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 aminesDE 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)