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.
References: [1]: Organic Letters 4 (23), 4033-4036 (2002)https://www.thevespiary.org/rhodium/Rhodium/pdf/dmt.synthesis.solid-phase.article.pdf
https://www.thevespiary.org/rhodium/Rhodium/pdf/dmt.synthesis.solid-phase.data.pdf
[2]: Bioorg. Med. Chem. Lett. 10, 1707-1709 (2000)https://www.thevespiary.org/rhodium/Rhodium/pdf/dmt.synthesis.solid-phase.resin1.pdf
[3]: Tetrahedron Lett. 38, 8573-8576 (1997)https://www.thevespiary.org/rhodium/Rhodium/pdf/dmt.synthesis.solid-phase.resin2.pdf
