Consider a collection of things with simple geometric sides (a side is a latus in Latin). One would speak of a one-sided object as being unilateral, and a bilateral object has two sides. A trilateral, and quadrilateral, and way up there to multilateral objects, are referred to as having three or four or a lot of sides, respectively. Just the opposite occurs with geometric objects with faces. A face is a hedra in Greek, so one really should use the Greek structure. If one has just one face, one has a monohedron, a dihedron has two faces, and there are trihedron, tetrahedron, and polyhedron for things that have three, four, or a lot of faces. Actually, the prefix RpolyS swings both ways. It was initially a Greek term, but as was the fate of many Greek words, it wandered its way from East to West, and ended up as a Latin term as well.
But back to the problem of how to refer to something that is more than one or two, but not as much as a lot? If you know exactly how many, you should use the proper prefix. But what if you donUt know how many? There are terms such as Rsome.S And there is Rseveral.S There is a RfewS and a Rnumber ofS and RnumerousS and Ra hand full.S One desperately looks for a term that is a collective, but which carries the meaning of an undefined number. There are English gems such as a pride of lions and a host of daffodils. But without a specific animal or plant of reference, one must have a target collective that is appropriate, to let the term RmanyS or RfewS imply the proper size.
There were many hundreds of persons (a few thousands of persons) at the rally. Several dozen hunters (a few score hunters) were gathered at the lake. A wonderful prefix is RoligoS which means a few, not a lot, and it means that I am not sure just how many are meant. Say, for example, that you have synthesized something in a biochemical mixture that contains three or four peptides. Di-and tri- and tetrapeptides are exact terms, but they do not describe what you have done. Polypeptide is way too big. However, an oligopeptide means that there are a few peptide units, IUm not sure how many. This may well be the most accurate description of just what you have.
I love the British modesty that is shown by hiding a person's physical weight by referring to it with the dimension known as the stone. This is, as I remember, something like 14 pounds. So, if stones were the weight equivalent of 10 milligrams, the activity of TA would be several stone. And since the synthetic intermediate 1-allyl-2,3,4,5-tetramethoxybenzene is one of the ten essential oils, the amination step from our hypothetical reaction in the human liver would make TA one of the so-called Ten Essential Amphetamines.
146 3-TASB; 3-THIOASYMBESCALINE;
4-ETHOXY-3-ETHYLTHIO-5-METHOXYPHENETHYLAMINE
SYNTHESIS: Without any solvent, there was combined 21.7 g of solid 5-bromovanillin and 11.4 mL cyclohexylamine. There was the immediate generation of a yellow color and the evolution of heat. The largely solid mass was ground up under 50 mL of boiling IPA to an apparently homogeneous yellow solid which was removed by filtration and washed with IPA. There was thus obtained about 27 g of 3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine with a mp of 229-231 !C and which proved to be insoluble in most solvents (EtOH, CH2Cl2, acetone). A solution in dilute NaOH was unstable with the immediate deposition of opalescent white solids of the phenol sodium salt. A small scale recrystallization from boiling cyclohexanone yielded a fine yellow solid with a lowered mp (210-215 !C). Anal.
(C14H18BrNO2) C,H.
A solution of 32.5 g
3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine in 60 mL of hot DMF was cooled to near room temperature, treated with 24.5 g ethyl iodide and followed by 14.0 g of flake KOH. This mixture was held at reflux for 1 h, cooled, and added to 1 L H2O. Additional base was added and the product was extracted with 3x150 mL CH2Cl2. These pooled extracts were washed with dilute NaOH, then with H2O, and finally the solvent was removed under vacuum. The crude amber-colored residue was distilled. The fraction coming over at 118-135 !C at 0.4
mm/Hg weighed 8.7 g, spontaneously crystallized, and proved to be 3-bromo-4-ethoxy-5-methoxybenzaldehyde, melting at 59-60 !C after recrystallization from MeOH. Anal. (C10H11BrO3) C,H. The fraction that came over at 135-155 !C at 0.2 mm/Hg weighed 10.5 g and also solidified in the receiver. This product was 3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine which, upon recrystallization from two volumes MeOH, was a white crystalline material with a mp of 60-61 !C. Anal. (C16H22BrNO2) C,H. The two materials have identical mps, but can be easily distinguished by their infra-red spectra. The aldehyde has a carbonyl stretch at 1692 cm-1, and the Schiff base a C=N stretch at 1641 cm-1.
