DIETHOXY-5-METHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A solution of 11.5 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidinimine (see under ASB for its preparation) in 150 mL anhydrous Et2O was placed in a He atmosphere, well stirred, and cooled in an external dry ice/acetone bath to -80 deg C. There was light formation of fine crystals. There was then added 25 mL of 1.6 N butyllithium in hexane and the mixture stirred for 15 min. This was followed by the addition of 4.3 mL dimethyldisulfide over the course of 20 min, during which time the solution became increasingly cloudy and then thinned out again. The mixture was allowed to come to room temperature over the course of an additional h, and then added to 400 mL of dilute HCl. There was the generation of a lot of yellow solids, and the Et2O phase was almost colorless. This was separated, the solvent removed under vacuum, and the residue combined with the original aqueous phase. This phase was then heated on the steam bath for 2 h. The aqueous solution was cooled to room temperature, extracted with 3x100 mL CH2Cl2, the extracts pooled, washed with H2O, and the solvent removed under vacuum to yield 9.4 g of an amber oil which spontaneously crystallized. This was distilled at 125-132 deg C at 0.2 mm/Hg to yield 7.1 g of 3,4-diethoxy-5-(methylthio)benzaldehyde as a white oil that spontaneously crystallized. The crude product had a mp of 73-74 deg C that actually decreased to 72-73 deg C after recrystallization from MeOH. Anal. (C12H16O3S) C,H.

 

A solution of 16.2 g methyltriphenylphosphonium bromide in 200 mL anhydrous THF was placed under a He atmosphere, well stirred, and cooled to 0 deg C with an external ice water bath. There was then added 30 mL of 1.6 N butyllithium in hexane which resulted in the generation of a clear yellow solution. The reaction mixture was brought up to room temperature, and 7.0 g 3,4-diethoxy-5-(methylthio)benzaldehyde in 50 mL THF was added dropwise, dispelling the color, and the mixture was held at reflux on the steam bath for 1 h. The reaction was quenched in 800 mL H2O, the top hexane layer separated, and the aqueous phase extracted with 2x75 mL of petroleum ether. The organic fractions were combined and the solvents removed under vacuum to give 12.0 g of the crude 3,4-diethoxy-5-methylthiostyrene as a pale amber-colored oil.

 

A solution of 6.0 mL of borane-methyl sulfide complex (10 M BH3 in methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to 0 deg C, treated with 12.6 g of 2-methylbutene, and stirred for 1 h while returning to room temperature. To this there was added a solution of the impure 3,4-diethoxy-5-methylthiostyrene in 25 mL THF. This was stirred for 1 h during which time the color deepened to a dark yellow. The excess borane was destroyed with about 2 mL MeOH (all this still in the absence of air). There was then added 11.4 g elemental iodine followed by a solution of 2.4 g NaOH in 30 mL of boiling MeOH, added over the course of 10 min. This was followed by sufficient 25% NaOH to discharge the residual iodine color (about 4 mL was required). The reaction mixture was added to 500 mL water, and sodium hydrosulfite was added to discharge the remaining iodine color (about 4 g). This was extracted with 3x100 mL petroleum ether, the extracts pooled, and the solvent removed under vacuum to provide 25.9 g of crude 1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane as a pale yellow fluid oil. Thin layer chromatographic analysis of this material on silica gel plates (using a 90:10 mixture of CH2Cl2/methylcyclopentane as solvent) showed largely the iodo-product (Rf 0.9) with no visible starting aldehyde (Rf 0.7).

 

To this crude 1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane there was added a solution of 12 g potassium phthalimide in 90 mL anhydrous DMF, and all was held at reflux in a heating mantle. The reaction progress was followed by TLC, and at 1.5 h it was substantially complete. After adding to 500 mL 5% NaOH, the organic phase was separated, and the aqueous phase was extracted with 2x75 mL Et2O. The organic fractions were combined, and the solvent removed under vacuum providing 19.3 g of an amber oil. The residual volatiles were removed by distillation up to 170 deg C at 0.2 mm/Hg. The distillate weighed 7.0 g and contained little if any phthalimide by TLC. The pot residue was a viscous amber oil, and also weighed 7.0 g. About half of this was employed in the following hydrolysis step, and the rest was rubbed under an equal volume of MeOH providing 1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane as a white solid. A small sample was recrystallized from an equal volume of MeOH to give white crystals with a mp of 79.5-81 deg C. Re-recrystallization from MeOH produced an analytical sample with a mp of 83-84 deg C. Anal. (C21H23NO4S) C,H.

