ETHOXY-4-METHOXY-5-METHYLTHIOPHENETHYLAMINE

 

SYNTHESIS: A solution of 10.4 g of 3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine (see under ME for its preparation) in 150 mL anhydrous Et2O in a He atmosphere was cooled with an external dry ice acetone bath to -80 deg C with good stirring. The addition of 52 mL 1.6 M butyllithium in hexane produced a thick precipitate which was stirred for 5 min. There was then added 8.5 mL of dimethyl disulfide and the reaction mixture gradually became thinner and lighter. The dry ice bath was removed and the reaction allowed to come to room temperature over the course of 15 min. This was then added to 400 mL of dilute HCl. The two phases were separated, and the aqueous phase was heated on the steam bath for 1 h which generated a separate yellow oily phase. On cooling, this set to a yellow solid, which was removed by filtration, washed with H2O, and sucked relatively free of H2O. These yellow solids weighed 14.4 g and were ground under 20 mL of cold cyclohexane which removed almost all the color and, after filtering and air drying, there remained 12.9 g of an off-white crystalline solid that melted at 83-84 deg C. Recrystallization from cyclohexane produced 3-ethoxy-4-methoxy-5-(methylthio)benzaldehyde as a white fluffy crystalline material with a melting point of 84-85 deg C. Anal. (C11H14O3S) C,H.

 

To a solution of 8.0 g 3-ethoxy-4-methoxy-5-(methylthio)benzaldehyde in 100 mL nitromethane, there was added 0.5 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 1.5 h, at which time most of the aldehyde had disappeared and there was a sizeable quantity of nitrostyrene as well as a cascade of wrong things down to the origin, as seen by TLC on silica gel, with CH2Cl2. The excess nitromethane was removed under vacuum, and the residual red oil was dissolved in 25 mL of hot MeOH and decanted from a small amount of insoluble material. With cooling in an ice bath for 20 min, bright yellow crystals were formed which were removed by filtration, washed with MeOH and air dried, producing 4.1 g 3-ethoxy-4-methoxy-5-methylthio-beta-nitrostyrene which melted at 80-82 deg C. This sample, on resolidification and remelting, melted at 109-110 deg C. This higher-melting polymorphic form was also produced by recrystallization of the product from cyclohexane. The two polymorphs were chromatographically and analytically identical. Anal. (C12H15NO4S) C,H.

 

AH was prepared in the usual manner from a suspension of 3.0 g LAH in 100 mL anhydrous THF, cooled to 0 deg C, well stirred in an inert atmosphere of He, and treated with 2.0 mL of 100% H2SO4 added dropwise. There was then added a solution of 2.4 g 3-ethoxy-4-methoxy-5-methylthio-beta-nitrostyrene in 20 mL anhydrous THF. The reaction was exothermic, and had come nearly to a boil at the half-addition point. The reaction was cooled again to 0 deg C and the remaining nitro-styrene then added. This was brought to a reflux briefly on the steam bath, then cooled again and stirred for an additional 1 h. IPA was carefully added to decompose the excess hydride followed by sufficient 10% NaOH to convert the aluminum oxide to a white, easily filterable mass. This was filtered, the filter cake washed with additional IPA, and 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 sodium hydroxide, extracted with 2x50 mL CH2Cl2, and the extracts pooled, dried over anhydrous K2CO3, and stripped of solvent under vacuum to yield a nearly colorless residue. This was distilled at 125-135 deg C at 0.3 mm/Hg producing 2.0 g of a water-white oil. This was dissolved in 8 mL IPA, neutralized with 23 drops of con-centrated HCl and, with good stirring, diluted with 20 mL anhydrous Et2O. The product 3-ethoxy-4-methoxy-5-methylthiophenethylamine hydrochloride (5-TME) was removed by filtration, washed with Et2O, and air dried to provide a white solid that weighed 2.0 g and melted at 168-169 deg C. Anal. (C12H20ClNO2S) C,H.

 

DOSAGE: greater than 200 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 200 mg) There was a noticeable tinnitus, but then that comes and goes at odd times without any reason needed. There was perhaps a brush of light-headedness at the third hour point, but other than that, nothing. No effect that can be ascribed to today's drug trial.

 

EXTENSIONS AND COMMENTARY: Nothing comes to mind. This, along with most of the di- and triethylated thiomescaline analogues, represents a lot of synthetic effort without useful qualitative data. If there is any activity, it would only be seen with monster dosages, and why put the body through such potential impact?      

 

 

 

#166 2T-MMDA-3a; 3,4-METHYLENEDIOXY-2-METHYLTHIOAMPHETAMINE

 

SYNTHESIS: A solution of 30 g piperonal in 25 mL cyclohexylamine was brought to a boil on a hot plate, until there was no more water apparently being evolved. The resulting melt was distilled giving 45 g of N-cyclohexyl-3,4-methylenedioxybenzylideneimine boiling at 114-135 deg C at 0.2 mm/Hg as a light yellow oil.

