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G.Patton

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Introduction

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 positions, usually resulting in more potent and more metabolically stable and longer acting compounds. Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines I Have Known And Loved). Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group. You can find most popular 2C- member syntheses in this topic such as 2C-E, 2C-D, 2C-B, 2C-I, 2C-F, 2C-P, 2C-T-2, 2C-T-7.

Procedures

2C-E (6) synthesis
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A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 100 g acetyl chloride. This slurry was added to a vigorously stirred solution of 110 g p-dimethoxybenzene (1) in 300 mL CH2Cl2. Stirring was continued at ambient temperature for an additional 40 min, then all was poured into 1 L water and the phases separated. The aqueous phase was extracted with 2 x 100 mL CH2Cl2 and the combined organic phases washed with 3 x 150 mL 5 % NaOH. These washes, after combination and acidification, were extracted with 3 x 75 mL CH2Cl2 and the extracts washed once with saturated NaHCO3. Removal of the solvent under vacuum provided 28.3 g of 2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on recrystallization from 2 volumes of boiling MeOH and air drying, provided 21.3 g of product with a mp of 49-49.5 °C. The CH2Cl2 fraction from the base wash, above, was stripped of solvent on the rotary evaporator to give a residual oil that, on distillation at 147-150 °C at the water pump, provided 111.6 g of 2,5-dimethoxyacetophenone (2) as an almost white oil.
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In a round bottom flask equipped with a reflux condenser, a take-off adapter, an immersion thermometer, and a magnetic stirrer, there was placed 100 g 2,5-dimethoxyacetophenone (2), 71 g 85 % KOH pellets, 500 mL of triethylene glycol (TEG), and 125 mL 65 % hydrazine. The mixture was brought up to a boil by heating with an electric mantle, and the distillate was removed, allowing the temperature of the pot contents to continuously increase. When the pot temperature had reached 210 °C, reflux was established and maintained for an additional 3 h. After cooling, the reaction mixture and the distillate were combined, poured into 3 L water, and extracted with 3 x 100 mL hexane. After washing the pooled extracts with water, the solvent was removed, yielding 22.0 g of a pale straw-colored liquid that was free of both hydroxy and carbonyl groups by infrared. This was distilled at 120-140 °C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a white fluid product. Acidification of the spent aqueous phase with concentrated HCl produced a heavy black oil, which was extracted with 3 x 100 mL CH2Cl2. Removal of the solvent on the rotary evaporator yielded 78 g. of a black residue that was distilled at 90-105 °C at 0.5 mm/Hg to provide 67.4 g of an orange-amber oil that was largely 2-ethyl-4-methoxyphenol (3). This material could eventually be used as a starting material for ethoxy homologues. However, remethylation (with CH3I and KOH in methanol) provided some 28 g additional 2,5-dimethoxyethylbenzene.
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A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene (3) in 30 mL CH2Cl2 was cooled to 0 °C with good stirring and under an inert atmosphere of He (or nitrogen N2). There was then added 11.7 mL anhydrous stannic chloride, followed by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5 h. The stirred reaction mixture was allowed to come up to room temperature, then held on the steam bath for 1 h. The reaction mixture was poured into 1 L water, extracted with 3 x 75 mL CH2Cl2, and the pooled extracts washed with dilute HCl. The organic phase was stripped under vacuum, yielding 10.8 g of a dark viscous oil. This was distilled at 90-110 °C at 0.2 mm/Hg to yield a colorless oil that, on cooling, set to white crystals. The yield of 2,5-dimethoxy-4-ethylbenzaldehyde (4) was 5.9 g of material that had a mp of 46-47 °C. After purification through the bisulfite complex, the mp increased to 47-48 °C. The use of the Vilsmeier aldehyde synthesis (with POCl3 and N-methylformanilide) gave results that were totally unpredictable. The malononitrile derivative (from 0.3 g of this aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of triethylamine) formed red crystals which, on recrystallization from toluene, had a mp of 123-124 °C.
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A solution of 21.0 g of the unrecrystallized 2,5-dimethoxy-4-ethylbenzaldehyde (4) in 75 g nitromethane was treated with 4 g of anhydrous ammonium acetate and heated on the steam bath for about 2 h. The progress of the reaction was best followed by TLC analysis of the crude reaction mixture on silica gel plates with CH2Cl2 as the developing solvent. The excess solvent/reagent was removed under vacuum, yielding granular orange solids that were recrystallized from seven volumes of boiling MeOH. After cooling in external ice-water for 1 h, the yellow crystalline product was removed by filtration, washed with cold MeOH and air dried to give 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5). The mp was 96-98 °C which improved to 99-100 °C, after a second recrystallization from MeOH.
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A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M) was transferred to a 3 neck 500 mL flask, under an inert atmosphere with good magnetic stirring. This solution was cooled to °C with an external ice-water bath, and there was then added 3.0 mL of 100 % H2SO4 over the course of 0.5 h. This was followed by a solution of 5.85 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5), in 40 mL of warm THF. The reaction mixture was stirred for 0.5 h, brought to room temperature, heated on the steam bath for 0.5 h, and then returned to room temperature. The addition of IPA dropwise destroyed the excess hydride, and some 4.5 mL of 5 % NaOH produce a white cottage cheese, in a basic organic medium. This mixture was filtered, washed with THF, and the filtrate evaporated to produce 2.8 g of an almost white oil. The filter cake was resuspended in THF, made more basic with additional 15 mL of 5 % NaOH, again filtered, and the filtrate removed to provide an additional 2.8 g of crude product. These residues were combined and distilled at 90-100 °C at 0.25 mm/Hg to give a colorless oil. This was dissolved in 30 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O to provide, after spontaneous crystallization, filtration, washing with Et2O, and air drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as magnificent white crystals.
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A similar yield can be obtained from the reduction of the nitrostyrene in a suspension of LAH in THF, without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there was added, dropwise, a solution of 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5) in 75 mL THF over the course of 2 h. The mixture was kept at reflux for an additional 8 h, and killed by the careful addition of 11 mL H2O, followed with 11 mL 15 % NaOH, and finally another 33 mL of H2O. This mass was filtered, washed with THF, and the combined filtrates and washes evaporated to a residue under vacuum The approximately 15 mL of residue was dissolved in 300 mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated HCl. On shaking the mixture, there was deposited a mass of the hydrochloride salt, which was diluted with a quantity of additional H2O. The organic phase was extracted with additional dilute HCL, and these aqueous phases were combined. After being made basic with 25 % NaOH, this phase was again extracted with 3 x 75 mL CH2Cl2 and after the removal of the solvent, yielded 12.6 g of a colorless oil. This was dissolved in 75 mL of IPA and neutralized with concentrated HCl. The solidified mass that formed was loosened with another 50 mL IPA, and then filtered. After Et2O washing and air drying, there was obtained 7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as lustrous white crystals.
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2C-D (6) synthesis

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Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone (1), 160 mL 25% NaOH, and 126 g dimethyl sulfate (DMS). After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3 x 100 mL CH2Cl2 and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 °C at 0.5 mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 °C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 °C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene. This gave 2.53 g of a white crystalline product with a mp of 66-68 °C. A second recrystallization (from hexane) raised this mp to 71-72 °C. The literature value given for the m.p. of 2-methyl-4-methoxyphenol (2) is 70-71 °C. The literature value given for the m.p. of the isomeric 3-methyl-4-methoxyphenol is 44-46 °C.
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A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide (3) was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene (2). Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4 x 100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product. This, upon recrystallization from 150 mL boiling hexane, gave pale yellow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde (4), and had a mp of 83-84 °C. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3 g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 °C.
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A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde (4) in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2 g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when dry, 7.70 g. The m.p. was 117-118 °C, and this was increased to 118-119 °C upon recrystallization from benzene/heptane 1:2.
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To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-beta-nitrostyrene (5) in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA. There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2 x 50 mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 °C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl, which produced immediate crystals of the salt. These were dispersed with 80 mL anhydrous Et2O, filtered, and washed with Et2O to give, after air drying to constant weight, 4.9 g of fluffy white crystals of 2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D) (6).
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The m.p. was 213-214 °C which was not improved by recrystallization from CH3CN/IPA mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 °C. The acetamide, from the free base in pyridine treated with acetic anhydride, was a white crystalline solid which, when recrystallized from aqueous MeOH, had a mp of 116-117 °C.

2C-B (4) synthesis

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A solution of 100 g of 2,5-dimethoxybenzaldehyde (1) in 220 g nitromethane was treated with 10 g anhydrous ammonium acetate, and heated on a steam bath for 2.5 h with occasional swirling. The deep-red reaction mixture was stripped of the excess nitromethane under vacuum, and the residue crystallized spontaneously. This crude nitrostyrene was purified by grinding under IPA, filtering, and air-drying, to yield 85 g of 2,5-dimethoxy-beta-nitrostyrene (2) as a yellow-orange product of adequate purity for the next step. Further purification can be achieved by recrystallization from boiling IPA.
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2,5-dimethoxy-beta-nitrostyrene (2)
In a round-bottomed 2 L flask equipped with a magnetic stirrer and placed under an inert atmosphere, there was added 750 mL anhydrous THF, containing 30 g LAH. There was then added, in THF solution, 60 g 2,5-dimethoxy-beta-nitrostyrene (2). The final solution was a dirty yellow-brown color, and it was kept at reflux temperature for 24 h. After cooling, the excess hydride was destroyed by the dropwise addition of IPA. Then 30 mL 15% NaOH was added to convert the inorganic solids to a filterable mass. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. The combined mother liquors and washings were freed of solvent under vacuum and the residue suspended in 1.5 L H2O. This was acidified with HCl, washed with 3 x 100 mL CH2Cl2, made strongly basic with 25 % NaOH, and reextracted with 4 x 100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, yielding 26 g of oily residue, which was distilled at 120-130 °C at 0.5 mm/Hg to give 21 g of a white oil, 2,5-dimethoxyphenethylamine (2C-H) (3) which picks up carbon dioxide from the air very quickly.
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2,5-dimethoxyphenethylamine (2C-H) (3) hydrochloride
To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine (3) in 40 mL glacial acetic acid, there was added 22 g elemental bromine dissolved in 40 mL acetic acid. After a couple of mins, there was the formation of solids and the simultaneous evolution of considerable heat. The reaction mixture was allowed to return to room temperature, filtered, and the solids washed sparingly with cold acetic acid. This was the hydrobromide salt. There are many complicated salt forms, both polymorphs and hydrates, that can make the isolation and characterization of 2C-B treacherous. The happiest route is to form the insoluble hydrochloride salt by way of the free base. The entire mass of acetic acid-wet salt was dissolved in warm H2O, made basic to at least pH 11 with 25 % NaOH, and extracted with 3 x 100 mL CH2Cl2. Removal of the solvent gave 33.7 g of residue, which was distilled at 115-130 °C at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 mL H2O containing 7.0 g acetic acid. This clear solution was vigorous stirred, and treated with 20 mL concentrated HCl. There was an immediate formation of the anhydrous salt of 2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B) (4). This mass of crystals was removed by filtration (it can be loosened considerably by the addition of another 60 mL H2O), washed with a little H2O, and then with several 50 mL portions of Et2O. When completely air-dry, there was obtained 31.05 g of fine white needles, with a mp of 237-239 °C with decomposition.
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2C-B salt (4) precipitating out of reaction mixture

