SYNTHESIS: (from indole) To a well-stirred solution of 1.6 g indole in 30 mL anhydrous Et2O there was added, dropwise over the course of 30 min, a solution of 3.8 g (2.6 mL) oxalyl chloride in 30 mL anhydrous Et2O. Stirring was continued for an additional 15 min during which time there was the separation of indol-3-ylglyoxyl chloride as a yellow crystalline solid. This intermediate was removed by filtration and washed with Et2O. It was used directly in the following step. This solid acid chloride was added to 3.6 g anhydrous ethyl amine in Et2O and stirred until the color had largely faded. Then there was added 100 mL of 2 N HCl. The mixture was cooled, and the resulting product N-ethyl-3-ylglyoxylamide N-ethylindol-3-ylglyoxylamide was removed by filtration. The air-dried product was obtained in a 67% yield (mp 208–210 °C from benzene).
A solution of 1.6 g N-ethyl-3-ylglyoxylamide N-ethylindol-3-ylglyoxylamide in 50 mL anhydrous THF was added, dropwise, to 1.5 g LAH in 50 mL anhydrous THF which was well-stirred and under an inert atmosphere. This was brought to reflux and held there for 3 h. The reaction mixture was cooled, and the excess hydride destroyed by the cautious addition of wet THF. A 15% NaOH solution was then added until the solids had a loose white cottage cheese character to them, and the mobile phase tested basic by external damp pH paper. These formed solids were removed by filtration, washed with first THF and then MeOH. The filtrate and washings were combined, dried over anhydrous MgSO4, and the solvent removed under vacuum. The residue set up to a crystalline mass. This was converted to the hydrochloride salt (mp 188–190 °C from benzene/methanol MeOH) in a 35% yield.
(from tryptamine) To a well-stirred solution of 16.0 g tryptamine base in 25 g triethylamine, there was added dropwise 11.2 g acetic anhydride. The mixture was heated on the steam bath overnight, then the volatiles were removed under vacuum. The residue was dissolved in 100 mL CH2Cl2 and washed with 100 mL dilute aqueous HCl. The water phase was extracted twice with additional CH2Cl2, the organic phases were combined, washed with aqueous NaHCO3 solution, and the solvent removed under vacuum. The resulting residue (12.5 g of a dark viscous oil) was distilled at the KugelRohr to give N-acetyltryptamine as a viscous amber oil boiling at 185–200 °C, which set to a fused glass at room temperature. It weighed 9.45 g, for a yield of 47% of theory. This glass ground glass-ground under hexane had a mp of 70–73 °C and formed white crystal from toluene, with a mp 73–74 °C. IR(in cm-1) 756, 810, 1022, 1073, 1103, C=O at 1640. MS (in m/z): indolemethylene+ 130 (100%); 143 (86%); parent ion 202 (7%).
A solution of 2.31 g of N-acetyltryptamine in 30 mL anhydrous THF was added dropwise to 60 mL of 1 M LAH in THF, and held at a reflux under argon. After 12 h reflux, the reaction was returned to room temperature and the excess hydride destroyed by the addition of 20 mL of 50% aqueous THF. The mixture was filtered through paper, washed with 3×25 mL THF, and the combined filtrates and washings stripped of volatiles under vacuum. The remaining pale cream-colored oil was distilled at 0.1 mm/Hg to give a white oil, bp 125–135 °C, 1.58 g for a yield of 73%. This free-base product spontaneously crystallized to a white waxy solid, with a mp of 80–81 °C. IR (in cm-1): 751, 887, 940, 1021, 1051, 1118. MS (in m/z): C3H8N+ 58 (100%); indolemethylene+ 131, 130 (48%, 33%); parent ion 188 (2%). N-ethyltryptamine base, dissolved in 5× its weight of isopropanol IPA, acidified with concentrated HCl, and Et2O added dropwise, yields the hydrochloride salt, N-ethyltryptamine hydrochloride or NET, with a melting point of 181–182 °C. IR (in cm-1); 750, 761, 825, 1020, 1108, 1142.
