Author Topic: Two new DOM analogs made and evaluated  (Read 1870 times)

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Rhodium

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Two new DOM analogs made and evaluated
« on: February 05, 2004, 09:11:00 PM »
Synthesis and 5-HT2A Radioligand Receptor Binding Assays of DOMCl and DOMOM, Two Novel 5-HT2A Receptor Ligands
Antje Harms, Ernst Ulmer, Karl-Artur Kovar

Archiv der Pharmazie, Volume 336, Issue 3, 155-158 (2003)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/domcl-domom.pdf)
DOI:

10.1002/ardp.200390014



Abstract
A synthesis of two new active substances, DOMCl (1-(4-chloromethyl-2,5-dimethoxyphenyl)-2-propanamine (2)  and DOMOM (1-(2,5-dimethoxy-4-methoxymethylphenyl)-2-propanamine (3), was developed. Unexpectedly, the Blanc reaction permitted successful synthesis of 2,5-dimethoxyphenylpropylamine derivatives having a substituted methyl group in position 4 since solvation of the reactant occurs during the reaction. Afterwards, their affinities towards the 5-HT2A receptor were examined in 5-HT2A radioligand receptor binding assays. The study of these substances is of considerable interest because they were predicted, by preliminary molecular modeling studies based on mescalin units, to be potential new hallucinogens that should be added to the list of substances prohibited by law. It was assumed that DOMCl would be 82 times more potent as a hallucinogen than mescalin, and DOMOM would be 94 times more potent. The 5-HT2A radioligand receptor binding studies showed that the affinities of DOMCl and DOMOM for the 5-HT2A receptor are less than expected but are nevertheless 1.6 and 8.7 times higher, respectively, than that of mescalin. Therefore, scheduling these substances as potential drugs of abuse might be considered.


Lilienthal

  • Guest
Abusing those idiots might be considered :-S
« Reply #1 on: February 05, 2004, 11:38:00 PM »
Abusing those idiots might be considered  ::)

hypo

  • Guest
no violence, please ;)
« Reply #2 on: February 06, 2004, 10:09:00 AM »
the irony is that practically every compound in this class would have
2-100 mescaline units, wouldn't it? why synth them at all?


Rhodium

  • Guest
They're just trying to top Glennon...
« Reply #3 on: February 06, 2004, 10:43:00 AM »
Well, because it is the first examples this far of a -CH2X group in the 4-position where X is something else than C or H...

I'd say it's a very interesting finding (even though the research motivations given above was the stupidest thing I've read in a phenethylamine abstract since Glennon forced newly hatched chickens to ingest 2C-B/MDMA so that he could distinguish entheogens from entactogens by observing the various spasms and odd behavious the poor critters displayed...)


Bandil

  • Guest
What a nice molecule 8-) !
« Reply #4 on: February 06, 2004, 01:02:00 PM »
What a nice molecule  8) !

Any idea on how a R-CH2Br version would compare to the chloro version potency wise? My immediate guess would be that it ought to be less potent (with R-CF3 being somewhat more potent).

Anyhow, i would really like to try out this method on some DMA and a bromomethylation ala

Post 475109

(Lego: "Amphetamines/PEAs w/o benzaldehyde or nitroethane", Novel Discourse)
(bromomethylations are preferred as my current religion does not approve of chloromethylations). Shouldn't be very diffucult.

Regards
Bandil


GC_MS

  • Guest
DOM-X
« Reply #5 on: February 06, 2004, 02:53:00 PM »
What a coincidence... I discussed this class of substances (DOMCl, DOMBr, DOMI) with a colleague, even not that long ago  :) .

Concerning the comment on putting this substance on the Lists, it should be noted that these articles usually have to pass reviewers. I wouldn't be surprised if there has been a fervent puritan reviewer pressing to add this comment. Note that this article has been written by ppl from the pharmaceutical industry. Ever seen a pharmacist not on drugs?  ;D  Anyway, it still is possible they added the comment themselves, but as been noted, it sounds rediculous.

Also, it rather suprises me that the amine doesn't condense with formaldehyde. I guess I should give it a try...

Bandil, don't forget about iodomethylation  ;) .


moo

  • Guest
A potential risk?
« Reply #6 on: February 06, 2004, 02:57:00 PM »
In theory the halomethyl group could alkylate eg. DNA when ingested and have carcinogenic properties, couldn't it? I don't really know - what do you think?


