This is as good a place as any to discuss two or three simple compounds, phenethylamines, with only one substituent on the benzene ring. The 2-carbon analog of 4-MA, is 4-methoxyphenethylamine, or MPEA. This is a kissing cousin to DMPEA, of such fame in the search for a urine factor that could be related to schizophrenia. And the end results of the search for this compound in the urine of mentally ill patients are as controversial as they were for DMPEA. There has been no confirmed relationship to the diagnosis. And efforts to see if it is centrally active were failures Q at dosages of up to 400
milligrams in man, there was no activity. The 4-chloro-analogue is 4-chlorophenethylamine (4-Cl-PEA) and it has actually been pushed up to even higher levels (to 500 milligrams dosage, orally) and it is also without activity. A passing bit of charming trivia. A positional isomer of MPEA is 3-methoxyphenethylamine (3-MPEA) and, although there are no reported human trials with this, it has been graced with an Edgewood Arsenal code number, vis., EA-1302.
143 PROPYNYL; 3,5-DIMETHOXY-4-(2-PROPYNYLOXY)PHENETHYLAMINE
SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for its preparation) in 50 mL acetone containing 100 mg decyltriethylammonium iodide, there was added 12 g of an 80% solution of propargyl bromide in toluene and 6.9 g of finely powdered anhydrous K2CO3. This mixture was held at reflux on the steam bath for 12 h, after which the solvent was removed under vacuum. The residues were added to 0.5 L H2O, acidified, and extracted with 3x75 mL CH2Cl2. The extracts were pooled, washed with 5% NaOH, and then with dilute HCl which discharged the deep color. Removal of the organic solvent under vacuum yielded 6.6 g of crude product. This was distilled at 138-148
!C at 0.25 mm/Hg, yielding 4.3 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile which spontaneously crystallized. A small sample from MeOH had a mp of 94-95 !C. Anal.
(C13H13NO3) C,H.
A suspension of 2.8 g LAH in 70 mL anhydrous THF was cooled to 0 !C
with good stirring under He, and treated with 2.0 g 100% H2SO4. To this, a solution of 4.2 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile in 30 mL anhydrous THF was added very slowly. After the addition had been completed, the reaction mixture was held at reflux on the steam bath for 0.5 h, cooled to room temperature, treated with IPA to decompose the excess hydride, and finally with 15% NaOH to convert the solids to a white filterable mass. The solids were separated by filtration, the filter cake was washed with THF, and the filtrate and washes were pooled.
After removal of the solvent, the residue was added to 100 mL dilute H2SO4, and washed with 3x75 mL CH2Cl2. The aqueous phase was made basic with dilute NaOH, and the product extracted with 2x75 mL CH2Cl2.
After removal of the solvent under vacuum, the residue was distilled at 125-155 !C at 0.3 mm/Hg to provide 2.4 g of a light amber viscous liquid. This was dissolved in 10 mL IPA, acidified with concentrated HCl until a droplet produced a red color on dampened, external universal pH paper, and then diluted with 40 mL anhydrous Et2O with good stirring. After a short delay,
3,5-dimethoxy-4-(2-propynyloxy)phenethylamine hydrochloride (PROPYNYL) spontaneously crystallized. The product was removed by filtration, washed first with an IPA/Et2O mixture, and finally with Et2O. The yield was 3.0 g of white needles.
DOSAGE: 80 mg or more.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 55 mg) I have cold feet Q literally Q I donUt mean that in the spiritual or adventurous sense. But also I am somewhat physically fuzzy. I feel that if I were in public my behavior would be such that someone would notice me. Everything was OK without any question at the ninth hour. I could walk abroad again.
(with 80 mg) There is a body load. The flow of people around me all day has demanded my attention, and when I had purposefully retreated to be by myself, there was no particular reward as to visuals or anything with eyes closed, either. Sleep was easy at midnight (the twelth hour of the experiment) but the morning was sluggish, and on recalling the day, I am not sure of the events that had taken place.
Higher might be all right, but watch the status of the body. There certainly wasnUt that much mental stuff.
EXTENSIONS AND COMMENTARY: No experiments have been performed that describe the action of this drug at full level. This compound does not seem to have the magic that would encourage exploration at higher levels.
