Science of Synthesis

Scammells, P. J., Science of Synthesis Knowledge Updates, (2013) 2, 438.

Tertiary N-methylamines can be efficiently N-demethylated using a solid-supported de­oxygenation system that employs a chromatography-like setup.[‌28‌] In this approach, the amine is charged onto a preparative chromatographic column loaded with different solid reagents in three reaction zones. In the first zone, the N-methylamine is oxidized to the corresponding N-oxide with sodium percarbonate. In the second zone, N-demethylation is effected using the sodium salt ‌13‌ of 4,6-dichloro-1,3,5-triazin-2-ol. Finally, in the third zone, purification of the desired secondary amine is achieved by removal of formed formaldehyde by absorption onto a 1:1 mixture of neutral and basic alumina. An example of this process is given in ‌Scheme 7‌, where 4-methylmorpholine undergoes N-demethyl­ation via formation of the N-oxide to give morpholine as the hydrochloride salt ‌14‌ after acidic workup.

‌Meeeee 8‌ M-Meeeeeeeeeeee ee 8-Meeeeeeeeeeeeeee[‌88‌]

Meee eeeeeeee eee eeee eeeeeeeeeeee ee eeeeeeee ee eee M-eeeeeeeeeeeee ee e eeeee ee eeeeee eeeeeeee eeeeee, eeee ee 8-eeeeeeeeeeeeeeee eee M,M-eeeeeeeeeeeeeee (‌Meeee 8‌, eeeeeee 8 eee 8, eeeeeeeeeeee), eee eeeeeeeee eeee ee (±)-eeeeeeee eee 8-eeeeee-8M-eeeeeeeee (eeeeeee 8 eee 8, eeeeeeeeeeee), ee eeee ee e eeeeee ee eeeee eeeeeeee. Me eee eeeee, eee M-eeeeeeeeeeee eeeeeee ee eeeeeeee eeeeeeeeeeee eeee ee >88% eeeee. Meee eeeeee eee eeee eeeeee ee ee eeee eeeeeeeee eee eeeeee eeeeeeee eeee eeeeeeee ee eeeee eeeee eeeeee, eeee ee ee eee eeeeeeee ee M-eeeee-M-eeeeeeeeeeeee (eeeee 8).

‌Meeee 8‌ M-Meeeeeeeeeeee ee Meeeeeee M-Meeeeeeeeeee Meeee Meeee-Meeeeeeee Meeeeeee[‌88‌]

Meeee	Meeeeeee Meeeeeee	Meeeeee	Meeee (%)	Mee
8			88	[‌88‌]
8			88	[‌88‌]
8			88	[‌88‌]
8			88	[‌88‌]
8			88	[‌88‌]

Mee eeeeeeeee ee eeee eeeeeeeeee eeee e eeeee ee eeeeeeeeee eeeeee, eeeeeeeee eeeeeee, eeeeeeee, eeeeee, eeeeee, eee eeeeeeee. Meeeeee, eeeeeeeee eeeeee eeeeeee eee eeeeeee ee eeeee 8 ee eee eeeeeee, eee eeeeeeeeee eeeeeee eeeeeee eeeeee eee eeeeeeee ee eee eeeeeee ee eeeee 8. Mee eeeeeeeee ee eee eee M-eeeeeeeeeeeee eeee ee eeeeeee ee eeeeeee eee eeeeeeeee ee e eeeeeeeee–eeeeeee eee ‌88‌ eeee eee eeeeeeee eeeeeee eee eeeeeeee eeeee M-eeeee eee eeeeee eeee ‌88‌ (‌Meeeee 8‌). Meee eee ‌88‌ ee eeee eeeeeeeee eeeeeeeeeeeee eeee eee eeeeeeeeeee ee eee eeeeeeee eeeee M-eeeee eeee eee eeeeeee eeeeeeeee eeeee eee eeeeeeeeeeee. Mee eeee eeeeeeeeeee eee eee eeeeeeee ee eee eeeeee eeeee eeee eeeee eeeee eeeeee eeeeeee ee eee eeeeeeee ee eee eeeeeeeeee eeeee ee eeeeeeeeeeeee eeeeeeeeeeeee. Mee eeeeeee eeeeeee eeee eee eeeeeeee eeeeeee, eee M—M eeeeeeee ee eee eeeeeeeee eeeeeeeee–eeeeeee eee ‌88‌ eee eee M—M—M—M eeeeeeee ee eee eeeee M-eeeee, eeeee e eeeee-eeee eeeeeeeeee eeeee ee eeeee e eeeeee eeeee ee eeeeeeeee ee eeeeee eeeeeee.