When there is too much H2O present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. The hydrobromide salt melts at 214.5-215 °C. The acetate salt was reported to have a m.p. of 208-209 °C.
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Dried crude 2C-B salt (4)

2C-I (4) synthesis

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A mixture of 7.4 g phthalic anhydride and 9.05 g of 2,5-dimethoxyphenethylamine (1) (see the recipe for 2C-B synthesis for its preparation) was heated with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was poured out into a crystallizing dish, yielding 14.8 g of a crude solid product. This was recrystallized from 20 mL CH3CN, with care taken for an endothermic dissolution, and an exothermic crystallization. Both transitions must be done without haste. After filtration, the solids were washed with 2 x 20 mL hexane and air dried to constant weight. A yield of 12.93 g of N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) was obtained as electrostatic yellow crystals, with a mp of 109-111 °C. A sample recrystallized from IPA was white, with a mp of 110-111 °C.
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To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) in 130 mL warm (35 °C) acetic acid which was being vigorously stirred, there was added a solution of 10 g iodine monochloride in 40 mL acetic acid. This was stirred for 1 h, while being held at about 30 °C. The reaction mixture was poured into 1500 mL H2O and extracted with 4 x 75 mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O containing 2.0 g sodium dithionite, and the solvent removed under vacuum to give 16.2 g of N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) as yellow amber solids with a m.p. of 133-141 °C. This mp was improved by recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow solid with mp 149-151 °C. A small sample from a large quantity of IPA gives a white product melting at 155.5-157 °C.
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A solution of 12.2 g N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) in 150 mL hot IPA was treated with 6.0 mL of hydrazine hydrate, and the clear solution was heated on the steam bath. After a few minutes, there was the generation of a white cottage cheese-like solid (1,4-dihydroxyphthalizine). The heating was continued for several additional hours, the reaction mixture cooled, and the solids removed by filtration. These were washed with 2 x 10 mL EtOH, and the pooled filtrate and washes stripped of solvent under vacuum giving a residue which, when treated with aqueous hydrochloric acid, gave 3.43 g of voluminous white crystals.
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This, after recrystallization from 2 weights of H2O, filtering, washing first with IPA and then with Et2O, and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) (4) as a white microcrystalline solid, with a mp of 246-247 °C.
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Crude and recrystallized 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) (4)


2C-F (5) synthesis

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A solution of 76.6 g 2,5-dimethoxyaniline (1) in 210 mL H2O containing 205 mL fluoroboric acid was cooled to 0 °C. with an external ice bath. There was then added, slowly, a solution of 35 g sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the precipitated solids were removed by filtration, washed first with cold H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g of the fluoroborate salt of the aniline as dark purple-brown solids. This salt was pyrolyzed with the cautious application of a flame, with the needed attention paid to both an explosion risk, and the evolution of the very corrosive boron trifluoride. The liquid that accumulated in the receiver was distilled at about 120 °C at 20 mm/Hg, and was subsequently washed with dilute NaOH to remove dissolved boron trifluoride. The product, 2,5-dimethoxyfluorobenzene (2), was a fluid, straw-colored oil that weighed 7.0 g.
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To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene (2) in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135 g of anhydrous stannic chloride. There was then added, dropwise, 26 g of dichloromethyl methyl ether at a rate that precluded excessive heating. The reaction mixture was allowed to come to room temperature over the course of 0.5 h, and then quenched by dumping into 500 g shaved ice containing 75 mL concentrated HCl. This mixture was stirred for an additional 1.5 h. The separated organic layer was washed with 2 x 100 mL dilute HCl, then with dilute NaOH, then with H2O and finally with saturated brine. Removal of the solvent under vacuum yielded a solid residue that was recrystallized from aqueous EtOH yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) with a m.p. of 99-100 °C.
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A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) in 15 mL acetic acid containing 1 g nitromethane was treated with 0.2 g anhydrous ammonium acetate, and heated on the steam bath for 4 h. After cooling, and following the judicious addition of H2O, crystals separated, and additional H2O was added with good stirring until the first signs of oiling out appeared. The solids were removed by filtration, and recrystallized from acetone to give 2.0 g of 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4) with a mp of 159-162 °C.
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To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an inert atmosphere, there was added a THF solution of 2.0 g 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4). The reaction mixture was stirred at room temperature for 2 h and then heated briefly to reflux. After cooling, the excess hydride was destroyed by the cautious addition of H2O, and when the reaction was finally quiet, there was added 2 mL of 15 % NaOH, followed by another 6 mL of H2O. The basic insolubles were removed by filtration, and washed with THF. The combined filtrate and washes were stripped of solvent, yielding a residual oil that was taken up in 10 mL of IPA, neutralized with concentrated HCl, and the generated solids diluted with anhydrous Et2O.
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The white crystalline 2,5-dimethoxy-4-fluorophenethylamine hydrochloride (5) (2C-F) was recrystallized from IPA to give an air-dried product of 0.5 g with a m.p. of 182-185 °C.

2C-P synthesis

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To a stirred solution of 138 g p-dimethoxybenzene (1) in 400 mL CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for 1.5 h the reaction mixture was poured into 2 L H2O containing ice. The phases were separated, and the aqueous fraction was extracted with 2 x 100 mL CH2Cl2. The organic phase and the extracts were pooled, washed once with H2O, and then with 2x 100 mL 5 % NaOH. The solvent from the organic phase was removed under vacuum, yielding a deeply colored residue. This was distilled at 150-165 °C at 20 mm/Hg, yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored oil. Acidification of the sodium hydroxide extract, extraction with CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that slowly crystallized. These solids, on recrystallization from MeOH, provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a m.p. of 47-48 °C. The same Friedel Crafts reaction, conducted on the same scale in CS2 rather than in CH2Cl2, required reduced temperature (5 °C) and a 24 h reaction period. This solvent variation, with the same workup and isolation, gave 76 g of 2,5-dimethoxypropiophenone (2) as a pale amber oil boiling at 130-137 °C at 4 mm/Hg.
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A total of 150 g mossy zinc was amalgamated by treatment with a solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5 h, the H2O phase was removed by decantation and the zinc added to a 1 L three neck flasks. To this, there was added 20 mL H2O and 20 mL concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone (2) dissolved in 50 mL EtOH. This mixture was held at reflux with a heating mantle overnight, with the occasional addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids were removed by filtration, and the filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase). Sufficient H2O was then added to allow extraction with 2 x 100 mL additional CH2Cl2, with the organic solvent being the lower phase. The combined organic extracts were washed twice with 5 % NaOH, followed by one washing with dilute acid. Removal of the solvent under vacuum yielded 18 g of a dark brown oil that was distilled at the water pump to yield 7.2 g of 2,5-dimethoxypropylbenzene (3) as a light yellow oil boiling at 90-130 °C.
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A mixture of 22 g 2,5-dimethoxypropylbenzene (3), 23 g POCl3 and 22 g N-methylformanilide was heated on the steam bath for 1.5 h. The hot, dark reaction mass was poured into 1 L H2O, which allowed the eventual separation of 2,5-dimethoxy-4-n-propylbenzaldehyde (4) as a clear yellow oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl benzaldehydes were clean crystalline solids, this propyl homologue remained an oil. Gas chromatographic analysis showed it to be about 90 % pure, and it was used as obtained in the nitrostyrene steps with either nitromethane (here) or nitroethane (under DOPR).
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To a solution of 13 g 2,5-dimethoxy-4-n-propylbenzaldehyde (4) in 100 mL nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture held at reflux for 1 h. Removal of the solvent/reactant under vacuum yielded a spontaneously crystallizing mass of orange solids that was removed with the help of a little MeOH. After filtering and air drying, there was obtained 7.5 g 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) with a mp of 118-122 °C. Recrystallization from CH3CN gave an analytical sample with a mp 123-124 °C.
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In a 1 L round bottomed flask with a magnetic stirrer under an inert atmosphere, there was added 120 mL 1 M LAH in tetrahydrofuran. This stirred solution was cooled with an external ice bath, and there was added, dropwise, 3.2 mL of 100 % H2SO4, freshly made by the addition of 13.5 g 20 % fuming H2SO4 to 15.0 g of ordinary 96 % concentrated H2SO4. When the addition was complete, a total of 7.2 g of dry 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) was introduced as solids in several batches, against a flow of He, over the course of 20 min. The reaction mixture was allowed to come to room temperature, and stirred for an additional 0.5 h, then brought to reflux for 10 min on the steam bath. The excess hydride was destroyed with 18 mL IPA, and then sufficient 15 % NaOH was added, which made the aluminum oxides distinctly basic and of a filterable texture. The inorganics were removed by filtration, and the filter cake washed with additional THF. The combined filrate and washes were stripped of solvent, yielding several g of a pale yellow oil that was suspended in a large quantity of dilute H2SO4. The aqueous phase was filtered free of insolubles, washed with a little CH2Cl2, and made basic with aqueous NaOH. This was extracted with 3 x 40 mL CH2Cl2 and, after the removal of the solvent under vacuum, the residual 2 g of off-white oil was distilled. A fraction that distilled at 100-110 °C at 0.3 mm/Hg was water white, weighed 1.59 g and spontaneously crystallized. This fraction was dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated HCl.
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The spontaneous crystals of 2,5-di-methoxy-4-n-propylphenethylamine hydrochloride (2C-P) (6) were suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air dried. The weight was 1.65 g and the mp was 207-209 °C with prior sintering at 183 °C.

2C-T-2 (7) synthesis

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To a solution of 165 g 1,4-dimethoxybenzene (1) in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride (2), a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.
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The following reaction is also a very vigorous one and must be performed in a well-ventilated place. To a solution of 400 mL 25% H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinc was placed. Additional dollups of zinc were added, and each small exothermic reaction site was spread about with the glass stirring rod. Finally, the reaction spread to the entire solid surface layer, with a melting of the acid chloride and an apparent boiling at the H2O surface. The remainder of the 80 g of zinc dust was added as fast as the size of the reaction co of 165 g 1,4-dimethoxybenzene in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase, and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.