SYNTHESIS: To a solution of 3.2 g tryptamine base (20 mMol) in 25 mL isopropanol IPA there was added 6.8 g isopropyl iodide and the solution was held at reflux for 36 h. All volatiles were removed under vacuum, and the residue suspended in dilute aqueous NaOH and extracted three times with 40 mL portions of CH2Cl2. These extracts were pooled and, after removal of the solvent, yielded 2.19 g of a dark oil which crystallized on standing. This was distilled at the KugelRohr at 130–150 °C at 0.08 mm/Hg to give 1.51 g of a white oil that set to a solid in the receiver. An analytical sample was recrystallized from isopropanol IPA, and had an mp 94–95 °C. A solution of the free base in 10 mL warm isopropanol IPA was treated with concentrated HCl dropwise until the solution was red to external damp pH paper. The spontaneous crystals that formed were diluted, with stirring, with 20 mL anhydrous Et2O, the resulting curdy crystalline mass removed by filtration, washed with additional Et2O, and air dried to constant weight. Thus there was obtained 1.58 g N-isopropyltryptamine hydrochloride (NIPT) as fine white crystals, with a mp of mp 224–227 °C. MS (in m/z): C4H10N+ 72 (100%); indolemethylene+ 131,130 (50%, 35%); parent ion 202 (2%). IR (in cm-1): 751, 860, 1024, 1036, 1112.
EXTENSIONS AND COMMENTARY: Why two complete recipes, for two monoalkyltryptamines which have received only modest human trials but which have yet to have any active levels discovered? For several very good reasons.
Firstly First, these two monosubstituted tryptamines are described here are easily made as pure entities, in acceptable yields.
Secondly, they are prepared here by completely different processes, each of which is amenable to modification to other, potentially useful mono-substituted tryptamines (NRT'S, where the R is a sizable alkyl group). There is the oxalylamine route (used here with ethylamine for NET) and the alkyl halide route (used here with isopropyliodide for NIPT but which proved to be rather useless in making NET where the major product was the quaternary salt). With these two procedures available, there is almost no limit to the potential identity of that mono-group on the nitrogen atom of tryptamine. Quite a few have already been made. Let me list some examples.
The normal-propylamine NPT has been made by the oxalylamide route, with the amide with having a mp 179–181 °C (75%) from benzene and NPT hydrochloride mp 186–187 °C (33%) from MeOH/benzene. An attempt to make NPT by the alkyl halide procedure failed. Using these same ratios of reactants, there was the formation of a sizable quantity of DPT with appreciable unreacted tryptamine presence (T:NPT:DPT/1:5:4). A recycling under the same conditions gave T:NPT:DPT/0:3:7) and a third cycle gave only DPT, but with a loss of almost 90% of the material presumably to quaternary salt formation. Interestingly NPT is less toxic than DPT in experimental mice, but has not been assayed yet in man.
NBT (N-butyltryptamine) is also an oxalylamide product. The amide with has a mp 167–169 °C (81%) from benzene and NBT hydrochloride with has a mp 203–205 °C (13%) from benzene/methanol MeOH.
The two geometric isomers, mono-isobutyl and mono-sec-butyl tryptamines are best called NIBT and NSBT. They also have been made by the oxalylamide route and the hydrochloride salts melt at 150–151 °C and 175–177 °C resp. Interestingly, NSBT is one of the two mono-substituted tryptamines that just might have CNS activity. It has shown a generalized and somewhat diffuse intoxication with several studies covering the 25 to 75 milligram range. Short lived, intellectual excitement with some modest sensory enhancements. Promising, and a lot of erotic horniness, but no plus threes three’s, yet.
The tertiary-butyl analogue, NTBT, is the remaining mono-substituted tryptamine that just might have psychotropic potential. In the 5 to 20 milligram mg area, there is a light-headed intoxication that is a totally pleasant buzz, but nothing more profound than that. Wouldn’t it be fascination of fascinating if it turned out that all of the mono-tryptamines (the NRT’s) were GHB-like intoxicants, and totally devoid of psychedelic activity. ? That would be a true challenge to the SAR crowd. I was told many years ago that NTBT was extremely potent when smoked, but I never received any particulars, and I must leave that as a baseless rumor.
