Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

Abstract

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.

Keywords: azabicyclo[1.1.0]butane; azetidines; epoxides; ring expansion; strained molecules.

Scheme 1

a) Marketed drugs containing 1,3‐substituted azetidine scaffolds. b) Electrophilic activation of ABB, nucleophilic addition to ABB and lithiation of ABB followed by reaction with boronic esters. c) Reaction of ABB‐Li with carbonyls and subsequent divergent reactivity.

Scheme 2

Synthesis of ABB‐carbinols by the reaction of ABB‐Li with carbonyl compounds. Reactions performed on 2.0 mmol scale at 0.31 M initial concentration. Yields determined by ¹H NMR. [a] 4.0 mmol scale. [b] 1.0 mmol scale. [c] Purified by flash column chromatography.

Scheme 3

Divergent reactivity of 5 a with a) CbzCl vs. b) TFAA. c) Investigations into the cause of divergence.

Scheme 4

Scope of ABB‐carbinols employed in the semipinacol rearrangement reaction. Reactions performed on 0.25 mmol scale at 0.1 M. [a] Reaction also performed on 1.0 mmol scale to give 6 a in 90 % yield. [b] Reactions stirred for 15 min at −78 °C then 30 min at 0 °C. [c] Product isolated after reduction by NaBH₄ to the primary alcohol. [d] From purified 5 r. [e] Formed under conditions B and yield determined by ¹H NMR.

Scheme 5

Scope of ABB‐carbinols employed in the epoxide formation reaction. Reactions performed on 0.25 mmol scale and 0.1 M initial concentration. [a] Reaction also performed on 1.0 mmol scale to give 8 a in 93 % yield. [b] Intermediate iodohydrin purified before second step. [c] Stirred for 42 h after addition of K₂CO₃. [d] 0.05 M initial concentration. [e] From purified 5 r. [f] Semipinacol reaction also occurred in 36 % yield. [g] After addition of Boc₂O, heated at 80 °C for 18 h without K₂CO₃.