144 SB; SYMBESCALINE; 3,5-DIETHOXY-4-METHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 15 g 1,3-diethoxybenzene and 15 mL of N,N,NU,NU-tetramethylethylenediamine in 200 mL anhydrous Et2O was placed in a He atmosphere, magnetically stirred, and cooled to 0 !C
with an ice bath. Over the course of 10 min there was added 63 mL of a 1.6 M solution of butyllithium in hexane, which produced a fine white precipitate. After an additional 15 min stirring, 20 mL of tributyl borate was added which dissolved the precipitate. The stirring was continued for an additional 15 min. The reaction was quenched by the addition of 50 mL of a concentrated aqueous solution of ammonium sulfate. The resulting Rcottage cheeseS mass was transferred to a beaker, treated with an additional 300 mL of the ammonium sulfate solution, and allowed to stir until the solids had dispersed to a fine texture. The organic phase was separated and the aqueous phase extracted with 2x100 mL Et2O. The organic phases were combined, evaporated under vacuum, and the off-white residue dissolved in 100 mL MeOH. This cloudy solution was cooled (ice bath) and, with stirring, 20 mL of 35% hydrogen peroxide was added portionwise, . The reaction was allowed to continue stirring for 15 min, and then with the addition of 600 mL H2O, crystalline solids were formed. These were removed, washed with H2O, and upon drying yielded 15.4 g of 2,6-diethoxyphenol with a mp of 79.5-81.5 !C. Efforts to diethylate pyrogallol produced mixtures of 2,6-diethoxyphenol and the isomer, 2,3-diethoxyphenol, and these proved difficult to separate. The pure 2,3-isomer was synthesized from ortho-diethoxybenzene by the process used above, and the product was an oil. Both phenols yielded crystalline 3,5-dinitrobenzoates. This derivative of 2,6-diethoxyphenol, upon recrystallization from CH3CN had a mp of 161-162 !C. The derivative from 2,3-diethoxyphenol, also upon recrystallization from CH3CN, melted at 167-168 !C. The mixed mp was appropriately depressed (mp 137-140 !C.).
A solution of 7.6 g 2,6-diethoxyphenol in 40 mL MeOH was treated with 4.9 g of a 40% aqueous solution of dimethylamine followed by 3.6 g of a 40% aqueous solution of formaldehyde. The mixture was heated 1 h on the steam bath, and all volatiles were removed under vacuum. The residual dark oil was dissolved in 36 mL IPA and 10.3 g of methyl iodide was added. There was spontaneous heating, and the deposition of fine white solids. After standing for 10 min, these were removed by filtration, and the filter cake washed with more IPA. The crude product was freed from solvent (air dried weight, 1.7 g) and dissolved in 7 mL hot H2O. To this hot solution there was added 1.7 g sodium cyanide which slowly discharged the color and again deposited flocculant white solids. After cooling, these were removed by filtration, washed with H2O, and after thorough drying the isolated 3,5-diethoxy-4-hydroxyphenylacetonitrile weighed 0.5 g and had a mp of 107.5-108.5 !C. Anal. (C12H15NO3) C,H.
To a solution of 2.1 g 3,5-diethoxy-4-hydroxyphenylacetonitrile in 20
mL anhydrous acetone, there was added 30 mg triethyldecylammonium iodide, 4.6 g methyl iodide, and finally 2.3 g powdered anhydrous K2CO3. This mixture was held at reflux for 5 h. The reaction mixture was quenched with 200 mL acidified H2O and extracted with 3x75 mL
CH2Cl2. The extracts were pooled, washed with 2x75 mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residue distilled at 110-115 !C at 0.3 mm/Hg to provide 3,5-diethoxy-4-methoxyphenylacetonitrile as a solid. This weighed 1.3
g and had a mp of 58-59 !C. Anal. (C13H17NO3) C,H.
To 30 mL of a 1 M solution LAH in THF that had been cooled to 0 !C
with vigorous stirring, under a He atmosphere, there was added dropwise 0.78 mL of 100% H2SO4. When the addition was complete, there was added dropwise a solution of 1.3 g of 3
,5-diethoxy-4-methoxyphenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was brought to room temperature and stirred an additional 10 min, then refluxed on a steam bath for 1.5 h. After cooling to room temperature the excess hydride was destroyed by the addition of about 2 mL IPA, followed by sufficient 15% NaOH to make the reaction basic to external pH paper and to render the aluminum oxides white and filterable. These were removed by filtration, the filter cake was washed with IPA, then the filtrate and washes were combined. The solvents were removed under vacuum and the residue dissolved in dilute H2SO4. This was washed with 2x75 mL CH2Cl2, the aqueous phase made basic with 5% NaOH, and extracted with 3x75 mL
CH2Cl2. The extracts were pooled, the solvent removed under vacuum, and the residue distilled at 120-140 !C at 0.3 mm/Hg to yield 0.9 g of a white oil. This was dissolved in 4 mL of IPA and neutralized with concentrated HCl to an end-point determined by damp external pH paper.
