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All 6 posts   Subject: 2,5-dimethoxy-4-methylthiobenzaldehyde   Please login to post   Down

(Hive Addict)
03-28-03 13:44
No 421991
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(Rated as: excellent)

I was reading this Nichols & Shulgin article today about the synthesis of 2,5-dimethoxy-4-methylthiobenzaldehyde, and found something I was unfamiliar with.

Sulfur analogs of psychotomimetic amines
DE Nichols, AT Shulgin
J Pharm Sci 65(10) (1976) 1554-1555

[...]2,5-dimethoxy-4-methylthiobenzaldehyde (IX) - The aldehyde was prepared using the method of Rieche et al. 1. A solution of 6.07 g (0.033 mole) of VIII [2,5-dimethoxymethylthiophenol] in 40 mL of dry DCM under nitrogen was cooled in an ice bath. To the solution was added 13.02 g (0.05 mole) of stannic chloride over 2 min. Dichloromethyl methyl ether, 3.45 g (0.03 mole), was then added dropwise over 5 min, and stirring was continued with ice bath cooling for 15 min. The reaction was allowed to warm to room temperature over 30 min and was stirred for an additional 1 h, at which time hydrogen chloride evolution had ceased.
Then the mixture was slowly poured onto 15 g of ice in a separator, and the aqueous layer was separated and discarded. The organic phase was washed with 3 x 25 mL of 3 N HCl and 3 x 25 mL of saturated sodium chloride solution and dried (sodium sulfate), and the solvent was removed in vacuo. The solid residue was dissolved in methanol, filtered, and recrystallized from methanol-water to give 5.86 g (92%) of yellow needles. TLC (silica gel, chloroform) showed only one product. An analytical sample was further purified via the sodium bisulfite adduct and recrystallized from methanol-water, mp 99-100°[...]

1. A Rieche, H Gross and E Hoeft. Org Syn 47(1) (1967)

Preparation of the PEA and the amphetamine occurs in the "traditional" Shulgin way, with nitromethane/ethane and LAH. What fascinated me here was the application of the Rieche formylation. I have never seen it applied in PEA synthesis. Even more, I was actually forgotten this benzaldehyde synthesis method existed. The only thing I don't like about it is the price of dichloromethyl methyl ether... frown

Edit: Full article in Post 495328 (Rhodium: "Nichols & Shulgin: Synthesis of Aleph and 2C-T", Novel Discourse)

The faster you run, the quicker you die.
(Hive Bee)
03-28-03 14:47
No 421997
      I think I have seen Shulgin use this method a...     

I think I have seen Shulgin use this method a lot in the past. Just searching pihkal for "dichloromethyl" I get the following hits


> The only thing I don't like about it is the price of dichloromethyl methyl ether...

I seem to recall it is very carcinogenic. Probably just as carninogenic as the chloro methyl ether formed in chloromethylation.

But it's a curious reaction, given the normal chloromethyl product of these types of chlorinated methyl ethers
(Hive Bee)
03-28-03 21:45
No 422084

Although dichloromethyl methyl ether is carcinogenic, I'm pretty sure that bis-chloromethyl ether is much more so than alpha,alpha-dichloromethyl methyl ether. Both can be used for formylations, but luckily the former (and more carcinogenic) isomer gives lower yields; 55% compared to 90% for the formylation of dihydrobenzofuran.

The price of either is also incredibly high, most likely because not many people use this formylation method: they would be easy to produce on a commercial scale for far less than they sell for. I don't want to crosspost, so I won't ask for anyone to comment on my recent (30 minutes ago) post in Serious Chemistry on the possible synthesis of alpha,alpha-dichloromethyl methyl ether.
(Hive Bee)
03-30-03 14:55
No 422491
      >Although dichloromethyl methyl ether is...     

>Although dichloromethyl methyl ether is carcinogenic, I'm pretty sure that bis-chloromethyl ether is much more so than alpha,alpha-dichloromethyl methyl ether

Well. (http://)

"Numerous epidemiological studies [ref: 1-9] and case reports [ref: 10-13] from around the world have demonstrated that workers exposed to chloromethyl methyl ether and/or bis(chloromethyl)ether have an increased risk for lung cancer. Among heavily exposed workers, the relative risks are ten fold or more."

Doesn't sound all that nice to me. I'm not that crazy about cancer, but if one ultimately had to use something like this, I think I'd prefer that method mentioned by Post 382264 (Antoncho: "Zealot: azomethinic (Haack) formylation", Novel Discourse) where the carcinogens are at least only made in situ, or just simple chloromethylation/oxidation. Also, I don't think that tin is so good for the environment.
(Chief Bee)
03-15-04 19:34
No 495328
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      Nichols & Shulgin: Synthesis of Aleph and 2C-T
(Rated as: excellent)

Sulfur Analogs of Psychotomimetic Amines
David E. Nichols and Alexander T. Shulgin
J. Pharm. Sci. 65(10), 1554-1555 (1976) (

The syntheses and physical properties are described for 2,5-dimethoxy-4-methylthiophenylethylamine and 2,5-dimethoxy-4-methylthiophenylisopropylamine. The latter compound is the sulfur analog of the psychotomimetic phenylisopropylamines 2,4,5-trimethoxyphenylisopropylamine and 2,5-dimethoxy-4-methylphenylisopropylamine wherein the methylthio group replaces a methoxy group or a methyl group, respectively. This compound is predicted to be about 30 times as active as mescaline.

The Hive - Clandestine Chemists Without Borders
(Chief Bee)
11-11-04 04:24
No 540963
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      Shulgin: Sulfur analogs of psychotomimetic agents
(Rated as: excellent)

Sulfur Analogues of Psychotomimetic Agents. 1.
Monothio Analogues of Mescaline and Isomescaline

Peyton Jacob III and Alexander T. Shulgin
J. Med. Chem. 24, 1348-1353 (1981) (

Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3- and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.
____ ___ __ _

Sulfur analogs of psychotomimetic agents. 2.
Analogs of (2,5-dimethoxy-4-methylphenyl)- and of (2,5-dimethoxy-4-ethylphenyl)isopropylamine

Peyton Jacob, , III Alexander T. Shulgin
J. Med. Chem. 26(5), 746-752 (1983) (

The two thio analogues of each of the well-known psychotomimetic drugs DOM [(2,5-dimethoxy-4-methylphenyl)isopropylamine] and DOET [ (2,5-dimethoxy-4-ethylphenyl)isopropylamine] have been synthesized and pharmacologically evaluated in man. The 5-thio isomers are more potent as psychotomimetic agents than the 2-thio isomers but still represent a drop of an order of magnitude in potency from the sulfur-free counterparts. The dithio analogue of DOM was synthesized and found to be without central activity at a dosage of ~50 times the mean effective dose of DOM.
____ ___ __ _

Sulfur analogs of psychotomimetic agents. 3.
Ethyl homologs of mescaline and their monothioanalogs

Peyton Jacob, , III Alexander T. Shulgin
J. Med. Chem. 27, 881-888 (1984) (

All possible monothio analogues of the mono-, di-, and triethoxy homologues of mescaline have been synthesized and pharmacologically evaluated in man. Modifications at the ring position para to the ethylamine chain, either with a sulfur atom, a longer alkyl chain, or both, lead to compounds of high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also synthesized and pharmacologically evaluated. The propyl homologues retain high potency, but a butyl group (either with or without a sulfur atom) leads to a decrease in activity. The m-ethyl or m-thio analogues retain some central action but the diethoxy and especially the triethoxy homologues are relatively inactive as psychotomimetic drugs.

The Hive - Clandestine Chemists Without Borders

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