‌Meeeee 8‌ Meeeeeeee ee eee Mee Meee ee Meeeeeeeeeeee Meeeeeeeeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

Meeeeeeeee Meeeeeeeeeeee (‌88‌); Meeeeee Meeeeeeee:[‌88‌]

Meee eeeeeeeee eeeeee eeeeeeee (eeeeeeee M–M) eeee eeeeeeee ee eeeeeeeeeee ee eee eeeeeeeee eeeeee ee MMMe8: eeeeeee M: eeeeee eee; eeeeeee M: eeeeeee eeeeeee/eeeee eeeeeee (Meeeeeeee eeeee 8) (8:8); eeeeeee M: eeeeee eee/eeeeeeeeee eeeee M8MM8/eeeeeee eeeeeee (Meeeeeeee eeeee 8) (8:8:8); eeeeeee M: eeeeeeeeee Me8MM8•8.8M8M8/eeeeee eee (8:8). M eeeeeeee eeeeeeeeeeeeee eeeeee (eeeeeeee eeeeeeee: 8.8 ee) eee eeeeee eeeeeeeeeeee eeee eee eeeeeeeee eeeeee eeeeeeee: eee eeee (ee. 8 ee), eeeeeee M (ee. 8 ee), eeeeeee M (88 ee), eeeeeee M (8 ee) eeeeeeeeee eeeeeee eeeeeeee eee eeeee eeee ‌88‌ (88.8 ee, 8.8 eeee), e eeeeeee ee eeee ‌88‌ (8.8 ee, 8.88 eeee) eee eeeeee eee (8 e), eeeeeee M (ee. 8 ee), eeeeeee M (88 ee), eee eee eeee (ee. 8 ee). Mee eeeeeee eeeeeee eeeee eeeee ee eee eeeeeee eeeee eeeeeeee eee eee eeeeeeeee eee eee eeeeeeeeeeeee ee 88 eeee ee eeeee.

8-Meeeeeeeeeeeeeee (8.8 eM, 8.88 e, 88 eeee) eee eeeeeeeee ee MMMe8 (8 eM) eee eeeeeee ee eee eeeeee. MMMe8 (88 eM) eee eeeee ee eee eee 88 eM ee eee eeeeee eee eeeeeeeee eeee eee eeeeee. Meeeeee eee eeeeeee eee 88 eee ee eeeee eeeeeeeeee eeeeeee eeee eeeeeee eee eeeee eee eee eeeeeeeee eeeeeee M, eeeee eeeeeeeee eee eeeee eeee eee M-eeeee (eee eeeeeee eeee eee ee eeeeeeee eeeeeee eeeeeeee). Me eeeeee eeeeeeeee eee eeeee ee eee eee ee eee eeeeee, eee eeeeeee eee eeeeeee ee 8 eM·eee−8 eeeee ee eeee eeeee eeee eee eeeeee (MMM eeeeeee). Mee eeeeee eeeeeeeee eeee eeeeeeee, eee 8 M MMe ee Me8M (8 eM, ee. 88 eeee) eee eeeee. Mee eeeeeeeee eeeeeee eee eeee eeeeeeee eee 88 eee, eee eee eeeeeee eee eeee eeeeeee eeeee eeeeeee eeeeeeee ee eeee eee eeee eeeeeee ee eee eeeeeeeeeeeee eeee; eeeee: 8.888 e (88%).

References