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40.1.1.5.4.5.1.6 Method 6: The Polonovski Reaction

DOI: 10.1055/sos-SD-140-00180

Scammells, P. J.Science of Synthesis Knowledge Updates, (20132440.

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.[‌32‌‌37‌]

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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%).

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