The same reaction with di-(4-bromophenyl) disulfide produced 2,5-dimethoxyphenyl 4-bromophenyl sulfide which distilled at 150-170
!C at 0.5 mm/Hg and could be recrystallized from MeOH to give a product that melted at 72-73 !C. Anal. (C14H13BrO2S) C,H. This was being directed towards
2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine (2C-T-11) but it also was abandoned.
The same reaction with N,N-dimorpholinyl disulfide produced virtually no product at all, completely defusing any plans for the synthesis of a novel sulfur-nitrogen bonded base
2,5-dimethoxy-4-(1-morpholinothio)phenethylamine (2C-T-12). One additional effort was made to prepare a 2C-T-X thing with a sulfur-nitrogen bond. The acid chloride intermediate in the preparation of 2,5-dimethoxythiophenol (as described in the recipe for 2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride. It reacted smoothly with an excess of diethylamine to produce 2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 !C
at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of cyclohexane/benzene to give a product with a melting point of 41-42 !C
and an excellent proton NMR. This amide proved totally refractory to all efforts at reduction, so the target compound, 2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made. It has not even been given a 2C-T-X number.
46 2C-T-13; 2,5-DIMETHOXY-4-(2-METHOXYETHYLTHIO)PHENETHYLAMINE
SYNTHESIS: To a solution of 3.25 g of KOH pellets in 25 mL hot MeOH, there was added 6.8 g of 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) followed by 4.73 g of 2-methoxyethylchloride. This mixture was heated on the steam bath for 0.5 h, then added to 500 mL
H2O. This very basic aqueous phase was extracted with 3x100 mL
CH2Cl2, the extracts pooled, and back-washed with 5% NaOH. The solvent was removed under vacuum to give 8.82 g of a white oil.
Distillation gave 2,5-dimethoxyphenyl 2-methoxyethyl sulfide with a bp 115-125 !C at 0.3 mm/Hg, and a weight of 6.65 g.
A mixture of 10 g POCl3 and 10 g N-methylformanilide was heated for 10
min on the steam bath. To this claret-colored solution was added 6.16
g of 2,5- dimethoxyphenyl 2-methoxyethyl sulfide. There was an immediate exothermic reaction and gas evolution. The mixture was heated for 15 min on the steam bath, at which time there was no starting sulfide present by TLC. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued until only a thin oily phase remained. This was extracted with CH2Cl2, the extracts were combined, and the solvent removed under vacuum. The residue was extracted with 5 sequential 20 mL portions of boiling hexane which deposited crystals on cooling. Filtering gave a total of 4.12 g crystalline solids. Recrystallization from MeOH gave a poor yield of a cream-colored crystal with a mp of 68-69 !C. A more efficient purification was achieved by distillation (155-168 !C at 0.3
mm/Hg) yielding 3.50 g of
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde as a pale yellow solid, with a mp of 67-68 !C. A faster moving (by TLC) trace component with an intense fluo-rescence persisted throughout the entire purification scheme, and was still present in the analytical sample. Anal. (C12H16O4S) C,H.
To a solution of 3.41 g
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde in 50 g of nitromethane there was added 0.11 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h, at which time the starting aldehyde had largely disappeared by TLC (silica gel plates with CH2Cl2 as the developing solvent) and a faster moving nitrostyrene product was clearly visible. The clear orange solution was stripped of the excess nitromethane under vacuum producing a yellow oil that crystallized yielding 3.97 g of a yellow solid with a mp of 99-104 !C. Recrystallization of a small sample from MeOH
produced (when dry) yellow electrostatic crystals of 2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene with a mp of 107
!C sharp. From IPA the product is a burnished gold color with the mp 106-107 !C. Anal. (C13H17NO5S) C,H.
A solution of LAH (40 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.07 g
2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene in small portions, as a solid, over the course of 10 min. There was a considerable amount of gas evolved, and a little bit of charring. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 8 mL IPA followed by 3 mL 15% NaOH which gave the reaction mixture a curdy white granular character. The reaction mixture was filtered, the filter cake washed with THF, and filtrate and washes were stripped of solvent under vacuum providing about 3 g of a pale amber oil. This was dissolved in about 40 mL CH2Cl2 and extracted with 200 mL dilute H2SO4 in three portions. All of the color remained in the organic phase. The pooled aqueous extracts were washed with CH2Cl2, then made basic with 25%
NaOH, extracted with 3x75 mL CH2Cl2, and the combined extracts pooled and stripped of solvent under vacuum. The 2 g pale yellow oily residue was distilled at 155-165 !C at 0.2 mm/Hg to give 1.23 g of a clear white oil. This was dissolved in IPA, neutralized with concentrated HCl, and diluted with anhydrous Et2O to produce crystals of 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine hydrochloride (2C-T-13). After filtration, washing with Et2O, and air drying, this white crystalline product weighed 0.89 g.
