05-07-03 13:58
No 431982
      Article on DMT derivate synths
(Rated as: excellent)

Tetrahedron, 2001, 57, 1041-1048

The authors of this article prepare some N,N-Dimethyl-5-substituted-tryptamines via an interesting route.

There are two interesting parts:

a) The methylation of a 5-substituted tryptamine to a 5-substituted DMT with HCHO (formaldehyde) and NaBH4 (sodium borhydride) (according to the authors "following standard procedures"). The only difference to DMT itself is the CH2SO2N(cyclopropyl) in 5 position.

3-[(2-Dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl) indole (9b).
A solution of 35% formaldehyde (35 mL, 416 mmol) in MeOH (35 mL) and a solution of NaBH4 (5 g, 132 mmol) in H2O (70 mL) were added dropwise, simultaneously, at 15C to a well-stirred solution of tryptamine 8 (8.1 g, 26 mmol) in MeOH (150 mL). The mixture was stirred at 15C for 0.5 h, 2N aqueous HCl was cautiously added to bring the pH to 3, and the resulting mixture was stirred for 10 min. Then, the pH was adjusted to 6.5-7 with saturated aqueous NaHCO3, MeOH was evaporated, and H2O (50 mL) was added. The mixture was washed with EtOAc (2x150 mL), basified with K2CO3, and extracted with EtOAc (2x130 mL). The organic extracts were dried, filtered, and concentrated to give 9b4 (7.70 g, 88%) as a brown solid.

[4] Fernandez, M.-D.; Puig, C.; Crespo, M.-I.; Moragues, J. Patent ES2084560, 1994; Chem Abstr. 1996, 125, 221573.

They use simple NaBH4, no expensive derivate like NaBH3CN. The 5-substitution seems not to influence the reaction in anyway.

The corresponding beta-carboline is synthesized by Pictet-Spengler reaction:

2-Methyl-6-(1-pyrrolidinylsulfonylmethyl)-1,2,3,4-tetrahydro-b-carboline (11b).
A solution of tryptamine 8 (4 g, 13 mmol) in 35% HCHO (5 mL) and AcOH (18 mL) was refluxed for 6 h. After cooling to rt, saturated aqueous Na2CO3 was added, and the mixture was extracted with 95:5 CH2Cl2-MeOH. The residue was dissolved in THF (20 mL) and saturated aqueous Na2CO3 (20 mL). After stirring at rt overnight, the mixture was extracted with CH2Cl2 (2x30 mL). The organic extracts were washed with H2O (2x20 mL), dried, ltered, and concentrated to give beta-carboline 11b as a yellow oil (3.60 g, 87%). The oxalate precipitated on treating a solution of the base in EtOH with oxalic acid in EtOH; mp decomposed above 145C.

b) Another interesting point of this article is the synthesis of the indole core. The Fischer-Indole synthesis uses substituted phenylhydrazines as the key starting material. Unfortunately phenylhydrazines are not OTC, they are quite toxic and presumably carcinogenic. But the method presented offers an OTC route. An unsubstituted or 4-substituted aniline (anilines can be prepared from the corresponding benzoic acids, Post 431119 (Lego: "Aromatic carboxylic acids to anilines", Novel Discourse), for 4-hydroxyaniline one might use 4-hydroxybenzoates which are incredible cheap and commonly used as preservatives), convert it to the diazonium salt with NaNO2 ( ( and then reduce it to the phenylhydrazine with SnCl2 (Post 355617 (Mountain_Girl: "Prep of anhydrous SnCl2 & SnCl2.H2O", Chemistry Discourse)). The phenylhydrazine is then reacted with 4-chlorobutanal diethyl acetal to tryptamine or more elegant with 4-(N,N-dialkylamino)butanal diethyl acetal to the N,N-dialkylated tryptamine.

