Author Topic: 2,5-dimethoxy-4-methylthiobenzaldehyde  (Read 1688 times)

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  • Guest
« on: March 28, 2003, 05:44:00 AM »
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...  :(

Edit: Full article in

Post 495328

(Rhodium: "Nichols & Shulgin: Synthesis of Aleph and 2C-T", Novel Discourse)


  • Guest
I think I have seen Shulgin use this method a...
« Reply #1 on: March 28, 2003, 06:47:00 AM »
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


  • Guest
« Reply #2 on: March 28, 2003, 01:45:00 PM »
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.


  • Guest
>Although dichloromethyl methyl ether is...
« Reply #3 on: March 30, 2003, 07:55:00 AM »
>Although dichloromethyl methyl ether is carcinogenic, I'm pretty sure that bis-chloromethyl ether is much more so than alpha,alpha-dichloromethyl methyl ether



"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.


  • Guest
Nichols & Shulgin: Synthesis of Aleph and 2C-T
« Reply #4 on: March 15, 2004, 11:34:00 AM »
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.