A solution of 20.5 g
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine in about 300 mL
anhydrous Et2O was placed in a He atmosphere, well stirred, and cooled in an external dry ice acetone bath to -80 !C. There was then added 50 mL of 1.6 N butyllithium in hexane. The mixture became yellow and very viscous with the generation of solids. These loosened up with continuing stirring. This was followed by the addition of 10.7 g diethyldisulfide. The reaction became extremely viscous again, and stirring was continued while the reaction was allowed to warm to room temperature. After an additional 0.5 h stirring, the reaction mixture was added to 800 mL of dilute HCl. The Et2O phase was separated and the solvent removed under vacuum. The residue was returned to the original aqueous phase, and the entire mixture heated on the steam bath for 2 h. The bright yellow color faded and there was the formation of a yellowish phase on the surface of the H2O. The aqueous solution was cooled to room temperature, extracted with 3x100 mL
CH2Cl2, the extracts pooled, washed first with dilute HCl, then with saturated brine, and the solvent removed under vacuum. The residue was an amber oil weighing 20.4 g, and was distilled at 130-140 !C at 0.3 mm/Hg to yield 12.9 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde as a straw colored oil that did not crystallize. Anal. (C12H16O3S) C,H.
A solution of 1.0 g 4-ethoxy-3-ethylthio-5-methoxybenzaldehyde in 20 g nitromethane was treated with about 0.2 g of anhydrous ammonium acetate and heated on the steam bath. TLC analysis showed that the aldehyde was substantially gone within 20 min and that, in addition to the expected nitrostyrene, there were four scrudge products (see the discussion of scrudge in the extensions and commentary section under 3-TSB). Removal of the excess nitromethane under vacuum gave an orange oil which was diluted with 5 mL cold MeOH but which could not be induced to crystallize. A seed was obtained by using a preparative TLC plate (20x20 cm) and removing the fastest moving spot (development was with CH2Cl2). Placing this in the above MeOH solution of the crude nitrostyrene allowed crystallization to occur. After filtering and washing with MeOH, 0.20 g of fine yellow crystals were obtained which melted at 75-77 !C. Recrystallization from MeOH gave a bad recovery of yellow crystals of
4-ethoxy-3-ethylthio-5-methoxy-'-nitrostyrene that now melted at 78.5-79 !C. Anal. (C13H17NO4S) C,H. This route was discarded in favor of the Wittig reaction described below.
A mixture of 27 g methyltriphenylphosphonium bromide in 150 mL
anhydrous THF was placed under a He atmosphere, well stirred, and cooled to 0 !C with an external ice water bath. There was then slowly added 50 mL of 1.6 N butyllithium in hexane which resulted in the initial generation of solids that largely redissolved by the completion of the addition of the butyllithium and after allowing the mixture to return to room temperature. There was then added 11.7 g of 4-ethoxy-3-ethylthio-5-methoxybenzaldehyde without any solvent. There was the immediate formation of an unstirrable solid, which partially broke up into a gum that still wouldnUt stir. This was moved about, as well as possible, with a glass rod, and then all was added to 400
mL H2O. The two phases were separated and the lower, aqueous, phase extracted with 2x75 mL of petroleum ether. The organic fractions were combined and the solvents removed under vacuum to give the crude 4-ethoxy-3-ethylthio-5-methoxystyrene as a pale yellow fluid liquid.
A solution of 10 mL of borane-methyl sulfide complex (10 M BH3 in methyl sulfide) in 75 mL THF was placed in a He atmosphere, cooled to 0 !C, treated with 21 mL o
f 2-methylbutene, and stirred for 1 h while returning to room temperature. This was added directly to the crude 4-ethoxy-3-ethylthio-5-methoxystyrene. The slightly exothermic reaction was allowed to stir for 1 h, and then the excess borane was destroyed with a few mL of MeOH (in the absence of air to avoid the formation of the dialkylboric acid). There was then added 19 g of elemental iodine followed, over the course of about 10 min, by a solution of 4 g NaOH in 50 mL hot MeOH. The color did not fade.
Addition of another 4 mL 25% NaOH lightened the color a bit, but it remained pretty ugly. This was added to 500 mL H2O containing 5 g sodium thiosulfate and extracted with 3x100 mL petroleum ether. The extracts were pooled, and the solvent removed under vacuum to provide crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane as a residue.
