DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE. #155 3-TM; 3-THIOMESCALINE; 3,4-DIMETHOXY-5-METHYLTHIOPHENETHYLAMINE. #156 TM; 4-TM; 4-THIOMESCALINE

 

SYNTHESIS: The mother liquors from the initial crystallization of the 2-TIM nitrostyrene (see under 2-TIM) was the source and raw material for all 4-TIM chemistry. Once the bulk of the 2-TIM nitrostyrene has been removed, these mother liquors could be processed to give the 4-TIM nitrostyrene. The easier procedure was to evaporate these mother liquors to a residue under vacuum, and hope for a spontaneous crystallization. If this failed, flash chromatography could be used. For reference purposes, the three nitrostyrenes involved in the 2-TIM/4-TIM problem movedon silica gel TLC with CHCl3 solvent in the following manner: 2,3-dimethoxy-4-methylthio-beta-nitrostyrene (leading to 4-TIM), Rf = 0.61; 3,4-dimethoxy-2-methylthio-beta-nitrostyrene (leading to 2-TIM), Rf = 0.54; and 3,4-dimethoxy-beta-nitrostyrene (leading to DMPEA), Rf = 0.47. For flash chromatography, a small portion of the residue from the mother liquor was dissolved in CHCl3, and placed on a silica gel column. CHCl3 was used as the eluding solvent. The first material breaking through from the column was the 4-TIM nitrostyrene and on evaporation of this fraction, seed was obtained as gold-colored crystals that had a mp of 71-73 deg C. This, when added to the residues from the described 2-TIM synthesis nitrostyrenes, started the crystallization process. The gummy solid that was produced was triturated under MeOH, and the crystals so revealed were removed by filtration. Recrystallization from 10 mL MeOH gave 1.9 g of solids. A second recrystallization from 5 mL MeOH provided 0.7 g of pumpkin-colored crystals of 2,3-dimethoxy-4-methylthio-beta-nitrostyrene with a mp of 70-71 deg C.

 

A solution of 1.2 g LAH in 20 mL anhydrous THF was cooled to 0 deg C under He and stirred. There was added, dropwise, 0.8 mL of 100% H2SO4, followed by 0.9 g of 2,3-dimethoxy-4-methylthio-beta-nitrostyrene dissolved in 20 mL THF. Stirring was continued for a few min as the reaction returned to room temperature, and then it was heated to a reflux for 5 min on the steam bath. The reaction was cooled again, EtOAc was added to destroy the excess hydride, followed by 25% NaOH added dropwise until a white granular precipitate was obtained. This was removed by filtration, and the filter cake was washed with 2x35 mL Et2O. The filtrate was extracted into 50 mL dilute H2SO4 which was washed with Et2O and, in turn, made basic again and extracted with 2x50 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give a residue of crude product. This distilled cleanly from 100-115 deg C at 0.3 mm/Hg yielding 0.45 g of a clear white oil. This was dissolved in 6 mL IPA, neutralized with 5 drops of concentrated HCl, and diluted with 25 mL anhydrous Et2O. There was a deposition of white solids which were removed by filtration, washed with Et2O, and air dried. The 2,3-dimethoxy-4-methylthiophenethylamine hydrochloride so obtained (4-TIM) weighed 0.3 g and contained a molecule of H2O of crystallization. The mp was 212-213 deg C. Anal. (C11H18ClNO2SaH2O) C,H,N.

 

DOSAGE: greater than 160 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 160 mg) Everything seemed normal. Pulse was under 80, there was nothing with eyes-closed, my appetite was normal. The compound was completely inactive.

 

EXTENSIONS AND COMMENTARY: There has been much noise made about the effectiveness of an unusual substitution group at the 4-position of the phenethylamine molecule. Here is a methylthio group at this position, and it is an inactive compound. I was just a little bit surprised.      

 

 

 

#155 3-TM; 3-THIOMESCALINE; 3,4-DIMETHOXY-5-METHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: To an ice cold and well stirred solution of 15 g vanillin and 20 g sodium thiocyanate in 150 mL acetic acid there was added, dropwise over the course of 15 min, a solution of 16 g elemental bromine in 40 mL acetic acid. This was followed by the addition of 30 mL of 5% HCl and 300 mL EtOH, and stirring was continued for an additional 30 min. The mixture was heated to its boiling point, and filtered while hot. The mother liquor was diluted with an equal volume of H2O, which initiated the crystallization of crude 5-formyl-7-methoxy-2-oxo-1,3-benzoxathiole as a flocculant yellow solid. On filtration and air-drying, this weighed 12.5 g. After recrystallization from EtOH, the product was white and had a mp of 164 deg C sharp.

 

A suspension of 12.5 g of crude 5-formyl-7-methoxy-2-oxo-1,3-benzoxathiole in 100 mL MeOH containing 28.4 g methyl iodide was treated with a solution of 12 g NaOH in 100 mL warm MeOH. The mixture was held at reflux for 1 h and then the solvents were removed under vacuum. A solution of 14.2 g methyl iodide in 100 mL DMSO was added and the mixture stirred for 1 h. An additional 2.4 g of NaOH and 16 g methyl iodide were added, and the stirring was continued for another 2 h. The reaction mixture was poured into 800 mL H2O, acidified with HCl, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with 5% NaOH, then water, and the solvent removed under vacuum. Distillation at 110-130 deg C at 0.4 mm/Hg gave 0.9 g 3,4-dimethoxy-5-(methylthio)benzaldehyde which had a mp of 57-58 deg C after crystallization from EtOH. Anal. (C10H12O3S) C,H.