Rhodium

  • Guest
Or why not a bis(2-chloroethyl)amino group? ;-)
« Reply #7 on: February 06, 2004, 03:35:00 PM »
I would personally not ingest something which could stick an ugly halomethyl group right into my serotonin receptors. I'd definitely settle for DOMOM...


Osmium

  • Guest
> I would personally not ingest something...
« Reply #8 on: February 06, 2004, 06:00:00 PM »
> I would personally not ingest something which could stick an
> ugly halomethyl group right into my serotonin receptors.

So the molecule goes into the receptor, but will it come out again voluntarily or firmly implant itself onto the nitrogen it will meet there?


Lego

  • Guest
Academic crap?
« Reply #9 on: February 06, 2004, 06:36:00 PM »

Moreover, the resulting benzyl halide 2 (DOMCl) is reactive and unstable against bases. Therefore it is essential to perform the synthesis in one step



Aha, this compound will never bee ingested as a hallucinogen. If it does not survive the in-vitro conditions it will not even survive the in-vivo conditions. It is unstable against bases so if it is taken orally it might not bee hydrolysed in the acidic stomach but from there it will not bee absorbed. In the more basic areas of the intestinum where basic drugs are absorbed it will react with any base to form some pharmacological crap. This more a carcinogen than a hallucinogen.


To a solution of NaOCH3, prepared by addition of sodium metal (0.2 g, 8.7 mmol) and methanol (30 mL), was added 2 HCl (1.5 g, 5.4 mmol).
[...]
Yield 0.8 g (24 %)




5.4 mmol hydrochloride are added to 8.7 mmol NaOCH3. The methoxide will first react with the ammonium group forming MeOH and R-NH2. 2.7 mmol NaOCH3 are left which is only half the amount of the amphetamine.
Does anybee understands this?  ::)


Another strange point in this article is that the authors do not mention whether the compounds are agonists or antagonists at the 5HT2 receptor. This makes a big difference, a ligand is not necessarily a drug.




Nicodem

  • Guest
DOMCl is useless but its friends are not!
« Reply #10 on: February 07, 2004, 07:19:00 PM »
I agree, DOMCl is useless. It would not survive more than a few minutes in vivo. It would most probably bind already to the tongue giving you a nasty-bitter-toxic taste for days, just like the benzylchloride vapors do  ::) . It looks like one of those ugly irreversible ligands having the azido or isotiocianide group that binds to the first nucleophile (like a receptors amino acid residue) they aproach.

However, there is a halogen, unlike Cl, Br or I that could serve well on that position. If I remember well the fluoride ion can easily substitute that banzylic chloride in certain conditions (glycol of glycerin solution?). So, what about DOMF?
Its synthesis looks easy if only there would be a way to avoid protecting the amino group and still have a decent yield without to much self condensation of DOMCl. But even if the amino group should be protected it should still be easier to prepare than its older brother DOTFM.
There are other things that would like to be there instead of chlorine, even if their metabolic resistance is not as good as it would be for DOMF (I think benzylmethyl ethers are also metabolically instable). Maybe a thio analogue of DOMOM; should it be DOMSM?
I think DOMCl might open a whole new range of “potential new hallucinogens that should be added to the list of substances prohibited by law” (I almost can’t believe a scientist would write something like that, except maybe for fond raising  :o ).

5.4 mmol hydrochloride are added to 8.7 mmol NaOCH3. The methoxide will first react with the ammonium group forming MeOH and R-NH2. 2.7 mmol NaOCH3 are left which is only half the amount of the amphetamine.
Does anybee understands this?


It is even worse than that. They even miscalculated the yield. 0.8g would be 54% and not 24%! If they are so lousy in calculations I would not be surprised if they also miscalculated the amount of Na needed. Given that the amount of methoxide left was only 3.3mmol instead of at least 5.4mmol the reaction gives a yield of 87% based on the aviable methoxide, which is not bad at all. Especially considering that the remaining freebase DOMCl’s amine group could also act as a nucleophile. Indeed I’m puzzled by the fact that it did not. Why they didn’t get some tar in addition of DOMOM? Or was that “yellow fraction” actually the self-condensation product? Really weird.


azole

  • Guest
methylthiomethylation
« Reply #11 on: February 09, 2004, 07:15:00 PM »
This is an old story, almost forgotten. After reading some reviews on sulfur chemistry, SWIM became convinced that by reacting the N-phthalimido derivative of 2,5-DMA with MeSCH2Cl in nitromethane in the presence of a Lewis acid (SWIM chose ZnCl2 for the 1st try), it is possible to obtain DOMTM-NPhth. Incidentally, SWIM had some chloromethyl methyl sulfide (MTM-Cl) and 2,5-DMA-NPhth.