DOSAGE: 25 - 40 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 25 mg) I felt it was somewhat noisy as we went into the experience. This noisiness lasted only about an hour, then stopped. At the peak, which seemed to be at about 1 to maybe 1.5
hours, some eyes-closed visuals appeared. There was a white field with colored visuals, at times geometric in shape. These eye-closed images were pleasant and I enjoyed them when I did not concern myself with, or listen to, the conversation. There was an eyes-open change in color, the ivy became a little lighter or maybe a little stronger in color. IUm not sure which. I felt there was a gradual diminishing of activity (whatever that undefined activity was) starting at 2 to 2.5 hours, and coming close to baseline at 6 PM. The descent was pleasant and I would say pleasurable. The experience did not lead to any confusion which I sometimes notice in other experiences. There was no problem with anorexia. We ate constantly during the experience. The grapes and other fruit were lovely. This is one of the few times I would say that I would try a higher dose. Maybe 30 or 33 milligrams. I suspect the experience would be similar, with just a heightened peak at 1 hour and perhaps a little more body effect. It may well be one to try with one's wife.
(with 28 mg) There was a strange, disturbing twinge exactly eight minutes after starting this, that asked me, TShould I have done this?U
I answered, TYesU and the twinge disappeared. And then there was nothing until the expected time of development, at a half hour when I felt a light head and slight dizziness. There was a solid plus two for a couple of hours. I paid careful attention for auditory oddities that I had noted before, but they were not there. In an earlier trial (with 20 milligrams) the radio had the sound of being located in the outdoors with the sounds coming through the wall and into the room where I was. I was at a neutral baseline at about seven hours.
(with 35 mg) There was a quiet climb, but it was marred with some tummy unquiet, and an annoying persistence of diarrhea. I was very impressed with eyes-closed patterning, which seemed to do its own thing independently of the music. I was clearly up to a +++, but there was a feeling that as soon as it got there it started to go away again. There was no there, there. Yet there were a couple of touches of introspection, of seriousness which I had to respect.
(with 40 mg) There were four of us, and the entry was individual for each of us. Two of us were nauseous. One volunteered a statement, almost a confession, of too much food and drink in the immediate p
ast.
One of us needed his cigarette right now, and then he saw that he was killing himself, and he swore off. DonUt know if it will last, however. At the two and a half hour point there is a consensus that this has gone its route and will lose its impact, so three of us decided to supplement on 2C-T-2. Six milligrams proves to be a little light so, some four hours later, we each took another six milligrams.
Excellent. In a while we discoved that we were very hungry, and food tasted marvelous. Headaches acknowledged in the early evening, but the extension from T-13 to T-2 seemed to be absolutely correct. And as of the next day, the non-smoker was still a non-smoker.
EXTENSIONS AND COMMENTARY: Most of the synthetic adventures of putting a basic something aways out from the benzene ring, at the four-position, have involved subtle things such as unsaturated bonds or three-membered rings. This was the first try with the actual use of a different atom (an oxygen). What about other heteroatoms such as sulfur or nitrogen or silicon or phosphorus, or some-such?
The sulfur counterpart of 2C-T-13 was named 2C-T-14, and was immediately launched. The reaction of 2,5-dimethoxythiophenol and KOH
with 2-methyl-thioethyl chloride in hot MeOH gave 2,5-dimethoxyphenyl 2-methylthioethyl sulfide as a white oil (boiling point of 140-160 !C
at 0.3 mm/Hg). This underwent a normal Vilsmeier reaction (phosphorous oxychloride and N-methylformanilide) to give 2,5-dimethoxy-4-(2-methylthioethylthio)benzaldehyde with a melting point of 64-64.5 !C from MeOH. This, in nitromethane containing a little ammonium acetate, was heated on the steam bath for 10 hours and worked up to give an excellent yield of 2,5-dimethoxy-4-(2-methylthioethylthio))-'-nitrostyrene as garish orange-red RLas VegasS colored crystals from acetonitrile, with a melting point of 126-127 !C. And as of the moment, this is sitting on the shelf waiting to be reduced to the target compound 2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine hydrochloride, or 2C-T-14. Will it be active? I rather suspect that it will be, and IUll bet it will be longer-lived than the oxygen model, 2C-T-13.
