ETHOXY-5-METHOXY-3-METHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A solution of 10.4 g of 3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine (see under 3-TASB for its preparation) in 125 mL anhydrous Et2O, in a He atmosphere, was cooled with an external dry ice acetone bath to -80 deg C with good stirring. To this clear pale yellow solution there was added 25 mL 1.6 M butyllithium in hexane (about a 25% excess) which produced a fine white precipitate over the following 15 min. There was then added 4.2 g dimethyl disulfide. At the half-addition point, the generated solids became so heavy that stirring became difficult, but towards the end of the addition the reaction thinned out again and became quite loose. The dry ice bath was removed and the reaction allowed to come to room temperature, which again allowed the formation of a heavy solid phase while warming and, again, a loose and easily stirred mixture when finally at room temperature. All was added to 400 mL H2O which had been strongly acidified with HCl. The two phases were separated, and the aqueous phase (which contained a small amount of yellow oily matter insoluble in either phase) was heated on the steam bath for 0.75 h. On cooling, the oily component set to a yellow solid, which was removed by filtration and washed with H2O. This crude product, 5.9 g of yellow solid, was distilled 115-125 deg C at 0.3 mm/Hg to give 4.9 g of 4-ethoxy-3-methoxy-5-(methylthio)benzaldehyde as a pale yellow solid that had a mp of 43-45 deg C. Recrystallization from MeOH gave a mp of 47-48 deg C. Anal. (C11H14O3S) C,H. This product can also be prepared from the anion of 3-thiosyringaldehyde (mp 141-143 deg C as crystals from MeOH) by reaction with ethyl iodide in the presence of phase-transfer catalyst, but the yield is quite poor.

 

To a solution of 4.4 g 4-ethoxy-5-methoxy-3-(methylthio)benzaldehyde in 75 mL nitromethane, there was added 0.5 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 80 min. Care must be taken in the length of time, and there must be frequent TLC montoring, as there is a rapid scrudge buildup (see under 3-TSB for a discussion of scrudge). The reaction mixture was stripped of nitromethane under vacuum, and the residual deep-yellow oil was dissolved in 20 mL of boiling MeOH. This was decanted from a small amount of insoluble matter and, upon cooling, deposited bright yellow crystals of 4-ethoxy-5-methoxy-3-methylthio-beta-nitrostyrene. This was removed by filtration and, after washing with cold MeOH and air drying, weighed 2.4 g. The mp was ambiguous. The above crude material melted at 92-93 deg C, which is probably too high! Earlier samples which melted in the low 80's appeared to have a mp, after repeated recrystallization from MeOH, of 87-88 deg C. This latter was the property of the analytical sample. Anal. (C12H15NO4S) C,H. The mp of the TLC low-moving component is always quite high, and might have been a factor in the assignment of this physical property.

 

AH was prepared in the usual manner from a suspension of 2.0 g LAH in 75 mL anhydrous THF, cooled to 0 deg C, well stirred in an inert atmosphere of He, and treated with 1.33 mL of 100% H2SO4 added dropwise. There was added, dropwise and over the course of 10 min, a solution of 2.4 g 4-ethoxy-5-methoxy-3-methylthio-beta-nitrostyrene in 15 mL anhydrous THF. The reaction was exothermic, and was heated on the steam bath at reflux for an additional 10 min. After cooling again, there was added enough IPA to decompose the excess hydride and sufficient 10% NaOH to convert the aluminum oxide solids to a white, easily filterable mass. This was filtered, the filter cake washed with additional IPA, the filtrate and washes combined, and the solvent removed under vacuum. This was dissolved in 100 mL of dilute H2SO4 which was washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with NaOH, extracted with 2x50 mL CH2Cl2, and the extracts pooled and the solvent removed under vacuum to yield a residue of a colorless oil. This distilled at 118-122 deg C at 0.4 mm/Hg producing 1.9 g of a colorless oil. This was dissolved in 10 mL IPA, neutralized with 30 drops of concentrated HCl and, with good stirring, diluted with 20 mL anhydrous Et2O. The product 4-ethoxy-5-methoxy-3-methylthiophenethylamine hydrochloride (3-TE) was removed by filtration, washed with Et2O, and air dried to provide a white solid that weighed 1.0 g and melted at about 180 deg C. Anal. (C12H20ClNO2S) C,H.

 

DOSAGE: 60 - 80 mg.

 

DURATION: 8 - 12 h.

 

QUALITATIVE COMMENTS: (with 60 mg) There may well be time slowing. I noticed that the voices on the radio seemed to be of a deeper pitch. And with music there is a most easy flight of fantasy. I tried to keep a logical conversation going on the telephone, but I am pretty sure there were problems. I found myself down sooner than I would have liked.