DOMTM-NPhth
   Indeed, when freshly distilled (awful stench!) MTM-Cl (4.5 eq.) was added to the solution of 2,5-DMA-NPhth and ZnCl2 (1eq.) in nitromethane at rt, HCl began to evolve, and after 1/2 h at rt the reaction was stopped by adding PhMe and aq. NaHCO3 to the mixture. The organic layer was separated and the aqueous layer was extracted several times with PhMe to remove the traces of the product trapped in the suspension of Zn carbonate. The combined extracts were dried by filtering through a pad of the mixture of silica gel with Na2SO4 and evaporated. After column chromatography (gradient elution, hexane - benzene 2:3 v/v --> EtOAc - benzene 1:3 v/v) and crystallization (probably EtOAc-hexane or CHCl3-MeOH, no notes were kept), approx. 50% yield of the product was obtained.
   Its Rf was identical to that of the starting compound in several eluents tested. However, specially prepared TLC plates could be used to follow the course of the reaction. A solution of AgNO3 in a minimum volume of water was diluted with MeOH to achieve 3 g/100 ml concentration. TLC silica plates (glass) were impregnated with this solution for 1/2 h, and the excess of it was removed using a filter paper. After drying in a vacuum, the plates were kept protected from light. On such plates, the Rfs of the compounds containing divalent sulfur (mercaptans, sulfides or thioacetals) are considerably lower than on common TLC plates, while the Rfs of the compounds which cannot form stable complexes with silver remain largely unaffected.

DOMTM hydrochloride
   Then DOMTM-NPhth was dissolved in hot 95% EtOH. Hydrazine monohydrate (1/10 by volume) was added, and the mixture was refluxed under argon for 3h. After evaporation, the residue was distributed between PhMe (which don't extract hydrazine) and 10% aq. Na2CO3 (which dissolves phthaloyl hydrazide), the organic layer was separated, and the aqueous layer was extracted with PhMe several times. The combined extracts were evaporated, and the residue was purified by a/b extraction. Crystalline hydrochloride was obtained in high yield (details forgotten).

   SWIM dared to biotest the compound only up to 1 mg level. At this dosage, there was slight tinnitus, emotional instability, and an unpleasant feeling in the stomach. So, by these rather doubtful results SWIM can suggest that the  substance doesn't have the potency of DOB or DOEt (which SWIM found definitely active at this level).

DOMTM --> DOMTM-NHAc --> DOM-NHAc
   The next idea was to convert DOMTM to DOM by desulfurization on Raney nickel. SWIM realized that with an unprotected amine, there might be formation of complexes with nickel, and possibly oxidative deamination or formation of secondary amines. To avoid these potential difficulties, the amino group was acetylated with Ac2O/Et3N. The acetamide was a crystalline solid, individual by TLC. After desulfurization (3 h refluxing in EtOH with large excess of Raney Ni), no remarkable change in Rf was observed. Again, AgNO3-impregnated silica plates had to be used to follow the course of the reaction. The spots were visualized by spraying with 1:1 v/v aq. H2SO4 and heating on a hotplate.
The product was crystalline, too.

The hydrolysis of DOM-NHAc (failed attempt)
   The attempt to hydrolyse the acetamido group by refluxing the amide in 20% aq. HCl was completely unsuccessful. The reaction is extremely slow. After perhaps 24 h refluxing and subsequent evaporating the mixture, some amide still remained unchanged. It is insoluble in water, and was removed by filtration. After the aq. solution of the supposed DOM hydrochloride had been made basic, a violet coloration began to evolve. SWIM ended up with some 30 mg of very dark hydrochloride crystals (from 120 mg of the amide). :(

   A bunch of methylthiomethylation references will be posted soon.

