Magic Mushrooms and Other Indole Trips

by Michael Valentine Smith

Various trees, vines, etc. and mushrooms containing dimethyltryptamine (DMT) and analogs have been used by the natives of Central and South America for millennia. Precise chemical and botanical identification have been made on a number of species, the first and most famous of these being certain species of mushrooms of the genus Psilocybe, species of which are found in the U.S.A., Canada, Scotland, Australia, etc. as well as Central America. Psychedelic species of the closely related genera Conocybe, Stropharia, Pholiota, Copelandia and Panaeolus are found widely scattered around the world. Not all species of each genus necessarily contain significant amounts of hallucinogens, but it seems that most do. A general test is that the stem of indole containing species tends to turn blue several hours after it is picked and slightly crushed. These are generally found in late summer and fall in the U.S.A. Pictures are given in many mushroom books including R. Heim, LES CHAMPIGNONS HALLUCINOGENES DU MEXIQUE (1958), and L. Enos, A KEY TO THE AMERICAN PSILOCYBIN MUSHROOM (1971).

It turns out that the home cultivation of psilocybin mushrooms is quite easy. See Oss and Oeric PSILOCYBlN: MAGIC MUSHROOM GROWER'S GUIDE (1976 - And/Or Press) or THE COMPLEAT PSILOCYBIN MUSHROOM CULTIVATOR'S BIBLE (1976 - Hongero Press). Strains of Stropharia cubensis being grown on the West Coast are sufficiently strong that I have seen people who were very experienced with acid get higher than they had ever been on three fresh mushrooms. Remember that psilocybin is cross-tolerant with LSD, so you won't get off as well if you've done acid recently.

Puffballs of the genus Lycoberdon are also hallucinogenic, and activity has been claimed for Boletus satana, which occurs in the southeastern U.S.

In THE TEACHINGS OF DON JUAN, Don Juan seems to have taught Carlos to smoke the mushrooms, which might provide a different or heavier trip than ingesting them since they undoubtedly contain many compounds like DMT and 5-methoxy-DMT which are not orally active.

Puffballs seem to usually produce only auditory hallucinations. L. marginatum found over much of Europe and America is active ( 1 or 2 constitutes a dose).

New Guinea "mushroom madness" is apparently due to species of Boletus, Russula and Heimiella. See R. Heim NOUVELLES INVESTICATIONS SUR LES CHAMPIGNONS HALLUCINOGENES (1967). Also see FIELD GUIDE TO THE PSILO- CYBIN MUSHROOM (available from P.O. Box 15667, New Orleans, LA 70175).

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and psilocin (4-hydroxy-DMT) are among the active indoles in the mushrooms. Upon ingestion, psilocybin is hydrolyzed to psilocin; consequently there is no point in carrying the synthesis past the psilocin step. All the active naturally occurring compounds in this group seem to have the dimethylamine moiety, which is usually obtained in the course of chemical synthesis by using dimethylamine (DMA). If however, the DMA is replaced by diethylamine (DEA), dipropylamine (DPA), methylethylamine (MEA), pyrrolidine, etc., the potency and duration of action might be considerably increased. Likewise, an increased activity might be seen when the OH position of psilocin is replaced by methoxy or acetoxy. Human data are lacking for most of these compounds, but judging from animal experiments, the order of potency should be roughly as follows (MET is methylethyltryptamine, DET is diethyltryptamine):

4 or 5 AcO-MET > 4 or 5 MET > 4 or 5 MeO-DET >4 or 5 MeO-DMT > 4-OH-DMT > DMT 5-AcO-DMT DET

Compounds with a low relative activity (e.g., DMT, DET, 5 methoxy-DMT) have very little activity orally and must be smoked or sniffed. Unfortunately, these compounds taste and smell like burning plastic when smoked and are harder to smoke than hash. There is, however, no evidence for the notion that they are damaging. With the exception of DMT, DET, psilocin and psilocybin, most of these compounds are probably legal in most states.

In the case of the unsubstituted N, N-diakyltryptamines, duration of action increases as the chain gets longer in the order DMT, DET, DPT, and seems to decrease with further increase in length. The trip produced by a good dose of DMT typically lasts about one-half hour, whereas that for DPT can last three to four hours or more. There is some evidence that DET produces a better (i.e., more meditative and euphoric) trip than DMT.

If the alkyl side chain at the 3 position of the indole nucleus is shortened (e.g., gramine) or lengthened (e.g., 3-(3-dimethylamino)-propyl indole) activity seems to decrease strikingly. Also, as the substituents are moved around the benzene ring of indole, activity decreases greatly in the order 4,5,6,7. For example, whereas 4-OH-DMT(psilocin) is active at about 5 mg orally (i.e., about as active as STP), 5-OH-DMT (bufotenin) is not psychedelic at all.

The effects of 5-methoxy-DMT are unpleasant for most people (smoking it gives me nausea plus the feeling that I'm being sat on by an elephant), but it is not known whether other substituents in the 5 position or in the 4 and 5 positions simultaneously will be similarly distressing.

DMT, DET, etc. are remarkably fast acting (peaking in ca. 2 minutes after a good toke or snort) and produce very strong visual effects (my first toke of DMT produced a large grinning green dragon with red ruby eyes that lasted as long as the Stones' "Sympathy for the Devil"). It is unfortunate that it is usually DMT rather than the longer acting DET or DPT that is available, especially since the latter cpds. are no more difficult to produce. Also, it is rumoured that N,N-dibutyl and longer alkyls are not only active but (along with the dipropyl, diisopropyl etc. cpds.) orally active.

Ken Kesey has reputedly said that alpha-methyltryptamine, in oral doses of ca. 30 mg, peaks in about 12 hours, produces a trip similar to psilocybin, but nicer, and is the "Rolls Royce of psychedelics," but others find it unpleasant. Alpha-ethyltryptamine produces minimal LSD-type effects at 150 mg orally, but effects of these when smoked or inhaled are unknown. N,N-disubstituted tryptamines which have substituents in the alpha or beta positions should also be quite interesting.

Identification of Indoles

Keller Test

Add a little of the powdered substance (about 0.2 mg to 1 ml glacial acetic acid containing 0.5% FeCl3, layer underneath with 1 ml concentrated sulfuric acid and shake. The color varies with the indole, being olive green for psilocin and red-violet for psilocybin.

Van Urk Test

Prepare Van Urk reagent by adding 0.5 g p-dimethylaminobenzaldehyde, 100 ml water, 100 ml concentrated sulfuric acid. Dissolve 1 mg substance in 1 ml ethanol and mix with 2 ml Van Urk reagent and illuminate for 10 minutes with an ultraviolet lamp (black light). Psilocin gives a blue-grey, psilocybin a red-brown color. Colors produced in these two tests by many indole derivatives are given in HCA 42,2073(1959).

Quick, Easy, On-the-Spot Test JPS 56,1526(1967)

Saturate strips of filter paper with 2% p-dimethylaminobenzaldehyde in 45% ethanol; air dry and store in tightly stoppered amber bottles (or keep in stoppered container in dark) which will keep them useful for several months. Put a little of the suspect substance in a few drops of ethanol (gin may do, but do a control), wet a filter paper strip in this and allow to dry. Put one drop concentrated HCl on the dried paper (don't let it touch anything). Alternatively, the powder can be placed directly on the strip and the HCl dropped on it. A violet red or violet blue spot indicates indole derivatives such as LSD. With DMT or psilocybin the color is redder. The color must be observed soon after adding the HCl since it rapidly changes.

Dialkyltryptamine Syntheses

Dialkyltryptamines HCA 42,2073(1959) and many others

To 25 g indole (or 50 g 4-benzyloxyindole or 0.21 M other indole) in 1 L dry ether at 0ø add a solution of 50 ml (75 g) oxalyl chloride in 1 L dry ether carefully and with good stirring a little at a time over 1/2 hour and stir until bubbling ceases (about one-half hour more). Some indoles require a longer reaction time (e.g., 4-Cl-indole requires fifteen hours refluxing) and some will not react (e.g., 4-Br-indole). Add portionwise, carefully with stirring at 0ø, a solution of 225 ml (160 g) diethylamine (DEA) (or 0.46M dipropylamine, pyrrolidine, etc.) in 100 ml dry ether at 0ø. Stir and let warm to room temperature; cool, filter, and wash precipitate two times with ether to get (I). This can be recrystallized by dissolving in the minimum volume of 1:1 methanol:benzene (or 95% ethanol), gently heated, cooled to 0ø and filtered (or add petroleum ether to induce precipitation). Dissolve 25 g (or 0.102 M) (I) in the least volume (about 200 ml) THF and add very carefully and slowly (preferably dropwise) to 20 g lithium aluminum hydride dissolved in the least volume (about 200 ml) tetrahydrofuran at room temperature. Stir and heat under reflux for about fifteen hours. Cool to Oø and slowly and carefully add a little cold methanol and water until no more bubbles are formed. Filter, wash precipitate with hot tetrahydrofuran and add washings to filtrate. Dry, evaporate in vacuum the tetrahydrofuran (or add petroleum ether) to precipitate the dialkyltryptamine. To purify, add 500 ml saturated sodium sulfate and filter. Wash precipitate with tetrahydrofuran; acidify with a few ml 0.1 M HCl and shake with ether. Separate the organic layer and neutralize with 0.1 M NaOH. Extract with CHCl3 and dry, evaporate in vacuum the extract (or can evaporate until a few ml left and precipitate by adding petroleum ether). The 4-benzyloxy-DET which would be produced if 4-benzyloxyindole is used as the starting material is probably a good psychedelic. lf however, it is desired to change this to 4-OH-DET, add 37.5 g 4-benzyloxy-DET in 1.2 L methanol to 20 g 5% Palladium catalyst on alumina (or 14 g 10% Palladium-Carbon) with 2.8 kg/cm2 H2 in a Parr hydrogenator and shake twelve hours. Filter, evaporate in vacuum. Other hydrogenating methods might also split off the benzene ring. Other methods (LAC 576,69(1952)) must be used for reducing a methoxy group to a OH group (another demethylation method is given here later).

If (I) has an alkyl group in position 1 (as in some of the following syntheses), reduction will give the indolylhydroxylamine. This may be active, but if the indolamine is desired (I) (substituted or not) may be reduced with the diborane method given later in this section. Dialtryltryptamines JCS (C) 2220(1967)

This procedure gives about 20% yield with indole, but the yield with substituted indoles (e.g., 4-OH-indole for producing psilocin) has not been reported.

Cool 32 g ethyl iodide to 0øC; dissolve in 50 ml anisole (other solvents won't work) and add 8 ml to 5.28 g Mg turnings in 50 ml anisole, and add the rest gradually. Warm gently to start the reaction, and if necessary add a crystal of iodine or a small amount of ether for a rapid rate. Stir well and heat at 50-60ø for one hour (under N2 if possible). Cool to 10ø and add dropwise over one-half hour 12 g (0.1 M) indole in 50 ml anisole (keep temperature below 25ø). Stir forty-five minutes at 50ø and cool to -5ø. Finely grind 0.2 M (34 g) 1-Cl-2-diethylaminoethane-HCl (or the corresponding diisopropyl, pyrrolidyl, etc. compounds) and suspend in about 20 ml benzene at Oø. The free base in benzene can also be used, if obtainable. Stir and take pH to 8.5 with 40% NaOH. Add anhydrous potassium carbonate until the water layer is semisolid. Decant the benzene and extract the residue with 4X 15 ml benzene. Dry the combined benzene extracts with KOH pellets for less than an hour and quickly proceed to the next step. Add the benzene solution (about 80 ml) slowly over one hour to the above solution of indole in anisole at -5ø. Stir three hours at -5ø and let sit five hours at -5ø. Then let warm to room temperature and dry, evaporate in vacuum (or to purify, break up the precipitate and pour the solution on 500 ml saturated aqueous NH4Cl. Stir one-half hour; separate the organic layer and extract the aqueous layer with ether. Combine the organic solutions and extract three times with 10% HCl. Wash HCl extract with ether; cool to Oø, basify with 40% NaOH and extract three times with ether. Dry, evaporate in vacuum this second ether extract to get the oily DET or analog).

