Synthesis of 2,4-Disubstituted Oxazoles by a Copper-Catalyzed [3+2] Annulation/Olefination Cascade between Amides and I^III/P^V Hybrid Ylides

Abstract

We report a novel and efficient method for oxazole synthesis through a copper-catalyzed [3+2] annulation/olefination cascade between readily available iodonium–phosphonium hybrid ylides and amides. An unprecedented α-phosphonium Cu carbenoid acts as the key intermediate. This method features excellent regioselectivity with mild reaction conditions and a broad substrate scope. Its synthetic utility is demonstrated by its application in late-stage functionalizations and the rapid synthesis of a chiral ligand based on an oxazole motif.

Key words

oxazoles - copper catalysis - carbenoids - [3+2] annulation - cascade reaction - amides

Publikationsverlauf

Eingereicht: 24. August 2023

Angenommen nach Revision: 02. Oktober 2023

Accepted Manuscript online:
02. Oktober 2023

Artikel online veröffentlicht:
06. November 2023

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• 22 2-(4-Methylphenyl)-4-phenyl-1,3-oxazole (3a); Typical Procedure A dry clean test-tube equipped with a stirrer bar was charged with p-methylbenzamide 2a (16.2 mg, 0.12 mmol), Na₂CO₃ (25.4 mg, 0.24 mmol), I^III/P^V hybrid ylide 1a (67.0 mg, 0.1 mmol), Cu(acac)₂ (1.31 mg, 5 mol%), and 3 Å MS (50 mg). DCE (1.0 mL) was then added from a syringe under a N₂ atmosphere. The resulting mixture was stirred for 3 h at 40 °C (water-bath temperature), then cooled to r.t. After removal of the volatiles under reduced pressure, the residue was purified by column chromatography [silica gel, PE–EtOAc (20:1)] to give a white solid; yield: 21.2 mg (90%). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 7.3 Hz, 2 H), 7.95 (s, 1 H), 7.83 (d, J = 7.9 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.34 (dd, J = 6.8 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 2.42 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 162.3, 142.0, 140.8, 133.3, 131.4, 129.6, 128.9, 128.2, 126.6, 125.8, 125.0, 21.7. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1069.