3-Aza-4-oxa-Cope rearrangements

The most frequent rearrangement of substituted hydroxylamines is the thermal [3,3]-sigmatropic rearrangement, the 3-aza-4-oxa-Cope rearrangement also called 3-aza-4-oxy-Cope rearrangement, that proceeds by a cyclic six-membered transition state (equation 1). Albeit the difficulty to prepare hydroxylamine derivatives, this rearrangement proceeds in mild conditions and is useful in the synthesis of several heterocyclic compounds. 

Cope rearrangement 3-oxa-Cope or Claisen rearrangement 3-aza-Cope or 3-aza-Claisen rearrangement 3-aza-4-oxa-Cope rearrangement hetero-Cope rearrangement... 

The 3-aza-4-oxa-Cope rearrangement in which the weak N—O bond is cleaved and a new carbon-carbon bond is generated (equation 6) is the most frequently used hydrox-ylamine rearrangement. Low temperature and moderated reaction conditions make this rearrangement an important synthetic tool. 

A formal synthesis of ( )-Eseroline (69) via a 3-aza-4-oxa-Cope rearrangement was reported. An iV-aryl A-hydroxycarbamate was reacted with 2-phenylsulfanylpropanoic acid to yield the O-acylhydroxamic acid derivative 65, R = H that rearranged in the presence of potassium bis(trimethylsilyl)amide. The [3,3] and [3,5] rearrangement products, respectively 66 and 67, were formed (equation 22). If the para-substituted hydroxamic acid 65, R = OCOBu-t is used, no [3,5] rearrangement product is observed and the [3,3] rearrangement product 68 is the only product formed (equation 23). The authors proposed two parallel mechanisms, a concerted pathway and an ionic mechanism by an ion-pair recombination. 

Aliphatic 3-aza-4-oxa-Cope rearrangement of ester-amide dienolates increases the synthetic utility of anionic [3,3]-sigmatropic rearrangement initiated by N—O bond cleavage. Treatment of the enehydroxylamine 94 with KHMDS in the presence of TMSCl at —80°C provided a mixture of iV,0-disilylated 95 and 0,0-disilylated 96 derivatives (equation 30). Both of these would, on [3,3]-sigmatropic rearrangement, provide the corresponding silyl ethers 97 and 98, from which 99 and 100 are obtained on workup. 

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