Catalytic Friedel–Crafts/Lactonization Domino Reaction: Facile Access to 3‐Hydroxybenzofuran‐2‐one Scaffold

Abstract

A valuable Lewis-acid-catalysed domino reaction involving a Friedel–Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98?%). This protocol tolerates not only opposite electron demand substituents on the starting materials, but also drastic modifications of the alkylating agents, and gives direct access to the corresponding 3-hydroxy-benzofuran-2-ones, which could easily undergo further chemical transformation. The relevance of our method was further confirmed by the straightforward synthesis of rac-BHFF, the recently discovered and extremely promising positive allosteric modulator of the GABAB receptor

Synthesis of Benzofuran-2-One Derivatives and Evaluation of Their Antioxidant Capacity by Comparing DPPH Assay and Cyclic Voltammetry

“…Within this context, although several elegant strategies for the construction of the 3 H -benzofuran-2-one scaffold [ 23 , 36 , 37 , 38 ] have been reported, the number of approaches to the corresponding 3-hydroxy derivatives is much more limited. Nevertheless, following our recent development of alternative, short, and practical route to 3-hydroxy-3 H -benzofuran-2-one [ 39 , 40 ], we have figured out the possibility of obtaining various phenolic derivatives by domino reaction involving a first Friedel–Crafts alkylation and a subsequent intramolecular lactonization. Specifically, the reaction was performed employing the polyphenols 1–6 as substrates and either ketomalonate 7 or 3,3,3-trifluoromethyl pyruvate 8 as the electrophilic counterpart in the presence of TiCl 4 (10 mol%) as catalyst, which should activate the alkylating agent as well as the postulated intermediate A ( Table 1 ).…”

In Situ Anodically Oxidized BMIm-BF4: A Safe and Recyclable BF3 Source

“…Different Lewis acids in catalytic amounts in CH 2 Cl 2 at room temperature were used, with good yields. 13 We tested the anodically generated BF 3 in BMIm-BF 4 in this reaction, and the results are reported in Table 1, along with the corresponding literature data, for a useful comparison.…”

“…BMIm-BF 4 (1-butyl-3-methylimidazolium tetrafluoroborate, Iolitec) was kept at 40 °C under vacuum for 3 h before use. 1 H and 13 C spectra were recorded at ambient temperature on a Bruker Avance spectrometer (400 MHz) or with a Gemini Varian spectrometer (300 MHz), using the solvent as internal standard. The chemical shifts (δ) are given in ppm relative to TMS.…”

“…The reaction between a phenol 1 and diethyl ketomalonate 2 , in the presence of a Lewis acid, leads to the formation of a 3-hydroxybenzofuran-2-one 3 and, in the case of incomplete reaction, of the 2-substituted phenol 4 ( Table 1 ). 13 These products derive from a Friedel–Crafts phenol alkylation in the 2-position, followed by a cyclization with ethanol elimination. The increase of the temperature to 60 °C promoted the lactonization, giving selectively the 3-hydroxybenzofuran-2-one 3 .…”

“…Different Lewis acids in catalytic amounts in CH 2 Cl 2 at room temperature were used, with good yields. 13 …”