3-(2-Aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-indole (8)
A solution of NaNO2 (1.36 g, 19.7 mmol) in H2O (8 mL) was added dropwise at -20C to a suspension of aniline 618 (3.5 g, 14.6 mmol) in 35% aqueous HCl (30 mL). The mixture was stirred at -20C for 15 min and then was added at -20C to a solution of SnCl2 2H2O (16.46 g, 73 mmol) in 35% aqueous HCl (12 mL). After stirring at -20C for 25 min and at -5C for another 25 min period, the precipitated hydrazine 7 hydrochloride was collected by filtration and successively washed with cool H2O and Et2O (3.06 g, 82%). A solution of 4-chlorobutyraldehyde diethyl acetal 17 (21.8 g, 120.5 mmol) in 35% aqueous HCl (5.3 mL) and H2O (270 mL) was stirred at rt for 1 h and added to a solution of hydrazine 7 (28.0 g, 109.6 mmol) in 35% aqueous HCl (9.8 mL), H2O (65 mL), and MeOH (300 mL). The mixture was stirred at rt for 1 h and cooled to 0C. The precipitated yellow solid was collected by filtration and successively washed with 9:1 H2O-MeOH (150 mL) and cool H2O (300 mL) to afford the intermediate hydrazone hydrochloride as an  range solid. A solution of this hydrazone and Na2HPO4 (12.4 g, 69.6 mmol) in H2O (70 mL), MeOH (450 mL), and 35% aqueous HCl (9.8 mL) was refluxed overnight. MeOH was evaporated, H2O (300 mL) was added to the mixture, and the pH was adjusted to 6.5-7 with solid Na2CO3. The aqueous solution was washed with CH2Cl2 (2x300 mL) and then saturated with Na2CO3, extracted with CH2Cl2 (3x200 mL), dried, filtered, and concentrated to give 8 (19.6 g, 58%) as a brown solid.

[12] (a) Hydrazine 13 was prepared from aniline 1212b by diazotization followed by reduction of the resulting diazonium salt with SnCl2 (78% overall yield). (b) Wyrick, S. D.; Hall, I. H.; Dubey, A. J. Pharm. Sci. 1984, 73, 374-377.
[17] Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 1365-1366.
[18] Sulfonamides 6 and 14 were prepared from (p-nitrophenyl)-methanesulfonyl chloride, following the procedure reported12b for the preparation of 12, but using pyrrolidine or tert-butylamine instead of NH3.


Molecule: 6 ("c1cc(ccc1N)CS(=O)(=O)N2CCCC2")


Molecule: 7 ("c1cc(ccc1NN)CS(=O)(=O)N2CCCC2")


Molecule: 8 ("c21cc(ccc2ncc1CCN)CS(=O)(=O)N3CCCC3")


Molecule: 9b ("c21cc(ccc2ncc1CCN(C)C)CS(=O)(=O)N3CCCC3")


Molecule: 11b ("c31cc(ccc3nc2c1CCN(C2)C)CS(=O)(=O)N4CCCC4")

The candle that burns twice as bright burns half as long
(Hive Addict)
05-08-03 07:57
No 432152
      Great find,i've been always wondering if ...     

Great find,i've been always wondering if tryptamine could also be methylated with HCHO/NaBH4.NaBH3CN is very expensive...

For those about to synth,we salute you
(Official Hive Translator)
05-10-03 09:50
No 432491

Isn't aniline__>Ph-diazonium__>Ph-hydrazine (very simple, one-pot, bisulfite as a reducing agent) a known process at The Hive???

Will post upon request.

05-10-03 11:16
No 432505
      Yes! Please do so     

Lego did a quick search:
TFSE was fed with:
(NH2 or amine) and (NHNH2 or hydrazine)

It was briefly mentioned by PrimoPyro in Post 362349 (PrimoPyro: "More Kickass Reactions", Chemistry Discourse):

yes there is a much easier way to prepare phenylhydrazines from anilines than the guess I had written above utilizing carbamic acid. Page 1556 of March's 5th cites a simple reaction between a diazonium salt and sodium sulfite.