47 2C-T-15; SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 3.3 g of KOH pellets in 150 mL hot MeOH, there was added 10 g 2,5-dimethoxythiophenol (see recipe for 2C-T-2
for its preparation) followed by 10 g 1-bromo-3-chloropropane. The reaction was exothermic, and immediately deposited white solids of KCl. The reaction mixture was warmed for a few min on the steam bath, and then quenched in H2O. The basic reaction mixture was extracted with 3x75 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum. The residual oil was distilled at 145-155 !C at 0.2
mm/Hg to give 16.5 g of 2,5-dimethoxyphenyl 3-chloropropyl sulfide as a clear, colorless oil.
A solution of the lithium amide of 2,2,6,6-tetramethylpiperidine was prepared by the addition of 20 mL of 2.6 M butyllithium in hexane to a well stirred hexane solution of the piperidine in 100 mL hexane, under an atmosphere of He. The reaction was exothermic, formed a white solid precipitate, and was allowed to continue stirring for a few min.
There was then added 6.5 g 2,5-dimethoxphenyl 3-chloropropyl sulfide, and a strongly exothermic reaction ensued. This was stirred for 30
min and then poured into dilute H2SO4 (the progress of the reaction must be followed by TLC, silica gel plates, CH2Cl2:petroleum ether 50:50 to determine when it is done; in one run over 2 h were required for completion of the reaction). The organic phase was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The combined organic phases were washed first with dilute NaOH, then with dilute HCl, then the solvents were removed under vacuum. The residue was distilled to provide 2,5-dimethoxyphenyl cyclopropyl sulfide as a pale yellow liquid that boiled at 100-115 !C at 0.1 mm/Hg. The use of other bases to achieve this cyclization were less successful. Incomplete cyclization resulted from the use of lithium diisopropyl amide and, if the conditions were made more vigorous, there was dehydrohalogenation to the allyl sulfide. An unexpected difficulty was that the allyl sulfide (from elimination) and the 3-chloropropyl sulfide (starting material) behaved in an identical manner on TLC analysis. They were easily separated, however, by GC analysis.
A completely different approach to the synthesis of this sulfide was explored through the reaction of cyclopropyllithium with an aromatic disulfide, thus avoiding the base-promoted cyclization step. A solution of 2.6 g di-(2,5-dimethoxyphenyl)disulfide (from 2,5-dimethoxythiophenol and hydrogen peroxide, bp 220-230 !C at 0.3
mm/Hg) was made in anhydrous Et2O, and well stirred. In a separate flask, under an atmosphere of He, 4 mL of 2.6 M butyllithium was added to a solution of 1.2 g cyclopropyl bromide in 20 mL anhydrous Et2O.
This mildly exothermic combination turned a bit cloudy, was stirred for 1 h, then trans-ferred with an air-tight syringe to the above-described Et2O solution of the aromatic disulfide. A heavy precipitate formed, and stirring was continued for an additional 0.5
h. The reaction mixture was then poured into H2O, the layers separated, and the aqueous phase extracted with CH2Cl2. The extracts were pooled, washed with dilute aqueous KOH, and the solvents removed under vacuum. Distillation gave 0.7 g of 2,5-dimethoxyphenyl cyclopropyl sulfide with identical gas chromatographic behavior to the sample prepared by the cyclization of the chloropropylthio compound.
A mixture of 7.2 g POCl3 and 6.7 g N-methylformanilide was heated on the steam bath until it was claret red. To this there was added 4.5 g of 2,5-di-methoxyphenyl cyclopropyl sulfide, and the exothermic combination heated on the steam bath for about 5 min. The deep red, bubbling reaction mixture was added to 150 mL H2O and stirred until all oils had been converted into loose solids. These were then removed by filtration, washed with H2O, and sucked as dry as possible.
They were dissolved in boiling MeOH which, after cooling in an ice-bath, deposited yellow crystals of 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde that weighed 3.43 g after air drying, and had a mp of 97-99 !C. Anal. (C12H14O3S) C,H.