 

(with 70 mg) I found myself in a good, rich place, and thoroughly enjoyed my introspection. I didn't want to talk and interact, and that seemed just fine with everyone else. Several of the others seemed restless, but I lay back and let them do their thing. My appetite was fine towards the end, and I might have actually overeaten. I was able to drive home that evening, but there seemed to be some slight residual something after waking in the morning. I would certainly repeat without hesitation.

 

(with 80 mg) Art interpretation and imagery with music are remarkable. This material touches on the psychedelic Q rather than just being stoned. The body is higher than the mind, but where the mind is makes it all OK. It's worth the cost. My getting to sleep was easy that evening, but sleep was not too restful and there was something strange about it.

 

EXTENSIONS AND COMMENTARY: There is a good lesson to be learned in the attempts to predict the potency of 3-TE before it was actually explored. All pharmacological prediction follows pretty much a single mechanism. Find things that are close in some way, and arrange them in a manner that allows comparison. A relates to B in this way, and A relates to C in that way, and since D incorporates both this and that of each, it will probably be such-and-such. The Roman square.

 

Here is the square with the horizontal arrow adding a sulfur in the 3-position and the vertical arrow adding an ethyl group in place of a methyl group at the 4-position:

 

Mescaline                      x 3.5                   3-TM

 

200-400 mg                                                      60-100 mg

 

           x 6

 

 Escaline                                                          3-TE Rx20S

 

40-60 mg                                           = 10-20 mg

 

and one would predict a potency of some 20x that of mescaline, or something in the range of 15 mg.

 

Here is an equally likely square, based on the horizontal arrow relocating a sulfur from the 4-position to the 3-position, and the vertical arrow again adding an ethyl group in place of a methyl group in the 4-position:

 

Thiomescaline                  x 0.3                  3-Thiomescaline

 

20-30 mg                                                   60-100 mg

 

           x 1

 

Thioescaline                                                     3-TE Rx0.3S

 

20-30 mg                                                     = 60-100 mg

 

and one would predict a potency of some one third of that of thiomescaline, or something in the range of 80 milligrams.

 

This latter square gave a prediction that was very close to the observed potency, but it would be careless, and probably wrong, to assume that the latter relationships had any more significance than the former ones. As one accumulates the potencies of many compounds it is tempting to draw complex relationships such as these, and to be seduced into believing that they must explain things. And, especially, beware the multivariable power of the computer which can explore monstrous numbers of variables at breakneck speeds, and spew forth fantastic correlations with marvelous ease.

 

But nothing can ever substitute for the simple art of tasting something new.     

 

 

 

#151 TE; 4-TE; 4-THIOESCALINE; 3,5-DIMETHOXY-4-ETHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A solution was made of 45.2 g N,N,N',N'-tetramethylethylenediamine and 41.4 g of 1,3-dimethoxybenzene in 300 mL hexane. This was stirred vigorously under a He atmosphere and cooled to 0 deg C with an external ice bath. There was added 225 mL of 1.6 M butyllithium in hexane which produced a white granular precipitate. The reaction mixture was stirred for 15 min. There was then added 38 mL of diethyl disulfide which changed the granular precipitate to a creamy character. Stirring was continued for an additional 5 min, then the reaction mixture was poured into 1 L of dilute H2SO4. The two phases were separated, and the aqueous phase extracted with 2x150 mL Et2O. The organic phases were combined, and the solvent removed under vacuum to provide 60 g of 2-ethylthio-1,3-dimethoxybenzene as an off-white oil that spontaneously crystallized. It was distilled nonetheless, boiling at 85-96 deg C at 0.4 mm/Hg. This distillate can be recrystallized from hexane to form long needles with a mp of 45-46 deg C. Anal. (C10H14O2S) C,H.

 

To a stirred solution of 60 g of 2-ethylthio-1,3-dimethoxybenzene in 300 mL CH2Cl2 there was added 49 g elemental bromine dissolved in 100 mL CH2Cl2. The reaction was not exothermic, and it was allowed to stir for 2 h. The reaction mixture was washed with H2O, then with aqueous NaOH, and finally with H2O that contained sodium hydrosulfite. The solvent was removed under vacuum leaving 84 g of an amber oil as residue. This was distilled at 105-115 deg C at 0.15 mm/Hg yielding 73.3 g of 4-bromo-2-ethylthio-1,3-dimethoxybenzene as a light yellow oil. Anal. (C11H15BrO2S) C,H.