Antoncho: Could you please a more detailed procedure as Lego was unable to find it?

The candle that burns twice as bright burns half as long
(Hive Bee)
05-10-03 13:41
No 432526
      Yes, post     

Yes antoncho, post it please, if it is not one of those: ../rhodium/chemistry /phenylhydrazine.html

If you have one synth from nitrobenzene too i would bee happy to read it!

And the synth of 4-MeO-phenylhydrazine at rhodium's is not that good, if you have another, more high yielding and/or easy and/or which does not use stannous chloride i would like too know it too.

06-27-03 05:42
No 442894
      Standart method & some troubles     

I've reproduced the method from Tetrahedron, 2001, 57, 1041-1048 using unsubstituted tryptamine. But I've got brown resin on my stirrig rod which hadn't dissolve after addition of HCl (yield ~50-55%). I've tried to recristalize it from boiling hexane (such method is recommended in different sources), but it's amounts were really great
madfrown! Then I dissolved the product in DMFA & reprecipitate by acetone. The final pure DMT was OK (by NMR), but yield was less then 15%frown.. Can anyone help my with a piece of advise? Did anyone use such method? HELP!!!shocked

Unknown Chemist
06-27-03 06:10
No 442902
      How closely did you follow that procedure...     

How closely did you follow that procedure (mode of addition, temperature, times...)?
06-27-03 07:08
No 442917

I followed the method carefully, but instead of 15'C I allowed it up to 20'C. All propotions & time were the same. And did you use this procedure?
06-27-03 08:31
No 442931
      The paper doesn't tell us how fast to add the...     

The paper doesn't tell us how fast to add the reagents (just 'dropwise'), there might be a difference between 15C and RT, and there might be an effect of the substituent. There is only one way to find out... smile Did you monitor the reaction by TLC? Is there a 'main byproduct'?
06-28-03 01:08
No 443082
      I didn't control the reaction by TLC.     

I didn't control the reaction by TLC. As for product, I did. There was an unknown by-product in trace amounts (so I saw it in NMR (H'). And as for speed of dropwising, it was 1 drop per 3 seconds (and I saw that NaBH4 was decomposing in the drop-funnelfrown
06-28-03 14:56
No 443167
      Comments from the peanut gallery     

First off, thank you so much BadMan. As far as I know youre the first to report a go at this.

Well Im no expert (but that wont stop me) if I was to try this reaction I would keep the two addition solutions as cold as possible (at least as cold as 15 C) especially the NaBH4 solution. Then I would start to vary the addition rates of the solutions. I would for surely keep the reaction at no more than 15 C.

Gosh, I sure hope that the sub at the 5 position is not so responsible for the lovely yields.

BTW, any bee ever play with a tryptophan decarb via microwave? Any thoughts even? Any bee have any comments regarding their favorite OTC decarb?

Best of luck BadMan
(Chief Bee)
06-28-03 15:54
No 443172

I suggest that you do the additions with the reaction flask situated in an ice-bath (making the internal temperature 0-5C) and then add the solutions dropwise (and even slower if the temperature get closer to 10C than 5C), then keep the solution at 0-5C for another 30 min, and first then allow the temperature to rise to 15C or so and keep it there for 30-60 min.

For the purification, try the workup described in Post 435056 (Rhodium: "DMT from Tryptamine/NaBH3CN/37% HCHO", Tryptamine Chemistry) - it's an easy separation, and you will easily be able to get a product which is crystallizable from hexane.
07-01-03 07:31
No 443788
      About Rhodium's suggestion     

I see... may be it was the point, not mentioned in the article, but very important in syn(temperature control).
About solvents & recristallization: 1)I've no opportunity for use of flash chromatography frown2)hexane (petroleum ether), ethyl acetate (EtOAc) or am mixture of both--too pore solubility...

