The article gives no examples of N-demethylation of secondary amines, and usually the Hypophosphorous Acid/Iodine reduction of (pseudo)ephedrine is conducted under less harsh conditions, but this may be something to bear in mind...Hypophosphorous Acid-Iodine: An Efficient and Mild Reagent for Cleavage of N–C BondGe Meng, Yan-Ping He, and Fen-Er ChenSynth. Commun. 33(15), 2593–2598 (2003) (https://www.thevespiary.org/rhodium/Rhodium/pdf/h3po2-i2.n-dealkylation.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/h3po2-i2.n-dealkylation.pdf)
DOI:
10.1081/SCC-120021978 (http://dx.doi.org/10.1081/SCC%2D120021978)
AbstractA mixture of hypophosphorous acid (H
3PO
2) and iodine in acetic acid can selectively cleave the N-alkyl bond in a variety of substituted heterocylic compounds in good to excellent yields without any damage to amide bond present in the substrates.
Rhodium can you give one or two examples of secondary amines, and also what N-demethylation would do to those theoretically? (theoretically if it happened to work using this route)
Well, I'd know what the demethylation did from looking at the starting material, but I want you to choose one yo like!
I inferred that amphetamine could perhaps be formed from methamphetamine (which is an N-methylated secondary amine) if either the precursor (pseudo)ephedrine or the product was demethylated.
fuck! a revelation, I didn't think that was possible, thanks!
Rhodium stated:
I inferred that amphetamine could perhaps be formed from methamphetamine (which is an N-methylated secondary amine) if either the precursor (pseudo)ephedrine or the product was demethylated.
The -OH reduction of the ephedrine WILL predominate completely, before demethylation occurs.
Wiz, are you saying that an ephedrine reduction using H3PO2, I2 and acetic will first reduce to methamphetamine, and then on to amphetamine?
Yes! BUT ONLY under VERY EXTREME reaction condition. ie. very long reflux time.
Methamphetamine has a secondary amine, and this demethylation reagent will not be very effective.
A mixture of hypophosphorous acid (H3PO2) and iodine in acetic acid can selectively cleave the N-alkyl bond in a variety of substituted heterocylic compounds in good to excellent yields without any damage to amide bond present in the substrates.
Note that the demethylation of substrates are tertiary amines.