are One oxygen is re-
ethyl groups oxygen atoms placed
with sulfur
none M 3-TM
4-TM
one E 3-TE
4-TE ME 3-TME 4-TME 5-TME
two SB 3-TSB
4-TSB ASB 3-TASB 4-TASB 5-TASB
three TRIS 3-T-TRIS
4-T-TRIS
164 4-TME; 4-THIOMETAESCALINE;
3-ETHOXY-5-METHOXY-4-METHYLTHIOPHENETHYLAMINE
SYNTHESIS: A solution of 5.1 g N,N,NU,NU-tetramethylethylenediamine and 6.8 g of 3-ethoxyanisole was dissolved in 80 mL hexane. This was stirred vigorously under a He atmosphere and cooled to 0 !C with an external ice bath. There was added 27.5 mL of 1.6 M solution of butyllithium in hexane. The stirred reaction mixture deposited a fine white precipitate. It was warmed to room temperature and stirred for 15 min. After cooling again to 0 !C, there was added 4.6 mL of dimethyl disulfide which converted the precipitate to a creamy white material. Stirring was continued while the reaction mixture was brought up to room temperature, and continued for an additional h.
All was then added to 200 mL dilute H2SO4. The solids dissolved and there was the formation of two phases. These were separated, the aqueous phase extracted with with 2x75 mL Et2O, the organic phases combined and evaporated under vacuum. The residue weighed 11.1 g and set up to a waxy solid. This was ground under 1 mL of hexane, filtered, washed sparingly with hexane, and air dried yielding 7.6 g of 3-ethoxy-2-(methylthio)anisole as white crystals. The mp was 35-36
!C which was not improved following recrystallization from hexane.
Anal. (C10H14O2S) C,H.
To a stirred solution of 7.6 g of 3-ethoxy-2-(methylthio)anisole in 100 mL CH2Cl2 there was added 6.2 g elemental bromine dissolved in 50
mL CH2Cl2. The initial dark red color gradually faded to a pale yellow and there was a steady evolution of HBr. An added crystal of iodine did not appear to increase the rate of reaction. After 4 min the color was a pale orange. The reaction mixture was extracted with H2O containing sufficient dithionite to remove most of the residual color. The solvent was removed under vacuum leaving 12.2 g of a pale yellow fluid oil. This was distilled at 100-110 !C at 0.3 mm/Hg to yield a mixture of 4-bromo-3-ethoxy-2-(methylthio)anisole and 6-bromo-3-ethoxy-2-(methylthio)anisole as a pale yellow, highly refractory oil that was used as such in the following reaction. Anal.
(C10H13BrO2S) C,H.
To a solution of 12 mL diisopropylamine in 75 mL anhydrous THF that was stirred under an N2 atmosphere and cooled to -10 !C with an external ice/MeOH bath, there was added in sequence 35 mL of 1.6 M
butyllithium in hexane, 1.8 mL of dry acetonitrile, and 5.0 g of 4-bromo- (and 6-bromo)-3-ethoxy-2-(methylthio)anisole. The reaction mixture changed color from yellow to red to reddish brown. Stirring was maintained for an additional 0.5 h, and then the reaction mixture was poured into 80 mL of dilute H2SO4. The phases were separated, and the aqueous phase was extracted with 100 mL CH2Cl2. The organic phases were combined, and the solvent was removed under vacuum. The oily residue was distilled at 0.2 mm/Hg yielded two fractions. The first fraction boiled at 90-115 !C and weighed 1.7 g. This material proved to be largely the unreacted bromo starting materials. The second fraction came over at 140- 170 !C, weighed 1.7 g, and it crystallized when seeded with a small crystal obtained externally with dry ice. This fraction was recrystallized from 10 mL MeOH, filtered, and washed sparingly with cold MeOH. After air drying, there was obtained 0.5 g 3-ethoxy-5-methoxy-4-methylthiophenylacetonitrile which had a mp of 65-66 !C. Anal. (C12H15NO2S) C,H.