The following reaction is also a very vigorous one and must be performed in a well-ventilated place. To a solution of 400 mL 25 % H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride (2), and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinntainer would allow. After things subsided again, the heating was continued for 1 h on the steam bath. After the reaction mixture had cooled to room temperature, it was filtered through paper in a Buchner funnel, and the residual metal washed with 100 mL CH2Cl2. The two-phase filtrate was separated, and the lower, aqueous phase was extracted with 2 x 75 mL CH2Cl2. The addition of 2 L H2O to the aqueous phase now made it the upper phase in extraction, and this was again extracted with 2 x 75 mL CH2Cl2. The organic extracts were pooled (H2O washing is more trouble than it is worth) and the solvent removed under vacuum. The light amber residue (30.0 g) was distilled at 70-80 °C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol (3) as a white oil. This chemical is certainly not centrally active, but it is a most valuable precursor to all members of the 2C-T family.
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To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was added a solution of 10.0 g 2,5-dimethoxythiophenol (3) in 60 mL EtOH followed by 10.9 g ethyl bromide. The reaction was exothermic, with the immediate deposition of white solids. This was heated on the steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and extracted with 3 x 100 mL CH2Cl2. The pooled extracts were washed with 100 mL of 5 % NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl ethyl sulfide (4) which was a pale amber oil, weighed about 10 g and which was sufficiently pure for use in the next reaction without a distillation step.
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A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated briefly on the steam bath. To this claret-colored solution there was added the above 2,5-dimethoxyphenyl ethyl sulfide (4), and the mixture heated an additional 20-min on the steam bath. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued for 1.5 h by which time the oily phase had completely solidified to a brown sugar-like consistency. The solids were removed by filtration, and washed with additional H2O. After being sucked as dry as possible, these solids were dissolved in 50 mL boiling MeOH which, after cooling in an ice-bath, deposited almost-white crystals of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde (5). After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 11.0 g of product with a mp of 86-88 °C. Recrystallization of a small sample again from MeOH provided an analytical sample with mp 87-88 °C.
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To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde (5) in 100 g of nitromethane there was added 0.5 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 80 min (this reaction progress must be monitored by TLC, to determine the point at which the starting aldehyde has been consumed). The excess nitromethane was removed under vacuum, leaving a residue that spontaneously set to orange-red crystals. These were scraped out to provide 12.9 g crude 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) with a m.p. of 152-154 °C. A sample recrystallized from toluene was pumpkin colored and had a mp of 148-149 °C. Another sample from acetone melted at 149 °C sharp, and was light orange. From IPA came spectacular fluorescent orange crystals, with a mp 151-152 °C.
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A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under He. To this, there was added 12.4 g 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) in a little THF, and the mixture was held at reflux for 24 h. After the reaction mixture had returned to room temperature, the excess hydride was destroyed by the cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed, in turn, by sufficient H2O to give a white granular character to the oxides. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. Removing the solvents from the combined filtrate and washings under vacuum provided 9.5 g of a yellow oil. This was added to 1 L dilute HCl and washed with 2 x 100 mL CH2Cl2, which removed all color. After making the aqueous phase basic with 25 % NaOH, it was extracted with 3 x 100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum to provide 7.3 g of a pale amber oil. Distillation at 120-130 °C at 0.3 mm/Hg gave 6.17 g of a clear white oil. This was dissolved in 80 mL IPA and neutralized with concentrated HCl, forming immediate crystals of 2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2) (7).
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An equal volume of anhydrous Et2O was added and, after complete grinding and mixing, the salt was removed by filtration, washed with Et2O, and air dried to constant weight. The resulting white crystals weighed 6.2 g.

2C-T-7 (5) synthesis

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To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (1) (see under the recipe for 2C-T-2 for its preparation) and 7.4 g n-propylbromide dissolved in 20 mL MeOH. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for 0.5 h, added to 800 mL H2O, additional aqueous NaOH added until the pH was basic, and extracted with 3 x 75 mL CH2Cl2. The pooled extracts were washed with dilute NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl n-propyl sulfide (2) which was obtained as a pale yellow oil, and which weighed 8.9 g. It had a light, pleasant fruity smell, and was sufficiently pure for use in the next reaction without distillation.
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A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 8.9 g of 2,5-dimethoxyphenyl n-propyl sulfide (2), and the mixture heated an additional 25-min on the steam bath. This was then added to 800 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued until the oily phase had completely solidified (about 15 minutes). The resulting brown sugar-like solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, they were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 8.3 g of 2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde (3) with a m.p. of 73-76 °C. Recrystallization from 2.5 volumes of MeOH provided a white analytical sample with mp 76-77 °C.
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To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde (3) in 20 g of nitromethane there was added 0.23 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The clear orange solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. The orange-yellow crystalline material that remained was crystallized from 70 mL boiling IPA which, on slow cooling, deposited 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) as orange crystals. After their removal by filtration and air-drying to constant weight, they weighed 3.6 g, and had a mp of 120-121 °C.
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A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under an inert atmosphere, to 0 °C with an external ice bath. With good stirring, there was added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.4 g 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) in 50 mL anhydrous THF. 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, then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of IPA (21 mL required) followed by sufficient 5 % NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (15 mL was used). The reaction mixture was filtered, and the filter cake washed first with THF and then with IPA. The filtrate and washes were combined and stripped of solvent under vacuum, providing about 6 g of a pale amber oil. Without any further purification, this was distilled at 140-150 °C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl, forming immediate crystals of the hydrochloride salt in the alcohol solvent. An equal volume of anhydrous Et2O was added, and after complete grinding and mixing, 2,5-dimethoxy-4-n-propylthiophenethylamine hydrochloride (2C-T-7) (5) was removed by filtration, Et2O washed, and air dried to constant weight. The resulting spectacular white crystals weighed 5.2 g.
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DocX

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Thank you, always nice to read Schulgin ;).

I love it when write-ups on DIY forums are completed with an list of ingredients. Since I would never ask for anyone to spoonfeed me that hard, I took the liberty of doing one from the text. If I missed or misinterpreted anything, please holler. It's quite an impressive list, not easily obtainable for an amateur clandestine chemist. But Schulgin was neither. But this list is from all the synths, can be divided into separate synths when I have the time!

Acetyl Chloride
P-dimethoxybenzene
Nitromethane
Ammonium acetate, anhydrous
Lithium Aluminum Hydride, LAH
Elemental Bromine
Nitrostyrene
N-methylformanilide
2,5-dimethoxytoluene
2,5-dimethoxybenzaldehyde
Phtalic anhydride
Iodine monochloride
Propionyl chloride
Mercuric chloride
Zink, mossy and dust
Phosphorus Oxychloride, POCl3


Sodium Hydroxide (NaOH)
Potassium Hydroxide (KOH)
Aluminium Chloride, anhydrous (AlCl3)
Sodium Bicarbonate
Stannic Chloride
Sodium dithionite
Sodium Nitrite

Hydrochloric acid, HCl
Sulphuric Acid, 100%
Glacial Acetic Acid
Fluoroboric acid
Chlorosulfonic acid

Methanol, MeOH
Ethanol, 100%, EtO2
Dichloromethane, DCM (CH2Cl2)
Triethylene glycol, TEG
Dimethyl Sulphate, DMS
Hydrazine, 65%
Hexane
Dichloromethyl methyl ether
Tetrahydrofuran, THF
Isopropyl Alcohol, IPA
Toluene

Helium, Argon or Nitrogen gas to create inert atmospheres
 

karamelosanto

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Thank you !!
This is awesome!
I really love 2c-x phenetylamines!
I hope some day I can reach the level necessary to do something like 2c-e.
 

HIGGS BOSSON

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The topic reveals the synthesis of substituted benzaldehydes, which can be bought ready-made and significantly simplify the synthesis. Almost any phenylethylamine can be synthesized according to the scheme:
Nitromethane + desired benzaldehyde = corresponding phenylnitrostyrene
Phenylnitrostyrene is reduced to the appropriate phenylethylamine
 

smithS

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View attachment 4418

Introduction

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds. Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines i Have Known And Loved). Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group. You can find most popular 2C- member syntheses in this topic such as 2C-E, 2C-D, 2C-B, 2C-I, 2C-F, 2C-P, 2C-T-2, 2C-T-7.

Procedures

2C-E (6) synthesis
View attachment 4425
A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 100 g acetyl chloride. This slurry was added to a vigorously stirred solution of 110 g p-dimethoxybenzene (1) in 300 mL CH2Cl2. Stirring was continued at ambient temperature for an additional 40 min, then all was poured into 1 L water and the phases separated. The aqueous phase was extracted with 2 x 100 mL CH2Cl2 and the combined organic phases washed with 3 x 150 mL 5 % NaOH. These washes, after combination and acidification, were extracted with 3 x 75 mL CH2Cl2 and the extracts washed once with saturated NaHCO3. Removal of the solvent under vacuum provided 28.3 g of 2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on recrystallization from 2 volumes of boiling MeOH and air drying, provided 21.3 g of product with a mp of 49-49.5 °C. The CH2Cl2 fraction from the base wash, above, was stripped of solvent on the rotary evaporator to give a residual oil that, on distillation at 147-150 °C at the water pump, provided 111.6 g of 2,5-dimethoxyacetophenone (2) as an almost white oil.
In a round bottom flask equipped with a reflux condenser, a take-off adapter, an immersion thermometer, and a magnetic stirrer, there was placed 100 g 2,5-dimethoxyacetophenone (2), 71 g 85 % KOH pellets, 500 mL of triethylene glycol (TEG), and 125 mL 65 % hydrazine. The mixture was brought up to a boil by heating with an electric mantle, and the distillate was removed, allowing the temperature of the pot contents to continuously increase. When the pot temperature had reached 210 °C, reflux was established and maintained for an additional 3 h. After cooling, the reaction mixture and the distillate were combined, poured into 3 L water, and extracted with 3 x 100 mL hexane. After washing the pooled extracts with water, the solvent was removed yielding 22.0 g of a pale straw-colored liquid that was free of both hydroxy and carbonyl groups by infrared. This was distilled at 120-140 °C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a white fluid product. Acidification of the spent aqueous phase with concentrated HCl produced a heavy black oil which was extracted with 3 x 100 mL CH2Cl2. Removal of the solvent on the rotary evaporator yielded 78 g. of a black residue that was distilled at 90-105 °C at 0.5 mm/Hg to provide 67.4 g of an orange-amber oil that was largely 2-ethyl-4-methoxyphenol (3). This material could eventually be used as a starting material for ethoxy homologues. However, remethylation (with CH3I and KOH in methanol) provided some 28 g additional 2,5-dimethoxyethylbenzene.
A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene (3) in 30 mL CH2Cl2 was cooled to 0 °C with good stirring and under an inert atmosphere of He (or nitrogen N2). There was then added 11.7 mL anhydrous stannic chloride, followed by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5 h. The stirred reaction mixture was allowed to come up to room temperature, then held on the steam bath for 1 h. The reaction mixture was poured into 1 L water, extracted with 3 x 75 mL CH2Cl2, and the pooled extracts washed with dilute HCl. The organic phase was stripped under vacuum yielding 10.8 g of a dark viscous oil. This was distilled at 90-110 °C at 0.2 mm/Hg to yield a colorless oil that, on cooling, set to white crystals. The yield of 2,5-dimethoxy-4-ethylbenzaldehyde (4) was 5.9 g of material that had a mp of 46-47 °C. After purification through the bisulfite complex, the mp increased to 47-48 °C. The use of the Vilsmeier aldehyde synthesis (with POCl3 and N-methylformanilide) gave results that were totally unpredictable. The malononitrile derivative (from 0.3 g of this aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of triethylamine) formed red crystals which, on recrystallization from toluene, had a mp of 123-124 °C.
A solution of 21.0 g of the unrecrystallized 2,5-dimethoxy-4-ethylbenzaldehyde (4) in 75 g nitromethane was treated with 4 g of anhydrous ammonium acetate and heated on the steam bath for about 2 h. The progress of the reaction was best followed by TLC analysis of the crude reaction mixture on silica gel plates with CH2Cl2 as the developing solvent. The excess solvent/reagent was removed under vacuum yielding granular orange solids that were recrystallized from seven volumes of boiling MeOH. After cooling in external ice-water for 1 h, the yellow crystalline product was removed by filtration, washed with cold MeOH and air dried to give 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5). The mp was 96-98 °C which improved to 99-100 °C after a second recrystallization from MeOH.
A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M) was transferred to a 3 neck 500 mL flask, under an inert atmosphere with good magnetic stirring. This solution was cooled to °C with an external ice-water bath, and there was then added 3.0 mL of 100 % H2SO4 over the course of 0.5 h. This was followed by a solution of 5.85 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5), in 40 mL of warm THF. The reaction mixture was stirred for 0.5 h, brought to room temperature, heated on the steam bath for 0.5 h, and then returned to room temperature. The addition of IPA dropwise destroyed the excess hydride, and some 4.5 mL of 5 % NaOH produce a white cottage cheese, in a basic organic medium. This mixture was filtered, washed with THF, and the filtrate evaporated to produce 2.8 g of an almost white oil. The filter cake was resuspended in THF, made more basic with additional 15 mL of 5 % NaOH, again filtered, and the filtrate removed to provide an additional 2.8 g of crude product. These residues were combined and distilled at 90-100 °C at 0.25 mm/Hg to give a colorless oil. This was dissolved in 30 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O to provide, after spontaneous crystallization, filtration, washing with Et2O, and air drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as magnificent white crystals.
A similar yield can be obtained from the reduction of the nitrostyrene in a suspension of LAH in THF, without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there was added, dropwise, a solution of 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5) in 75 mL THF over the course of 2 h. The mixture was kept at reflux for an additional 8 h, and killed by the careful addition of 11 mL H2O, followed with 11 mL 15 % NaOH, and finally another 33 mL of H2O. This mass was filtered, washed with THF, and the combined filtrates and washes evaporated to a residue under vacuum The approximately 15 mL of residue was dissolved in 300 mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated HCl. On shaking the mixture, there was deposited a mass of the hydrochloride salt which was diluted with a quantity of additional H2O. The organic phase was extracted with additional dilute HCL, and these aqueous phases were combined. After being made basic with 25 % NaOH, this phase was again extracted with 3 x 75 mL CH2Cl2 and after the removal of the solvent, yielded 12.6 g of a colorless oil. This was dissolved in 75 mL of IPA and neutralized with concentrated HCl. The solidified mass that formed was loosened with another 50 mL IPA, and then filtered. After Et2O washing and air drying there was obtained 7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as lustrous white crystals.