Nicodem

  • Guest
Azole, that's a nice and ingenious synth
« Reply #12 on: February 09, 2004, 11:42:00 PM »
Azole, that's a nice and ingenious synth of DOMTM (I never thought of any methylthiomethylation before). To bad it isn't nice on the stomach (like many other thio cmpnds), but did you had the impression that it might be a psychedelic at a higher dose?
Your post also made think again of DOMCl. Maybe I took the outrageous political background of the paper too personally, but I took it as a challenge to use their research against their ugly motives. So, I thought of this: Could the reaction they used for DOMCl be used for the synthesis of DOM, maybe even without isolating the DOMCl intermediate, simply by adding SnCl2×2H2O at the end of the chloromethylation (see

Post 486611

(Rhodium: "Reference #5: C-Methylation of Vanillin", Novel Discourse)
). Well, I was just about to post this and I read that Bandil already had almost the same idea (see

Post 487517

(Bandil: "Novel DOM synthesis", Novel Discourse)
). It keeps on surprise me all the time how syncronised the Bees are  :-[ . (However, Bandil forgot that the DOMBr just like DOMCl must not be free-based and to choose the reducing agent appropriately to this.)

BTW, does anybody understand their rationalization on how the clorobenzene solvent helped them avoiding the Pictet-Spengler rxn, yielding DOMCl instead of the isoquinoline?

Does anybody know anything at all about DOMF (4-flouromethyl-2,5-diMeO-amphetamine)? By simple extrapolation it should be more active than DOM and less than DOTFM (maybe at 2mg?).


Rhodium

  • Guest
I've also been thinking about DOMF, but...
« Reply #13 on: February 09, 2004, 11:55:00 PM »
It seems like 2,5-dimethoxybenzyl fluorides have a tendency to decompose easily:

J. Fluorine Chem. 35, 677-683 (1987)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/bnoh2bnf.pdf)


Rhodium

  • Guest
Another technique for Methylthiomethylation
« Reply #14 on: February 18, 2004, 03:16:00 AM »
Selective ortho-Methylthiomethylation of Phenols with Dimethyl Sulphoxide and Thionyl Chloride
Kikumasa Sato, Seiichi Inoue, and Kimio Ozawa

J. Chem. Soc. Perkin Trans. 1, 2715-2719 (1984

(https://www.thevespiary.org/rhodium/Rhodium/pdf/methylthiomethylation.pdf)

Abstract
Thionyl chloride and phenyl chlorosulphinate have been shown to be useful activators for dimethyl sulphoxide in the selective preparation of ortho-methylthiomethylphenol via a [2,3]sigmatropic rearrangement. By this process, ortho-methylthiomethylated phenols having a variety of 2- or 4-substituents (Me, Cl, OMe, NO2, and CO2Me) have been prepared in good yields. In contrast, similar reactions of 3-substituted phenols were affected by the electronic characters of the substituents. With more electron-donating groups such as OH and OMe in the 3-position, none of the expected products were obtained, but in the case of other 3-substituted phenols, two possible rearrangement products were obtained in moderate yields.


azole

  • Guest
More sulfur-containing electrophiles
« Reply #15 on: February 19, 2004, 11:39:00 AM »
Ring alkylthioalkylation with RSCHClR' - Lewis acid.

Post 423031

(GC_MS: "New, convenient route to erbstatin", Novel Discourse)


Post 439768 (missing)

(Lego: "P2Ps from benzenes by Friedel-Crafts reaction", Methods Discourse)


Ethoxycarbonylmethylthiomethylation of Aromatic Compounds by Friedel-Crafts Reaction with Ethyl alpha-(Chloromethylthio)-acetate
Y. Tamura, T. Tsugoshi, H. Annoura, H. Ishibashi
Synthesis, 1984, 326-327.



Methylation of Polysubstituted Electron-Rich Aromatics and Their Birch Reduction
James B. Hendrickson and P. Myshkin DeCapite
J. Org. Chem., 50, 2112-2115 (1985).




Methylthiomethylation with DMSO-(CF3CO)2O-SnCl4

Alkylation of Aromatic Compounds with Pummerer Rearrangement Intermediates. Application to the Preparation of Methyl-Aryl Compounds
I. K. Stamos
Tetrahedron Lett., 26(23), 2787-2788 (1985).




Methylthioalkylation with MeS(O)CHR-SMe or TolSO2CHR-SMe - AlCl3.

