DOM analogs (Can J chem 51 1402 1973)

[Chimimanie]

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.

[Chimimanie]

2,5-dimethoxy-4-nitrophenylacetone (12):

To a solution of 2,5-dimethoxyphenylacetone (4.0 g) and sodium nitrite (0.03 g) in glacial acetic acid (25 ml), stirred and cooled to 5°, was slowly added a solution of 80% nitric acid (6 ml) in water (15 ml). Stirring for 2 h, then dilution with water (100 ml) caused the precipitation of the title compound (3.71 g) which, when crystallized from ethanol, had m.p. 77-79°. The i.r. vmax 1350, 1515 (NO2); 1730 (C=O) cm-1.

1-(4-Amino-2,5-dimethoxyphenylacetone Hydrochloride (13):

A solution of 2,5-dimethoxy-4-nitrophenylacetone (3.5g) in ethanol (100 ml) and hydrochloric acid (5 ml) was hydrogenated at room temperature and normal pressure under 10% palladium-charcoal (1.0 g) until the theoretical amount of hydrogen was absorbed. The catalyst was removed and the filtrate evaporated in vacuo to give a colorless solid (3.1 g). Crystallization from ethanol-ether afforded the title compound, m.p. 195-198°. The i.r. vmax 1711 (C=O); 1980, 2550 (N-H) cm-1.

4-Acetamido-2,5-dimethoxyphenylacetone (14):

This compound (2.4 g) was prepared from the amine (13, 3.0 g) by the method described for the preparation of compound 5. The title compound, when crystallized from ethanol, had m.p. 138-140°. The i.r. vmax 1670 (amide C=O); 1710 (ketone C=O); 3390 (NH) cm-1.

4-Acetamido-2,5-dimethoxyphenylacetone Oxime (15):

A solution of 4-acetamido-2,5-dimethoxyphenylacetone (2.0 g) and hydroxylamine hydrochloride (2.0 g) in ethanol (30 ml) and pyridine (5 ml) was heated at 75° for 7 h. The solvent was removed in vacuo and water (30 ml) was added to the residue. Extraction with chloroform (3 x 30 ml) followed by evaporation of the chlorform gave a pale yellow oil which solidified (1.4 g) On triturating with ether. Crystallization from ethanol yielded the title compound, m.p. 141-144. The i.r. vmax 1660 (C=O); 3250 broad peak (OH)cm-l.

1-(4-Acetamido-2,5-dimethoxyphenyl)-2-aminopropane Hydrochloride (1j) (inactive):

A solution of 4-acetamido-2,5-dimethoxyphenylacetone oxime (1.0 g) in ethanol (50 ml) and hydrochloric acid (1.0 ml) was hydrogenated at room temperature and 50 p.s.i. pressure in the presence of platinum dioxide (0.1 g) for 14 h (arbitrary). Evaporation of the filtrate gave a solid which, when crystallized from ethanol and ether gave the title compound (0.72g), m.p. 249-250°. The i.r. vmax 1600, 2500-2700 (N-H); 1660 (C=O); 3250 (NH) cm-1.

N-(2,5-dimethoxy-4-methylphenethyl)-hydroxylamine (19):

A solution of 1-(2,5-dimethoxy-4-methylphenyl)-2-nitroethane (1.5 g) in ethanol (50 ml) and water (10 ml) was stirred with ammonium chloride (1.5 g) and zinc powder (1.5 g) for 30 min, then heated under reflux for 5 min. The suspension was cooled and filtered and the filtrate basified with 5% sodium bicarbonate solution (50 ml) then extracted with chloroform (3 x 100 ml). The combined extract was saturated with dry hydrogen chloride and evaporated. The solid residue was treated with water (100 ml) and filtered. The filtrate was basified with ammonium hydroxide solution and extracted with chloroform (100 ml). The chloroform extract was washed with water, saturated with hydrogen chloride, and evaporated to give a solid (0.52g) which when crystallized from ethanol-ether yielded the title compound as the hydrochloride, m.p. 137-138°. The i.r. vmax 1610, 2510-2750 (N-H) cm-1; mass spectrum: 211 (10) (C10H17NO3) m/e (% relative abundance).

ref:

[7] Barfknecht and Nichols, J med Chem 14, 370 (1971) -

Post 453897 (missing)

(weedar: "J. Med. Chem. 14(4), 370-372 (1971)", Methods Discourse)
[12]

Patent FR1496706

and chem. abstr. 69, 36445n (1968)
[13] B.T. Ho, McIsaac, R. An, Tansey, Walker, Englert and Noel, J Med Chem 13, 26 (1970)

[pHarmacist]

This is very interesting. N-OH should be as active as nor-OH so to say. Thank you Chimimanie and keep it up, good work!

[Chimimanie]

I was still editing my post! FAST reply!

Yes it is cool, I always hoped to have an easy way to HOB, now it is, the yield is a bit shitty, you have to chose between legality or quantity.


...I choose legality

[Kinetic]

I choose legality too, but remember that N-OH PEA's are generally quite unstable, and can decompose to give illegal PEA's! There was a case a few years back in the UK where this exact situation occured, and although I don't know the method used to produce the analogues,

Post 324207 (missing)

(obia: "UK analogues", Law and Order) regarding N-OH 2C-B and DOM shows how careful you must be; it makes an interesting (although rather depressing) read.

Very interesting post though; I have been interested in making N-OH analogues for some time now, but haven't got round to doing it yet.

