Divergent, Strain?Release Reactions of Azabicyclo[1.1.0]butyl 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 azabicyclo[1.1.0]butyl carbinols, readily obtained from the strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic triggered semipinacol rearrangement to give keto 1,3,3-substituted azetidines. More than 20 examples were explored, enabling us evaluate selectivity migratory aptitude of different groups. Alternatively, treatment same alcohols benzyl chloroformate presence NaI led iodohydrin intermediates which gave spiroepoxy azetidines base. electronic nature activating agent dictates pathway operates.