laughI'm going to try another way: 3-indolylacetic acid-[1]---(carbodiimidazol+HNEt2)->3-indolylacetamide-[2]-(NaBH4+AlCl3)--> DMT
[1]well-known Staabe reaction
1st step is over, but NMR is not yet...
(Chief Bee)
07-01-03 14:47
No 443845
      DMT recrystallization     

I would myself recommend petroleum ether (the fraction with bp 60-90C, it might as you say have too low solubility in the 30-60C fraction) - others like EtOAc better though, KrZ for example, but I think you will need to concentrate the filtrate and chill that to be able to recover all of your product using that solvent.
(Chief Bee)
07-09-03 17:40
No 445987
      EtOAc is apparently no good     

I take that statement about EtOAc back, I know the amine is soluble in it, but it is apparently a lousy crystallization solvent: Post 270917 (Lilienthal: "Re: DMT synthesis 3", Tryptamine Chemistry)
(Hive Bee)
07-12-04 14:53
No 518988
      In defense of HCHO/NaBH4
(Rated as: excellent)

DMT may bee synthesized by dozens of methods1 but the the N,N-dimethylation of tryptamine with HCHO2 is still a very interesting method as all compounds are either commercial available or can be prepared with OTC methods. The reduction agent of choice is Na[BH3CN] (sodium cyanoborohydride) but this reagent is toxic and therefore quite difficult to purchase for many bees and about 5 times more expensive than NaBH4 (sodium borohydride).
As the first step of the methylation is the formation of an imine between formaldehyde and tryptamine it is essential that this intermediate is reduced as soon as possible, otherwise it will form a form cyclization product in the so-called Pictet-Spengler reaction. Essential for the formation of the Pictet-Spengler product is the pH of the reaction, usually the Pictet-Spengler is carried in a acidic medium, either by using the hydrochloride salt of the tryptamine, by addition of lewis acids or protic acids3. Another important reaction condition is the temperature. The Pictet-Spengler product is favored by heating, the dimethylation is carried at room temperature or below. Also two competing reductions take place in this reaction, on the one hand the wanted reduction of the imine and on the other hand the reduction of formaldehyde to methanol, therefore first the imine has to bee formed which has to bee reduced immediately, this is why usually the the reagents are added alternately.
This parameter (not the temperature but the pH) seems to bee neglected when this reaction is discussed. This might explain the poor yields obtained when trying this method4.
As many N,N-dimethylated tryptamines are important pharmaceutical drugs for the treatment of migraine (the so-called triptanes) it was interesting to see how they are synthesized. Sumatriptan for example is synthesized on a industrial scale by the dimethylation of a 5-substituted tryptamine with HCHO/NaBH4. Lego had the possibility to talk to a person who is quite experienced in the field of indoles and harmalines and it became clear that the main product depends on carefully selecting the right reaction conditions.

Here are some examples, either from the patent literature or from the scientific literature, in order to show that this method is still worth trying it.

Patent WO0134561

More preferably the reducing agent is present in the range of 0.75-3 molar equivalents with respect to the compound of formula V [tryptamine derivative].
Most preferably the formaldehyde equivalent is formaldehyde as an aqeuous solution.
More preferably the formaldehyde equivalent is present in the range of 1.9-5 molar equivalents with respect to the compound of formula V [tryptamine derivative].

Suitably the buffer used keeps the pH of the reaction solution between pH 6 and pH 14. Preferably the buffer keeps the pH of the reaction solution between pH 7 and pH 11. More preferably the buffer keeps the pH of the raction between pH 8 and pH 10. Most preferably the buffer is sodium hydrogenphosphate.

Suitably the buffer is present in the range of 0.1-10 molar equivalents with respect to the compound of formula V [tryptamine derivative]. Preferably the buffer is present in the range of 0.2-5 molar equivalents with respect to the compound of formula V [tryptamine derivative]. Most preferably the buffer is present in the range of 0.5-3 molar equivalents with respect to the compound of formula V
[tryptamine derivative].