 

A solution of 3.2 g of the impure 1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane in 150 mL of n-butanol there was added 20 mL of 66% hydrazine, and the mixture was heated on the steam bath for 2 h. This was added to 600 mL of dilute H2SO4, and the two layers were separated. The butanol layer was extracted with 2x100 mL dilute H2SO4. These extracts were added to the original aqueous phase, and this was washed with 3x75 mL CH2Cl2. This was then made basic with 5% NaOH, extracted with 3x75 mL CH2Cl2, and the solvent from these pooled extracts removed under vacuum. The residue (which weighed 9.7 g and contained much butanol) was distilled at 140-145 deg C at 0.3 mm/Hg to give 0.7 g of a colorless oil. This was dissolved in 3.0 mL IPA, neutralized with concentrated HCl, and diluted with 12 mL anhydrous Et2O to give a solution that immediately crystallized to provide white crystals of 3,4-diethoxy-5-methylthiophenethylamine hydrochloride (5-TASB). These weighed 0.7 g after washing with Et2O and drying to constant weight. The mp was 182-183 deg C, and an analytical sample was dried at 100 deg C for 24 h. Anal. (C13H22ClNO2S) C,H.

 

DOSAGE: about 160 mg.

 

DURATION: about 8 h.

 

QUALITATIVE COMMENTS: (with 120 mg) Maybe there is something at about hour 5. My talking with innocent people had hints of strangeness. And there was the slightest suggestion of some physical effect. Call it an overall (+).

 

(with 160 mg) I am immediately warm at the extremities. An awareness grows upon me for a couple of hours. I am a little light-headed, and I feel that there is more physical than there is mental, and it is not all entirely nice. I am slightly hyperreflexive, and there is a touch of diarrhea. I am happy that I held this at 160 milligrams. I am mentally flat at the eighth hour, although there are some physical residues. The effects are real, but I don't want to go higher. Some trace physical memory seems to stay with me as a constant companion.

 

EXTENSIONS AND COMMENTARY: There is a ponderousness about adding a couple of ethyl groups and a sulfur that seems to say, Rno fun. 5-TASB has something going for it (but not much) and 3-TASB is quite a bit more peppy and, actually, 4-TASB has quite a bit of life. But there is a sense of "why bother?" There were a couple of bouts of light-headedness, but there was no unexpected excitement discovered in this methodical study. No surprises. Keep the chain lengths down.      

 

 

 

#149 TB; 4-THIOBUSCALINE; 3,5-DIMETHOXY-4-(n)-BUTYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A solution was made of 12.1 g N,N,N',N'-tetramethylethylenediamine and 13.8 g of 1,3-dimethoxybenzene in 200 mL 30-60 deg C petroleum ether. This was stirred vigorously under a He atmosphere and cooled to 0 deg C with an external ice bath. There was added 66 mL of 1.6 M butyl lithium in hexane which produced a white granular precipitate. The reaction mixture was brought up to room temperature for a few minutes, and then cooled again to 0 deg C. There was then added 18.7 g of di-(n)-butyl disulfide (this reagent was quite yellow, but was used without any purification) which changed the granular precipitate to a strange salmon color. Stirring was continued while the reaction mixture was brought up to room temperature and finally up to reflux. The reaction mixture was then added to 600 mL of dilute H2SO4. The two phases were separated, and the aqueous phase extracted with 2x75 mL Et2O. The organic phases were combined and the solvent removed under vacuum. The residue weighed 33.0 g and was a dark yellow oil. Efforts to remove this color by reductive extraction of a CH2Cl2 solution with aqueous sodium hydrosulfite were futile. The residue was distilled at 0.3 mm/Hg to give two fractions. The first boiled at 95-115 deg C, weighed 4.1 g and was largely recovered dibutyl disulfide. The product 2-(n)-butylthio-1,3-dimethoxybenzene boiled at 115-135 deg C and weighed 19.5 g. It was a pale amber oil that could not be induced to crystallize. Anal. (C12H18O2S) C,H.

 

To a stirred solution of 19.5 g of 2-(n)-butylthio-1,3-dimethoxybenzene in 75 mL CH2Cl2 there was added 14.5 g elemental bromine dissolved in 75 mL CH2Cl2. The evolution of HBr was evident, but the reaction was not exothermic. The reaction was allowed to stir for 1 h and then heated briefly to a reflux on the steam bath. It was then washed with H2O containing sodium hydrosulfite which discharged the residual color. After washing with saturated brine, the solvent was removed under vacuum leaving 26.0 g of a pale amber oil. This was distilled at 120-140 deg C at 0.4 mm/Hg yielding 4-bromo-2-(n)-butylthio-1,3-dimethoxybenzene as a yellow-orange oil. It could not be crystallized. Anal. (C12H17BrO2S) C,H.

 

To a solution of 11.5 mL diisopropylamine in 50 mL hexane that was stirred under N2 there was added 50 mL of 1.6 M butyllithium. After 15 min stirring, the reaction mixture became very viscous, and it was diluted with 150 mL anhydrous THF. After cooling in an ice bath there was added 2.0 mL CH3CN followed in 1 min with 6.0 g of 4-bromo-2-(n)-butylthio-1,3-dimethoxyanisole a bit at a time over the course of 1 min. There was the immediate formation of a deep red color. After stirring for 0.5 h, the mixture was poured into dilute H2SO4. The organic layer was separated, and the aqueous layer extracted with 3x75 mL CH2Cl2. These extracts were pooled, dried with anhydrous K2CO3, and the solvent was removed under vacuum. The residue was distilled at 0.25 mm/Hg and yielded two fractions. The first fraction boiled at 125-145 deg C, weighed 0.8 g and was discarded. The second fraction came over at 145-175 deg C as a light yellow oil and weighed 2.2 g. This product, 4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile, was reduced as such without further purification or analysis.