A suspension of 0.5 g LAH in 50 mL anhydrous THF under N2 was cooled to 0 !C and vigorously stirred. There was added, dropwise, 0.35 mL
100% H2SO4, followed by 0.45 g
3-ethoxy-5-methoxy-4-methylthiophenylacetonitrile in 10 mL anhydrous THF. The reaction mixture was stirred at 0 !C for a few min, then brought to a reflux for a few min on the steam bath. After allowing the mixture to return to room temperature, there was added IPA sufficient to destroy the excess hydride followed by 10% NaOH to bring the reaction to a basic pH and to convert the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed with 50 mL IPA. The filtrate and washes were stripped of solvent in vacuo, and the residue suspended in dilute H2SO4. This was washed with 2x75 mL CH2Cl2, made basic with aqueous NaOH, and the product extracted with 2x75 mL CH2Cl2. After combining these extracts, the solvent was removed under vacuum providing 1.2 g of a residue which was distilled at 132-140 !C at 0.4 mm/Hg to give 0.35 g of a colorless oil. This was dissolved in 7 mL of IPA, neutralized with 7 drops of concentrated HCl and diluted with 3 volumes of anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 0.30 g
3-ethoxy-5-methoxy-4-methylthiophenethylamine hydrochloride (4-TME) as white crystals with a mp of 164-165 !C. Anal. (C12H20ClNO2S) C,H.
DOSAGE: 60 - 100 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 60 mg) There was a strange off-baseness for several hours in the middle of the day, which was replaced by a mild gastric upset in the evening. The mild mental disturbance is neither visual nor particularly interesting.
(with 100 mg) A benign and gentle altered state became progressively sad and morbid. Nothing went together well Q I could not empathize with anyone, and trying to write at the typewriter was useless. So were efforts to sleep at midnight, but this was totally relieved with 200 milligrams of Miltown. In the morning I seemed still to be off baseline, and I was extremely sleepy, with much lethargy. Even several days later there were problems trying to integrate my emotions and feelings. I am not yet completely at peace.
EXTENSIONS AND COMMENTARY: Sometimes things work well in their mysterious ways. The reports with 4-TME were more to the toxic than to the joyous side, and this by chance with a compound that could only be obtained in an atrociously small yield.
165 5-TME; 5-THIOMETAESCALINE;
3-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 !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 !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 !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-'-nitrostyrene which melted at 80-82
!C. This s
ample, on resolidification and remelting, melted at 109-110
!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 !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-'-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 !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 !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 !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 !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,NU,NU-tetramethylethylenediamine (TMEDA). This solution was put under an inert atmosphere, and with good stirring brought to -78 !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 !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 !C. The mixed mp with the nitrostyrene from piperonal (mp 97-98 !C) was soundly depressed (mp 67-79 !C).
A solution of AH was prepared by the treatment of a solution of 0.5 g LAH in 10 mL THF, at 0 !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 !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. LetUs 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,NU,NU-tetramethylethylenediamine, which has been abbreviated TMEDA. There is a pattern, within any active inner clique of re
search chemists intently pursuing a goal, to begin condensing complex comcepts into deceptively simple terms. We RMOM-ed the hydroxy group of the T-BOC-ed amine.S 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 RtomatoS spoken by a native of the Bronx.
167 4T-MMDA-2; 6-(2-AMINOPROPYL)-5-METHOXY-1,3-BENZOXATHIOL; 2-METHOXY-4,5-METHYLENETHIOOXYAMPHETAMINE
SYNTHESIS: To a well-stirred solution of 120 g thiourea in 800 mL 2N
HCL, there was added a solution of 100 g benzoquinone in 500 mL acetic acid over the course of 15 min. Stirring was continued for an additional 0.5 h at room temperature, and then the reaction mixture was heated on the steam bath for 1 h. With cooling in ice water, a heavy crop of crystals separated. These were removed by filtration and air dried to provide 90.1 g of 5-hydroxy-1,3-benzoxathiol-2-one (2-mercaptohydroquinone cyclic carbonate ester) with a melting point of 170.5-172.5 !C.
To a suspension of 100 g finely powdered anhydrous K2CO3 in 400 mL
acetone containing 50 g methyl iodide there was added 41 g 5-hydroxy-1,3-benzoxathiol-2-one, and the mixture stirred overnight at room temperature. The solids were removed by filtration, and the solvent removed under vacuum. The residue was distilled to give a fraction subliming over as a solid at an oven temperature of 110 !C at 0.1 mm/Hg. This was a yellowish solid, weighing 27.4 g and having a mp of 66-72 !C. Recrystallization from MeOH gave 5-methoxy-1,3-benzoxathiol-2-one as a white solid with a mp of 75.5-76.5 !C.
To a solution of 30 g 85% KOH in 75 mL warm H2O, there was added an equal volume of warm MeOH followed by 16 g 5-methoxy-1,3-benzoxathiol-2-one, and the mixture was held under reflux conditions for 2 h. After cooling to room temperature, the mix was acidified with HCl and extracted with 2x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a yellow oil that crystallized on standing. The product, 2-mercapto-4-methoxyphenol, weighed 14 g and had a mp of 56-57 !C.
Pihkal Page 130