4-Substituted Dialkyltryptamines CT 279( 1970) (cf. JOC 30,339( 1965))

Beta-carbomethoxypropionyl chloride (Org. Synth. 25,19 (1945)). Dissolve 400 g succinic anhydride in 190 ml methanol in 1 L round bottom flask and reflux (steam bath) one-half hour. Stir until homogeneous (about twenty minutes) and reflux one-half hour. Evaporate in vacuum and cool the residual liquid to precipitate about 500 g methyl-hydrogen succinate (I). Dissolve 264 g (I) in 200 ml SOCl2 in a 1 L round bottom flask with a reflux condenser and warm at 30-40ø in water bath for three hours. Evaporate in vacuum the SOCl2 (can heat flask in steam bath) to get 270 g of the title compound (can distill 92/ 18).

Add excess diethylamine to beta-carbomethoxypropionyl-Cl in dry ether to get (see above JOC reference) 3-carbo-methoxy-N,N- diethylpropionamide (I). 206 g (I) in 3 L, three-necked round bottom flask in ice bath with stirrer, dropping funnel and reflux head. Keep temperature at 10-20ø and add 169 g POCl3 dropwise over fifteen minutes. Remove ice bath and stir fifteen minutes and replace ice bath. Add 250 ml ethylene chloride, cool to 5ø. Stir and slowly add 67 g pyrrole in 250 ml ethylene chloride over 1 hour. Remove ice bath and reflux fifteen minutes (HCl evolution). Cool to room temperature and add solution of 750 g sodium acetate trihydrate in 1 L water dropwise at first, then as rapidly as possible. Reflux fifteen minutes with stirring, cool and remove ethylene chloride in separatory funnel. Extract aqueous phase with 3x200 ml ether and wash combined ethylene chloride and ether with 3x100 ml saturated aqueous Na carbonate (add carefully at first). Dry, evaporate in vacuum the organic phase to get 132 g methyl (pyrrolyl-2')-4-keto-4 butyrate (II) (can distill 135-45/0.2) (recrystallize from cyclohexane). Alternatively, (Chem. Commun. 1429(1968)), condense 1,3-cyclohexanedione and aminoacetaldehyde dimethylacetal in benzene with p-toluenesulfonic acid. Azeotropic removal of water gives a compound which, when treated with 3N HCl, gives compound (IV). But it has been claimed that this alternative method does not work.

94 g (II), 1.5 L diethylene glycol, 93 g hydrazine hydrate and heat at 100ø fifteen minutes. Add 150 g potassium carbonate a little at a time and raise temperature slowly. Heat four hours at 190-200ø and pour onto 5 kg ice. Acidify and then extract with 5x400 ml ether. Wash extract with a little saturated NaCl and evaporate in vacuum to get about 48 g 4-(pyrroly-2')-butyric acid (III) (recrystallize-cyclohexane). Can purify the oily compound by filtering through 80 g silica and 80 g Celite (elute with benzene). 24 g (III) in 400 ml 1,2-dichloroethane; cool to -5ø and add 15.8 g triethylamine and 17 g ethyl chloroformate. Let stand 1 hour at 15ø; filter and wash precipitate with 100 ml dichloroethane. Add 0.5 L anhydrous ZnCl2 (freshly fused) and let stand two hours at -5ø. Add 0.5 L 2N HCl, decant and wash the aqueous phase three times with CHCl3; dry, evaporate in vacuum (can chromatograph as for (III)) to get about 11 g 4,5,6,7-tetrahydro-4-indolone (IV). 7.35 g (IV), 5 g 10% palladium-carbon, 700 ml mesitylene and reflux eight hours or more. Filter hot, wash precipitate with methanol, cool and evaporate in vacuum (can chromatograph as for (III)) to get 5 g 4-OH-indole (V) (recrystallize from petroleum ether), which can be converted to the diakyltryptamine by any of the methods described here or as follows (the first step leading to (VI) may not be necessary). 5 g (V), 20 ml pyridine, 10 ml acetic anhydride and heat in water bath 10 minutes. Pour on ice, stir and add NaHCO3. After one-half hour extract with ethyl acetate, wash extract with NaCl and dry, evaporate in vacuum to get about 6.3 g 4-acetoxy-indole (VI). 6 g (VI), 150 ml ether; cool in ice-salt bath and add carefully 6 ml oxalyl-Cl. After four hours add 20 g dry dimethylamine or equimolar amount other amine and stir twenty hours. Filter, wash precipitate with ether and then water to get about 2.8 g 4-acetoxy-3-indolyl-N, N-dimethylglyoxylamide (VIIa) (recrystallize- isopropanol). Shake the ether with water and filter to get about 5 g of the 4-OH compound (VIIb) (recrystallize-isopropanol). 7.8 g (VIIa or b or mixture obtained by evaporating in vacuum the ether above), 17 g lithium aluminum hydride, 150 ml tetrahydrofuran or dioxane; reflux seventeen hours, carefully add water and stir until bubbling ceases and evaporate in vacuum to get about 4.7 g of psilocin or analog (about 5% overall yield). For other methods of synthesizing (1V) see JOC 36,1232(1971) and references therein. For another method of reducing (IV) see Chem. Het. Cpds. (Russian), 572(1972).

4-Substituted Dialkyltryptamines HCA 42,2073(1959), 38,1452 (1955), CT 276( 1970)

Method is illustrated for 4-benzyloxyindole (I) but will probably work for most other substituted indoles.

A: Convert (I) to 4-benzyloxygramine (II) as described elsewhere here. B: Add 30 g (II) over one-half hour to 420 ml methyl iodide and let stand fifteen hours at 5ø. Separate the iodomethylate which precipitates, dry briefly at 50ø and heat with vigorous stirring at 80ø for two hours with 60 g NaCN in 1 L water. Extract with CHCl3, dry and evaporate in vacuum the extract and dissolve the residue in 250 ml ether. Filter, evaporate in vacuum to a few ml and precipitate the acetonitrile (III) by adding petroleum ether. The acetonitrile can also be prepared directly from the indole via the Grignard reagent as given elsewhere here. B (Alternative): 0.05 M (II), 0.76 ml glacial acetic acid in 75 ml tetrahydrofuran (dry) are added slowly with stirring and cooling over one-half hour to a solution of 25.2 ml dimethylsulfate and 0.76 ml glacial acetic acid in 30 ml dry tetrahydrofuran. After two hours, filter and wash the precipitate with ether. Dissolve precipitate in 10% aqueous solution of KCN and heat one hour at 70ø. Filter, wash precipitate with water and dry to get (III). C: 0.04 M (III) in 200 ml 33% ethanol solution of DMA or other amine, 2.5 g Raney-NI, 40o, 100 kg/cm2 (about 100 atmospheres) H2. Heat about three hours; filter and evaporate in vacuum to get the dialkyltryptamine. C (Alternative): 5.8 g (III), 12 g KOH, 36 ml ethanol, 28 ml water; reflux fifteen hours, add 15 ml glacial acetic acid, filter and add 150 ml water to precipitate 4-benzyloxyindole acetic acid (IV). Filter, wash precipitate with water and recrystallize from methanol. D 1.76 g (IV), 1.4 g PCl5, 50 ml ether at Oø. Stir until dissolved and add dropwise to solution of 5.36 g DEA (or equimolar amount other amine) in 10 ml ether. Let warm to room temperature, let stand one-half hour and precipitate by adding water. Filter, dry, evaporate in vacuum the ether and add the residue to the precipitate to get the diethylacetamide (V) (recrystallize-benzene). D (Alternative): 20.6 g (IV) in 50 ml methanol; add excess diazomethane in ether, evaporate in vacuum and dissolve the oil in 90 ml dry hydrazine. Heat at 135ø 1 1/2 hours, add 150 ml water and cool to precipitate the hydrazide (recrystallize-aqueous methanol). 14.7 g of the hydrazide in 250 ml tetrahydrofuran or dioxane and add 50 ml 1 N NaNO2. Cool to 4ø and add dropwise over 4 minutes with vigorous stirring, 60 ml 1N HCl; let stand fifteen minutes at 4ø and add 500 ml water. Extract the oily azide with ether and dry, evaporate in vacuum. Add 77 ml (0.75 M) DEA (dry) to the azide and let stand three hours at 5o with care to exclude moisture. Evaporate in vacuum and take up the residue in NaHCO3. Extract with CHCl3 and dry, evaporate in vacuum the extract to get (V). E. 0.7 g (2.28 mM) (V) in 20 ml dry tetrahydrofuran; add slowly to a well stirred solution of 0.35 g lithium aluminum hydride in 20 ml tetrahydrofuran and keep one hour at 40ø. Carefully add 5 ml water and stir twenty minutes. Add 15 ml 20% NaOH and extract with ether. Dry, evaporate in vacuum the extract to get 4-benzyloxy-DET or analog (recrystallize-ether). E (Alternative): To 0.4 g (V) in 15 ml tetrahydrofuran add 2.9 ml 1M borane in tetrahydrofuran and reflux one hour. Cool and heat with 5 ml 2N HCl; evaporate in vacuum to get about 0.15 g product.

4-Nitro and 4-Amino-Dialkyltryptamines CJC 41,2585(1963)

153 g alpha-Cl-butyryl-Cl, 16 g Pd on BaSO4, 1.66 ml sulfurquinoline (Org. Synthesis 21,84(1941)), 900 ml toluene; reflux and stir while bubbling H2 through for seven hours or until HCl evolution ceases (can bubble effluent HCl through water to monitor evolution). Filter, wash toluene with water, NaHCO3, water and dry, evaporate in vacuum to get 100 g gamma-Cl-butyraldehyde (I) (can distill 28/2). 10 g (I), 20 g 3-nitro-phenylhydrazine; dissolve in the minimum volume of hot ethanol containing 10% glacial acetic acid. Heat on steam bath one hour; cool and add water until dark oil separates. Evaporate in vacuum the ethanol and decant the water to get the oily gamma-Cl-butyraldehyde-3-intro-phenyl- hydrazone(II). 29 g (II), 300 ml concentrated HCl, 200 ml benzene; stir three hours, replace benzene with fresh benzene and stir four hours. Combine the two benzene portions, wash with water and dry, evaporate in vacuum to get 4 g 3-(beta-Cl-ethyl)-4 and 6-nitroindole (III). 3.56 g (III), 200 ml ethanol, 200 ml 34% aqueous DMA (or other amine) and let stand at room temperature for one week. Evaporate in vacuum the ethanol, filter, dissolve the precipitate in dilute HCl and filter. Basify the filtrate with dilute NaOH to precipitate 3 g 4 and 6-nitro-DMT (IV). 5.2 g (IV), 350 ml ethanol, 100 ml 1N NaOH; heat to 50ø and add a solution of 3 g Na dithionite in 15 ml 0.2N NaOH. filter hot and evaporate in vacuum to get 2 g 4 and 6 amino-DMT (can purify by dissolving in HCl, filter, basify, extract with ether and dry and evaporate in vacuum the extract).

5-Acetyl-DMT JMC 7,144(1964)

40 g p-aminoacetophenone, 250 ml water, 143 ml concentrated HCl. Slowly add 21 g NaNO2 in 200 ml water and keep temperature at 0-5ø. Add 70 g ethyl-alpha-(2-dimethyl-amino-propyl)-acetoacetate, then 63 g sodium acetate and keep pH at 5.5-6.0 with 3N NaOH. Stir in cold two hours; basify with NaOH and extract with 3x400 ml CHCl3. Dry, evaporate in vacuum the extract to get 70 g ethyl-alpha-keto-delta-dimethylaminovalerate (I) (recrystallize-benzene-petroleum ether). 50 g (I), 430 g polyphosphoric acid and heat slowly with stirring. Foaming starts about 60ø. Slowly raise temperature to 105ø and keep two hours. Cool to 70o; pour into 700 ml ice water; stir to dissolve; cool, basify, extract with 3x400 ml CHCl3 and dry, evaporate in vacuum to get 10 g 5-acetyl-2-carbethoxy-DMT (II). Test for activity. 11.2 g (II) in 190 ml 20% HCl; reflux four hours; cool and filter. Basify with 40% KOH and extract with 4X125 ml CHCl3 and dry, evaporate in vacuum to get 5-acetyl-DMT.