 

A solution of 0.9 g 3,4-dimethoxy-5-(methylthio)benzaldehyde in 100 mL nitromethane containing 0.5 g anhydrous ammonium acetate was held at reflux for 4 h. The excess nitromethane was removed under vacuum, and the deep brown residue was dissolved in 4 mL hot MeOH. On cooling, the yellow crystals were removed by filtration, washed with cold MeOH and air dried yielding 0.4 g yellow crystals of 3,4-dimethoxy-5-methoxy-beta-nitrostyrene, with a mp of 119.5-120.5 deg C after recrystallization from EtOH. Anal. (C11H13NO4S) C,H.

 

To a solution of 1.0 g LAH in 25 mL anhydrous THF under He, cooled to 0 deg C and vigorously stirred, there was added, dropwise, 0.7 mL of 100% H2SO4, followed by a solution of 0.7 g 3,4-dimethoxy-5-methylthio-beta-nitrostyrene in 10 mL anhydrous THF. The mixture was brought briefly to a reflux, cooled again, and the excess hydride destroyed with H2O in THF, followed by the dropwise addition of 15% NaOH until the solids became white and granular. The solids were removed by filtration, the filter cake washed with THF, the mother liquor and filtrates combined, diluted with an equal volume of Et2O, and extracted with 2x40 mL dilute H2SO4. The aqueous extracts were combined, washed with Et2O, made basic with aqueous NaOH, and extracted with 2x50 mL CH2Cl2. The solvent was removed from these extracts and the residue distilled to provide 0.4 g of a white oil boiling at 124-130 deg C at 0.2 mm/Hg. This oil was dissolved in 8 mL IPA, neutralized with concentrated HCl, and diluted with 30 mL anhydrous Et2O. The white crystalline product was the monohydrate of 3,4-dimethoxy-5-methylthiophenethylamine hydrochloride (3-TM) which melted at 167-168 deg C and weighed 0.29 g. Anal. (C11H18ClNO2SaH2O) C,H,N.

 

DOSAGE: 60 - 100 mg.

 

DURATION: 8 - 12 h.

 

QUALITATIVE COMMENTS: (with 80 mg) I went into the experience with the question of whether it (3-TM) might be a writing aid. I found a considerable color enhancement (this was at the one hour point) and there seems to be no problem in writing physical words. But there is no urge to, as there are no new things. This is progressing into something more complex and there is an interesting shielding effect. I still have the desire to write and I sense that many things are going on underneath, but my conscious control suppresses their availability. It is now the third hour. Music. I would like to try this material at 100 milligrams. Now awareness seems much more pointed. I have need to build a writing table. This material is physically relaxing, insisting repose, but with conflicting energy. Seated in a chair, but I seem unable to find a comfortable position in order to write.

 

"Pine trees seem a good place

To start. Notwithstanding this table

Of pine, unfinished, unruled,

The pulp upon which we reveal

The unnerved thoughts.

How casual we are at discarding

Our feelings, a rubble we

Leave behind for the living.

Who among us can absorb

The spiritual load we see as

What others carry."

 

This material is not poetic, I should say, does not enhance poetry, prose is much more comfortable. I think I should let the experience develop further. It is now the fifth hour. There is something of a violence (emotional) suppressed in all of us, a socially repressed vision of oneself in a direct conflict with oneself. The music has a lot to do with this material. And it changes with time. In the first part there is sublimity, peacefulness, mild intoxication. And a lot more tension in the part that followed the four hour point. There the territories seem much better defined, with the benign shielding of the first half largely dissipated. I have developed a slightly irritated view of myself, probably wanting once again to regain the serenity.

 

(with 80 mg) Delightful day. Not insight depth but persistent feeling of pleasant good humor. It is good-natured and very verbal. Everyone talked and the instinct was to express and comment on everything. There were no visuals during the first three to four hours Q with the eyes open one could barely detect the intoxication. Eyes closed Q quiet lovely window, no images. About +2. And then someone brought in a radio with music on, into the room. There was a tremendous eruption of closed-eyes visual images and fantasy. Bright colors, funny, rich and elaborate. Marvelous. I was suddenly at +3. Next day, no hangover. Pleasant feeling persisted.

 

(with 100 mg) I found the day had two halves. The first few hours were characterized by occasional defensiveness (paranoia) and irritability. In interpersonal interactions there was a guardedness, due to a feeling of vulnerability. I went off by myself, and with eyes closed, there was rich imagery and color synthesis to musical imput. And then things smoothed out, and I could express an easy flow of ideas and concepts without always watching my step. And then all too soon, the intensity of the experience began fading away.

 

EXTENSIONS AND COMMENTARY: The amphetamine which would correspond with this base would be 3,4-dimethoxy-5-methylthioamphetamine (3-T-TMA) and should be an active compound. Its synthesis should be straightforward from the benzaldehyde described above, employing nitroethane rather than nitromethane. It is apparently an unknown compound.     

 

 

 

#156 TM; 4-TM; 4-THIOMESCALINE;

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