To this crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane there was added a solution of 20 g potassium phthalimide in 150 mL
anhydrous DMF, and all was held at reflux overnight. After adding to 500 mL of dilute NaOH, some 1.4 g of a white solid was generated and removed by filtration. The aqueous filtrate was extracted with 2x75
mL Et2O. These extracts were combined, washed with dilute HCl, and the solvent removed under vacuum providing 23.6 g of a terpene-smelling amber oil. This was stripped of all volatiles by heating to 170 !C at 0.4 mm/Hg providing 5.4 g of a sticky brown residue. This consisted largely of the desired phthalimide. The solids proved to be a purer form of
1-(4-ethoxy-3-ethylthio-5-methoxy)-2-phthalimidoethane and was recrystallized from a very small amount of MeOH to give fine white crystals with a mp of 107.5-108.5 !C. Anal. (C21H23NO4S) C,H. The white solids and the brown impure phthalimide were separately converted to the final product, 3-TASB.
A solution of 1.2 g of the crystalline 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-phthalimidoethane in 40 mL
of warm n-butanol was treated with 3 mL of 66% hydrazine, and the mixture was heated on the steam bath for 40 min. The reaction mixture was added to 800 mL dilute H2SO4. The solids were removed by filtration, and the filtrate was washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, extracted with 3x75 mL
CH2Cl2, and the solvent from these pooled extracts removed under vacuum yielding 6.2 g of a residue that was obviously rich in butanol.
This residue was distilled at 138-144 C. at 0.3 mm/Hg to give 0.6 g of a colorless oil. This was dissolved in 2.4 mL IPA, neutralized with concentrated HCl, and diluted with 25 mL anhydrous Et2O. The solution remained clear for about 10 seconds, and then deposited white crystals. These were removed by filtration, washed with additional Et2O, and air dried to give 0.4 g
4-ethoxy-3-ethylthio-5-methoxyphenethylamine hydrochloride (3-TASB) with a mp of 140-141 !C. Anal. (C13H22ClNO2S) C,H. The amber-colored impure phthalimide, following the same procedure, provided another 0.9
g of the hydrochloride salt with a mp of 138-139 !C.
DOSAGE: about 160 mg.
DURATION: 10 - 18 h.
QUALITATIVE COMMENTS: (with 120 mg) This is no more than a plus one, and it didnUt really get there until about the third hour. By a couple of hours later, I feel that the mental effects are pretty much dissipated, but there is some real physical residue. Up with some caution.
(with 160 mg) The taste is completely foul. During the first couple of hours, there was a conscious effort to avoid nausea. Then I noticed that people's faces looked like marvelous parodies of themselves and that there was considerable time slowing. There was no desire to eat at all. Between the eighth and twelth hour, the mental things drifted away, but the body was still wound up. Sleep was impossible until about 3:00 AM (the 18th hour of the experiment) and even the next day I was extremely active, anorexic, alert, excited, and plagued with occasional diarrhea. This is certainly a potent stimulant. The next night I felt the tensions drop, and finally got an honest and easy sleep. There is a lot of adrenergic push to this material.
EXTENSIONS AND COMMENTARY: No pharmacological agent has an action that is pure this or pure that. Some pain-killing narcotics can produce reverie and some sedatives can produce paranoia. And just as surely, some psychedelics can produce stimulation. With 3-TASB we may be seeing the shift from sensory effects over to out-and-out stimulation.
It would be an interesting challenge to take these polyethylated phenethylamines and assay them strictly for their amphetamine-like action. Sadly, the potencies are by and large so low, that the human animal canUt be used, and any sub-human experimental animal would not enable the psychedelic part of the equation to be acknowledged. If an order of magnitude of increased potency could be bought by some minor structural change, this question could be addressed. Maybe as the three-carbon amphetamine homologs, or as the 2,4,5- or 2,4,6-
substitution patterns, rather than the 3,4,5-pattern used in this set.
147 4-TASB; 4-THIOASYMBESCALINE;
3-ETHOXY-4-ETHYLTHIO-5-METHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 20.5 g N,N,NU,NU-tetramethylethylenediamine and 22.3 g of 3-ethoxyanisole was made in 100 mL hexane under a He atmosphere with good stirring. There was added 125 mL 1.6 M
butyllithium in hexane, which formed a white granular precipitate.