 

In 400 mL anhydrous Et2O there was dissolved 40.3 g N-cyclohexyl-3,4-methylenedioxybenzylidenimine and 30 mL N,N,N',N'-tetramethylethylenediamine (TMEDA). This solution was put under an inert atmosphere, and with good stirring brought to -78 deg C with an external dry ice/acetone bath, which produced a light white crystalline precipitate. There was then added 120 mL of 1.55 M butyllithium, which produced an immediate darkening and a dissolving of the fine precipitate. After 10 min stirring, there was added 20 mL of dimethyl disulfide. The color immediately vanished and there was the formation of a white precipitate. The temperature was allowed to return to ice bath temperature, and then all volatiles were removed under vacuum. The residue was poured into 500 mL H2O and acidified with HCl. After heating for 1 h on the steam bath, the reaction mixture was cooled, producing a gummy solid that was shown to be a complex mixture by TLC. But there was a single fluorescent spot that was the product aldehyde and it was pursued. Extraction with 3x75 mL CH2Cl2 gave, after pooling and stripping of the solvent, a residue which was extracted with four separate passes, each with 75 mL boiling hexane. The deposited crystals from each were separated, and all recrystallized from boiling MeOH to give 3.3 g of 3,4-methylenedioxy-2-(methylthio)benzaldehyde, with a mp of 77-80 deg C.

 

To a solution of 3.0 g 3,4-methylenedioxy-2-(methylthio)benzaldehyde in 25 mL IPA there was added 2 mL nitroethane, 0.11 mL ethylenediamine and 0.1 mL acetic acid. This was held at reflux temperature for 18 h, and the solvents removed under vacuum. The residue showed a total of eight spots on TLC analysis, extending from the origin to the spot of the product nitrostyrene itself. Trituration of this residue under 25 mL MeOH gave a crude nitrostyrene which was, after separation, recrystallized from 20 mL of boiling MeOH. The final isolation of 1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene gave 0.5 g of a product that had a mp of 94-95 deg C. The mixed mp with the nitrostyrene from piperonal (mp 97-98 deg C) was soundly depressed (mp 67-79 deg C).

 

A solution of AH was prepared by the treatment of a solution of 0.5 g LAH in 10 mL THF, at 0 deg C and under He, with 0.32 mL 100% H2SO4. A solution of 0.45 g 1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene in 10 mL THF was added dropwise, and the stirring was continued for 1 h. After a brief period at reflux, the reaction mixture was returned to room temperature, and the excess hydride destroyed by the addition of IPA. The salts were converted to a filterable mass by the addition of 5% NaOH, and after filtering and washing with IPA, the combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4 which was washed with 3x75 mL CH2Cl2. After alkalinification with 25% aqueous NaOH, the product was extracted with 2x75 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. Distillation of the residue gave a fraction that boiled at 137-150 deg C at 0.3 mm/Hg and weighed 0.3 g. This was dissolved in 1.6 mL IPA, neutralized with 6 drops of concentrated HCl, warmed to effect complete solution, and diluted with 4 mL of anhydrous Et2O. The formed crystals were collected by filtration, and after Et2O washing and air drying to constant weight, gave 0.3 g 3,4-methylenedioxy-2-methylthioamphetamine hydrochloride (2T-MMDA-3a).

 

DOSAGE: greater than 12 mg.

 

DURATION: unknown.

 

EXTENSIONS AND COMMENTARY: And visions of sugar-plums danced through their heads. There are many trisubstituted amphetamine analogues that have been documented with varying degrees of activity. There are six TMA's and if one were to systematically make every possible thio-analogue of each of these, there would be a total of sixteen thio-analogues of the TMA. Let's go for it, said I to myself. Let's get the 16 thio analogues in hand. That is where the action's at. But hold on a minute. Each and every MMDA isomer has, by definition, three possible thio analogues, so there are eighteen more possible thio compounds just with them. Sure, let's make them all! It will be an unprecedented coup for students of structure-activity relationships. Let's whip out some 34 compounds, and test them all, and maybe we will begin to understand just why those which are active are, indeed, active. And maybe not.

 

Anyway, this was the most manic of all manic programs ever, involving thio-analogues. And it was totally compelling. Another synthetic clue stemmed from the fact that vanillin also formed the cyclic carbonate with sodium thiocyanate and it could, in principle, be brought around in time to 3-methoxy-5,4-methylenethiooxyamphetamine, or 5T-MMDA. That made two of the magic analogues, and only some 32 to go. What a marvelous task for a graduate student. (What a horribly dull task for a graduate student.) But in any case there was no graduate student, and this appeared to be the end of the line. Some day, let's make all these possibilities. A magnificent tour-de-force, but at the present time, not worth the effort. Other directions are more exciting and more appealing.

 

A last note of simple humor. One of the compounds used in this preparation was N,N,N',N'-tetramethylethylenediamine, which has been abbreviated TMEDA. There is a pattern, within any active inner clique of research chemists intently pursuing a goal, to begin condensing complex comcepts into deceptively simple terms. We "MOM-ed the hydroxy group of the T-BOC-ed amine." I have recently heard the above tetramethyl monster referred to in the chemist's jargon as a pronounced, rather than a spelled out, word. It sounds very much like "tomato" spoken by a native of the Bronx.      

 

 

 

#167 4T-MMDA-2; 6-(2-AMINOPROPYL)-5-METHOXY-1,3-BENZOXATHIOL;

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