1-Methyl-DET BSC 1056(1962)

135 g acetoacetic acid in two-necked flask fitted with two condensers atop one another, the upper air cooled only, and a dropping funnel with a tube running to the bottom of the flask. Heat to boiling and add over forty minutes, as a vapor, 80 g DEA dried (e.g., with Na wire). The residue can be distilled (120-140/12) and redistilled (123-4/12) to give 100 g N,N-diethylacetoacetamide (I). 15.7 g (I) in 80 ml CHCl3 and add dropwise 16 g Br2 in 10 ml CHCl3. Heat gently to a boil for one-half hour and cool to precipitate.Filter, wash precipitate with CHCl3 and dry to get 25 g gamma-Br-diethylacetoacetamide (II) (use crude since decomposes on distillation). 4.72 g (II), 4.28 g N-methyl-aniline, 20 ml dimethyl formamide and let stand twelve hours (or 90 ml ethanol and reflux eighteen hours) at room temperature. Slowly add 300 ml water and extract the oil which forms with benzene. Wash with water and dry, evaporate in vacuum the benzene extract to get 4 g precipitate (recrystallize-80% ethanol). 4 g precipitate, 4 g ZnCl2 finely ground; heat in oil bath and keep temperature 100-110ø for forty-five minutes. Cool and dissolve precipitate in 40 ml 4N HCl and 160 ml benzene. Separate the benzene and wash with water; basify and dry, evaporate in vacuum to get 1.3 g 1-methyl-3-indole-N, N-diethyl- acetamide (III) (recrystallize-ethanol). Test for activity. Recover N-methyl-aniline by basifying the water or ethanol, extract precipitate with ether, wash extract to neutrality and dry, evaporate in vacuum. 1.1 g (III), 0.38 g finely ground lithium aluminum hydride, 300 ml ether and reflux two days. Carefully add a little water and filter, evaporate in vacuum to get 1-methyl-DET (recrystallize-ethanol). (III) can probably also be reduced by the method described in the chemical hints section or even more simply as follows: Dissolve 1M NaBH4 and 0.1 M (III) in 500 ml pyridine or other solvent and reflux eight hours or more.

Alpha-alkyl-DMT TET 29,971(1973)

21.6 g (0.1M) alpha-bromopropionyl (or butyryl etc.) bromide is added dropwise over 1 hour to a well stirred mixture of 11.7 g (0.1 M) indole and 8.1 ml (0.1 M) pyridine in 300 ml toluene at 60ø. Stir 1 hour, cool and pour into 500 ml water. Separate the oil and dissolve in methanol. Let stand 1-24 hours until crystals separate. Filter (recrystallize from acetonitrile) to get 18.4 g (72%) 3-(2-bromopropionyl)indole (I). 5.2 g (0.02M) (I), 7 ml 33% aq. dimethylamine and 3 g NaI in 100 ml ethanol are refluxed for 20 hours, concentrated to 25 ml and poured into 200 ml aqueous 0.5M HCl. Extract with ether and basify with concentrated NH4OH. Recrystallize from ethanol to get ca. 3g (50%) 3-(2-dimethylaminopropionyl)- indole (II). 2.7g (II) in 50 ml tetrahydrofuran is added to a well stirred mixture of 2.7 g lithium aluminum hydride in 60 ml tetrahydrofuran. Reflux 23 hours, carefully add 5 ml 2N KOH, filter and wash the the ppt. with ether and dry, evaporate in vacuum the ether to get 1.65 g (66%) alpha-methyl-DMT (recrystallize-benzene-n-hexame).

Alpha-methyl-DET JMC 9,343(1966)

46.8 g (0.4 M) indole in 100 ml toluene; add to 54.5 g ethylbromide and 12.5 g Mg turnings in 125 ml ether. After one-half hour convert the indolyl-Mg-Br to 3-indolyl-2-propanol with propylene oxide (CA 56,3455(1962)). 8.8 g of the indolyl-propanol, 200 ml ether; add 4.4 g PBr3 and let stand four hours. Add excess DEA and stir for a few minutes. Evaporate in vacuum or extract with dilute HCl and basify the extract with NaOH to precipitate the alpha-methyl-DET.

Dialkyltryptamines from Tryptamines BCSJ 11,221(1936)

Illustrated for 5-methoxy-tryptamine (I). 1.5 g (I), 30 ml ethanol; add 5 g methyl iodide (or equimolar amount ethyl iodide) and 4.5 g dry sodium carbonate and heat five hours on water bath. Filter hot, heat precipitate with ethanol and filter hot again. Evaporate in vacuum to get 2.5 g 1-methyl-5-methoxy-DMT.

Dialkyltryptamines AP 294,486(1961)

Convert indole to indolyl-3-methyl-ketone (I) by treating indolyl- Mg-Br (preparation already described) with acetyl-Cl, by treating indole in POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole with diketene (ACS 22,1064(1968)). 15.9 g (I) in 50 ml methanol; cool, stir and add dropwise 16 g Brz. Reflux 1 1/2 hours on water bath; cool, filter, wash with ether and recrystallize-methanol to get 18 g indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (11) in 60 ml warm isopropanol and add 11 g 38% aqueous DMA (or equimolar amount other amine); reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g indolyl-3-dimethylamino- methyl ketone (III). Add 4.6 g (0.02 M) (III) in 30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml tetrahydrofuran, stir one-half hour at room temperature and reflux two hours. Add a little water dropwise and extract the precipitate with acetone. Dry, evaporate in vacuum the combined organic phases to get an oil which will precipitate with ether-petroleum ether to give DMT. (III) should be tested for psychedelic activity.

Dialkyltryptamines BCSJ 11,221(1936), BSC 2291(1966)

30 g 5-methoxy-indolyl-3-acetonitrile is heated with KOH in aqueous methanol until no more ammonia is evolved (about 20 hours). Evaporate the methanol in vacuum and extract the water remaining with ether. Acidify the aqueous layer with HCl to precipitate 28 g 5-methoxy-tryptophol (I). Alternatively, dissolve 2.3 g indole in 15 ml glacial acetic acid and 5 ml acetic anhydride. Add with stirring 0.025M ethylene oxide, heat to 70ø for 25 hours, then hold at 20o for 50 hours in a closed flask. Pour into water and extract with ether. Wash with water, dry, evaporate in vacuum and saponify (e.g., heat with NaOH) the residue to get 1.5 g tryptophol (can purify on alumina; benzene elutes indole, ether elutes tryptophol). 2g (I) or tryptophol in 100 ml ether. Mix with 1 g PBr3 dissolved in ether and let stand 12 hours at room temperature. Decant the liquid from the precipitate; wash with water and NaHCO3 and dry, evaporate in vacuum the ether to get 1.3 g of the oily bromide (II). 1 g (II), 4 ml methanol, 4 ml 33% aqueous DMA (or DEA etc.) and heat on steam bath in sealed container 15 hours. Acidify with about 50 ml dilute HCl, extract with ether and dry, evaporate in vacuum the ether to get about 0.5 g DMT or analog.

Dialkyltryptamines BSC 1335(1966)

To 600 ml liquid NH3 add 23.5 g Na: 40 g Na-amide are thus prepared and the NH3 evaporated in vacuum. Mix 170 g 5-CI-2-methoxy-phenylaceto- nitrile (preparation given elsewhere) in 900 ml benzene with the Na-amide and stir and reflux two hours. Cool to 40ø and add dropwise 111 g 2-dimethylaminochloroethane (or diethyl etc. analogs) prepared freshly in benzene as described in a previous method, or use the base freshly distilled. Reflux two hours, cool and add a little ethanol and water and extract the amine by evaporating in vacuum or pouring on cool water and filtering to get 157 g (I) (recrystallize-petroleum ether). 105 g (I) in 150 ml methanol containing 15% NH3. Hydrogenate at 50ø, 70 kg pressure, in presence of Raney-Ni. Filter, dry and evaporate in vacuum to get 97 g of the phenethylamine (II). Cyclise (II) with Na and naphthalene as described later for 4-methoxyindole to get the yellow, oily indoline (111) (recrystallize-ethanol). Test this for activity. If desired, the noncyclised material can be eliminated by tosylation. 3.1 g (III), preferably as the HCl salt, 200 ml water; stir and heat fifteen hours with 10 g Raney-Ni and 1.5 g maleic anhydride. Filter, dry and evaporate in vacuum to get 4-methoxy-DMT.


A: CCCC 22,1848 (1957). 5.5 g indole, 15 ml cyclohexan, 1/2 g copper. Reflux and add dropwise 2.9 g diazoacetone. After a time, the reaction goes very rapidly and forms two layers. Filter, evaporate in vacuum or distill (130-145/0.2) to get 2.6 g 3-indolyl-acetone (I). A (Alternative): JCS 3175( 1952). 2 g 3-indolyl-acetic acid (preparation given elsewhere here), 1.55 g freshly fused sodium acetate, 5 ml acetic anhydride. Heat I 35-140ø on oil bath for eighteen hours; cool, wash with water and extract with CHCl3-ether ( 1:4). Wash organic phase with 3x20 ml saturated KHCO3 and dry, evaporate in vacuum to get the 1-acetyl-3-indolyl- acetone, which can be reduced to the alpha-methyl-tryptophol derivative with lithium aluminum hydride, and then converted to the dialkyltryptamine as already described (as can (I)), or used in step B, or reduced to (I) as follows: dissolve 1 g in 1 ml 1 N Na-methoxide in methanol and 60 ml methanol, and keep at 40ø for 10 minutes: acidify with dilute HCl and extract with ether. Dry, evaporate in vacuum to get (I) (recrystallize-methanol).

A (Alternative): JCS 2834(1962). 4.8 g Mg turnings, 32 g ethyl iodide in 20 ml dry anisole. Cool to 0ø and add dropwise 15.6 g indole in 20 ml anisole. Stir one-half hour at 20ø; cool to 0ø and treat with 20 ml prop-2-ynyl-bromide in 10 ml anisole over 20 minutes. Continue stirring one hour at 0ø and let stand at room temperature twelve hours. Cool to 0ø, add 100 ml ether, 200 ml water, 12 ml glacial acetic acid, 100 ml water, and extract with 5x25 ml ether. Wash with NaHCO3 and dry, evaporate in vacuum the extract to get 8 g oily material which precipitates on standing in refrigerator. Add 1/2g HgSO4 to 100 ml 2N sulfuric acid; stir and heat on steam bath and add 15 g of the precipitate in 100 ml ethanol. Stir and heat two hours and pour into water. Basify with NaHCO3 to get 3 g (I) (recrystallize-benzene).

B: JMC 9,343(1966). 3.3 g (I) in 100 ml ethanol; reduce over palladium-carbon catalyst in presence of 0.04 M DEA (or other amine). After two hours filter and evaporate in vacuum to get the DET or analog.

Methylethyltryptamines HCA 49,1199(1966)

82 ml acetic anhydride, 35 ml formic acid; heat two hours at 50-60ø with stirring and then add dropwise a solution of 100 g 4-benzyloxytryptamine (or equimolar amount other tryptamine) in 250 ml tetrahydrofuran. Cool to room temperature and stand twelve hours. Evaporate in vacuum, add 100 ml water and let stand two hours to precipitate the oily N-formyltryptamine (I) (recrystallize- 700 ml 50% ethanol). 35 g (I) in I 50 ml tetrahydrofuran; add dropwise to 20 g lithium aluminum hydride in 400 ml tetrahydrofuran and reflux twelve hours. Cool to 15o, slowly add 35 ml ethyl acetate and reflux two hours. Slowly add 10 ml water, 10 ml 15% NaOH, 30 ml water. Filter, wash precipitate with tetrahydrofuran and evaporate in vacuum to get 20 g 4-benzyloxymethylethyltryptamine (II) or analog (can recrystallize by dissolving in 100 ml methanol and precipitating with 10 g oxalic acid (anhydrous)).

Alternatively, dissolve 220 g 4-benzyloxy-3-indoleacetic acid (or equimolar amount other indoleacetic acid) in 2 L absolute methanol and reflux six hours in the presence of 20 g Dowex 50x8 sulfonic acid resin. Filter (decolor with carbon if desired) and concentrate below 35ø until precipitation starts; then cool to precipitate and filter to get 200 g of the methyl ester. Add 200 g of the ester to 600 ml 40% aqueous methylamine over twelve hours with vigorous stirring. Filter, wash precipitate with water and dry to get 187 g of the N-methyl-acetamide (reflux two hours in 500 ml benzene to remove unreacted ester). 24 g of the acetamide in 300 ml tetrahydrofuran is added dropwise to 10 g lithium aluminum hydride in 300 ml tetrahydrofuran; reflux ten hours, cool to 15ø and add dropwise with stirring 50 ml ethyl acetate. Reflux two hours and proceed as above to get 15 g (II) or analog.