Both the mono-amyl and the mono-hexylamines have been described (NAT and NHT), both having been made by the glyoxylamide process. These, too, as has been mentioned above, it appears to be inactive in man, as reported by Stephen Szara at the famous “Ethnopharmacologic Search for Psychoactive Drugs” conference, organized by the late Dan Efron of the National Institute of Mental Health, in San Francisco, in 1967.
Thirdly, this is where the staggering potential power of this recipe comes into focus. One can make, easily, pure mono-ethyl, mono-propyl, mono-isopropyl, mono-n-, sec-, iso and tert-NBT’s. And using these directions, one can systematically react these mono’s with every different alkyl halide. Thus, there suddenly becomes available a “this” times “that” squared possibilities of new tryptamines, every one easily made, every one potentially psychoactive, and almost every one totally unknown to the scientific literature. The oxalylamide process goes out to lunch when one considered the unlikelihood of finding N-sec-butyl-N-isobutyl amine as a commercially available product. It is no longer required. Make IBSBT (how would you ever encode that product) by the simple treatment of one of these mono’s with an appropriate alkyl halide, and clean up the mess with a dash of acetic anhydride.
Fourthly, and most important, every one of these adventures has an exact counterpart with the inclusion of that magical 5-methoxy group. Whatever is found with the 5-H archetype is certain to be more potent, and correspondingly unpredictable, with a 5-methoxy-substituent. Some have already been made. Most have not. This is open territory. Go west West, young man.
Back to the mundane. I really have to justify the “N” in the NET. I will try to hold to the convention that is expanded on at length in the recipe for DBT, that if there is one alkyl group (a monoalkyl tryptamine) then it is N-alkyl-tryptamine, with the reserving the M for methyl rather than for mono, even in the case of monomethyltryptamine. There is wide use of MMT for monomethyltryptamine in the literature, but the ambiguity comes from the higher mono-substituted homologues, and this makes NMT a much safer name. As there can be several places for the ethyl group, perhaps it is best to give the location as a number or letter, such as 1, 2, α (for alpha) or N.
A detail for spectroscopists amongst us. With the mono-N-substituted tryptamines, there is always a 131
e/m mass peak, larger than the 130 e/m mass peak. This peak is a minor one with the disubstituted analogue. The same relationship exists with the 5-methoxy analogues, where N-monosubstituted compounds have a 161/160 m/e fragment (the 5-methoxymethylene indole fragment, with the 161 m/e peak always the larger. The primary amine shows this same character. The disubstituted analogue has only the 160 m/e fragment.
Meyers-Riggs, B. N-Alkylated tryptamines. countyourculture: rational exploration of the underground, 10 Mar 2012.
This version of Book II of TiHKAL is based on the Erowid online version created by Bo Lawler with the help of Erowid, from content generously provided in electronic format by the Authors.
The Erowid online version does not always match the printed version—I’ve found over 300 inconsistencies. Text has been inserted, deleted, or changed at various points. Perhaps the Erowid version was created from an earlier (or later) draft? In several places the Erowid version is plainly wrong; elsewhere it’s a tougher call. I don’t claim to have found every discrepancy; in those cases I have found, both the Erowid and print versions are given and marked as such. I would be grateful if any sharp-eyed readers would report any I have missed.
As with PiHKAL • info, I’ve again attempted to reproduce the typographic style of the printed edition. And again, I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.
“I would like to take a moment to reiterate that at the present time restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.
“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
Alexander T. Shulgin
The Copyright for Part 1 of TiHKAL has been reserved in all forms and it may not be distributed. Part 2 of TiHKAL may be distributed for non-commerical reproduction provided that the introductory material, copyright notice, cautionary notice and ordering information remain attached.
TiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of tryptamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Although Sasha and Ann have put Book II of TiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them—and there’s still nothing quite like holding a real book in your hands.
TiHKAL (ISBN 0-9630096-9-9) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,