solution in dry ice, filtering the generated crystals, and washing with cold MeOH. This product melts at 36.5-37 !C. Anal. (C9H12O2S) C,H,S. The picrate can be formed by treatment with a saturated EtOH
solution of picric acid. It formed orange crystals with a mp of 73-78
!C. Anal. (C15H15N3O9S) N.
To 18 mL of POCl3 there was added 25 mL N-methylformanilide and the solution allowed to stand at room temperature for 0.5 h, until the color had developed to a rich claret. There was then added 25.0 g of 2,3-dimethoxythioanisole and the mixture heated on the steam bath for 2.5 h. This was added to 500 mL H2O and stirred at ambient temperature for 2 h. The product was extracted with 4x150 mL CH2Cl2, the extracts combined, and the solvent removed under vacuum. The residue was distilled through a Vigreaux column under vacuum (0.1 mm/Hg) with the fraction boiling at 125-135 !C being richest in aldehydes, as determined by GC analysis. If the starting 2,3-dimethoxythioanisole contains appreciable veratrole as a contaminant, then this aldehyde fraction contains three components. There is present both 2,3-dimethoxy-4-(methylthio)benzaldehyde and 3,4-dimethoxy-2-(methylthio)benzaldehyde (the two desired precursors to 4-TIM and 2-TIM, respectively), but also present is 3,4-dimethoxybenzaldehyde from the veratrole contamination. The weight of this fraction was 11.9 g and was a white oil free of starting thioether.
Although efforts to separate this mixture were not effective, one of the aldehydes could be isolated in small yield by derivative formation. This was too wasteful to be of preparative value, but it did allow the generation of seed that was of great value in the later separation of the mixed nitrostyrenes that were prepared. If a 1 g portion of this mixture was fused with 0.6 g p-anisidiine over an open flame and then cooled, the melt set up as a solid. Triturating under MeOH gave a yellow solid (0.45 g, mp 77-80 !C) which on recrystallization from hexane appeared to be a single one of the three possible Schiff's bases that could theoretically be prepared. It had a mp of 80-81 !C. Anal. (C17H19NO3S) C,H. Hydrolysis with hot 3 N
HCl freed the benzaldehyde which was isolated by quenching in H2O and extraction with CH2Cl2. The extracts were stripped of solvent under vacuum and the residue distilled bulb-to-bulb under vacuum to give white crystals of 3,4-dimethoxy-2-(methylthio)benzaldehyde (the 2-TIM
aldehyde) with a mp of 23-24 !C. A micro-scale conversion of this to the corresponding nitrostyrene provided the seed that was effectively used in the large scale preparation described below.
A solution of 9.0 g of a mixture of
3,4-dimethoxy-2-(methylthio)benzaldehyde and 2,3-dimethoxy-4-(methylthio)benzaldehyde in 50 mL of nitromethane was treated with 1.5 g anhydrous ammonium acetate and held at reflux for 5
h. The excess nitromethane was removed under vacuum to yield 10.4 g of a dark orange oil which, upon dissolving in 40 mL hot MeOH and being allowed to cool and slowly evaporate at ambient temperatures, provided dark colored crystals. Filtration (save the mother liquors!) and recrystallization from 40 mL MeOH provided 6.3 g of a yellow crystalline solid. A second recrystallization from 50 mL MeOH gave 5.0 g of lemon yellow plates 3,4-dimethoxy-2-methylthio-'-nitrostyrene with a mp of 102-103.5 !C. An analytical sample, from IPA, had a mp of 103-104 !C and a single spot on TLC with CHCl3, with an Rf of 0.54.
Anal. (C11H13NO4S) C,H. When there had been veratrole left as a contaminant in the original 2,3-dimethoxythioanisole, the nitrostyrene that was isolated by this method had, after recrystallization, a mp of 93-95 !C. This substance acted as a single compound through a number of recrystallization trials, but on TLC analysis always gave two components (silica gel, chloroform) with Rf's of 0.54 and 0.47. It proved to be a mixture of 3,4-dimethoxy-2-methylthio-'-nitrostyrene and 3,4-dimethoxy-'-nitro-styrene in an exact molecular ratio of 2:1.
This latter nitrostyrene is the precursor to DMPEA, q.v. Anal.
(C32H37N3O12S2) C,H. The mother liquor above is the source of the 4-TIM nitrostyrene, and its isolation is described in the recipe for 4-TIM.
A solution of 4.2 g LAH in 70 mL anhydrous THF was cooled to 0 !C
under He and with stirring. There was added, dropwise, 2.8 mL of 100%
H2SO4, followed by 4.4 g of
3,4-dimethoxy-2-(methylthio)-'-nitrostyrene dissolved in 25 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 10 min on the steam bath. The reaction was cooled again, and 25% NaOH was added dropwise until a white granular precipitate was obtained. This was removed by filtration, and the filter cake was washed with 2x50 mL
Et2O. The filtrate was extracted into 100 mL dilute H2SO4 which was, in turn, made basic again and extracted with 2x100 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give a residue of crude product. This was distilled from 100-115 !C at 0.3
mm/Hg yielding 3.2 g of a clear white oil. This was dissolved in 25
mL IPA, neutralized with 23 drops of concentrated HCl, and diluted with 75 mL anhydrous Et2O. There was a deposition of beautiful white platelets of 3,4-dimethoxy-2-methylthiophenethylamine hydrochloride (2-TIM) which were removed by filtration, washed with ether, and air dried. This hydrochloride salt contained a quarter mole of H2O of crystallization. The mp was 183-184 !C. Anal. (C11H18ClNO2Sa1/4 H2O) C,H,N.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 160 mg) There was perhaps some awareness in an hour or so, but in another hour there was absolutely nothing. A small amount of wine in the evening was quite intoxicating.