To a solution of 3.0 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde in 40 g of nitromethane there was added 0.2 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 3 h. The excess nitromethane was removed under vacuum yielding 3.4 g orange crystals. These were recrystallized from 150 mL boiling IPA containing a little toluene. After cooling, filtering, and air drying there were obtained 2.75 g of
2,5-dimethoxy-4-cyclopropylthio-'-nitro-styrene as pumpkin-colored crystals with a mp of 159-160 !C. Anal. (C13H15NO4S) C,H.
A solution of LAH (40 mL of a 1 M. solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 2.5 g
2,5-dimethoxy-4-cyclopropylthio-'-nitrostyrene in 40 mL anhydrous THF
over the course of 15 min. There was an immediate loss of color.
After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath and held there for 2 h. After recooling, there was added IPA (to destroy the excess hydride) followed by sufficent 15% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed with THF.
The filtrate and washes were stripped of solvent under vacuum providing a yellow oil that was treated with dilute H2SO4. This produced a flocculant white solid, apparently the sulfate salt of the product. This was washed with 4x75 mL CH2Cl2 which removed most of the yellow color. The aqueous phase was made basic with aqueous NaOH
and extracted with 3x75 mL CH2Cl2. Removal of the solvent under vacuum gave a light yellow colored oil that was distilled at 0.3
mm/Hg. The fraction boiling at 140-150 !C was a colorless, viscous oil that weighed 1.97 g. This was dissolved in a few mL IPA, and neut-ralized with concentrated HCl forming immediate cottage cheese-like crystals of the hydrochloride salt. This was diluted by suspension in anhydrous Et2O, removed by filtration, and air dried to give 1.94 g of 2,5-dimethoxy-4-cycl
opropylthiophenethylamine hydrochloride (2C- T-15) that had a mp of 203-5-204.5 !C. Anal.
(C13H20ClNO2S) C,H.
DOSAGE: greater than 30 mg.
DURATION: several hours.
QUALITATIVE COMMENTS: (at 30 mg) I was somewhere between a threshold and a plus one for several hours, and appeared to be quite talkative in the evening.
EXTENSIONS AND COMMENTARY: The commonly used name for 2C-T-15, during its synthesis, was SESQUI. The general name for a 15-carbon terpene is sesquiterpene, from the Latin prefix for one and a half. The active level of 2C-T-15 is not known. The highest level yet tried was 30 milligrams orally, and there had been threshold reports pretty regularly all the way up from 6 milligrams. But no definite activity yet. This compound is isosteric with the isopropyl group as seen in the analogous compound 2C-T-4 (the three carbons are in exactly the same positions, only the electrons are located differently) and it is a little surprising that the potency appears to be considerably less.
Just over 20 milligrams of the latter compound was overwhelmingly psychedelic.
The entire mini-project of hanging cyclic things onto the sulfur atom was an interesting problem. This is the three carbon ring. The six carbon ring (the cyclohexyl homologue) was discussed as 2C-T-5 in the recipe for of ALEPH-2. The cyclobutyl and cyclopentyl homologs were assigned the names of 2C-T-18 and 2C-T-23, respectively, and their preparations taken as far as the nitrostyrene and the aldehyde stages, respectively, before the project ran out of steam.
Towards the cyclobutyl homologue, a solution of 2,5-dimethoxythiophenol and cyclobutyl bromide in DMSO containing anhydrous potassium carbonate was stirred for several hours at room temperature and yielded 2,5-dimethoxyphenyl cyclobutyl sulfide as a white oil that boiled at 135-140 !C at 0.3 mm/Hg. Anal. (C12H16O2S) C,H. This was brought to react with a mixture of phosphorus oxy-chloride and N-methylformanilide producing 2,5-dimethoxy-4-(cyclobutylthio)benzaldehyde that had a melting point of 108-109.5 !C from MeOH. Anal. (C13H16O3S) C,H. Coupling with nitromethane in the presence of ammonium acetate produced 2,5-dimethoxy-4-cyclobutylthio-'-nitrostyrene as lustrous orange crystals from boiling acetonitrile, melting point 160-161 !C. Anal, (C14H17NO4S) C,H. This will some day be reduced to 2,5-dimethoxy-4-cyclobutylthiophenethylamine hydrochloride, 2C-T-18.
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