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)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/domcl-domom.pdf)
DOI:10.1002/ardp.200390014 (http://dx.doi.org/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.
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 (https://www.thevespiary.org/talk/index.php?topic=11892.msg47510900#msg47510900)
(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
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.
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 (https://www.thevespiary.org/talk/index.php?topic=11797.msg48661100#msg48661100)
(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 (https://www.thevespiary.org/talk/index.php?topic=11583.msg48751700#msg48751700)
(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?).
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)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/bnoh2bnf.pdf)
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)
(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.
Ring alkylthioalkylation with RSCHClR' - Lewis acid.
Post 423031 (https://www.thevespiary.org/talk/index.php?topic=11667.msg42303100#msg42303100)
(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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
Methylation of Polysubstituted Electron-Rich Aromatics and Their Birch Reduction
James B. Hendrickson and P. Myshkin DeCapite
J. Org. Chem., 50, 2112-2115 (1985).
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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).
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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).
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
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)
(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.
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000486635-ortho-methylthiomethyl.gif)
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.
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
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/pdf.gif)
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).