Divergent, Strain‐Release Reactions of Azabicyclobutyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo diverge...

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Bibliographic Details
Published in:Angewandte Chemie 2021-03, Vol.133 (13), p.7436-7441
Main Authors: Gregson, Charlotte H U, Noble, Adam, Aggarwal, Varinder K
Format: Article
Language:English
Subjects:
Alcohols
Anhydrides
Butane
Chemistry
Chloroformate
Divergence
Intermediates
Selectivity
Trifluoroacetic anhydride
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Summary:The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain‐release reactions upon N‐activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202100583