Synthesis of 1,2,4-Oxadiazolines on Soluble Polymer Support

Abstract

A general method for the liquid-phase syntheses of 1,2,4-oxadiazolines through a 1,3-dipolar cycloaddition is described. The poly(ethylene glycol) (PEG)-supported imines reacted with nitrile oxides generated in situ from aldoximes, and then the adducts were cleaved from the PEG, to give 1,2,4-oxadiazolines in high yields and excellent purities.

poly(ethylene glycol) (PEG) - oxadiazolines - imines - cycloaddition - liquid-phase

References

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The polymer supported aldehyde was characterized by 500 MHz ¹H NMR analysis in CDCl₃:δ = 8.19 (s, 1 H), 8.12 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 4.53 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.70-3.90 (m, PEG) ppm. The polymer supported imine 2c (R = p-FC₆H₄) was characterized by 500 MHz ¹H NMR analysis in CDCl₃: δ = 8.51 (s, 1 H), 8.15 (d, J = 8.1 Hz, 2 H), 7.96 (d, J = 8.1 Hz, 2 H), 7.26 (m, 2 H), 7.11 (m, 2 H), 4.51 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.50-3.78 (m, PEG) ppm.

<A NAME="RU14202ST-20">20</A>

Typical Procedure for the Synthesis of 1,2,4-Oxadiazolines: N-Chlorosuccinimide (NCS, 2 mmol) was stirred in a flask containing dry CH₂Cl₂ (5 mL). The oxime (2 mmol) was added at 25 °C in one portion.The polymer-supported acrylate (0.25 mmol) was added in one portion after the chlorination was over. Usually after ca 30 min, Et₃N (0.14 mL in 2 mL of CH₂Cl₂) was added drop by drop over ca 2 h. The reaction mixture was stirred overnight at r.t. To this was added a five fold excess of dry benzene and the resulting triethylamine hydrochloride was removed by filtration. The solution was concentrated and Et₂O was added to afford the polymer-supported 1,2,4-oxadiazolines 3. The resin 3 is then cleaved with CH₃ONa/CH₃OH at r.t. to give the desired 1,2,4-oxadiazolines 4. Compound 3a:
¹H NMR (500 MHz, CDCl₃): δ = 8.13 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.80-7.10 (m, 5 H), 6.54 (s, 1 H), 4.25 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.80 (s, 3 H), 3.50-3.78 (m, PEG) ppm. Compound 4a: ¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.80-7.10 (m, 5 H), 6.54 (s, 1 H), 4.11 (s, 3 H), 3.88 (s, 3 H) ppm. GC/MS: m/z = 388 (M⁺).