Dialkyltryptamines JACS 84,4917(1962) Illustrated for the piperidine analog of DMT

2.5 g methyl or ethyl-indoleacetic acid (see previous method and elsewhere for preparation), 12 ml dry piperidine and reflux twentyfour hours. Evaporate in vacuum, dissolve residue in CHCl3; wash with dilute HCl, NaHCO3, and dry and evaporate in vacuum to get 2.6 g 3-indolyl-aceto-piperidide (I) (test for activity). 2.6 g (I) in 80 ml tetrahydrofuran; add 2.5 g lithium aluminum hydride in 200 ml ether and reflux five hours. Carefully add a little water until bubbling stops. Filter, dry and evaporate in vacuum to get the piperidine analog of DMT.

Tryptamine from Tryptophan JCS 3993(1965)

10 g tryptophan in 500 ml diphenyl ether; reflux one hour under N2; cool and extract with 3x40 ml 2N HCl. Wash extract with ether, basify with 6N NaOH and extract with 5X50 ml ether. Wash extract with water, NaCl; dry and evaporate in vacuum and recrystallize-benzene to get tryptamine which can be alkylated to dialkyltryptamine as described previously. (Tryptophan, if oxidized by H2O2 and cyclised with HCl, gives a psychedelic compound.) Much interest has been generated by the mention of tryptophan oxidation to a psychedelic compound, but the original reference gives no details of the method.

Dialkyltryptamines CCCC 24,3984(1959)

A: 4 g 3-indoleacetic acid (I) in ether. Treat with PCl5 as described elsewhere here to get 2.7 g of the chloride (II). Dissolve 2.7 g (II) in 40 ml ethyl acetate and add 2 ml piperidine (or equimolar amount other amine), 3.5 ml N-ethyl-piperidine in 40 ml ethyl acetate. Let stand three hours at room temperature and filter. Wash filtrate with 1N HCl, 10% Na carbonate and evaporate in vacuum to get 1 g of the amide (III) (test for activity). Add 1 g (III) in 25 ml ether to 1.4 g lithium aluminum hydride in 50 ml ether; stir four hours at room temperature and reflux one-half hour. Cool and carefully add water until no more bubbling. Add 3 ml 20% NaOH and dry, evaporate in vacuum to get 1 g piperidine analog of DMT (IV). A (Alternative): Treat 4 g (I) in pyridine with SOCl2 as described elsewhere here to get (II). Treat (II) with 2.3 g triethylamine and 2 g piperedine (or other amine) in 5 ml ether. Stir fifteen hours at room temperature; extract with 200 ml water, and after precipitation, wash precipitate with 10% Na carbonate, 3N HCl and dry, evaporate in vacuum the ether solution to get (III). Reduce (III) to (IV) as above or with the NaBH4 method or possibly with hydrogenation.

A (Alternative): To 6 g (I) in 250 ml ether add 3.1 g piperidine (or other amine) in 20 ml ether. Let precipitate form and filter. Heat 7 g precipitate three-and-one-half hours at 190-215ø; cool and dissolve in 100 ml ether. Wash with 10% K carbonate and 5N HCl and evaporate in vacuum to get (III), which is reduced to (IV) as above.

Dialkyltryptamines JCS 7175,7179( 1965)

6.3 g N-Methyltryptamine in 40 ml methylformate; heat in autoclave six hours at 100ø and evaporate in vacuum to get 7.4 g precipitate (test for activity). Dissolve precipitate in 50 ml tetrahydrofuran and add to 2.6 g lithium aluminum hydride in 50 ml tetrahydrofuran and reflux three hours. Carefully add a little water or methanol; filter, evaporate in vacuum to get DMT or analog. This paper also gives four ways to prepare hydroxylamine analogs of DMT, but their activity is unknown.

5-Methoxy-DET BSC 1062(1962)

If 3-methoxy-aniline is used, 6-methoxy-DET will probably result, but if 3,5-dimethoxyaniline is used, 4,6-dimethoxy-DET should be obtained. A: 1M p-methoxy-aniline (p-anisidine), 0.5 M ethyl-gamma-Br-acetoacetate (brominate as described above for 1-methyl-DET synthesis); cool and add 250 ml ether. Filter, evaporate in vacuum and reflux residue fifteen hours with 60 g ZnCl2 in 250 ml ethanol. Evaporate in vacuum, wash precipitate with water and dissolve residue in benzene. Wash with 4N HCl and water and dry, evaporate in vacuum. Reflux precipitate two hours in ethanol-KOH to get about 70% yield of 5-methoxy-indoleacetic acid (I). B: Dissolve 4.26 g triethylamine and 8 g (I) in 200 ml CHCl3; cool to -5ø, add rapidly 4.58 g ethyl-CI-carbonate and agitate fifteen minutes. Bubble dry NH3 through for five minutes (can possibly substitute concentrated NH4OH) and let stand one hour at room temperature. Add water, wash with NaHCO3 and water and dry, evaporate in vacuum the CHCl3 to get 5-methoxy-diethyl-indolyl-acetoacetamide(II). Test this for activity. B (Alternative): 0.5 g (I) and 0.28 g triethylamine in 5 ml methylene Cl. Add 0.33 g dicyclohexylcarbodiimide and let stand for sixteen hours at room temperature. Add a little glacial acetic acid, wash with dilute HCl, NaHCO3 and water and dry, evaporate in vacuum to get (II). B (Alternative): Do not reflux the precipitate in ethanol-KOH in the last part of step A. Heat 8 g of the precipitate with equimolar amount DEA (or other amine) in 80 ml methanol in a sealed bomb or tube in autoclave for twenty-four hours at 105ø and filter, evaporate in vacuum to get (II) (recrystallize-ethanol). B (Alternative): 20 g of the unrefluxed precipitate (ethyl-ester of (I)) from last part of step A in 100 ml ether. Add dropwise to a solution of 4 g lithium aluminum hydride in 900 ml ether at 0ø. Reflux three hours and isolate the resulting tryptophol as described earlier. Dissolve 3 g of the tryptophol in 140 ml ether and stir at 0ø. Add dropwise 1.8 g PBr3 in 30 ml ether and let stand sixteen hours at room temperature. Decant the ether and wash the precipitate with ether. Wash ether with water, NaHCO3 and water, and dry, evaporate in vacuum the ether to get the bromide (recrystallize-ethanol). 2 g of the bromide and 1.5 g piperidine (or equimolar amount DEA, etc.) in 65 ml methanol and heat in sealed tube fifteen hours at 100ø (or let stand room temperature twenty-four hours). Evaporate in vacuum to get the 5-methoxy-dialkyltryptamine. C: Reduce (II) to 5-methoxy-DET or analog with lithium aluminum hydride or diborane as described previously.

Tryptamine CA 54,13018( 1960)

15.4 g indole (or substituted indole) in 40 ml ether under N2; add to 50 ml methyl MgBr in ether (2.62 M) and reflux fifteen minutes. Cool on ice bath and add 68 ml ethyleneimine in 30 ml dry xylene. Stir 1 1/2 hours at room temperature (add xylene to keep volume constant), reflux one hour and cool to room temperature. Add dropwise 75 ml water and take pH to 1 with HC1. Filter, wash precipitate with ether and dissolve in 150 ml hot water. Cool to 10ø for fifteen minutes and decolorize. Filter, neutralize with 80 ml 10 N NaOH and stir at 5ø. Filter and dry to get the tryptamine which can be converted to the dialkyltryptamine as described previously. More tryptamine can be had by adjusting pH of solution to 10 with NH3 (or NH4OH) and extract with methylene Cl: evaporate in vacuum.

Dialkyltryptamines BSC 1417(1965)

Dissolve 456 g o-vanillin (2-OH-3-methoxy-benzaldehyde) and 150 g NaOH in 1 L water and add dropwise 660 g benzenesulfonyl-Cl. Filter, wash precipitate with water, ethanol and recrystallize-acetic acid to get 805 g of the benzenesulfonate (I). Can probably also protect the OH group by methylating with dimethylsulfate as described elsewhere here. However, OH protection may be unnecessary to yield an active final product. Quickly add 250 g (I) to 2.5 L fuming HNO3 at 0ø and let stand five minutes. Pour onto ice and filter after melting. Wash precipitate with water, ethanol and recrystallize-acetic acid to get 171 g (II). Dissolve 170 g (II) in 2 L methanol and reflux ten minutes. With vigorous stirring add 100 g K2CO3 in 200 ml water and 400 ml methanol. Reflux one-half hour, filter and dissolve precipitate in boiling water; acidify to precipitate 6-NO2-o-vanillin (about 86 g) (III). Dissolve 50 g (III) and 40 g K2CO3 in 1.2 L DMF and 60 ml water. Stir 1 1/2 hours and add dropwise benzyl-Cl and continue stirring eighteen hours under N2 if possible and in the presence of NaI. Precipitate by pouring on ice; filter, dry and recrystallize-benzene-petroleum ether to get about 52 g 2-benzyloxy-3-methoxy-6-NO7-benzaldehyde (1V). Again, methylation can probably be done instead, and this step may be unnecessary. To 50 g (1V) in 1 L ethanol add 18 ml nitromethane, and then at -15ø add 25 g K2CO3 (or KOH) in 40 ml water and 400 ml ethanol in small portions over a period of one hour. Keep two hours at -10ø, then acidify with 50 ml concentrated HCl (keep temperature below 0ø). Add 2 L water, filter (or extract five times with ether and dry, evaporate in vacuum). Heat precipitate five minutes at 140ø with 60 g anhydrous sodium acetate and 250 ml acetic anhydride and pour on ice, filter to get 52 g of the nitrostyrene (V) (recrystallize-methanol). 60 g (V) and 300 g iron filings in 1 L 80% acetic acid and heat forty minutes at 95ø. Add 1 L saturated Na bisulfite and extract with benzene; dry and evaporate in vacuum (can chromatograph on alumina with benzene) to get 33 g 4-benzyloxy-5-methoxy-indole (VI) (recrystallize-benzene-petroleum ether), which can be converted to the dialkyltryptamine by any of the methods described here or as follows. 320 ml dioxane, 320 ml glacial acetic acid, 24.8 g 40% formaldehyde, 25 g DMA (or other amine) in 40% aqueous solution. To this stirred mixture at 0ø add 34 g (VI) in 300 ml dioxane, let stand twelve hours and pour on ice. Basify, filter and extract with HCl; basify and extract with ether (or just dry and evaporate in vacuum after pouring on ice) to get 30 g of the gramine (VII) (recrystallize-ethyl acetate). To 20 g (VII) in 400 ml methanol add a solution of 9 g KCN in 20 ml water and 25 g methyl iodide below 10ø. Stir at room temperature for twenty-four hours and evaporate in vacuum. Dissolve residue in ether, wash with dilute HCl, NaHCO3, water and dry, evaporate in vacuum to get the acetonitrile (VIII) (recrystallize-ethanol). Dissolve 14 g (VIII) in 300 ml 33% ethanol solution of DMA (or other amine) and hydrogenate at 40o and 100 atmospheres pressure in presence of 3 g Raney-Ni for about three hours. Filter, evaporate in vacuum (can dissolve residue in ether, dry and evaporate in vacuum) to get 7 g of the dialkyltryptamine.

Indoleacetonitrile BER 58,2043(1925)

To the Grignard reagent prepared from 2.4 g Mg, 10 ml anisole and 16 g ethyl iodide, add 7.8 g indole in 10 ml anisole. Stir and cool to 0ø. Slowly add dropwise 5.5 g Cl-acetonitrile in 40 ml anisole. Warm to room temperature and stir; heat to 60-70ø on water bath (a reddish precipitate forms over about twenty minutes). Cool and purify and convert to the dialkyltryptamine as described earlier.

Tryptamines JOC 24,894(1959)

Add a 1 M excess of nitroethylene dropwise to liquid 5-benzyloxyindole (or other indole) on a steam bath over two hours. Cool, filter and recrystallize from methylene chloride-petroleum ether. Hydrogenate at two atmospheres over 10% palladium-carbon catalyst to get 5-OH-tryptamine in 30% yield. Can probably also reduce with lithium aluminum hydride or diborane methods.

4-Nitration of 5-methoxy-DMT JMC 12,321 (1969)

Dissolve 35 g 5-methoxy-DMT (or analog) in 100 ml glacial acetic acid, cool to 10ø, stir and add dropwise a solution of 30 ml concentrated HNO3 in 50 ml glacial acetic acid over one-half hour. Let warm to room temperature, stir eight hours and dilute with 1 L ice-water. Filter, wash precipitate with water and dry to get 4.5 g 5-methoxy-4-NO2-DMT (recrystallize-methanol).