 

A solution of LAH under N2 (20 mL of a 1 M solution in anhydrous THF) was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 0.53 mL 100% H2SO4, followed by 2.0 g 4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was stirred at 0 deg C for a few min, then brought to room temperature for 1 h, and finally to a reflux for 1 h on the steam bath. After cooling back to room temperature, there was added IPA (to destroy the excess hydride) followed by 10% NaOH which brought the reaction to a basic pH and converted the aluminum oxides to a loose, white, filterable consistency. These were removed by filtration, and washed with THF and IPA. The filtrate and washes were stripped of solvent under vacuum, the residue was suspended in 150 mL of dilute NaOH and extracted with 3x100 CH2Cl2. These extracts were pooled and extracted with 2x75 mL diluteH2SO4. Emulsions required that a considerable additional quantity of H2O be added. The aqueous phase was made basic, and extracted with 2x100 mL CH2Cl2. After combining these extracts, the solvent was removed under vacuum providing a residue that was distilled. The product distilled at 138-168 deg C at 0.4 mm/Hg as a white oil weighing 0.7 g. This was dissolved in a small amount of IPA, neutralized with concentrated HCl and, with continuous stirring, diluted with several volumes of anhydrous Et2O. After filtering, Et2O washing, and air drying, 4-(n)-butylthio-3,5-dimethoxyphenethylamine hydrochloride (TB) was obtained, weighed 0.6 g, and had a mp of 154-155 deg C. Anal. (C14H24ClNO2S) C,H.

 

DOSAGE: 60 - 120 mg.

 

DURATION: about 8 h.

 

QUALITATIVE COMMENTS: (with 35 mg) I was aware of something at about an hour, and it developed into a benign and beautiful experience which never quite popped into anything psychedelic. At the fifth hour there was a distinct drop, and I made what might be thought of as a foolish effort to rekindle the state with an additional 20 milligrams but it was too little and too late. There was no regeneration of anything additional.

 

(with 60 mg) A very subtle threshold, probably, and six hours into it there seems to have been little if any effect. My memory of it is not that certain and now I am not sure that there had been anything at all.

 

(with 80 mg) I am vaguely aware of something. The body discomfort may reflect the use of sardines in tomato sauce for lunch, but still things are not quite right. Five hours into it I am still in a wonderful place spiritually, but there seem to be some dark edges. I might be neurologically sensitive to this.

 

(with 120 mg) The course of the action of this is extremely clear. The development was from 5 PM to 7 PM [the experiment started at 4 PM] and by 10 PM I was dropping and by midnight I went to bed and slept well. Food was not too interesting, and a glass of wine before sleeping produced no noticeable effect. This was an uneventful experience that never really made it off the ground. It was pleasant, but certainly not psychedelic.

 

EXTENSIONS AND COMMENTARY: There is a term "dose-dependent" in pharmacology. When there is a complex action produced by a drug, then each of the components of this mixture of effects should be expected to become more intense following a bigger dose of the drug. This is certainly true with most of the actions of psychoactive drugs.

 

As to the psychedelic aspects of some drugs, there can be visual effects, eyes-open (edge-ripples or colors or retinal games) or eyes-closed (images of the elaborately decorated doors of the mosque, or of an orchestra floating suspended by its music) or fantasy (you are moving beyond the confines of your body and invading someone else's space). The same applies to tactile enhancement, to the anaesthetic component, to the depth of insight realized from a drug. The more the drug, as a rule, the more the effect, up to the point that new and disruptive effects are realized. This latter is called toxicity.

As to the stimulant component, the same is true. The person gets wired up, and there is no sleep because there is no hiding from a cascade of images and meanings, and the body lies there unwilling to yield guard since both the pounding heart and the interpretive psyche are demanding attention. These aspects also intensify with increasingly higher doses.

 

But an exception to this is the euphoria-producing aspect of a drug. One sees with increasing doses a continuing "threshold" that makes you aware, that fluffs the senses, but which seems not, at any level, to take over or to command the ship. It is truly a catalytic on or off. You are or you are not. In the "Tomso" effect, this action is produced by alcohol. There is disinhibition with alcohol which allows a central intoxication from the drug TOMSO regardless of the amount of drug used (see under TOMSO). One sees again, here with TB, the case of a perpetual series of "thresholds." Never the psychedelic or the stimulant action that increases with increased dose. Always the simple and ephemeral catalyst of euphoria without substance and without body. It is a compound that can never be pinned and labeled in the butterfly collection since it defies an accepted classification.

 

This action was seen first with the compound called ARIADNE and when it was called an anti-depressant, it proved to be commercially interesting. It is fully possible that TB would be of value to certain depressed people in exactly the same way.     

 

#150 3-TE; 3-THIOESCALINE;

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