2C-D (6) synthesis

View attachment 4430
Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone (1), 160 mL 25% NaOH, and 126 g dimethyl sulfate (DMS). After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3 x 100 mL CH2Cl2 and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 °C at 0.5 mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 °C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 °C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene. This gave 2.53 g of a white crystalline product with a mp of 66-68 °C. A second recrystallization (from hexane) raised this mp to 71-72 °C. The literature value given for the m.p. of 2-methyl-4-methoxyphenol (2) is 70-71 °C. The literature value given for the m.p. of the isomeric 3-methyl-4-methoxyphenol is 44-46 °C.
A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide (3) was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene (2). Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4 x 100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product. This, upon recrystallization from 150 mL boiling hexane, gave pale yellow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde (4), and had a mp of 83-84 °C. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3 g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 °C.
A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde (4) in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2 g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when dry, 7.70 g. The m.p. was 117-118 °C, and this was increased to 118-119 °C upon recrystallization from benzene/heptane 1:2.
To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-beta-nitrostyrene (5) in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA. There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2 x 50 mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 °C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl which produced immediate crystals of the salt. These were dispersed with 80 mL anhydrous Et2O, filtered, and washed with Et2O to give, after air drying to constant weight, 4.9 g of fluffy white crystals of 2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D) (6).
The m.p. was 213-214 °C which was not improved by recrystallization from CH3CN/IPA mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 °C. The acetamide, from the free base in pyridine treated with acetic anhydride, was a white crystalline solid which, when recrystallized from aqueous MeOH, had a mp of 116-117 °C.

2C-B (4) synthesis


A solution of 100 g of 2,5-dimethoxybenzaldehyde (1) in 220 g nitromethane was treated with 10 g anhydrous ammonium acetate, and heated on a steam bath for 2.5 h with occasional swirling. The deep-red reaction mixture was stripped of the excess nitromethane under vacuum, and the residue crystallized spontaneously. This crude nitrostyrene was purified by grinding under IPA, filtering, and air-drying, to yield 85 g of 2,5-dimethoxy-beta-nitrostyrene (2) as a yellow-orange product of adequate purity for the next step. Further purification can be achieved by recrystallization from boiling IPA.
In a round-bottomed 2 L flask equipped with a magnetic stirrer and placed under an inert atmosphere, there was added 750 mL anhydrous THF, containing 30 g LAH. There was then added, in THF solution, 60 g 2,5-dimethoxy-beta-nitrostyrene (2). The final solution was a dirty yellow-brown color, and it was kept at reflux temperature for 24 h. After cooling, the excess hydride was destroyed by the dropwise addition of IPA. Then 30 mL 15% NaOH was added to convert the inorganic solids to a filterable mass. The reaction mixture was filtered and the filter cake washed first with THF and then with MeOH. The combined mother liquors and washings were freed of solvent under vacuum and the residue suspended in 1.5 L H2O. This was acidified with HCl, washed with with 3 x 100 mL CH2Cl2, made strongly basic with 25 % NaOH, and reextracted with 4x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, yielding 26 g of oily residue, which was distilled at 120-130 °C at 0.5 mm/Hg to give 21 g of a white oil, 2,5-dimethoxyphenethylamine (2C-H) (3) which picks up carbon dioxide from the air very quickly.
To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine (3) in 40 mL glacial acetic acid, there was added 22 g elemental bromine dissolved in 40 mL acetic acid. After a couple of min, there was the formation of solids and the simultaneous evolution of considerable heat. The reaction mixture was allowed to return to room temperature, filtered, and the solids washed sparingly with cold acetic acid. This was the hydrobromide salt. There are many complicated salt forms, both polymorphs and hydrates, that can make the isolation and characterization of 2C-B treacherous. The happiest route is to form the insoluble hydrochloride salt by way of the free base. The entire mass of acetic acid-wet salt was dissolved in warm H2O, made basic to at least pH 11 with 25 % NaOH, and extracted with 3 x 100 mL CH2Cl2. Removal of the solvent gave 33.7 g of residue which was distilled at 115-130 °C at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 mL H2O containing 7.0 g acetic acid. This clear solution was vigorous stirred, and treated with 20 mL concentrated HCl. There was an immediate formation of the anhydrous salt of 2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B) (4). This mass of crystals was removed by filtration (it can be loosened considerably by the addition of another 60 mL H2O), washed with a little H2O, and then with several 50 mL portions of Et2O. When completely air-dry, there was obtained 31.05 g of fine white needles, with a mp of 237-239 °C with decomposition.
When there is too much H2O present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. The hydrobromide salt melts at 214.5-215 °C. The acetate salt was reported to have a m.p. of 208-209 °C.

2C-I (4) synthesis

A mixture of 7.4 g phthalic anhydride and 9.05 g of 2,5-dimethoxyphenethylamine (1) (see the recipe for 2C-B synthesis for its preparation) was heated with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was poured out into a crystallizing dish yielding 14.8 g of a crude solid product. This was recrystallized from 20 mL CH3CN, with care taken for an endothermic dissolution, and an exothermic crystallization. Both transitions must be done without haste. After filtration, the solids were washed with 2 x 20 mL hexane and air dried to constant weight. A yield of 12.93 g of N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) was obtained as electrostatic yellow crystals, with a mp of 109-111 °C. A sample recrystallized from IPA was white, with a mp of 110-111 °C.
To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) in 130 mL warm (35 °C) acetic acid which was being vigorously stirred, there was added a solution of 10 g iodine monochloride in 40 mL acetic acid. This was stirred for 1 h, while being held at about 30 °C. The reaction mixture was poured into 1500 mL H2O and extracted with 4 x 75 mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O containing 2.0 g sodium dithionite, and the solvent removed under vacuum to give 16.2 g of N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) as yellow amber solids with a m.p. of 133-141 °C. This mp was improved by recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow solid with mp 149-151 °C. A small sample from a large quantity of IPA gives a white product melting at 155.5-157 °C.
A solution of 12.2 g N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) in 150 mL hot IPA was treated with 6.0 mL of hydrazine hydrate, and the clear solution was heated on the steam bath. After a few minutes there was the generation of a white cottage cheese-like solid (1,4-dihydroxyphthalizine). The heating was continued for several additional hour, the reaction mixture cooled, and the solids removed by filtration. These were washed with 2 x 10 mL EtOH, and the pooled filtrate and washes stripped of solvent under vacuum giving a residue which, when treated with aqueous hydrochloric acid, gave 3.43 g of voluminous white crystals.
This, after recrystallization from 2 weights of H2O, filtering, washing first with IPA and then with Et2O, and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) (4) as a white microcrystalline solid, with a mp of 246-247 °C.

2C-F (5) synthesis

A solution of 76.6 g 2,5-dimethoxyaniline (1) in 210 mL H2O containing 205 mL fluoroboric acid was cooled to 0 °C. with an external ice bath. There was then added, slowly, a solution of 35 g sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the precipitated solids were removed by filtration, washed first with cold H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g of the fluoroborate salt of the aniline as dark purple-brown solids. This salt was pyrolyzed with the cautious application of a flame, with the needed attention paid to both an explosion risk, and the evolution of the very corrosive boron trifluoride. The liquid that accumulated in the receiver was distilled at about 120 °C at 20 mm/Hg, and was subsequently washed with dilute NaOH to remove dissolved boron trifluoride. The product, 2,5-dimethoxyfluorobenzene (2), was a fluid, straw-colored oil that weighed 7.0 g.
To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene (2) in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135 g of anhydrous stannic chloride. There was then added, dropwise, 26 g of dichloromethyl methyl ether at a rate that precluded excessive heating. The reaction mixture was allowed to come to room temperature over the course of 0.5 h, and then quenched by dumping into 500 g shaved ice containing 75 mL concentrated HCl. This mixture was stirred for an additional 1.5 h. The separated organic layer was washed with 2 x 100 mL dilute HCl, then with dilute NaOH, then with H2O and finally with saturated brine. Removal of the solvent under vacuum yielded a solid residue that was recrystallized from aqueous EtOH yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) with a m.p. of 99-100 °C.
A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) in 15 mL acetic acid containing 1 g nitromethane was treated with 0.2 g anhydrous ammonium acetate, and heated on the steam bath for 4 h. After cooling, and following the judicious addition of H2O, crystals separated, and additional H2O was added with good stirring until the first signs of oiling out appeared. The solids were removed by filtration, and recrystallized from acetone to give 2.0 g of 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4) with a mp of 159-162 °C.
To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an inert atmosphere, there was added a THF solution of 2.0 g 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4). The reaction mixture was stirred at room temperature for 2 h and then heated briefly at reflux. After cooling, the excess hydride was destroyed by the cautious addition of H2O, and when the reaction was finally quiet, there was added 2 mL of 15 % NaOH, followed by another 6 mL of H2O. The basic insolubles were removed by filtration, and washed with THF. The combined filtrate and washes were stripped of solvent, yielding a residual oil that was taken up in 10 mL of IPA, neutralized with concentrated HCl, and the generated solids diluted with anhydrous Et2O.
The white crystalline 2,5-dimethoxy-4-fluorophenethylamine hydrochloride (5) (2C-F) was recrystallized from IPA to give an air-dried product of 0.5 g with a m.p. of 182-185 °C.