Methylation of OH indoles JOC 23,1977(1958), CA 74,53525 (1971)

The procedure will not work for tryptamines. This and the two following procedures may be used to protect the OH group during subsequent steps, or simply to give the alkyloxy compounds which may be more active than the OH compounds. Dissolve the OH-indole in ethanol (0.14 M in 50 ml) and add 28 ml dimethylsulfate and 1.2 g Na hydrosulfite. Add slowly with stirring and cooling (under N2 if possible) 12 g NaOH dissolved in 26 ml water (keep temperature at 20-25ø). Heat to 70ø for one-half hour, cool and dilute with an equal volume water. Extract the yellow oil into ether-benzene and dry, filter, and evaporate in vacuum to get the methoxyùindole.

Methylation of OH-tryptamines LAC 513,16( 1934)

This should work well with OH-dialkyltryptamines Dissolve 1 g OH-tryptamine in methanol or ether; add 2.5 g diazomethane in ether and heat twenty hours. Evaporate in vacuum to get the methoxy-tryptamine. Acetylation of OH-tryptamines May require modification for OH-indoles, but probably not for OH-dialkyltryptamines. Dissolve 4.1 g OH-tryptamine in 20 ml 1 N NaOH and evaporate to dryness under N2. Dry in vacuum at 90ø and dissolve in 50 ml dimethoxyethane. Add to 1.9 g acetyl-Cl in 50 ml dimethoxyethane and stir four hours at room temperature. Add to dilute NaHCO3 and CHCl3; shake and dry, evaporate in vacuum the CHCl3 layer to get the acetyltryptamine. This will also work with benzoyl-Cl for benzoylation and with chlorsulfonic acid for sulfonylation. Acetylation can also be done with acetic anhydride in NaOH at 5ø.

Demethylation of methoxy-oxyindoles BER 96,253(1963) The procedure may require modification for tryptamines, and indoles.

Mix 1.63 g 4-methoxy-oxyindole and 1.5 g finely ground AlCl3 and heat ten minutes at 220-230ø in oil bath. Cool, powder and dissolve in ice water, evaporate in vacuum to get 4-OH-oxyindole (recrystallize-water).

4-Substituted Indoles from 5-OH-indoles HCA 51,1209(1968); see also: TL4459(1966), JOC 35,3764(1970), TET 26,3685(1970)

This method, although described for indoles, probably also works with 5-OH-tryptamine (serotonin), and 5-OH-DMT (bufotenin); with compounds of the latter type, orally active psilocybin analogs will be obtained in one step. Dissolve 5 g 5-OH-indole (or analog) in 25 ml ethanol. Add 5.5 g 33% aqueous dimethylamine (or other amine, e.g., piperidine) and add slowly dropwise with stirring 3.5 g 38% aqueous formaldehyde. Two minutes after the end of the addition shake with water and CHCl3: dry and evaporate in vacuum the CHCl3 phase to get 5 g oily 4-dimethyl-aminomethyl-5-OH-indole (I) (can chromatograph on 100 g alumina and elute with ethyl acetate). It has been claimed that this method does not work.

Alternatively (CA 72,66732(1970)), add 1.6 g 5-OH-indole, 1g bis-dimethyl-aminomethane in 5 ml dioxane. Heat 2 1/2 hours on water bath to get 1 g (I) (recrystallize-methanol-dimethylformamide). For the transformation of the dimethylaminomethyl substituent of (I) into methyl, aminomethyl, formyl or cyanomethyl see BSC 2046(1973).

4-Hydroxydimethyltryptamine (Psilocin) from DMT C.R. Acad. Sci. Paris 275,613(1972) See also C.R.A.S.P. 269,51(1969) and BSC 1523(1959).

Mix 0.01 M dimethyltryptamine, 0.02 M phosphate buffer pH 7.2 containing 5 mM ascorbic acid, 0.02 M disodium EDTA and 0.01 M ferrous sulfate (CuCl may substitute) and add with stirring at 20-22ø 0.02M H2O2 (0.01 M may increase yield). Let reaction proceed to completion (2 hours or less) and extract with ethyl acetate. Dry and evaporate in vacuum to get about 30% yield of psilocin. The product, which contains the other OH-DMT's as well, can be chromatographed on silica thin layer with t-butanol-acetic acid-water (ACS 22,1210 (1968)) or on a 5% alumina-Nickel column or 10% alumina-Nickel plate with CHCl3-methanol and the psilocin eluted with methanol.

Tryptamine from Tryptophan Synthesis 475(Sept. 1972)

Cently reflux a suspension of 250 mg L-tryptophan in 10g warm diphenylmethane in a stream of nitrogen (if possible) for 5-20 minutes until there is no more CO2 evolution. Cool and evaporate in vacuum or treat with 20 ml benzene saturated with dry HCl and filter, wash precipitate with hexane and dry to get about 60% yield of tryptamine.

4-Acetylation of 5-OH-indoles BCSJ 44,550(1971)

To 2 g 5-OH-indole (or analog) in 50 ml nitrobenzene add 4 g AlCl3 in 50 ml nitrobenzene. Add 1.26 g Acetyl-Cl and heat three hours at 50ø; evaporate in vacuum or add dilute HCl to get 1g 4-Acetyl-5-OH-indole (recrystallize-ethyl acetate).

4-Substituted Tryptamines JMC 8,200(1965)

Heat 85.5 g 3-carbethoxy-2-piperidone and 30 g KOH in 1 L water for twelve hours at 30o. Filter, cool to 0ø, add 50 ml 6N HCl. Prepare a fresh solution by diazotizing at 0-5ø a mixture of 85 g 3-amino-4-Cl-acetophenone, 250 ml concentrated HCl and 750 ml water with a solution of 36 g Na nitrite in 125 ml water. Add the piperidone solution at 0ø to the diazonium salt solution and stir five hours at 10ø. Filter, wash precipitate with water to get 80% yield of the hydrazone (I) (recrystallize-95% ethanol). Reflux 62 g (I) in 310 ml 88% formic acid to get 40 g of the carboline (II) (recrystallize-absolute ethanol) (test for activity). Reflux 40 g (II), 100 g KOH, 480 ml ethanol and 360 ml water for eighteen hours and evaporate in vacuum. Add 480 ml water to the residue, cool and adjust pH to 6 with glacial acetic acid. Scratch glass to precipitate; filter, wash precipitate with cold water to get 41 g 4-acetyl-2-COOH-7-Cl-tryptamine (recrystallize-50% ethanol) which can be alkylated to the active dialkyltryptamine as described elsewhere here.

Alpha,alpha-DMT from Gramine or Indole-3-aldehyde JCS 7165 (1965),3493(1958)

81 g (0.465 M) gramine (or analog), 405 ml 2-nitropropane and 20.4 g NaOH are stirred and boiled under nitrogen for 20 hours. Cool and treat with excess 2N acetic acid and ether and wash the ether Iayer with 2N acetic acid and water and dry, evaporate in vacuum to get ca. 90% 3-(2-methyl-2-nitropropyl)indole (1a) (recrystallize-benzene-light petroleum). See JCS 3493( 1958) for the use of the indole-3-aldehyde to get the corresponding nitronium salt (1b). (1a) is then reduced (e.g., with PtO at 20ø/1 Atm. in EtOH or one of the methods given elsehwere here) or (1b) is reduced (e.g., with lithium aluminum hydride as described many times, e.g., JMC 6,378(1963)) to give the tryptamine, which can be alkylated as described. This paper also gives a route to other alpha and beta mono and disubstituted tryptamines.

Reduction of Indolyglyoxamides with Diborane JOC 38,1504(1973),TET 1145(1968)

A solution of 7mM of the indolyglyoxamide in 160 ml tetrahydrofuran and 30 ml (30mM) 1.0M borane in THF is refluxed 2 hours and cooled. Carefully add water, then evaporate in vacuum and dissolve residue in ether. Wash twice with saturated saline, dry and evaporate in vacuum. Triturate with ether and filter to get the tryptamine-borane in ca. 30% yield. Diss. 200 mg in 2 ml xylene and 2 mI octene-1 and reflux 4 hours. Cool, dilute with hexane and filter to get ca. 80 mg white tryptamine (or dialkyltryptamine) (recrystallize-acetone-hexane etc.).

Alternatively, 63 g (0.45M) BF3 etherate in 180 ml diglyme is added dropwise with stirring to 0.15 M of the indolyglyoxamide and 12 g NaBH4 in 300 ml diglyme. Stir 12 hours at room temperature and evaporate in vacuum. Boil residue 2 hours with methanolic NaOH and evaporate in vacuum. Take up residue in ether, wash with water and dry, evaporate in vacuum to get the dialkyltryptamine in ca. 80% yield.

Indole Syntheses

4-7-Dimethoxyindoles Farmaco 25,972(1970)

Heat 1 g Cl-acetone and 7 g 2,5-dimethoxyaniline (or analog) at boiling until complete fusion; then one-half hour at 180ø on a metal bath. Cool, dissolve in a little ethanol and pour into 100 ml 7% HCl. Cool, filter and dry (can distill 100/.001) to get 160 mg 4,7-dimethoxy-2-methyl- indole (recrystallize-benzene:petroleum ether, 1:1).

4-Carboxyindoles CJC 49,2784,2797(1971)

To a stirred solution of 0.05 M 2-methyl-5-nitroisoquinolinium iodide in 250 ml water, add a solution of 11.2 g KOH in 110 ml water and immediately add a solution of 49.4 g K ferricyanide in 300 ml water; stir one hour at room temperature. Add 50 ml methylene chloride and 100 ml benzene and stir until solids dissolve. Separate organic phase and extract aqueous phase with benzene. Wash combined organic layers with 10% HCl, water and dry and evaporate in vacuum to get about 90% yield of 2-methyl-5-nitroisocarbostyril (I) (recrystallize-cyclohexane). Mix 8.16g (I), 18 ml acetic anhydride, 5 drops concentrated sulfuric acid and heat on steam bath four hours. Cool to room temperature, add 25 ml water and heat on steam bath until a single phase is produced (about ten minutes). Pour into a large volume of water, extract with methylene chloride, wash methylene chloride five times with water and dry and evaporate in vacuum to get 6.8 g 2-methyl-4-acetyl-5-nitro-isocarbostyril (II) (recrystallize- benzene). 1.64 g (ll), 200 mg 10% palladium-carbon in 100 ml ethanol and hydrogenate at room temperature and initial pressure of 60 pounds per square inch for one hour. Transfer to 500 ml round bottom flask under N2. Evaporate in vacuum and add solution of 8.4 g KOH in 120 ml 50% dimethylsulfoxide to residue. Stir and reflux seventeen hours under N2 and then add concentrated HC1 until the dissolved silica precipitates from the basic solution. Filter, wash precipitate with water and acidify filtrate with concentrated HCl. Extract filtrate with ethyl acetate and then shake ethyl acetate with Na carbonate (100g/L). Acidify solution with concentrated HCl and extract with ethyl acetate. Wash extract with water and dry, evaporate in vacuum to get 400 mg 2-methyl-indole-4-COOH (recrystallize-60% ethanol). Can dissolve in methanol and chromatograph on 5 g silica gel-250 ml ethyl acetate elutes the indole.

4-OH-Indole JCS 1605(1948)

Dissolve 0. 7 g KOH in 10 ml ethanol, cool to -10ø and add with stirring over twenty minutes to 1 g 2-nitro-6-OH-benzaldehyde and 0.4 g nitromethane in ethanol at -10ø. Acidify with cold HCl, add water and extract with ether. Dry and evaporate in vacuum the ether to get a yellow oil. Warm the oil with 2 g Na acetate and 3 ml acetic anhydride for fifteen minutes. Add 20 ml water, separate the precipitate and add water to crystallize about 1.3 g 2,beta-dinitro-6-acetoxy-styrene (I) (recrystallize-ethanol). Warm gently a solution of 0.5 g (I), 2 g iron filings, 4 ml ethanol and 4 ml glacial acetic acid until hydrogen evolution is vigorous and continue to warm gently for ten minutes. Filter, wash precipitate with a little warm ethanol and add water to filtrate. Basify with Na carbonate, extract three times with ether and dry and evaporate in vacuum the ether to get about 0.1 g 4-acetoxyindole (II) (recrystallize-petroleum ether). If 4-OH-indole is desired, dissolve 0.1 g (II) in 3 ml methanol and saturate at 0ø with NH3 and keep below 5ø for sixteen hours. Evaporate in vacuum, add 50 ml water and extract with ether, dry and evaporate in vacuum to get 4-OH-indole (recrystallize-petroleum ether).

