Lewis acid‐mediated defluorinative [3+2] cycloaddition/aromatization cascade of 2,2‐difluoroethanol systems with nitriles

Abstract

The properties of C−F bonds, including high thermal and chemical stability, make derivatization of organic fluorine‐containing compounds by the activation of the C−F bond and subsequent functionalization quite challenging. We herein report a Lewis acid‐mediated defluorinative cycloaddition/aromatization cascade of 2,2‐difluoroethanols with nitriles as a novel synthetic method for the preparation of 2,4,5‐trisubstituted oxazoles. This reaction, which involves cleavage of two C−F bonds and the consecutive formation of C−O and C−N bonds in a one‐pot fashion, features a broad substrate scope and moderate to high reaction yields. Mechanistic studies revealed that the reaction is initiated by the Lewis acid‐mediated ring closure of the 2,2‐difluoroethanol to produce the fluoroepoxide intermediate.magnified image

(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

“…First of all, reaction of compound 2 with phenyl iodide was performed under conditions described previously for ethyl bromodifluoroacetate (Cu, DMSO, 60 °C, 12 h) . Unfortunately, complete decomposition of the starting enone was observed, and no traces of target product 1a were detected in the reaction mixture.…”

Lewis Acid-Catalyzed Rearrangement of Fluoroalkylated Propargylic Alcohols: An Alternative Approach to β-Fluoroalkyl-α,β-enones

“…A stirred solution of compound 1a (100 mg, 0. ized according to their 1 H NMR, 13 C NMR, 19 F NMR, and mass spectra. The stereochemistry of (E)-β-alkyl-β-fluoroalkyl-α,βenones was unequivocally determined by comparing their NMR spectra to those of structurally identical or similar compounds.…”

“…However, synthesis of β-trifluoromethyl-α,β-enones directly from the Meyer-Schuster rearrangement of trifluoromethylated propargylic alcohols is rare. Recently, our group reported a new Lewis acid-catalyzed defluorinative cycloaddition/aromatization cascade reaction, 13 in which the difluorophenylmethylated propargylic alcohols were prone to cyclizing with nitriles but did not rearrange to α,β-enone products. Activated benzylic C-F bonds were found to be necessary for the cascade reaction.…”

Selective synthesis of spirobiindanes, alkenyl chlorides, and monofluoroalkenes from unactivated gem-difluoroalkanes controlled by aluminum-based Lewis acids

“…Subsequently, the S N 2′-type alkylation of difluorohomoallyl alcohols can be controlled by trialkylaluminum compounds, which can coordinate to fluorine and adjacent oxygen atoms 36,37 . Recently, it has been reported that Al(OTf) 3 enables the defluorinative cycloaddition/aromatization between benzylic 2,2-difluoroethanol and nitriles to afford oxazoles 38 . Nevertheless, breaking C(sp 3 )–F bonds in unactivated gem -difluoroalkanes remains highly challenging 39–41 .…”