This interesting article was often cited but it was not posted before despite lots of cool synthesis tricks in it:
- the sandmeyer reaction to get the para halo compounds (how to make DOI or DOC without the need to pass through the illegal 2,5 DMA). See also
https://www.thevespiary.org/rhodium/Rhodium/chemistry/doc.synth.html
for the sandmeyer reaction to DOC.
- the reduction of the nitroalkane to the hydroxy-amine with Zn/NH4Cl. VERY interesting since nitroalkanes are easily synthetised now thanks to Beaker and Barium). This prove that there isn't a need to have diborane to get those hydroxy-amines.
A new world open to us: the world of the legal HOH, HOB, HOI and HOC instead of our favorite 2C-H, 2C-B and the like. Those N-OH compounds are as active as their NH2 counterpart (see the HOT chapters in Pihkal).
Hmm, a nomenclature problem: what is the little name of N-Hydroxy-DOM? MDA->MDOH; MDMA->FLEA; 2C-X->HOX but what about the DOX compounds?
The synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ronald T Coutts and Jerry L Malicky, Can J Chem 51, 1402 (1973)Abstract:The synthesis of a series of 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes, in which the 4-substituent is Br, Cl, I, NO2, NH2, and NHAc, is described. These compounds are analogs of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), a known hallucinogen. A synthesis of N-(2,5-dimethoxy-4-methylphenetyl)hydroxylamine, the N-hydroxy homolog of DOM, is also reported. Brief reference is made to the preliminary pharmacology of these compounds.Experimental:1-(2,5-dimethoxyphenyl)-2-nitropropene-1:A solution of 2,5-dimethoxybenzaldehyde (10.0 g), ammonium acetate (4.0 g), and nitroethane (6.8 g) in glacial acetic acid (50 ml) was heated on a boiling water-bath for 3 h, then the solvent was evaporated. The residue which remained was suspended in water and extracted with chloroform. Evaporation of the chloroform left the title compound (11.2 g). Crystallization from ethanol gave m.p. 73-75°; no lit. [12] m.p. reported; i.r. v max 1300, 1502 (NO2), 1645 (C=C) cm-1.
1-(2,5-dimethoxyphenyl)-2-aminopropane HCl:A solution of 1-(2,5-dimethoxyphenyl)-2-nitropropene-1 (17.0 g) in dry ether (500 ml) was added slowly to a stirred suspension of lithium aluminum hydride (12.0 g) in the same solvent (150 ml). When the addition was complete the mixture was refluxed for 20 h, cooled, and the excess lithium aluminum hydride was decomposed by the careful addition of water. The resulting suspension was filtered and the solid which was removed was washed with ether. The combined ether solutions were dried (MgSO4), then saturated with dry hydrogen chloride. This precipitated the title compound (16.3 g), m.p. 114-116° (from ethanol); lit. [13] m.p. 111.5-112.5°; i.r. Vmax 1600; 2000-2550 (weak bands) (N-H) cm-l.
N-Acetyl-1-(2,5-dimethoxyphenyl)-2-aminopropane (5):Acetic anhydride (40 ml) was added to a solution of 1-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (5.0 g) and sodium acetate (25.0 g) in water (300 ml) and the mixture was shaken vigorously until the exothermic reaction ceased. The cooled solution was filtered and gave the title compound (4.2 g), m.p. 104-105.5° when crystallized from ethanol. The i.r. V max 1635 (C=O); 3100 (NH) cm-l.
N-Acetyl-1-(2,5-dimethoxy-4-nitrophenyl)-2-aminopropane (6):A solution of 70% nitric acid (50 ml) in water (400 ml) was added to a solution of N-acetyl-1-(2,5-dimethoxyphenyl)-2-aminopropane (40.0 g) and sodium nitrite (0.5g) in glacial acetic acid (400 mi). The solution was stirred for 4 h, cooled, then diluted with water (400 ml). The title compound (42.1 g) precipitated and, when crystallized from ethanol, had m.p. 166-168°. The i.r. vmax 1350, 1515 (NO2); 1640 (C=O); 3310 (NH) cm-1.
N-Acetyl-1-(4-amino-2,5-dimethoxyphenyl)-2-aminopropane HCl (7):A solution of N-acetyl-1-(2,5-dimethoxy-4-nitrophenyl)-2-aminopropane (39.0 g) in ethanol was hydrogenated over 10% palladium-charcoal (1.0 g) until the theoretical amount of hydrogen was absorbed (3 days). The catalyst was removed and the filtrate evaporated. The residue was suspended in 5% sodium hydroxide solution (100 ml) and extracted with chloroform (3 x 100 ml). The combined chloroform solution was evaporated and the solid which remained was dissolved in dry ether. When dry hydrogen chloride was passed through this solution, the title compound (31.5 g) precipitated. It had m.p. 237-239° when crystallized from ethanol-ether. The i.r. Vmax 1635 (C=O); 2450-2600 (weak bands} (N-H) cm-l.