This was cooled in an ice bath, and there was added 24.4 g of diethyldisulfide which produced an exothermic reaction and changed the precipitate to a creamy phase. After being held for a few min at reflux temperature, the reaction mixture was added to 500 mL dilute H2SO4 which produced two clear phases. The hexane phase was separated, and the aqueous phase extracted with 2x75 mL methylcyclopentane. The organics were combined, and the solvents removed under vacuum. There was obtained a residue which was distilled under a vacuum. At 0.3
mm/Hg the fraction boiling at 95-105 !C was a yellow liquid weighing 28.5 g which was largely 3-ethoxy-2-(ethylthio)anisole which seemed to be reasonably pure chromatographically. It was used as such in the bromination step below.
To a stirred solution of 15.0 g of 3-ethoxy-2-(ethylthio)anisole in 100 mL CH2Cl2 there was added 12 g elemental bromine dissolved in 25
mL CH2Cl2. There was the copious evolution of HBr. After stirring at ambient temperature for 3 h, the dark solution was added to 300 mL H2O
containing sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase was separated, The aqueous phase was extracted once with 100 mL CH2Cl2, the pooled extracts washed with dilute base, and then the solvent was removed under vacuum to give a light brown oil. This wet product was distilled at 112-122 !C at 0.3 mm/Hg to yield 4-bromo (and/or 6-bromo)-3-ethoxy-2-(ethylthio)anisole as a light orange oil. This was used in the following benzyne step without separation into its components.
To a solution of 36 mL diisopropylamine in 150 mL anhydrous THF under a He atmosphere, and which had been cooled to -10 !C with an external ice/MeOH bath, there was added 105 mL of a 1.6 M solution of butylithium in hexane. There was then added 5.1 mL of dry CH3CN
followed by the dropwise addition of 15.0 g 4-bromo-(and/or 6-bromo)-3-ethoxy-2-(ethylthio)anisole diluted with a little anhydrous THF. There was an immediate development of a dark red-brown color.
The reaction was warmed to room temperature and stirred for 0.5 h.
This was then poured into 600 mL of dilute H2SO4. The organic phase was separated, and the aqueous fraction extracted with 2x50 mL CH2Cl2.
These extracts were pooled and the solvent removed under vacuum. The residue was a dark oil and quite complex as seen by thin layer chromatography. This material was distilled at 0.3 mm/Hg yielding two fractions The first boiled at 112-125 !C and weighed 3.9 g. It was largely starting bromo compound with a little nitrile, and was discarded. The second fraction distilled at 130-175 !C and also weighed 3.9 g. This fraction was rich in the product 3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile, but it also contained several additional components as seen by thin layer chromatographic analysis. On standing for two months, a small amount of solid was laid down which weighed 0.5 g after cleanup with hexane.
Bu
t even it consisted of three components by TLC, none of them the desired nitrile. The crude fraction was used for the final step without further purification or microanalysis.
A solution of LAH in anhydrous THF under N2 (15 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred. There was added, dropwise, 0.40 mL 100% H2SO4, followed by about 3 g of the crude 3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile diluted with a little anhydrous THF. The reaction mixture was stirred until it came to room temperature, and then held at reflux on the steam bath for 2 h. After cooling to room temperature, there was added IPA to destroy the excess hydride (there was quite a bit of it) and then 15% 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 first with THF followed by IPA. The filtrate and washes were stripped of solvent under vacuum, the residue added to 100 mL dilute H2SO4. This was washed with 2x75 mL CH2Cl2, made basic with 25% NaOH, and extracted with 2x50 mL CH2Cl2. After combining, the solvent was removed under vacuum providing a residue that was distilled. A fraction boiling at 122-140 !C at 0.3 mm/Hg weighed 1.0 g and was a colorless oil. This was dissolved in 10 mL of IPA, and neutralized with 20 drops of concentrated HCl and diluted, with stirring, with 40
mL anhydrous Et2O. There was the slow formation of a fine white crystalline salt, which was removed by filtration, washed with Et2O, and air dried. The product
3-ethoxy-4-ethylthio-5-methoxyphenethylamine hydrochloride (4-TASB), weighed 0.5 g, and had a mp 139-140 !C. Gas chromatographic analysis by capillary column chromatography of the free base (in butyl acetate solution on silica SE-54) showed a single peak at a reasonable retention time, verifying isomeric purity of the product. Anal.
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