Science of Synthesis

Scammells, P. J., Science of Synthesis Knowledge Updates, (2013) 2, 440.

Tertiary N-methylamines can be N-demethylated via the Polonovski reaction following their conversion into the corresponding amine N-oxides using an appropriate oxidizing agent (typically hydrogen peroxide or a peracid such as 3-chloroperoxybenzoic acid). The Polonovski reaction was first reported in 1927 as a means of N-demethylation in tropane N-oxide derivatives,[‌29‌] and has subsequently proven to be a versatile method for the N-dealkylation of numerous tertiary amines, including a wide range of N-methyl alkaloids.[‌30‌,‌31‌] This reaction proceeds via an iminium ion intermediate whose formation is promoted by activation of the amine N-oxide oxygen. There are three main categories of activating agents, namely acylating agents (acid anhydrides, acid chlorides, or chloroformate esters), iron-based reagents, and sulfur dioxide. The term „classical“ in relation to the Polonovski reaction refers to the use of acylating agents, which were the original activating agents employed in this reaction (‌Scheme 9‌, method A). The tertiary amine N-oxide reacts with the acylating agent to ultimately form an N,N-dialkylacetamide, which can subsequently be hydrolyzed to the corresponding secondary amine. The „nonclassical“ Polonovski reaction in which the amine N-oxide is reacted with an iron(II) salt (‌Scheme 9‌, method B) has also proven to be an effective method for the N-demethylation of a range of bioactive alkaloids.[‌32‌–‌37‌]

‌Meeeee 8‌ M-Meeeeeeeeeeee eee eee Meeeeeeeee Meeeeeee

Meee „eeeeeeeeeeee“ eeeeeeee eee eeee eeee eee eee M-eeeeeeeeeeeee ee eee Meeeeeeeeeeeee eeeeeeee eeeeeeeeeeee, eeeee eee eeeeeeeeee eeeeee ee ee eeeeeeeeeee.[‌88‌,‌88‌] Meeee eeee eeeeeeeee, eeeeeeeeeeee ee eeeeeeeee eeee eee eeeeeeeeeeeee M-eeeee eee eeeeeee eeee eeee(MM) eeeeeee eeeeeeeeeeee ee eeee eee eeeeeeeeeeee eeee eeeee ee 88% eeeee.[‌88‌] Meee eeeeeeee eee eeee eeee eeee eee eee M-eeeeeeeeeeeee ee e eeeee ee eeeeee eeeeeeeee, eeee ee eeeee eee eeeeeeeee eeeeeeeeee ee eeeeeeeeeeeee eeeeeeeeeeeeeee eeee ee eeeeeeeeeeeee, eeeeeeeeee, eee eeeeeeee. Mee eeeeeee, eeeeeeeee ee eeeeeeee (‌88‌) ee eeeeeeee M-eeeee (eeeeeeee ee eee eeeeeeeeeeeee eeee), eeeeeeee ee eeeeeeee eeee eeee(MM) eeeeeee eeeeeeeeeeee (8 eeeee), eeeeeee eee eeeeeeeeeeeee eeee eeeee ‌88‌ ee 88% eeeee (‌Meeeee 88‌).[‌88‌] Meeee eeee(MM) eeeee eee eeeeeeeee eeee eeee eeee eeeeeeee ee eeeeee eeeeeeeeeeeeeee ee eeee eeee. Mee eeeeeee, eeeeeeeee eeeeeee ee eeeeeeeeeee [8,88,88,88-eeeeeeee(8-eeeee­eeee­ee)eeeeeeeeeeee]eeee(MM) eeeeee eee M-eeeeeeeeeeeee ee eeeeeeee (‌88‌) ee e eeeeeeeeee eeeee ee 88% eeeeeeeee eeeeeeeeee eeee eee M-eeeee.[‌88‌] Meee eeeeeeee eee eeeeee eeee eeeeeeee eeee eee eee-eeeeeeeee eeeeeeee ee eeeeeeeeee ee ee eeeeeee eeeeee. Me eee eeeee eeeeeeeeee eeee eee eeeeeeeeee eeeeeeeeeee eee eee-eeeeee eeee eeeeeee eeeeeeeee ee eeee ee eeeeeeeee eeeeeeee eee eeee eeeeeeee, eeeeeeeee eee eeeee ‌88‌ ee 88% eeeee.[‌88‌]

‌Meeeee 88‌ M-Meeeeeeeeeeee ee Meeeeeee Meeee eee Meeeeeeeeeee Meeeeeeeee Meeeeeee[‌88‌]

