Structurally Divergent Lithium Catalyzed Friedel–Crafts Reactions on Oxetan‐3‐ols: Synthesis of 3,3‐Diaryloxetanes and 2,3‐Dihydrobenzofurans

Abstract

The first examples of 3,3‐diaryloxetanes are prepared in a lithium‐catalyzed and substrate dependent divergent Friedel–Crafts reaction. para‐Selective Friedel–Crafts reactions of phenols using oxetan‐3‐ols afford 3,3‐diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho‐selective Friedel–Crafts reactions of phenols afford 3‐aryl‐3‐hydroxymethyl‐dihydrobenzofurans by tandem alkylation–ring‐opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.

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

“…The study started with oxetane derivatives 1 . As was previously observed,[23a] the Friedel–Crafts reaction was successful with PMP‐substituted oxetanol 1c with each of the three catalyst systems. The lithium triflimide/ n Bu 4 NPF 6 catalyst system was most effective, though the reaction was marginally lower yielding in CH 2 Cl 2 rather than CHCl 3 as used in our previous report.…”

“…However, for both the 5‐ and 6‐membered rings, olefin products from the elimination of water ( 15 , 16 ) were observed (in grey, Scheme ). Elimination products were not observed in the 4‐membered ring derivatives, but there was evidence for their formation from decomposition products,[23b] and it is likely this pathway led to a loss of yield.…”

Lithium‐Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3‐Sulfanyl‐Oxetanes as Bioisosteres

“…Oxetanes can act as suitable polar replacement groups for gem ‐dimethyl linkers and as bioisosteres for carbonyl functionality . In recent years, oxetane isosteres have been presented for amide, ketone and carboxylic acid derivatives . These developments continue to accelerate the exploration of oxetanes in medicinal chemistry …”

“…We envisaged an S N 1 process for the formation of oxetane sulfides from 3‐aryloxetan‐3‐ols (Figure ). We recently reported a Li‐catalyzed Friedel–Crafts reaction using oxetanols to form diaryloxetanes, invoking an oxetane carbocation . The catalytic activation of alcohols through C−O activation has become an attractive alternative to replace more toxic alkyl halides .…”

Catalytic Regioselective Isomerization of 2,2‐Disubstituted Oxetanes to Homoallylic Alcohols

“…Theo xetanes have also been used as lithiation directing groups on aromatic rings. [11,17] Our group has recently explored the metal-catalyzed isomerization of strained heterocyclic compounds ( Figure 2). Particularly,w er eported the selective iridium-catalyzed isomerization of N-sulfonyl aziridines into allylic amines using Crabtreesc atalyst (1)u nder very mild reaction conditions and without external activation.…”