2C-P synthesis

View attachment 4449
To a stirred solution of 138 g p-dimethoxybenzene (1) in 400 mL CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for 1.5 h the reaction mixture was poured into 2 L H2O containing ice. The phases were separated, and the aqueous fraction was extracted with 2 x 100 mL CH2Cl2. The organic phase and the extracts were pooled, washed once with H2O, and then with 2x 100 mL 5 % NaOH. The solvent from the organic phase was removed under vacuum, yielding a deeply colored residue. This was distilled at 150-165 °C at 20 mm/Hg yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored oil. Acidification of the sodium hydroxide extract, extraction with CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that slowly crystallized. These solids, on recrystallization from MeOH, provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a m.p. of 47-48 °C. The same Friedel Crafts reaction, conducted on the same scale in CS2 rather than in CH2Cl2, required reduced temperature (5 °C) and a 24 h reaction period. This solvent variation, with the same workup and isolation, gave 76 g of 2,5-dimethoxypropiophenone (2) as a pale amber oil boiling at 130-137 °C at 4 mm/Hg.
A total of 150 g mossy zinc was amalgamated by treatment with a solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5 h, the H2O phase was removed by decantation and the zinc added to a 1 L three neck flask. To this there was added 20 mL H2O and 20 mL concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone (2) dissolved in 50 mL EtOH. This mixture was held at reflux with a heating mantle overnight, with the occasional addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids were removed by filtration, and the filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase). Sufficient H2O was then added to allow extraction with 2 x 100 mL additional CH2Cl2 with the organic solvent being the lower phase. The combined organic extracts were washed twice with 5 % NaOH, followed by one washing with dilute acid. Removal of the solvent under vacuum yielded 18 g of a dark brown oil that was distilled at the water pump to yield 7.2 g of 2,5-dimethoxypropylbenzene (3) as a light yellow oil boiling at 90-130 °C.
A mixture of 22 g 2,5-dimethoxypropylbenzene (3), 23 g POCl3 and 22 g N-methylformanilide was heated on the steam bath for 1.5 h. The hot, dark reaction mass was poured into 1 L H2O, which allowed the eventual separation of 2,5-dimethoxy-4-n-propylbenzaldehyde (4) as a clear yellow oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl benzaldehydes were clean crystalline solids, this propyl homologue remained an oil. Gas chromatographic analysis showed it to be about 90 % pure, and it was used as obtained in the nitrostyrene steps with either nitromethane (here) or nitroethane (under DOPR).
To a solution of 13 g 2,5-dimethoxy-4-n-propylbenzaldehyde (4) in 100 mL nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture held at reflux for 1 h. Removal of the solvent/reactant under vacuum yielded a spontaneously crystallizing mass of orange solids that was removed with the help of a little MeOH. After filtering and air drying there was obtained 7.5 g 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) with a mp of 118-122 °C. Recrystallization from CH3CN gave an analytical sample with a mp 123-124 °C.
In a 1 L round bottomed flask with a magnetic stirrer under an inert atmosphere there was added 120 mL 1 M LAH in tetrahydrofuran. This stirred solution was cooled with an external ice bath, and there was added, dropwise, 3.2 mL of 100 % H2SO4, freshly made by the addition of 13.5 g 20 % fuming H2SO4 to 15.0 g of ordinary 96 % concentrated H2SO4. When the addition was complete, a total of 7.2 g of dry 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) was introduced as solids in several batches, against a flow of He, over the course of 20 min. The reaction mixture was allowed to come to room temperature, and stirred for an additional 0.5 h, then brought to reflux for 10 min on the steam bath. The excess hydride was destroyed with 18 mL IPA, and then sufficient 15 % NaOH was added which made the aluminum oxides distinctly basic and of a filterable texture. The inorganics were removed by filtration, and the filter cake washed with additional THF. The combined filrate and washes were stripped of solvent, yielding several g of a pale yellow oil that was suspended in a large quantity of dilute H2SO4. The aqueous phase was filtered free of insolubles, washed with a little CH2Cl2, and made basic with aqueous NaOH. This was extracted with 3 x 40 mL CH2Cl2 and, after the removal of the solvent under vacuum, the residual 2 g of off-white oil was distilled. A fraction that distilled at 100-110 °C at 0.3 mm/Hg was water white, weighed 1.59 g and spontaneously crystallized. This fraction was dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated HCl.
The spontaneous crystals of 2,5-di-methoxy-4-n-propylphenethylamine hydrochloride (2C-P) (6) were suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air dried. The weight was 1.65 g and the mp was 207-209 °C with prior sintering at 183 °C.

2C-T-2 (7) synthesis

View attachment 4456
To a solution of 165 g 1,4-dimethoxybenzene (1) in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride (2), a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.
The following reaction is also a very vigorous one and must be performed in a well ventilated place. To a solution of 400 mL 25% H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinc was placed. Additional dollups of zinc were added, and each small exothermic reaction site was spread about with the glass stirring rod. Finally, the reaction spread to the entire solid surface layer, with a melting of the acid chloride and an apparent boiling at the H2O surface. The remainder of the 80 g of zinc dust was added as fast as the size of the reaction co of 165 g 1,4-dimethoxybenzene in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.

The following reaction is also a very vigorous one and must be performed in a well ventilated place. To a solution of 400 mL 25 % H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride (2), and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinntainer would allow. After things subsided again, the heating was continued for 1 h on the steam bath. After the reaction mixture had cooled to room temperature, it was filtered through paper in a Buchner funnel, and the residual metal washed with 100 mL CH2Cl2. The two-phase filtrate was separated, and the lower, aqueous phase was extracted with 2 x 75 mL CH2Cl2. The addition of 2 L H2O to the aqueous phase now made it the upper phase in extraction, and this was again extracted with 2 x 75 mL CH2Cl2. The organic extracts were pooled (H2O washing is more trouble than it is worth) and the solvent removed under vacuum. The light amber residue (30.0 g) was distilled at 70-80 °C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol (3) as a white oil. This chemical is certainly not centrally active, but it is a most valuable precursor to all members of the 2C-T family.
To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was added a solution of 10.0 g 2,5-dimethoxythiophenol (3) in 60 mL EtOH followed by 10.9 g ethyl bromide. The reaction was exothermic with the immediate deposition of white solids. This was heated on the steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and extracted with 3 x 100 mL CH2Cl2. The pooled extracts were washed with 100 mL of 5 % NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl ethyl sulfide (4) which was a pale amber oil, weighed about 10 g and which was sufficiently pure for use in the next reaction without a distillation step.
A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated briefly on the steam bath. To this claret-colored solution there was added the above 2,5-dimethoxyphenyl ethyl sulfide (4), and the mixture heated an additional 20 min on the steam bath. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued for 1.5 h by which time the oily phase had completely solidified to a brown sugar-like consistency. The solids were removed by filtration, and washed with additional H2O. After being sucked as dry as possible, these solids were dissolved in 50 mL boiling MeOH which, after cooling in an ice-bath, deposited almost-white crystals of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde (5). After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 11.0 g of product with a mp of 86-88 °C. Recrystallization of a small sample again from MeOH provided an analytical sample with mp 87-88 °C.
To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde (5) in 100 g of nitromethane there was added 0.5 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 80 min (this reaction progress must be monitored by TLC, to determine the point at which the starting aldehyde has been consumed). The excess nitromethane was removed under vacuum leaving a residue that spontaneously set to orange-red crystals. These were scraped out to provide 12.9 g crude 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) with a m.p. of 152-154 °C. A sample recrystallized from toluene was pumpkin colored and had a mp of 148-149 °C. Another sample from acetone melted at 149 °C sharp, and was light orange. From IPA came spectacular fluorescent orange crystals, with a mp 151-152 °C.
A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under He. To this there was added 12.4 g 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) in a little THF, and the mixture was held at reflux for 24 h. After the reaction mixture had returned to room temperature, the excess hydride was destroyed by the cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed, in turn, by sufficient H2O to give a white granular character to the oxides. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. Removing the solvents from the combined filtrate and washings under vacuum provided 9.5 g of a yellow oil. This was added to 1 L dilute HCl and washed with 2 x 100 mL CH2Cl2 which removed all color. After making the aqueous phase basic with 25 % NaOH, it was extracted with 3 x 100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum to provide 7.3 g of a pale amber oil. Distillation at 120-130 °C at 0.3 mm/Hg gave 6.17 g of a clear white oil. This was dissolved in 80 mL IPA and neutralized with concentrated HCl, forming immediate crystals of 2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2) (7).
An equal volume of anhydrous Et2O was added and, after complete grinding and mixing, the salt was removed by filtration, washed with Et2O, and air dried to constant weight. The resulting white crystals weighed 6.2 g.

2C-T-7 (5) synthesis

To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (1) (see under the recipe for 2C-T-2 for its preparation) and 7.4 g n-propylbromide dissolved in 20 mL MeOH. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for 0.5 h, added to 800 mL H2O, additional aqueous NaOH added until the pH was basic, and extracted with 3 x 75 mL CH2Cl2. The pooled extracts were washed with dilute NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl n-propyl sulfide (2) which was obtained as a pale yellow oil, and which weighed 8.9 g. It had a light pleasant fruity smell, and was sufficiently pure for use in the next reaction without distillation.
A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 8.9 g of 2,5-dimethoxyphenyl n-propyl sulfide (2), and the mixture heated an additional 25 min on the steam bath. This was then added to 800 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued until the oily phase had completely solidified (about 15 minutes). The resulting brown sugar-like solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, they were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 8.3 g of 2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde (3) with a m.p. of 73-76 °C. Recrystallization from 2.5 volumes of MeOH provided a white analytical sample with mp 76-77 °C.
To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde (3) in 20 g of nitromethane there was added 0.23 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The clear orange solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. The orange-yellow crystalline material that remained was crystallized from 70 mL boiling IPA which, on slow cooling, deposited 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) as orange crystals. After their removal by filtration and air-drying to constant weight, they weighed 3.6 g, and had a mp of 120-121 °C.
A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under inert atmosphere, to 0 °C with an external ice bath. With good stirring there was added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.4 g 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) in 50 mL anhydrous THF. There was an immediate loss of color. After a few min further stirring, the tem-perature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of IPA (21 mL required) followed by sufficent 5 % NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (15 mL was used). The reaction mixture was filtered and the filter cake washed first with THF and then with IPA. The filtrate and washes were combined and stripped of solvent under vacuum providing about 6 g of a pale amber oil. Without any further purification, this was distilled at 140-150 °C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. An equal volume of anhydrous Et2O was added, and after complete grinding and mixing, 2,5-dimethoxy-4-n-propylthiophenethylamine hydrochloride (2C-T-7) (5) was removed by filtration, Et2O washed, and air dried to constant weight. The resulting spectacular white crystals weighed 5.2 g.
can we go through direct substitution on PEA...? or any route you can suggest on substitution on PEA.
 