4-Substituted Indoles MON 100,1599(1969),101,161(1970)

To a solution of 1.84 g Na metal in 60 ml ethanol at 5-10ø add over 1/2 hour with vigorous stirring a mixture of 0.08 M ethyl azidoacetate and 0.02 M 2 (or 2,5; 2,3 etc. but not 6) substituted benzaldehyde and continue stirring at 5-10ø until nitrogen evolution ceases (about 1/2-1 hour); then stop immediately and rapidly evaporate in vacuum 1/2 the ethanol (keep temperature below 30ø). Basify the solution with solid NH4Cl, dilute with 500 ml water and extract 3 times with ether. Filter, wash with water to neutrality and dry, evaporate in vacuum the ether (or can dissolve the residue in petroleum ether, or 1:1 petroleum ether:benzene for methoxy compounds, and filter through silica gel) to get the ethyl-alpha-azido- cinnamates (I) in about 50% yield. Store in freezer until used in next step. Dissolve 1g (I) in 100 ml p-xylol and reflux 10 minutes. Evaporate in vacuum (or add 5 ml pentane, filter, evaporate in vacuum) to get about 90% yield of the 4-substituted 2-carbethoxyindole which can be decarboxylated as described elsewhere here.

4-Methoxy-indole JCS 3909(1952)

4.5 g 2-methoxy-6-nitro-benzyl-Cl (JOC 6,217(1941)), 4.5 ml ethanol, 1.6 g KCN, 1.5 ml water; reflux six hours, cool and extract with ether. Wash with water, dry and evaporate in vacuum the extract to get 4 g of the cyanide (I). 4.2 g (I), 125 ml concentrated HCl; reflux six hours, cool and filter. Add precipitate to dilute aqueous Na carbonate; stir and warm until dissolved and filter. Acidify and let stand one hour at 0ø; filter to get 1.8 g 2-methoxy-6-nitro-phenylacetic acid (II). 5 g (II) in 100 ml glacial acetic acid catalyzed with palladium-carbon at room temperature gives 3.8 g 4-methoxy-indole. Filter, evaporate in vacuum and recrystallize-1:5 ethanol/water.

Indoles CA 74,87819(1971)

To 30 g polyphosphoric acid (prepared by adding 2:1 P2O5:85% phosphoric acid) add 3.3 g phenylhydrazine and 4 g phenylacetone (or equimolar amount ethylacetone) and heat twenty minutes at 130-140ø in N2 stream. Pour over 200 ml water and extract with methylene chloride to get about 45% yield 2-benzylindole or 30% 2-ethyl-indole (recrystallize-ether).

Indole-3-acetic acid CA 72,66815(1970)

To 21.6 g phenylhydrazine dissolved in 300 ml 0.3N sulfuric acid, add 9.8 g concentrated sulfuric acid. Add dropwise with stirring and heating at 100ø, 11.6 g methyl-beta-formyl-propionate in 300 ml 0.3 N sulfuric acid and continue heating six hours to get 14 g indole-3-acetic acid. Convert to the dialkyltryptamine as already described.

Alpha,alpha-Dimethyl-indoleacetic acid ACS 8,122( 1954)

117 g indole in 1 L acetone; add 220 g NaOH pellets and stir in three-neck, 3 L flask with thermometer and dropping funnel. Cool in ice bath and add CHCl3 dropwise over about two hours, keeping temperature below 15ø. Let warm to room temperature over one hour with stirring and continue stirring four hours. Warm on water bath and evaporate the acetone. Dissolve the residue in 1.5 L water and extract four times with ether (dry and evaporate in vacuum the extract to get about 50 g unreacted indole). Acidify the aqueous phase with dilute sulfuric acid and extract the oil with ether. Wash with water and dry and evaporate in vacuum the extract to get the title compound (recrystallize-aqueous methanol), which can be converted to the dialkyltryptamine as described elsewhere here.

4-Nitroindole JACS 80,4621 (1958) -cf. Chem.Het.Cpds.(Russian) 37(1973).

21 g ethyl-pyruvate-meta-nitro-phenylhydrazone (I) in 100 g polyphosphoric acid; warm in oil bath with stirring and cool to keep temperature below 125o. Stir at 105-11 So for one-half hour and then add ice water. Filter, extract water with ether to remove unreacted (I), wash precipitate with water and dry to get 9.5 g ethyl-4-nitroindole-2-carboxylate (II) (recrystallize-ethanol or 800 ml benzene). It may be possible to use this directly for diakyltryptamine synthesis, otherwise proceed as follows. Dissolve 9.7g (II) in 75 ml hot ethanol and add solution of 7.5 g KOH in 18 ml water, let stand six hours at room temperature. Add 350 ml warm water and add the mixture to excess dilute HCl so that the pH is acid. Filter, wash precipitate with water and dry to get 9 g 4-nitroindole-2-COOH (III). 11.3 g (III) and 1.1 g CuO or Cu powder in 90 ml quinoline and reflux 2 hours. Add 100 ml concentrated HCl and 200 g ice; filter and extract both precipitate and filtrate with ether. Evaporate in vacuum or wash with dilute NaHCO3, water and dry and evaporate in vacuum to get the title compound (recrystallize-dilute ethanol).

Methoxyindoles from Methoxynitrostyrenes JOC 22,331(1957)

Illustrated for 5,6,7-trimethoxyindole (for the trimethyl-indole see JOC 25,1542(1960)). 2-methoxy-beta-nitro-styrene, if nitrated at the 6 position and used in place of (I), should give 4-methoxy-indole.

7.9 g 3,4,5-trimethoxy-beta-nitrostyrene (preparation described in mescaline section) in 40 ml acetic anhydride at -8o: stir well and add dropwise 5 ml fuming HNO3. Stir twenty minutes and pour on 200 ml ice water. Add some solid Na carbonate, filter, wash with water to get the 2-nitro derivative (I) (recrystallize-aqueous ethanol). 2.5 g (I) in 18 ml ethanol; add 8.8 g iron powder and 18 ml glacial acetic acid and stir and warm (cooling is eventually necessary). Stir about ten minutes until solution thickens and about five minutes more, then add 50 g Na bisulfite in 220 ml water and extract the indole with 5x200 ml ether. Wash combined extracts with NaHCO3, water, and dry and evaporate in vacuum to get the indole (can purify on alumina, eluting with 1:1 benzene:petroleum ether, discarding the precipitate that won't dissolve in the benzene-petroleum ether).

4-Substituted Indoles from Pyrrolyl Aldehydes J. Prakt. Chem. 315,295(1973)

A mixture of 9.5 g pyrrolyl-2-aldehyde, 29.2 g dimethyl-succinate and NaH (9.6 g of 50% suspension in oil) in 100 ml benzene is stirred at room temperature 6 hours, cooled and carefully acidified with glacial acetic acid. Add water and ether and dry, evaporate in vacuum or work up (JACS 72,501 (1950), JCS 1025(1959)) to get ca. 17 g (80%) 3-methoxycarbonyl-4-(2'-pyrrolyl)-3-butenoic acid (I) (recrystallize-acetone-benzene). A mixture of 12 g (I), 7 g sodium acetate and 70 ml acetic anhydride is left overnight at room temperature with occasional shaking. Then gradually raise the temperature to 70-75ø over 2 hours, maintain for 4 hours and work up (see JCS 1714(1955), 986(1958)) to get ca. 8 g (60%) methyl-4-acetoxy-indole-6-carboxylate (II) (recrystallize-petroleum ether). If desired, this can be converted to 4-OH-indole-6-COOH and 4-methoxyindole-COOH as described in the ref. or decarboxylated as described elsewhere here. If the 1-methyl cpd. is used, 1-Me-indole results.

Dialkyltryptamines from Indoles BSC 1424(1973)

Dissolve 2.75 g anhydrous sodium carbonate in a mixture of 50 ml acetic acid and 25 ml propionic acid. Add 11. 7 g (0.1 M) indole and 8.8 g (0.11M) dimethylamine hydrochloride (or other amine) in 5 ml diglyme. Cool to between zero and minus 5ø and add 11 g chloracetaldehyde hydrate (containing 75% chloracetaldehyde-0.1 M). Stir 1 hour, keeping temperature below zero and put in refrigerator at ca. 5ø for ca. 5 days. Pour on crushed ice and filter out the white, flocculent ppt. Shake the cold acid filtrate with cold ether (vigorous cooling) and separate the ether. Slowly with stirring neutralize by adding NaOH dropwise. Rapidly decant the ether phase, dry rapidly over sodium sulfate and quickly, with stirring, at a low temperature add HCl in ether. Decant the ether and treat the thick oil which formed with a small amount of absolute ethanol to bring about crystallization (add dry ether if necessary). Can recrystallize 3 times from ethanol-ether or acetonitrile to get 8.2 g (32%) alpha-chloromethylgramine (I).

Add 1 g (I) to a suspension of 2.5.g NaBH4 in 75 ml diglyme heated to 55ø with stirring. Heat to 85-90ø and keep at this temperature for 48 hours (the yellow color disappears). After 24 hours, cool and pour on ice. Extract with ethyl acetate and evaporate to get about 37% yield of the oil DMT (or analog). Can purify on 1:1 silica:celite column; benzene elutes the skatole, methanol the DMT (recrystallize-hexane).

4-Acetylindoles from 5-Hydroxyindoles BCS 2046( 1973)

Heat 1.1 g 2-ethoxycarbonyl-5-hydroxyindole/5-OH-indole and perhaps 5-OH-DMT will work) and 0.9 g powdered AlCl3 at 145ø in orthodichlorobenzene. Add 2-3 ml acetylchloride and keep the temperature at 145-150o for 2 hours. Cool and hydrolyze with ice cold 2N HCl. Extract with chloroform and dry, evaporate in vacuum to get 4-acetyl-2-ethoxy-carbonyl- 5-hydroxyindole in ca. 50% yield. This paper also gives a method for brominating the starting cpd. in the 4 position.

5-Methoxy-indole REC 81,317(1961)

Again, if 3,5-dimethoxyaniline is used, 4,6-dimethoxy-indole should result. To 123 g p-anisidine (p-methoxy-aniline) in 1L 15% HCl; add 1 Kg ice and while stirring, quickly add dropwise below the surface, a solution of 75 g NaNO2 in 200 ml water (temperature below 5ø). Add 5 g activated carbon, stir and filter and quickly add filtrate with stirring to a mix of 160 g ethyl-alpha-methyl-acetoacetate in 1 L methanol, 1Kg ice and 820 g Na acetate. Stir two hours and extract with 4x500 ml benzene. Wash extract with water, dry and evaporate in vacuum and dissolve residue in 1/2 L ethanol. Cool to 0ø and quickly add 1/2 L cold ethanol saturated with dry HCl gas (violent boiling). Stir one hour, add 100 ml hot water and refrigerate twelve hours. Filter, wash precipitate with 2x100 ml ethanol, 2x200 ml hot water and dry to get 135 g ethyl-5-methoxy-indole-2-COOH (I). (I) might be used directly to synthesize a dialkyl-tryptamine. 135 g (I) and 56 g KOH in 1 L 90% ethanol; reflux 1 1/2 hours and pour into 6 L water. Acidify with concentrated HCl, filter, wash with water and dry to get 108 g 5-methoxy-indole-2-COOH (II). To a stirred mixture of 45.6 g (II) in 60 ml fresh quinoline, add 2 g Cu chromite and heat to 210-230ø in a metal bath until CO evolution stops (or just heat at 210-230ø five minutes under N2. Cool, filter, dry and evaporate in vacuum or add 1/2 L ether, filter and extract filtrate with 3x200 ml 2N HCl, 3x200 ml water, 2x100 ml 2N NaOH, 2x100 ml water and dry, filter, evaporate in vacuum to get 24 g 5-methoxy-indole.