 

To a solution of 27 mL diisopropylamine in 150 mL anhydrous THF that was stirred under a N2 atmosphere and cooled to -10 deg C with an external ice/MeOH bath, there was added in sequence 83 mL of 1.6 M butyllithium in hexane, 4.4 mL of dry CH3CN over the course of 5 min, and finally 12.1 g of 4-bromo-2-ethylthio-1,3-dimethoxybenzene which had been dissolved in 20 mL THF (also added over the course of 5 min). The color progressed from yellow to orange to deep red-brown. Stirring was continued for 10 min, and then the reaction mixture was poured into 300 mL dilute H2SO4. The organic layer was separated, and was washed with more dilute H2SO4. The aqueous phases were combined, and extracted with 2x100 mL CH2Cl2. These extracts were pooled with the original organic phase, and the solvents removed under vacuum. The residue was distilled into two fractions at 0.3 mm/Hg. The first fraction boiled at 95-115 deg C and weighed 4.9 g. It was made up of several components, but it contained little nitrile material and was discarded. The second fraction came over at 145->200 deg C and weighed 2.9 g. By thin layer chromatography this fraction was largely 3,5-dimethoxy-4-ethylthiophenylacetonitrile, and was used as such in the following reduction.

 

A suspension of 1.25 g LAH in 50 mL anhydrous THF under N2 was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 0.8 mL 100% H2SO4, followed by 2.7 g 3,5-dimethoxy-4-ethylthiophenylacetonitrile, neat, over the course of 5 min. The reaction mixture was stirred at 0 deg C for a few min, then brought to a reflux for 15 min on the steam bath. After cooling back to room temperature, there was added 15 mL IPA to destroy the excess hydride and 10% NaOH to bring the reaction to a basic pH and convert the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed with 50 mL portions of IPA. The filtrate and washes were stripped of solvent under vacuum, and the residue suspended between 50 mL CH2Cl2 and 50 mL dil. H2SO4. The organic phase was separated, and extracted with 2x50 mL dilute H2SO4. The original aqueous phase and these two extracts were combined, made basic with aqueous NaOH, and extracted with 3x50 mL CH2Cl2. These extracts were stripped of solvent under vacuum. The residue was distilled at 112-135 deg C at 0.2 mm/Hg to give 1.1 g of a slightly yellow viscous liquid. This was dissolved in 4 mL IPA, neutralized with 14 drops of concentrated HCl and, with continuous stirring, diluted with 10 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 1.0 g of 3,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (TE) as white crystals with some solvent of crystallization. The crude mp of 101-106 deg C was only slightly improved by recrystallization from CH3CN (mp 106-109 deg C). But upon fusion and resolidification, the melting point was 167-168 deg C and this sample was further dried by heating at 100 deg C for 24 h before analysis. Anal. (C12H20ClNO2S) C,H.

 

DOSAGE: 20 - 30 mg.

 

DURATION: 9 - 12 h.

 

QUALITATIVE COMMENTS: (with 20 mg) I feel it in my ovaries. It is very sensuous. This is total energy, and I am aware of my every membrane. This has been a marvelous experience, very beautiful, joyous, and sensuous. But maybe the dose is a little too high as there is too much body tingling. I am jangly.

 

(with 20 mg) The predominant characteristic was the feeling of clean burning, pure energy, a long-lasting clear-headedness and clarity of thought, and an ease of talking and sharing. I did not have a strong feeling of Presence, but more a wonderful feeling of converting energy into action. I found that my initial look inwards was always a look of fear, and I wondered if this might not be the same feeling that others express as excitement. They were certainly of the same nature, they arose at the same point on the fringe of the unknown, and they point to a basic difference in attitude. The excitement is for the new, and is based on trust. The fear is a return to the past, and is defensive, with reluctance to reexperience past pain. The aftermath of this experience was the most profound of any that I have had in a long time. For the following week, I found myself on a new level of functioning, very energetic and very much in the flow of life and free of mental distractions. I have become a great deal more aware of the traps of meditation, and how you can build walls around yourself and around certain concepts, if you are not careful.

 

(with 22 mg) Totally developed at 2 hours, to a +++. No clearing of the sinuses, so it is not a decongestant. There is a lot of visual activity. In the group there is good communication, and a lot of laughter.

 

(with 25 mg) There is a disconnection, there is complex depth without definition. Without music, this is almost negative, as I can find no definition. But talking gives me some structure. And I got into some pretty extraordinary conversations. About President Hoover, Omni magazine, the colors of spices, and a couple of personal relatives. This is extra-good for ideas and talking. It is indeed a clean experience, and superb for communication.

