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#35 2C-O-4


[3D .mol structure]
SYNTHESIS: To a solution of 3.10 g 85% KOH pellets in 30 mL warm MeOH there was added 6.16 g 2,5-dimethoxyphenol (there was immediate darkening) followed by 8.5 g isopropyl iodide. The reaction mixture was heated on the steam bath for 3.5 h. White crystals of KI appeared at the end of the first h. The mixture was poured into 800 mL H2O (it was still basic) and acidified with HCl. This was extracted with 3x100 mL CH2Cl2, and the combined extracts washed with 2x100 mL 5% NaOH. The organic phase was stripped of solvent under vacuum, and the residual dark amber oil (6.4 g) distilled at 110-130 °C at 0.7 mm/Hg. There was obtained 5.7 g of 1,4-dimethoxy-2-(i)-propoxybenzene as a white oil.

A mixture of 10 g N-methylformanilide and 10 g POCl3 was heated on the steam bath for 10 min producing a deep claret color. To this there was added 5.1 g of 1,4-dimethoxy-2-(i)-propoxybenzene, and the immediately exothermic reaction mixture was heated on the steam bath for 45 min. It was then poured into 800 mL H2O which was stirred until the dark oil changed into loose, light-colored solids. These were removed by filtration giving 5.7 g of an amber crystalline product with a mp of 76-78 °C. This was dissolved in an equal weight of MeOH, and heated to a solution which was clear at the boiling point. This was brought to 0 °C and held there for several hours, yielding 2,5-dimethoxy-4-(i)-propoxybenzaldehyde as a fine, off-white crystalline product which, after filtering and air drying, weighed 4.03 g. The mp was 79-80 °C with prior shrinking at 71 °C. Anal. (C12H16O4) C,H.

A solution of 3.9 g 2,5-dimethoxy-4-(i)-propoxybenzaldehyde in 20 g nitromethane was treated with 0.17 g anhydrous ammonium acetate and heated on the steam bath for 1.25 h. The progress of the condensation was readily followed by a TLC analysis of the reaction mixture. With silica gel plates, the starting aldehyde and the product nitrostyrene had Rf's of 0.16 and 0.50 resp., using CH2Cl2 as a developing solvent. The excess solvent was removed under vacuum to give a red residue that was dissolved in 10 mL boiling MeOH. The solution spontaneously crystallized giving, after filteration and air drying, 4.1 g of orange crystals of 2,5-dimethoxy-beta-nitro-4-(i)-propoxystyrene.

A solution of LAH (60 mL of a 1 M solution in THF) was cooled, under He, to 0 °C with an external ice bath. With good stirring there was added 1.60 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 4.0 g 2,5-dimethoxy-beta-nitro-4-(i)-propoxystyrene as a solid, perhaps 200 mg at a time. There was an immediate loss of color after each addition. The final pale salmon-colored solution was stirred for 2 h as it returned to room temperature. The excess hydride was destroyed by the cautious addition of 8 mL IPA, which was followed by 5 mL 15% NaOH followed, in turn, by sufficient additional THF to make the suspension of inorganic salts loose and filterable. The reaction mixture was filtered, and the filter cake washed with additional THF. The filtrate and washings were combined and stripped of solvent under vacuum providing 4.6 g of a pale amber oil. This was dissolved in dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent under vacuum yielded 2.3 g of residue which was distilled at 115-125 °C at 0.3 mm/Hg to give 0.94 g of a clear white oil. This was dissolved in 5 mL IPA, neutralized with 12 drops of concentrated HCl, and diluted with 10 mL anhydrous Et2O. White crystals of 2,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (2C-O-4) separated, and were removed by filtration, Et2O washed, and air dried. The final weight was 0.58 g.

DOSAGE: greater than 60 mg.

DURATION: unknown

QUALITATIVE COMMENTS: (with 60 mg) I became aware of something in the front part of my head, and there was a lot of yawning. The body was aware of the experiment. But also there was a general exhilaration and excitement, which lasted for a few hours. At best, I am at a plus one.

EXTENSIONS AND COMMENTARY: The full activity of 2C-O-4 is yet to be discovered. It represents an interesting hybrid lying in between several fascinating compounds.

First and foremost, all these carry the 2,4,5-trisubstitution which has consistently proven to be the most interesting and the most active of the phenethylamines. And with very few exceptions, the 2- and the 5- are methoxyl groups.

The sulfur analogues in this area, compounds with an alkylthio group at the 4-position of the 2,5-dimethoxyphenethylamine backbone, are the 2C-T things. The replacement of a sulfur with an oxygen, quite rightly, should give rise to the 2C-O counterparts. And they have been given the same numbering system that was bestowed upon the RTS series. 2C-T-4 was the 4-isopropylthio compound and one of the most interesting of this family. And so, quite reasonably, the oxygen coun-terpart should be the 2C-O-4 analogue, and should be one of the first explored.

The extension of the 4-alkoxy-group led to the discovery of the TMA-2 --MEM--MIPM--MPM--MBM series of amphetamine analogues. The 2-carbon counterparts of these would be a fascinating series to explore, I thought, if there was some encouragement to be had from a preliminary try in this field.

This was a first shot in the dark, the actual trial example, and it certainly didn't provide much encouragement. The three-carbon analogue, MIPM, was made (q.v.) but not explored, following the disappointing trials of MPM. If this area is ever re-opened, the numbering should reasonably follow the sulfur materials. The 4-ethoxy material would be 2C-O-2, the 4-(n)-propoxy compound 2C-O-7, and the 4-(n)-butoxy compound 2C-O-19. These are the exact analogues of 2C-T-2, 2C-T-7, and 2C-T-19, resp., and the 2-carbon homologues of MEM, MPM, and MBM. The simplest member of this series, the methyl counterpart, is 2C-O, and it is the obvious analogue of 2C-T. This is also called 2,4,5-TMPEA, and its story is presented elsewhere.

But, with the probable low eventual potency of 2C-O-4, I feel that the 2C-O series will not be an exciting one.

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