could diisopropylethylamine be synthesised from ethyliodide and acetone? or similarly simple rxn?
(Chief Bee)
11-11-02 13:37
No 378771
      Modifications for atom economy?  Bookmark   

If we would want to perform the synthesis without the use of a resin, what would we use instead?  Nothing - just exhaustive methylation?

What is the mechanism behind the i-PrNEt2 dealkylation of the ethylsulfonyl group? Would i-PrNEt2 remove any alkyl group from a quaternary amine, or is it a special thing with ethylsulfonyls (perhaps re-forming the vinyl unit somehow?)?
(Hive Bee)
11-11-02 15:45
No 378812
      Mechanism  Bookmark   

What is the mechanism behind the i-PrNEt2 dealkylation of the ethylsulfonyl group? Would i-PrNEt2 remove any alkyl group from a quaternary amine, or is it a special thing with ethylsulfonyls (perhaps re-forming the vinyl unit somehow?)?

This is a typical case of the Hofmann elimination.
One has a R3N+-CH2-CH2-SO2-resin structure.  The SO2 is a strong electron withdrawing group, so the hydrogens of the methylene in the alpha position are acidic.  The strong, sterically hindred base will grab a blue proton and the free electron pair will expell the NR3 while forming a vinyl type compound.  So indeed, this reaction is quite general and will work for every quaternary ammonium salt.

From a theoretical point of view, the resin can be reused since the cleavage will regenerate the original resin.  Isn't this nice.  Up and ready for the following Michael type addition of another tryptamine smile.

My guess it that one could use just as well triethylamine for the cleavage.  Monkpea, one does not make DIEA from scratch.  It is a commonly used organic base.  Just buy it!

"If I mix CH2 with NH4 and boil the atoms in osmotic fog, I should get speckled nitrogen!"  Donald Duck is talking chemical talk, but he knows nothing ... about chemicals.
(Chief Bee)
11-24-02 12:49
No 382894
      what about acrylates?  Bookmark   

The vinylsulfonyl resin used in the article in the beginning of this thread is upon a second glance prohibitively expensive (as are all vinyl- and haloalkyl-sulfonates), so we need to find another easily removed "protecting group". Shopping around for other agents that could be used for alkylating tryptamine, I found http://www.mimotopes.com/files/pdf/ChemNote16.pdf where an OH-resin is acylated  with acryloyl chloride, to give a resin-bound acrylic ester, which is used exactly as the vinylsulfonic resin above.

If the reaction works all right with acrylates, then perhaps we could make it all even cheaper by skipping the solid support altogether? Reflux tryptamine in methanol with ethyl acrylate to give the michael addition product N-carbethoxyethyl-tryptamine, which is exhaustively methylated with either methyl iodide or dimethyl sulfate in the ordinary fashion, followed by elimination of ethyl acrylate by reacting the quaternary salt with diisopropylethylamine.

Any obstacles I'm overlooking here?
(Hive Bee)
11-24-02 14:50
No 382931
      Use methyl acrylate  Bookmark   

I see no problem whatsoever.  Refluxing a methanolic solution of tryptamine with 1 eq. of methyl acrylate will give the condensation product alright.

However, I 've an important remark: use methyl acrylate.  Ethyl acrylate is a carcinogen!

The workup in the solution synthesis will be a bit more difficult (in comparison with the resin) ... but hey, there 's no free ride smile.  However, if I were to perform the synthesis, I 'd chose the acrylated resin - if it can be bought as such (although not carcinogenic, methyl acrylate is a nasty compound in its own right).
(Chief Bee)
11-24-02 15:37
No 382948
      Yes, but the vinyl sulfone resin is €60/g from ...  Bookmark   

Yes, but the vinyl sulfone resin is €60/g from Acros... And I did a literature search on the synthesis of vinylsulfones, and you have to alkylate a thiol with 1,2-dichloroethane or oxirane, followed by oxidation of the sulfur with H2O2 and then a base-catalyzed elimination to form the alkene. Too much work.
(Hive Bee)
11-24-02 15:50
No 382950
      And how much costs an acrylated resin such as the ...  Bookmark   

And how much costs an acrylated resin such as the one described in  http://www.mimotopes.com/files/pdf/ChemNote16.pdf ?

I bet it will be cheaper.  I hope it can be bought in the acrylated state ... I 'd pass if it comes to playing with acryloyl chloride ...
(Chief Bee)
05-11-03 11:51
No 432659
      Here is cheaper solid-phase synthesis of amines
(Rated as: excellent)

Soluble Polymer-Supported Synthesis of Tertiary Amines


The synthesis of tertiary amines on a modified soluble polymer, poly(ethylene glycol) (PEG), is described. The PEG-bound quaternary intermediates were assembled via Michael addition reaction, followed by alkylation. Cleavage from the soluble polymer support was induced by insoluble weak basic resin, to afford the target tertiary amines in excellent purity.

Syn. Comm. 33(5), 729–734 (2003) (../rhodium/pdf /peg-supported.tertiary.amine.synthesis.pdf)
07-03-03 08:12
No 444241
      Synthetic approaches towards indoles on solid phas
(Rated as: excellent)

In Tetrahedron 59 (2003) 5395–5405 (http://www.angelfire.lycos.com/scifi2/lego/journals/13.pdf) a review on synthetic approaches towards indoles on solid phase is presented.


Indoles or molecules containing the indole moiety have efficiently been synthesised for more than 100 years in solution. The first preparation of indole dates from 1866 and the Fischer indole synthesis was introduced as the most versatile method for preparing indoles in 1883. Efficient preparation on solid phase, however, dates back only about 10 years.

Although most of the published papers have focused on synthetic methods developed for the addition or modification of substituents on the indole ring, a few very efficient methods for the preparation of indoles from benzenoid precursors have been introduced on solid phase. Most of these methods are palladium-catalysed cyclisations, but a few examples describe the indole synthesis through other cyclisation methods such as the Fischer indole synthesis, Madelung synthesis, the intramolecular Wittig reaction or the solid-phase Nenitzescu indole synthesis. Furthermore, a few miscellaneous cyclisations leading to indoles or structurally related compounds have been performed on solid phase.

The addition or modification of substituents on the indole ring, on the other hand, includes functional group transformations and direct functionalisations adopted to solid-phase organic synthesis.

This part covers only circumstances where readily adorned indole cores have been attached to a solid support and the ring system has been modified. Occasions where indoles have been used as a part of the linker system are not included. This report summarises the literature published until July 2002 describing methods for either the preparation of the indole moiety or the modification of the indole core on a variety of polymer-supported resins. Further details of the experimental conditions are available from the primary literature references. All of the publications cited are from refereed journals and not from patents.

A search in Chemical Abstracts, using the keyword ‘indole’ combined with other keywords such as ‘solid-phase synthesis’, ‘combinatorial chemistry’ and ‘solid support’,  has been performed to ensure that most of the references on the subject have been covered.

The candle that burns twice as bright burns half as long