[moo]

Please rate the abovementioned post by obia excellent, as Nemo_Tenetur suggested in that thread!

[Rhodium]

obia's post has been rated.

As for the nomenclature, I propose DOHM/DOHB etc for the N-OH DOX compounds - short and understandable.

[Barium]

When making a N-OH compound by reducing a R-NO₂ with NH₄Cl/Zn I´m certain that some -NH₂ is formed too. Since it´s impossible to remove all the amine from the N-OH no matter how careful you are you would still posess a regulated compound. In other words; they would still be able to fuck you.

[Kinetic]

... What I was trying to say!  

What we need now is a sure-fire way to produce N-OH and only N-OH analogues... I haven't checked TFSE yet, but I have just discovered the delights of Beilstein, so if anything useful turns up there I'll post it.

If there is a way to produce pure N-OH 2C-B from 1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethane or 1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethene I'll be a very happy bee indeed!

[Barium]

If there is a way to produce pure N-OH 2C-B from 1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethane or 1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethene

Reducing the aliphatic nitro group to R-NH-OH will give you some amine no matter how you do it. One can also reduce the oxime (R=N-OH) to the N-hydroxy amine (R-NH-OH). I´m leaning more towards the latter method since we have very selective catalysts nowdays. Most likely this selective catalyst will be found among the homogenous catalysts. Another possibility is to use borane in some form. 

[moo]

Even if you do it electrolytically with a controlled potential electrolysis setup?

Edit: Or does the hydroxylamine disproportionate into the amine and the oxime under certain conditions? Obia's post gives me that kind of impression.

[Chimimanie]

Another possibility is to use borane in some form.

Barium, are you saying that Shulgin's way to get the hydroxy-compounds from the nitrostyrenes, stirring borane/dimethylsulfide for a week like in

http://www.erowid.org/library/books_online/pihkal/pihkal087.shtml

selectively reduce to the hydroxyamines and no amines are formed this way (in contrast with the NH4Cl/Zn method); or are you speaking about reduction of the oxime with diborane?

Also, isn't it anyway to remove the formed 2C-H from the HOH? like two or three consecutive careful recristallisations? when there is still a step after the hydroxy-amine to do like the bromination step for HOB, it doesn't matter if some amine are formed before the bromination, because this amine is the still legal 2c-h. For the others compounds like hydroxy-mescaline for instance, it is another story...

Also if its an artefact of the synthesis and we didn't want this compound (the amine) but the aim was the hydroxy-amine, it is considered an impurity and I think there are some law which deal with the case of the accidental/unwanted manufacture of a controlled substance. It seem to me that the defense in obia's post mentioned in this thread was based on this. Poor guy

[Rhodium]

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, 1402-1409 (1973)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/coutts-malicky-1.pdf)

Abstract
The synthesis of a series of 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes, in which the 4-substituent is Br, CI, 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-methylphenethyl)hydroxylamine, the N-hydroxy homolog of DOM, is also reported. Brief reference is made to the preliminary pharmacology of these compounds.
____ ___ __ _

The Synthesis of Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM). II. Some Ring-methoxylated 1-Amino- and 2-Aminoindanes
Ronald T. Coutts and Jerry L. Malicky

Can. J. Chem. 52, 381-389 (1974)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/coutts-malicky-2.pdf)

Abstract
The synthesis of 2-amino-4,7-dimethoxy-5-methylindane (12a), the cyclic analog of the known hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), is described. The key intermediate was trans-2-amino-4,7-dimethoxy-6-methyl-1-indanol (trans-10a) which was converted to 12a in two ways. The prolonged action of hydrochloric acid on trans-10a gave 4,7-dimethoxy-5-methyl-2-indanone (11d), the oxime of which, on catalytic reduction, was converted to 12a in low yield. A direct catalytic reduction of trans-10a in the presence of hydrochloric acid also gave 12a, together with cis-2-amino-4,7-dimethoxy-6-methyl-1-indanol (cis-10a). The synthesis and properties of other derivatives of 2-aminoindane, and some derivatives of 1-aminoindane are also described.
____ ___ __ _

The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM). III. Some Derivatives of 3-phenylalanine
Ronald T. Coutts and Jerry L. Malicky

Can. J. Chem. 52, 390-394 (1974)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/coutts-malicky-3.pdf)

Abstract
Syntheses of the hydrochlorides of 3-(2,5-dimethoxyphenyl)alanine, 3-(2,5-dimethoxy-4-methylphenyl)-alanine, and 3-(4-bromo-2,5-dimethoxyphenyl)alanine are described. A phenol, C₁₀H₁₄ClNO₄, related to the second of these three compounds was also prepared and is concluded to be a monohydrate of the lactone, 3-amino-6-hydroxy-7-methylhydrocoumarin hydrochloride.
____ ___ __ _

The Synthesis of Four Possible in vitro Metabolites of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM)
Ronald T. Coutts and Jerry L. Malicky

Can. J. Chem. 52, 395-399 (1974)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/coutts-malicky-4.pdf)

Abstract
The synthesis of four possible in vitro metabolites of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyll-2-aminopropane (DOM) is described. These compounds, 1-(2,5-Dimethoxy-4-methylphenyl)-2-propanone, the corresponding oxime, 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone, and 1-(2,5-dimethoxy-4-methylphenyl)-2-(hydroxylamino)propane, could be products of side chain metabolic oxidation of DOM.