Uber die Synthese des Bufotenin-methyl-athers (5-Methoxy-N-dimethyl-tryptamin) und Bufotenins
Authors: Toshio Hoshino and Kenya Shimodaira Journal: Annalen der Chemie, Vol. 520, 1936, pp. 221-224 Series: Synthesen in der Indol-Gruppe, XV
Summary
First total synthesis of bufotenin methyl ether (5-methoxy-N,N-dimethyltryptamine, now known as 5-MeO-DMT) and its conversion to bufotenin (5-hydroxy-N,N-dimethyltryptamine). Part of a broader program on indole alkaloid synthesis connected to the eserine (physostigmine) problem.
Synthetic Route
Starting material to bromide
- 5-Methoxy-indolyl-3-acetonitril hydrolyzed to 5-methoxy-indolyl-3-acetic acid (mp 146-147 C)
- Esterification to the ethyl ester (mp 97-98 C)
- Bouveault-Blanc reduction (Na/EtOH) to 5-methoxy-tryptophol (bp 194 C/4 mm)
- Bromination with PBr3 in ether to 5-methoxy-indolyl-3-ethyl-beta-bromide
Bromide to 5-MeO-DMT
- Reaction with 33% dimethylamine in methanol, sealed tube, 100 C, 16 h
- Acid-base extraction, vacuum distillation (bp 208-210 C/4 mm)
- Crystallization from ether/petroleum ether: colorless prisms, mp 66-67 C
5-MeO-DMT to bufotenin
- O-Demethylation with AlCl3 in benzene, 100 C, 15 h
- Acid-base workup, ether extraction
- Identity confirmed by mixed melting point of dipikrate (mp 177-178 C) and monopikrate with authentic bufotenin from the ethyl ether route
Alternative route via quaternary salt
- Exhaustive methylation of 5-methoxy-tryptamine with MeI/Na2CO3 in ethanol (>90% yield of trimethylammonium iodide, mp 183 C)
- Conversion to chloride via AgCl exchange (mp 144 C)
- Hofmann elimination by high-vacuum pyrolysis at 240-250 C to yield 5-MeO-DMT (confirmed by pikrate mp 174-175 C)
Key Data
| Compound | mp (C) | Notes |
|---|---|---|
| 5-MeO-DMT (free base) | 66-67 | Colorless prisms |
| 5-MeO-DMT monopikrate | 176-177 | From benzol-acetone |
| 5-MeO-DMT jodmethylat | 183 | Matches Wieland’s natural bufotenin derivative |
| Bufotenin dipikrate | 177-178 | Identical to authentic |
| Trimethylammonium iodide | 183 | >90% yield from tryptamine + MeI |
| Trimethylammonium chloride | 144 | Via AgCl exchange |
Historical Context
- Part XV of Hoshino’s “Synthesen in der Indol-Gruppe” series
- Connected to physostigmine (eserine) synthesis program
- Acknowledges R.H. Manske (Canada) for concurrent work on tryptamine methylation
- Compares data with Wieland, Konz, and Mittasch (1934) who isolated natural bufotenin
- Manske demonstrated the difficulty of selective monomethylation of tryptamine (yields mixture of mono-, di-, and trimethyl products)