Novel and Effective Methods for alpha-Thioalkylation of Aromatic Compounds
Y. Torisawa, A. Satoh, S. Ikegami
Tetrahedron Lett., 29(14), 1729-1732 (1988).




Amides are N-methylated by 1) methylthiomethylation (MTM-Cl/ CF3COOH); 2) desulfurization with Raney Ni.

Simple Methylation of Amides
L. Bernardi, R. de Castiglione, and U. Scarponi
J. Chem. Soc., Chem. Commun., 1975, 320-321.




Intramolecular ring alkylsulfenylation with RSSO2Me - AlCl3 in MeNO2.

Improved Syntheses of Benzo-1,4-dithiin and of Benzo-1,4-oxathiin
J. H. Verheijen, H. Kloosterziel
Synthesis, 1975, 451-452.


Rhodium

  • Guest
The ortho-Methylthiomethylation of Phenols
« Reply #16 on: June 17, 2004, 12:31:00 PM »
The ortho-Methylthiomethylation of Phenols
P.G. Gassman & D.R. Amick

Tetrahedron Letters, No. 11, pp 889-892 (1974)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/ortho-methylthiomethylation.ncs-r2s.pdf)

Summary:
Treatment of phenols with an azasulfonium salt prepared from NCS and (CH3)2S at -25°C, followed by triethylamine gives an ylide, which via a complex cyclic rearrangement yields the corresponding o-methylthiomethyl-phenol in 60-70% overall yield on most substrates.
Methylthiomethyl functions easily undergoes reductive desulfurization with Raney-Ni to give methylbenzenes, so this is a viable route to ortho-methylphenols from phenols in two steps.




Excerpt from the article:
We now wish to report a new method for the synthesis of ortho-alkylated phenols from phenols and dialkyl sulfides. The process involves the reaction of N-chlorosuccinimide (3) with a dialkyl sulfide, to give an azasulfonium salt, 5. When phenol is added to a methylene chloride solution of an intermediate is formed, which has been assigned structure 6 on the basis of mechanistic considerations. Treatment of 6 with a base, such as triethylamine, should give the ylide 7, which would be expected to yield the dienone 8 via a Sommelet-Hauser type rearrangement. Proton transfer and accompanying rearomatization would then produce the o-methylthiomethylphenol, 2.

General procedure:
0.40 mole of N-chlorosuccinimide (3) in 2 liters of dry methylene chloride was combined with 0.50 mole of dialkyl sulfide at 0 to -5°C to give the azasulfonium salt, 5. The temperature was lowered to -25°C and 0.8 mole of a suitable phenol, 1, in 100 ml of methylene chloride was added over a 15-min period. The reaction mixture was stirred for 30 min, 0.41 mole of triethylamine was added at -25°C, and the reaction mixture was allowed to warm slowly to room temperature. Removal of the solvent and salts, and distillation of the residue gave the o-methylthiomethylphenol, 2, and also permitted recovery of any unreacted phenol.   



demorol

  • Guest
Methylthiomethylation with MeSCH2Cl/AlCl3
« Reply #17 on: October 16, 2004, 06:12:00 PM »
Superelectrophilic Methylthiomethylation of Aromatics with Chloromethyl Methyl Sulfide/Aluminum Chloride (MeSCH2Cl:2 AlCl3) Reagent
George A. Olah, Qi Wang, Gebhard Neyer
Synthesis 1994, 3, 276-278




Abstract - Effective methylthiomethylation of aromatics was achieved by using chloromethyl methyl sulfide /aluminum chloride (MeSCH2Cl:2 AlCl3) as the alkylating agent. Excess aluminum chloride activates the thiocarboxonium ion intermediate by coordinating with sulfur and thus disminishes back donation of "electron density" into the carbocationic center, rendering it a superelectrophilic methylthiomethylating agent.


Methylthiomethylation of Aromatics; Typical Procedure:
To a stirred mixture of AlCl3 (2.7 g, 20 mmol) and the corresponding arene (10.2 mmol) was added chloromethyl methyl sulfide (1.01 g, 95%, 10 mmol) in CH2Cl2 (25 mL) at 0°C. After stirring at 0°C for 30 min, the mixture was quenched with ice, and extracted with CH2Cl2 (3×20 mL), the combined organic layers were washed sequentially with water, aq NaHCO3, brine, and dried (CaCl2). After filtration and evaporation of the solvent, the products were obtained by distillation (Table 1).