Mee eeeeeeeee ee eee eeee(MM)-eeeeeeee eeeeeee ee eee Meeeeeeeee eeeeeeee ee eeeeeeee ee eeeeeee eee eeeeeeeeee eee-eeeeeeee eeeeeeeee eeeeeeeee eeee(MM)/eeee(MMM) eeeee eeeeeeeee (‌Meeeee 88‌). Me eeee eeeeeeee eeeeeeeee, eee eeee(MM) eeeeeee eeeeeeeee eeeeeeeeeee ee eee eeeeeeeeee M-eeeee eee eeee eeeeeee eeeeeeeeeeee eeeeeeeee e eee-eeeeeeee eeeeeeeee, eeeee eeeeeee ee eeeeeeee ee eee M—M eeee eee eeeeeeeee ee ee eeeeeeeeee eeeeeee eeeeee. Meee eeeeeee eeeeee eeeee ee α-eeeeee eee eeeeeeeee ee eeeeeeee eeeeeeeeeeeeee ee eeee e eeee eeeeee eeeeee-eeeeeeee eeeeeee (eeeee eeeee eeeee ee eeee). Meeeeeeee ee eee eeeeee-eeeeeeee eeeeeee ee eeee(MMM) eeeee ee eeeeeee eee eee eeeeeeeeee eeeeeeeeee eeeeeee eee eeeeeee eeeeeeeee eeeee. Me eeeeeeeeeee eeeeeeeee eee eeee eeeeeeee ee eeeee eee eeeeeeeeee eeeeeee eeeeee ee eeeeeeeee eeee eee eeeeeee eee eeeeeeee eee eeeeeeee ee e eeeeeeee eeee ee eeee(MMM), eeeee ee eeeeee eeeeeee ee eeee(MM) eeee eee eeeeeeeeee ee e eeeeee.[‌88‌] Mee eeeee eeeeeeeee ee eee eeeeeee ee eee eeeeee eeeeeeee M-eeeeee­eeeee, eeeee ee eeeeeeee ee eeee eeee eee eeeeeeeeeeee eeeeeeeeee eeeeeee eeeeee eeeeeeeeeee eeee eee eeeeeeee eeee eeeeeee eee eeeeeeeee eeeeeee eeeeeeeee ee eeee(MM).

‌Meeeee 88‌ Meeeeeee Meeeeeeee ee eee Meeeeeeeeeee Meeeeeeeee Meeeeeee[‌88‌]

Meee eeeeeeee, ee eee eeee eeeeeeeeee eeee eeee(8) ee eee eeee ee eeee eeeeee ee eeeeeeeee eeeee eee eeeee ee ee eeeeeeeee eeeeeeee eee Meeeeeeeee-eeee eeeeeeeee.[‌88‌,‌88‌] Meee ee eee ee eee eeee eeeeeeee eeeeee ee eeeee eee ee eeee ee eeeeeeeee eeeee eee eeeeee eeeeeeeee.[‌88‌] Me e eeeeee, ee ee eeeeeeeeeee eee eeeeeeeeeeeeeee eeeeeeee, eee eeeeeeeeeee eee ee ee eeeeeeeeee eeeeeeee eee eeeee-eeeee eeeeeeeeeeee eeee ee eeeee eeeeeeeee ee eee eeeeeeeeeeeeee eeeeeeee. M eeeeee ee eeeeeeee M-eeeeeeeeeeee, eeeeeeeee eeeeeeeeeeeeeeee, eeeeeee eeeeee eeeee, eeeeeeee (‌88‌) (‌Meeeee 88‌),[‌88‌] eee eeeeeeee, eee M-eeeeeeeeeeee ee >88% eeeee eeeee eeee eeeeeeeeeee.

‌Meeeee 88‌ M-Meeeeeeeeeeee ee Meeeeeee Meeee ee Meee(8)-Meeeeeee Meeeeeeeee-Meee Meeeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

(8eM,88eM)-8,8-Meeeeeeee-8,8,8,8e-eeeeeeeeee-8M-8,88-eeeeeeeeeeeeeeee[8,8-e]eee­eeeeeeeee (‌88‌); Meeeeee Meeeeeeee Meeee Meee(MM) Meeeeee:[‌88‌]

Meeeeeee (‌88‌; 8.8 e, 8.8 eeee) eee eeeeeeeee ee MeMM (88 eM) eee eee eeee eee eeeeee ee 8 °M. Meee, 88% e/e M8M8 (8 eM, 88 eeee) eee eeeee eeeeeeee, eee eee eeeeeee eee eeeeeee ee ee eee 88 e. Me eee eeee eeeeee ee 8 °M eee MeM8 eee eeeee ee eeeee eeeeeeee eeeee MM–eeeeee eeeee eeeeeeeee eeee eee eeeeee M8M8 eee eeee eeeeeeee. Mee eeeeeeeee eeeeeee eee eeeeeeee eeeeeee e eeee ee Meeeee, eee eee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee ee eeee eeeeeeee M-eeeee. Meee M-eeeee eee eeeeeeeee ee eeeee, eeeee eee eeeeeeeee ee eM 8 ee eeeeeeee ee 8 M MMe eee eeee eeeeeeeee eeee MMMe8. Mee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8) eee eeeeeeee, eee eee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee ee eeee eee eeeeeeee M-eeeee eeeeeeeeeeeee eeee ee ee eee-eeeee eeee; eeeee: eeeee.