 

(with 30 mg) I was at a plus three for certainly three hours. There were some visuals, some eyes-closed fantasy, but little imagery. Somehow I could at no time interlock with music. It seemed always to get in the way. Sexual activity is an excellent way to relieve the muscular tension and the body's heaviness. There was little hunger and I ate lightly, and I felt somehow depleted. Sleep OK at the twelth hour. The AM was fine, but on retrospect the experience was overall strangely cloudy, not negative, but there was not enough mental to balance the physical.

 

(with 30 mg) My alert was in 40 minutes, and I was completely developed by 2 hours. There was a large measure of erotic fantasy, but the body load was also quite heavy. I had a slight cloak effect, where I was over-energized but somehow under a blanket of quietness. I would certainly repeat this, but at maybe 25 milligrams.

 

EXTENSIONS AND COMMENTARY: Although the ethyl group (of the ethylthio on the 4-position) is just one carbon atom longer than the methyl group (of TM) that small change already produces hints and indicators of some physical toxicity. The propyl compound (see TP) is still of similar potency, but appears to be yet more difficult, physically. The butyl homolog never made it off the ground at all as a psychedelic, but the physical difficulties seem less as well. All that was left to come through was the euphoria. If this 4-position sulfur analogue series of mescaline is ever to be more carefully explored, it must almost certainly be with the shortest possible chain (TM, as a psychedelic) or with long, long chains (the four-carbon chain of the butyl group in TB), as a feel-good compound.     

 

 

 

#152 2-TIM; 2-THIOISOMESCALINE; 3,4-DIMETHOXY-2-

METHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A short foreword to the synthetic portion is needed. First, although the required thioanisole, 2,3-dimethoxythioanisole, is now commercially available, it is of the utmost importance that it be free of the impurity, veratrole. I know that the material presently available from Aldrich Chemical Company is satisfactory, as I have had a hand in making it. But, if veratrole is present, there are very difficult separations encountered during these preparations. And secondly, the synthesis of 2-TIM and 4-TIM requires a separation of isomers. The first intermediates are common to both. They will be presented here, under this recipe for 2-TIM.

 

A solution of 150 mL of 1.6 M butyllithium in hexane under N2 was vigorously stirred and diluted with 150 mL petroleum ether (30-60 deg C) and then cooled with an external ice bath to 0 deg C. The addition of 26.7 g of veratrole produced a flocculant white precipitate. Next, there was added a solution of 23.2 g of N,N,N',N'-tetramethylethylenediamine in 100 mL anhydrous Et2O and the stirred reaction mixture was allowed to come to room temperature. The subsequent addition of 20.7 g of dimethyl disulfide over the course of several min produced an exothermic response, and this was allowed to stir for an additional 30 min. There was then added 10 mL EtOH followed by 250 mL of 5% NaOH. The organic phase was washed first with 150 mL 5% NaOH, followed by 2x100 mL portions of 5% dilute HCl. The removal of solvent and bulb-to-bulb distillation of the residue provided 2,3-dimethoxythioanisole boiling at 72-80 deg C at 0.4 mm/Hg as a white oil. This product contained some 20% unreacted veratrole as a contaminant and the isolation of subsequent products from this impure material was extraordinarily difficult. The effort needed for careful purification at this point was completely justified. The product could be obtained in a pure state by distillation at 0.1 mm/Hg through a 6 cm Vigreaux column with collection of several fractions. Those that distilled at 84-87 deg C were pure 2,3-dimethoxythioanisole. An analytical sample can be obtained by cooling a concentrated MeOH solution in dry ice, filtering the generated crystals, and washing with cold MeOH. This product melts at 36.5-37 deg 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 deg 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 deg 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 deg 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 deg 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 deg 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-beta-nitrostyrene with a mp of 102-103.5 deg C. An analytical sample, from IPA, had a mp of 103-104 deg 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 deg 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-beta-nitrostyrene and 3,4-dimethoxy-beta-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 deg 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)-beta-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 deg 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 deg 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 deg C. Recrystallization from either MeOH or cyclohexane tightened the mp, but lowered it to 67-68 deg C and 66-67 deg 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-beta-nitrostyrene were obtained which were removed by filtration and air-dried, and weighed 0.9 g. The mp was 130-133 deg C and could be improved to 136-137 deg 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 deg C under He. There was added, dropwise, 0.4 mL of 100% H2SO4, followed by 0.6 g of 2,4-dimethoxy-3-methylthio-beta-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 deg 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 deg 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 can't 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 "non-active" 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 "non-active," if that makes sense!     

 

 

 

#154 4-TIM; 4-THIOISOMESCALINE;

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