Example 5
3-(2-aminoethyl)-N-1H-indole-5-methanesulphoneamide (5.0 g, 18.7 mmol), prepared by the method of Example 1, and sodium hydrogenphosphate (5.0 g, 35.2 mmol) were heated to 40C in methanol (50 ml) for 15 minutes and then recooled to room temperature. Solutions of 37% aqueous formaldehyde (5 ml) and sodium borohydride (0.72 g) in water (5 ml stabilised with one drop of 46/48% w/w sodium hydroxide) were added simultaneously over one hour at a room temperature between 17 and 21C. The mixture was stirred at room temperature for a further 0.5 hours, then filtered and the filter bed wasehd with methanol (10 ml). The combined filtrates were then adjusted to pH 6 by addition of 4M hydrochloric acid, concentrated under reduced pressure (to approximately 20 g) and acidified to pH with more 4M hydrochlorid acid. Ethyl acetate (30 ml) was added and the potassium carbonate was added to give a pH about 11 and the product extracted in a seperating funnel. The aqueous layer was further extracted with ethyl acetate (30 ml) and the combined organic layers dried over sodium sulphate, filtered and concentrated to give sumatriptan free base (4.7 g, 85%, HPLC showed 87% compound).
This material was of suitable quality for conversion into sumatriptan mono-succinate or sumatriptan hemisulphate as described in Patent GB2162522 and Patent EP490689 respectively.

Similiar reaction without buffering the reaction:

Synthesis of carbon-14 labelled indolic 5HT1 receptor agonists
Ian Waterhouse, Karl M. Cable, Ian Fellows, Mark D. Wipperman, Derek R. Sutherland
J. Labelled Compd. Radiopharm., 1996, 38(11), 1021-1030

The solid [1.674 mmol of C-14-labeled sumatriptane freebase, 10b] was dissolved in methanol (25 ml) at 0. Solutions of sodium borohydride (284 mg, 7.5 mmol) in water (1.7 ml) and of formaldehyde (37% aqueous solution, 2.20 ml, 27 mmol) in methanol (1.93 ml) were prepared. An aliquot (180 l) of the sodium borohydride solution was added to the solution of 10b in methanol every 4 min, followed each time by an aliquot (410 l) of the formaldehyde solution. When the additions were complete the reaction was stirred at <5 for 1 h. Sodium borohydride (30 mg, 0.79 mmol) and then 5N hydrochloric acid (3.2 ml) were added and the mixture stirred for 5 min then concentrated under reduced pressure to a volume of 10 ml. Water (45 ml) and 2N hydrochlorid acid (25 ml) were then added and the solution stirred for a a further 10 min. The solution was saturated with solid potassium carbonate and the product extracted into methyl isobutyl ketone (4 x 60 ml). The methyl isobutyl ketone solution was decolourised with charcoal and evaporated under reduced pressure to a volume of 5 ml, cooled to 0 and ether (10 ml) was added. After storing at 0 for 30 min, the resulting solid was recovered by filtration and crystallised from isopropanol-water to give sumatriptan free base (172 mg, 35%).

1. See for example:
Classical synthesis by reaction of oxalyl chloride on indole, dialkylamide formation and reduction with LAH:
../rhodium/chemistry /dmt.det.html
By Fischer indol synthesis:
../rhodium/chemistry /dmten.html
By alkylation of indole grignards with 2-(dimethylamino)-ethyl chloride:
../rhodium/chemistry /dmt.indole.grignard.html
2. Post 431982 (Lego: "Article on DMT derivate synths", Tryptamine Chemistry)
3. See for example Post 419132 (pashov: "Different reducing agents", Newbee Forum) and Post 431982 (Lego: "Article on DMT derivate synths", Tryptamine Chemistry) for a practical example
4. Post 442894 (BadMad: "Standart method & some troubles", Tryptamine Chemistry)

The tendency is to push it as far as you can