A [3+2] Cyclization of Siloxyalkynes and Isocyanides for the Synthesis of Oxazoles

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A mild and efficient [3+2] cyclization of siloxyalkynes for the synthesis of aromatic heterocycles is developed. It is a new addition to the cyclization reactions of these versatile species. In the presence of TBAF as promoter, siloxyalkynes react with electron-withdrawing isocyanides to form a range of oxazole products. In this reaction, siloxyalkynes contribute the C–O unit for the cyclization, which is different from previous typical examples where it is a two-carbon contributor. Mechanistic studies provided insights into the mechanism, which involves a ketene intermediate. Based on the mechanistic insight, an alternative catalytic system was also demonstrated to be effective for the same transformation.

Key words

oxazoles - siloxyalkynes - isocyanides - cyclization

• References and Notes


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• 9 5-Pentyl-4-tosyl-1,3-oxazole (3a); Typical Procedure CH₂Cl₂ (4 mL) was added to a 10 mL vial charged with isocyanide 1a (0.4 mmol, 1.0 equiv) at r.t. under N₂. Siloxyalkyne 2a (0.48 mmol, 1.2 equiv) and a 1.0 M solution of TBAF in THF (0.4 mmol, 1.0 equiv) were added sequentially, and the mixture was stirred at r.t. for 4 h. Next, H₂O (5 mL) was added, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The residue was purified by chromatography [silica gel, hexanes–EtOAc (10:1)] to give a pale-yellow semisolid; yield: 97.9 mg (83%). IR (neat): 3134, 3057, 2932, 2865, 1589, 1516, 1455, 1325, 1145, 1084 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 8.3 Hz, 2 H), 7.71 (s, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 3.08 (t, J = 7.6 Hz, 2 H), 2.40 (s, 3 H), 1.75–1.62 (m, 2 H), 1.38–1.26 (m, 4 H), 0.92–0.83 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 157.2, 149.4, 144.7, 137.3, 135.1, 129.7, 127.9, 31.0, 27.5, 25.2, 22.1, 21.5, 13.8. HRMS (CI): m/z [M + H]⁺ calcd for C₁₅H₂₀NO₃S: 294.1164; found: 294.1158.
• 10 CCDC 1869561 contains the supplementary crystallographic data for compound 3i. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.