G.Patton

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can we go through direct substitution on PEA...? or any route you can suggest on substitution on PEA.
In most cases, this is not possible. Which reaction are you interested in?
 
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Gale

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Kickass, Thanks for sharing.
 

DocX

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Would it be possible to use Sodium Borohydride instead of LAH in these reactions? Should be right?
 

smithS

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Would it be possible to use Sodium Borohydride instead of LAH in these reactions? Should be right?
yes you can use , and with excess of acetic acid for selective reduction..
 

smithS

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In most cases, this is not possible. Which reaction are you interested in?
what can we make from PEA which is useful in terms substituted PEA skeleton..
 

Joker_333

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Hi
View attachment 4418

Introduction

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 positions, usually resulting in more potent and more metabolically stable and longer acting compounds. Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines I Have Known And Loved). Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group. You can find most popular 2C- member syntheses in this topic such as 2C-E, 2C-D, 2C-B, 2C-I, 2C-F, 2C-P, 2C-T-2, 2C-T-7.

Procedures

2C-E (6) synthesis
View attachment 4425
A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 100 g acetyl chloride. This slurry was added to a vigorously stirred solution of 110 g p-dimethoxybenzene (1) in 300 mL CH2Cl2. Stirring was continued at ambient temperature for an additional 40 min, then all was poured into 1 L water and the phases separated. The aqueous phase was extracted with 2 x 100 mL CH2Cl2 and the combined organic phases washed with 3 x 150 mL 5 % NaOH. These washes, after combination and acidification, were extracted with 3 x 75 mL CH2Cl2 and the extracts washed once with saturated NaHCO3. Removal of the solvent under vacuum provided 28.3 g of 2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on recrystallization from 2 volumes of boiling MeOH and air drying, provided 21.3 g of product with a mp of 49-49.5 °C. The CH2Cl2 fraction from the base wash, above, was stripped of solvent on the rotary evaporator to give a residual oil that, on distillation at 147-150 °C at the water pump, provided 111.6 g of 2,5-dimethoxyacetophenone (2) as an almost white oil.
In a round bottom flask equipped with a reflux condenser, a take-off adapter, an immersion thermometer, and a magnetic stirrer, there was placed 100 g 2,5-dimethoxyacetophenone (2), 71 g 85 % KOH pellets, 500 mL of triethylene glycol (TEG), and 125 mL 65 % hydrazine. The mixture was brought up to a boil by heating with an electric mantle, and the distillate was removed, allowing the temperature of the pot contents to continuously increase. When the pot temperature had reached 210 °C, reflux was established and maintained for an additional 3 h. After cooling, the reaction mixture and the distillate were combined, poured into 3 L water, and extracted with 3 x 100 mL hexane. After washing the pooled extracts with water, the solvent was removed, yielding 22.0 g of a pale straw-colored liquid that was free of both hydroxy and carbonyl groups by infrared. This was distilled at 120-140 °C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a white fluid product. Acidification of the spent aqueous phase with concentrated HCl produced a heavy black oil, which was extracted with 3 x 100 mL CH2Cl2. Removal of the solvent on the rotary evaporator yielded 78 g. of a black residue that was distilled at 90-105 °C at 0.5 mm/Hg to provide 67.4 g of an orange-amber oil that was largely 2-ethyl-4-methoxyphenol (3). This material could eventually be used as a starting material for ethoxy homologues. However, remethylation (with CH3I and KOH in methanol) provided some 28 g additional 2,5-dimethoxyethylbenzene.
A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene (3) in 30 mL CH2Cl2 was cooled to 0 °C with good stirring and under an inert atmosphere of He (or nitrogen N2). There was then added 11.7 mL anhydrous stannic chloride, followed by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5 h. The stirred reaction mixture was allowed to come up to room temperature, then held on the steam bath for 1 h. The reaction mixture was poured into 1 L water, extracted with 3 x 75 mL CH2Cl2, and the pooled extracts washed with dilute HCl. The organic phase was stripped under vacuum, yielding 10.8 g of a dark viscous oil. This was distilled at 90-110 °C at 0.2 mm/Hg to yield a colorless oil that, on cooling, set to white crystals. The yield of 2,5-dimethoxy-4-ethylbenzaldehyde (4) was 5.9 g of material that had a mp of 46-47 °C. After purification through the bisulfite complex, the mp increased to 47-48 °C. The use of the Vilsmeier aldehyde synthesis (with POCl3 and N-methylformanilide) gave results that were totally unpredictable. The malononitrile derivative (from 0.3 g of this aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of triethylamine) formed red crystals which, on recrystallization from toluene, had a mp of 123-124 °C.
A solution of 21.0 g of the unrecrystallized 2,5-dimethoxy-4-ethylbenzaldehyde (4) in 75 g nitromethane was treated with 4 g of anhydrous ammonium acetate and heated on the steam bath for about 2 h. The progress of the reaction was best followed by TLC analysis of the crude reaction mixture on silica gel plates with CH2Cl2 as the developing solvent. The excess solvent/reagent was removed under vacuum, yielding granular orange solids that were recrystallized from seven volumes of boiling MeOH. After cooling in external ice-water for 1 h, the yellow crystalline product was removed by filtration, washed with cold MeOH and air dried to give 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5). The mp was 96-98 °C which improved to 99-100 °C, after a second recrystallization from MeOH.
A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M) was transferred to a 3 neck 500 mL flask, under an inert atmosphere with good magnetic stirring. This solution was cooled to °C with an external ice-water bath, and there was then added 3.0 mL of 100 % H2SO4 over the course of 0.5 h. This was followed by a solution of 5.85 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5), in 40 mL of warm THF. The reaction mixture was stirred for 0.5 h, brought to room temperature, heated on the steam bath for 0.5 h, and then returned to room temperature. The addition of IPA dropwise destroyed the excess hydride, and some 4.5 mL of 5 % NaOH produce a white cottage cheese, in a basic organic medium. This mixture was filtered, washed with THF, and the filtrate evaporated to produce 2.8 g of an almost white oil. The filter cake was resuspended in THF, made more basic with additional 15 mL of 5 % NaOH, again filtered, and the filtrate removed to provide an additional 2.8 g of crude product. These residues were combined and distilled at 90-100 °C at 0.25 mm/Hg to give a colorless oil. This was dissolved in 30 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O to provide, after spontaneous crystallization, filtration, washing with Et2O, and air drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as magnificent white crystals.
A similar yield can be obtained from the reduction of the nitrostyrene in a suspension of LAH in THF, without the use of H2SO4. With 11.3 g of LAH in 300 mL dry THF, there was added, dropwise, a solution of 13.4 g of 2,5-dimethoxy-4-ethyl-beta-nitrostyrene (5) in 75 mL THF over the course of 2 h. The mixture was kept at reflux for an additional 8 h, and killed by the careful addition of 11 mL H2O, followed with 11 mL 15 % NaOH, and finally another 33 mL of H2O. This mass was filtered, washed with THF, and the combined filtrates and washes evaporated to a residue under vacuum The approximately 15 mL of residue was dissolved in 300 mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated HCl. On shaking the mixture, there was deposited a mass of the hydrochloride salt, which was diluted with a quantity of additional H2O. The organic phase was extracted with additional dilute HCL, and these aqueous phases were combined. After being made basic with 25 % NaOH, this phase was again extracted with 3 x 75 mL CH2Cl2 and after the removal of the solvent, yielded 12.6 g of a colorless oil. This was dissolved in 75 mL of IPA and neutralized with concentrated HCl. The solidified mass that formed was loosened with another 50 mL IPA, and then filtered. After Et2O washing and air drying, there was obtained 7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) (6) as lustrous white crystals.

2C-D (6) synthesis

View attachment 4430
Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone (1), 160 mL 25% NaOH, and 126 g dimethyl sulfate (DMS). After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3 x 100 mL CH2Cl2 and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 °C at 0.5 mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 °C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 °C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene. This gave 2.53 g of a white crystalline product with a mp of 66-68 °C. A second recrystallization (from hexane) raised this mp to 71-72 °C. The literature value given for the m.p. of 2-methyl-4-methoxyphenol (2) is 70-71 °C. The literature value given for the m.p. of the isomeric 3-methyl-4-methoxyphenol is 44-46 °C.
A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide (3) was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene (2). Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4 x 100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product. This, upon recrystallization from 150 mL boiling hexane, gave pale yellow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde (4), and had a mp of 83-84 °C. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3 g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 °C.
A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde (4) in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2 g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-beta-nitrostyrene which weighed, when dry, 7.70 g. The m.p. was 117-118 °C, and this was increased to 118-119 °C upon recrystallization from benzene/heptane 1:2.
To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-beta-nitrostyrene (5) in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA. There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2 x 50 mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 °C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl, which produced immediate crystals of the salt. These were dispersed with 80 mL anhydrous Et2O, filtered, and washed with Et2O to give, after air drying to constant weight, 4.9 g of fluffy white crystals of 2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D) (6).
The m.p. was 213-214 °C which was not improved by recrystallization from CH3CN/IPA mixture, or from EtOH. The hydrobromide salt had a mp of 183-184 °C. The acetamide, from the free base in pyridine treated with acetic anhydride, was a white crystalline solid which, when recrystallized from aqueous MeOH, had a mp of 116-117 °C.