5-Nitroindole JGC 29,2508(1959); see also JOC 20,1541(1955)

11.9 g indoline dissolved in 150 ml acetic anhydride. Add 8.5 ml concentrated HNO3 dropwise with stirring (temperature 10-12ø). Pour the mixture into water and filter. Add the precipitate (or 1-acetyl-indoline, prepared by boiling indoline in acetic anhydride) to 100 ml concentrated HCl and boil one-half hour. Basify with NaHCO3 (can filter to remove black precipitate formed after adding first portion of NaHCO3) to get 12 g 5-nitro-indoline (I) (recrystallize-heptane). 7.9 g (I) and 11.7 g chloranil in xylene. Reflux ten hours, cool, evaporate in vacuum or wash two times with 20% NaOH, filter, wash xylene with water, 50% HCl, water and dry, evaporate in vacuum to get 5.4 g 5-nitro indole (II). Can reduce (II) to the aminoindole as described for preparation of 4-amino-DMT or as follows. To 5.4 g (11) in 50 ml ethanol add a little Raney-Ni and add dropwise over two hours 100 ml hydrazine hydrate to the boiling solution. Filter, evaporate in vacuum (can distill 190/6) to get 5-NH2-indole (recrystallize-heptane). Can benzoylate by dissolving in benzene and shaking with 20% NaOH and excess benzoyl-Cl, let stand twelve hours and dry, evaporate in vacuum (recrystallize-benzene). The dialkyltryptamine of the benzoylated compound may be more active than that of the amino compound.

4-CN-indole JACS 71,761 (1949) (See BER 89,270 (1956),90,1980(1957) for a more involved method.)

To 23 g Na in 350 ml ethanol add 146 g ethyl-oxalate and 171 g 2-nitro-6-Cl-toluene and reflux forty minutes. Dilute the red solution with water and steam distill until no more starting material is distilled. The aqueous residue is filtered, acidified with HCl and filtered to get 102 g 2-nitro-6-Cl-phenylpyruvic acid (I) (recrystallize-benzene). Add 81 g (I) in dilute NH4OH to a solution of 560 g FeSO4*7H20 and 230 ml concentrated NH4OH and 2 L water and boil five minutes. Filter, wash precipitate with dilute NH4OH, water and acidify filtrate with dilute HCl to get 60 g 4-Cl-2-indole-COOH (II) (recrystallize-aqueous ethanol). 9.78 g (ll) and 6.7 g CuCN in 35 g quinoline and reflux (about 237ø) for twenty hours. Pour the hot solution into a mixture of 25 ml concentrated HCl and ice. Stir and filter; wash precipitate with water and extract the filtrate and precipitate three times with ether. Wash the ether with HCl, water and dry, evaporate in vacuum to get 3.6 g 4-CN-indole (recrystallize-water). Or, heat (II) alone at 290ø until fusion; then heat at 250ø for ten minutes until CO2 evolution ceases to get 4-CN-indole. For conversion to 4-formyl-indole see HCA 51,1616(1968).

4-Alkyloxyindoles TET 24,6093(1968), JMC 13,983(1970) and a longer route in CT 274(1970).

Add solution of 150 g 2-amino-6-nitrotoluene (prepared by reduction of 2,6-dinitrotoluene with H2S in ammoniacal ethanol and recrystallize- water or ethanol) in 550 g concentrated sulfuric acid slowly to 5 Kg crushed ice and then add dropwise a solution of 75 g Na nitrite in 100 ml water with stirring and cool (0-5ø). Continue stirring two hours and add 2 L 10% sulfuric acid containing 0.1 % Cu sulfate. Heat at 75-80ø twelve hours or until N evolution ceases. Filter, cool to precipitate 135 g 2-OH-6-nitrotoluene (I) (recrystallize-aqueous ethanol) (can also prepare by nitrating o-cresol). Add 20 g (I) in 100 methanol to a solution of 5.8 g Na metal in 60 ml methanol or ethanol. Add dropwise with stirring, 34 g diethyl or dimethylsulfate. After addition reflux one hour, evaporate in vacuum most of the methanol, add 100 ml water and extract with 3x50 ml ether. Wash ether with 50 ml 5% NaOH, 2x50 ml water: dry, filter, evaporate in vacuum (can distill 116/2.2 for ethyl-, 94-6/0.5 for methyl-) to get 20 g 2-alkyloxy-6-nitrotoluene (11). Can also use 1-Br-propane and reflux four hours; evaporate in vacuum the ether extract and distill residue (180/17) to get the 2-n-propoxy-6-nitrotoluene (recrystallize-aqueous methanol). To a suspension prepared from 7.8 g K metal (Na may do) and 25 ml absolute ethanol in 160 ml dry ether, add dropwise a solution of 0.1 M (II) and 29.2 g diethyloxalate in 50 ml dry xylene. Stir four hours and let stand at room temperature three days. Extract the precipitate with 100 ml ice water and extract the resulting dark red aqueous layer with 3x50 ml ether. Filter and remove the residual ether by blowing air through the aqueous solution. Cool in ice bath and treat alternately with a little 20% NaOH and 30% H202 (16 ml each total) until the dark red color is gone. Filter and acidify with concentrated HCl to get 9 g of the 2-alkyloxy-6-nitrophenylacetic acid (III). 2 g (III) in 40 ml glacial acetic acid. Add 0.1 g 10% palladium-carbon and hydrogenate at room temperature and atmospheric pressure about one hour. Filter, evaporate in vacuum to get 1.2 g 4-alkyloxyindole (recrystallize-toluene). For the n-propoxy compound, hydrogenate one-half hour in 30 ml 5% NaOH, filter, acidify with concentrated HCl and heat on steam bath for one-half hour. Cool and filter and recrystallize-aqueous ethanol. If desired, these indoles can be dealkylated as described elsewhere here. Alternatively, dissolve 45 g (III) in 600 ml water with the minimum amount of 2N NaOH (about 80 ml). Add Na2S2O4 to the well stirred solution in small amounts until no further increase in temperature occurs. Add 2N NaOH dropwise, at the same time add further Na hydrosulfite, until the red color disappears (about 80 ml NaOH, 70 g Na hydrosulfite). This takes about one hour and final temperature is about 35ø. Stir in 200 ml dilute (1:1) HCl to precipitate the alkyloxyindole-COOH (IV) which can be used as is, or decarboxylated with quinoline and Cu powder by heating to 245ø and cool, filter and evaporate in vacuum as described elsewhere here.

Methoxyindoles from Methoxyanilines JOC 20,1454(1955), 23,19 (1958)

Illustrated for preparation of 4,5,6-trimethoxyindole (IV). 1.8 g 3,4,5-trimethoxyaniline in 10 ml glacial acetic acid; add 1.9 g ethyloxomalonate-dihydrate and heat ten minutes on steam bath. Let stand two hours at room temperature and add 125 ml water and then solid ammonium carbonate till pH is 8 to precipitate 2.7 g 4,5,6-trimethoxy-3-OH-3- carbethoxyindole (I) (recrystallize-benzene-petroleum ether). 4.5 g (I) in 50 ml 5% NaOH and heat on water bath with aeration ten minutes. Take pH to 4 with dropwise addition of formic acid. Filter, wash with water and recrystallize from aqueous ethanol to get 1 g 4,5,6-trimethoxyisatin (II). To a stirred suspension of 7.2 g (II) in 30 ml boiling water, add 7 g Na hydrosulfite and let clear solution stand twelve hours in refrigerator. Filter, recrystallize the precipitate from boiling water and dry to get the dioxindole (III). To a stirred slurry of 1.9 g lithium aluminum hydride in 100 ml dry ether add 4.3 g (III) in 120 ml dry benzene and reflux four hours. Cool and carefully add a little water. When bubbling stops, filter and dry, evaporate in vacuum the organic layer to get (IV).

4-Methoxyindole BSC 1335(1966)

Methylate p-Cl-phenol to get p-Cl-methoxy-benzene which is then converted (BSC 643(1953)) to 5-Cl-2-methoxy-benzyl-Cl (I). 50 g (I) in 50 ml dimethylformamide is added to a solution of 16 g KCN in 80 ml dimethylformamide and 70 ml water at 70ø. Add a pinch of KI and heat at 85-90ø 1 1/2 hours. Pour on cold water; filter, dry (can purify by distilling 167/12) to get 38 g 5-Cl-2-methoxy-phenyl-acetonitrile (II). Alternatively, dissolve 29 g (I) in 200 ml acetone, add 8 g NaCN and 1.6 g NaI and reflux twenty-four hours. Cool, filter, and evaporate in vacuum to get 21 g (II). 174 g (II) in 174 g concentrated sulfuric acid, 174 ml water and 174 g glacial acetic acid; reflux and stir three hours. Cool, filter and dissolve the brown crystals in Na carbonate solution (can add decolorizing carbon and filter) and acidify to precipitate I 79 g (III) (recrystallize-ethanol) (2-methoxy-5-Cl-phenylacetic acid). Alternatively, dissolve 50 g (II) in 350 ml methanol containing 15% NH3 and hydrogenate at 70 Kg pressure, 50ø in presence of Raney-Ni (or other reducing method) to get 40 g colorless liquid (after filtering, and evaporating in vacuum) 2-methoxy-5-CI-á-phenethylamine (VIb). 76 g (III) carefully mixed with 60 g SOCl2 and heated until dissolved. Let stand twelve hours and evaporate in vacuum to get 58 g yellow oily 2-methoxy-5-Cl-phenylacetyl-Cl (IV) (can distill 145/10). See preparation of mescaline for alternatives to this and other steps. 6 g (IV) and I 4 ml 10% NaOH are added at the same time to 10 ml 33% aqueous methylamine at 0ø and stirring is continued for one-half hour. Filter, wash precipitate with water and dry to get 5 g of the N-methyl-phenylacetamide (V). Carefully add 20 g pure and dry (V) to 10 g lithium aluminum hydride in 800 ml dry ether (can first reflux lithium aluminum hydride and ether twelve hours under N2 and filter), reflux about four days and carefully add a little water until no more bubbles. Filter, extract filtrate with 2N HCl and extract the HCl with ether (evaporate in vacuum the ether to recover 3 g (V)). Basify the HCl extract and extract it with ether. Dry and evaporate in vacuum the ether to get 8 g oily N-methyl-2-methoxy-5-CI-beta-phenethyl-amine (VIa) (can distill 110/0.5).12 g (VIa or b) and 4.5 g DEA or DMA in 500 ml ether; mix rapidly with 270 ml 0.9 M phenyl-Li, boil fifteen hours and extract as for (VI) or as described previously to get 8 g oily 4-methoxy-indoline (or its 1-methyl derivative) (VII). Alternatively, add 36 g naphthalene to 300 ml tetrahydrofuran and add 1 I g Na metal cut in small pieces. Reflux and stir three hours and add 18 g (VI) and 8 g DEA in 200 ml tetrahydrofuran rapidly and boil twelve hours. Evaporate in vacuum, dissolve the oily residue in 2N HCl and extract with ether. Proceed as described to get (VII). 4 g (VII) in 200 ml dry pyridine; add to 6 g Cu chloride in 400 ml pyridine and reflux 1 1/2 hours. Pour on water and extract with ether. Wash extract with 4N HCl and then water and dry and evaporate in vacuum the ether to get 2 g of the indole (VIII). Alternatively, dissolve 4 g (VII) and 9.5 g cinnamic acid in 700 ml mesitylene, add 1 g 5% palladium-carbon and reflux five hours. Filter, wash with HCl and NaHCO3 and dry and evaporate in vacuum the mesitylene to get the red, oily (VIII) (can chromatograph on alumina and elute with benzene-petroleum ether).

5-OH-indole JCS 2525(1952)

To a solution of 4.3 g 2,5-dihydroxyphenylalanine and 2 g NaHCO3 in 150 ml water, add with stirring during ten minutes, a solution of 13 g K ferricyanide and 3 g NaHCO3 in 200 ml water (dark solution turns pale yellow). Extract with 3x200 ml ether and dry, evaporate in vacuum to get 2.3 g 5-OH-indole.

