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21.1.5.3.3 Variation 3: From Hydroxyalkyl Azides

DOI: 10.1055/sos-SD-021-00115

Judd, W. R.; Katz, C. E.; Aubé, J.Science of Synthesis, (200521154.

The reactions of hydroxyalkyl azides with ketones in the presence of a Lewis or protic acid constitute a broadly effective approach to amide synthesis.[‌49‌,‌56‌‌60‌] The overall process is formally equivalent to the intermolecular reaction of alkyl azides with ketones, but the mechanism and scope are different. The reaction proceeds by an initial in situ hemiketalization resulting from attack of the alcohol moiety of the hydroxyalkyl azide onto the activated ketone; for example, see Scheme 26. Dehydration followed by intramolecular addition of the now-attached azido group onto the resulting oxonium ion and rearrangement with loss of nitrogen gives an iminium ether, e.g. 54. Hydrolytic workup affords the same ring-expanded N-hydroxyalkyl lactam, e.g. 55, that would have resulted from the direct reaction of the azide portion of the molecule. This procedure thus allows the synthesis of N-substituted lactams from ketones by a one-pot, two-reaction sequence. This process is described as in situ tethering, because the hemiketal linkage is formed and released without additional synthetic operations.

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