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Author: Subject: DMT via tryptamine and NaBH4

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[*] posted on 24-6-2017 at 17:53
DMT via tryptamine and NaBH4


I just found this interesting method for synthesis DMT by using tryptamine and NaBH4 as a starting material. Usually NaBHCN is used as reducing agent.

So did anyone this route successfully?

Successful synthesis, reduced yields.
(Rated as: pretending illegal activity)

The synthesis outlined in the message 'NaBH4 in water' was attempted as follows (1/4 scale):

A solution of 37% formaldehyde in H2O (8.6 mL, 104 mmol) in MeOH (9.5 mL) and a solution of NaBH4 (1.25 g, 33 mmol) in H2O (17.5 mL) were added dropwise, simultaneously, at 15°C to a well-stirred solution of tryptamine (1.06 g, 6.5 mmol) in MeOH (37.5 mL). The mixture was stirred at 15°C for 0.5 h, 6N aqueous HCl was cautiously added to bring the pH to 3.02, 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 on the rotovap, and H2O (12 mL) was added. The mixture was washed with EtOAc (2x37.5 mL), basified to pH 10.4 with K2CO3, and extracted with EtOAc (2x32.5 mL). The organic extracts were dried, over K2CO3, vacuum filtered, and EtOAc evaporated to give DMT. Products were obtained in (1) 0.46 g (2.44 mmol 37.6 % yield) and (2) 0.58 g (3 mmol, 46% yield).

Results: The entire process was completed twice, T1 and T2. Two differences existed between these trials. In T1 the simultaneous addition of NaBH4 and formaldehyde was rapid (ca. 2 minutes), whereas in T2 the addition took at least 7 minutes. In T1 the rotovap step was minimised to 45 minutes, whereas in T2 it was 1.5 hours.
The T1 product was crystalline, whereas the T2 product was an oil that solidified upon freezing and repeated collection with a razor in the evaporating dish. Both products were analyzed with GC-MS. Positive identification of the N,N-DMT product was established by comparing the spectrum with a reference from Molecular ion peak is present at 188 m/z, with the largest peak at 58 m/z. The T1 product was 99.0% pure (by integration), whereas the T2 product was 91.6% pure. The T2 sumultaneous addition of reagents was executed with more precision than the T1, so it is probable that the longer rotovap time was responsible for the lower purity.
The T1 product was, in addition, analyzed with 1H NMR, in d-acetone, 300 MHz. The indole region from 7-9 ppm was unchanged from the tryptamine starting material. However, the production of N,N-DMT was supported by appearance of two triplets between 2 and 3 ppm (corresponding to the CH2) and a singlet at slightly under 2 ppm (corresponding to the double methylation). Integration of the singlet was 6 units, and each triplet 2 units.
This procedure shows promise...good yield can be obtained (46%) even in sub-optimal conditions. Furthermore, reagents are easy to obtain, and are inexpensive.
Some developments might include finding a way to avoid the rotovap step, since this appears to have an adverse effect on product purity. Instead of dissolving the tryptamine in MeOH, H2O will be used as solvent in a future trial. It is interesting to note that the original paper

Tetrahedron 57(6), 1041-1048 (2001)

reports yields of 80-90%. The difference between that procedure and this present one is a large sulfur-containing group at the 4-position on the benzene ring. Could this have activating effects that are not seen when the ring is unsubstituted?

Maybe the best conclusion to make from this venture is that individuals could do well to give up the difficult and time-consuming bromination/methylation/reduction procedures (eg. NaBH4 reduction of Keto-DMT thread), if the goal is production and not chemistry games. This procedure takes a total of 3.5 hours, does not depend on dry solvents, uses only one nasty reagent (formaldehyde), and costs very little. If the trial with water as solvent instead of methanol is successful, then 45 minutes will be taken off preparation time, and the rotovap step will be avoided. Product purity is generally high. But even when compromised (91.6%), the contaminants were identfied as N-methyltryptamine and unreacted tryptamine, so there is low potential for toxic byproducts or retention of formaldehyde.
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National Hazard

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[*] posted on 25-6-2017 at 11:34

Looks a lot like the Eschweiler-Clarke, only using HCl instead of HCOOH. I'm dubious about this at best. Although if its been done and reported in a respectable journal with proper analysis my skepticism will have to take a back seat.

Its just that its been well known for quite some time that the Eschweiler-Clarke won't work on tryptamine because the primary reaction is toward formation of an unwanted side-product, cyclization to the corresponding beta-carboline.

Now. Keto-DMT. Is this beta-keto-DMT being spoken of? that would be a curious one to bioassay indeed, to compare the tryptamine and cathinone pharmacophores.

IIRC, it might not have the expected activity. Or at least, it might have some rather unexpected properties. I recall reading that some of the indoleglyoxylamides were GABAa agonists (probably meaning positive allosteric modulator, given the relatively restrictive requirements structurally for a muscimol-like orthosteric agonist.
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