2C-B (4) synthesis


A solution of 100 g of 2,5-dimethoxybenzaldehyde (1) in 220 g nitromethane was treated with 10 g anhydrous ammonium acetate, and heated on a steam bath for 2.5 h with occasional swirling. The deep-red reaction mixture was stripped of the excess nitromethane under vacuum, and the residue crystallized spontaneously. This crude nitrostyrene was purified by grinding under IPA, filtering, and air-drying, to yield 85 g of 2,5-dimethoxy-beta-nitrostyrene (2) as a yellow-orange product of adequate purity for the next step. Further purification can be achieved by recrystallization from boiling IPA.
View attachment 4431
View attachment 5062
2,5-dimethoxy-beta-nitrostyrene (2)
In a round-bottomed 2 L flask equipped with a magnetic stirrer and placed under an inert atmosphere, there was added 750 mL anhydrous THF, containing 30 g LAH. There was then added, in THF solution, 60 g 2,5-dimethoxy-beta-nitrostyrene (2). The final solution was a dirty yellow-brown color, and it was kept at reflux temperature for 24 h. After cooling, the excess hydride was destroyed by the dropwise addition of IPA. Then 30 mL 15% NaOH was added to convert the inorganic solids to a filterable mass. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. The combined mother liquors and washings were freed of solvent under vacuum and the residue suspended in 1.5 L H2O. This was acidified with HCl, washed with 3 x 100 mL CH2Cl2, made strongly basic with 25 % NaOH, and reextracted with 4 x 100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, yielding 26 g of oily residue, which was distilled at 120-130 °C at 0.5 mm/Hg to give 21 g of a white oil, 2,5-dimethoxyphenethylamine (2C-H) (3) which picks up carbon dioxide from the air very quickly.
2,5-dimethoxyphenethylamine (2C-H) (3) hydrochloride
To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine (3) in 40 mL glacial acetic acid, there was added 22 g elemental bromine dissolved in 40 mL acetic acid. After a couple of mins, there was the formation of solids and the simultaneous evolution of considerable heat. The reaction mixture was allowed to return to room temperature, filtered, and the solids washed sparingly with cold acetic acid. This was the hydrobromide salt. There are many complicated salt forms, both polymorphs and hydrates, that can make the isolation and characterization of 2C-B treacherous. The happiest route is to form the insoluble hydrochloride salt by way of the free base. The entire mass of acetic acid-wet salt was dissolved in warm H2O, made basic to at least pH 11 with 25 % NaOH, and extracted with 3 x 100 mL CH2Cl2. Removal of the solvent gave 33.7 g of residue, which was distilled at 115-130 °C at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 mL H2O containing 7.0 g acetic acid. This clear solution was vigorous stirred, and treated with 20 mL concentrated HCl. There was an immediate formation of the anhydrous salt of 2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B) (4). This mass of crystals was removed by filtration (it can be loosened considerably by the addition of another 60 mL H2O), washed with a little H2O, and then with several 50 mL portions of Et2O. When completely air-dry, there was obtained 31.05 g of fine white needles, with a mp of 237-239 °C with decomposition.
2C-B salt (4) precipitating out of reaction mixture

When there is too much H2O present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. The hydrobromide salt melts at 214.5-215 °C. The acetate salt was reported to have a m.p. of 208-209 °C.
Dried crude 2C-B salt (4)

2C-I (4) synthesis

A mixture of 7.4 g phthalic anhydride and 9.05 g of 2,5-dimethoxyphenethylamine (1) (see the recipe for 2C-B synthesis for its preparation) was heated with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was poured out into a crystallizing dish, yielding 14.8 g of a crude solid product. This was recrystallized from 20 mL CH3CN, with care taken for an endothermic dissolution, and an exothermic crystallization. Both transitions must be done without haste. After filtration, the solids were washed with 2 x 20 mL hexane and air dried to constant weight. A yield of 12.93 g of N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) was obtained as electrostatic yellow crystals, with a mp of 109-111 °C. A sample recrystallized from IPA was white, with a mp of 110-111 °C.
To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide (2) in 130 mL warm (35 °C) acetic acid which was being vigorously stirred, there was added a solution of 10 g iodine monochloride in 40 mL acetic acid. This was stirred for 1 h, while being held at about 30 °C. The reaction mixture was poured into 1500 mL H2O and extracted with 4 x 75 mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O containing 2.0 g sodium dithionite, and the solvent removed under vacuum to give 16.2 g of N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) as yellow amber solids with a m.p. of 133-141 °C. This mp was improved by recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow solid with mp 149-151 °C. A small sample from a large quantity of IPA gives a white product melting at 155.5-157 °C.
A solution of 12.2 g N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide (3) in 150 mL hot IPA was treated with 6.0 mL of hydrazine hydrate, and the clear solution was heated on the steam bath. After a few minutes, there was the generation of a white cottage cheese-like solid (1,4-dihydroxyphthalizine). The heating was continued for several additional hours, the reaction mixture cooled, and the solids removed by filtration. These were washed with 2 x 10 mL EtOH, and the pooled filtrate and washes stripped of solvent under vacuum giving a residue which, when treated with aqueous hydrochloric acid, gave 3.43 g of voluminous white crystals.
This, after recrystallization from 2 weights of H2O, filtering, washing first with IPA and then with Et2O, and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) (4) as a white microcrystalline solid, with a mp of 246-247 °C.
View attachment 5072View attachment 5073
Crude and recrystallized 2,5-dimethoxy-4-iodophenethylamine hydrochloride (2C-I) (4)


2C-F (5) synthesis

A solution of 76.6 g 2,5-dimethoxyaniline (1) in 210 mL H2O containing 205 mL fluoroboric acid was cooled to 0 °C. with an external ice bath. There was then added, slowly, a solution of 35 g sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the precipitated solids were removed by filtration, washed first with cold H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g of the fluoroborate salt of the aniline as dark purple-brown solids. This salt was pyrolyzed with the cautious application of a flame, with the needed attention paid to both an explosion risk, and the evolution of the very corrosive boron trifluoride. The liquid that accumulated in the receiver was distilled at about 120 °C at 20 mm/Hg, and was subsequently washed with dilute NaOH to remove dissolved boron trifluoride. The product, 2,5-dimethoxyfluorobenzene (2), was a fluid, straw-colored oil that weighed 7.0 g.
To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene (2) in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135 g of anhydrous stannic chloride. There was then added, dropwise, 26 g of dichloromethyl methyl ether at a rate that precluded excessive heating. The reaction mixture was allowed to come to room temperature over the course of 0.5 h, and then quenched by dumping into 500 g shaved ice containing 75 mL concentrated HCl. This mixture was stirred for an additional 1.5 h. The separated organic layer was washed with 2 x 100 mL dilute HCl, then with dilute NaOH, then with H2O and finally with saturated brine. Removal of the solvent under vacuum yielded a solid residue that was recrystallized from aqueous EtOH yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) with a m.p. of 99-100 °C.
A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde (3) in 15 mL acetic acid containing 1 g nitromethane was treated with 0.2 g anhydrous ammonium acetate, and heated on the steam bath for 4 h. After cooling, and following the judicious addition of H2O, crystals separated, and additional H2O was added with good stirring until the first signs of oiling out appeared. The solids were removed by filtration, and recrystallized from acetone to give 2.0 g of 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4) with a mp of 159-162 °C.
To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an inert atmosphere, there was added a THF solution of 2.0 g 2,5-dimethoxy-4-fluoro-beta-nitrostyrene (4). The reaction mixture was stirred at room temperature for 2 h and then heated briefly to reflux. After cooling, the excess hydride was destroyed by the cautious addition of H2O, and when the reaction was finally quiet, there was added 2 mL of 15 % NaOH, followed by another 6 mL of H2O. The basic insolubles were removed by filtration, and washed with THF. The combined filtrate and washes were stripped of solvent, yielding a residual oil that was taken up in 10 mL of IPA, neutralized with concentrated HCl, and the generated solids diluted with anhydrous Et2O.
The white crystalline 2,5-dimethoxy-4-fluorophenethylamine hydrochloride (5) (2C-F) was recrystallized from IPA to give an air-dried product of 0.5 g with a m.p. of 182-185 °C.

2C-P synthesis

View attachment 4449
To a stirred solution of 138 g p-dimethoxybenzene (1) in 400 mL CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for 1.5 h the reaction mixture was poured into 2 L H2O containing ice. The phases were separated, and the aqueous fraction was extracted with 2 x 100 mL CH2Cl2. The organic phase and the extracts were pooled, washed once with H2O, and then with 2x 100 mL 5 % NaOH. The solvent from the organic phase was removed under vacuum, yielding a deeply colored residue. This was distilled at 150-165 °C at 20 mm/Hg, yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored oil. Acidification of the sodium hydroxide extract, extraction with CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that slowly crystallized. These solids, on recrystallization from MeOH, provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a m.p. of 47-48 °C. The same Friedel Crafts reaction, conducted on the same scale in CS2 rather than in CH2Cl2, required reduced temperature (5 °C) and a 24 h reaction period. This solvent variation, with the same workup and isolation, gave 76 g of 2,5-dimethoxypropiophenone (2) as a pale amber oil boiling at 130-137 °C at 4 mm/Hg.
A total of 150 g mossy zinc was amalgamated by treatment with a solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5 h, the H2O phase was removed by decantation and the zinc added to a 1 L three neck flasks. To this, there was added 20 mL H2O and 20 mL concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone (2) dissolved in 50 mL EtOH. This mixture was held at reflux with a heating mantle overnight, with the occasional addition of HCl as needed to maintain acidic conditions. After cooling to room temperature, the residual solids were removed by filtration, and the filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase). Sufficient H2O was then added to allow extraction with 2 x 100 mL additional CH2Cl2, with the organic solvent being the lower phase. The combined organic extracts were washed twice with 5 % NaOH, followed by one washing with dilute acid. Removal of the solvent under vacuum yielded 18 g of a dark brown oil that was distilled at the water pump to yield 7.2 g of 2,5-dimethoxypropylbenzene (3) as a light yellow oil boiling at 90-130 °C.
A mixture of 22 g 2,5-dimethoxypropylbenzene (3), 23 g POCl3 and 22 g N-methylformanilide was heated on the steam bath for 1.5 h. The hot, dark reaction mass was poured into 1 L H2O, which allowed the eventual separation of 2,5-dimethoxy-4-n-propylbenzaldehyde (4) as a clear yellow oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl benzaldehydes were clean crystalline solids, this propyl homologue remained an oil. Gas chromatographic analysis showed it to be about 90 % pure, and it was used as obtained in the nitrostyrene steps with either nitromethane (here) or nitroethane (under DOPR).
To a solution of 13 g 2,5-dimethoxy-4-n-propylbenzaldehyde (4) in 100 mL nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture held at reflux for 1 h. Removal of the solvent/reactant under vacuum yielded a spontaneously crystallizing mass of orange solids that was removed with the help of a little MeOH. After filtering and air drying, there was obtained 7.5 g 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) with a mp of 118-122 °C. Recrystallization from CH3CN gave an analytical sample with a mp 123-124 °C.
In a 1 L round bottomed flask with a magnetic stirrer under an inert atmosphere, there was added 120 mL 1 M LAH in tetrahydrofuran. This stirred solution was cooled with an external ice bath, and there was added, dropwise, 3.2 mL of 100 % H2SO4, freshly made by the addition of 13.5 g 20 % fuming H2SO4 to 15.0 g of ordinary 96 % concentrated H2SO4. When the addition was complete, a total of 7.2 g of dry 2,5-dimethoxy-beta-nitro-4-n-propylstyrene (5) was introduced as solids in several batches, against a flow of He, over the course of 20 min. The reaction mixture was allowed to come to room temperature, and stirred for an additional 0.5 h, then brought to reflux for 10 min on the steam bath. The excess hydride was destroyed with 18 mL IPA, and then sufficient 15 % NaOH was added, which made the aluminum oxides distinctly basic and of a filterable texture. The inorganics were removed by filtration, and the filter cake washed with additional THF. The combined filrate and washes were stripped of solvent, yielding several g of a pale yellow oil that was suspended in a large quantity of dilute H2SO4. The aqueous phase was filtered free of insolubles, washed with a little CH2Cl2, and made basic with aqueous NaOH. This was extracted with 3 x 40 mL CH2Cl2 and, after the removal of the solvent under vacuum, the residual 2 g of off-white oil was distilled. A fraction that distilled at 100-110 °C at 0.3 mm/Hg was water white, weighed 1.59 g and spontaneously crystallized. This fraction was dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated HCl.
The spontaneous crystals of 2,5-di-methoxy-4-n-propylphenethylamine hydrochloride (2C-P) (6) were suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air dried. The weight was 1.65 g and the mp was 207-209 °C with prior sintering at 183 °C.

