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40.1.1.4.2.4.1 Variation 1: Hofmann Rearrangement

DOI: 10.1055/sos-SD-040-00241

Purchase, R.; Sainsbury, M.Science of Synthesis, (200940396.

The Hofmann rearrangement[‌189‌‌192‌] is a venerable reaction that is traditionally used for the conversion of a primary amide 156 into an amine 159 (Scheme 47). The classical reagents are bromine and aqueous sodium hydroxide (essentially sodium hypobromite), which initially give rise to an intermediate N-bromoamide 157; this species then undergoes deprotonation and loses bromide ion with concomitant migration of the substituent R1 to generate an isocyanate 158. After some debate, a concerted process is now generally favored[‌188‌] over a suggestion that a nitrene is formed at the point where bromide ion is lost and it is this species that undergoes rearrangement to the isocyanate.[‌193‌‌196‌] At the end of the rearrangement step the isocyanate is often hydrolyzed to afford the corresponding amine or captured by an alcohol such as methanol to form a carbamate,[‌197‌] which is then hydrolyzed to give the amine.

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References