There was the immediate formation of solids which were removed by filtration and washed first with IPA and then with Et2O. This provided 1.0 g of 3,5-diethoxy-4-methoxyphenethylamine hydrochloride (SB) as white crystals, with a mp of 186-187 !C. Anal. (C13H22ClNO3) C,H.
DOSAGE: above 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 120 mg) There were no effects. Sleep that evening was strange, however, and I was fully awake at 4:00 AM, alert, and mentally restless. And there was a strange outburst of anger in the mid-morning. Might these be related to the material the previous day?S
(with 240 mg) There was a slight chill that reminded me that I had taken symbescaline a half hour earlier. There was what might be called a vague threshold for about three hours, then nothing more.
This material had a God-awful taste that lingers in the mouth far too long. If ever again, it will be in a gelatin capsule.
EXTENSIONS AND COMMENTARY: It must be concluded that SB is RprobablyS
not active. There was no convincing evidence for much effect at levels that would clearly be active for mescaline. This is the kind of result that puts some potentially ambiguous numbers in the literature. One cannot say that it is inactive, for there might well be something at 400 or 800 or 1200 milligrams. But since it has been tried only up to 240 milligrams, I have used the phrase that the activity is greater than 240 milligrams. This will be interpreted by some people as saying that it is active, but only at dosages higher than 240 milligrams. What is meant, is that there was no activity observed at the highest level tried, and so if it is active, the active dose will be greater than 240 milligrams, and so the potency will be less than that of mescaline. However you phrase it, someone will misinterpret it.
145 TA; 2,3,4,5-TETRAMETHOXYAMPHETAMINE
SYNTHESIS: To a solution of 50 g 2,3,4-trimethoxybenzaldehyde in 157
mL glacial acetic acid which was well stirred and preheated to 25 !C
there was added 55.6 g 40% peracetic acid in acetic acid. The rate of addition was adjusted to allow the evolved heat of the exothermic reaction to be removed by an external ice bath at a rate that kept the internal temperature within a degree of 25 !C. When the addition was complete and there was no more heat being evolved, the reaction mixture was diluted with 3 volumes of H2O, and neutralized with solid K2CO3. All was extracted with 3x250 mL Et2O, and the removal of the solvent from the pooled extracts under vacuum gave 42 g of residue that appeared to be mainly phenol, with a little formate and aldehyde.
This was dissolved in 200 mL of 10% NaOH, allowed to stand for 2 h at ambient temperature, washed with 2x75 mL CH2Cl2, acidified with HCl, and extracted with 3x100 mL Et2O. The pooled extracts were washed with saturated NaHCO3, and the solvent removed to give 34.7 g of 2,3,4-trimethoxyphenol as an amber oil which was used without further purification. The infra-red spectrum showed no carbonyl group, of either the formate or the starting aldehyde.
A solution of 11.4 g flaked KOH in 100 g EtOH was treated with 33.3 g 2,3,4-trimethoxyphenol and 21.9 g allyl bromide. The mixture was held at reflux for 1.5 h, then poured into 5 volumes of H2O, made basic with the addition of 25% NaOH, and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave about 40 g of a crude 2,3,4-trimethoxy-1-allyloxybenzene that clearly had unreacted allyl bromide as a contaminant.
A 39 g sample of crude 2,3,4-trimethoxy-1-allyloxybenzene in a round-bottomed flask with an immersion thermometer was heated with a soft flame. At 225 !C there was a light effervescence and at 240 !C
an exothermic reaction set in that raised the temperature immediately to 265 !C. It was held there for 5 min, and then the reaction was allowed to cool to room temperature. GC and IR analysis showed the starting ether to be gone, and that the product was largely 2,3,4-trimethoxy-6-allylphenol. It weighed 34.4 g.
To a solution of 9.4 g KOH in 100 mL MeOH, there was added 33.3 g of 2,3,4-trimethoxy-6-allylphenol and 21.2 g methyl iodide and the mixture was held on the steam bath for 2 h. This was poured into aqueous base, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave 30 g of an amber oil residue that was distilled at 100-125 !C at 0.5 mm/Hg to provide 23.3 g of nearly colorless 2,3,4,5-tetramethoxyallylbenzene.
