Synthesis of 3,3-Diarylazetidines by Calcium(II)-Catalyzed Friedel–Crafts Reaction of Azetidinols with Unexpected Cbz Enhanced Reactivity

Abstract

Azetidines are valuable motifs that readily access under explored chemical space for drug discovery. 3,3-Diarylazetidines are prepared in high yield from N-Cbz azetidinols in a calcium(II)-catalyzed Friedel-Crafts alkylation of (hetero)aromatics and phenols, including complex phenols such as b-estradiol. Electron poor phenols undergo O-alkylation. The product azetidines can be derivatized to drug-like compounds through the azetidine nitrogen and the aromatic groups. The N-Cbz group is crucial to reactivity by providing stabilization of an intermediate carbocation on the 4-membered ring.

Catalytic Friedel‐Crafts Reactions on Saturated Heterocycles and Small Rings for sp3‐sp2 Coupling of Medicinally Relevant Fragments

“…The 4‐ to 6‐membered N‐heterocyclic alcohols 4 – 6 were assessed as carbamate protected derivatives due to the synthetic flexibility and ease of removal of the carbamate group. In our prior studies on azetidines, the NCbz‐group was uniquely reactive, with no reaction occurring on the NBoc derivative , . We proposed a π‐cation stabilizing interaction between the phenyl group of the Cbz group and the azetidine carbocation.…”

“…We examined Li, Ca and Fe catalysts, chosen to represent different Lewis acidic metals considered to be relatively environmentally benign and sustainable. These Lewis acid catalysts were also those previously shown to be reactive with oxetane and azetidine substrates . Cyclic tertiary alcohol substrates 1 – 7 were prepared from the corresponding commercially available ketones by the addition of the aryllithium or Grignard regents .…”

“…Under related conditions, we reported Li‐catalyzed thiol alkylation procedures with oxetanols . We also reported 3,3‐diarylazetidines by Friedel–Crafts alkylation of electron rich aromatics with azetidinols, where a calcium triflimide catalyst was optimal (Figure b) . On the other hand, very recently we have shown that thiol alkylation with azetidinols proceeds most efficiently with an FeCl 3 catalyzed procedure …”

Rearrangement of 3-Hydroxyazetidines into 2-Oxazolines

“…We note that after this work had been performed, we became aware of an intramolecular by-product reported by Denis et al which gives precedent to this type of ring opening in a similar context. 16 Scheme 4. Products 7 -10 obtained from using the use of aromatic nucleophiles.…”

Divergent Functionalizations of Azetidines and Unsaturated Azetidines

“…In contrast to the α‐lithiation and electrophilic trapping reactivity of azetidines described above, nucleophilic substitution processes are also being developed for divergent access to diversely functionalized azetidines. Bull and coworkers have recently disclosed that N ‐CBz azetidinols 45 are reactive under Lewis acid catalyzed conditions towards Friedel‐Crafts arylation at the 3‐position . As shown in Scheme A, when 45 is treated with a phenol or a heteroarene under Ca(NTf 2 ) 2 ‐catalyzed conditions, a variety of 3,3‐disubstituted azetidines 46 can be isolated in good yield.…”