4-Indolecarboxylic Acid CPB 20,2123(1972)

Heat 3-nitrophthalic anhydride with ammonium carbonate to get 3-nitrophthalimide (I). Dissolve 4.3 g (I) in 50 ml 90% methanol and add 1.9 g sodium borohydride over 30 minutes while stirring vigorously at room temperature. Stir 2 hours, acidify with 20% HCl, evaporate in vacuum and treat the dry residue with acetone. Evaporate in vacuum to get 3.9 g (88%) 3-OH-4-nitrophthalimidine (II) (recrystallize from acetone). Dissolve 3.9 g (II) in 40 ml 20% HCl and stir for 10 hours on water bath at 80-90ø. Distill off HCl and stir residue with acetone. Filter and evaporate in vacuum to get 3.4 g 3-OH-4-nitrophthalide (III) (recrystallize from CHCl3 and can purify on column). Prepare an ether solution of CH2N2 and add to 1.93 g (III) in a 100 ml flask until a reaction is no longer evident. Add acetic acid to decompose excess diazomethane and evaporate in vacuum to get about 2 g of 2-methoxycarbonyl-6-nitrostyrene oxide (IV) (can purify on column). Dissolve 560 mg (IV) in 50 ml absolute methanol, add 50 mg PtO2 and hydrogenate as described elsewhere here (other reducing methods should work). Filter, evaporate in vacuum and recrystallize from benzene to get 270 mg methyl-4-indolecarboxylate(V). Dissolve 250 mg (V) in 2 ml 0.05M KOH and stir at room temperature 6 hours. Neutralize with 10% HCl carefully to prevent excessive heat and collect the crystals by filtration. Dry to get 126 mg 4-indolecarboxylic acid.

Indole Russian Patent 306,126(29 July 1971)

To a stirred suspension of 1.9 g orthocarbamoyl cinnamamide in 50 ml methanol add 26 ml 0.77 N NaOCl and heat in a distillation apparatus at 40ø for 2 hours, or until no more indole is distilled off (can use the indole tests described earlier). Extract the distillate with CHCl3 and dry, evaporate in vacuum (or steam distill the solvent) to get about 45% indole.

Indole German Patent 2,052,678(6 May 1971)

A molar ration of 2-(o-nitrophenyl)-ethanol to reducing gas of 1:5 is best (greater than 90% yields). The catalyst is Al2O3 or silica gel containing 7-14% by weight of copper (or Ni, Co, Cu chromite, etc.), with some potassium sulfate if necessary. Reducing gas is NH3 or H2, which can be mixed with nitrogen. The temperature is 250-300ø. The 2-(o-nitrophenyl)-ethanol is vaporized over 30 ml catalyst in a quartz tube 56 cm long with an inner diameter of 15 mm, containing along its whole length a thermoelement tube with an outer diameter of 8 mm. The tube is filled to 28 cm with quartz glass fragments. The gas flow rate is 80-240 ml/minute with a contact time of 7-14 seconds. Compare CA 79,105065-66(1973).

Indole Analogs

Replacement of one or more of the C or N atoms of the indole nucleus by atoms of N, C, O or S will result in dialkyltryptamine analogs some of which are very likely to be psychedelic. Among the indole analogs are isoindole, indene, indazole, diazindoles, benzofuran, benzothiophene and benzimidazole. The syntheses of several such compounds follows.

Benzimidazole Analog of DET JCS 1671 (1957)

17.3 g benzimidazole dissolved in 300 ml ethanol containing 3.4 g Na metal. Slowly add 22.4 g alpha-Cl-N, N-diethyl-acetamide (or 18.2 g dimethyl analog) in 100 ml ethanol and reflux four hours. Filter, evaporate in vacuum to get 2-1'-benzimidazolyl-N,N-diethylacetamide (I) (recrystallize-acetone). Add 16 g (I) to 6 g lithium aluminum hydride in 300 ml tetrahydrofuran and reflux six hours. Cautiously add a little water and filter, evaporate in vacuum to get the DET analog (recrystallize-water). (I) may be active.

Alternatively, dissolve 10 g N,N-diethyl-N'-o-nitrophenyl-ethyl- enediamine in 100 ml ethanol. Add Raney-Ni and 5 atmospheres hydrogen and hydrogenate one hour. Filter, evaporate in vacuum and reflux the oil forty minutes with 100 ml 4N HCl and 20 ml 87% formic acid. Basify with NH4OH; extract four times with CHCl3 and evaporate in vacuum to get the DET analog (recrystallize-water).

Indene Analogs of DETJMC 10,856(1967), JOC 30,3231 (1965). Illustrated for 6-methoxy-DET analog.

Prepare 6-methoxy-1-indanone (I) (JCS 1986(1962)) using polyphosphoric acid made by diluting 500 g of the commercial acid with 120 g 85% phosphoric acid. 2.5 g (I) in 176 ml ether and reflux one hour with 0.27 g lithium aluminum hydride. Cool and carefully add water and filter when bubbling stops (can use Celite filter aid). Dry and evaporate in vacuum and store twelve hours at 15ø (under N2 if possible) to precipitate the white 6-methoxy-1-indanol (II) (recrystallize-n-hexane). 2.5 g (II) in 73 ml benzene and reflux one-half hour with 0.2 g p-toluenesulfonic acid. Cool, add water and separate the phases. Extract the aqueous phase with ether and combine with benzene phase and dry, evaporate in vacuum to get 5-methoxy-indene (III) (can distill 110-45/10). 1.53 g (III) and 1.39 g N,N-diethyl-aminoethyl-CI-HCl in benzene (prepare the free base in benzene as described previously). Reflux four hours with 0.42 g sodamide, cool, wash with water and dry, evaporate in vacuum to get the indene analog of 6-methoxy DET as a dark liquid (can crystallize as oxalate). Alternatively, dissolve 2.51 g (III) in ether and treat (under N if possible) with 12 ml 1.6M butyl-Li in hexane at 0-10ø. After two hours cool to -30ø and add 12 ml more of butyl-Li. Add ether suspension of 2.5 g N,N-diethylaminoethyl-Cl. HCl over one-half hour and warm to room temperature. Filter, evaporate in vacuum to get the 6-methoxy-DET analog.

The following are some other syntheses of indole analogs:

Indene JOC 37,1545(1972); TL 2869(1972); CT 7,205(1972)
Indazole analog of 5-benzyloxy-DMT JACS 79,5246(1957),80,966(1958)
Benziminazole analog of 5-OH-trybtamine JCS 1671(1957)
5-BR-benzothiophene analog of DMT JMC 10,270(1967)
Tryptamine analogs using pyrrolidine and piperidine JMC 10,1015 (1967)
Benzoluran derivatiues LAC 662,147(1963), CA 60,2901 (1963)
Benzothiophene preparation JOC 10,381 (1945)
4-Azindoles CA 72,66934(1970),73,56000(1970)
Isoindoles J.Prakt. Chem. 312,440(1970)
Various analogs JMC 9,819(1966),10,856(1967 ),13,1205 (1970);
ACS 17,2724(1963); JACS 77,4324(1955); J.Het.
Chem. 6,775(1969); JCS (C) 2317(1959), 1612(1969), 498 (1970);
JOC 37,51(1972). CT 7,205(1972)

The following are syntheses of indoles and derivatives: For an extensive review of indole syntheses and reactions see CHEMISTRY OF HETEROCYCLIC COMPOUNDS (W.J. Houlihan, Ed.), 25, parts 1, 2 and 3 (1972-3).

5-OH-DMT (which can be substituted in the 4 position as described
here) from 2,5-dimethoxybenzaldehyde JCS 1165(1954)
5-Nitro-DMT (in six steps from tetrahydrofurfuryl alcohol) JACS 75,1880(1953)
N-acylation of tryptamines JPS 58,563( 1969), cf. JACS 74,101 (1952)
4-Acetylindole-3-acetic acid (in ten steps from m-amino-benzyl alcohol)
BER 87,229(1954)
4,5-Benzindole JOC 24,565(1959)
5-methyl-indole JOC 24,2030(1959)
Indolyl-3-acetaldehyde JCS 3172(1952)
DMT derivatiues JACS 77,4322(1955)
5-substituted indoles JCS 1424(1965), Israel J. Chem. 5,129(1967)
5-6-Methylenedioxyindole JCS 78 (1949)
Dibhenyltryptamine CA 73,109616 (1970)
Tryptamines (via ethyleneimine) CA 55,19897(1961)
Indoles (from phenylhydrazones) CA 72,66814(1970)
Indoles (possible route to methylethyltryptamine, using N-ethyl-aziridinium
tetraflouroborates) Angew. Chem. 79,188 (1967)
3-(4-pyridyl)indoles (if this is not active, the 4-n-alkyl-pyridyl analog
will probably be) J. Het. Chem. 7,1071 (1970), ACS 22,1064(1968)
Indoles (from o-acylanilines and dimethylsulfonium methylide)
GCI 100,652(1970), TL 679(1969)
Indoles BSC 643, 741 (1960), 1051,2263(1962), 861,2175 (1965), 3359(1966)
Indole Crignard Reagents (review) Adv. Het. Chem. 10,43(1969)
Indoles (reviews) Het. Compounds (Elderfield-Ed.) 3,1(1952);
Prog. Drug Res. 6,75(1963); THE INDOLE ALKALOIDS, W.
Taylor (1966); THE CHEMISTRY OF INDOLES, R. Sundberg (1970)
4-Aminoindole from 5-Br-indole C.R. Acad. Sci. Paris 265,110(1967)
Indole derivatives JPS 60,304(1971); AP 304, 73(1971)
5-OH-indoles from substituted phenylethylamines TL 723(1970)
4-Alkylindoles from 4-Br or iodoindoles BER 104,2027(1971)
Indoles from cyclohexanones and allylamines C.R. Acad. Sci. Paris
For a general, simple high yield indole synthesis from anilines and
methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508
(1973). For indoles from N-(á-hydroxy-ethyl aniline esters see BSC
2485(1973). For a 2-acyl-indoles in one step from orthoaminoketones and
alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-amino-
carbonyls see JOC 38,3622-24(1972).
Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het.
Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972).
4-substituted indoles: from N-methylpyrrole in 5 steps Compt. Rend.
276C,1327(1973); in 20% yield by irradiation of 1-substituted
indoles TL 2451 ( 1973); in one step Swiss Patent 536,840(29 June
1973); French Patent 2,154,485(15 June, 1973); from parabenzoquinone etc.
German Patent 2,145,573(15 March 1973);
from 4-aminobenzofurans CA 78,147795(1973) (Japanese Patent 73 08,777
(03 Feb 1973)).
Indoles Review: lnt. Rev. Sci. Orgn. Chem. Ser. 14,29(1973).
Sulfur analog of psilocin JCS (P.T.1) 3011(1972); JHC 10,297
(1973); DMT analog CPB 19,603(1972). Benzothiophenes from thiophenes
JOC 38,1056(1973).
Dialkyltryptamines from tryptamines: CA 78,147730(1973).
Tryptamines: J. Het. Chem. (Russ.)213(1973).
Indoles from Nitrosoanilines JHC 10,883(1973); from N-(beta-hydroxyethyl)-
aniline by thermal cracking: BSC 2485(1973); from isonitrile and
diazomethane: TL 2133(1973).
CA 79,146321(1973) gives a one step synthesis of tryptamine from
phenylhydrazine and 4-chlorobutyraldehyde by refluxing in aqueous
ethanol for 6 hours (70% yield). CA 80,3381(1974) gives the
preparation of DMT analogs.
JPS 62,490(1973) gives an indoline synthesis which can be carried one step
further (dehydrogenation described in this chapter) to give DMT
derivatives. See JOC 41,1118( 1976) for indoles from betaketosulfoxides.
Indoles JOC 2,235(1937), TET 27,775,1167(1971); CA 75, 35735,63605,88424,
98445,11 8230(1971), 76,14237(1972); ACS 25,1277(1971); JOC 37,43(1972); CA
77,75123(1972); CPB 20,1395(1972); J. Heterocyclic Chem. 8,903(1972); Diss.
Abst. Int. 31 B,5871 (1971); AP 305,159(1972); JCS (Chem. Comm.) 415(1972).
4-Fluorotryptamines Israel J. Chem. 2,25(1964)
Tryptophan 4-acetic acid from tryptophan JACS 88,3941 (1966)
Indoles from o-azidobenzaldehydes JOC 37,719(1972)
Indoles from isatins or oxindoles via diborane Synthesis 2,84(1972)
Indoles from 2-oxindoles TL 1081 (1972)
Indole Derivtives JOC 37,2010(1972)
Psilocin Derivatives Diss. Abst. Int. 32B,2606(1971)
Benzothiobhene and Benzofuran TET 28,5397(1972)
Isoindoles TL 4295(1972); JCS(C) 1149(1972)
5-OH-indoles Diss. Abst. lnt. 33B,107(1972)
Alkoxyindoles from Hydroxyindoles CA 77,151,914(1972)