Hello Bees,
SWIM was recently (theoretically!) considering the possibility of making (di)bromo/iodo derivatives of the p-methoxyphenethylamine. These compounds are relatively unknown with a little info available here on Hive (...) and seem a worthy synthetic target. The chemist-wanna-bee envisioned the synthesis like this:
1) Oxidize anethole to anisaldehyde. As might bee seen in
Anise oil as para-methoxyamphetamine (PMA) precursor
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/anethole.pma.precursor.pdf), anethole doesn't have to bee isolated from anise oil which is exactly what SWIM is gonna do. The only problem is whether he should use the bichromate method from above (ca 50%, looks straightforward but K2Cr2O7 is toxic/suspicious) or the great-looking permanganate on alumina method (like here:
Post 237918 (missing)
(jim: "Simple KMnO4 method of benzaldehyde formation", Chemistry Discourse) Post 293705
(otto: "using permanganate", Chemistry Discourse) Post 511939
(Kinetic: "Cinnamic acid to benzaldehyde", Newbee Forum)). The KMnO4 procedure would bee ridiculously cheap, excellent yielding (ca 95%), and easy to work up. The obvious problem is gargantuic amounts of solvent and oxidizer. SWIM has an impression this could be reduced substantially, good stirring warranted, as anethole is easily soluble in DCM and wonders whether someone here has tried this. If not, he is going to experiment on this himself with like 3-5x less solvent/oxidizer and hope it works.
2) Condense anisaldehyde with nitromethane under Henry rxn conditions. He is definitely gonna use the ethylenediamine/EtOH method (
Post 508451 (missing)
(azole: "ethylenediamine as a catalyst", Methods Discourse), yield 97%).
3) Reduce the nitrostyrene to p-MeO-PEA. SWIM is a little stuck on this too. He is aware of the beautiful nitrostyrene reduction method of Leminger (
Post 245040
(Rhodium: "O Leminger's Phenethylamines - posted by Karel", Novel Discourse)) but was unable to find any published specifics on p-MeO-nitrostyrene Anyone? If this fails, he is gonna try Urushibara type catalyst like
https://www.thevespiary.org/rhodium/Rhodium/chemistry/amph.urushibara.html
. If this fails, in a fit of despair he will try to use the well-known Al/Hg method and/or Clemmensen conditions 9(
Post 507331
(Rhodium: "Clemmensen reduction of nitrostyrenes", Methods Discourse)). Again, no specifics were found on p-methoxynitrostyrene. Would bee glad to hear your comments on that.
4) Brominate/iodinate the PEA. There is a lot of possibilities here, the UHP/iodine method (
Post 488372
(Rhodium: "Aromatic Iodination with I2 and Urea-H2O2 (UHP)", Chemistry Discourse)) looks promising, then we have oxone/KI (
Post 428701
(Barium: "Can it be true?", Novel Discourse) and
https://www.thevespiary.org/rhodium/Rhodium/chemistry/oxone.aromatic.iodination.html
, BTW is the formation of 2C-I under these conditions confirmed?), oxone/KBr (
https://www.thevespiary.org/rhodium/Rhodium/chemistry/oxone.aromatic.bromination.html
), iodine/KNO3, plain old Br2/AcOH, HBr/H2O2, iodine/silver sulfate etc... Hell, KI/persulfate should work also... SWIM is gonna try the above methods more or less in the order listed. Any advices?
5) Workup and isolate as sulfate from DCM or acetone solution
The project is starting in at most month, the literature is gathered and read, most reagents waiting on the shelf... SWIM will keep you informed on this for sure!
Thank you for any and all comments.