A Direct Synthesis of Highly Substituted π‐Rich Aromatic Heterocycles from Oxetanes

Abstract

The ubiquitous use of π-rich five-membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis-acid-catalyzed oxetane rearrangement. Notably, this methodology employs a keto-oxetane motif as a 1,4-dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4-dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo-fused versions thereof.

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

“…In fact, two byproducts formed and were identified as β-hydroxymethyl-α-fluorolactone 14 and β-bromomethyl-α-fluorolactone 15 ( Table 4 ) [ 30 ]. This ring expansion has been already reported in the literature from oxetane-containing α,β-unsaturated carbonyl derivatives through a Lewis acid-catalyzed rearrangement [ 31 ]. When the previous conditions (HBr/AcOH) were tried (3.5 h, 0 °C to 20 °C), hydroxymethyllactone 14 (87%, Table 4 , entry 1) was the main product with traces of the corresponding acetate (4%, not shown), the bromomethyllactone 15 (8%), and alkene Z - 13 (1%).…”

“…The contrasting result observed with HBr/AcOH and TBAB/CSA highlighted the importance of the acidity of the medium on the reaction course of the ring-opening reaction (Scheme 5). The former, using an excess of acid (33% HBr in AcOH solution) favored the direct nucleophilic attack (path b) leading to lactone 14, whereas the latter in the presence of TBAB/CSA allowed bromide addition on the same side of the fluorine atom (path a) leading to lactone 15 [31]. However, the reaction can be stopped at the alcohol stage when performed in the presence of BF 3 •Et 2 O instead of CSA to afford alkene Z-13 as the major product.…”

Facile Diastereoselective Synthesis of Highly Substituted Alkylene‐oxetanes from 3‐Alkyl Allenoates and Diaryl 1,2‐Diones/α‐Ketoamides Mediated by DBU

“…As already mentioned, oxetanes are excellent building blocks for five‐membered heterocycles. Vanderwal et al recently reported the synthesis of π‐rich aromatic heterocycles from oxetanes Against this backdrops, we conducted the reaction of an amide appended oxetanes in the presence of BF 3 · OEt 2 in toluene. The reaction provided an interesting product, viz., as 5‐methylene‐1 H ‐pyrrol‐2(5 H )‐one derivative 6a (Table ).…”

Organocatalytic Asymmetric Synthesis of α-Oxetanyl and α-Azetidinyl Tertiary Alkyl Fluorides and Chlorides

“…The oxetane ring provides additional synthetic opportunities. 26 Since several groups have discovered oxetane desymmetrizations in recent years, 27 we decided to highlight the general utility of our oxetanyl fluorides with a modified Lewis acid promoted ring opening protocol. 28 After some reaction optimization using benzylthiol as the nucleophile we obtained ( R,S )- 13 in 68% yield, 95% ee and with >99:1 dr from ( R )- 3a .…”