N-Acetyl-1-(4-chloro-2,5-dimethoxyphenyl)-2-aminopropane (8a):A solution of N-acetyl-1-(4-amino-2,5-dimethoxyphenyl)-2-aminoprorane hydrochloride (5,0 g) in hydrochloric acid (15 ml) and water (30 ml) was cooled to O°. To this stirred solution, sodium nitrite (1.4 g) in water (10 ml) was slowly added with cooling. This cold solution of diazonium salt was added slowly with shaking to a solution of cuprous chloride (2.5 g) in hydrochloric acid (9 ml). The reaction mixture was allowed to come to room temperature, then heated to 70° and cooled. The title compound (2.8 g) precipitated. It gave a m.p. 150-152°C when crystallized from ethanol, The i.r, vmax 1630 (C=O); 3310 (NH) cm-1.
N-Acetyl-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (8b):The diazonium salt of 7 (5.0 g) was prepared as described immediately above and to the cooled (0°) solution was added gradually a solution of potassium iodide (8.0 g) in water (10 ml). The reaction was allowed to warm to room temperature and left until the evolution of nitrogen ceased. The dark brown viscous semi-solid which separated was dissolved in ethanol. On cooling, the title material (1.97 g) separated. It had a m.p. 167-168° when crystallized from ethanol. The i.r. vmax 1645 (C=O); 3310 (NH) cm-1.
N-Acetyl-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (9):A slight excess or bromine water was added to a solution of N-acetyl-1-(2,5-dimethoxyphenyl)-2-aminopropane (3.0 g) in dioxane (30 ml), and the solution was stirred for 6 h. The solvent was removed, leaving the title compound (3.0 g) which was crystallized from ethanol and had a m.p. 153-155°. The i.r. vmax 1630 (C=O); 3310 (NH) cm-1.
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane HCl (1e)(a) A suspension of N-acetyl-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (2.5 g) in hydrochloric acid (60 ml) and water (60 ml) was heated at reflux temperature for 18 h during which time most of the N-acetyl compound dissolved. Unreacted starting material was removed and the filtrate evaporated to give a yellow solid (1.7 g). Crystallization from ethanol-ether gave the title compound as a colorless solid, m.p. 195-196°. Reported [7] m.p. 198-199°.
(b) N-Acetyl-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminoprorane (1.5 g) was added to a solution of sodium hydroxide (5.0 g) in water (25 ml) and ethylene glycol (50 ml) and the mixture was heated under reflux for 15 h then cooled. The solution was extracted with chloroform and the combined chloroform extracts evaporated. The resulting solid was dissolved in 5% hydrochloric acid (15 ml) and the solution filtered. The title compound (0.85 g) was the product obtained, m.p. 197-198° after crystallization from ethanol-ether. The i.r. vmax 1610, 1980, 2010-2740 (N-H) cm-1.
1-(4-Chloro-2,5-dimethoxyphenyl)-2-aminopropane Hydrochloride (1f):The title compound (0.46 g), m.p. 193-194.5 (from ethanol-ether) was obtained when N-acetyl-1-(4-chloro-2,5-dimethoxyphenyl)-2-aminopropane (1.5 g) was treated as described for the synthesis of 1e, method b. The i.r. vmax 1610, 2010, 25OO-2640 (N-H) cm-1.
1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane Hydrochloride (1g):The title compound (0.75 g), m.p. 198-200° (from ethanol-ether) was prepared from N-acetyl-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1.5 g) using method b procedure for the synthesis of compound le. The i.r. vmax 1605, 2000, 2500-2710 (N-H) cm-1.
1-(2,5-Dimethoxy-4-nitrophenyl)-2-aminopropane Hydrochloride (1h):Hydrolysis of N-acetyl-1-(2,5-dimethoxy-4-nitrophenyl)-2-aminopropane (2.0 g) using procedure b for the synthesis of compound le gave the title compound (0.76 g), m.p. 203-204° when crystallized from ethanol-ether. The i.r. vmax 1340, 1520 (NO2); 1610, 2000, 2500-2610 (N-H) cm-1.
1-(4-Amino-2,5-dimethoxyphenyl)-2-aminopropane Dihydrochloride (1i) (inactive):
A solution of 1-(2,5-dimethoxy-4-nitrophenyl)-2-aminopropane hydrochloride (1 g) in ethanol (25 ml) and hydrochloric acid (2 ml) was hydrogenated over 10% palladium-charcoal (0.1 g) until the theoretical amount of hydrogen was absorbed. The catalyst was removed and the filtrate evaporated to give a solid (0.92 g) which when crystallized from ethanol-ether gave the title compound, m.p. 248-250°. The i.r. vmax 1610, 2010, 2500-2610 (N-H) cm-1.