Mee eeee eeee eeeeeeee eee eeeeeeeee ee MeMM (88 eM) eee MeMM8•8M8M (8.8 e, 8.8 eeee) eee eeeee ee 8 °M. Mee eeeeeeeee eeeeeee eee eeee eeee ee eeee ee ee eee 8 e, eeeee eeeee eeee MMM eeeeeeee (MMMe8/MeMM/ee MM8MM 88:88:8) eeeeeeeee eeeeeeeeee eeee eeeeeeee (‌88‌) eee eee eeeeeee eeeeeee. Mee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee eee eee eeeeeee eee eeeeeeeeeee ee 8.8 M ee eeee eeeeeeee ee eM 88 ee eeeeeeee ee 88% MM8MM (88 eM) (ee eeeee 8 eeeee ee 8.8 M ee eeee eee eeee ee eeeee ee eeeeeee eeee). Mee eeeeeee eeeee eee eeee eeeeeeeee eeee MMMe8 (8 × 88 eM), eee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8) eee eeeeeeee, eee eee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee ee eeee e eeee eeeeee eee. Meee eeeee eeeeeeee eee eeeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee) ee eeee eee eeeeeee ee e eeee eeeeee eeeee; eeeee: 8.88 e (88%).

(8eM,88eM)-8,8-Meeeeeeee-8,8,8,8e-eeeeeeeeee-8M-8,88-eeeeeeeeeeeeeeee[8,8-e]eee­eeeeeeeee (‌88‌); Meeeeee Meeeeeeee Meeee Meee Meeeee:[‌88‌]

MMMMM (eee. 88% eeeeeee; 8.88 e, ee. 8.88 eeee) eee eeeee eeeeeeeeeee eeee 8 eee ee e eeeeeee eeee ee eeeeeeee (‌88‌; 8.88 e, 8.88 eeee) ee MMMe8 (888 eM) ee −8 °M, eee eee eeeeeeeee eeeeeee eee eeeeeee eee 88 eee. Mee eeeee eeee eeeeeeee eee eeeeee eeee eeee 8% MeMM ee eeeee (8 × 88 eM) eee eeee eeee eeeee (8 × 88 eM). Mee eeeeeee eeeee eee eeeeeeeeee eeeeee eeee 8 M MMe ee eeeee (eM 8; 88 eM), eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee ee eeee eee M-eeeee eeeeeeeeeeeee eeee ee ee eee-eeeee eeee eeeeeeeeee ee e eeeeeee ee eeeee/eeeeeeeeee M—Me eeeeeee (ee. 8:8 ee 8M MMM); eeeee: 8.88 e (88%).

Me eeeeee (88 ee, 8.88 eeee) eee eeeee ee e eeee ee eeee eeeeeeeeeeeee eeee (888 ee, 8.88 eeee) ee MMMe8 (88 eM). Mee eeeeeeeee eeeeeeeeeeeee eeeeeee eee eeee ee eeee eee 8 e eee eeee eeeeeeee eeeeeee Meeeee. Mee eeeeee eee eee eeeeee eeee e eeeeeeee eeeeeee (8 × 88 eM), eeee ee MMMe8 ee MMMe8/eMeMM (8:8), eee eeee eee eeeeeeee eeeeeeee eee eeeeeeee eeee eeeeeeee eee eeeeeeeeeeee ee eeeeeee ee eeee e eeeee eeeeeee ee eeeeeeee (‌88‌) eee eee eeeeeee eeeeeee. MMMe8 ee MMMe8/eMeMM (8:8; 88 eM) eee eeeee eee eee eeeeeeeee eeee eee eeeeee eeee eeeeee eeeee MM8 ee eeeee (8 eM) ee 88% ee MeMM (8 eM), eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee. Mee eeeeeee eeeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MMMe8/MeMM/MM8MM 88:88:8 ee 88:88:8) ee eeee eee eeeeeee ee ee eee-eeeee eeeee; eeeee: 88 ee (88%).

References