The total distillation fraction, 23.3 g 2,3,4,5-tetramethoxyallylbenzene, was dissolved in a solution of 25 g flaked KOH in 25 mL EtOH and heated at 100 !C for 24 h. The reaction mixture was poured into 500 mL H2O, and extracted with 2x100 mL
CH2Cl2. The aqueous phase was saved. The pooled organic extracts were stripped of solvent under vacuum to give 13.8 g of a fluid oil that was surprising pure 2,3,4,5-tetramethoxypropenylbenzene by both GC and NMR analysis. The basic aqueous phase was acidified, extracted with 2x100 mL CH2Cl2, and the solvent stripped to give 7.5 g of an oil that was phenolic, totally propenyl (as opposed to allyl), and by infra-red the phenolic hydroxyl group was adjacent to the olefin chain. This crude 2-hydroxy-3,4,5-trimethoxypropenylbenzene was methylated with methyl iodide in alcoholic KOH to give an additional 5.6 g of the target 2,3,4,5-tetramethoxypropenylbenzene. This was identical to the original isolate above. The distilled material had an index of refraction, nD24 = 1.5409.
A well stirred solution of 17.9 g 2,3,4,5-tetramethoxypropenylbenzene in 80 mL distilled acetone was treated with 6.9 g pyridine, and cooled to 0 !C with an external ice bath. There was then added 14 g tetranitromethane over the course of a 0.5 min, and the reaction was quenched by the addition of a solution of 4.6 g KOH in 80 mL H2O. As the reaction mixture stood, there was a slow deposition of yellow crystals, but beware, this is not the product. This solid weighed 4.0
g and was the potassium salt of trinitromethane. This isolate was dried and sealed in a small vial. After a few days standing, it detonated spontaneously. The filtrate was extracted with 3x75 mL
CH2Cl2, and the removal of the solvent from these extracts gave a residue of 20.8 g of crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene which did not crystallize.
A solution was made of 20.3 g of the crude 2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene in 200 mL anhydrous Et2O, and this was filtered to remove some 2.7 g of insoluble material which appeared to be the potassium salt of trinitromethane by infra-red analysis. A suspension of 14 g LAH in 1 L anhydrous Et2O
was stirred, placed under an inert atmosphere, and brought up to a gentle reflux. The above clarified ether solution of the propene was added over the course of 1 h, and the mixture was held at reflux for 24 h. After cooling, the excess hydride was destroyed by the cautious addition of 1 L 1.5 N H2SO4 (initially a drop or two at a time) and when the two phases were complete clear, they were separated. The aqueous phase was treated with 350 g potassium sodium tartrate, and brought to a pH >9 with base. This was extracted with 3x150 mL
CH2Cl2, and the removal of the solvent from the pooled extracts gave a residue that was dissolved in 200 mL anhydrous Et2O, and saturated with anhydrous HCl gas. An Et2O-insoluble oil was deposited and, after repeated scratching with fresh Et2O, finally gave a granular white solid. Thi
s product was recrystallized from acetic anhydride, giving white crystals that were removed by filtration, Et2O washed, and air dried. The yield of 2,3,4,5-tetramethoxyamphetamine hydrochloride (TA) was 1.9 g and had a mp of 135.5-136.5 !C.
DOSAGE: probably above 50 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 30 mg) Definite threshold. There was eye dilation, and some unusual humor Q a completely wild day with chi-square calculations on the PDP-7 that were on the edge of bad taste. But I was definitely baseline in the afternoon during the Motor Vehicle Department interactions.
(with 35 mg) I had some gastric upset, but nonetheless there was a distinct intoxication. The next morning I had a foul headache.
EXTENSIONS AND COMMENTARY: This is pretty thin stuff from which to go out into a world that is populated by pharmacological sharks and stake out claims as to psychedelic potency. The structure of this molecule has everything going for it. It is an overlay of TMA (active) and TMA-2 (even more active) so it is completely reasonable that it should be doing something at a rational dosage. But that dosage might well be in the many tens of milligrams.
Tens of milligrams. Now there is a truly wishy-washy phrase. There is an art to the assignment of an exact number or, as is sometimes desperately needed, a fuzzy number, to a collection of things. In my youth (somewhere way back yonder in the early part of the century) I had been taught rules of grammer that were unquestionably expected of any well-educated person. If you used a Latin stem, you used a Latin prefix. And if you used a Greek stem, you used a Greek prefix.
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