(with 240 mg) No effects of any kind.
EXTENSIONS AND COMMENTARY: The problems that might be associated with the making of the three amphetamines that correspond to 2-TIM, 3-TIM
and 4-TIM might very well prove quite exciting. These would be the three thio analogues of TMA-3; vis,
3,4-dimethoxy-2-methylthioamphetamine, 2,4-dimethoxy-3-methylthioamphetamine, and 2,3-dimethoxy-4-thioamphetamine. The first challenge would be to name them. Using the 2C-3C convention, they would be the 3C analogs of trivially named 2-carbon compounds, namely 3C-2-TIM, 3C-3-TIM and 3C-4-TIM. Using the thio convention (the number before the T is the position of the sulfur atom), they would be 2-T-TMA-3, 3-T-TMA-3 and 4-T-TMA-3. The second challenge would be their actual synthesis. The information gained from the separation of the 2-carbon nitrostyrenes and that most remarkable mixed-nitrostyrene thing that acted as a single pure material, would not be usable. But it is intriguing to speculate if there might be some parallel problems in the 3-carbon world. It seems almost certain that none of the compounds would be pharmacologically active, so the incentive would be the challenge of the chemistry. Some day, maybe.
153 3-TIM; 3-THIOMESCALINE; 2,4-DIMETHOXY-3-METHYLTHIOPHENETHYLAMINE
SYNTHESIS: A mixture of 3.1 g POCl3 2.8 g N-methylformanilide was heated on a steam bath until it was a deep claret color (about 5 min).
To this there was then added 3.0 g of 2,6-dimethoxythioanisole (see under 4-TM for its preparation), and heating was continued for 30 min.
The reaction mixture was then added to 75 mL H2O and stirred overnight. The dark oily mixture was extracted with 3x75 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was extracted with 3x20 mL boiling hexane, each extract being poured off from the insoluble residue. Pooling and cooling these extracts yielded 1.5 g of 2,4-dimethoxy-3-(methylthio)benzaldehyde as an off-white crystalline solid with a mp of 67-69 !C.
Recrystallization from either MeOH or cyclohexane tightened the mp, but lowered it to 67-68 !C and 66-67 !C, resp. Anal. (C10H12O3S) C,H.
To a solution of 1.3 g 2,4-dimethoxy-3-(methylthio)benzaldehyde in 60
mL nitromethane there was added 0.3 g anhydrous ammonium acetate and the mixture was heated at reflux for 3 h. The hot solution was decanted from a little insoluble material, and the excess nitromethane was removed under vacuum. The residue dissolved in 10 mL hot MeOH.
On cooling, yellow crystals of
2,4-
dimethoxy-3-methylthio-'-nitrostyrene were obtained which were removed by filtration and air-dried, and weighed 0.9 g. The mp was 130-133 !C and could be improved to 136-137 !C following recrystallization from MeOH (10 g/g). Anal. (C11H13NO4S) C,H.
A well-stirred solution of 0.6 g LAH in 10 mL anhydrous THF was cooled to 0 !C under He. There was added, dropwise, 0.4 mL of 100% H2SO4, followed by 0.6 g of 2,4-dimethoxy-3-methylthio-'-nitrostyrene dissolved in a little 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, and 25% NaOH was added dropwise until a white granular precipitate was obtained. This was removed by filtration, and the filter cake was washed with 2x25 mL Et2O. The filtrate was extracted into 25 mL
dilute H2SO4 which was, in turn, made basic again and extracted with 2x25 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give a residue of crude product. This was distilled from 120-140 !C at 0.3 mm/Hg yielding 0.25 g of a clear white oil.
This was dissolved in 5 mL IPA, neutralized with about 3 drops of concentrated HCl, and diluted with 15 mL anhydrous Et2O. Scratching with a glass rod instigated crystallization of bright white solids which were filtered, washed with Et2O, and air dried. The weight of 2,4-dimethoxy-3-methylthiophenethylamine hydrochloride (3-TIM) was 0.2
g and the mp was 204-206 !C with decomposition. This hydrochloride appeared to be a hemihydrate. Anal. (C11H18ClNO2Sa1/2 H2O) C,H,N.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 240 mg) Briefly I thought that there might have been an alert at the 2 to 3 hour point, but I now think it was nothing. During the following day I had a mild stomach upset off and on, but I canUt believe that it was connected with 3-TIM.
EXTENSIONS AND COMMENTARY: Isomescaline itself is not active, but there is no way of knowing just how Rnon-activeS it really is. If it were to be active just beyond the levels assayed, then the introduction of a sulfur into the molecule in place of an oxygen could have increased the potency to where it might have some effect. The absence of any activity from this TIM, and the other two TIMs, might well suggest that isomescaline is really very Rnon-active,S if that makes sense!
154 4-TIM; 4-THIOISOMESCALINE;
2,3-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE
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-'-nitrostyrene (leading to 4-TIM), Rf = 0.61; 3,4-dimethoxy-2-methylthio-'-nitrostyrene (leading to 2-TIM), Rf = 0.54; and 3,4-dimethoxy-'-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 !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-'-nitrostyrene with a mp of 70-71 !C.
A solution of 1.2 g LAH in 20 mL anhydrous THF was cooled to 0 !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-'-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 !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 !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
!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 !C at 0.4
mm/Hg gave 0.9 g 3,4-dimethoxy-5-(methylthio)benzaldehyde which had a mp of 57-58 !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-'-nitrostyrene, with a mp of 119.5-120.5 !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 !C and vigorously stirred, there wa
s added, dropwise, 0.7 mL of 100%
H2SO4, followed by a solution of 0.7 g 3,4-dimethoxy-5-methylthio-'-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 !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 !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.
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