2C-T-2 (7) synthesis

View attachment 4456
To a solution of 165 g 1,4-dimethoxybenzene (1) in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride (2), a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.
The following reaction is also a very vigorous one and must be performed in a well-ventilated place. To a solution of 400 mL 25% H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinc was placed. Additional dollups of zinc were added, and each small exothermic reaction site was spread about with the glass stirring rod. Finally, the reaction spread to the entire solid surface layer, with a melting of the acid chloride and an apparent boiling at the H2O surface. The remainder of the 80 g of zinc dust was added as fast as the size of the reaction co of 165 g 1,4-dimethoxybenzene in 1 L of CH2Cl2, in a well ventilated place and well stirred, there was cautiously added 300 mL chlorosulfonic acid. With about half the acid chloride added, there was a vigorous evolution of HCl gas and the generation of a lot of solids. As the addition was continued, these redissolved to form a clear, dark green solution. Towards the end of the addition, some solids were again formed. When everything was stable, there was added 2 L H2O, a few mL at a time, commensurate with the vigor of the reaction. The two phases were separated, and the aqueous phase extracted with 2 x 75 mL CH2Cl2. The original organic phase, and the extracts were combined and the solvent removed under vacuum. The residue weighed 162 g and was quite pure 2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with a mp of 115-117 °C. It need not be further purified for the next step, and it appears to be stable on storage. The sulfonamide, from this acid chloride and ammonium hydroxide, gave white crystals from EtOH, with a mp of 147.5-148.5 °C.

The following reaction is also a very vigorous one and must be performed in a well-ventilated place. To a solution of 400 mL 25 % H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of 2,5-dimethoxybenzenesulfonyl chloride (2), and the mixture was heated on a steam bath. The yellow crystals of the acid chloride floated on the surface of the aqueous layer. There should be 80 g of zinc dust at hand. A small amount of Zn dust was placed at one spot on the surface of this chapeau. With occasional stirring with a glass rod, the temperature was allowed to rise. At about 60 or 70 °C an exothermic reaction took place at the spot where the zinntainer would allow. After things subsided again, the heating was continued for 1 h on the steam bath. After the reaction mixture had cooled to room temperature, it was filtered through paper in a Buchner funnel, and the residual metal washed with 100 mL CH2Cl2. The two-phase filtrate was separated, and the lower, aqueous phase was extracted with 2 x 75 mL CH2Cl2. The addition of 2 L H2O to the aqueous phase now made it the upper phase in extraction, and this was again extracted with 2 x 75 mL CH2Cl2. The organic extracts were pooled (H2O washing is more trouble than it is worth) and the solvent removed under vacuum. The light amber residue (30.0 g) was distilled at 70-80 °C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol (3) as a white oil. This chemical is certainly not centrally active, but it is a most valuable precursor to all members of the 2C-T family.
To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was added a solution of 10.0 g 2,5-dimethoxythiophenol (3) in 60 mL EtOH followed by 10.9 g ethyl bromide. The reaction was exothermic, with the immediate deposition of white solids. This was heated on the steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and extracted with 3 x 100 mL CH2Cl2. The pooled extracts were washed with 100 mL of 5 % NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl ethyl sulfide (4) which was a pale amber oil, weighed about 10 g and which was sufficiently pure for use in the next reaction without a distillation step.
A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated briefly on the steam bath. To this claret-colored solution there was added the above 2,5-dimethoxyphenyl ethyl sulfide (4), and the mixture heated an additional 20-min on the steam bath. This was then added to 500 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued for 1.5 h by which time the oily phase had completely solidified to a brown sugar-like consistency. The solids were removed by filtration, and washed with additional H2O. After being sucked as dry as possible, these solids were dissolved in 50 mL boiling MeOH which, after cooling in an ice-bath, deposited almost-white crystals of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde (5). After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 11.0 g of product with a mp of 86-88 °C. Recrystallization of a small sample again from MeOH provided an analytical sample with mp 87-88 °C.
To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde (5) in 100 g of nitromethane there was added 0.5 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 80 min (this reaction progress must be monitored by TLC, to determine the point at which the starting aldehyde has been consumed). The excess nitromethane was removed under vacuum, leaving a residue that spontaneously set to orange-red crystals. These were scraped out to provide 12.9 g crude 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) with a m.p. of 152-154 °C. A sample recrystallized from toluene was pumpkin colored and had a mp of 148-149 °C. Another sample from acetone melted at 149 °C sharp, and was light orange. From IPA came spectacular fluorescent orange crystals, with a mp 151-152 °C.
A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under He. To this, there was added 12.4 g 2,5-dimethoxy-4-ethylthio-beta-nitrostyrene (6) in a little THF, and the mixture was held at reflux for 24 h. After the reaction mixture had returned to room temperature, the excess hydride was destroyed by the cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed, in turn, by sufficient H2O to give a white granular character to the oxides. The reaction mixture was filtered, and the filter cake washed first with THF and then with MeOH. Removing the solvents from the combined filtrate and washings under vacuum provided 9.5 g of a yellow oil. This was added to 1 L dilute HCl and washed with 2 x 100 mL CH2Cl2, which removed all color. After making the aqueous phase basic with 25 % NaOH, it was extracted with 3 x 100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum to provide 7.3 g of a pale amber oil. Distillation at 120-130 °C at 0.3 mm/Hg gave 6.17 g of a clear white oil. This was dissolved in 80 mL IPA and neutralized with concentrated HCl, forming immediate crystals of 2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2) (7).
An equal volume of anhydrous Et2O was added and, after complete grinding and mixing, the salt was removed by filtration, washed with Et2O, and air dried to constant weight. The resulting white crystals weighed 6.2 g.

2C-T-7 (5) synthesis

To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (1) (see under the recipe for 2C-T-2 for its preparation) and 7.4 g n-propylbromide dissolved in 20 mL MeOH. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for 0.5 h, added to 800 mL H2O, additional aqueous NaOH added until the pH was basic, and extracted with 3 x 75 mL CH2Cl2. The pooled extracts were washed with dilute NaOH, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl n-propyl sulfide (2) which was obtained as a pale yellow oil, and which weighed 8.9 g. It had a light, pleasant fruity smell, and was sufficiently pure for use in the next reaction without distillation.
A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 8.9 g of 2,5-dimethoxyphenyl n-propyl sulfide (2), and the mixture heated an additional 25-min on the steam bath. This was then added to 800 mL of well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued until the oily phase had completely solidified (about 15 minutes). The resulting brown sugar-like solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, they were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals. After filtration, modest washing with cold MeOH, and air drying to constant weight, there was obtained 8.3 g of 2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde (3) with a m.p. of 73-76 °C. Recrystallization from 2.5 volumes of MeOH provided a white analytical sample with mp 76-77 °C.
To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde (3) in 20 g of nitromethane there was added 0.23 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The clear orange solution was decanted from some insoluble material and the excess nitromethane removed under vacuum. The orange-yellow crystalline material that remained was crystallized from 70 mL boiling IPA which, on slow cooling, deposited 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) as orange crystals. After their removal by filtration and air-drying to constant weight, they weighed 3.6 g, and had a mp of 120-121 °C.
A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under an inert atmosphere, to 0 °C with an external ice bath. With good stirring, there was added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.4 g 2,5-dimethoxy-beta-nitro-4-n-propylthiostyrene (4) in 50 mL anhydrous THF. 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, then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of IPA (21 mL required) followed by sufficient 5 % NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (15 mL was used). The reaction mixture was filtered, and the filter cake washed first with THF and then with IPA. The filtrate and washes were combined and stripped of solvent under vacuum, providing about 6 g of a pale amber oil. Without any further purification, this was distilled at 140-150 °C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl, forming immediate crystals of the hydrochloride salt in the alcohol solvent. An equal volume of anhydrous Et2O was added, and after complete grinding and mixing, 2,5-dimethoxy-4-n-propylthiophenethylamine hydrochloride (2C-T-7) (5) was removed by filtration, Et2O washed, and air dried to constant weight. The resulting spectacular white crystals weighed 5.2 g.
Thank you for your explanation in the reduction step 2C-H, if we use Hgcl2 instead of LAH, how much will the yield be?
Please also explain the process if you use this reagent, thank you very much
 

Joker_333

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Hello. I can't say exactly. I think same or higher.
Nitrostyrene reduction by Al/Hg.

Recently I was dreaming about to reduce 2,5-dimethoxynitrostyrene to the amine 2C-H with Al/Hg and acetic acid. I anticipated a yield of about 50-60% but I got only 35%. Yields are not good, but Shulgin reports 40% for 2C-B and 50% for 2C-H with LAH, so might be interesting to avoid buy / use LAH.

Proportions used:

  • 1 g 2,5-Dimethoxynitrostyrene
  • 10 ml Acetic acid
  • 15 ml 96% Ethanol
  • 5 ml Water
  • 50 mg HgCl2
  • 2 g Aluminum foil
The reaction must be carried at about 60øC, otherwise all of the starting nitrostyrene won't be dissolved. Some tips are:

  • Make a solution of everything but the Al, then add the foil, cut to oneinch squares at a rate enough to keep the temp around 60øC, and add until the orange colour disappear. About the double weight of nitro will be enough, maybe less.
  • Filter off the Al sludge, wash it with alcohol, then basify the solution with 25% NaOH. Filter again to remove the crystallized sodium acetate, and wash the filter cake with water.
  • Remove the solvent under vacuum, dissolve the residue in dilute H2SO4, and wash with 3x20 ml CH2Cl2. Basify with 25% NaOH and extract the solution with 3x25 ml CH2Cl2. Dry the pooled extracts over MgSO4, remove the solvent under vacuum, dissolve the residue in anhydrous ether, and saturate the solution with anhydrous HCl gas to precipitate pure 2C-H hydrochloride. To recover the 2C-H freebase, distill the residue above under vacuum instead
Hi, this text from erowid
 
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