Begin Write-up: 5.95 g (26.25 mmol) of 5-MeO-Tryptamine HCL was added to a 3-neck round bottom flask with a thermocouple inserted into the middle neck, and dissolved in 150 mL MeOH. Crushed KOH pellets were added to convert the tryptamine salt to the freebase form (pH ~9). MeOH and dry ice were placed in a bath below the flask, and the mixture was allowed to cool to between -15 and -20 degrees Celsius. 5.0 g NaBH4 (132.15 mmol) was dissolved in 12.5 mL of a 3% aqueous KOH solution and placed in the freezer to cool to below 15 degrees Celsius. A second solution of 37% aqueous formaldehyde stabilized by 12% methanol was placed in the freezer to cool below 15 degrees.
Once cooled, both solutions were added to addition funnels and the dropwise addition of both solutions began. Due to stoichiometric and mechanistic concerns, the formaldehyde solution was added at twice the rate of the borohydride solution (See my previous post for helpful comments explaining why this is). The temperature of the reaction during this addition should be monitored closely, as the formation and subsequent reduction of the imine is an exothermic process. After both additions were complete, the reaction mixture was allowed to continue stirring, with additional dry ice and methanol added to the bath containing the reaction flask to maintain reaction temperatures between -15 and -20 degrees. In the snippet of his show, I believe Hamilton says to just below 0 degrees, and this initially confused me, but I cannot stress enough that this reaction should be kept below -15. Just trust me. Your yield and reaction specificity is greatly aided by the reduced temperature.
The reaction was periodically monitored by TLC, by removing an aliquot of the reaction mixture, adding a small amount of water, and then extracting this aliquot with a small amount of ether, and then spotting the ether layer against 5-MeO-Tryptamine freebase. This was originally one of my main gripes with the original synthesis, as the solvent system used in the show produced non-ideal separation which caused me to quench my reaction prematurely the first time this reaction was running. From previous experience, I know that 8:2 CHCl3/MeOH is an excellent solvent system for tryptamine compounds, so this was what I used. It may not be the perfect solvent system, but when combined with a few drops of NH4OH, the separation between the methylated and non-methylated tryptamine was more than adequate (Rf difference of ~0.3).
After running for 2 hs, the TLC showed no more consumption of the starting material, so a small amount (0.25g) of NaBH4 was added to see if the reaction would proceed further. At 3 h, the starting material spot had decreased a small amount, and at 4 h the consumption of the starting material had stopped once again. Hamilton mentions the possibility of spots for both the N-methyl 5-MeO-Tryptamine and the Pictet-Spengler cyclization product 6-MeO-THBC, but like him, I only observed spots for the 5-MeO-Tryptamine and 5-MeO-DMT.
In order to not alter the process of the reaction any further, no further formaldehyde or NaBH4 were added, and the reaction was allowed to warm to room temperature. The MeOH was stripped from the reaction and the residue was resuspended in water, and extracted with CHCl3. The use of extraction solvent was another part of the reaction which deviated from Hamiltons approach, as previously published (see last post) papers had found chloroform to be more efficient than ethyl acetate, but ethyl acetate can be used to keep the reaction green or if chloroform is not readily available. I am not sure why the tryptamine was not entirely consumed, as the ratio of reagents that were used matched those used in Hamiltons' show, and he saw complete transformation of the starting material. I can only assume that the reagents I have are of a lesser quality (old) or that I kept the NaBH4 in the freezer for too long, and that it had lost some of its potency by the time I had added it. But I digress.
The CHCl3 was removed under vacuum and the resulting brown-pink oil was dried under reduced pressure. I have found that the presence of a pink color in the product tends to signify some amount of 5-MeO-Tryptamine still remaining. The weight of the dry oil was 5.8 grams before any purification. After sitting over the weekend at room temperature, some delicate tan crystals appeared in the oil. Attempts at removing the solid from the oil were unsuccessful, so column chromatography was employed now that a suitable solvent system with acceptable separation had been found. 8:2 CHCl3/MeOH with a few drops of NH4OH was used, and many fractions were obtained which contained only the 5-MeO-DMT, and no 5-MeO-Tryptamine. The progress of the 5-MeO-DMT down the column was distinctly noticeable via long wave UV light, although the product continued to come down off of the column long after the initial luminescent band had passed.
I am not sure what the consensus is here, but I prefer not to distill partially because I am bad at it, and secondly because I am terrified of heating low boiling point compounds such as these, as I have had some bad luck with this in the past. If you have the ability and/or the technique to do fractional vacuum distillation, go for it. I wouldn't say that I am particularly good at column chromatography, either, but the solvent system used makes this almost-foolproof. Once again, I digress.
The fractions containing the product and only the product were combined and stripped of solvent under reduced vacuum. The resulting amber colored oil was allowed to sit once again at room temperature, and the product was of sufficient purity that it spontaneously crystallized into long, thin, waxy amber crystals of pure 5-MeO-DMT freebase. The oxalate salt is very easily prepared by dissolving the freebase in ether, and adding a saturated solution of oxalic acid in ether to that. I kept mine as the freebase.
Theoretical yield: 5.73 g. Actual yield: 4.44 g. Percent yield: 73%.
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